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WO2005097191A2 - Combinaisons comprenant de la (s)-amlodipine et un inhibiteur de la hmg-coa reductase ou un inhibiteur de l'absorption de cholesterol ou les deux a la fois et methodes permettant de reduire l'hypertension - Google Patents

Combinaisons comprenant de la (s)-amlodipine et un inhibiteur de la hmg-coa reductase ou un inhibiteur de l'absorption de cholesterol ou les deux a la fois et methodes permettant de reduire l'hypertension Download PDF

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WO2005097191A2
WO2005097191A2 PCT/US2005/009910 US2005009910W WO2005097191A2 WO 2005097191 A2 WO2005097191 A2 WO 2005097191A2 US 2005009910 W US2005009910 W US 2005009910W WO 2005097191 A2 WO2005097191 A2 WO 2005097191A2
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pharmaceutically acceptable
solvate
hydrate
acceptable salt
hmg
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WO2005097191A3 (fr
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Timothy J. Barberich
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Sepracor Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • HMG-CoA reductase inhibitors or calcium-channel blockers Some of the conditions for which HMG-CoA reductase inhibitors or calcium-channel blockers have been used or are believed useful include hypertension, angina, hyperlipidemia, arteriosclerosis, coronary artery disease, myocardial infarction, arrhythmia, congestive heart failure, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, stroke, and headache. Plasma cholesterol levels have been positively correlated with the incidence of clinical events associated with coronary heart disease. The regulation of whole-body cholesterol homeostasis in humans and animals involves modulation of cholesterol biosynthesis, bile acid biosynthesis, and the catabolism of cholesterol-containing plasma lipoproteins.
  • the liver is the major organ responsible for cholesterol biosynthesis and catabolism and, for this reason, it is a prime determinant of plasma cholesterol levels.
  • the liver is the site of synthesis and secretion of very low density lipoproteins (VLDL) which are subsequently metabolized to low density lipoproteins (LDL) in the circulation.
  • VLDL very low density lipoproteins
  • LDL low density lipoproteins
  • HMG-CoA reductase inhibitors are currently one of the most therapeutically effective drugs available for reducing the level of LDL in the blood stream of a patient at risk for cardiovascular disease.
  • HMG-CoA reductase inhibitors disrupt the synthesis of cholesterol and other sterols in the liver by competitively inhibiting the 3-hydroxy-3- methyl-glutaryl-coenzyme A reductase enzyme ("HMG-CoA reductase").
  • HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate, which is the rate- determining step in the biosynthesis of cholesterol. Consequently, compounds that inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase are effective in lowering the level of blood-plasma cholesterol, especially low-density lipoprotein cholesterol (LDL-C), in man.
  • LDL-C low-density lipoprotein cholesterol
  • the process of cholesterol absorption is complex and multifaceted. It has been reported that approximately 50% of the total cholesterol within the intestinal lumen is absorbed by the cells lining the intestines (i.e., enterocytes). This cholesterol includes both diet-derived and bile- or hepatic-derived cholesterol. Much of the newly- absorbed cholesterol in the enterocytes is esterified by the enzyme acyl-CoA:cholesterol acyltransferase (ACAT). Subsequently, these cholesteryl esters are packaged along with triglycerides and other components (i.e., phospholipids, apoproteins) into another lipoprotein class, chylomicrons.
  • ACAT acyl-CoA:cholesterol acyltransferase
  • Chylomicrons are secreted by intestinal cells into the lymph where they can then be transported to the blood. Virtually all of the cholesterol absorbed in the intestines is delivered to the liver by this route. When cholesterol abso ⁇ tion in the intestines is reduced, by whatever means, less cholesterol is delivered to the liver. The consequence of this action is a decreased hepatic lipoprotein (NLDL) production and an increase in the hepatic clearance of plasma cholesterol, mostly as LDL. Thus, the net effect of an inhibition of intestinal cholesterol abso ⁇ tion is a decrease in plasma cholesterol levels.
  • Calcium-channel blockers are a chemically diverse class of compounds having important therapeutic value in the control of a variety of diseases including several cardiovascular disorders, such as hypertension, angina, and cardiac arrhythmias.
  • Such disorders include, for example, pulmonary hypertension, peripheral vascular disease, mild congestive heart failure, hypertrophic subaortic stenosis, protection against ischemic injury, stroke, migraine, tumor resistance to anti-neoplastic drugs, achalasia, esophageal spasms, bronchial asthma, premature labor, dysmenorrhea, and enhancement of success in renal transplantation.
  • pulmonary hypertension peripheral vascular disease
  • mild congestive heart failure hypertrophic subaortic stenosis
  • protection against ischemic injury stroke
  • migraine tumor resistance to anti-neoplastic drugs
  • achalasia esophageal spasms
  • bronchial asthma premature labor, dysmenorrhea
  • Enhancement The Science and Practice of Pharmacy, Nineteenth Edition, Mack Publishing Company, Eaton, Pa., p. 963 (1995)
  • Cellular calcium flux is regulated by receptor-operated and voltage-dependent channels, which are sensitive to inhibition by calcium entry blockers.
  • calcium antagonist was introduced by Fleckenstein when two drugs, prenylamine and verapamil, originally found as coronary dilators in the LANGENDORFF-experiment, were shown to mimic the cardiac effects of simple Ca 2+ -withdrawal, diminishing Ca 2+ -dependent high energy phosphate utilization, contractile force, and oxygen requirement of the beating heart without impairing the Na + -depen ent action potential parameters. These effects were clearly distinguishable from ⁇ -receptor blockade and could promptly be neutralized by elevated Ca 2+ , ⁇ -adrenergic catecholamines, or cardiac glycosides, measures that restore the Ca 2+ supply to the contractile system. In the following years many Ca 2+ -antagonists were introduced to therapy.
  • Specific Ca 2+ -antagonists interfere with the uptake of Ca 2+ into the myocardium and prevent myocardial necrotization arising from deleterious intracellular Ca 2+ overload. They act basically as specific inhibitors of the slow transsarcolemnal Ca 2+ influx, but do not or only slightly affect the fast Na + current that initiates normal myocardial excitation.
  • Amlodipine is a dihydropyridine calcium-channel blocker that is used to treat hypertension. Racemic amlodipine cosists of two chiral forms, (S)-amlodipine and (R)- amlodipine. The S-enantiomer is known to be much more active than the R-enantiomer.
  • (S)-amlodipine avoids the adverse effects, including headache and edema, dizziness, flushing, palpitation, fatigue, nausea, abdominal pain and somnolence, associated with administration of racemic amlodipine.
  • (S)-Amlodipine is useful in treating cerebral ischemia, cerebral disorders, arrhythmias, cardiac hypertrophy, heart failure, coronary vasospasm, myocardial infarction, renal impairment, viral infection, thrombosis, atherosclerosis, peripheral vascular disease, migraine headache, restenosis following vascular surgery or injury and acute renal failure while avoiding the above- described adverse effects associated with the administration of the racemic mixture of amlodipine.
  • compositions comprising optically pure (S)-amlodipine and a HMG-CoA reductase inhibitor or cholesterol abso ⁇ tion inhibitor or both will fulfill this need and provide other related advantages.
  • Summary of the Invention One aspect of the present invention relates to pharmaceutical compositions comprising optically pure (S)-amlodipine and a HMG-CoA reductase inhibitor.
  • the HMG-CoA reductase inhibitor is lovastatin.
  • Another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising optically pure (S)- amlodipine and a cholesterol abso ⁇ tion inhibitor.
  • the cholesterol abso ⁇ tion enhancer is ezetimibe.
  • Another aspect of the present invention relates to a pharmaceutical composition comprising optically pure (S)-amlodipine, a HMG- CoA reductase inhibitor, and a cholesterol abso ⁇ tion inhibitor.
  • Another aspect of the present invention relates to the aforementioned pharmaceutical compositions further comprising niacin.
  • the pharmaceutical compositions of the invention are useful in the treatment of hypertension and hyperlipidemia.
  • the present invention also relates to a method of treating a patient suffering from hypertension, hyperlipidemia, or a cardiac disorder, comprising administering a therapeutically effective amount of a pharmaceutical composition of the invention.
  • Figure 1 depicts a procedure for the preparation of (S)-amlodipine-L-malate (form A). Note: If the free base of (S)-amlodipine is used as the starting material, then the first step (NaOH/MTBE) may be eliminated.
  • Figure 2 depicts a procedure for the preparation of (S)-amlodipine hemi-D-tartrate DMAC solvate.
  • Figure 3 depicts a procedure for the preparation of (S)-amlodipine free base from (S)-amlodipine hemi-D-tartrate DMAC solvate.
  • Figure 4 depicts a procedure for the preparation of (S)-amlodipine-L-malate (form A) from (S)-amlodipine free base.
  • Figure 5 depicts solid state stability data for (S)-amlodipine L-malate (form A).
  • Figure 6 depicts solid state stability data for (S)-amlodipine L-malate (form A).
  • Figure 7 depicts representative plasma concentration-time relationship after a single oral dose of a hypothetical drug. Area under the plasma concentration-time curve is indicated by shading.
  • the present invention relates generally to pharmaceutical compositions containing two or more active agents that when taken together reduce hypertension.
  • the present invention relates to a pharmaceutical composition comprising optically pure (S)-amlodipine and a HMG-CoA reductase inhibitor.
  • Another aspect of the present invention relates to a pharmaceutical composition comprising optically pure (S)- amlodipine, a HMG-CoA reductase inl ibitor, and a cholesterol abso ⁇ tion inhibitor.
  • the present invention relates to a pharmaceutical composition comprising optically pure (S)-amlodipine and a cholesterol abso ⁇ tion inhibitor.
  • the aforementioned pharmaceutical compositions further comprise niacin.
  • compositions of the invention are useful for treating a patient suffering from hypertension, hyperlipidemia, or related cardiac disorders.
  • Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle.
  • Amlodipine is known to exist in two chiral forms designated (S)-amlodipine and (R)-amlodipine.
  • the S-enantiomer is known to be much more active than the R-enantiomer.
  • Methods of treatment using (S)-amlodipine are described in U.S. Patent 6,476,058. See Burges et al. Cardiovas DrugDev.
  • (S)-Amlodipine can be prepared by separation of the R- and S-enantiomers via fractional crystallization of diastereomeric mixtures formed by basic resolving agents and racemic carboxylic-acid-containing precursors of amlodipine. See T. Shibanuma et al. Chem. Pharm. Bull. 1980, 28(9), 2809-2812 and M. Eltze et al. Chirality 1990, 2, 233-240.
  • (S)-amlodipine may be obtained by resolution of the corresponding racemic 4- aryl-l-ethoxymethyl-l,4-dihydro-5-methoxycarbonyl-2,6-dimethylpyridine-3-carboxylic acids followed by subsequent alkylation and esterification as described in WO 88/07524 and WO 88/07525.
  • Optically pure cinchonine and cinchonidine salts are basic resolving agents that have proven useful in the resolution of amlodipine.
  • a technique for separation of the (S)-amlodipine isomer from the racemic mixture has been illustrated schematically by J. E. Arrowsmith in EP 331,315. See also U.S. Published Patent
  • Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses.
  • Serum calcium concentration is not affected by amlodipine.
  • the metabolites of amlodipine apparently do not possess significant calcium- channel blocking activity, while the parent drug offers a biological half-life of some 35-40 hours, prompting a once-daily dosage regimen (Lorimer, A. R., et al., J. Hum. Hypertens.
  • SHR Spontaneously Hypertensive Rat
  • ultrasonic two-dimensional echocardiography and anesthetized dog assays can be used to assess the cardiovascular effects of a pharmaceutical agent on a subject. See P. Gueret et al. Circulation 1980, 62, 1308 and M. Tripp American J. of Physiology 1977, 232, H173. After oral administration of therapeutic doses of racemic amlodipine, abso ⁇ tion produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of amlodipine is not altered by the presence of food.
  • Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine. Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Elimination from the plasma is biphasic with a terminal elimination half-life of about 30-50 hours. Steady state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing. The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.
  • the magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105-114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90-104 mmHg).
  • Normotensive subjects experienced no clinically significant change in blood pressures (+1/-2 mmHg).
  • hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume.
  • amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co- administered with beta-blockers to-man. Similar findings, however, have been observed in normals or well-compensated patients with heart failure with agents possessing significant negative inotropic effects. In a double-blind, placebo-controlled clinical trial involving 118 patients with well compensated heart failure (NYHA Class II and Class III), treatment with racemic amlodipine did not lead to worsened heart failure, based on measures of exercise tolerance, left ventricular ejection fraction and clinical symptomatology.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient, hi general, the total daily dose ranges, for the conditions described herein, is from about 0.5 mg to about 50 mg.
  • a daily dose range should be between about 1 mg to about 25 mg.
  • a daily dose range should be between about 1 mg to about 10 mg.
  • the daily dose range should be about 2, 4, 6, or 8 mg.
  • the therapy may be initiated at a lower dose, perhaps about 0.05 mg to about 1 mg and increased up to about 5 mg or higher depending-on the patient's global response.
  • (S)-Amlodipine may be useful in the treatment of cerebral ischemia.
  • Cerebral ischemia often the result of atherosclerotic disease or hypertension, results from insufficient cerebral circulation. Under normal circumstances, an extensive collateral circulation ensures adequate blood flow. However, cerebral ischemia may result from either an intra- or extracranial interruption of arterial blood flow. If interruption is transient, the cerebral tissues recover, and neurologic symptoms disappear. If the ischemia lasts for a somewhat more extended period, infarction results and the resulting neurologic damage is permanent. In the case of extended ischemia resulting in infarction, treatment is directed to the underlying vascular disease, to blood platelet aggregation inhibitors, and anticoagulant therapy. Because of its activity as a calcium channel antagonist, (S)-amlodipine may also be useful in treating cardiac arrhythmias.
  • Cardiac arrhythmias represent a broad, complex group of electrophysiologic disorders that affect the mechanical properties of the heart and vasculature, altering normal cardiac rhythm, function and output.
  • Normal cardiac rhythm originates with the sinoatrial node, which possesses high intrinsic automaticity. Adequate automaticity and conduction lead to activation of atrial and ventricular fibers, producing in sequence the elements of normal functional heart beat.
  • Calcium antagonists maybe of value in conditions where calcium-related changes in membrane potential and conduction alter normal rhythm. In the absence of treatment, symptoms vary with individual arrhythmias, but are often the consequence of inadequate cardiac filling and output and often include fatigue, decreased exercise tolerance, syncope, shortness of breath, nausea, lightheadedness and the like.
  • (S)-Amlodipine may be useful to treat cardiac hypertrophy.
  • Cardiac hypertrophy can result from excessive workload either due to an obstruction to outflow, termed systolic overload, or to excessive volumes presented to the heart in diastole, termed diastolic overload.
  • Systolic overload results in concentric ventricular hypertrophy, in which there is an increased thickness in the walls of the heart not associated with increased volume.
  • Diastolic overload causes dilation and hypertrophy with an increased blood volume.
  • An inadequate cardiac output results from the heart's failure in systolic or diastolic overload, leading to fatigue, shortness of breath, pulmonary congestion, edema and the like.
  • Calcium channel antagonists effect workload and, as such, may be useful in treating cardiac hypertrophy due to the effect of the calcium antagonist on cardiac and vascular smooth muscle in reducing blood pressure.
  • (S)-Amlodipine could be used to treat coronary arterial spasm. Coronary arterial spasm can occur in the absence of significant coronary atherosclerosis and is thought to be an initiating event in variant angina and in myocardial infarction. Coronary spasm may occur without the patient feeling any significant discomfort. In an electrically unstable heart, diverse neural impulses to the heart may provoke coronary vascular spasm. This may result in enhanced myocardial ischemia and arrhythmia, which in turn may culminate in ventricular fibrillation and sudden cardiac death.
  • the calcium channel antagonists may be of particular usefulness due to their effect on cardiac and vascular smooth muscle.
  • (S)- Amlodipine may be useful in the treatment of myocardial infarction, ischemic myocardial necrosis, and ischemia reperfusion injury.
  • Myocardial infarction or ischemic myocardial necrosis generally results from the abrupt reduction of coronary blood flow to a portion of the myocardium.
  • the condition likely originates from atherosclerosis of the coronary arteries. Either coronary artery vasospasm or acute coronary thrombosis precipitates the condition, although the etiology is the subject of continuing research.
  • Myocardial infarction is predominantly a disease of the left ventricle. Precordial pain and left ventricular dysfunction characterize the disease. The pain, which can be severe aching or pressure, leads to apprehension. Symptoms include left ventricular heart failure, pulmonary edema, shock or significant cardiac arrhythmia. Calcium channel antagonists may find utility in the management of myocardial infarction patients due to their effects on coronary artery vasospasm, blood pressure or other effects on cardiac function or vascular smooth muscle. (S)-Amlodipine may be used to treat congestive heart failure. Congestive heart failure can be caused by hypertension, cardiomyopathy, coronary artery disease or valvular heart disease.
  • (S)-Amlodipine may be of use in treating migraine.
  • Classic migraine typically begins with visual auras followed by severe headaches, often accompanied by nausea and vomiting.
  • Common migraine has similar symptoms without the preceding visual aura.
  • the causes of migraine have been studied intensely, and are still a matter of debate. The most generally accepted cause is hypoxia due to reduced cerebral blood flow.
  • Calcium channel antagonists have been used for migraine prophylaxis since they can increase cerebral blood flow.
  • (S)-Amlodipine may be useful for treating Raynaud's phenomenon, which is characterized by vascular spasm of the extremities. These vasospasms can be caused by cold or stress. A pallor or cyanosis is usually present due to severe constriction of the digital arteries. The phenomenon is often seen as a secondary disorder with arterial diseases or connective tissue diseases such as scleroderma, arthritis or lupus erythematosus. Calcium channel antagonists have been shown to be effective in treating Raynaud's phenomenon. Interestingly, (S)-Amlodipine L-malate has been found to be unexpectedly bioavailable in mammals (in particular humans).
  • AUC Area Under the Curve and indicates the total amount of the drug in plasma over a period of time; see discussion below
  • HMG-CoA Reductase Inhibitors A large number compounds are known to inhibit HMG-CoA reductase and are amenable to the present invention.
  • HMG-Co reductase inhibitors are effective antihyperlipidemic agents in a variety of animal models and are clinically useful for the treatment of hyperlipidemia and other related cardiac disorders.
  • One method of evaluating the ability of a compound to inhibit HMG-CoA reductase is by measuring the IC 50 - value of the compound using procedures known in the art. Representative examples of procedures to determine the IC50, I , and ED50 can be found in P. J. Connolly et al. J. Med. Chem. 1993, 36, 3674-85; F. McTaggart et al. Am. J. Cardiol. 2001, 87, 28B-32B; H. Bischoff et al.
  • IC 50 - values of several commercially-marketed compounds are as follows: rosuvastatin (5.4 nM), atorvastatin (8.2 nM), cerivastatin (10.0 nM), simvastatin (11.2 nM), fluvastatin (27.6 nM), and pravastatin (44.1 nM). See F. McTaggart et al. Am. J. Cardiol. 2001, 87, 28B-32B.
  • the compounds of the present invention have an IC 50 - value of less than about 500 nM against HMG-CoA reductase.
  • the compounds of the present invention have an IC 50 - value of less than about 200 nM against HMG-CoA reductase.
  • the compounds of the present invention have an IC 50 -value of less than about 100 nM against HMG-CoA reductase.
  • the compounds of the present invention have an IC50- value of less than about 50, 25, 10, or 5 nM against HMG-CoA reductase.
  • a dose of the HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof suitable for administration to a human will be in the range of 0.01 to 50 mg per kilogram body weight of the recipient per day, preferably in the range of 0.1 to 3 mg per kilogram body weight per day. Unless otherwise stated all weights of active ingredients are calculated in terms of drug per se. h certain embodiments, the desired dose is presented as two, three, four, five or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example, containing about 5 to 50 mg.
