US20110065800A1 - Formulations for cathepsin k inhibitors - Google Patents
Formulations for cathepsin k inhibitors Download PDFInfo
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- US20110065800A1 US20110065800A1 US12/992,124 US99212409A US2011065800A1 US 20110065800 A1 US20110065800 A1 US 20110065800A1 US 99212409 A US99212409 A US 99212409A US 2011065800 A1 US2011065800 A1 US 2011065800A1
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- Prior art keywords
- cathepsin
- inhibitor
- leucinamide
- cyanocyclopropyl
- trifluoro
- Prior art date
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- ROOUTIXDLXPRAM-UPVQGACJSA-N C#CC1(CC(=O)[C@H](CC(C)(C)F)N[C@@H](C2=CC=C(C3=CC=C(S(C)(=O)=O)C=C3)C=C2)C(F)(F)F)CC1 Chemical compound C#CC1(CC(=O)[C@H](CC(C)(C)F)N[C@@H](C2=CC=C(C3=CC=C(S(C)(=O)=O)C=C3)C=C2)C(F)(F)F)CC1 ROOUTIXDLXPRAM-UPVQGACJSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K31/42—Oxazoles
- A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K9/10—Dispersions; Emulsions
-
- 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
-
- 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
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- A61K31/275—Nitriles; Isonitriles
-
- 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
Definitions
- This invention relates to formulations of cathepsin K inhibitors.
- cathepsin K inhibitors have been disclosed for the treatment of various disorders related to cathepsin K functioning, including osteoporosis, glucocorticoid induced osteoporosis, Paget's disease, abnormally increased bone turn over, tooth loss, bone fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, atherosclerosis, obesity, glaucoma, chronic obstructive pulmonary disease and cancer including metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma.
- Representative examples of cathepsin K inhibitors include those disclosed in International Publication WO03/075836, which published on Sep. 18, 2003, to Merck & Co., Inc. & Axys Pharmaceuticals, which is hereby incorporated by reference in its entirety.
- Cathepsin K inhibitors can be formulated for oral dosing as tablets, by using a direct compression, wet granulation or roller compaction method.
- cathepsin K inhibitors can be formulated for oral dosing as gelatin capsules, being a liquid in a soft capsule, or dry powder or semi-solid in a hard capsule.
- cathepsin K inhibitors can be formulated for intravenous dosing.
- the formulations of the instant invention have advantages over other formulations of cathepsin K inhibitors. Specifically, the formulations of the instant invention significantly improve the absorption of the cathepsin K inhibitor. The formulations of the instant invention also improve the bioavailability of the cathepsin K inhibitor and reduce the variability in exposure. Exposure can vary due to many factors, including whether the cathepsin K inhibitor is taken with or without food.
- the instant invention relates to pharmaceutical compositions containing cathepsin K inhibitors.
- the cathepsin K inhibitor solid dispersion formulations of the present invention are made by spray drying or hot melt extrusion processes.
- the cathepsin K inhibitor is combined with a polymer, thus forming an amorphous system after spray drying.
- the spray dried amorphous systems are made by combining 10-20% of the cathepsin K inhibitor with 80-90% polymer.
- the amorphous system is then combined with excipients to form tablets, or combined with water to form a suspension. Also disclosed are processes for making said pharmaceutical compositions.
- the cathepsin K inhibitor solid dispersion formulations of the present invention are made by spray drying or hot melt extrusion processes.
- the cathepsin K inhibitor is combined with a polymer, thus forming an amorphous system after spray drying.
- the spray dried amorphous systems are made by combining 10-20% of the cathepsin K inhibitor with 80-90% polymer.
- the amorphous system is then combined with excipients to form tablets, or combined with water to form a suspension.
- a particularly effective cathepsin K inhibitor is N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 - ⁇ (1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl ⁇ -L-leucinamide,
- the invention contemplates the use of any pharmaceutically acceptable fillers/compression aids, disintegrants, super-disintegrants, lubricants, binders, surfactants, film coatings, and solvents. Examples of these components are set forth below and are described in more detail in the Handbook of Pharmaceutical Excipients, Second Edition, Ed. A. Wade and P. J. Weller, 1994, The Pharmaceutical Press, London, England.
