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WO1990008537A1 - Compositions pharmaceutiques administrees oralement - Google Patents

Compositions pharmaceutiques administrees oralement Download PDF

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Publication number
WO1990008537A1
WO1990008537A1 PCT/US1990/000721 US9000721W WO9008537A1 WO 1990008537 A1 WO1990008537 A1 WO 1990008537A1 US 9000721 W US9000721 W US 9000721W WO 9008537 A1 WO9008537 A1 WO 9008537A1
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WIPO (PCT)
Prior art keywords
oil
composition according
erythromycin
pyrrolidone
group
Prior art date
Application number
PCT/US1990/000721
Other languages
English (en)
Inventor
Akwete L. Adjei
Howard S. Cheskin
Madhu K. Vadnere
Eugene Bush
Edwin S. Johnson
Original Assignee
Abbott Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of WO1990008537A1 publication Critical patent/WO1990008537A1/fr

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Classifications

    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds

Definitions

  • This invention relates to liquid, solid or semisolid oral dosage forms for the administration of pharmaceutical compounds.
  • erythromycin antibiotics are highly effective against a variety of common pathogens and achieve high concentrations in tissues at infection sites, which further enhances their activity against intracellular pathogens, such as legionella.
  • difficulty is experienced in achieving adequate bioavailability when administering these drugs orally due to their extremely bitter taste, their limited solubility in water, their susceptibility to acid degradation in the alimentary tract, and other factors well known to pharmaceutical chemists.
  • Peptides ' also have poor bioavailability when administered by nonparenteral routes due to their poor- permeability through biological membranes. This may be due to their large molecular size and their susceptibility to enzymatic or hydrolytic degradation in body fluids. Peptides are also readily ionizable.
  • N-methyl—2-pyrrolidone containing solvent systems for promoting percutaneous absorption of topical formulations discloses aerosol formulations of luteinizing hormone releasing hormone (LHRH) polypeptides that contain lipophilic counterions as solubilizing agents.
  • LHRH luteinizing hormone releasing hormone
  • the present invention relates to pharmaceutical compositions for oral administration.
  • compositions for the oral administration of pharmaceutical compounds that comprise a therapeutically effective amount of a pharmaceutical compound, an organic solvent and an oil in a capsule.
  • the compositions of the present invention may contain pharmaceutical compounds having ionizable groups such as free amines in peptides.
  • the formulation may also contain a stabilizing agent, a lipophilic counterion and a surfactant.
  • the compositions of the present invention may also contain membrane penetrants, preservatives, emulsifiers, flavoring and coloring agents, antioxidants and buffers.
  • FIGURE 1 is a graph that plots plasma LH response versus dose and compares a leuprolide composition of the present invention to intravenous and intraduodenal saline solutions of leuprolide.
  • FIGURE 2 is a graph that plots plasma concentration versus time and compares a tosufloxacin composition of the present invention to a conventional capsule composition;
  • FIGURE 3 is a graph that plots plasma concentration versus time and compares a progesterone composition of the present invention to a conventional tablet composition
  • FIGURE 4 is a graph that plots plasma concentration versus time and compares erythromycin compositions of the present invention to a conventional oral dosage form of erythromycin.
  • compositions of the present invention comprise a therapeutically effective amount of a pharmaceutical compound, an organic solvent, and an oil.
  • the compositions of the present invention may also contain a stabilizing agent, a lipophilic counterion and a surfactant.
  • the term "pharmaceutical compound” is intended to include any poorly absorbed drug such as antibiotics, as for example, erythromycin, doxorubicin, gentamicin or tosufloxacin and its salts such as tosylate, methane sulfonate, sulfate, and HC1; steroids, as for example dexamethasone; peptides, as for example, human growth hormone, bovine growth hormone including hormones, such as progesterone (which is also a steroid) , or LHRH analogs such as
  • peptidomimetics for example, captopril, enalapril, and morphine
  • renin inhibitors as for example, the H-((beta, beta-dimethyl)-beta-Ala)-(4-OCH 3 )-Phe-H