  • HMG-CoA reductase inhibitors In addition to the IC 50 -value of a compound, a variety of assays are known in the art for evaluating the therapeutic potential of HMG-CoA reductase inhibitors, e.g., measurement of serum cholesterol levels and HMG-CoA reductase activity. A variety of assays are described below for evaluating the therapeutic potential of HMG-CoA reductase inhibitors. See also U.S. Patent 6,462,091. Measurement of Hepatic Cholesterol Concentration (HEPATIC CHOL) Liver tissue is to be weighed and homogenized in chloroform:methanol (2:1). After honiogenization and centrifugation the supernatant is separated and dried under nitrogen. The residue is to be dissolved in isopropanol and the cholesterol content will be measured enzymatically, using a combination of cholesterol oxidase and peroxidase as described by HEPATIC CHOL
  • Hepatic microsomes are to be prepared by homogenizing liver samples in a phosphate/sucrose buffer, followed by centrifugal separation. The final pelleted material is resuspended in buffer and an aliquot will be assayed for HMG-CoA reductase activity by incubating for 60 minutes at 37 °C in the presence of 1 C-HMG-CoA (Dupont-NEN). The reaction is stopped by adding 6N HC1 followed by centrifugation.
  • HMG COA Hepatic HMG-CoA Reductase Activity
  • HDL cholesterol (HDL-CHOL) will be assayed using this same kit after precipitation of VLDL and LDL with Sigma Chemical Co.
  • HDL Cholesterol reagent Catalog No. 352-3 (dextran sulfate method).
  • Total serum triglycerides (blanked) (TGI) will be assayed enzymatically with Sigma Chemical Co.
  • GPO-Trinder Catalog No. 337-B.
  • VLDL and LDL (VLDL+LDL) cholesterol concentrations will be calculated as the difference between total and HDL cholesterol.
  • Hepatic Cholesterol 7- a-Hydroxy las e Activity 7 -OHase
  • Hepatic microsomes are to be prepared by homogenizing liver samples in a phosphate/sucrose buffer, followed by centrifugal separation. The final pelleted material is resuspended in buffer and an aliquot will be assayed for cholesterol 7- ⁇ -hydroxylase activity by incubating for 5 minutes at 37 °C. in the presence of NADPH. Following extraction into petroleum ether, the organic solvent is evaporated and the residue is dissolved in acetonitrile/methanol.
  • the enzymatic product will be separated by injecting an aliquot of the extract onto a C ⁇ 8 reversed phase HPLC column and quantitating the eluted material using UV detection at 240 nm. See J. D. Horton et al. J. Clin. Invest. 1994, 93, 2084.
  • Rat Gavage Assay Male Wister rats (275-300 g) are to be administered IB AT inhibitors using an oral gavage procedure. Drug or vehicle (0.2% TWEEN 80 in water) is administered once a day (9:00-10:0) a.m.) for 4 days at varying dosages in a final volume of 2 mL per kilogram of body weight.
  • Total fecal samples are collected during the final 48 hours of the treatment period and analyzed for bile acid content using an enzymatic assay as described below. Compound efficacy will be detennined by comparison of the increase in fecal bile acid (FBA) concentration in treated rats to the mean FBA concentration of rats in the vehicle group. Measurement of Rat Fecal Bile Acid Concentration (FBA) Total fecal output from individually housed rats is to be collected for 24 or 48 hours, dried under a stream of nitrogen, pulverized, mixed, and weighed.
  • FBA Rat Fecal Bile Acid Concentration
  • Approximately 0.1 gram is weighed out and extracted into an organic solvent (butanol/water). Following separation and drying, the residue is dissolved in methanol and the amount of bile acid present will be measured enzymatically using the 3 -hydroxysteroid steroid dehydrogenase reaction with bile acids to reduce NAD. See F. Mashige et al. Clin. Chem. 1981, 27, 1352. ⁇ HJTaurocholate Uptake in Rabbit Brush Border Membrane Vesicles (BBMV) Rabbit brush border membranes are to be prepared from frozen ileal mucosa by the calcium precipitation method describe by Malathi et al. (Biochimica Biophysica Acta 1979, 554, 259).
  • the method for measuring taurocholate is performed as described by Kramer et al. (Biochimica Biophysica Acta, 1111, 93 (1992)) except the assay volume will be 200 ⁇ L instead of 100 ⁇ L Briefly, at room temperature a 190 ⁇ L solution containing 2 ⁇ M [ 3 H]- taurocholate(0.75 ⁇ Ci), 20 mM tris, 100 mM NaCl, 100 mM mannitol pH 7.4 is incubated for 5 sec with 10 ⁇ L of brush border membrane vesicles (60-120 ⁇ g protein).
  • Dogs may be randomly assigned to a dosing groups consisting of 6 to 12 dogs each, such as: vehicle, i.g.; 1 mg/kg, i.g.; 2 mg/kg, i.q.; 4 mg/kg, i.g.; 2 mg/kg, p.o. (powder in capsule), fritra-gastric dosing of a therapeutic material dissolved in aqueous solution (for example, 0.2% Tween 80 solution [polyoxyethylene mono-oleate, Sigma Chemical Co., St. Louis, Mo.]) may be done using a gavage tube.
  • aqueous solution for example, 0.2% Tween 80 solution [polyoxyethylene mono-oleate, Sigma Chemical Co., St. Louis, Mo.]
  • blood samples may be drawn from the cephalic vein in the morning before feeding in order to evaluate serum cholesterol (total and HDL) and triglycerides.
  • serum cholesterol total and HDL
  • triglycerides For several consecutive days animals are dosed in the morning, prior to feeding. Animals are to be allowed 2 hours to eat before any remaining food is removed. Feces are to be collected over a two-day period at the end of the study and may be analyzed for bile acid or lipid content. Blood samples are also to be taken, at the end of the treatment period, for comparison with pre-study serum lipid levels. Statistical significance will be determined using the standard student's T-test with p ⁇ 0.05.
  • Blood is to be collected from the cephalic vein of fasted dogs in serum separator tubes (Vacutainer SST, Becton Dickinson and Co., Franklin Lakes, N.J.). The blood is centrifuged at 2000 ⁇ m for 20 minutes and the serum decanted. Total cholesterol may be measured in a 96 well format using a Wako enzymatic diagnostic kit (Cholesterol CH) (Wako Chemicals, Richmond, Va.), utilizing the cholesterol oxidase reaction to produce hydrogen peroxide which is measured calorimetrically. A standard curve from 0.5 to 10 ⁇ g cholesterol is to be prepared in the first 2 columns of the plate.
  • the serum samples (20-40 ⁇ L, depending on the expected lipid concentration) or known serum control samples are added to separate wells in duplicate. Water is added to bring the volume to 100 ⁇ L in each well. A 100 ⁇ L aliquot of color reagent is added to each well and the plates will be read at 500 nm after a 15 minute incubation at 37 degrees centigrade.
  • HDL cholesterol may be assayed using Sigma kit No. 352-3 (Sigma Chemical Co., St. Louis, Mo.) which utilizes dextran sulfate and Mg ions to selectively precipitate LDL and VLDL. A volume of 150 ⁇ L of each serum sample is to be added to individual microfuge tubes, followed by 15 ⁇ L of HDL cholesterol reagent (Sigma 352-3).
  • Samples are to be mixed and centrifuged at 5000 ⁇ m for 5 minutes. A 50 ⁇ L aliquot of the supernatant is to be then mixed with 200 ⁇ L of saline and assayed using the same procedure as for total cholesterol measurement. Triglycerides are to be measured using Sigma kit No. 337 in a 96 well plate format. This procedure will measure glycerol, following its release by reaction of triglycerides with lipoprotein lipase. Standard solutions of glycerol (Sigma 339-11) ranging from 1 to 24 ⁇ g are to be used to generate the standard curve. Serum samples (20-40 ⁇ L, depending on the expected lipid concentration) are added to wells in duplicate.
  • the separate two-day collections from each animal are to be weighed, combined and homogenized with distilled water in a processor (Cuisinart) to generate a homogeneous slurry.
  • About 1.4 g of the homogenate is to be extracted in a final concentration of 50% tertiary butanol/distiUed water (2:0.6) for 45 minutes in a 37 °C water bath and centrifuged for 13 minutes at 2000 x g.
  • the concentration of bile acids (mmoles/day) may be determined using a 96-well enzymatic assay system (1,2).
  • a 20 ⁇ L aliquot of the fecal extract is to be added to two sets each of triplicate wells in a 96-well assay plate.
  • a standardized sodium taurocholate solution and a standardized fecal extract solution (previously made from pooled samples and characterized for its bile acid concentration) will also analyzed for assay quality control. Twenty-microliter aliquots of sodium taurocholate, serially diluted to generate a standard curve are similarly to be added to two sets of triplicate wells. A 230 ⁇ L reaction mixture containing 1 M hydrazine hydrate, 0.1 M pyrophosphate and 0.46 mg/ml NAD is to be added to each well.
  • a 50 ⁇ l aliquot of 3a-hydroxysteroid dehydrogenase enzyme (HSD; 0.8 units/ml) or assay buffer (0.1 M sodium pyrophosphate) are then added to one of the two sets of triplicates. All reagents may be obtained from Sigma Chemical Co., St. Louis, Mo. Following 60 minutes of incubation at room temperature, the optical density at 340 nm will be measured and the mean of each set of triplicate samples will be calculated. The difference in optical density HSD enzyme is to be used to determine the bile acid concentration (mM) of each sample based on the sodium taurocholate standard curve.
  • HSD 3a-hydroxysteroid dehydrogenase enzyme
  • assay buffer 0.1 M sodium pyrophosphate
  • the bile acid concentration of the extract, the weight of the fecal homogenate (grams) and the body weight of the animal are to be used to calculate the corresponding FBA concentration in mmoles/kg/day for each animal.
  • the mean FBA concentration (mmoles/kg/day) of the vehicle group is to be subtracted from the FBA concentration of each treatment group to determine the increase (delta value) in FBA concentration as a result of the treatment.
  • Plasma Lipids Assay in Rabbits Plasma lipids can be assayed using standard methods as reported by J. R. Schuh et al., J. Clin. Invest., 91, 1453-1458 (1993).
  • Plasma Lipids Plasma for lipid analysis is obtained by withdrawing blood from the ear vein into EDTA-containing tubes (Vacutainer; Becton Dickenson & Co., Rutherford, N.J.), followed by centrifugal separation of the cells.
  • Total cholesterol is determined enzymatically, using the cholesterol oxidase reaction. See C. A. Allain et al. Clin. Chem. 1974, 20, 470-475. HDL cholesterol is also measured enzymatically, after selective precipitation of LDL and VLDL by dextran sulfate with magnesium. See G. R. Warnick et al. Clin. Chem. 1982, 28, 1379-1388. Plasma triglyceride levels are determined by measuring the amount of glycerol released by lipoprotein lipase through an enzyme-linked assay. See G. Bucolo et al. Clin. Chem. 1973, 19, 476-482. Atherosclerosis Animals are killed by pentobarbital injection.
  • Thoracic aortas are rapidly removed, immersion fixed in 10% neutral buffered formalin, and stained with oil red O (0.3w). After a single longitudinal incision along the wall opposite the arterial ostia, the vessels are pinned open for evaluation of the plaque area. The percent plaque coverage is determined from the values for the total area examined and the stained area, by threshold analysis using a true color image analyzer (Videometric 150; American Innovision, Inc., San Diego, Calif.) interfaced to a color camera (Toshiba 3CCD) mounted on a dissecting microscope. Tissue cholesterol will be measured enzymatically as described, after extraction with a chloroform/methanol mixture (2:1) according to the method of Folch et al. (J. Biol.
  • Statins are effective antihyperlipidemic agents in a variety of animal models and are clinically useful for the treatment of hyperlipidemia and other related cardiac disorders. A large number of statins are known and are amenable to the present invention. Representative statin compounds are described below. Atorvastatin Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase used to treat patients suffering from elevated levels of cholesterol. Procedures for the synthesis of atorvastatin are described in U.S. Patent 5,273,995 and European Patent Application 409,281. The pharmacological properties are described in T. M. A. Bocan et al. Biochim. Biophys. Acta 1992, 1123, 133; T. M. A. Bocan et al.
  • Atorvastatin can reduce total cholesterol, low-density lypoprotein choloesterol, and apolipoprotein B in patients with homozygous and heterozygous familial hypercholesterolemia, nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia. Atorvastatin can also reduce very low- density lypoprotein choloesterol and triglycerides. Atorvastatin in known to provide variable increases in high-density lypoprotein cholesterol and apolipoprotein A-l .
  • atorvastatin can reduce total cholesterol, low-density lypoprotein choloesterol, very low-density lypoprotein choloesterol, apoolipoprotein B, triglycerides, and non-high-density lypoprotein cholesterol, and can increase high-density lypoprotein cholesterol.
  • atorvastatin can reduce intermediate density lipoprotein cholesterol in patients with dysbetalipoproteinemia. Food often decreases the rate and extent of drug abso ⁇ tion as assessed by C ma and AUC, but low-density lypoprotein cholesterol reduction is similar whether atorvastatin is given with or without food.
  • Atorvastatin has the chemical name [R-(R*,R*)]-2-(4-fluorophenyl)- ⁇ , ⁇ -dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid and has the structure presented below.
  • atorvastatin Various salt forms of atorvastatin are known.
  • the calcium salt of atorvastatin marketed under the tradename LIPITOR®, is described in U.S. Patent 5,273,995.
  • Atorvastatin calcium (2:1 mixture of atorvastatin and calcium) is a white to off-white crystalline trihydrate powder that is insoluble in aqueous solutions of p ⁇ 4 and below.
  • the calcium salt of atorvastatin is very slightly soluble in distilled water, pH 7.4 phosphate buffer, and acetonitrile; slightly soluble in ethanol; and freely soluble in methanol. Procedures for the preparation of various amo ⁇ hous, crystalline, and hydrate forms of atorvastatin calcium are described in U.S.
  • the sodium salt of atorvastatin is soluble in water.
  • the free carboxylic acid form of atorvastatin exists predominantly as the lactone.
  • the term "atorvastatin" is mean to encompass the carboxylic acid, the lactone, and a mixture of carboxylic acid and lactone.
  • a prophylactic or therapeutic dose of atorvastatin, or one of its salts, in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 1 mg to about 200 mg.
  • a daily dose range should be between about 2 mg to about 100 mg.
  • a daily dose range should be between about 5 mg to about 80 mg.
  • the daily dose range should be about 10, 20, 40, or 60 mg.
  • Cerivastatin Cerivastatin is a penta-substituted pyridine that is a competitive inhibitor of HMG- CoA reductase. Procedures for the preparation of cerivastatin are described in European Patent Application 325130 and U.S. Patents 5,006,530 and 5,177,080. The pharmacological properties are described in G. C. Ness et al. Arch. Biochem. Biophys. 1996, 325, 242; N. Nakaya et al. Japan. Pharmacol. Ther. 1996, 24 (Suppl.
  • cerivastatin sodium can produce reduced levels of plasma total cholesterol, low-density lypoprotein cholesterol, and apolipoprotein B, very low-density lypoprotein cholesterol, and plasma triglycerides. Cerivastatin sodium increases plasma high-density lypoprotein cholesterol and apolipoprotein A-l. Cerivastatin systemic exposure (area under the curve, AUC) and C max are not sensitive to a food effect, but once daily doses of 0.2 mg can be more efficacious than twice daily doses of 0.1 mg. Cerivastatin can exist the free carboxylic acid, the lactone, or a mixture of the carboxylic acid and the lactone.
  • cerivastatin is meant to encompass the carboxylic acid, the lactone, and a mixture of carboxylic acid and lactone.
  • the chemical name of cerivastatin is [3R,5S,6E]-7-[4-(4-fluorophenyl)-5-(methoxymethyl)-2,6-bis(l- methylethyl)-3-pyridinyl]-3,5-dihydroxy-6-heptenoic acid and the structure is presented below.
  • a prophylactic or therapeutic dose of cerivastatin, or one of its salts, in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient, hi general, the total daily dose ranges, for the conditions described herein, is from about 0.05 mg to about 3 mg.
  • a daily dose range should be between about 0.1 mg to about 1 mg.
  • a daily dose range should be between about 0.15 mg to about 0.4 mg. In certain embodiments, the daily dose range should be about 0.20, 0.25, 0.30, or 0.35 mg.
  • the therapy may be initiated at a lower dose, perhaps about 0.1 mg to about 0.15 mg and increased up to about 0.25 mg or higher depending-on the patient's global response.
  • Fluvastatin Fluvastatin is an indole derivative shown to cause significant reductions in low- density lypoprotein cholesterol, Apo B, and triglycerides in patients suffering from Type Ila or lib hyperlipoproteinemia. It is also indicated to slow the progression of coronary atherosclerosis in patients with coronary heart disease as part of a treatment strategy to lower total cholesterol and LDL cholesterol to target levels. Procedures for the preparation of fluvastatin are described in U.S. Patent 4,739,073. The pharmacological activity is described in J. Yuan et al.
  • Fluvastatin has the chemical name [R*,S*-(E)]-( ⁇ )-7-(3-(4-fluorophenyl)-l-(l- methylethyl)-lH-indol-2-yl)-3,5-dihydroxy-6-heptenoic acid.
  • the structure of fluvastatin in its 3R,5S form is presented below.
  • Fluvastatin has a stereogenic center at both carbon atoms bearing a hydroxyl group.
  • fluvastatin can exist as a single enantiomer, mixture of enantiomers, or mixture of diastereomers.
  • fluvostatin can exist as the carboxylic acid, lactone, or a •mixture of carboxylic acid and lactone.
  • fluvastatin is meant to encompass a single enantiomer, a mixture of enantiomers, and a mixture of diastereomers of the carboxylic acid, lactone, and mixture of carboyxlic acid and lactone.
  • the sodium salt of fluvastatin is marketed under the tradename L ⁇ SCOL®. In U.S. Patent 4,739,073, the sodium salt of fluvastatin is obtained by lyophilization.
  • WO-A- 97/49681 and U.S. Patent 6,124,340 describe that lyophilization of fluvastatin sodium yields a mixture of forms, designated as Form A, and amo ⁇ hous material.
  • WO-A-97/49681 discloses crystalline Form B of fluvastatin sodium.
  • the estimated amount of Form A obtained by lyophilization as described in these patents is about 50%.
  • the crystalline Form B is obtained either by transformation of material containing Form A in a slurry of a mixture of an organic solvent and water, or by crystallization from a mixture comprising an organic solvent and water. It is reported that Form B is less hygroscopic than Form A.
  • Fluvastatin sodium is a white to pale yellow, hygroscopic powder soluble in water, ethanol and methanol. Following oral administration, fluvastatin is absorbed rapidly and completely with peak concentrations reached in less than 1 hour. Administration with food reduces the rate but not the extent of abso ⁇ tion.
  • the size of a prophylactic or therapeutic dose of fluvastatin, or one of its salts, in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration. The dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges is from about 1 mg to about 250 mg.
  • a daily dose range should be between about 10 mg to about 150 mg.
  • a daily dose range should be between about 20 mg to about 100 mg.
  • the daily dose range should be about 40, 60, or 80 mg.
  • the therapy may be initiated at a lower dose, perhaps about 5 mg to about 15 mg and increased up to about 30 mg or higher depending on the patient's global response.
  • the therapy should be less than about 60 mg.
  • Lovastatin Lovastatin is a fungal metabolite used to treat patients suffering from hypercholesterolemia and coronary atherosclerosis.
  • Lovastatin is produced as a secondary metabolite of Aspergillus terreus (U.S. Patent 4,231,938) deposited in American Type Culture Collection under Nos. ATCC 20541, ATCC 20542, and Monascus ruber deposited in Fermentation Research Institute Agency of Industrial Science and Technology, Ministry of International Trade and Industry, Japan (DE 30 06 216 Al) under No. Ferm 4822. Procedures for the preparation of lovastatin are described in Hirama, M.; Iwashita, M. Tetrahedron Letters 1983, 24, 1811; D. L. J. Clive et al. J. Am. Chem. Soc. 1988, 110, 6914; and U.S.
