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WO2010065489A1 - Composition d’agoniste alpha2-adrénergique et d’antagoniste de récepteur d’angiotensine ii - Google Patents

Composition d’agoniste alpha2-adrénergique et d’antagoniste de récepteur d’angiotensine ii Download PDF

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Publication number
WO2010065489A1
WO2010065489A1 PCT/US2009/066176 US2009066176W WO2010065489A1 WO 2010065489 A1 WO2010065489 A1 WO 2010065489A1 US 2009066176 W US2009066176 W US 2009066176W WO 2010065489 A1 WO2010065489 A1 WO 2010065489A1
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WIPO (PCT)
Prior art keywords
angiotensin
receptor antagonist
pharmaceutical formulation
adrenergic agonist
optionally
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PCT/US2009/066176
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English (en)
Inventor
Larry Dillaha
Ed Schutter
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Sciele Pharma, Inc.
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Publication of WO2010065489A1 publication Critical patent/WO2010065489A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/288—Compounds of unknown constitution, e.g. material from plants or animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

  • the present invention relates to the field of pharmaceutical compositions and in particular compositions comprising an ⁇ 2 -adrenergic agonist, an angiotensin II receptor antagonist, and optionally a thiazide diuretic.
  • compositions for example a unitary or single dosage form comprising an ⁇ 2 -adrenergic agonist and an angiotensin II receptor antagonist, and optionally a thiazide diuretic. This composition will be useful in treating patients for relief of hypertension and other conditions.
  • a 2 -adrenergic agonists are a class of compounds which inhibit adenylyl cyclase activity.
  • a 2 -adrenergic agonists are used as antihypertensives and sedatives.
  • a 2 -adrenergic agonists are also used to lessen the withdrawal symptoms associated with opiate and alcohol.
  • Alpha-2 adrenergic agonists are known to decrease the stimulation-induced release of norepinephrine from central and peripheral adrenergic neurons leading to a decrease of sympathetic outflow. These compounds reduce brainstem vasomotor center-mediated sympathetic nervous system activation.
  • a 2 -adrenergic agonists include, but are not limited to, clonidine, guanfacine, dexmedetomidine, lofexidine, tizanidine, guanabenz, guanoxabenz, guanethidine, as well as pharmacologically acceptable salts thereof.
  • Clonidine is known chemically as N-(2,6-dichlorophenyl)-4,5-dihydro-lH-imidazol- 2-amine.
  • Clonidine, and pharmaceutically acceptable salts thereof, e.g., the hydrochloride salt thereof, are well known in the art.
  • Clonidine in particular, is a potent ⁇ 2 -adrenergic partial agonist used primarily for the treatment of hypertension. Clonidine stimulates ⁇ 2 - adrenoceptors in the vasomotor centers, causing a reduction of sympathetic outflow from the central nervous system. Both cardiac output and peripheral resistance are reduced resulting in a decrease in blood pressure. Higher concentrations cause a vasoconstriction by activation of postsynaptic receptors in vascular smooth muscle.
  • Clonidine has a half life of approximately 12 to 16 hours and generally exhibits effectiveness within 30 to 60 minutes. Clonidine can be administered in doses in sufficient quantities to allow for once daily dosing without excessive difficulty. It is soluble in water and alcohol and is generally provided in dosage strengths of 0.05 to 0.6 mg.
  • Clonidine is commercially available under the tradenames CATAPRES®, CATAPRES-TTS® and DURACLON®. Clonidine is also available under the tradename CLORPRES® as a combination product with the diuretic chlorthalidone.
  • the combination of clonidine and chlorthalidone treats edema in individuals with congestive heart failure, cirrhosis of the liver, or kidney disorders, or edema caused by taking steroids or estrogen.
  • the combination of clonidine and chlorthalidone is also used to treat hypertension.
  • the CLORPRES® product is available in dosage strengths of 0.1 mg of clonidine and 15 mg of chlorthalidone; 0.2 mg of clonidine and 15 mg of chlorthalidone; and 0.3 mg of clonidine and 15 mg of chlorthalidone.
  • Angiotensin II receptor antagonists also known as angiotensin receptor blockers, or ARB's
  • ARB's angiotensin receptor blockers
  • Blockade of ATi receptors directly causes vasodilation, reduces secretion of vasopressin, reduces production and secretion of aldosterone, amongst other actions, the combined effect of which is reduction of blood pressure.
  • Angiotensin II receptor antagonists are primarily used for the treatment of hypertension where the patient is intolerant to angiotensin converting enzyme (ACE) inhibitor therapy. These compounds do not inhibit the breakdown of bradykinin or other kinins, and are therefore only rarely associated with the persistent dry cough and/or angioedema, which limits the use of ACE inhibitor therapy.
  • Possible angiotensin II receptor antagonist include, but are not limited to, valsartan, telmisartan, losartan, irbesartan, olmesartan, eprosartan, candasartan, as well as pharmacologically acceptable salts thereof.
  • Valsartan is an angiotensin II receptor antagonist which acts on the ATi receptor subtype, and is known to be effective in the treatment of congestive heart failure and reducing blood pressure irrespective of age, sex or race and is also well tolerated.
  • Valsartan has the generic name N-(I- oxopentyl)-N-[[2'-(lH-tetrazol-5-yl)[l,r-biphenyl]-4-yl]methyl]-L-valine.
  • Valsartan is currently sold under the tradenames DIOVAN® and DIOVAN HCT® (valsartan and hydrochlorothiazide, a known diuretic), both of which are indicated for the treatment of hypertension. Valsartan is also sold in combination with amlodipine besylate, under the tradename EXFORGE®.
  • the present invention may also optionally include a thiazide diuretic.
  • Thiazide diuretics are used to treat hypertension. They are also used to treat congestive heart failure and symptomatic edema. Thiazide diuretics have been shown to prevent hypertension-related morbidity and mortality. Thiazide diuretics lower blood pressure by causing diuresis, a fall in plasma volume and a reduction in cardiac output.