  • erythromycin When any of these drugs is utilized, it is intended to include the free base and its pharmaceutically acceptable salts, esters and derivatives.
  • erythromycin when used, it is intended to include the erythromycin 9-oximes, erythromycin 11,12-cyclic carbonates and 4'-deoxy-ll,12-carbonates, 6-0-methyl-, 11-0-methyl-, and 6,ll-di-0-methyl erythromycin, 8-fluoroerythromycin, erythromycin 11,12-cyclic carbamates, erythromycin 4'-carbamates, and compounds having various combinations of these structural modifications, as well as their pharmaceutically acceptable salts and esters.
  • peptide includes molecules built of amino acid building blocks which are linked together by amide bonds.
  • peptidomimetic includes those molecules which mimic the actions of a peptide but are not comprised of natural amino acid building blocks or do not contain amide bonds.
  • oil is intended to include triglyceride oils and other edible oils.
  • triglyceride oil is intended to include triglycerides which are liquid at room temperature (22°C) and consist primarily of triglycerides of C g to C, g fatty acids such as capric, caproic, caprylic, stearic, palmitic, lauric, margaric, linoleic, linolenic and myristic acid. Oils such .as olive oil and vegetable oil may be used as a source of triglyceride oils.
  • lipophilic counterion is intended to include organic acids or their salts having a pKa sufficiently low to render them ionizable at the formulation's pH. These acids include oleic acid, alkyl sulfonic acids, bile acids, salicylic acid, palmitic acid, and other aliphatic acids.
  • surfactant is intended to include nonionic surfactants such as mono and diglycerides, sorbitan fatty acid esters and ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitan esters and ethers, polyoxyethylene acids, polyoxyethylene alcohols and polyoxyethylene adducts.
  • stabilizing agent is intended to include polyelectrolytes such as polyethylene glycol, propylene glycol, sorbitol and glycerine.
  • the preferred organic solvent is 2-pyrrolidone or N-methyl-2-pyrrolidone.
  • alkyl is used to mean C.-Cg straight and branched chain radicals, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
  • compositions of the present invention will generally contain the following relative amounts of ingredients:
  • compositions of the present invention are from about 1 to 25 weight percent pharmaceutical compound, 10 to 40 weight percent organic solvent, 30 to 80 weight percent oil, 15 to 25 weight percent stabilizing agent, and when the pharmaceutical compound has ionizable groups such as a free amine, 0.5 to 5 weight percent lipophilic counterion and 1 to 10 weight percent surfactant.
  • compositions of the present invention can be utilized in soft or hard gelatin capsules.
  • the capsules can be coated with a polymer such as cellulose acetate phthalate or hydroxypropylmethyl cellulose phthalate to resist the acidity of the stomach.
  • compositions of the present invention can also be utilized in a variety of microencapsulation methods, as for example in the method described in CHEMTECH, Vol. 4, October, 1974, pp 623-636.
  • the capsule compositions of this invention may also desirably contain minor and pharmaceutically acceptable amounts of emulsifiers, flavoring and coloring agents, antioxidants, preservatives, buffers and like materials well known to the pharmaceutical chemist.
  • an especially preferred additive in the compositions of this invention is an essential oil. While not intending to be limited by theory, it appears that the inclusion of an essential oil or penetrant in the formulation alters the biokinetics of the dosage form, favoring more prompt absorption of the active drug. The result is an earlier and higher peak blood level for the drug and sustained subsequent blood levels.
  • Preferred for use in the compositions of this invention are essential oils having from 6 to 12 carbon atoms, preferably from 8 to 12 carbon atoms.
  • Such essential oils include, but are not limited to, eucalyptol, spearmint oil, peppermint oil, cinnamon oil, geraniol, geraniol acetate, and their synthetic equivalents.
  • the essential oil will preferably be incorporated in the compositions of this invention in an amount of about 25 g. to about 750 mg., more preferably about 100 mg. to about 300 mg. , most preferably about 150 mg. oil of peppermint per capsule.
  • the capsule compositions of this invention will also preferably contain a pharmaceutically acceptable alcohol solvent for the combination, particularly if oil of peppermint is included in the composition.