  • Patents 5,712,130; 5,409,820; and 4,231,938 Procedures for the purification of lovastatin are described in U.S. Patent 6,521,762.
  • the pharmacological properties are described in J. A. Tobert Circulation 1987, 76, 534-538 and G. S. Brenner et al. in Analytical Profiles of Drug Substances and Excipients vol. 21, H. G. Brittain, Ed. (Academic Press, San Diego, 1992) pp 277-305.
  • Lovastatin has the chemical name [1S- [l ⁇ (R*), 3 ⁇ , 7 ⁇ , 8 ⁇ (2S*, 4S*), 8a ⁇ ]]-2-methylbutanoic acid 1, 2, 3, 7, 8, 8a-hexahydro-3,7- dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-l-naphthalenyl ester and has the structure presented below.
  • Lovastatin an inactive lactone
  • Lovastatin is a white, nonhygroscopic crystalline powder that is insoluble in water and sparingly soluble in ethanol, methanol, and acetonitrile.
  • lovastatin is hydrolyzed to a ⁇ -hydroxyacid which is an inhibitor of ⁇ MG-CoA reductase.
  • Lovastatin is marketed by Merck & Co. under the tradename MEVACOR®. Lovastatin has been shown to reduce plasma total cholesterol, low-density lypoprotein cholesterol, the ratio of total cholesterol to high-density lypoprotein cholesterol, and the ratio of low-density lypoprotein cholesterol to high-density lypoprotein cholesterol.
  • lovastatin increases the amount of high-density lypoprotein cholesterol.
  • the term "lovastatin” is meant to encompass the lactone and the ⁇ -hydroxyacid.
  • Lovastatin can be manufactured by a fermentation process. In the fermentation broth, lovastatin is present mostly in its hydroxy-acid form, mevinolinic acid.
  • the isolation of lovastatin from the fermentation broth can be categorised into two routes. The first route comprises of solvent extraction of mevinolinic acid and isolation of ammonium salt of mevinolinic acid as an intermediate and its further lactonization to lovastatin (U.S. Pat. No. 4,319,039).
  • the second route entails solvent extraction of mevinolinic acid, lactonization in the solvent phase and isolation as lovastatin (WO 97/20834).
  • the isolation of lovastatin as disclosed in EP 033536 comprises extraction of the broth with ethyl acetate. The extract is concentrated by vacuum distillation followed by lactonization in toluene at 106 °C for 2 hours. After the lactonization is complete, the solution is concentrated to a small volume and then subjected to column chromatography using solvents like ethyl acetate or n-hexane and the collected fractions are again concentrated in vacuum and then pure lovastatin crystallizes in the lactone form.
  • Both the routes may employ a final purification step to obtain lovastatin of pharmacopoeial grade.
  • the size of a prophylactic or therapeutic dose of lovastatin, or one of its salts, in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient, hi general, the total daily dose ranges, for the conditions described herein, is from about 1 mg to about 200 mg.
  • a daily dose range should be between about 10 mg to about 120 mg.
  • a daily dose range should be between about 20 mg to about 80 mg.
  • the daily dose range should be about 30, 40, 50, 60, or 70 mg.
  • the therapy may be initiated at a lower dose, perhaps about 5 mg to about 15 mg and increased up to about 25 mg or higher depending on the patient's global response.
  • Mevastatin is a fungal metabolite that is a potent inhibitor of HMG-CoA reductase. Procedures for the synthesis of mevastatin are described in D. L. J. Clive et al. J. Am. Chem. Soc. 1988, 110, 6914 and Rosen, T.; Heathcock, C. H. Tetrahedron 1986, 42, 4909.
  • mevastatin can be isolated from Penicillium citrinum as described in U.S. Patent 3,983,140.
  • the pharmacological properties are described in A. Endo et al. FEBS Letters 1976, 72, 323; A. Yamamoto et al. Atherosclerosis 1980, 35, 259; and S. Amin- Hanjani et al. Stroke 2001, 32, 980-986.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient. In general, the total daily dose ranges, for the conditions described herein, is from about 1 mg to about 900 mg. Preferably, a daily dose range should be between about 10 mg to about 200 mg.
  • Mevastatin has the chemical name [lS-[l ⁇ (R*),7 ⁇ ,8 ⁇ (2S*,4S*),8a ⁇ ]]-2- methylbutanoic acid 1 ,2,3,7,8,8a-hexahydro-7-methyl-8-[2-(tetrahydro-4-hydroxy-6-oxo- H-pyran-2-yl)ethyl]-l-naphthalenyl ester and has the structure presented below.
  • Pitavastatin has the chemical name (3R,5S,6E)-7-[2-cyclopropyl-4-(4- fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoic acid.
  • Pitavastatin is often administered in the form of its calcium salt.
  • Pitavastatin is also known as itavastatin, nisvastatin, and NK-104.
  • Pitavastatin is described in U.S. Patents 5,011,930; 5,856,336; 5,872,130; and 6,335,449. The pharmacological properties are described in K. Ohnaka et al. Biochem. Biophys. Res. Commun. 2001, 287(2), 337-342 and K.
  • the total daily dose ranges is from about 1 mg to about 900 mg.
  • a daily dose range should be between about 1 mg to about 200 mg. More preferably, the daily dose range should be between about 1 mg to about 50 mg.
  • Pravastatin is a hexahydro-naphthalene derivative first isolated as a metabolite of compactin. Pravastatin exhibits an important therapeutic advantage over other statins. Pravastatin selectively inhibits cholesterol synthesis in the liver and small intestine but leaves cholesterol synthesis in the peripheral cells substantially unaffected. T. Koga et al. Biochim. Biophys. Acta 1990, 1045, 115-120. This selectivity appears to be due to the presence of a hydroxyl group at the C-6 position of the hexahydronaphthalene nucleus. The
  • C-6 position is occupied by a hydrogen atom in compactin and a methyl group in lovastatin.
  • Pravastatin is less able to permeate the lipophilic membranes of peripheral cells than the other more lipophilic congeners. See Serajuddin et al. J. Pharm. Sci. 1991, 80, 830-34.
  • pravastatin can be prepared as described in N. Serizawa et al. J.
  • Pravastatin has the chemical name [lS-[l ⁇ ( ⁇ S*, ⁇ S*)2 ⁇ ,6 ⁇ ,8 ⁇ (R*),8a ⁇ ]]-l,2,6,7,8,8a-hexahydro- ⁇ , ⁇ ,6- trihydroxy-2-methyl-8-(2-methyl-l-oxobutoxy)-l-naphthaleneheptanoic acid and the structure is presented below.
  • Pravastatin, lovastatin, simvastatin, and fluvastatin each possess an alkyl chain that is terminated by a carboxylic acid group, wherein the alkyl chain bears two hydroxyl groups. It is thought that the alkyl chain is the portion of the molecule that binds to HMG- CoA reductase. The carboxylic acid group and the hydroxyl group at the delta-position are prone to lactonize. Lactonizable compounds like the statins may exist in the free acid form or the lactone form or as an equilibrium mixture of both forms. As used herein, the term "pravastatin" refers to the carboxylic acid, the lactone, and mixture of the carboxylic acid and lactone.
  • Pravastatin can be obtained by fermentation of compactin using a variety of microorganisms: Absidia coerulea IFO 4423 spores, Cunninghamella echinulata IFO 4445, Streptomyces rosochromogenus ⁇ RRL 1233, Syncephalastrum racemosum IFO 4814 and Syncephalastrum racemosum IFO 4828. See U.S. Patent 4,346,227. After fermentation, pravastatin was separated from the fermentation broth by acidifying the broth to a pH of 3 and extracting pravastatin and other non-hydrophilic organics with ethyl acetate, followed by washing with brine.
  • pravastatin free acid was lactonized by addition of a catalytic amount of trifluoroacetic acid, then neutralized with dilute sodium bicarbonate, dried over sodium sulfate and evaporated to dryness. The residue was purified by preparative reverse- phase high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • PCT/USOO/19384 relates to the microbial hydroxylation of compactin to pravastatin using a strain of Micromonospora maculata that is unusually resistant to the antifungal effects of compactin.
  • Industrial production of pravastatin can be achieved by two fermentation processes. In the first, microbiological stage compactin is prepared, then in the course of a second fermentation the sodium salt of compactin acid is converted to pravastatin by microbial hydroxylation at the 6 ⁇ -position.
  • the microbial hydroxylation of compactin can be accomplished to various extents with mold species belonging to different genera, and with filamentous bacteria belonging to the Nocardia genus, with Actinomadura and Streptomyces genera. See European Patent Application 0605230 and U.S.
  • Patents 4,537,859 and 4,346,227 Various procedures for the preparation of pravastatin are described in the following U.S. Patents and U.S. Published Patent Applications: 6,696,599; 6,682,913; 6,566,120; 6,306,629; 6,274,360; 6,204,032; 5,942,423; 20040039225; 20030216596; 20030207413; 20030204105;
  • pravastatin sodium salt Several new crystalline forms of pravastatin sodium salt are described in U.S. Patent Application 20010041809.
  • the size of a prophylactic or therapeutic dose of pravastatin, or one of its salts, in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient, hi general, the total daily dose ranges, for the conditions described herein, is from about 1 mg to about 150 mg.
  • a daily dose range should be between about 5 mg to about 80 mg.
  • a daily dose range should be between about 10 mg to about 40 mg.
  • the daily dose range should be about 15, 20, 25, 30, or 35 mg.
  • the therapy may be initiated at a lower dose, perhaps about 5 mg to about 15 mg and increased up to about 20 mg or higher depending on the patient's global response.
  • Rosuvastatin Rosuvastatin is a pyrimidine derivative that inhibits HMG-CoA reductase selectively in hepatocytes cells. Procedures for the preparation of rosuvastatin are described in U.S. Patent 5,260,440. The data from a parallel-group multicenter trial revealed that administration of rosuvastatin to patients with hypertriglyceridemia
  • Rosuvastatin is often administered in the form of its calcium salt marketed under the name CR ⁇ STOR®. Procedures for the preparation of the calcium salt of rosuvastatin are described in U.S. Patent 5,260,440. Rosuvastatin has the chemical name [S-[R*,S*- (E)]]-7-[4-(4-fluorophenyl)-6-(l -methylethyl)-2-[methyl(methylsulfonyl)amino]-5- pyrimidinyl]-3,5-dihydroxy-6-heptenoic acid and has the structure presented below.
  • a prophylactic or therapeutic dose of rosuvastatin, or one of its salts, in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient, general, the total daily dose ranges, for the conditions described herein, is from about 1 mg to about 150 mg.
  • a daily dose range should be between about 2 mg to about 80 mg.
  • a daily dose range should be between about 5 mg to about 40 mg.
  • the daily dose range should be about 10, 15, 20, 25, 30, or 35 mg.
  • the therapy may be initiated at a lower dose, perhaps about 3 mg to about 9 mg and increased up to about 20 mg or higher depending on the patient's global response.
  • Simvastatin is the synthetic derivative of a fermentation product obtained from Aspergillus terreus. Simvastatin is marketed under the tradename ZOCOR® and can reduce total cholesterol, low-density lypoprotein cholesterol, the ratio of total cholesterol to high-density lypoprotein cholesterol, the ratio of low-density lypoprotein cholesterol to high-density lypoprotein cholesterol, and triglyceride levels. Procedures for the preparation of simvastatin are described in U.S. Patent 4,444,784; European Patent Application 33,538; and W. F. Hoffman et al. J. Med. Chem. 1986, 29, 849. The pharmacological properties are described in M. j. Mol. et al. Lancet 1986, 2, 936; L. A. Simons et al. Med. J. Aust. 1987,
  • Simvastatin has the chemical name [1S-
  • Simvastatin is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in chloroform, methanol and ethanol.
  • simvastatin which is an inactive lactone, is hydrolyzed to the corresponding beta-hydroxyacid form which is HMG-CoA reductase inhibitor.
  • Simvastatin shows no fed-fasted effect when administered immediately before a low-fat meal.
  • simvastatin is absorbed in the gastrointestinal tract, it is known to undergo hepatic metabolism. The hepatic metabolism is primarily via cytochrome CYP 3A4. See Clin. Pharmacokinet. 1993, 24(3), 195-202.
  • a dihydroxy open-acid salt form of simvastatin is described in U.S. Patent Application 20030176501.
  • Two general strategies have been reported for the preparation of simvastatin.
  • the 2-(S)-methylbutyryloxy side chain of lovastatin is alkylated.
  • the 2-(S)-methylbutyryloxy side chain of lovastatin is methylated using a methyl alkyl amide and a methyl halide in a single step. Additional studies have revealed that minor adjustments to this procedure can significantly improve the yield of the reaction.
  • Patent 4,820,850 discloses a process for methylation of the 2-(S)-methylbutyrylox side chain of lovastatin using a single charge of amide base and alkyl halide. The overall process disclosed involves six steps. The second strategy is de-esterification of the 2-methylbutyrate side chain of lovastatin followd by re-esterification forming the desired 2,2-dimethylbutyrate (simvastatin).
  • the second strategy is de-esterification of the 2-methylbutyrate side chain of lovastatin followd by re-esterification forming the desired 2,2-dimethylbutyrate (simvastatin).
  • Patent 4,444,784 discloses a process comprising de-esterification of the 2-methylbutyrate side chain of lovastatin, protection of the 4-hydroxy group on the pyranone ring with t-butyldimethyl-chlorosilane, re-esterification with 2,2-dimethylbutyryl chloride, and deprotection of the 4-hydroxy group.
  • EP 0287340 discloses an improvement of the acylation step in the above process which involves the addition of alkali metal bromides under the presence of dialkylaminopyridine as a catalyst in a solvent, preferably pyridine.
  • the presumed mechanism of reaction is characterized by in situ generation of reactive acylated intermediates such as acyl bromides, a pyridinium complex, or a dialkylaminopyridinium complex.
  • reactive acylated intermediates such as acyl bromides, a pyridinium complex, or a dialkylaminopyridinium complex.
  • the reaction times are shorter (6 to 8 hours), and the temperatures required are lower.
  • acylated intermediates such as acyl bromides, a pyridinium complex, or a dialkylaminopyridinium complex.
  • the size of a prophylactic or therapeutic dose of simvastatin, or one of its salts, in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges is from about 1 mg to about 200 mg.
  • a daily dose range should be between about 5 mg to about 100 mg.
  • a daily dose range should be between about 10 mg to about 50 mg.
  • the daily dose range should be about 20, 30, or 40 mg.
  • the therapy may be initiated at a lower dose, perhaps about 5 mg to about 15 mg and increased up to about 25 mg or higher depending on the patient's global response.
  • Gemcabene Gemcabene is a lipid-lowering agent being developed by Pfizer. Gemcabene lowers low-density lypoprotein cholesterol, apolipoprotein C-ffl, and triglyceride levels.
  • gemcabene increases the amount of high-density lypoprotein cholesterol.
  • the lipid-lowering affects are described in H. E. Bays et al. Am. J. Cardiol. 2003, 92, 538. In general, the total daily dose range is from about 1 mg to about 900 mg. Preferably, a daily dose range should be between about 10 mg to about 200 mg.
  • Gemcabene has the chemical name 6,6'-oxylbis(2,2,dimethylhexanoate)calcium and the structure is presented below.
  • Probucol Probucol is lipid-lowering antioxidant. Procedures for the preparation of probucol are described in U.S. Patent 3,576,883. The pharmacological properties are described in R. C. Heel et al.
  • Probucol has the chemical name 4,4'-[(l- methylethylidene)bis(thio)]bis[2,6-bis(l,l-dimethylethylphenol] and has the structure presented below.
  • a prophylactic or therapeutic dose of probucol, or one of its salts, in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient, hi general, the total daily dose ranges, for the conditions described herein, is from about 0.1 g to about 8.0 g.
  • a daily dose range should be between about 1.0 g to about 6.0 g.
  • a daily dose range should be between about 3.0 g to about 5.0 g.
  • the daily dose range should be about 3.5, 4.0, or 4.5 g.
  • the therapy may be initiated at a lower dose, perhaps about 1.5 g to about 2.0 g and increased up to about 3.5 g or higher depending on the patient's global response.
  • Additional HMG-CoA inhibitors contemplated in the present invention are described in the following U.S.
  • Niacin is a member of the Vitamin B-complex group which is widely distributed in nature. Niacin can be purchased from Aldrich (Milwaukee, Wisconsin). Alternatively, niacin can be prepared using the procedures described in U.S. Patents 6,376,677; 6,229,018; and 6,077,957. The pharmacological properties are described in DiPahna, J. R.; Thayer, W. S. Ann. Rev. Nutr. 1991, 11, 169-187 and in the review "Niacin: Nicotinic Acid, Nicotinamide, NAD(P)" in Vitamins, W. Friedrich, Ed. (Walter de Gruyter, Berlin, 1988) pp 473-542.
  • Niacin inhibits production of very low-density lypoprotein in the liver and increases high-density lypoprotein cholesterol. It also decreases triglycerides, remnant lipoproteins, and total plasma and low-density lypoprotein (LD) cholesterol, changing LDL particles from small and dense to large and buoyant forms. See J. R. Guyton, et al. Arch. Intern. Med. 2000, 160, 1177. Lower doses (1500 to 2000 mg/day) can affect triglycerides and HDL cholesterol markedly; higher doses may be required for substantial reductions of LDL cholesterol.
  • Niacin has the chemical name 3-pyridinecarboxylic acid and the structure is presented below.
  • a prophylactic or therapeutic dose of niacin, or one of its salts, in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient, h general, the total daily dose ranges, for the conditions described herein, is from about 0.01 g to about 4.0 g.
  • a daily dose range should be between about 0.1 g to about 2.5 g.
  • a daily dose range should be between about 0.25 g to about 1.0 g.
  • the daily dose range should be about 0.40, 0.60, or 0.80 g.
  • the therapy may be initiated at a lower dose, perhaps about 0.15 g to about 0.30 g and increased up to about 0.75 g or higher depending on the patient's global response.
  • Cholesterol abso ⁇ tion inhibitors block abso ⁇ tion of cholesterol in the enterocyte cells of the gut lumen. The unabsorbed cholesterol is excreted in the feces. Blocking cholesterol abso ⁇ tion in the intestine decreases the uptake of dietary cholesterol.' Administration of a cholesterol abso ⁇ tion inhibitor can lower low-density lypoprotein cholesterol by 10-20%. Many cholesterol abso ⁇ tion inhibitors generally do not remain in the liver in significant amounts or enter the systemic circulation in significant amounts. Therefore, many cholesterol abso ⁇ tion inhibitors have minimal toxicity and a reduced potential for drug interactions. The mechanism by which cholesterol moves from the lumen into the epithelial layer lining the small intestine is not well understood.
  • Certain sulfur-substituted azetidinones described in U.S. Patents 4,774,467; 5,633,246; and 5,624,920 can inhibit cholesterol abso ⁇ tion.
  • Patent 5,661,145 are potent inhibitors of intestinal cholesterol abso ⁇ tion, leading to decreased plasma cholesterol levels in several animal species (hamsters, rats, rabbits, and monkeys). See WO 93/02048, EP 524595, EP 675714, and U.S. Patent 5,661,145 for additional beta- lactam cholesterol abso ⁇ tion inhibitors. Furthermore, compounds that inhibit cholesterol abso ⁇ tion include acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors such as Cl-976 (B. R. Krause et al. Clin. Biochem. 1992, 25, 371-377), 58-035 (J. G. Heiden et al. J. Up. Res.
  • ACAT cholesterol acyltransferase
  • phytosterols and phytostanols inhibit intestinal abso ⁇ tion of cholesterol.
  • phytosterols and phytostanols described in U.S. Patent Application 20020068095 inhibit intestinal abso ⁇ tion of cholesterol.