  • Known thiazide diuretics include chlorothiazide, chlorthalidone, bendroflumetiazide, hydroflumethiazide, hydrochlorothiazide, chlortalidone, methyclothiazide, polythiazide, quinethazone, trichlormethiazide and metolazone.
  • Combinations of angiotensin II receptor antagonist and diuretics are known for the treatment of hypertension. It has been found that valsartan, combined in a dose range from about 10 to 250 mg with hydrochlorothiazide in a dose range from about 6 to 60 mg, is suitable for more efficient treatment of hypertension. With these dose ranges of the combined active agents, valsartan is found to have a greater efficacy in reducing elevated blood pressure to normal levels than it would have if used at the same dose range in monotherapy. Moreover, when hydrochlorothiazide is administered in combination with valsartan, the diuretic agent is more effective as compared to monotherapy at the dose range indicated.
  • Embodiments have a dose range from about 50 and 200 mg valsartan and from about 10 to 30 mg hydrochlorothiazide. Another is a unit dose of about 80 mg valsartan and 12.5 mg or 25 mg of hydrochlorothiazide and 160 mg valsartan and 12.5 mg or 25 mg of hydrochlorothiazide.
  • the weight ratio of valsartan to hydrochlorothiazide is from about 1:6 to about 42: 1, 2: 1 to 13: 1, or 2: 1 to 10: 1.
  • Valsartan has an effective half life of about 6 hours. Valsartan is soluble in ethanol and methanol and slightly soluble in water.
  • composition should be stable, economical and easy to manufacture. It is therefore an objective of the present invention to provide a safe and effective pharmaceutical compositing comprising an 01 2 -adrenergic agonist, an angiotensin II receptor antagonist, and optionally a thiazide diuretic.
  • the present invention is a pharmaceutical composition that combines a 01 2 -adrenergic agonist with an angiotensin II receptor antagonist.
  • the present invention further comprises a pharmaceutical composition that optionally comprises a thiazide diuretic. It has been surprisingly found that the combination of these active ingredients provides safe and effective reduction in blood pressure.
  • the present invention more specifically is directed towards a pharmaceutical composition wherein the (X 2 -adrenergic agonist is clonidine, the angiotensin II receptor antagonist is valsartan, and the optional thiazide diuretic is hydrochlorothiazide.
  • This composition may be, but is not limited to, a solid oral dosage form, a transdermal dosage form, an aqueous liquid, an implantable pump or an ophthalmic insert.
  • the pharmaceutical composition is a solid dosage form that is useful for oral administration.
  • the solid oral dosage form may be an immediate release composition, a controlled release composition or a delayed release composition, namely a tablet or capsule.
  • the controlled release dosage formulation may be a matrix tablet, an osmotic tablet or a multi-particulate tablet or capsule comprising controlled release beads, pellets or mini-tablets.
  • the delayed release composition may be a tablet, enteric coated capsule or a multi-particulate tablet or capsule comprising delayed release beads, pellets or mini-tablets.
  • the controlled release composition may provide an immediate release amount of the (X 2 -adrenergic agonist and/or the angiotensin II receptor antagonist and a controlled release of the (X 2 -adrenergic agonist and/or the angiotensin II receptor antagonist.
  • the controlled release composition may also provide either a controlled release of the thiazide diuretic and/or an immediate release of the thiazide diuretic.
  • a seal coat may optionally be applied to the tablet core followed by the application of an immediate release angiotensin II receptor antagonist coating.
  • the angiotensin II receptor antagonist coating may then optionally be seal coated and a second immediate release coating comprising an oi 2 -adrenergic agonist may be applied to the seal coat.
  • the (X 2 -adrenergic agonist coating also may be applied directly to the angiotensin II receptor antagonist coating if a seal coating is not employed. The order in which the two immediate release coatings are applied can be reversed, or the angiotensin II receptor antagonist and (X 2 -adrenergic agonist may be combined into a single immediate release coating. Depending upon how the core is formed, an immediate release angiotensin II receptor antagonist or oi 2 -adrenergic agonist coating may not be needed.
  • the matrix tablet may be formulated in a manner that allows for a therapeutic amount of ⁇ 2 - adrenergic agonist or angiotensin II receptor antagonist to be released in less than 2 hours, or less than 1 hour.
  • the controlled release composition may be optionally coated with a final seal coating and/or a polishing agent.
  • immediate release coating or “immediate release amount” means a therapeutic amount of the angiotensin II receptor antagonist, 01 2 -adrenergic agonist and/or thiazide diuretic is released from the final dosage formulation within 2 hours, within 60 minutes or less, or within 30 minutes or less when the composition is placed in 900 ml of simulated intestinal fluid, 37°C and tested using a United States Pharmacopoeia Type II apparatus at 75 rpms.
  • Certain embodiments of the present invention will comprise from 0.05 to 0.6 mg of (X 2 -adrenergic agonist and 20 to 200 mg of angiotensin II receptor antagonist.
  • One embodiment of the present invention may optionally include 5 to 300 mg of the thiazide diuretic.
  • the immediate release portions of the present invention can comprise about 10-65% of the total amount of the active ingredient(s) in the final dosage formulation, or about 15- 55% of the total amount of the active ingredient(s) in the final dosage formulation, or about 20-50% of the active ingredient(s) in the final dosage formulation.
  • the present invention may also include an angiotensin converting enzyme inhibitor in place of the angiotensin II receptor antagonist.
  • Angiotensin converting enzyme (or ACE) inhibitors are pharmaceutical compounds that are useful in treating hypertension and congestive heart failure. ACE inhibitors lower arteriolar resistance and increase venous capacity. ACE inhibitors increase cardiac output and cardiac index, lower renovascular resistance and lead to increased natriuresis.