  • the triglyceride oils of mid-chain fatty acids is represented by those oils which consist predominantly of glycerol triesters of C g to C, Q fatty acids.
  • oils can be prepared synthetically by well known techniques, or can be obtained from natural sources by known techniques of thermal or solvent fractionation of suitable natural oils, such as palm oil, to yield a fraction rich in the desired low-melting triglycerides.
  • Such mid-chain fatty acid triglycerides are especially preferred because they have high solubility in and high absorptivity from digestive secretions, so that they improve dispersibility and absorption of the active drug compared with relatively high melting point triglyceride oils having substantial amounts of esters of C,.
  • a preferred low melting, low molecular weight triglyceride oil is a low molecular weight fraction of palm oil which is rich in mixed esters of caprylic (octanoic) and capric (decanoic) acids.
  • Such an oil is commercially available as NEOBEE® M-5 oil from PVO International, Inc. of Boonton, New Jersey. Other low melting cuts of palm oil are also suitable.
  • triglyceride oils consists of triglyceride oils having a high percentage of glycerol triesters of unsaturated or polyunsaturated C c to C. réelle fatty acids.
  • a preferred example of such an oil is safflower oil, which typically has a fatty acid composition of over 90% oleic and linoleic acids or olive oil which has a glyceride composition of about 83.5% oleic acid, 9.4% palmitic acid, 4.0% linoleic acid, 2.0% stearic acid and 0.9% arachidic acid.
  • Triglycerides of these acids are liquid at 20°C, while the corresponding saturated triglyceride tristea in is a waxy solid at room temperature and melts at about 72°C.
  • Other low-melting vegetable oils or low-melting fractions of such oils obtained by conventional thermal or solvent fractionation are also suitable. While such unsaturated or polyunsaturated vegetable oils may offer a cost advantage in formulating compositions according to this invention, they also exhibit a greater tendency to oxidative deterioration, and may require the addition of oil soluble antioxidants, such as tocopherol ⁇ .
  • oils are typically absorbed from the gastrointestinal tract in the form of chylomicrons, which may slow ultimate delivery of the active drug to the blood stream and thereby aid in the maintenance of sustained blood levels.
  • the triglyceride oil may contain minor amounts of mono- and/or diglycerides to enhance solubility of the components or to enhance emulsification.
  • the oil may have a low polarity.
  • the preferred triglyceride oils will be low in content of mono- and diglycerides, as well as phospholipids, all of which have significant polarity.
  • Another component of a preferred embodiment of the present invention is a stabilizing agent, of which polyethylene glycol, propylene glycol, sorbitol and glycerine are examples. These polyelectrolytes may be added in an amount sufficient to improve the organoleptic qualities of the inventive composition. In particular, improvements in composition texture, dispersion integrity and viscosity may be obtained by the use of stablizing agents. Such agents may additionally provide steric stabilization of colloidal suspensions and, when a composition exhibits turbidity, may be used to improve clarity.
  • the ingredients of the compositions of the present invention can be incorporated into capsules in amounts well known to those of ordinary skill in the art.
  • the triglyceride oil is preferably incorporated in the dosage forms of this invention in an amount of from about 75 mg. per capsule to about 750 mg. per capsule, more preferably about 200 mg. per capsule to about 500 mg. per capsule, most preferably about 300 mg. triglyceride oil per capsule containing, for example, about 250 mg. erythromycin base.
  • N-methyl-2-pyrrolidone is incorporated into the composition preferably in an amount of from about 100 mg. to about 600 mg. per capsule, more preferably from about 150 mg. to about 300 mg. per capsule, most preferably about 200 mg. N-methyl-2-pyrrolidone per capsule containing, for example, about 250 mg. erythromycin base. While not intending to be limited by theory, it is understood that the function of the N-methyl-2-pyrrolidone is to compensate for differences in polarity between the erythromycin antibiotic and the triglyceride oil solvent. In addition to promoting compatibility in the mixture, this compensation permits the erythromycin antibiotic to appear to cell membranes to be more solvent-like in character. Since the triglyceride oil solvent has good membrane permeability, this effect appears to enhance the membrane permeability of the erythromycin antibiotic, and thus improve bioavailability.