  • Steroidal glycosides described in WO 93/07167-A1 and U.S. Patents 4,602,003 and 4,602,005 are potential therapeutic agents for controlling hypercholesterolemia. Pfizer, Inc.
  • the cholesterol inhibitors of the invention are those compounds that at least partially inhibit abso ⁇ tion of cholesterol in the intestine.
  • the cholesterol abso ⁇ tion inhibitor reduces the amount of cholesterol that is absorbed in the intestine by at least about 5% compared to the amount of cholesterol that is absorbed in the intestine in the absence of the cholesterol abso ⁇ tion inhibitor.
  • the cholesterol abso ⁇ tion inhibitor reduces the amount of cholesterol that is absorbed in the intestine by at least about 10% or 20% compared to the amount of cholesterol that is absorbed in the intestine in the absence of the cholesterol abso ⁇ tion inhibitor.
  • the cholesterol abso ⁇ tion inhibitor reduces the amount of cholesterol that is absorbed in the intestine by at least about 25%, 30% compared to the amount of cholesterol that is absorbed in the intestine in the absence of the cholesterol abso ⁇ tion inhibitor, hi a most prefered embodiment, the cholesterol abso ⁇ tion inhibitor reduces the amount of cholesterol that is absorbed in the intestine by at least about 60%, or 75% compared to the amount of cholesterol that is absorbed in the intestine in the absence of the cholesterol abso ⁇ tion inhibitor.
  • the amount of cholesterol that is prevented from being absorbed by the intestine following administration of a cholesterol abso ⁇ tion inhibitor can be determined using the assays described in the art.
  • the administration volume of the cholesterol abso ⁇ tion inhibitor is about 0.5 ml/mouse.
  • the cholesterol abso ⁇ tion inhibitor is administered immediately prior to the test meal (Intralipid labeled with 14 C-cholesterol) (cholesterol abso ⁇ tion test).
  • the feces are collected over a period of 24 h: fecal elimination of 14 C-cholesterol and 3 H-taurocholic acid (TCA) is determined after 24 hours.
  • the livers are removed and homogenized, and aliquots are incinerated in an oximate (Model 307, Packard) to determine the amount of 14 C-cholesterol which had been taken up/absorbed.
  • Liver Samples The amount of 14 C-cholesterol taken up by the liver is based on the administered dose.
  • the ED 50 values are inte ⁇ olated from a dose-effect curve as the dose at which the uptake of 14 C-cholesterol by the liver is halved (50%), based on a control group.
  • the cholesterol abso ⁇ tion inhibitor is only minimally absorbed by the intestine.
  • Minimally absorbed by the intestine is to be understood as meaning intestinal abso ⁇ tion of the cholesterol abso ⁇ tion inhibitor of less than about 25%, preferably less than about 10%, and more preferrably less than about 5%.
  • Pharmaceutically active compounds which are absorbed to a very low extent generally have considerably fewer side-effects.
  • a dose of the cholesterol abso ⁇ tion inhibitor or a pharmaceutically acceptable salt thereof suitable for administration to a human will be in the range of 0.01 to 50 mg per kilogram body weight of the recipient per day, preferably in the range of 0.1 to 3 mg per kilogram body weight per day. Unless otherwise stated all weights of active ingredients are calculated in terms of drug per se.
  • the desired dose is presented as two, three, four, five or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example, containing about 5 to 50 mg.
  • Ezetimibe Ezetimibe is a 2-azetidinone derivative that selectively inhibits intestinal abso ⁇ tion of cholesterol and related phytosterols.
  • Ezetimibe has been shown to lower LDL cholesterol by approximately 18% by administration of a 10 mg dose once per day.. See T. Meittinen Int. J. Clin. Pract. 2001; 55(10), 710-6. Procedures for the preparation of ezetimibe are described in WO 95/08532, EP 720599, and U.S. Patent 5,846,966. The pharmacological properties are described in M. H. Davidson Expert Rev. Cardiovasc. Ther. 2003, 1, 11-21; Manhas, A.; Farmer, J. A. Curr. Atheroscler. Rep. 2004, 6, 89-93; and Darkes, M. J.; Poole, R. M.; Goa, K. L. Am. J. Cardiovasc.
  • Ezetimibe is a white, crystalline powder soluble in ethanol, methanol, and acetone. Ezetimibe is marketed under the tradename ZETIATM. The results from clinical studies demonstrate that administration of ezetimibe to patients suffering from hypercholesterolemia lowers total cholesterol, low-density lypoprotein cholesterol, Apo B, and triglyceride levels, hi addition, administration of ezetimibe resulted in elevated levels of high-density lypoprotein cholesterol.
  • Ezetimibe has the chemical name l-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)- 3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone and structure is presented below.
  • a prophylactic or therapeutic dose of ezetimibe, or one of its salts, in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 1 mg to about 150 mg.
  • a daily dose range should be between about 2 mg to about 75 mg.
  • a daily dose range should be between about 5 mg to about 20 mg.
  • the daily dose range should be about 8, 10, 13, 15, or 18 mg.
  • the therapy may be initiated at a lower dose, perhaps about 4 mg to about 6 mg and increased up to about 12 mg or higher depending on the patient's global response.
  • Colesevelam Colesevelam is a polyallylamine polymer that is cross-linked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyl)-trimethylammonium bromide.
  • Colesevelam is marketed in the form of its hydrochloride salt under the tradename name WelCholTM.
  • Procedures for the preparation of colesevelam hydrochloride are described in U.S. Patent 5,693,675. The pharmacological properties are described in D. P. Rosenbaum et al. J. Pharm. Sci.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient, h general, the total daily dose ranges, for the conditions described herein, is from about 0.1 g to about 8.0 g.
  • a daily dose range should be between about 1.0 g to about 6.0 g.
  • a daily dose range should be between about 3.0 g to about 5.0 g.
  • the daily dose range should be about 3.5, 4.0, or 4.5 g.
  • the therapy may be initiated at a lower dose, perhaps about 1.5 g to about 2.0 g and increased up to about 3.5 g or higher depending on the patient's global response.
  • Pamaqueside Pamaqueside is a synthetic saponin described by DeNinno and coworkers. See M. P. DeNinno et al. J Med. Chem. 1997, 40, 2547-54. The pharmacological properties of pamaqueside are described in Dalvie, D.; O'Donnell, j. Xenobiotica. 1999, 29, 1043-56; L. A. Morehouse et al. J Lipid Res. 1999, 40, 464-7 '4; and P. A. McCarthy et al. J. Med. Chem. 1996, 39(10), 1935-7. The dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges for the conditions described herein, is from about 0.1 g to about 8.0 g.
  • a daily dose range should be between about 0.5 g to about 3.0 g.
  • the structure of pamaqueside is presented below.
  • ⁇ -Sitosterol ⁇ -Sitosterol is a common plant sterol that has been shown to inhibit cholesterol abso ⁇ tion. ⁇ -Sitosterol is found in a variety of fruits, vegetables, nuts, and seeds. Procedures for the preparation of ⁇ -sitosterol are described in Fujimoto, G. E.; Jacobson, A. E. J Org. Chem. 1964, 29, 3377 and Sucrow, W.; Slopianka, M. Ber. 1975, 108, 3721. The pharmacological properties, including the ability of ⁇ -sitosterol to inhibit cholesterol abso ⁇ tion, are described in Lees, R. S.; Leess, A. M. Lipoprotein Metabolism, H. Greten, Ed.
  • ⁇ -Sitosterol has the chemical name (3 ⁇ )-stigmast-5-en-3-ol and has the structure presented below.
  • the size of a prophylactic or therapeutic dose of ⁇ -sitosterol, or one of its salts, in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient, h general, the total daily dose ranges, for the conditions described herein, is from about 0.01 g to about 4.0 g.
  • a daily dose range should be between about 0.1 g to about 2.5 g.
  • a daily dose range should be between about 0.25 g to about 1.0 g.
  • the daily dose range should be about 0.40, 0.60, or 0.80 g.
  • the therapy may be initiated at a lower dose, perhaps about 0.15 g to about 0.30 g and increased up to about 0.75 g or higher depending on the patient's global response.
  • Tiqueside Tiqueside is a synthetic saponin described in U.S. Patents 4,602,003 and 4,602,005.
  • the pharmacological properties of tiqueside are described in M. P. DeNinno et al. J Med. Chem. 1997, 40, 2547-54; H. J. Harwood Jr et al. Journal of Lipid Research 1993, 34, 377- 395; and P. B. Inskeep et al. J. Pharm. Sci. 1995, 84, 12-4.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 0.1 g to about 8.0 g.
  • a daily dose range should be between about 0.5 g to about 3.0 g.
  • the structure of tiqueside is presented below.
  • FM-VP4 FM-VP4 is a cholesterol abo ⁇ tion inhibitor being developed by Forbes Medi-Tech Inc. Oral administration of FM-VP4 to gerbils resulted in a 53-56% reduction in total cholesterol after 4-8 weeks. See A.W. Ng et al. Cardiovasc. Drug Rev. 2003, 21(3), 151- 68. FM-VP4 is described in a PCT Application. The biological activity of FM-VP4 is described in T. Lukic et al. Metabolism 2003, 52(4), 425-31; K. M. Wasan et al. J Pharm. Sci. 2001; 90(11), 1795-1799; K. M. Wasan et al. J. Pharm. Pharmaceut. Sci.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient, hi general, the total daily dose ranges, for the conditions described herein, is from about 0.1 g to about 8.0 g. Preferably, a daily dose range should be between about 0.5 g to about 3.0 g.
  • FM-VP4 has the chemical name 2-[(3 ⁇ ,5 ⁇ )-stigmastan-3-yl hydrogen phosphate] L-ascorbic acid monosodium salt and the structure is presented below.
  • L-166,143 L- 166, 143 is a sterol glycoside that selectively inhibits cholesterol uptake by intestinal epithelium.
  • Autoradiographic data indicate that L-166,143 can effectively block the uptake of 3 H-cholesterol by enterocytes in vivo. These results have been inte ⁇ reted to mean that L-166,143 inhibits an early step in cholesterol abso ⁇ tion. See P. A. Detmers et al. Biochim. Biophys. Acta. 2000, 1486(2-3), 243-52.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient. In general, the total daily dose ranges, for the conditions described herein, is from about 0.1 g to about 8.0 g.
  • a daily dose range should be between about 0.5 g to about 3.0 g.
  • Assessment of Bioavailablity Assessment of bioavailability from plasma concentration-time data usually involves determining the maximum (peak) plasma drug concentration, the time at which maximum plasma drug concentration occurs (peak time), and the area under the plasma concentration- time curve (AUC; see Figure 7).
  • the plasma drug concentration increases with the extent of abso ⁇ tion; the peak is reached when the drug elimination rate equals abso ⁇ tion rate. Bioavailability determinations based on the peak plasma concentration can be misleading, because drug elimination begins as soon as the drug enters the bloodstream.
  • the most widely used general index of abso ⁇ tion rate is peak time; the slower the abso ⁇ tion, the later the peak time.
  • AUC is the most reliable measure of bioavailability. It is directly proportional to the total amount of unchanged drug that reaches the systemic circulation. For an accurate measurement, blood must be sampled frequently over a long enough time to observe virtually complete drug elimination. Drug products may be considered bioequivalent in extent and rate of abso ⁇ tion if their plasma-level curves are essentially superimposable. Drug products that have similar AUCs but differently shaped plasma-level curves are equivalent in extent but differ in their abso ⁇ tion rate-time profiles.
  • Combination Therapy One aspect of the present invention relates to combination therapy.
  • This type of therapy is advantageous because the co-administration of active ingredients achieves a therapeutic effect that is greater than the therapeutic effect achieved by administration of only a single therapeutic agent.
  • the co-administration of two or more therapeutic agents achieves a synergistic effect, i.e., a therapeutic affect that is greater than the sum of the therapeutic effects of the individual components of the combination.
  • the active ingredients that comprise a combination therapy may be administered together via a single dosage form or by separate administration of each active agent.
  • the first and second therapeutic agents are administered in a single dosage form.
  • the agents may be formulated into a single tablet, pill, capsule, or solution for parenteral administration and the like.
  • the first therapeutic agent and the second therapeutic agents may be administered as separate compositions, e.g., as separate tablets or solutions.
  • the first active agent may be administered at the same time as the second active agent or the first active agent may be administered intermittently with the second active agent.
  • the length of time between administration of the first and second therapeutic agent may be adjusted to achieve the desired therapeutic effect, hi certain instances, the second therapeutic agent may be administered only a few minutes (e.g., 1, 2, 5, 10, 30, or 60 min) after administration of the first therapeutic agent.
  • the second therapeutic agent may be administered several hours (e.g., 2, 4, 6, 10, 12, 24, or 36 hr) after administration of the first therapeutic agent.
  • the second therapeutic agent may be administered at 2 hours and then again at 10 hours following administration of the first therapeutic agent.
  • the therapeutic effects of each active ingredient overlap for at least a portion of the duration of each therapeutic agent so that the overall therapeutic effect of the combination therapy is attributable in part to the combined or synergistic effects of the combination therapy.
  • the dosage of the active agents will generally be dependent upon a number of factors including pharmacodynamic characteristics of each agent of the combination, mode and route of administration of active agent(s), the health of the patient being treated, the extent of treatment desired, the nature and kind of concurrent therapy, if any, and the frequency of treatment and the nature of the effect desired.
  • dosage ranges of the active agents often range from about 0.001 to about 250 mg/kg body weight per day. For a normal adult having a body weight of about 70 kg, a dosage in the range of from about 0.1 to about 25 mg/kg body weight is typically preferred. However, some variability in this general dosage range may be required depending upon the age and weight of the subject being treated, the intended route of administration, the particular agent being administered and the like.
  • the potency of each agent and the interactive effects achieved using them together must be considered.
  • the determination of dosage ranges and optimal dosages for a particular mammal is also well within the ability of one of ordinary skill in the art having the benefit of the instant disclosure.
  • the pharmaceutical combination may be advantageous for the pharmaceutical combination to have a relatively large amount of the first component compared to the second component, hi certain instances, the ratio of the first active agent to second active agent is 30:1, 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, or 5:1.
  • the ratio of the first active agent to the second active agent is 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, or 1 :4.
  • the ratio of the second active agent to the first active agent is 30:1, 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, or 5:1.
  • a composition comprising any of the above-identified combinations of first therapeutic agent and second therapeutic agent may be administered in divided doses 1, 2, 3, 4, 5, 6, or more times per day or in a form that will provide a rate of release effective to attain the desired results.
  • the dosage form contains both the first and second active agents, h a more preferred embodiment, the dosage form only has to be administered one time per day and the dosage form contains both the first and second active agents.
  • a formulation intended for oral administration to humans may contain from 0.1 mg to 5 g of the first therapeutic agent and 0.1 mg to 5 g of the second therapeutic agent, both of which are compounded with an appropriate and convenient amount of carrier material varying from about 5 to about 95 percent of the total composition.
  • Unit dosages will generally contain between from about 0.5 mg to about 1500 mg of the first therapeutic agent and 0.5 mg to about 1500 mg of the second therapeutic agent.
  • the dosage comprises 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg, etc., up to 1500 mg of the first therapeutic agent. In a preferred embodiment, the dosage comprises 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg, etc., up to 1500 mg of the second therapeutic agent.
  • the optimal ratios of the first and second therapeutic agent can be determined by standard assays known in the art.
  • equieffective dose substitution model and a curvilinear regression analysis utilizing all the data for the individual compounds and various dose ratios for the combinations can be used to establish the existence of unexpectedly enhanced antihypertensive, antihyperlipidemic, or other related cardiac activity of combinations of active agents, i.e., the resulting activity is greater than the activity expected from the sum of the activities of the individual components.
  • the toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LDso/ED 50 .
  • Compounds which exhibit large therapeutic indices are preferred.
  • the data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC 50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of RT production from infected cells compared to untreated control as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography (HPLC). Synergism The term "synergistic" refers to a combination which is more effective than the additive effects of any two or more single agents. A synergistic effect permits the effective treatment of a disease using lower amounts (doses) of either individual therapy. The lower doses result in lower toxicity without reduced efficacy.
  • synergistic effect can result in improved efficacy, e.g., improved antiviral activity.
  • synergy may result in an improved avoidance or reduction of disease as compared to any single therapy.
  • Combination therapy often allows for the use of lower doses of the first therapeutic or the second therapeutic agent (referred to as "apparent one-way synergy” herein), or lower doses of both therapeutic agents (referred to as “two-way synergy” herein) than would normally be required when either drug is used alone. By using lower amounts of either or both drugs, the side effects associated with them are reduced.
  • the synergism exhibited between the second therapeutic agent and the first therapeutic agent is such that the dosage of the first therapeutic agent would be sub-therapeutic if administered without the dosage of the second therapeutic agent.
  • the present invention relates to a pharmaceutical composition comprising an therapeutically effective dose of a first therapeutic agent together with a dose of a second therapeutic agent effective to augment the therapeutic effect of the first therapeutic agent.
  • the synergism exhibited between the second therapeutic agent and the first therapeutic agent is such that the dosage of the second therapeutic agent would be sub-therapeutic if administered without the dosage of the first therapeutic agent
  • the present invention relates to a pharmaceutical composition comprising an therapeutically effective dose of a second therapeutic agent together with a dose of a first therapeutic agent effective to augment the therapeutic effect of the second therapeutic agent.
  • the invention is directed in part to synergistic combinations of the first therapeutic agent in an amount sufficient to render a therapeutic effect together with a second therapeutic agent.
  • a therapeutic effect is attained which is at least about 2 (or at least about 4, 6, 8, or 10) times greater than that obtained with the dose of the first therapeutic agent alone.
  • the synergistic combination provides a therapeutic effect which is up to about 20, 30 or 40 times greater than that obtained with the dose of first therapeutic agent alone.
  • the synergistic combinations display what is referred to herein as an "apparent one-way synergy", meaning that the dose of second therapeutic agent synergistically potentiates the effect of the first therapeutic agent, but the dose of first therapeutic agent does not appear to significantly potentiate the effect of the second therapeutic agent.
  • the combination of active agents exhibit two-way synergism, meaning that the second therapeutic agent potentiates the effect of the first therapeutic agent, and the first therapeutic agent potentiates the effect of the second therapeutic agent.
  • other embodiments of the invention relate to combinations of a second therapeutic agent and a first therapeutic agent where the dose of each drug is reduced due to the synergism between the drugs, and the therapeutic effect derived from the combination of drugs in reduced doses is enhanced.
  • the two-way synergism is not always readily apparent in actual dosages due to the potency ratio of the first therapeutic agent to the second therapeutic agent.
  • two-way synergism can be difficult to detect when one therapeutic agent displays much greater therapeutic potency relative to the other therapeutic agent.
  • the synergistic effects of combination therapy may be evaluated by biological activity assays.
  • the therapeutic agents are be mixed at molar ratios designed to give approximately equipotent therapeutic effects based on the EC 90 values.
  • This program evaluates drug interactions by use of the widely accepted method of Chou and Talalay combined with a statistically evaluation using the Monte Carlo statistical package.
  • the data are displayed in several different formats including median- effect and dose-effects plots, isobolograms, and combination index [CI] plots with standard deviations.