  • ACE inhibitors include (and are sold under the tradename), catopril (CAPOTEN®), fosinopril (MONOPRIL®), zofenopril, enalapril (VASOTEC® and RENITEC®), ramapril (ALTACE®, TRITACE®, RAMACE®, RAMIWIN®), quinapril (ACCUPRIL®), perindopril (COVERSYL®, ACEON®), lisinopril (LISODUR®,
  • a 2 -adrenergic agonist for use in the present invention include, but are not limited to, clonidine, guanfacine, dexmedetomidine, lofexidine, tizanidine, guanabenz, guanoxabenz, guanethidine, as well as pharmacologically acceptable salts thereof.
  • ⁇ 2 - adrenergic agonist is clonidine.
  • Angiotensin II receptor antagonist for use in the present invention include, but are not limited to, valsartan, telmisartan, losartan, irbesartan, olmesartan as well as pharmacologically acceptable salts thereof.
  • Thiazide diuretics for use in the present invention include chlorothiazide, chlorthalidone, hydrochlorothiazide, bendroflumetiazide, hydroflumethiazide, chlortalidone, methyclothiazide, polythiazide, quinethazone, trichlormethiazide and metolazone.
  • salts encompasses both organic and inorganic acid addition salts including, for example those prepared from acids such as hydrochloric, hydrofluoric, sulfuric, sulfonic, tartic, fumaric, hydrobromic, glycolic, citric, maleic, sulfate, phosphoric, succinic, acetic, nitric, benzoic, ascorbic, p-toluene sulfonic, benzenesulfonic, naphthalenesulfonic, propionic, and the like.
  • acids such as hydrochloric, hydrofluoric, sulfuric, sulfonic, tartic, fumaric, hydrobromic, glycolic, citric, maleic, sulfate, phosphoric, succinic, acetic, nitric, benzoic, ascorbic, p-toluene sulfonic, benzenesulfonic, naphthalenesulfonic, propionic, and the like.
  • the composition can be any type of pharmaceutical composition that provides therapeutic amounts of the (X 2 -adrenergic agonist, angiotensin II receptor antagonist and optionally the thiazide diuretic to a patient in need of such treatment, in amounts useful to treat hypertension.
  • An immediate release composition of the (X 2 -adrenergic agonist, angiotensin II receptor antagonist and optionally the thiazide diuretic may be prepared using techniques commonly known in the art.
  • Pharmaceutical excipients and carriers commonly known in the art can be used to prepare the immediate release compositions. Commonly known pharmaceutically acceptable excipients and carriers are listed in Rowe et al., Handbook of Pharmaceutically Acceptable Excipients (4 th ed. 2003).
  • the immediate release composition can be in the form of a tablet, capsule, or oral solution of suspension.
  • the (X 2 -adrenergic agonist and angiotensin II receptor antagonist, and optionally the diuretic, and any excipients are mixed together using standard techniques known in the art.
  • the mixture is then compressed into tablets or filled into capsule shells using techniques commonly used in the art.
  • the on well known filler is lactose monohydrate (spray dried).
  • Other commonly used fillers or diluents are starch, dextrose, sucrose, hydroxypropyl cellulose, microcrystalline cellulose and the like, as described in United States Patent No. 5,436,249.
  • a fumed colloidal silicon dioxide such as CAB-O-SIL®, M5 may be used as the glidant, as described in United States Patent No. 6,521,261.
  • a tablet lubricant may be added to the composition.
  • suitable tablet lubricants include magnesium stearate or glyceryl mono-stearate.
  • EASTMAN® 600P is a commercially available material that may also be used as a lubricant.
  • the lubricants are passed separately through a mesh screen and then blended with a mixture of (X 2 -adrenergic agonist, angiotensin II receptor antagonist, (optionally a thiazide diuretic), filler and glidant which has been passed through a Comil.
  • the composition can also be granulated by wet or dry techniques prior to filling into the hard or soft gelatin capsules or compressed into tablets.
  • the composition may also be mixed with conventional tabletting aids and compressed into a tablet using direct compression techniques commonly known in the art.
  • the seal coating or aesthetic coating typically is a coating or layer that is soluble or rapidly disintegrates in water and does not materially affect the release of the active ingredients from the tablet core.
  • the most common seal coatings comprise low molecular weight hydroxypropyl methylcellulose or polyvinyl alcohol.
  • a controlled release composition of the (X 2 -adrenergic agonist, angiotensin II receptor antagonist and optionally the thiazide diuretic may also be prepared using techniques commonly known in the art.
  • Some of the controlled release compositions that are useful in the present invention include but are not limited to matrix tablets, osmotic tablets, pellet filled capsules or combinations of the foregoing. Release controlling agents such as hydrophilic and hydrophobic matrix polymers and polymeric coatings are known in the art and described in Rowe et al., Handbook of Pharmaceutically Acceptable Excipients (4 th ed. 2003).
  • the controlled release composition in accordance with the present invention should release therapeutically effective amounts of the (X 2 -adrenergic agonist, angiotensin II receptor antagonist and optionally the thiazide diuretic over a period of 4-24 hours, or 8-24 hours so the composition can be administered once or twice daily.
  • a controlled release composition in accordance with the present invention is a matrix tablet.
  • the matrix tablet should comprise therapeutically effective amount of the (X 2 -adrenergic agonist, angiotensin II receptor antagonist, and optionally the thiazide diuretic and a matrix forming agent which can be a hydrophobic material such as a wax, a hydrophilic material such as a hydrogel forming polymer or a combination of the two.
  • a hydrogel polymer is a polymeric material that gels or swells when placed in an aqueous environment such as the gastrointestinal tract of a human.
  • the matrix forming agent will control the release of the (X 2 -adrenergic agonist and angiotensin II receptor antagonist, and optionally the thiazide diuretic, by diffusion of the active ingredients from the matrix, erosion of the matrix or a combination of diffusion and erosion. The amount of diffusion and erosion will depend upon the materials selected for the formation of the matrix.