  • Soft gelatin capsules of erythromycin base according to this invention are made as follows:
  • erythromycin base As the mondhydrate, and the combination is mixed slowly until the erythromycin is completely dissolved, and then another 185.59 grams of erythromycin base monohydrate (to a total of 365.59 grams) is added. The solution is again mixed slowly until the erythromycin is completely dissolved, and then stirred at moderate speed until the solution is uniform. The resulting composition is- assayed for potency and will yield approximately 1000 capsules containing 333 mg. erythromycin base each.
  • a suitable polymer selected for its pH-dependent solubility is applied to the capsules. Selection and application of such polymer coatings is well known to the industrial pharmacist and by itself forms no part of the present invention. For example, in a typical procedure, 30 grams of hydroxypropylmethylcellulose phthalate (HPMCP) Type 55 is dissolved in 190 proof ethanol and U.S.P. purified water (distilled) . An appropriate plasticizer for the HPMCP, such as 6 grams castor oil, is added to the solution with thorough mixing. The resulting mixture is applied to the capsules as prepared above in an air suspension coater at a rate of approximately 1 liter of enteric coating solution per kilogram of capsules. The coated capsules are then dried, inspected and packaged.
  • HPCP hydroxypropylmethylcellulose phthalate
  • HPMCP hydroxypropylmethylcellulose phthalate
  • An appropriate plasticizer for the HPMCP such as 6 grams castor oil
  • Formulations A and B were prepared in the general manner of EXAMPLE 1.
  • Formulation C was a commercially available erythromycin tablet product providing good bioavailability.
  • Formulations A and B were prepared by the procedure described in EXAMPLE 1.
  • Formulation C is available from Abbott Laboratories.
  • AUC The area under the plasma level versus time curve (area under the curve).
  • composition was prepared that contained the following ingredients:
  • the leuprolide acetate was dissolved in a small amount of water-alcohol mixture containing oleic acid. Surfactant was added and carefully mixed until a uniform colloidal dispersion was formed. This dispersion was added to a flask containing N-methyl-2-pyrrolidone and olive oil and mixed until a uniform dispersion was formed.
  • composition was evaluated against saline solutions of leuprolide acetate by a procedure in which male Sprague/Dawley rats (about 200g) were castrated and shipped 3 weeks post surgery. These rats were used at about 5 weeks after surgery, at approximately 350-450g body weight, and had 10- to 20-fold elevated basal plasma luteinizing hormone (LH) levels compared to intact rats.
  • LH basal plasma luteinizing hormone
  • Compounds were administered as a single bolus dose by the intravenous (jugular), intraduodenal, and oral routes under light ether anesthesia. Plasma LH concentration was determined by a radio-immunoassay procedure (RIA) as described below.
  • RIA radio-immunoassay procedure
  • the bleeding schedule was adjusted to include an additional early bleeding at 10 minutes, and terminated at 180 minutes.
  • Compounds were administered intravenously and intraduodenally, and the concentration of compound was determined in timed blood samples by RIA.
  • the areas under the blood level vs time curves were calculated for both routes, and the intraduodenal bioavailability calculated with the equation:
  • AUC Dose F ID x IV x 100
  • 100 uL of the diluted sample (containing 15 uL plasma) was diluted to 400 uL with Medium 199 buffer (Medium 199, Hepes 10 mM pH adjusted to 7.4 with sodium hydroxide, bovine serum albumin 0.3%, gentamicin
  • 125 I-LH (20000 cpm) and 100 uL antibody. The mixture was incubated overnight (18-24 hours) at 4°C. 200 uL of NRS/PBS was added to the mixture, followed by 75 uL of goat-antirabbit antibody. After 4 hours at 4°C, antibody-bound 125I-LH was precipitated by centrifugation at 2300 rcf for 20 minutes, and. counted by gamma spectroscopy. Each sample was assayed in triplicate. The sensitivity of the assay was 50 picograms (pg) per tube, and range was 50 to 6000 pg. Plasma LH responses, which appear to be log-normally distributed, have been summarized an an integrated response over time (log[response LH
  • Leuprolide was labelled with 1 -2 * "5 ⁇ ⁇ _ via Chloramme-T oxidation and purified via ion exchange chromatography.
  • the RIA was conducted in a similar manner to the LH RIA, but 125 5