- the instant invention comprises a pharmaceutical composition
- a pharmaceutical composition comprising from about 1% to 95% by weight of an amorphous cathepsin K inhibitor system, or a pharmaceutically acceptable salt thereof, and from about 5% to 99% by weight of excipients comprising a diluent, a glidant, a lubricant, a surfactant and a disintegrant.
- a pharmaceutical composition comprising from about 44% to 57% by weight of an amorphous cathepsin K inhibitor system, or a pharmaceutically acceptable salt thereof, and from about 43% to 66% by weight of excipients comprising a diluent, a glidant, a lubricant, a surfactant and a disintegrant.
- a pharmaceutical composition comprising about 50.0% by weight of an amorphous cathepsin K inhibitor system, or a pharmaceutically acceptable salt thereof, and about 50.0% by weight of excipients comprising a diluent, a polymer, a glidant, a lubricant, a surfactant and a disintegrant.
- the amorphous cathepsin K inhibitor system comprises a cathepsin K inhibitor and a polymer.
- examples of the amorphous cathepsin K inhibitor systems of the instant invention include the spray dried material and the hot melt extrusion material.
- the cathepsin K inhibitor is N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 - ⁇ (1S)-2,2,2-trifluoro-1-[4′-(methyl sulfonyl)-1,1′-biphenyl-4-yl]ethyl ⁇ -L-leucinamide, or a pharmaceutically acceptable salt thereof.
- the polymer is hydroxypropyl methylcellulose acetate succinate (abbreviated as “HPMCAS”), copovidone (for example, Kollidon VA64), cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinylacetatephthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, methyl acrylate-methacrylic acid copolymer, methacrylate-methacrylic or acid-octyl acrylate copolymer.
- HPMCAS hydroxypropyl methylcellulose acetate succinate
- copovidone for example, Kollidon VA64
- cellulose acetate phthalate cellulose acetate succinate
- methylcellulose phthalate ethylhydroxycellulose phthalate
- polyvinylacetatephthalate polyvinylacetatephthalate
- HPMCAS can be selected from HPMCAS-HF, HPMCAS-MF or HPMCAS-LF.
- HPMCAS-HF has an acetyl content of 10.0-14.0%, a succinoyl content of 4.0-8.0%, a methoxyl content of 22.0-26.0% and a hydroxypropoxyl content of 6.0-10.0%, with an average particle size of not more than 10 ⁇ m (available from ShinEtsu).
- HPMCAS-MF has an acetyl content of 7.0-11.0%, a succinoyl content of 10.0-14.0%, a methoxyl content of 21.0-25.0% and a hydroxypropoxyl content of 5.0-9.0%, with an average particle size of not more than 10 ⁇ m (available from ShinEtsu).
- HPMCAS-LF has an acetyl content of 5.0-9.0%, a succinoyl content of 14.0-18.0%, a methoxyl content of 20.0-24.0% and a hydroxypropoxyl content of 5.0-9.0%, with an average particle size of not more than 10 ⁇ m (available from ShinEtsu).
- the polymer is HPMCAS-HF.
- the amorphous cathepsin K inhibitor system comprises 10-20% of the cathepsin K inhibitor and 80-90% polymer. In a class of the invention, the amorphous cathepsin K inhibitor system comprises 10% of the cathepsin K inhibitor and 90% polymer. In another class of the invention, the amorphous cathepsin K inhibitor system comprises 15% of the cathepsin K inhibitor and 85% polymer. In another class of the invention, the amorphous cathepsin K inhibitor system comprises 20% of the cathepsin K inhibitor and 80% polymer.
- the cathepsin K inhibitor comprises 5.0 to 8.334% of the total tablet formulation. In a class of the invention, the cathepsin K inhibitor comprises 5.0% of the total tablet formulation. In another class of the invention, the cathepsin K inhibitor comprises 6.667% of the total tablet formulation. In another class of the invention, the cathepsin K inhibitor comprises 6.675% of the total tablet formulation. In another class of the invention, the cathepsin K inhibitor comprises 7.5% of the total tablet formulation.