  • CI combination index
  • compositions of the Invention relate to a pharmaceutical composition, comprising optically pure (S)-amlodipine and a HMG-CoA reductase inhibitor.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said HMG-CoA reductase inhibitor is atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, gemcabene, probucol, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • said HMG-CoA reductase inhibitor is atorvastatin, lovastatin, simvastatin, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said HMG-CoA reductase inhibitor is lovastatin or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • a pharmaceutical composition comprising optically pure (S)-amlodipine and a cholesterol abso ⁇ tion inhibitor.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said cholesterol abso ⁇ tion inhibitor is ezetimibe, colesevelam, pamaqueside, ⁇ -sitosterol, tiqueside, FM-VP4, L-166,143, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said cholesterol abso ⁇ tion inhibitor is ezetimibe or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • a pharmaceutical composition comprising optically pure (S)-amlodipine, a HMG-CoA reductase inhibitor, and a cholesterol abso ⁇ tion inhibitor.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said HMG-CoA reductase inhibitor is atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, gemcabene, probucol, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • said HMG-CoA reductase inhibitor is atorvastatin, lovastatin, simvastatin, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said HMG-CoA reductase inhibitor is lovastatin or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • said cholesterol abso ⁇ tion inhibitor is ezetimibe, colesevelam, pamaqueside, ⁇ -sitosterol, tiqueside, FM-VP4, L-166,143, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said cholesterol abso ⁇ tion inhibitor is ezetimibe or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said HMG-CoA reductase inhibitor is lovastatin or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and said cholesterol abso ⁇ tion inhibitor is ezetimibe or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • Another aspect of the present invention relates to a pharmaceutical composition, comprising optically pure (S)-amlodipine, a HMG-CoA reductase inhibitor, and niacin.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said HMG-CoA reductase inhibitor is atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, gemcabene, probucol, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • said HMG-CoA reductase inhibitor is atorvastatin, lovastatin, simvastatin, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said HMG-CoA reductase inhibitor is lovastatin or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • a pharmaceutical composition comprising optically pure (S)-amlodipine, a cholesterol abso ⁇ tion inhibitor, and niacin.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said cholesterol abso ⁇ tion inhibitor is ezetimibe, colesevelam, pamaqueside, ⁇ -sitosterol, tiqueside, FM-VP4, L-166,143, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said cholesterol abso ⁇ tion inhibitor is ezetimibe or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • a pharmaceutical composition comprising optically pure (S)-amlodipine, a HMG-CoA reductase inhibitor, a cholesterol abso ⁇ tion inhibitor, and niacin.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said HMG-CoA reductase inhibitor is atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, gemcabene, probucol, or a phannaceutically acceptable salt, solvate, or hydrate of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said HMG-CoA reductase inhibitor is atorvastatin, lovastatin, simvastatin, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said HMG-CoA reductase inhibitor is lovastatin or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • said cholesterol abso ⁇ tion inhibitor is ezetimibe, colesevelam, pamaqueside, ⁇ -sitosterol, tiqueside, FM-VP4, L-166,143, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said cholesterol abso ⁇ tion inhibitor is ezetimibe or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • said present invention relates to the aforementioned pharmaceutical composition, wherein said HMG-CoA reductase inhibitor is lovastatin or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and said cholesterol abso ⁇ tion inhibitor is ezetimibe or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • Another aspect of the present invention relates to a pharmaceutical composition consisting essentially of optically pure (S)-amlodipine, a HMG-CoA reductase inhibitor, and at least one pharmaceutically acceptable carrier.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said HMG-CoA reductase inhibitor is atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, gemcabene, probucol, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • said HMG-CoA reductase inhibitor is atorvastatin, lovastatin, simvastatin, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said HMG-CoA reductase inhibitor is lovastatin or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • Another aspect of the present invention relates to a pharmaceutical composition consisting essentially of optically pure (S)-amlodipine, a cholesterol abso ⁇ tion inhibitor, and at least one pharmaceutically acceptable carrier.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said cholesterol abso ⁇ tion inhibitor is ezetimibe, colesevelam, pamaqueside, ⁇ -sitosterol, tiqueside, FM-VP4, L-166,143, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said cholesterol abso ⁇ tion inhibitor is ezetimibe or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • Another aspect of the present invention relates to a pharmaceutical composition consisting essentially of optically pure (S)-amlodipine, a HMG-CoA reductase inhibitor, a cholesterol abso ⁇ tion inhibitor, and at least one pharmaceutically acceptable carrier.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said HMG-CoA reductase inhibitor is atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, gemcabene, probucol, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said HMG-CoA reductase inhibitor is atorvastatin, lovastatin, simvastatin, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them. In certain embodiments, the present invention relates to the aforementioned pharmaceutical composition, wherein said HMG-CoA reductase inhibitor is lovastatin or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said cholesterol abso ⁇ tion inhibitor is ezetimibe, colesevelam, pamaqueside, ⁇ -sitosterol, tiqueside, FM-VP4, L-166,143, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said cholesterol abso ⁇ tion inhibitor is ezetimibe or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said HMG-CoA reductase inhibitor is lovastatin or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and said cholesterol abso ⁇ tion inhibitor is ezetimibe or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • a pharmaceutical composition consisting essentially of optically pure (S)-amlodipine, a HMG-CoA reductase inhibitor, niacin, and at least one pharmaceutically acceptable carrier.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said HMG-CoA reductase inhibitor is atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, gemcabene, probucol, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • said HMG-CoA reductase inhibitor is atorvastatin, lovastatin, simvastatin, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said HMG-CoA reductase inhibitor is lovastatin or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • a pharmaceutical composition consisting essentially of optically pure (S)-amlodipine, a cholesterol abso ⁇ tion inhibitor, niacin, and at least one pharmaceutically acceptable carrier.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said cholesterol abso ⁇ tion inhibitor is ezetimibe, colesevelam, pamaqueside, ⁇ -sitosterol, tiqueside, FM-VP4, L-166,143, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said cholesterol abso ⁇ tion inhibitor is ezetimibe or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • Another aspect of the present invention relates to a pharmaceutical composition consisting essentially of optically pure (S)-amlodipine, a HMG-CoA reductase inhibitor, a cholesterol abso ⁇ tion inhibitor, niacin, and at least one pharmaceutically acceptable carrier.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said HMG-CoA reductase inhibitor is atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, gemcabene, probucol, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said HMG-CoA reductase inhibitor is atorvastatin, lovastatin, simvastatin, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them. In certain embodiments, the present invention relates to the aforementioned pharmaceutical composition, wherein said HMG-CoA reductase inhibitor is lovastatin or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said cholesterol abso ⁇ tion inhibitor is ezetimibe, colesevelam, pamaqueside, ⁇ -sitosterol, tiqueside, FM-VP4, L-166,143, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said cholesterol abso ⁇ tion inhibitor is ezetimibe or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said HMG-CoA reductase inhibitor is lovastatin or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and said cholesterol abso ⁇ tion inhibitor is ezetimibe or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the present invention relates to any of the aforementioned pharmaceutical compositions in this section of the application, wherein said optically pure (S)-amlodipine is optically pure (S)-amlodipine malate, or a polymo ⁇ h, pseudopolymo ⁇ h or solvate thereof.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a medical condition selected from the group consisting of hypertension, congestive heart failure, angina, hyperlipidemia, coronary artery disease, atherosclerosis, congestive heart failure, myocardial infarction, arrhythmia, artheroscierosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, stroke, and headache; comprising the step of: co-administering to a patient in need thereof a therapeutically effective amount of optically pure (S)-amlodipine and a HMG-CoA reductase inhibitor.
  • a medical condition selected from the group consisting of hypertension, congestive heart failure, angina, hyperlipidemia, coronary artery disease, atherosclerosis, congestive heart failure, myocardial infarction, arrhythmia, artheroscierosis, diabetic nephropathy, diabetic cardiac
  • the present invention relates to the aforementioned method, wherein said HMG-CoA reductase inhibitor is atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, gemcabene, probucol, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • said HMG-CoA reductase inhibitor is atorvastatin, lovastatin, simvastatin, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • the present invention relates to the aforementioned method, wherein said HMG-CoA reductase inhibitor is lovastatin or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • said present invention relates to any of the aforementioned methods, wherein said optically pure (- ⁇ -amlodipine is optically pure (S)-amlodipine malate, or a polymo ⁇ h, pseudopolymo ⁇ h or solvate thereof.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a medical condition selected from the group consisting of hypertension, congestive heart failure, angina, hyperlipidemia, coronary artery disease, atherosclerosis, congestive heart failure, myocardial infarction, arrhythmia, artheroscierosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, stroke, and headache; comprising the step of: co-administering to a patient in need thereof a therapeutically effective amount of optically pure (S)-amlodi ⁇ ine and a cholesterol abso ⁇ tion inhibitor.
  • a medical condition selected from the group consisting of hypertension, congestive heart failure, angina, hyperlipidemia, coronary artery disease, atherosclerosis, congestive heart failure, myocardial infarction, arrhythmia, artheroscierosis, diabetic nephropathy, diabetic cardiac myopathy
  • the present invention relates to the aforementioned method, wherein said cholesterol abso ⁇ tion inhibitor is ezetimibe, colesevelam, pamaqueside, ⁇ - sitosterol, tiqueside, FM-VP4, L-166,143, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • the present invention relates to the aforementioned method, wherein said cholesterol abso ⁇ tion inhibitor is ezetimibe or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the present invention relates to any of the aforementioned methods, wherein said optically pure (S)-amlodipine is optically pure (S)-amlodipine malate, or a polymo ⁇ h, pseudopolymo ⁇ h or solvate thereof.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a medical condition selected from the group consisting of hypertension, congestive heart failure, angina, hyperlipidemia, coronary artery disease, atherosclerosis, congestive heart failure, myocardial infarction, arrhythmia, artheroscierosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, stroke, and headache; comprising the step of: co-administering to a patient in need thereof a therapeutically effective amount of optically pure (S)-amlodipine, a HMG-CoA reductase inhibitor, and a cholesterol abso ⁇ tion inhibitor.
  • a medical condition selected from the group consisting of hypertension, congestive heart failure, angina, hyperlipidemia, coronary artery disease, atherosclerosis, congestive heart failure, myocardial infarction, arrhythmia, artheroscierosis,
  • the present invention relates to the aforementioned method, wherein said HMG-CoA reductase inhibitor is atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, gemcabene, probucol, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • said HMG-CoA reductase inhibitor is atorvastatin, lovastatin, simvastatin, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • the present invention relates to the aforementioned method, wherein said HMG-CoA reductase inhibitor is lovastatin or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • said cholesterol abso ⁇ tion inhibitor is ezetimibe, colesevelam, pamaqueside, ⁇ - sitosterol, tiqueside, FM-VP4, L-166,143, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • the present invention relates to the aforementioned method, wherein said cholesterol abso ⁇ tion inhibitor is ezetimibe or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • said HMG-CoA reductase inhibitor is lovastatin or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and said cholesterol abso ⁇ tion inhibitor is ezetimibe or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the present invention relates to any of the aforementioned methods, wherein said optically pure (S)-amlodipine is optically pure (S)-amlodipine malate, or a polymo ⁇ h, pseudopolymo ⁇ h or solvate thereof.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a medical condition selected from the group consisting of hypertension, congestive heart failure, angina, hyperlipidemia, coronary artery disease, atherosclerosis, congestive heart failure, myocardial infarction, arrhythmia, artheroscierosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, stroke, and headache; comprising the step of: co-administering to a patient in need thereof a therapeutically effective amount of optically pure (S)-amlodipine, a HMG-CoA reductase inhibitor, and niacin.
  • a medical condition selected from the group consisting of hypertension, congestive heart failure, angina, hyperlipidemia, coronary artery disease, atherosclerosis, congestive heart failure, myocardial infarction, arrhythmia, artheroscierosis, diabetic n
  • the present invention relates to the aforementioned method, wherein said HMG-CoA reductase inhibitor is atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, gemcabene, probucol, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • said HMG-CoA reductase inhibitor is atorvastatin, lovastatin, simvastatin, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • the present invention relates to the aforementioned method, wherein said HMG-CoA reductase inhibitor is lovastatin or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the present invention relates to any of the aforementioned methods, wherein said optically pure (S)-amlodipine is optically pure (S)-amlodipine malate, or a polymo ⁇ h, pseudopolymo ⁇ h or solvate thereof.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a medical condition selected from the group consisting of hypertension, congestive heart failure, angina, hyperlipidemia, coronary artery disease, atherosclerosis, congestive heart failure, myocardial infarction, arrhythmia, artheroscierosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, stroke, and headache; comprising the step of: co-administering to a patient in need thereof a therapeutically effective amount of optically pure (S)-amlodipine, a cholesterol abso ⁇ tion inhibitor, and niacin.
  • a medical condition selected from the group consisting of hypertension, congestive heart failure, angina, hyperlipidemia, coronary artery disease, atherosclerosis, congestive heart failure, myocardial infarction, arrhythmia, artheroscierosis, diabetic nephropathy,
  • the present invention relates to the aforementioned method, wherein said cholesterol abso ⁇ tion inhibitor is ezetimibe, colesevelam, pamaqueside, ⁇ - sitosterol, tiqueside, FM-VP4, L-166,143, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • the present invention relates to the aforementioned method, wherein said cholesterol abso ⁇ tion inhibitor is ezetimibe or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the present invention relates to any of the aforementioned methods, wherein said optically pure (S)-amlodipine is optically pure (S)-amlodipine malate, or a polymo ⁇ h, pseudopolymo ⁇ h or solvate thereof.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a medical condition selected from the group consisting of hypertension, congestive heart failure, angina, hyperlipidemia, coronary artery disease, atherosclerosis, congestive heart failure, myocardial infarction, arrhythmia, artheroscierosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, stroke, and headache; comprising the step of: co-administering to a patient in need thereof a therapeutically effective amount of optically pure (S)-amlodipine, a HMG-CoA reductase inhibitor, a cholesterol abso ⁇ tion inhibitor, and niacin.
  • a medical condition selected from the group consisting of hypertension, congestive heart failure, angina, hyperlipidemia, coronary artery disease, atherosclerosis, congestive heart failure, myocardial infarction, arrhythmia, art
  • the present invention relates to the aforementioned method, wherein said HMG-CoA reductase inhibitor is atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, gemcabene, probucol, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • said HMG-CoA reductase inhibitor is atorvastatin, lovastatin, simvastatin, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • the present invention relates to the aforementioned method, wherein said HMG-CoA reductase inhibitor is lovastatin or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • said cholesterol abso ⁇ tion inhibitor is ezetimibe, colesevelam, pamaqueside, ⁇ - sitosterol, tiqueside, FM-VP4, L-166,143, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them.
  • the present invention relates to the aforementioned method, wherein said cholesterol abso ⁇ tion inhibitor is ezetimibe or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • said HMG-CoA reductase inhibitor is lovastatin or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and said cholesterol abso ⁇ tion inhibitor is ezetimibe or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the present invention relates to any of the aforementioned methods, wherein said optically pure (S)-amlodipine is optically pure (S)-amlodipine malate, or a polymo ⁇ h, pseudopolymo ⁇ h or solvate thereof.
  • said medical condition is hypertension, congestive heart failure, angina, hyperlipidemia, coronary artery disease, atherosclerosis, or myocardial infarction.
  • the present invention relates to any of the aforementioned methods, wherein said medical condition is hypertension or hyperlipidemia.
  • the present invention relates to any of the aforementioned methods, wherein said medical condition is hypertension.
  • Immediate/Sustained Release Combination Therapy Dosase Forms The combination therapy may be formulated in an immediate release dosage form or a sustained release dosage form.
  • the present invention relates to immediate release dosage forms of the first and second therapeutic agents.
  • An immediate release dosage form may be formulated as a tablet or multiparticulate which may be encapsulated. Other immediate release dosage forms known in the art can be employed.
  • the combination of therapeutic agents may be formulated to provide for an increased duration (sustained release) of therapeutic action.
  • the combination therapy can be formulated to delivery the therapeutic agents at the same time or at separate times.
  • the first and second therapeutic agents are administered via an oral solid dosage form that includes a sustained release carrier causing the sustained release of the first therapeutic agent, or both the first therapeutic agent and the second therapeutic agent when the dosage form contacts gastrointestinal fluid.
  • the sustained release dosage form may comprise a plurality of substrates which include the drugs.
  • the substrates may comprise matrix spheroids or may comprise inert pharmaceutically acceptable beads which are coated with the drugs.
  • the coated beads are then preferably overcoated with a sustained release coating comprising the sustained release carrier.
  • the matrix spheroid may include the sustained release carrier in the matrix itself; or the matrix may comprise a normal release matrix containing the drugs, the matrix having a coating applied thereon which comprises the sustained release carrier.
  • the oral solid dosage form comprises a tablet core containing the drugs within a normal release matrix, with the tablet core being coated with a sustained release coating comprising the sustained release carrier.
  • the tablet contains the drugs within a sustained release matrix comprising the sustained release carrier.
  • the tablet contains the first therapeutic agent within a sustained release matrix and the second therapeutic agent coated into the tablet as an immediate release layer.
  • sustained release is defined for pu ⁇ oses of the present invention as the release of the therapeutic agent from the formulation at such a rate that blood (e.g., plasma) concentrations (levels) are maintained within the therapeutic range (above the minimum effective hypertensive or hyperlipidemic concentration or "MEAC") but below toxic levels over a period of time of about 12 hours or longer.
  • the first and second therapeutic agents can be formulated as a controlled or sustained release oral formulation in any suitable tablet, coated tablet or multiparticulate formulation known to those skilled in the art.
  • the sustained release dosage form may optionally include a sustained released carrier which is inco ⁇ orated into a matrix along with the active agents, or which is applied as a sustained release coating.
  • the sustained release dosage form may include the first therapeutic agent in sustained release form and second therapeutic agent in the sustained release form or in immediate release form.
  • the first therapeutic agent may be inco ⁇ orated into the sustained release matrix along with the second therapeutic agent; inco ⁇ orated into the sustained release coating; inco ⁇ orated as a separated sustained release layer or immediate release layer; or may be inco ⁇ orated as a powder, granulation, etc., in a gelatin capsule with the substrates of the present invention.
  • the sustained release dosage form may have the first therapeutic agent in the sustained release form and the second therapeutic agent in the sustained release form or immediate release form.
  • An oral dosage form according to the invention may be provided as, for example, granules, spheroids, beads, pellets (hereinafter collectively referred to as "multiparticulates") and/or particles.
  • An amount of the multiparticulates which is effective to provide the desired dose of the therapeutic agents over time may be placed in a capsule or may be inco ⁇ orated in any other suitable oral solid form.
  • the sustained release dosage form comprises such particles containing or comprising the active ingredient, wherein the particles have diameter from about 0.1 mm to about 2.5 mm, preferably from about 0.5 mm to about 2 mm.
  • the particles comprise normal release matrixes containing the first therapeutic agent with the second therapeutic agent.
  • the first therapeutic agent may be included in separate normal release matrix particles, or may be co-administered in a different immediate release composition which is either enveloped within a gelatin capsule or is administered separately.
  • the particles comprise inert beads which are coated with the second therapeutic agent with the first therapeutic agents.
  • a coating comprising the sustained release carrier is applied onto the beads as an overcoat.
  • the particles are preferably film coated with a material that permits release of the active agents at a sustained rate in an aqueous medium. The film coat is chosen so as to achieve, in combination with the other stated properties, a desired in vitro release rate.
  • the sustained release coating formulations of the present invention should be capable of producing a strong, continuous film that is smooth and elegant, capable of supporting pigments and other coating additives, non-toxic, inert, and tack-free.
  • Coatings The dosage forms of the present invention may optionally be coated with one or more materials suitable for the regulation of release or for the protection of the formulation. In one embodiment, coatings are provided to permit either pH-dependent or pH- independent release, e.g., when exposed to gastrointestinal fluid.
  • a pH-dependent coating serves to release the first active agent, second active agent, or both in the desired areas of the gastro-intestinal (GI) tract, e.g., the stomach or small intestine, such that an abso ⁇ tion profile is provided which is capable of providing at least about twelve hours and preferably up to twenty-four hours of therapeutic benefit to a patient.
  • the coating is designed to achieve optimal release regardless of pH-changes in the environmental fluid, e.g., the GI tract. It is also possible to formulate compositions which release a portion of the dose in one desired area of the GI tract, e.g., the stomach, and release the remainder of the dose in another area of the GI tract, e.g., the small intestine.
  • the first therapeutic agent is released in one area of the GI tract and the second therapeutic agent is released in a second area of the GI tract.
  • the first and second therapeutic agents are released in nearly equal amounts at the same location in the GI tract.