  • FIGURE 1 is a graph that plots plasma LH response versus dose and compares a leuprolide composition of the present invention to intravenous and intraduodenal saline solutions of leuprolide.
  • compositions containing leuprolide acetate were further prepared using the formulations shown below, and were tested on dogs, monkeys and rats as shown in TABLES 4-6.
  • Formulation C was found to be especially representative of the leuprolide- containing compositions of the present invention.
  • Emulphor® EL719 10.00 ml olive oil q.s. to 100 ml
  • Emulphor® EL719 10.00 ml olive oil q.s. to 100 ml
  • compositions were tested for bioavailability using procedures identical or comparable to those of EXAMPLE 3, above.
  • inventive compositions were administered intraduodenally (ID) to rats via direct injection using a 30 gauge needle, and to dogs and monkeys via endoscope.
  • ID intraduodenally
  • TABLES 4-6 show the results obtained in dogs, monkeys and rats, respectively.
  • FIGURE 2 is a graph that plots plasma concentration versus time and compares a tosufloxacin composition of the present invention to a conventional tablet formulation which is an encapsulated form of tosufloxacin tosylate powder.
  • the tosufloxacin composition contained the following ingredients:
  • the tosylate salt of tosufloxacin was added to N-methyl-2-pyrrolidone and mixed for approximately five minutes until completely dissolved, then the total volume was brought up to the desired volume.
  • Capsules were prepared from this composition and.from a control formulation which contained only powdered tosufloxacin tosylate.
  • the capsules which contained sufficient quantities of each tosufloxacin formulation to deliver approximately 14.27 mg/kg of tosufloxacin tosylate were administered to beagle dogs.
  • the dogs were fasted for at least twelve hours and given a histamine pretreatment of 0.1 mg/kg of a 1.0 mg/ml solution to stimulate gastric activity.
  • Blood sampling was done at 0, 1, 2, 3, 4, 5, 6, 8, 12 and 24 hours after capsule administration.
  • 2.5 ml plasma samples were heparinized and assayed microbiologically by a procedure in which an appropriate quantity of a sterilized Antibiotic Medium containing:
  • the seeded medium is evenly dispensed into the desired number of sterile plastic petri dishes (243 x 243 x 18 mm) 90 to 100 ml/plate and the plates are set to harden on a level bench top. They are then inverted and refrigerated for a minimum of 30 minutes until ready to use.
  • the assay plates are spiked with plasmas containing known and unknown concentrations of tosufloxacin and are then incubated at 30°C + 2°C overnight.
  • the zones of inhibition are measured to the nearest 0.5 mm by the Optomax Zone Reader (Optomax, Inc.).
  • the data are transferred to the DEC-10 computer in random order and plasma calculations are made.
  • FIGURE 2 demonstrates the improvements in plasma concentration achieved by the tosufloxacin compositions of the present invention.
  • FIGURE 3 is a graph that plots plasma concentration versus time and compares a progesterone composition of the present invention versus a commercial capsule composition which was used as a control.
  • the progesterone formulation of the present invention contains the following ingredients:
  • the progesterone formulation of the present invention was prepared by adding ethyl alcohol to the Neobee oil and mixing until uniform.
  • the N-methyl-2-pyrrolidone was mixed into the emulphor in a separate container until uniform.
  • the progesterone was then added to the N-methyl-2-pyrrolidone solution and mixed until it dissolved.
  • the alcohol-Neobee mixture was then added to the progesterone solution and mixed well to form a uniform homogeneous solution. Appropriate amounts of this progesterone solution were filled into gelatin capsules so that each capsule contained 100 mg progesterone.
  • FIGURE 4 is a graph that plots plasma concentration versus time data generated in male beagle dogs and compares erythromycin compositions of the present invention with and without peppermint oil versus particle coated erythromycin (PCE®) , an oral dosage form of erythromycin.
  • PCE® particle coated erythromycin
  • This graph demonstrates the improvements in plasma concentration achieved by the erythromycin compositions of the present invention.
  • a leuprolide composition was prepared using ethyl alcohol as the organic solvent and following the general procedure described in EXAMPLE 1.
  • the composition contained the following ingredients:
  • Neobee® oil 49.90 gm. ethanol 43.50 gm. oleic acid 0.80 gm. surfactant (Emulphor®) 5.00 gm.