  • the following table provides an overview of a matrix tablet composition that can be used to prepare a controlled release matrix tablet in accordance with the present invention:
  • One known hydrogel forming polymer is a pharmaceutically acceptable polymeric substance such as hydroxypropyl methylcellulose.
  • the hydroxypropyl methylcellulose of the present invention is the USP substitution type 2208 and should have an average molecular weight above 100,000, or above 200,000.
  • the methyoxy content of the hydroxypropyl methylcellulose should be approximately 19-24 weight percent and the hydroxypropyl content of the hydroxypropyl methylcellulose should be approximately 7.5 to 8.5 weight percent.
  • a suitable grade of hydroxypropyl is available from Dow Chemical Co. of Midland, MI under the trade name METHOCEL® KlOOM which exhibits a viscosity in a 2% aqueous solution of approximately 100,000 cps, as described in United States Patent No. 5,484,607.
  • hydrogel forming polymers that can be used include carboxymethylcellulose calcium, carboxymethylcellulose sodium, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, acrylic acid crosslinked with polyalkenyl ethers or divinyl glycol, sodium alginate and poly(ethylene oxide) (POLY OXTM).
  • hydrogel polymer in the matrix described in Table 2 can be replaced with a hydrophobic material such as a wax or oil material that is a solid at room temperature.
  • a hydrophobic material such as a wax or oil material that is a solid at room temperature.
  • Some useful hydrophobic materials include beeswax, white wax, emulsifying wax, hydrogenated vegetable oil, hydrogenated castor oil, microcrystalline wax, cetyl alcohol, stearyl alcohol, free wax acids such as stearic acid, esters of wax acids; propylene glycol monostearate, glycerol monostearate, carnauba wax, palm wax, candelilla wax, lignite wax, ozokerite, ceresin wax, lardaceine and China wax.
  • rate controlling excipients useful in the present invention include saturated hydrocarbons having 25 to 31 carbon atoms, saturated alcohols having from 25 to 31 carbon atoms, saturated monocarboxylic acids having from 25 to 31 carbon atoms, and esters obtained from said alcohols and monocarboxylic acids which are described in United States Patent No. 6,923,984.
  • a combination of hydrophobic and hydrophilic materials may also be used in preparing a controlled release tablet matrix of the present invention.
  • the fillers, glidants and lubricants useful in preparation of the controlled release matrix tablet are those described previously. If a hydrophobic material is used in the present invention as a matrix forming material, the filler should be a water soluble material that will dissolve when administered to a patient. The dissolution of the filler will create pores and channels in the matrix and thereby allow the active ingredients to be released.
  • the matrix tablet may optionally be seal coated or coated with an aesthetic coating as described above with the respect to the immediate release composition.
  • An immediate release coating comprising the (X 2 -adrenergic agonist, the angiotensin II receptor antagonist and/or the thiazide diuretic, can be coated directly onto the controlled release matrix core or applied over the sealed coated matrix tablet.
  • the immediate release coating may comprise active ingredient(s) and a film forming material or binder and optionally other conventional additives such as lubricants, fillers and antiadherents.
  • the immediate release coating may be applied by any conventional technique such as pan coating or spray coating.
  • the immediate release coating is applied by spraying an aqueous solution or suspension over a pan containing the matrix tablets.
  • the matrix tablet may have the following compositions: TABLE 3
  • the film forming material or binder employed in the immediate release coating can be a water soluble or rapidly dispersing material such as a low molecular weight hydroxypropyl methylcellulose or povidone.
  • the matrix tablet core with or without an immediate release coating(s) can be coated with a polishing agent such as candellila wax or a color coating by any of the conventional coating techniques described in Remington 's Pharmaceutical Sciences 20 th Ed.
  • a polishing agent such as candellila wax or a color coating by any of the conventional coating techniques described in Remington 's Pharmaceutical Sciences 20 th Ed.
  • Another embodiment of the controlled release composition in accordance with the present invention is an osmotic tablet.
  • the osmotic tablet comprises: a core containing therapeutic amounts of the active ingredients; a semi permeable membrane surrounding the core and a passageway in the semi permeable membrane for release of the active ingredients.
  • the core of the osmotic tablet can be prepared with or without a gelling or swelling polymer and should comprise the (X 2 -adrenergic agonist, the angiotensin II receptor antagonist, optionally a thiazide diuretic and at least one pharmaceutically acceptable excipient.
  • the core can be a homogenously blend of active ingredients as described in United States Patent No. 5,654,005 or a multilayered structure comprising a drug composition and a push composition as described in United States Patent Nos. 4,612,008 or 4,873,337.
  • the osmotic tablet core may also comprise a three layer structure comprising a hydrogel or push layer between an 01 2 -adrenergic agonist composition layer and an angiotensin II receptor antagonist composition layer.
  • the osmotic core includes a homogeneous mixture of an 01 2 -adrenergic agonist, an angiotensin II receptor antagonist (and optionally a thiazide diuretic), a binding agent and an absorption enhancer.
  • the osmotic core is can be coated with a polymeric coating to form a semi permeable membrane around the tablet and drilled to create one passageway on each side of the membrane.
  • the osmotic tablet core of the present invention will comprise the following ingredients:
  • the binding agents used in the osmotic core are any conventionally known pharmaceutically acceptable binders such as polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, polymethacrylate, polyvinylalcohol, waxes and the like. Mixtures of the aforementioned binding agents may also be used. Binding agents can be water soluble materials such as polyvinyl pyrrolidone having an average molecular weight of 25,000 to 3,000,000. The binding agent may comprise approximately about 0% to about 40% of the total weight of the osmotic core or about 3% to about 15% of the total weight of the osmotic core.
  • the osmotic core may also optionally comprise an absorption enhancer.
  • the absorption enhancer can be any type of absorption enhancer commonly known in the art such as a fatty acid, a surfactant, a chelating agent, a bile salt or mixtures thereof.