  • Formulations according to the invention that utilize pH-dependent coatings to obtain formulations may also impart a repeat-action effect whereby unprotected drug is coated over the enteric coat and is released in the stomach, while the remainder, being protected by the enteric coating, is released further down the gastrointestinal tract.
  • Coatings which are pH-dependent may be used in accordance with the present invention include shellac, cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulose phthalate, and methacrylic acid ester copolymers, zein, and the like.
  • CAP cellulose acetate phthalate
  • PVAP polyvinyl acetate phthalate
  • hydroxypropylmethylcellulose phthalate and methacrylic acid ester copolymers
  • zein methacrylic acid ester copolymers
  • the substrate e.g., tablet core bead, matrix particle
  • the substrate containing the first therapeutic agent (with or without the second therapeutic agent) is coated with a hydrophobic material selected from (i) an alkylcellulose; (ii) an acrylic polymer; or (iii) mixtures thereof.
  • the coating may be applied in the form of an organic or aqueous solution or dispersion. The coating may be applied to obtain a weight gain from about 2 to about 25% of the substrate in order to obtain a desired sustained release profile.
  • the invention relates to instances wherein the substrate (e.g., tablet core bead, matrix particle) containing the second therapeutic agent (with or without the first therapeutic agent) is coated with a hydrophobic material.
  • sustained release formulations and coatings which may be used in accordance with the present invention include U.S. Pat. Nos. 5,324,351; 5,356,467, and 5,472,712.
  • Alkylcellulose Polymers Cellulosic materials and polymers, including alkylcelluloses, provide hydrophobic materials well suited for coating the formulations according to the invention.
  • one preferred alkylcellulosic polymer is ethylcellulose, although the artisan will appreciate that other cellulose and/or alkylcellulose polymers may be readily employed, singly or in any combination, as all or part of a hydrophobic coating.
  • aqueous dispersion of ethylcellulose is Aquacoat® (FMC Co ⁇ ., Philadelphia, Pa., U.S.A.). Aquacoat® is prepared by dissolving the ethylcellulose in a water-immiscible organic solvent and then emulsifying the same in water in the presence of a surfactant and a stabilizer.
  • the organic solvent is evaporated under vacuum to form a pseudolatex.
  • the plasticizer is not inco ⁇ orated in the pseudolatex during the manufacturing phase.
  • a suitable plasticizer prior to using the same as a coating, it is necessary to intimately mix the Aquacoat® with a suitable plasticizer prior to use.
  • Surelease® Colorcon, Inc., West Point, Pa., U.S.A.
  • This product is prepared by inco ⁇ orating plasticizer into the dispersion during the manufacturing process.
  • a hot melt of a polymer, plasticizer (dibutyl sebacate), and stabilizer (oleic acid) is prepared as a homogeneous mixture, which is then diluted with an alkaline solution to obtain an aqueous dispersion which can be applied directly onto substrates.
  • the hydrophobic material comprising the controlled release coating is a pharmaceutically acceptable acrylic polymer, including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.
  • acrylic acid and methacrylic acid copolymers including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid), poly(methacrylic
  • the acrylic polymer is comprised of one or more ammonio methacrylate copolymers.
  • Ammonio methacrylate copolymers are well known in the art, and are copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups, hi order to obtain a desirable dissolution profile, it may be necessary to inco ⁇ orate in a coating two or more ammonio methacrylate copolymers having differing physical properties, such as different molar ratios of the quaternary ammonium groups to the neutral (meth)acrylic esters.
  • Certain methacrylic acid ester-type polymers are useful for preparing pH-dependent coatings which may be used in accordance with the present invention.
  • Eudragit® E is an example of a methacrylic acid copolymer which swells and dissolves in acidic media.
  • Eudragit® L is a methacrylic acid copolymer which does not swell at about pH ⁇ 5.7 and is soluble at about pH>6.
  • Eudragit® S does not swell at about pH ⁇ 6.5 and is soluble at about pH>7.
  • Eudragit® RL and Eudragit® RS are water swellable, and the amount of water absorbed by these polymers is pH-dependent, however, dosage forms coated with Eudragit® RL and RS are pH-independent.
  • the acrylic coating comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the Tradenames Eudragit® RL30D and Eudragit® RS30D, respectively.
  • Eudragit® RL30D and Eudragit® RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit® RS30D.
  • the mean molecular weight is about 150,000.
  • the code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents.
  • Eudragit® RL/RS mixtures are insoluble in water and in digestive fluids. However, coatings formed from the same are swellable and permeable in aqueous solutions and digestive fluids.
  • the Eudragit® RL/RS dispersions of the present invention may be mixed together in any desired ratio in order to ultimately obtain a sustained release formulation having a desirable dissolution profile. Desirable sustained release formulations may be obtained, for instance, from a retardant coating derived from 100% Eudragit® RL, 50% Eudragit® RL and 50% Eudragit® RS, and 10% Eudragit® RL:Eudragit® 90% RS. Of course, one skilled in the art will recognize that other acrylic polymers may also be used, such as, for example, Eudragit® L.
  • Plasticizers In embodiments of the present invention where the coating comprises an aqueous dispersion of a hydrophobic material, the inclusion of an effective amount of a plasticizer in the aqueous dispersion of hydrophobic material will further improve the physical properties of the sustained release coating. For example, because ethylcellulose has a relatively high glass transition temperature and does not form flexible films under normal coating conditions, it is preferable to inco ⁇ orate a plasticizer into an ethylcellulose coating containing sustained release coating before using the same as a coating material. Generally, the amount of plasticizer included in a coating solution is based on the concentration of the film-former, e.g., most often from about 1 to about 50 percent by weight of the film-former.
  • plasticizers for ethylcellulose include water insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, and triacetin, although it is possible that other water-insoluble plasticizers (such as acetylated monoglycerides, phthalate esters, castor oil, etc.) may be used.
  • Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention.
  • plasticizers for the acrylic polymers of the present invention include, but are not limited to citric acid esters such as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate, and possibly 1,2-propylene glycol.
  • Other plasticizers which have proved to be suitable for enhancing the elasticity of the films formed from acrylic films such as Eudragit® RL/RS lacquer solutions include polyethylene glycols, propylene glycol, diethyl phthalate, castor oil, and triacetin.
  • Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention.
  • talc reduces the tendency of the aqueous dispersion to stick during processing, and acts as a polishing agent.
  • the stabilized controlled release bead formulations of the present invention slowly release the therapeutically active agent, e.g., when ingested and exposed to gastric fluids, and then to intestinal fluids.
  • the controlled release profile of the formulations of the invention can be altered, for example, by varying the amount of overcoating with the aqueous dispersion of hydrophobic material, altering the manner in which the plasticizer is added to the aqueous dispersion of hydrophobic material, by varying the amount of plasticizer relative to hydrophobic material, by the inclusion of additional ingredients or excipients, by altering the method of manufacture, etc.
  • the dissolution profile of the ultimate product may also be modified, for example, by increasing or decreasing the thickness of the retardant coating.
  • Spheroids or beads coated with a therapeutically active agent are prepared, e.g., by dissolving the therapeutically active agent in water and then spraying the solution onto a substrate, for example, nu pariel 18/20 beads, using a Wuster insert.
  • additional ingredients are also added prior to coating the beads in order to assist the binding of the active agents to the beads, and/or to color the solution, etc.
  • a product which includes hydroxypropylmethylcellulose, etc. with or without colorant e.g., Opadry , commercially available from Colorcon, Inc.
  • the resultant coated substrate in this example beads, may then be optionally overcoated with a barrier agent, to separate the therapeutically active agent from the hydrophobic controlled release coating.
  • a barrier agent is one which comprises hydroxypropylmethylcellulose.
  • any film-former known in the art may be used. It is preferred that the barrier agent does not affect the dissolution rate of the final product.
  • the beads may then be overcoated with an aqueous dispersion of the hydrophobic material.
  • the aqueous dispersion of hydrophobic material preferably further includes an effective amount of plasticizer, e.g. triethyl citrate.
  • plasticizer e.g. triethyl citrate.
  • Pre-formulated aqueous dispersions of ethylcellulose such as Aquacoat® or Surelease®, maybe used.
  • Surelease® it is not necessary to separately add a plasticizer.
  • pre-formulated aqueous dispersions of acrylic polymers such as Eudragit® can be used.
  • the coating solutions of the present invention preferably contain, in addition to the film-former, plasticizer, and solvent system (i.e., water), a colorant to provide elegance and product distinction. Color may be added to the solution of the therapeutically active agent instead, or in addition to the aqueous dispersion of hydrophobic material.
  • color be added to Aquacoat® via the use of alcohol or propylene glycol based color dispersions, milled aluminum lakes and opacifiers such as titanium dioxide by adding color with shear to water soluble polymer solution and then using low shear to the plasticized Aquacoat®.
  • any suitable method of providing color to the formulations of the present invention may be used.
  • Suitable ingredients for providing color to the formulation when an aqueous dispersion of an acrylic polymer is used include titanium dioxide and color pigments, such as iron oxide pigments. The inco ⁇ oration of pigments, may, however, increase the retard effect of the coating.
  • the plasticized aqueous dispersion of hydrophobic material may be applied onto the substrate comprising the therapeutically active agent by spraying using any suitable spray equipment known in the art.
  • a Wurster fluidized-bed system is used in which an air jet, injected from underneath, fluidizes the core material and effects drying while the acrylic polymer coating is sprayed on.
  • a further overcoat of a film-former such as Opadry®, is optionally applied to the beads.
  • This overcoat is provided, if at all, in order to substantially reduce agglomeration of the beads.
  • the release of the therapeutically active agent from the controlled release formulation of the present invention can be further influenced, i.e., adjusted to a desired rate, by the addition of one or more release-modifying agents, or by providing one or more passageways through the coating.
  • the ratio of hydrophobic material to water soluble material is determined by, among other factors, the release rate required and the solubility characteristics of the materials selected.
  • the release-modifying agents which function as pore-formers may be organic or inorganic, and include materials that can be dissolved, extracted or leached from the coating in the environment of use.
  • the pore-formers may comprise one or more hydrophilic materials such as hydroxypropylmethylcellulose.
  • the sustained release coatings of the present invention can also include erosion- promoting agents such as starch and gums.
  • the sustained release coatings of the present invention can also include materials useful for making microporous lamina in the environment of use, such as polycarbonates comprised of linear polyesters of carbonic acid in which carbonate groups reoccur in the polymer chain.
  • the release-modifying agent may also comprise a semi-permeable polymer.
  • the release-modifying agent is selected from hydroxypropylmethylcellulose, lactose, metal stearates, and mixtures of any of the foregoing.
  • the sustained release coatings of the present invention may also include an exit means comprising at least one passageway, orifice, or the like.
  • the passageway may be formed by such methods as those disclosed in U.S. Pat. Nos. 3,845,770; 3,916,889; 4,063,064; and 4,088,864.
  • the passageway can have any shape such as round, triangular, square, elliptical, irregular, etc.
  • Matrix Bead Formulations In other embodiments of the present invention, the controlled release formulation is achieved via a matrix having a controlled release coating as set forth above.
  • the present invention may also utilize a controlled release matrix that affords in- vitro dissolution rates of the active agent within the preferred ranges and that releases the active agent in a pH- dependent or pH-independent manner.
  • a controlled release matrix that affords in- vitro dissolution rates of the active agent within the preferred ranges and that releases the active agent in a pH- dependent or pH-independent manner.
  • the materials suitable for inclusion in a controlled release matrix will depend on the method used to form the matrix.
  • a matrix in addition to the first active agent and (optionally) the second active agent may include: (1) Hydrophilic and/or hydrophobic materials, such as gums, cellulose ethers, acrylic resins, protein derived materials; the list is not meant to be exclusive, and any pharmaceutically acceptable hydrophobic material or hydrophilic material which is capable of imparting controlled release of the active agent and which melts (or softens to the extent necessary to be extruded) may be used in accordance with the present invention.
  • Hydrophilic and/or hydrophobic materials such as gums, cellulose ethers, acrylic resins, protein derived materials; the list is not meant to be exclusive, and any pharmaceutically acceptable hydrophobic material or hydrophilic material which is capable of imparting controlled release of the active agent and which melts (or softens to the extent necessary to be extruded) may be used in accordance with the present invention.
  • the hydrophobic material is preferably selected from the group consisting of alkylcelluloses, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, or mixtures thereof.
  • the hydrophobic material is a pharmaceutically acceptable acrylic polymer, including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.
  • acrylic acid and methacrylic acid copolymers including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cynaoethyl methacryl
  • the hydrophobic material is selected from materials such as hydroxyalkylcelluloses such as hydroxypropylmethylcellulose and mixtures of the foregoing.
  • Preferred hydrophobic materials are water-insoluble with more or less pronounced hydrophilic and/or hydrophobic trends.
  • the hydrophobic materials useful in the invention have a melting point from about 30 to about 200 C, preferably from about 45 to about 90 C.
  • the hydrophobic material may comprise natural or synthetic waxes, fatty alcohols (such as lauryl, myristyl, stearyl, cetyl or preferably cetostearyl alcohol), fatty acids, including but not limited to fatty acid esters, fatty acid glycerides (mono-, di-, and tri-glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearic aid, stearyl alcohol and hydrophobic and hydrophilic materials having hydrocarbon backbones.
  • Suitable waxes include, for example, beeswax, glycowax, castor wax and carnauba wax.
  • a wax-like substance is defined as any material which is normally solid at room temperature and has a melting point of from about 30 to about 100 C.
  • Suitable hydrophobic materials which may be used in accordance with the present invention include digestible, long chain (C 8 -C50, especially C 12 -C 40 ), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and natural and synthetic waxes. Hydrocarbons having a melting point of between 25 and 90 C. are preferred.
  • fatty (aliphatic) alcohols are preferred in certain embodiments.
  • the oral dosage form may contain up to 60% (by weight) of at least one digestible, long chain hydrocarbon.
  • a combination of two or more hydrophobic materials are included in the matrix formulations.
  • an additional hydrophobic material may be selected from natural and synthetic waxes, fatty acids, fatty alcohols, and mixtures of the same. Examples include beeswax, carnauba wax, stearic acid and stearyl alcohol. This list is not meant to be exclusive.
  • One particular suitable matrix comprises at least one water soluble hydroxyalkyl cellulose, at least one -C 36 , preferably C ⁇ 4 -C 22 , aliphatic alcohol and, optionally, at least one polyalkylene glycol.
  • the at least one hydroxyalkyl cellulose is preferably a hydroxy (Ci to C 6 ) alkyl cellulose, such as hydroxypropylcellulose, hydroxypropylmethylcellulose and, especially, hydroxyethylcellulose.
  • the amount of the at least one hydroxyalkyl cellulose in the present oral dosage form will be determined, inter alia, by the precise rate of release desired for the therapeutic agent.
  • the at least one aliphatic alcohol may be, for example, lauryl alcohol, myristyl alcohol or stearyl alcohol. In certain embodiments of the present oral dosage form, however, the at least one aliphatic alcohol is cetyl alcohol or cetostearyl alcohol.
  • the amount of the at least one aliphatic alcohol in the present oral dosage form will be determined, as above, by the precise rate of release desired for the therapeutic agent. It will also depend on whether at least one polyalkylene glycol is present in or absent from the oral dosage form. In the absence of at least one polyalkylene glycol, the oral dosage form preferably contains between 20% and 50% (by wt) of the at least one aliphatic alcohol. When at least one polyalkylene glycol is present in the oral dosage form, then the combined weight of the at least one aliphatic alcohol and the at least one polyalkylene glycol preferably constitutes between 20% and 50% (by wt) of the total dosage.
  • the ratio of, e.g., the at least one hydroxyalkyl cellulose or acrylic resin to the at least one aliphatic alcohol/polyalkylene glycol determines, to a considerable extent, the release rate of the active agent from the formulation.
  • a ratio of the at least one hydroxyalkyl cellulose to the at least one aliphatic alcohol/polyalkylene glycol of between 1 :2 and 1 :4 is preferred, with a ratio of between 1 :3 and 1 :4 being particularly preferred.
  • the at least one polyalkylene glycol may be, for example, polypropylene glycol or, which is preferred, polyethylene glycol.
  • the number average molecular weight of the at least one polyalkylene glycol is preferred between 1,000 and 15,000 especially between 1,500 and 12,000.
  • Another suitable controlled release matrix would comprise an alkylcellulose (especially ethyl cellulose), a 2 to C 36 aliphatic alcohol and, optionally, a polyalkylene glycol.
  • the matrix includes a pharmaceutically acceptable combination of at least two hydrophobic materials, hi addition to the above ingredients, a controlled release matrix may also contain suitable quantities of other materials, e.g. diluents, lubricants, binders, granulating aids, colorants, flavorants and glidants that are conventional in the pharmaceutical art.
  • compositions which comprise a therapeutically-effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic abso ⁇ tion, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally
  • terapéuticaally-effective amount means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment.
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically-acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • manufacturing aid e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid
  • solvent encapsulating material involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydrox
  • certain embodiments of the present compounds may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable acids.
  • pharmaceutically-acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like.
  • sulfate bisulfate
  • phosphate nitrate
  • acetate valerate
  • oleate palmitate
  • stearate laurate
  • benzoate lactate
  • phosphate tosylate
  • citrate maleate
  • fumarate succinate
  • tartrate napthylate
  • mesylate glucoheptonate
  • lactobionate lactobionate
  • laurylsulphonate salts and the like See, for example,
  • the pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids.
  • such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
  • the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable bases.
  • pharmaceutically-acceptable salts refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be. prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al., supra) Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl pahnitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl pahnitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (
  • Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.
  • a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention.
  • an aforementioned formulation renders orally bioavailable a compound of the present invention.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non- aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • lozenges using a flavored basis, usually sucrose and acacia or tragacanth
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) abs
  • the pharmaceutical compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be fonnulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by inco ⁇ orating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile i ⁇ jectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs, hi addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubil
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Abso ⁇ tion enhancers can also be used to increase the flux of the compound across the skin.
  • the rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • antibacterial and antifungal agents for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions, hi addition, prolonged abso ⁇ tion of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay abso ⁇ tion such as aluminum monostearate and gelatin.
  • the therapeutic agent alone or on combination with other therapeutic agents can be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art.
  • conventional excipients i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art.
  • Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohols, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelate, carbohydrates such as lactose, amylose or starch, magnesium stearate talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidone, etc.
  • the pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like. They can also be combined where desired with other active agents, e.g., other analgesic agents.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like.
  • other active agents e.g., other analgesic agents.
  • particularly suitable are oily or
  • compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients which are suitable for the manufacture of tablets.
  • excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate.
  • the tablets may be uncoated or they may be coated by known techniques for elegance or to delay release of the active ingredients.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.
  • Aqueous suspensions contain the above-identified combination of drugs and that mixture has one or more excipients suitable as suspending agents, for example pharmaceutically acceptable synthetic gums such as hydroxypropylmethylcellulose or natural gums.
  • Oily suspensions may be formulated by suspending the above-identified combination of drugs in a vegetable oil or mineral oil.
  • the oily suspensions may contain a thickening agent such as beeswax or cetyl alcohol.
  • a syrup, elixir, or the like can be used wherein a sweetened vehicle is employed.
  • Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. It is also possible to freeze-dry the active compounds and use the obtained lyophilized compounds, for example, for the preparation of products for injection.
  • One aspect of combination therapy pertains to a method for providing effective therapeutic treatment in humans, comprising administering an effective or sub-therapeutic amount of a first therapeutic agent; and administering an effective amount of a second therapeutic agent in an amount effective to augment the therapeutic effect provided by said first therapeutic agent.
  • the second therapeutic agent can be administered before, simultaneously with, or after administration of the first therapeutic agent, as long as the dosing interval of the second therapeutic agent overlaps with the dosing interval of the first therapeutic agent (or its therapeutic effect), hi other words, according to the method of the present invention, in certain preferred embodiments the second therapeutic agent need not be administered in the same dosage form or even by the same route of administration as the first therapeutic agent.