- the diluents are selected from the group consisting of spray-dried lactose, lactose anhydrous, lactose monohydrate, mannitol, microcrystalline cellulose, calcium phosphate, calcium carbonate, magnesium carbonate and starch. In a class of the embodiment, the diluent is spray-dried lactose.
- the glidant, or flow aid is silicone dioxide, colloidal silica, talc or starch.
- the glidant is silicone dioxide.
- the lubricant is magnesium stearate, stearic acid or sodium stearyl fumerate. In a class of the embodiment, the lubricant is magnesium stearate.
- the surfactant is sodium laurel sulfate, ammonium lauryl sulfate, another alkyl sulfate salt or poloxamer.
- the disintegrant is croscarmellose sodium, starch, crospovidone, sodium starch glycolate or any mixtures thereof.
- the disintegrant is croscarmellose sodium.
- the instant invention further comprises a method of improving the absorption of a cathepsin K inhibitor by combining the cathepsin K inhibitor with a polymer to form an amorphous system.
- the cathepsin K inhibitor is N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 - ⁇ (1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl ⁇ -L-leucinamide, and the polymer is HPMCAS-HF.
- the instant invention further comprises a method of reducing a food effect observed when dosing a cathepsin K inhibitor by combining the cathepsin K inhibitor with a polymer to form an amorphous system.
- the cathepsin K inhibitor is N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 - ⁇ (1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl ⁇ -L-leucinamide
- the polymer is HPMCAS-HF.
- the instant invention further comprises a method of reducing variation in absorption observed when dosing a cathepsin K inhibitor by combining the cathepsin K inhibitor with a polymer to form an amorphous system.
- the cathepsin K inhibitor is N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 - ⁇ (1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl ⁇ -L-leucinamide
- the polymer is HPMCAS-HF.
- the pharmaceutical tablet compositions of the present invention may also contain one or more additional formulation ingredients that may be selected from a wide variety of excipients known in the pharmaceutical formulation art. According to the desired properties of the tablet, any number of ingredients may be selected, alone or in combination, based upon their known uses in preparing tablet compositions.
- additional formulation ingredients include, but are not limited to, diluents, binders, compression aids, disintegrants, lubricants, glidants, stabilizers (such as dessicating amorphous silica), flavors, flavor enhancers, sweeteners, preservatives, colorants and coatings.
- tablette as used herein is intended to encompass compressed pharmaceutical dosage formulations of all shapes and sizes, whether uncoated or coated. Substances which may be used for coating include hydroxypropylmethylcellulose, hydroxypropylcellulose, titanium dioxide, talc, sweeteners and colorants.
- compositions of the present invention are useful in the therapeutic or prophylactic treatment of disorders associated with cathepsin K functioning.
- disorders include: osteoporosis, glucocorticoid induced osteoporosis, Paget's disease, abnormal bone disease, tooth loss, bone fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, atherosclerosis, obesity, glaucoma, chronic obstructive pulmonary disease and cancer, including metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma.
- the tablets were prepared by a dry granulation process.
- the N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 - ⁇ (1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl ⁇ -L-leucinamide is combined with HPMC-AS-HF to form the spray dried material.
- the spray dried material was then blended with lactose, Croscarmellose sodium, cab-O-Sil and 1 ⁇ 2 of magnesium stearate and then dry granulated using a roller compaction equipment.
- the ribbon from the compaction was milled through a 1 mm screen.
- the milled granulation was blended for five minutes with the remaining of magnesium stearate.
- the 50 mg tablets were prepared using a tablet machine.
- the tablets were prepared by a dry granulation process.
- the N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 - ⁇ (1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl ⁇ -L-leucinamide is combined with HPMCAS-HF to form the spray dried material.
- the spray dried material was then blended with lactose, Croscarmellose sodium, sodium laurel sulfate, cab-O-Sil and 1 ⁇ 2 of magnesium stearate and then dry granulated using a roller compaction equipment.
- the ribbon from the compaction was milled through a 1 mm screen.
- the milled granulation was blended for five minutes with the remaining of magnesium stearate.
- the 50 mg tablets were prepared using a tablet machine.
- the tablets were prepared by a dry granulation process.
- the N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 - ⁇ (1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl ⁇ -L-leucinamide is combined with/HPMCAS-HF to form the spray dried material.