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  • Life Sciences & Earth Sciences (AREA)
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Abstract

L'invention concerne des formulations orales améliorées pour l'administration de composés pharmaceutiques, comprenant une quantité thérapeutiquement efficace d'un composé pharmaceutique, d'un solvant organique et d'une huile. On peut également inclure des contre-ions lipophiles, des agents de stabilisation et des tensio-actifs.
PCT/US1990/000721 1989-02-06 1990-02-06 Compositions pharmaceutiques administrees oralement WO1990008537A1 (fr)

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US30738589A 1989-02-06 1989-02-06
US307,385 1989-02-06

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Cited By (24)

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EP0592904A1 (fr) * 1992-10-10 1994-04-20 Röhm Pharma GmbH Formulations stables à utilisation topique avec un bon pouvoir de libération de l'agent actif et contenant au moins un antibiotique macrolide lipophilisé
WO1995005807A1 (fr) * 1993-08-20 1995-03-02 Novo Nordisk A/S Nouveau produit pharmaceutique destine a etre administre par voie orale et comprenant de la progesterone, un polyethylene glycol ainsi qu'un excipient
US5559110A (en) * 1994-03-09 1996-09-24 The Dupont Merck Pharmaceutical Company Pharmaceutical formulations of cyclic urea type compounds
EP0831870A1 (fr) * 1995-06-07 1998-04-01 Avmax, Inc. Utilisation d'huiles essentielles pour accroitre la biodisponibilite des composes pharmaceutiques oraux
US5981474A (en) * 1992-10-14 1999-11-09 University Technology Corporation Solubilization of pharmaceutical substances in an organic solvent and preparation of pharmaceutical powders using the same
US6121234A (en) * 1995-06-07 2000-09-19 Avmax, Inc. Use of essential oils to increase bioavailability of orally administered pharmaceutical compounds
US6258808B1 (en) 1991-06-27 2001-07-10 Novartis Ag Pharmaceutical composition
US6420355B2 (en) 1992-09-25 2002-07-16 Novartis Ag Pharmaceutical compositions containing cyclosporins
US6475519B1 (en) 1997-01-30 2002-11-05 Novartis Ag Oil-free pharmaceutical compositions containing cyclosporin A
US6486124B2 (en) 1994-11-03 2002-11-26 Novartis Ag Cyclosporin compositions and process therefor
US6582718B2 (en) 1992-05-13 2003-06-24 Novartis Ag Cyclosporin compositions
WO2003106382A2 (fr) * 2002-06-13 2003-12-24 Lyotropic Therapeutics, Inc. Phases cristallines liquides inversees comprenant des agents hydrophobes paraffiniques
US6919370B2 (en) 2000-11-28 2005-07-19 Transform Pharmaceuticals, Inc. Pharmaceutical formulations comprising paclitaxel, derivatives, and pharmaceutically acceptable salts thereof
US6951841B2 (en) 1995-11-29 2005-10-04 Novartis Ag Pharmaceutical compositions of macrolides or cyclosporine with a polyethoxylated saturated hydroxy-fatty acid
US7122204B2 (en) 2000-02-24 2006-10-17 Advancis Pharmaceutical Corporation Antibiotic composition with inhibitor
US7282221B2 (en) 2000-10-13 2007-10-16 Middlebrook Pharmaceuticals, Inc. Antiviral product, use and formulation thereof
WO2012013331A3 (fr) * 2010-07-26 2012-06-28 Gp-Pharm, S.A. Capsules d'ingrédients pharmaceutiques actifs et d'acides gras polyinsaturés pour le traitement de maladies de la prostate
US8303988B2 (en) 2000-10-13 2012-11-06 Shionogi Inc. Antifungal once-a-day product, use and formulation thereof
EP2739288A2 (fr) * 2011-08-05 2014-06-11 Lipocine Inc. Formes de posologie orale contenant de la progestérone et procédés associés
US8889187B2 (en) 2000-02-24 2014-11-18 Shionogi Inc. Once a day amoxicillin product comprising immediate and delayed release dosage forms
US9144548B2 (en) 2003-08-12 2015-09-29 Shionogi Inc. Antibiotic product, use and formulation thereof
US9358298B2 (en) 2011-07-28 2016-06-07 Lipocine Inc. 17-hydroxyprogesterone ester containing oral compositions and related methods
US9375437B2 (en) 2010-06-18 2016-06-28 Lipocine Inc. Progesterone containing oral dosage forms and kits
US11590147B2 (en) 2015-06-22 2023-02-28 Lipocine Inc. 17-hydroxyprogesterone ester-containing oral compositions and related methods