  • the method is directed to the su ⁇ rising synergistic and/or additive benefits obtained in humans, when therapeutically effective levels of a first therapeutic agent have been administered to a human, and, prior to or during the dosage interval for the second therapeutic agent or while the human is experiencing the therapeutic effect, an effective amount of a second therapeutic agent to augment the therapeutic effect of the first therapeutic agent is administered.
  • the second therapeutic agent is administered prior to the administration of the first therapeutic agent, it is preferred that the dosage intervals for the two drugs overlap, i.e., such that the therapeutic effect over at least a portion of the dosage interval of the first therapeutic agent is at least partly attributable to the second therapeutic agent.
  • the su ⁇ rising synergistic and/or additive benefits obtained in the patient are achieved when therapeutically effective levels of the second therapeutic agent have been administered to the patient, and, during the dosage interval for the second therapeutic agent or while the patient is experiencing the therapeutic effect by virtue of the administration of a second therapeutic agent, an effective amount of a first therapeutic agent to augment the therapeutic effect of the second therapeutic agent is administered.
  • Another aspect of combination therapy relates to an oral solid dosage form comprising an therapeutically effective amount of a first therapeutic agent together with an amount of a second therapeutic agent or pharmaceutically acceptable salt thereof which augments the effect of the first therapeutic agent.
  • delayed abso ⁇ tion of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • the compounds of the present invention When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of abso ⁇ tion, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect.
  • Such an effective dose will generally depend upon the factors described above.
  • oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for a patient, when used for the indicated analgesic effects will range from about 0.0001 to about 100 mg per kilogram of body weight per day.
  • the effective daily dose of the active compound maybe administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day. While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).
  • the compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other pharmaceuticals.
  • the present invention provides pharmaceutically acceptable compositions which comprise a therapeuticaliy-effective amount of one or more of the subject compounds, as described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension; (3) topical application, for example, as a cream, ointment or spray applied to the skin, lungs, or mucous membranes; or (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually or buccally; (6) ocularly; (7) transdermally; or (8) nasally.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes for application to the tongue
  • treatment is intended to encompass also prophylaxis, therapy and cure.
  • the patient receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep; and poultry and pets in general.
  • the compound of the invention can be administered as such or in admixtures with pharmaceutically acceptable carriers and can also be administered in conjunction with antimicrobial agents such as penicillins, cephalosporins, aminoglycosides and glycopeptides.
  • Conjunctive therapy thus includes sequential, simultaneous and separate administration of the active compound in a way that the therapeutical effects of the first administered one is not entirely disappeared when the subsequent is administered.
  • the addition of the active compound of the invention to animal feed is preferably accomplished by preparing an appropriate feed premix containing the active compound in an effective amount and inco ⁇ orating the premix into the complete ration.
  • an intermediate concentrate or feed supplement containing the active ingredient can be blended into the feed.
  • the way in which such feed premixes and complete rations can be prepared and administered are described in reference books (such as "Applied Animal Nutrition", W.H. Freedman and CO., San Francisco, U.S.A., 1969 or “Livestock Feeds and Feeding" O and B books, Corvallis, Ore., U.S.A., 1977).
  • Micelles Recently, the pharmaceutical industry introduced microemulsification technology to improve bioavailability of some lipophilic (water insoluble) pharmaceutical agents.
  • the formulations contain micelles formed from a compound of the present invention and at least one amphiphilic carrier, in which the micelles have an average diameter of less than about 100 nm.
  • More preferred embodiments provide micelles having an average diameter less than about 50 nm, and even more preferred embodiments provide micelles having an average diameter less than about 30 nm, or even less than about 20 nm. While all suitable amphiphilic carriers are contemplated, the presently preferred carriers are generally those that have Generally-Recognized-as-Safe (GRAS) status, and that can both solubilize the compound of the present invention and microemulsify it at a later stage when the solution comes into a contact with a complex water phase (such as one found in human gastro-intestinal tract).
  • GRAS Generally-Recognized-as-Safe
  • amphiphilic ingredients that satisfy these requirements have HLB (hydrophilic to lipophilic balance) values of 2-20, and their structures contain straight chain aliphatic radicals in the range of C-6 to C-20.
  • HLB hydrophilic to lipophilic balance
  • examples are polyethylene-glycolized fatty glycerides and polyethylene glycols.
  • Particularly prefened amphiphilic carriers are saturated and monounsaturated polyethyleneglycolyzed fatty acid glycerides, such as those obtained from fully or partially hydrogenated various vegetable oils. Such oils may advantageously consist of tri-.
  • di- and mono-fatty acid glycerides and di- and mono-polyethyleneglycol esters of the conesponding fatty acids with a particularly preferred fatty acid composition including capric acid 4-10, capric acid 3-9, lauric acid 40-50, niyristic acid 14-24, palmitic acid 4-14 and stearic acid 5-15%.
  • Another useful class of amphiphilic carriers includes partially esterified sorbitan and/or sorbitol, with saturated or mono-unsaturated fatty acids (SPAN- series) or corresponding ethoxylated analogs (TWEEN-series).
  • amphiphilic carriers are particularly contemplated, including Gelucire-series, Labrafil, Labrasol, or Lauroglycol (all manufactured and distributed by Gattefosse Co ⁇ oration, Saint Priest, France), PEG-mono-oleate, PEG-di- oleate, PEG-mono-laurate and di-laurate, Lecithin, Polysorbate 80, etc (produced and distributed by a number of companies in USA and worldwide).
  • Polymers Hydrophilic polymers suitable for use in the present invention are those which are readily water-soluble, can be covalently attached to a vesicle- forming lipid, and which are tolerated in vivo without toxic effects (i.e., are biocompatible).
  • Suitable polymers include polyethylene glycol (PEG), polylactic (also termed polylactide), polyglycolic acid (also termed polyglycolide), a polylactic-polyglycolic acid copolymer, and polyvinyl alcohol.
  • PEG polyethylene glycol
  • polylactic also termed polylactide
  • polyglycolic acid also termed polyglycolide
  • polyvinyl alcohol polyvinyl alcohol.
  • Preferred polymers are those having a molecular weight of from about 100 or 120 daltons up to about 5,000 or 10,000 daltons, and more preferably from about 300 daltons to about 5,000 daltons.
  • the polymer is polyethyleneglycol having a molecular weight of from about 100 to about 5,000 daltons, and more preferably having a molecular weight of from about 300 to about 5,000 daltons.
  • the polymer is polyethyleneglycol of 750 daltons (PEG(750)).
  • Polymers may also be defined by the number of monomers therein; a preferred embodiment of the present invention utilizes polymers of at least about three monomers, such PEG polymers consisting of three monomers (approximately 150 daltons).
  • Other hydrophilic polymers which may be suitable for use in the present invention include polyvinylpyrrolidone, polymethoxazoline, polyethyloxazoline, polyhydroxypropyl methacrylamide, polymethacrylamide, polydimethylacrylamide, and derivatized celluloses such as hydroxymethylcellulose or hydroxyethylcellulose.
  • a formulation of the present invention comprises a biocompatible polymer selected from the group consisting of polyamides, polycarbonates, polyalkylenes, polymers of acrylic and methacrylic esters, polyvinyl polymers, polyglycolides, polysiloxanes, polyurethanes and co-polymers thereof, celluloses, polypropylene, polyethylenes, polystyrene, polymers of lactic acid and glycolic acid, polyanhydrides, poly(ortho)esters, poly(butic acid), poly(valeric acid), poly(lactide-co- caprolactone), polysaccharides, proteins, polyhyaluronic acids, polycyanoacrylates, and blends, mixtures, or copolymers thereof.
  • a biocompatible polymer selected from the group consisting of polyamides, polycarbonates, polyalkylenes, polymers of acrylic and methacrylic esters, polyvinyl polymers, polyglycolides, polysiloxanes, polyurethanes and
  • Cyclodextrins are cyclic oligosaccharides, consisting of 6, 7 or 8 glucose units, designated by the Greek letter ⁇ , ⁇ ,or ⁇ , respectively. Cyclodextrins with fewer than six glucose units are not known to exist. The glucose units are linked by alpha- 1,4-glucosidic bonds. As a consequence of the chair conformation of the sugar units, all secondary hydroxyl groups (at C-2, C-3) are located on one side of the ring, while all the primary hydroxyl groups at C-6 are situated on the other side.
  • the external faces are hydrophilic, making the cyclodextrins water-soluble, hi contrast, the cavities of the cyclodextrins are hydrophobic, since they are lined by the hydrogen of atoms C-3 and C-5, and by ether-like oxygens.
  • These matrices allow complexation with a variety of relatively hydrophobic compounds, including, for instance, steroid compounds such as 17. beta. - estradiol (see, e.g., van Uden et al. Plant Cell Tiss. Org. Cult. 38:1-3-113 (1994)). The complexation takes place by Van der Waals interactions and by hydrogen bond formation.
  • cyclodextrins For a general review of the chemistry of cyclodextrins, see, Wenz, Agnew. Chem. Int. Ed. Engl., 33:803-822 (1994).
  • the physico-chemical properties of the cyclodextrin derivatives depend strongly on the kind and the degree of substitution. For example, their solubility in water ranges from insoluble (e.g., triacetyl-beta-cyclodextrin) to 147% soluble (w/v) (G-2-beta-cyclodextrin). In addition, they are soluble in many organic solvents.
  • the properties of the cyclodextrins enable the control over solubility of various formulation components by increasing or decreasing their solubility.
  • Parmeter (I), et al. (U.S. Pat. No. 3,453,259) and Gramera, et al. (U.S. Pat. No. 3,459,731) described electroneutral cyclodextrins.
  • Other derivatives include cyclodextrins with cationic properties [Parmeter (II), U.S. Pat. No. 3,453,257], insoluble crosslinked cyclodextrins (Solms, U.S. Pat. No. 3,420,788), and cyclodextrins with anionic properties [Parmeter (III), U.S. Pat. No. 3,426,011].
  • cyclodextrin derivatives with anionic properties carboxylic acids, phosphorous acids, phosphinous acids, phosphonic acids, phosphoric acids, thiophosphonic acids, thiosulphinic acids, and sulfonic acids have been appended to the parent cyclodextrin [see, Parmeter (III), supra]. Furthermore, sulfoalkyl ether cyclodextrin derivatives have been described by Stella, et al. (U.S. Pat. No.
  • Liposomes consist of at least one lipid bilayer membrane enclosing an aqueous internal compartment. Liposomes may be characterized by membrane type and by size. Small unilamellar vesicles (SUVs) have a single membrane and typically range between 0.02 and 0.05 ⁇ m in diameter; large unilamellar vesicles (LUVS) are typically larger than 0.05 ⁇ m Oligolamellar large vesicles and multilamellar vesicles have multiple, usually concentric, membrane layers and are typically larger than 0.1 ⁇ m.
  • SUVs Small unilamellar vesicles
  • LUVS large unilamellar vesicles
  • Oligolamellar large vesicles and multilamellar vesicles have multiple, usually concentric, membrane layers and are typically larger than 0.1 ⁇ m.
  • Liposomes with several nonconcentric membranes i.e., several smaller vesicles contained within a larger vesicle, are termed multivesicular vesicles.
  • One aspect of the present invention relates to formulations comprising liposomes containing a compound of the present invention, where the liposome membrane is formulated to provide a liposome with increased carrying capacity.
  • the compound of the present invention may be contained within, or adsorbed onto, the liposome bilayer of the liposome.
  • the compound of the present invention may be aggregated with a lipid surfactant and carried within the liposome's internal space; in these cases, the liposome membrane is formulated to resist the disruptive effects of the active agent-surfactant aggregate.
  • the lipid bilayer of a liposome contains lipids derivatized with polyethylene glycol (PEG), such that the PEG chains extend from the inner surface of the lipid bilayer into the interior space encapsulated by the liposome, and extend from the exterior of the lipid bilayer into the surrounding environment.
  • Active agents contained within liposomes of the present invention are in solubilized form. Aggregates of surfactant and active agent (such as emulsions or micelles containing the active agent of interest) may be entrapped within the interior space of liposomes according to the present invention.
  • a surfactant acts to disperse and solubilize the active agent, and may be selected from any suitable aliphatic, cycloaliphatic or aromatic surfactant, including but not limited to biocompatible lysophosphatidylcholmes (LPCs) of varying chain lengths (for example, from about C 14 to about C 20 ).
  • LPCs lysophosphatidylcholmes
  • Polymer-derivatized lipids such as PEG-lipids may also be utilized for micelle formation as they will act to inhibit micelle/membrane fusion, and as the addition of a polymer to surfactant molecules decreases the CMC of the surfactant and aids in micelle formation.
  • Liposomes according to the present invention may be prepared by any of a variety of techniques that are known in the art. See, e.g., U.S. Pat. No.
  • liposomes of the present invention may be prepared by diffusing a lipid derivatized with a hydrophilic polymer into preformed liposomes, such as by exposing preformed liposomes to micelles composed of lipid-grafted polymers, at lipid concentrations conesponding to the final mole percent of derivatized lipid which is desired in the liposome.
  • Liposomes containing a hydrophilic polymer can also be formed by homogenization, lipid-field hydration, or extrusion techniques, as are known in the art.
  • the active agent is first dispersed by sonication in a lysophosphatidylcholine or other low CMC surfactant (including polymer grafted lipids) that readily solubilizes hydrophobic molecules.
  • the resulting micellar suspension of active agent is then used to rehydrate a dried lipid sample that contains a suitable mole percent of polymer-grafted lipid, or cholesterol.
  • the liposomes are prepared to have substantially homogeneous sizes in a selected size range.
  • One effective sizing method involves extruding an aqueous suspension of the liposomes through a series of polycarbonate membranes having a selected uniform pore size; the pore size of the membrane will conespond roughly with the largest sizes of liposomes produced by extrusion through that membrane. See e.g., U.S. Pat. No. 4,737,323 (Apr. 12, 1988).
  • release Modifiers The release characteristics of a formulation of the present invention depend on the encapsulating material, the concentration of encapsulated drug, and the presence of release modifiers. For example, release can be manipulated to be pH dependent, for example, using a pH sensitive coating that releases only at a low pH, as in the stomach, or a higher pH, as in the intestine. An enteric coating can be used to prevent release from occurring until after passage through the stomach. Multiple coatings or mixtures of cyanamide encapsulated in different materials can be used to obtain an initial release in the stomach, followed by later release in the intestine. Release can also be manipulated by inclusion of salts or pore forming agents, which can increase water uptake or release of drug by diffusion from the capsule.
  • Excipients which modify the solubility of the drug can also be used to control the release rate.
  • Agents which enhance degradation of the matrix or release from the matrix can also be inco ⁇ orated. They can be added to the drug, added as a separate phase (i.e., as particulates), or can be co-dissolved in the polymer phase depending on the compound, hi all cases the amount should be between 0.1 and thirty percent (w/w polymer).
  • Types of degradation enhancers include inorganic salts such as ammonium sulfate and ammonium chloride, organic acids such as citric acid, benzoic acid, and ascorbic acid, inorganic bases such as sodium carbonate, potassium carbonate, calcium carbonate, zinc carbonate, and zinc hydroxide, and organic bases such as protamine sulfate, spermine, choline, ethanolamine, diethanolamine, and triethanolamine and surfactants such as Tween and Pluronic .
  • Pore forming agents which add microstructure to the matrices i.e., water soluble compounds such as inorganic salts and sugars
  • the range should be between one and thirty percent (w/w polymer).
  • Uptake can also be manipulated by altering residence time of the particles in the gut. This can be achieved, for example, by coating the particle with, or selecting as the encapsulating material, a mucosal adhesive polymer.
  • a mucosal adhesive polymer examples include most polymers with free carboxyl groups, such as chitosan, celluloses, and especially polyacrylates (as used herein, polyacrylates refers to polymers including acrylate groups and modified acrylate groups such as cyanoacrylates and methacrylates).
  • Processes for Preparing Matrix— Based Beads hi order to facilitate the preparation of a solid, controlled release, oral dosage form according to this invention any method of preparing a matrix formulation known to those skilled in the art may be used.
  • inco ⁇ oration in the matrix may be effected, for example, by (a) forming granules comprising at least one water soluble hydroxyalkyl cellulose and the active agent; (b) mixing the hydroxyalkyl cellulose containing granules with at least one C 12 -C 36 aliphatic alcohol; and (c) optionally, compressing and shaping the granules.
  • the granules are formed by wet granulating the hydroxyalkyl cellulose/active agent with water.
  • the amount of water added during tie wet granulation step is preferably between 1.5 and 5 times, especially between 1.75 and 3.5 times, the dry weight of the active agent.
  • a spheronizing agent together with the active ingredient can be spheronized to form spheroids.
  • Microcrystalline cellulose is preferred.
  • a suitable microcrystalline cellulose is, for example, the material sold as Avicel PH 101 (Trade Mark, FMC Co ⁇ oration).
  • the spheroids may also contain a binder. Suitable binders, such as low viscosity, water soluble polymers, will be well known to those skilled in the phannaceutical art. However, water soluble hydroxy lower alkyl cellulose, such as hydroxypropylcellulose, are prefened.
  • the spheroids may contain a water insoluble polymer, especially an acrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethyl acrylate copolymer, or ethyl cellulose.
  • the sustained release coating will generally include a hydrophobic material such as (a) a wax, either alone or in admixture with a fatty alcohol; or (b) shellac or zein.
  • Melt Extrusion Matrix Sustained release matrices can also be prepared via melt-granulation or melt- extrusion techniques. Generally, melt-granulation techniques involve melting a normally solid hydrophobic material, e.g.
  • the additional hydrophobic material may comprise one or more water-insoluble wax-like thermoplastic substances possibly mixed with one or more wax-like thermoplastic substances being less hydrophobic than said one or more water-insoluble wax-like substances.
  • the individual wax-like substances in the formulation should be substantially non-degradable and insoluble in gastrointestinal fluids during the initial release phases.
  • Useful water-insoluble wax-like substances may be those with a water-solubility that is lower than about 1 : 5, 000 (w/w).
  • a sustained release matrix may also contain suitable quantities of other materials, e.g., diluents, lubricants, binders, granulating aids, colorants, flavorants and glidants that are conventional in the pharmaceutical art. The quantities of these additional materials will be sufficient to provide the desired effect to the desired formulation.
  • a sustained release matrix inco ⁇ orating melt-extruded multiparticulates may also contain suitable quantities of other materials, e.g. diluents, lubricants, binders, granulating aids, colorants, flavorants and glidants that are conventional in the pharmaceutical art in amounts up to about 50% by weight of the particulate if desired.
  • suitable quantities of other materials e.g. diluents, lubricants, binders, granulating aids, colorants, flavorants and glidants that are conventional in the pharmaceutical art in amounts up to about 50% by weight of the particulate if desired.
  • the preparation of a suitable melt-extruded matrix according to the present invention may, for example, include the steps of blending the active agent, together with at least one hydrophobic material and preferably the additional hydrophobic material to obtain a homogeneous mixture.
  • the homogeneous mixture is then heated to a temperature sufficient to at least soften the mixture sufficiently to extrude the same.
  • the resulting homogeneous mixture is then extruded to form strands.
  • the extrudate is preferably cooled and cut into multiparticulates by any means known in the art.
  • the strands are cooled and cut into multiparticulates.
  • the multiparticulates are then divided into unit doses.
  • the extrudate preferably has a diameter of from about 0.1 to about 5 mm and provides sustained release of the therapeutically active agent for a time period of from about 8 to about 24 hours.
  • An optional process for preparing the melt extrusions of the present invention includes directly metering into an extruder a hydrophobic material, a therapeutically active agent, and an optional binder; heating the homogenous mixture; extruding the homogenous mixture to thereby form strands; cooling the strands containing the homogeneous mixture; cutting the strands into particles having a size from about 0.1 mm to about 12 mm; and dividing said particles into unit doses.