  • absorption enhancers examples include fatty acids such as capric acid, oleic acid and their monoglycerides, surfactants such as sodium lauryl sulfate, sodium taurocholate and polysorbate 80, chelating agents such as citric acid, phytic acid, ethylenediamine tetraacetic acid (EDTA) and ethylene glycol-bis( ⁇ -aminoethyl ether)-N,N,N,N-tetraacetic acid (EGTA).
  • the osmotic core may comprise approximately 0% to about 20% of the absorption enhancer based on the total weight of the osmotic core, or about 2% to about 10% of the total weight of the osmotic core.
  • the core of the present invention is formed by granulating the ⁇ 2 - adrenergic agonist, the angiotensin II receptor antagonist (and optionally a thiazide diuretic) with a binding agent and compressing the granules with the addition of a lubricant and absorption enhancer into a tablet.
  • the osmotic core may also be formed by dry granulating the osmotic core ingredients by passing them through a roller compactor and compressing the granules with the addition of a lubricant into tablets. Direct compression may also be employed for tabletting. Other commonly known granulation procedures are known in the art. Additionally, other excipients such as lubricants, pigments or dyes may also be employed in the formulation of the subject invention.
  • the osmotic core can optionally be seal coated prior to the application of a membrane, such as a semipermeable polymeric coating membrane.
  • the semipermeable membrane is permeable to the passage of an external fluids such as water or aqueous biological fluids and is impermeable to the passage of the active ingredients in the osmotic core.
  • Materials that are useful in forming the semipermeable membrane are ethylcellulose, cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester-ether, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate propionate and cellulose acetate butyrate.
  • One known semipermeable membrane material is cellulose acetate comprising an acetyl content of 39.3% to 40.3%, and is commercially available from Eastman Fine Chemicals.
  • the semipermeable membrane can include one of the above-described polymers and a flux-enhancing agent.
  • the flux enhancing agent can increase the volume of fluid imbibed into the core to enable the composition to dispense substantially all of the active ingredients through the passageway and/or the porous membrane.
  • the flux-enhancing agent can be a water-soluble material or an enteric material.
  • Examples of the materials that are useful as flux enhancers are sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycol (PEG), propylene glycol, hydroxypropyl cellulose, hydroxypropyl methycellulose, hydroxypropyl methycellulose phthalate, cellulose acetate phthalate, polyvinyl alcohols, methacrylic acid copolymers, poloxamers (such as LUTROL F68, LUTROL F 127, LUTROL F 108, which are commercially available from BASF) and mixtures thereof.
  • PEG 400 One well known flux-enhancer is PEG 400.
  • the flux enhancing agent comprises approximately 0% to about 40% of the total weight of the membrane coating, or about 2% to about 20% of the total weight of the membrane coating.
  • the flux enhancing agent dissolves or leaches from the semipermeable membrane to form paths in the semipermeable membrane which enables fluid to enter the osmotic core and dissolve the active ingredient.
  • the semipermeable membrane may also be formed using a commonly known excipient such as a plasticizer.
  • plasticizers include adipate, azelate, enzoate, citrate, stearate, isoebucate, sebacate, triethyl citrate, tri-n-butyl citrate, acetyl tri-n- butyl citrate, citric acid esters, and those described in the Encyclopedia of Polymer Science and Technology, Vol. 10 (1969), published by John Wiley & Sons.
  • plasticizers are triacetin, acetylated monoglyceride, grape seed oil, olive oil, sesame oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacate, triethylcitrate, tributylcitrate, glyceroltributyrate and the like.
  • amounts from about 0% to about 25%, or about 2% to about 15% of the plasticizer can be used based upon the total weight of the membrane coating.
  • the membrane coating around the core will comprise from about 1% to about 5%, or about 2% to about 3% based upon the total weight of the core and coating.
  • the membrane coating surrounding the core further comprises a passageway that will allow for controlled release of the drug from the core.
  • the term "passageway" includes an aperture, orifice, bore, hole, weakened area or an erodible element such as a gelatin plug that erodes to form an osmotic passageway for the release of the active ingredients from the dosage form. Passageways used in accordance with the subject invention are well known and are described in United States Patent Nos. 3,845,770; 3,916,899; 4,034,758; 4,077,407; 4,783,337 and 5,071,607. An immediate release coating(s) may be applied to the semi permeable membrane.
  • immediate release coatings are described above and may be applied by, but would not be limited to, the processes selected from the group consisting of drug layering, lamination, dry compression, deposition and printing.
  • a seal coat is applied to the semi permeable membrane before the immediate release layer is applied.
  • Another embodiment of the controlled release composition in accordance with the present invention comprises beads, pellets or mini-tablets comprising the active ingredients.
  • the beads, pellets or mini-tablets may be filled into hard or soft gelatin capsules or compressed into a tablet.
  • the bead, pellets or mini-tablets are prepared by methods commonly known in the art and typically range in size from about 0.1 mm to about 3 mm in diameter. Ideally, the beads or pellets are about 0.2 to about 1 mm in diameter and the mini-tablets are about 0.5 to about 2.5 mm in diameter.
  • Active or immediate release beads or pellets are prepared by applying a drug layer onto an inert substrate such as a non-pariel seed or a microcrystalline cellulose seed commercially available under the tradename CELPHERE®. Active beads or pellets can also be prepared by mixing the active ingredients with conventional pharmaceutical excipients such as binders and fillers and subjecting the mixture to extrusion spheronization techniques. The mixture of active ingredients and conventional pharmaceutical excipients can also be compressed in mini-tablets. The active beads or pellets can be prepared by the methods described in United States Patent No. 5,529,791 and 4,984,240.
  • the active or immediate release beads, pellets or mini-tablets may be coated with a release controlling polymer coating.
  • the controlled release coating should comprise a water insoluble water permeable polymer and a water or acid soluble channeling agent.
  • the controlled release coating may also comprise a lubricating or dusting agent and optionally a surfactant.