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USRE32534E (en) * 1982-10-27 1987-10-27 Amano Pharmaceutical Co., Ltd. Peptides, process for preparing the same and psychodepressant compositions containing the same
US4857506A (en) * 1987-01-12 1989-08-15 American Cyanamid Company Sustained release growth hormone compositions for parenteral administration and their use

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US4150128A (en) * 1976-03-15 1979-04-17 Jasionowski Edward A Method of treating atrophic vulvar dystrophy
USRE32534E (en) * 1982-10-27 1987-10-27 Amano Pharmaceutical Co., Ltd. Peptides, process for preparing the same and psychodepressant compositions containing the same
US4612364A (en) * 1984-10-05 1986-09-16 Takeda Chemical Industries Method for producing formed product of high molecular compounds
US4857506A (en) * 1987-01-12 1989-08-15 American Cyanamid Company Sustained release growth hormone compositions for parenteral administration and their use

Cited By (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6844459B2 (en) 1991-06-27 2005-01-18 Novartis Ag Pharmaceutical Composition
US6258808B1 (en) 1991-06-27 2001-07-10 Novartis Ag Pharmaceutical composition
US6582718B2 (en) 1992-05-13 2003-06-24 Novartis Ag Cyclosporin compositions
US6262022B1 (en) 1992-06-25 2001-07-17 Novartis Ag Pharmaceutical compositions containing cyclosporin as the active agent
US6420355B2 (en) 1992-09-25 2002-07-16 Novartis Ag Pharmaceutical compositions containing cyclosporins
US5476843A (en) * 1992-10-10 1995-12-19 Roehm Pharma Gmbh Stable topical formulations with good active ingredient release characteristics, containing at least one lipophilized macrolide antibiotic
US5559098A (en) * 1992-10-10 1996-09-24 Roehm Pharma Gmbh Stable topical formulations with good active ingredient release characteristics, containing at least one lipophilized macrolide antibiotic
EP0592904A1 (fr) * 1992-10-10 1994-04-20 Röhm Pharma GmbH Formulations stables à utilisation topique avec un bon pouvoir de libération de l'agent actif et contenant au moins un antibiotique macrolide lipophilisé
US5981474A (en) * 1992-10-14 1999-11-09 University Technology Corporation Solubilization of pharmaceutical substances in an organic solvent and preparation of pharmaceutical powders using the same
WO1995005807A1 (fr) * 1993-08-20 1995-03-02 Novo Nordisk A/S Nouveau produit pharmaceutique destine a etre administre par voie orale et comprenant de la progesterone, un polyethylene glycol ainsi qu'un excipient
US5559110A (en) * 1994-03-09 1996-09-24 The Dupont Merck Pharmaceutical Company Pharmaceutical formulations of cyclic urea type compounds
US6486124B2 (en) 1994-11-03 2002-11-26 Novartis Ag Cyclosporin compositions and process therefor
US6121234A (en) * 1995-06-07 2000-09-19 Avmax, Inc. Use of essential oils to increase bioavailability of orally administered pharmaceutical compounds
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