  • a relatively continuous manufacturing procedure is realized.
  • the diameter of the extruder aperture or exit port can also be adjusted to vary the thickness of the extruded strands.
  • the exit part of the extruder need not be round; it can be oblong, rectangular, etc.
  • the exiting strands can be reduced to particles using a hot wire cutter, guillotine, etc.
  • the melt extruded multiparticulate system can be, for example, in the form of granules, spheroids or pellets depending upon the extruder exit orifice.
  • melt-extruded multiparticulate(s) and “melt-extruded multiparticulate system(s)” and “melt-extruded particles” shall refer to a plurality of units, preferably within a range of similar size and/or shape and containing one or more active agents and one or more excipients, preferably including a hydrophobic material as described herein.
  • the melt-extruded multiparticulates will be of a range of from about 0.1 to about 12 mm in length and have a diameter of from about 0.1 to about 5 mm.
  • the melt-extruded multiparticulates can be any geometrical shape within this size range.
  • oral dosage forms are prepared to include an effective amount of melt-extruded multiparticulates within a capsule.
  • a plurality of the melt-extruded multiparticulates may be placed in a gelatin capsule in an amount sufficient to provide an effective sustained release dose when ingested and contacted by gastric fluid.
  • a suitable amount of the multiparticulate extrudate is compressed into an oral tablet using conventional tableting equipment using standard techniques.
  • the extrudate can be shaped into tablets as set forth in U.S. Pat. No. 4,957,681 (Klimesch, et. al.).
  • the sustained release melt-extruded multiparticulate systems or tablets can be coated, or the gelatin capsule can be further coated, with a sustained release coating such as the sustained release coatings described above.
  • Such coatings preferably include a sufficient amount of hydrophobic material to obtain a weight gain level from about 2 to about 30 percent, although the overcoat maybe greater depending upon the physical properties of the particular active agent utilized and the desired release rate, among other things.
  • the melt-extruded unit dosage forms of the present invention may further include combinations of melt-extruded multiparticulates containing one or more of the therapeutically active agents disclosed above before being encapsulated. Furthermore, the unit dosage forms can also include an amount of an immediate release therapeutically active agent for prompt therapeutic effect.
  • the immediate release therapeutically active agent may be inco ⁇ orated, e.g., as separate pellets within a gelatin capsule, or may be coated on the surface of the multiparticulates after preparation of the dosage forms (e.g., controlled release coating or matrix-based).
  • the unit dosage forms of the present invention may also contain a combination of controlled release beads and matrix multiparticulates to achieve a desired effect.
  • the sustained release formulations of the present invention preferably slowly release the therapeutically active agent, e.g., when ingested and exposed to gastric fluids, and then to intestinal fluids.
  • the sustained release profile of the melt-extruded formulations of the invention can be altered, for example, by varying the amount of retardant, i.e., hydrophobic material, by varying the amount of plasticizer relative to hydrophobic material, by the inclusion of additional ingredients or excipients, by altering the method of manufacture, etc.
  • the melt extruded material is prepared without the inclusion of the therapeutically active agent, which is added thereafter to the extrudate.
  • Such formulations typically will have the therapeutically active agent blended together with the extruded matrix material, and then the mixture would be tableted in order to provide a slow release formulation.
  • Such formulations may be advantageous, for example, when the therapeutically active agent included in the formulation is sensitive to temperatures needed for softening the hydrophobic material and/ or the retardant material.
  • pharmaceutically active agent included in the formulation is sensitive to temperatures needed for softening the hydrophobic material and/ or the retardant material.
  • compositions or methods of the present invention contains a significantly greater proportion of the specified enantiomer in relation to the non-specified enantiomer.
  • optically pure (S)-amlodipine contains a significantly greater proportion of the (S)-enantiomer in relation to the (R)-enantiomer.
  • compositions including the optically pure active ingredients contain at least 90%) by weight of the specified enantiomer and 10% by weight or less of the non-specified enantiomer. More preferably, such compositions contain at least 95% by weight of the specified enantiomer and 5% by weight or less of the non-specified enantiomer.
  • compositions contain at least 99% by weight of the specified enantiomer and 1% by weight or less of the non-specified enantiomer. These percentages are based upon the total amount of the active ingredient.
  • Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and tr ⁇ r ⁇ -isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group.
  • diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • Contemplated equivalents of the compounds described above include compounds which otherwise conespond thereto, and which have the same general properties thereof (e.g., functioning as antihypertensive agents, antianginal, antianhythmic), wherein one or more simple variations of substituents are made which do not adversely affect the efficacy of the compound in binding to receptors.
  • the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures, hi these reactions, it is also possible to make use of variants which are in themselves known, but are not mentioned here.
  • the term "patient” refers to a mammal in need of a particular treatment. In a prefened embodiment, a patient is a primate, canine, feline, or equine. In another prefened embodiment, a patient is a human.
  • solvate refers to a pharmaceutically acceptable form of a specified compound, with one or more solvent molecules, that retains the biological effectiveness of such compound.
  • solvates include compounds of the invention in combination with solvents such, for example, water (to form the hydrate), isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or acetone. Also included are formulations of solvate mixtures such as a compound of the invention in combination with two or more solvents.
  • solvents such as water (to form the hydrate), isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or acetone.
  • formulations of solvate mixtures such as a compound of the invention in combination with two or more solvents.
  • the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.
  • the reaction mass is held for one hour with agitation at about 70 °C.
  • the resulting sluny is then cooled with agitation to about 22 °C over 2.5 to 3 hours with a linear cooling profile at about 0.30 °C/min.
  • the slurry is held with agitation at about 22 °C for about 0.5 h.
  • the solid is isolated by filtration, washed by re-slunying with DMAC followed by a displacement wash with MTBE.
  • the wet cake is dried at about 45 °C in vacuo to produce (S Amlodipine-hemi-D-Tartrate-DMAC solvate (13.92 kg, 24.37 moles, 40.0 % yield).
  • a solution of L-Malic acid (6.68 kg, 49.82 moles) in isopropanol-water (25.45 kg IPA, 5.73 kg water 4.44/1 , wt/wt) is then added, and the reaction mixture is held with agitation for about one hour at about 50 °C to form a sluny.
  • the resulting slurry is then cooled with agitation to about 0 °C over 2.5 to 3 hours, with a linear cooling profile at about 0.25 °C/min.
  • the slurry is held with agitation at about 0 °C for about one hour.
  • R-120 The contents of R-120 were agitated for a minimum of 20 minutes and then the layers were allowed to separate for a minimum of 15 minutes. 9. The bottom aqueous layer was removed and USP water (66.0 kg) was charged to R-120. 10. The contents of R-120 were agitated for a minimum of 20 minutes and then the layers were allowed to separate for a minimum of 15 minutes. 11. The bottom aqueous layer was removed from R- 120. 12. The contents of R-120 were polish filtered through a 3 ⁇ m cartridge filter to R- 110 A, followed by a reactor and line rinse with MTBE (49.9 kg). 13. The contents of R-110A were concentrated under vacuum (maximum 50°C) to a calculated volume ( 109 L) . 14.
  • DMAC (152.8 kg) was charged to the contents of R-110A. 15. The contents of R- 110A were again concentrated under vacuum, this time until the batch temperature reached 45-55°C. The final volume was 208 L. 16. R-110A contents were cooled to 20 to 25°C, followed by the addition of the previously prepared D-tartaric acid solution (166.0 kg) at 20-25°C over 20 to 30 minutes. 17. The mixture was heated to 68-72°C over 55 to 65 minutes, and held at this temperature for 55 to 65 minutes. 18. The reaction mixture was cooled to 21 to 23 °C over 2 to 3 hours using a linear cooling profile and agitated at this temperature for 30 to 40 minutes. 19.
  • the bottom aqueous layer was removed and USP water (82.5 kg) was charged to R-120. 7. The contents of R-120 were agitated for 20-30 minutes and then the layers were allowed to separate for a minimum of 10 minutes. 8. The bottom aqueous layer was removed. 9. The volume of R-120 was recorded and the solution was transfened to a 100 gal reactor (R-110A) through a 3 ⁇ m polishing filter, followed by a reactor and line rinse of MTBE (45.0 kg) 10. The solution was distilled to a calculated volume (87 L) under vacuum at a maximum jacket temperature of 40°C. 11. The mixture in R- 110A was cooled to 20-25 °C, and while maintaining this temperature, heptane (80.4 kg) was charged over 45-60 minutes. 12.
  • L-Malic acid (6.68 kg), USP Water (5.73 kg) and IPA (17.0 kg) were charged to a suitable mixing vessel and mixed until a solution was obtained. 2. The L-Malic acid solution was drained through a 5 ⁇ polish filter into a HDPE drum, and TK-7 and the lines were rinsed forward to the drum with IPA (8.45 kg). This solution was held for later use. 3. (S)-Amlodipine Free Base (19.5 kg) was charged to R-110A, followed by IPA (141.9 kg) and MTBE (14.9 kg). 4. The temperature of R-110A was adjusted to 48-52°C over 20 to 30 minutes. 5.
  • the previously prepared L-malic acid solution was charged to the contents of R- 110A over 15 to 20 minutes while maintaining the temperature at 48-52°C. 6.
  • the contents of R-110A were held at 48-52°C for 55 to 65 minutes.
  • the mixture was cooled to -2 to 2°C over 2 to 3 hours and held for a minimum of 1 hour.
  • the sluny was filtered in one load on centrifuge CE-102, followed by washes of IPA (43.6 kg) and MTBE (43.8 kg and 43.5 kg).
  • the material was discharged from the centrifuge to yield 28.88 kg wet cake, and dried under vacuum in vacuum tray dryer D-401 at 56-60°C to an LOD of less than 1.0%. 10.
  • Example 8 Preparation of (S)-Amlodipine-L-Malate (form A) Tablets Drug substance and excipients were screened and blended using typical manufacturing equipment. A conventional tablet machine was used to compress this blend into tablets weighing nominally 200 mg each.
  • Tablets were packaged in HDPE bottles with C/R cap with no desiccant, and stored at ICH storage conditions of 25°C / 60% RH, 30°C / 60% RH, and 40°C / 75% RH. Tablets have been assayed at initial time and after 1, 2, 3 and 6 months storage. Stability results are given in Figures 5 and 6. Note that * indicates that 1 mg of (S)- Amlodipine is equivalent tol.328 mg of (S)-Amlodipine-L-Malate (Table 3). Table 3. Preparation of (S)-Amlodipine L-Malate Tablets
  • Example 9 Relative Bioavailability The pharmacokinetic parameters AUC and C max from three multiple-dose studies in male and female dogs were compared. The 28-day pharmacokinetic assessments were compared. Male and female dogs were administered an oral capsule once daily containing one of two different salts of (S)-amlodipine. One study used only the maleate salt form of (S)-amlodipine and two studies used only the malate salt form of (S)-amlodipine (form A). All doses were adjusted for salt form so all doses are in terms of mg base/kg. Table 4. Mean Dose-Normalized AUC and C max Parameters for (S)-Amlodipine Maleate and Malate Salts Following 28-Days of Oral Capsule Dosing in Dogs
  • Example 10 Method for Determination of (S)-Amlodipine in Plasma by LC/MS/MS for Preclinical Analysis An aliquot of each unknown, standard and control sample was analyzed on a high performance liquid chromatographic system equipped with a Positive-Ion mass spectrometer detector (condition tabled below in Table 5). Table 5. Determination of (S)-Amlodipine in Plasma by LC/MS/MS for Preclinical Analysis
  • Example 11 Method for Determination of (S)-Amlodipine in Human Plasma by LC/MS/MS An aliquot of each unknown, standard and control sample was analyzed on a high performance liquid chromatographic system equipped with a Positive-Ion mass spectrometer detector (condition tabled below in Table 7). Table 7. Conditions for the determination of (S)-Amlodipine in Human Plasma by LC/MS/MS
  • Example 12 Polymorphs and Solvates of (Sj-Amlodipine L-Malate (S)- Amlodipine L-malate has several polymo ⁇ hic and solvated forms. They were formed through crystallization and mechanical techniques. Characterization of crystal forms were performed using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetry (TG), hot stage microscopy, moisture balance, solution proton NMR spectroscopy, thermogravimetry-infrared spectroscopy (TG-IR), infrared (IR) and Raman spectroscopy. 1.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TG thermogravimetry
  • TG-IR thermogravimetry-infrared spectroscopy
  • IR infrared
  • a cryogrinder was also used to make amo ⁇ hous material.
  • Solution 1H NMR data indicated that the (S)-amlodipine L-malate molecule was intact.
  • the IR and Raman spectra of the amo ⁇ hous form are virtually identical to those for form A.
  • the DSC curve for the amo ⁇ hous form shows an exotherm at 81°C and an endotherm at 162 °C. This may be due to the crystallization to form A followed by the form A melt.
  • a glass transition was measured around 54 °C. 3.
  • Form B was obtained from water evaporation, slow evaporation from dioxane, fast and slow evaporations from EtOH, and a fast evaporation from IPA.
  • Solution 1H NMR indicated that the (S)-amlodipine molecule was intact.
  • the IR and Raman for form B are virtually identical.
  • the DSC curve for form B shows endotherms at -91, -152, and -190 °C.
  • Moisture balance data showed an increase in weight of 17.2% when equilibrated at 95% RH. The sample then lost this weight upon equilibrating back to 5% RH.
  • Form B was found to lose 1.3% volatiles up to 150 °C.
  • Karl Fischer water analysis esulted in 4.75% water.
  • TG-IR analysis confirmed the Karl Fischer water analysis.
  • Form B appears to be a hydrate because is was predominately crystallized from experiments involving water and the Karl Fischer data (1.5 moles of water) suggests more water than what can be attributed to just surface water.
  • Form B was also crystallized from dioxane, IPA and EtOH without the presence of water, however these solvents may have contained water sorbed from the atmosphere.
  • Form D was obtained from crystalization from ethanol: ethanol (2 mL) was added to (S)-amlodipine L-malate (68.4 mg). The sample was sonicated and then placed on a 60 °C shaker block. All solids had dissolved after approximately one day at 60 °C. The sample was then plunged into a dry ice/acetone bath and then placed in a freezer. After approximately five months, the solvent was decanted, and the solids were allowed to air dry. The DSC curve for the D form ( Figure 43) shows an endotherm at 162 °C. The TGA spectra shows 0.2% weight loss at 125 °C. Moisture balance experiments showed a 1.5% weight increase from 5% to 95% RH and a return to initial weight upon deso ⁇ tion.
  • Form E was only formed in 1,2-propanediol with high cooling rates and it is a solvated form with 1,2-propanediol.
  • Form F was obtained as single phase and is strongly conelated with DMF as crystallization solvent, which indicate that it is a solvated form with DMF.
  • the XRPD patterns of forms F and G are different, indicating that a different packing of the (S)- amlodipine molecules occurs in the two forms. It should be noticed that form F occuned in mixtures with form A also in other solvents, indicating that it is also a channel hydrate/solvate, but with a different crystal structure than form G.
  • form F can inco ⁇ orate DMF, methanol and mixtures water:acetone (10:90), water:THF (80:20) and water:2-propanol (20:80).
  • the TGA analysis of form F shows above 150 °C a high mass loss characteristic to a decomposition process occuned.
  • the DSC shows a melting endothermic peak at 106.6 °C after which it recrystallizes and melts at 149.3 °C.
  • Form G is a pyridine solvate.
  • the XRPD patterns of form G obtained in these different solvents are the same, indicating that different solvent molecules can be inco ⁇ orated in certain cavities present in the crystal structure (structures called channel hydrates/solvates) without leading to modifications in the XRPD patterns.
  • form G is likely to be such a channel hydrate/solvate structure.
  • form G can inco ⁇ orate pyridine, water and DMF:water (wet DMF).
  • the TGA analysis shows a 4.85 % mass loss in the 91-125 °C T interval after which a high mass loss characteristic to a decomposition process occuned.
  • the DSC shows a melting endothermic peak at 150.9 °C and a wide decomposition endothermic peak at 192.2 °C.

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Abstract

Un aspect de la présente invention concerne des compositions pharmaceutiques comprenant de la (S)-amlodipine optiquement pure et un inhibiteur de la HMG-CoA réductase. Dans un mode de réalisation préféré, l'inhibiteur de la HMG-CoA réductase est la lovastatine. Un autre aspect de la présente invention concerne une composition pharmaceutique qui comprend une (S)-amlodipine optiquement pure et un inhibiteur de l'absorption de cholestérol. Dans un mode de réalisation préféré, l'activateur de l'absorption de cholestérol est l'ézétimibe. Un autre aspect de la présente invention concerne une composition pharmaceutique qui comprend une (S)-amlodipine optiquement pure, un inhibiteur de la HMG-CoA réductase et un inhibiteur de l'absorption de cholestérol. Un autre aspect de la présente invention concerne lesdites compositions pharmaceutiques, lesquelles comprennent également de la niacine. L'invention concerne également des méthodes permettant de traiter un patient souffrant d'hypertension, d'hyperlipidémie ou d'un trouble cardiaque. L'invention concerne enfin des méthodes permettant de traiter l'hypertension et l'hyperlipidémie.
PCT/US2005/009910 2004-04-04 2005-03-25 Combinaisons comprenant de la (s)-amlodipine et un inhibiteur de la hmg-coa reductase ou un inhibiteur de l'absorption de cholesterol ou les deux a la fois et methodes permettant de reduire l'hypertension WO2005097191A2 (fr)

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WO2008048084A1 (fr) * 2006-10-17 2008-04-24 World-Trade Import-Export, Wtie, Ag. Combinaisons pharmaceutiques destinées au traitement de la dyslipidémie, accompagnée d'hypertension
EP2000137A2 (fr) * 2006-03-29 2008-12-10 Kowa Company. Ltd. Agent favorisant la baisse des triglycérides et agent améliorant l'hyperinsulinisme
US10716798B2 (en) 2007-02-21 2020-07-21 The Regents Of The University Of Michigan Compositions and methods for tranquilizing heart muscle
WO2020213010A1 (fr) * 2019-04-16 2020-10-22 Celagenex Research (India) Pvt. Ltd. Compositions synergiques de régulation des lipides
CN119424573A (zh) * 2024-02-05 2025-02-14 天津铭瑞医药科技有限公司 用于治疗高脂血症的中西药物组合

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Cited By (9)

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Publication number Priority date Publication date Assignee Title
EP2000137A2 (fr) * 2006-03-29 2008-12-10 Kowa Company. Ltd. Agent favorisant la baisse des triglycérides et agent améliorant l'hyperinsulinisme
EP2000137A4 (fr) * 2006-03-29 2010-02-24 Kowa Co Agent favorisant la baisse des triglycérides et agent améliorant l'hyperinsulinisme
US8124622B2 (en) 2006-03-29 2012-02-28 Kowa Co., Ltd. Triglyceride-lowering agent and hyperinsulinism-ameliorating agent
US8604054B2 (en) 2006-03-29 2013-12-10 Kowa Co., Ltd. Triglyceride-lowering agent and hyperinsulinism-ameliorating agent
KR101381076B1 (ko) * 2006-03-29 2014-04-02 코와 가부시키가이샤 트리글리세리드 저하제 및 고인슐린 혈증 개선제
WO2008048084A1 (fr) * 2006-10-17 2008-04-24 World-Trade Import-Export, Wtie, Ag. Combinaisons pharmaceutiques destinées au traitement de la dyslipidémie, accompagnée d'hypertension
US10716798B2 (en) 2007-02-21 2020-07-21 The Regents Of The University Of Michigan Compositions and methods for tranquilizing heart muscle
WO2020213010A1 (fr) * 2019-04-16 2020-10-22 Celagenex Research (India) Pvt. Ltd. Compositions synergiques de régulation des lipides
CN119424573A (zh) * 2024-02-05 2025-02-14 天津铭瑞医药科技有限公司 用于治疗高脂血症的中西药物组合

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