  • Suitable water insoluble water permeable polymers are ethylcellulose, cellulose acetate and polyacrylates or mixtures thereof. Additional water insoluble polymers are described in United States Patent No. 5,002,776.
  • the water insoluble water permeable polymer is a polymethacrylate ester copolymer, such as a poly(ethylarcylate methylmethacrylate) copolymer which is commercially available from Rohm Pharma under the tradename EUDRAGIT NE 3OD.
  • the channeling agent employed in the extended release coating can be any type of water or acid soluble pharmaceutically acceptable substance commonly known in the art such as polyvinyl pyrrolidone, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyacrylate, sucrose, drug itself or any combination of the foregoing.
  • One well known channeling agent is a water or acid soluble polymer such as hydroxypropyl methylcellulose.
  • Suitable lubricants or dusting agents that can be used in the present invention are talc, magnesium stearate, silicon dioxide, kaolin or a mixture of the foregoing.
  • the lubricant or dusting agent prevents the pellets from sticking to one another during processing.
  • the lubricant may be dusted onto the active pellets during the coating process or it may be incorporated into a coating suspension and applied to the core with the coating suspension.
  • the lubricant is a mixture of talc and magnesium stearate.
  • the ratio of talc to magnesium stearate should be about 1 :2 to about 2: 1. These ratios are based upon the weight of the talc to the weight of the magnesium stearate.
  • Suitable surfactants that may optionally be used in the present invention are sodium lauryl sulfate, sodium taurocholate or a polysorbate.
  • One well known surfactant is polysorbate 80.
  • the controlled release coating can be applied to the active beads, pellets or mini- tablets by any means commonly known in the industry such as a rotary granulator, pan coater or a fluidized bed coater.
  • active beads of the (X 2 -adrenergic agonist are prepared, active beads of the angiotensin II receptor antagonist are prepared and active beads of the thiazide diuretic are prepared. A portion of each type of different active beads is coated with a controlled release coating. Various blends of the six different beads (3 different active beads and 3 different controlled release beads) are prepared and filled into hard or soft gelatin capsules.
  • a blend of 20% ⁇ 2 -adrenergic agonist active beads, 20% angiotensin II receptor antagonist active beads, 30% (X 2 -adrenergic agonist controlled release beads, 30% angiotensin II receptor antagonist controlled release beads are filled into a hard gelatin capsule to prepare a once-a-day capsule dosage form in accordance with the present invention.
  • the controlled release formulations prepared in accordance with the present invention can exhibit the following 01 2 -adrenergic agonist/angiotensin II receptor antagonist/thiazide diuretic dissolution release rate when tested in 900 ml of simulated intestinal fluid using a United States Pharmacopoeia Type II apparatus at 75 rpm and 37°C.
  • a delayed release composition of the (X 2 -adrenergic agonist, the angiotensin II receptor antagonist and optionally the thiazide diuretic in accordance with the present invention may be prepared by first preparing an immediate release tablet core, a controlled release matrix tablet core or active pellet cores as described above. The cores are then coated with an enteric or pH sensitive coating using techniques commonly known in the art.
  • the enteric or pH dependent coating material useful in preparing a delayed release coating can be zein, shellac, methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, polyvinyl acetate phthalate or mixtures thereof.
  • methacrylic acid copolymer is commercially available under the tradename EUDRAGIT S.
  • the enteric or pH dependent coating should be applied so that the pharmaceutical active ingredients present in the core are released only after the composition has passed through the stomach.
  • the controlled release coating should be designed to dissolve at a pH greater than 4.5, greater than 5.5 or greater than a pH of 6.
  • the enteric or pH dependent coating may also comprise plasticizers.
  • Plasticizers which may be used include any of those known to those skilled in the art, including but not limited to acetyltributyl citrate, triacetin, acetylated monoglyceride, rape oil, olive oil, sesame oil, acetyltriethyl citrate, glycerin sorbitol, diethyloxalate, diethylmalate, diethylfumerate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylphthalate, dibutylsebacate, triethyl citrate, tributylcitrate, glyceroltributyrate, polyethylene glycol, propylene glycol and mixtures thereof.
  • the plasticizer can be acetyl tributyl citrate in an amount ranging from 0 to about 15%, or at about 3-10% based on the total
  • the enteric or pH dependent coating may further include an anti-adherent such as those selected from the group consisting of talc, colloidal silicon dioxide, magnesium stearate, magnesium silicate, glycerol monostearates, calcium stearate or stearic acid.
  • an anti-adherent such as those selected from the group consisting of talc, colloidal silicon dioxide, magnesium stearate, magnesium silicate, glycerol monostearates, calcium stearate or stearic acid.
  • talc colloidal silicon dioxide
  • magnesium stearate magnesium silicate
  • glycerol monostearates calcium stearate or stearic acid.
  • talc is talc, which may be employed in an amount ranging from about 30- 75%, or about 40-65% based on the total weight of the controlled release coating.
  • the delayed release composition in accordance with the present invention may also comprise an immediate release component.
  • the enteric or pH dependent coated tablet may be coated with an immediate release layer as described previously.
  • enteric coated pellets a blend of enteric coated pellets and immediate release pellets can be blended together and filled into a hard gelatin capsule or compressed into a tablet.
  • the combination of enteric or pH coated compositions and immediate release component will allow the pulsatile delivery of the (X 2 -adrenergic agonist, angiotensin II receptor antagonist and optionally the thiazide diuretic form a single dosage form.
  • a transdermal composition in accordance with the present invention and comprising an oi 2 -adrenergic agonist, an angiotensin II receptor antagonist, and optionally a thiazide diuretic can be formulated from the following ingredients: Glycerol and water are mixed together followed by heating of the solution. Next, polyvinylalcohol (PVA 100% hydrolyzed, molecular weight 115,000) and polyvinylpyrrolidone (mw 40,000) are added to the solution followed by continued heating. The mixture is then stirred until all components dissolve into solution. With larger quantities, a considerably longer period of time may be needed for heating.
  • the solution is mixed with an 01 2 -adrenergic agonist, an angiotensin II receptor antagonist, and optionally a thiazide diuretic; this mixture is then mechanically stirred until homogeneous.
  • the homogeneous mixture is then poured into forms made of glass or stainless steel which serve as templates to produce a diffusion matrix.
  • This diffusion matrix is then cut into pieces with a total surface area suitable for the administration of a pharmaceutically effective amount of an ⁇ 2 - adrenergic agonist, a angiotensin II receptor antagonist, and optionally a thiazide diuretic.
  • the diffusion matrix is administered to the skin of a patient in need of an antihypertensive effect, the (X 2 -adrenergic agonist, the angiotensin II receptor antagonist, and optionally the thiazide diuretic, being transdermally delivered to the skin of the patient.
  • the diffusion matrix can be applied to the skin of the patient by means of a single-piece bandage having the diffusion matrix in the center under the occlusive layer, the bandage being provided to the patient with a removable cover much like a BAND-AID® product.
  • oral liquid compositions in accordance with the present invention and comprising an oi 2 -adrenergic agonist, an angiotensin II receptor antagonist and optionally the thiazide diuretic may also be prepared using techniques commonly known in the art.
  • Oral liquid compositions may comprise the following components:
  • the ethanol component can be employed in about 15% by weight.
  • the upper limit is mainly determined by practical reasons. A high percentage of ethanol is undesirable due to the flammability hazards during processing and the potential for evaporative losses during manufacture. Because ethanol has a very discernible effect on taste perceptions when present at concentrations in excess of 20%, it is generally desirous to keep ethanol concentrations as low as possible.
  • the present invention allows using a relatively low concentration of ethanol.
  • the glycol component may, in principle, consist of any (poly) glycol, e.g. polyethylene glycol of varying molecular weights, but for the desired organoleptic characteristics, i.e. texture and flavor.
  • the glycol is of a low molecular weight glycol or glycerol.
  • the low molecular weight glycol can be propylene glycol, glycerol, or a mixture thereof. If propylene glycol is employed, the percentage thereof is about 10% by weight. If the percentage is lowered, care should be taken to maintain a physically stable solution. A high percentage of propylene glycol should be avoided because of the burning taste it can cause in patients. If glycerol is employed, the percentage should be about 40% to 50% by weight.
  • the percentage may be increased, but care should be taken that the resulting formulation does not become too viscous for processing.
  • the percentage may also be decreased, but in view of the relative increase of the amount of water, care should be taken that the (X 2 -adrenergic agonist, angiotensin II receptor antagonist, and optionally the thiazide diuretic, dissolves to a sufficient extent.
  • the glycol component should consist of a mixture of about 10% by weight of propylene glycol and of from about 40% to 50% by weight of glycerol.
  • the water component may comprise any suitable, conventional additive, such as flavor agents, sweeteners, and coloring agents.
  • Useful additives are bulk-sweetening agents such as sucrose, or any other sugar, hydrogenated glucose, or any other modified sugar or sorbitol.
  • the sugars may be added as dry powders or solutions.
  • the sorbitol solution can be a non-crystallizing solution containing 70% by weight of sorbitol. In all cases care should be taken that the resulting aqueous solution can still be processed. Sorbitol can be employed in an aqueous solution of from 15% to 25% by weight, or about 20% by weight.
  • An immediate release composition in accordance with the present invention is prepared by: forming an immediate release tablet core (I) comprising 0.2 mg of clonidine, 40 mg of valsartan, and 25 mg of hydrochlorothiazide, lactose monohydrate, colloidal silicon dioxide and magnesium stearate.
  • the tablet core is formed by direct compression of the above ingredients.
  • EXAMPLE II The immediate release tablet core (I) prepared according to Example I is then coated core with a (II) controlled release coating comprising Eudragit S 100, Zein, acetyl tributyl citrate and talc; followed by applying (III) an immediate release clonidine and valsartan coating to the controlled release coating comprising 0.1 mg of clonidine, 30 mg of valsartan, hydroxypropyl methylcellulose, polyethylene glycol and talc; (IV) seal coating the immediate release coating with OPADRY® White YS- 1-7003; and (V) applying a polishing coat to the seal coated product comprising Candelilla Wax.
  • a controlled release coating comprising Eudragit S 100, Zein, acetyl tributyl citrate and talc
  • an immediate release clonidine and valsartan coating to the controlled release coating comprising 0.1 mg of clonidine, 30 mg of valsartan, hydroxypropyl methylcellulose
  • a clonidine/valsartan tablet is prepared as described in Examples I and II wherein the core comprises 0.2 mg of clonidine and 60 mg of valsartan and the immediate release coating comprises 0.1 mg of clonidine and 20 mg of valsartan.
  • a clonidine/valsartan tablet is prepared as described in Examples I and II wherein the core comprises 0.4 mg of clonidine and 120 mg of valsartan and the immediate release coating comprises 0.2 mg of clonidine and 40 mg of valsartan.
  • An oral dosage formulation in accordance with the present invention is prepared by: (I) forming an immediate release tablet core comprising 0.1 mg of clonidine, 30 mg of valsartan, lactose monohydrate, colloidal silicon dioxide and magnesium stearate, and optionally 25 mg of hydrochlorothiazide; (II) coating the immediate release tablet core with a controlled release coating comprising Eudragit S 100, Zein, acetyl tributyl citrate and talc; (III) applying an immediate release valsartan coating to the controlled release coating comprising 10 mg of valsartan, hydroxypropyl methylcellulose, polyethylene glycol and talc; (IV) seal coating the immediate release valsartan coating with OPADRY® White YS- 1 -7003 ; (V) applying an immediate release clonidine coating to the seal coat comprising 0.1 mg of clonidine, hydroxypropyl methycellulose, polyethylene glycol and talc; (VI)
  • a clonidine/valsartan tablet is prepared as described in Example V wherein the core comprises 0.2 mg of clonidine and 60 mg of valsartan and the immediate release coating comprises 0.1 mg of clonidine and 20 mg of valsartan.
  • a clonidine/valsartan tablet is prepared as described in Example V wherein the core comprises 0.4 mg of clonidine and 120 mg of valsartan and the immediate release coating comprises 0.2 mg of clonidine and 40 mg of valsartan.
  • An oral dosage formulation in accordance with the present invention is prepared by: (I) forming an immediate release tablet core comprising 0.1 mg of clonidine, 30 mg of valsartan, lactose monohydrate, colloidal silicon dioxide and magnesium stearate; and optionally 25 mg of hydrochlorothiazide; (II) coating the immediate release tablet core with a controlled release coating comprising Eudragit S 100, Zein, acetyl tributyl citrate and talc; (III) applying an immediate release clonidine and valsartan coating to the controlled release coating comprising 0.1 mg of clonidine, 10 mg of valsartan, hydroxypropyl methylcellulose, polyethylene glycol and talc; (IV) seal coating the immediate release coating with OPADRY® White YS- 1 -7003 ; and (V) applying a polishing coat to the seal coated product comprising Candelilla Wax.
  • a clonidine/valsartan tablet is prepared as described in Example VIII wherein the core comprises 0.2 mg of clonidine and 60 mg of valsartan and the immediate release coating comprises 0.1 mg of clonidine and 20 mg of valsartan.
  • a clonidine/valsartan tablet is prepared as described in Example VIII wherein the core comprises 0.4 mg of clonidine and 120 mg of valsartan and the immediate release coating comprises 0.2 mg of clonidine and 40 mg of valsartan.
  • An oral dosage formulation in accordance with the present invention is prepared by: (I) forming an immediate release tablet core comprising 0.1 mg of clonidine, 30 mg of valsartan, lactose monohydrate, colloidal silicon dioxide and magnesium stearate; and optionally 25 mg of hydrochlorothiazide; (II) coating the immediate release tablet core with a controlled release coating comprising Eudragit S 100, Zein, acetyl tributyl citrate and talc; (III) applying an immediate release clonidine coating to the controlled release coating comprising 0.1 mg of clonidine, hydroxypropyl methycellulose, polyethylene glycol and talc; (IV) seal coating the immediate release clonidine coating with OPADRY® White YS-I-
  • a clonidine/valsartan tablet is prepared as described in Example XI wherein the core comprises 0.2 mg of clonidine and 60 mg of valsartan and the immediate release coatings comprises 0.1 mg of clonidine and 20 mg of valsartan.
  • a clonidine/valsartan tablet is prepared as described in Example XI wherein the core comprises 0.4 mg of clonidine and 120 mg of valsartan and the immediate release coating comprises 0.2 mg of clonidine and 40 mg of valsartan.
  • a transdermal formulation in accordance with the present invention is prepared by: combining 300 g of glycerol and 450 ml of water. This mixture is then heated to at least 70 0 C and then slowly add 15O g of polyvinylalcohol (PVA 100% hydro lyzed, molecular weight 115,000) and 80 g polyvinylpyrrolidone (mw 40,000) followed by continued heating up to 90 0 C. The mixture is stirred at 90 0 C until all components in the solution are fully dissolved. With larger quantities, a considerably longer period of time may be needed for heating.
  • PVA polyvinylalcohol
  • mw 40,000 polyvinylpyrrolidone
  • An aqueous liquid formulation in accordance with the present invention is prepared by: combining 300 g of glycerol and 450 ml of water. The mixture is stirred at 90 0 C until all components in the solution are fully dissolved. With larger quantities, a considerably longer period of time may be needed for heating. Next, 980 ml of the solution is mixed with 2 g of clonidine and 400 g of valsartan, and optionally 100 g of hydrochlorothiazide. This mixture is then mechanically stirred until homogeneous. The homogeneous mixture is then poured into individual aqueous solution containers.

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Abstract

La présente invention concerne une composition pharmaceutique comprenant un agoniste α2-adrénergique, un antagoniste de récepteur d’angiotensine II et facultativement un thiazide diurétique.
PCT/US2009/066176 2008-12-02 2009-12-01 Composition d’agoniste alpha2-adrénergique et d’antagoniste de récepteur d’angiotensine ii WO2010065489A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013098268A3 (fr) * 2011-12-26 2013-08-22 Novartis Ag Comprimés et agents enrobés à sec

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US20050182105A1 (en) * 2004-02-04 2005-08-18 Nirschl Alexandra A. Method of using 3-cyano-4-arylpyridine derivatives as modulators of androgen receptor function
US20060078604A1 (en) * 2004-10-08 2006-04-13 Noven Pharmaceuticals, Inc. Transdermal drug delivery device including an occlusive backing
WO2007081232A1 (fr) * 2006-01-13 2007-07-19 Bial- Portela & Ca, S.A. Melanges de medicaments
US20080020018A1 (en) * 2004-09-27 2008-01-24 Joey Moodley Combination Products

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Publication number Priority date Publication date Assignee Title
US20050013857A1 (en) * 2003-05-07 2005-01-20 Yourong Fu Highly plastic granules for making fast melting tablets
US20050182105A1 (en) * 2004-02-04 2005-08-18 Nirschl Alexandra A. Method of using 3-cyano-4-arylpyridine derivatives as modulators of androgen receptor function
US20080020018A1 (en) * 2004-09-27 2008-01-24 Joey Moodley Combination Products
US20060078604A1 (en) * 2004-10-08 2006-04-13 Noven Pharmaceuticals, Inc. Transdermal drug delivery device including an occlusive backing
WO2007081232A1 (fr) * 2006-01-13 2007-07-19 Bial- Portela & Ca, S.A. Melanges de medicaments

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013098268A3 (fr) * 2011-12-26 2013-08-22 Novartis Ag Comprimés et agents enrobés à sec

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