- the spray dried material was then blended with lactose, Croscarmellose sodium, cab-O-Sil and 1 ⁇ 2 of magnesium stearate and then dry granulated using a roller compaction equipment.
- the ribbon from the compaction was milled through a 1 mm screen.
- the milled granulation was blended for five minutes with the remaining of magnesium stearate.
- the 50 mg tablets were prepared using a tablet machine.
- the tablets were prepared by a dry granulation process.
- the N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 - ⁇ (1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl ⁇ -L-leucinamide, Cremophor EL and Kollidon VA64 were combined to form the hot melt extrudet.
- the hot melt extrudet was then blended with lactose, Avicel PH102, Croscarmellose sodium, cab-O-Sil and 1 ⁇ 2 of magnesium stearate and then dry granulated using a roller compaction equipment.
- the ribbon from the compaction was milled through a 1 mm screen.
- the milled granulation was blended for five minutes with the remaining of magnesium stearate.
- the 50 mg tablets were prepared using a tablet machine.
- the tablets were prepared by a dry granulation process.
- the N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 - ⁇ (1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl ⁇ -L-leucinamide was combined with HPMC-AS-HF to form the spray dried material.
- the spray dried material was then blended with lactose, Avicel PH102, Croscarmellose sodium, cab-O-Sil and 1 ⁇ 2 of magnesium stearate and then dry granulated using a roller compaction equipment.
- the ribbon from the compaction was milled through a 1 mm screen.
- the milled granulation was blended for five minutes with the remaining of magnesium stearate.
- the 50 mg tablets were prepared using a tablet machine.
- the tablets were prepared by a dry granulation process.
- the N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 - ⁇ (1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl ⁇ -L-leucinamide was combined with HPMC-AS-HF to form the spray dried material.
- the spray dried material was then blended with lactose, Croscarmellose sodium, cab-O-Sil and 1 ⁇ 2 magnesium stearate and then dry granulated using a roller compaction equipment.
- the ribbon from the compaction was milled through a 1 mm screen.
- the milled granulation was blended for five minutes with the remaining of magnesium stearate.
- the 50 mg tablets were prepared using a tablet machine.
- the wet granulate is dried in a fluid bed dryer, the dried granulate is then milled, and finally lubricated with 0.5% (wt./wt.) magnesium stearate in a blender. Tablets were then compressed on a rotary tablet press.
- the formulations containing the spray dried material (Examples 2 and 3) provided ⁇ 8-10 fold higher exposures compared to the formulation that does not contain the spray dried material or hot melt extrusion and ⁇ 5 folds higher than the hot melt extrusion (Example 4).
- the formulation containing the hot melt extrusion material (Example 4) increased the exposure by about 2.3 folds higher exposure compared to the standard formulation (Example 10).
- Feeding conditions AUC 0-24 hr C max T max Formulation (10 mg dose) ( ⁇ M *hr) ( ⁇ M) (hr) AUC Fed/Fasted Example 10 Fasted 7.3 (3.6) 0.46 (0.14) 4 (0.5, 4) 4.3 Fed (high fat) 31.4 (6.1) 1.77 (0.40) 8 (8, 8)
Abstract
Description
- This invention relates to formulations of cathepsin K inhibitors.
- A variety of cathepsin K inhibitors have been disclosed for the treatment of various disorders related to cathepsin K functioning, including osteoporosis, glucocorticoid induced osteoporosis, Paget's disease, abnormally increased bone turn over, tooth loss, bone fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, atherosclerosis, obesity, glaucoma, chronic obstructive pulmonary disease and cancer including metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma. Representative examples of cathepsin K inhibitors include those disclosed in International Publication WO03/075836, which published on Sep. 18, 2003, to Merck & Co., Inc. & Axys Pharmaceuticals, which is hereby incorporated by reference in its entirety.
- Cathepsin K inhibitors can be formulated for oral dosing as tablets, by using a direct compression, wet granulation or roller compaction method. Similarly, cathepsin K inhibitors can be formulated for oral dosing as gelatin capsules, being a liquid in a soft capsule, or dry powder or semi-solid in a hard capsule. In addition, cathepsin K inhibitors can be formulated for intravenous dosing.
- The formulations of the instant invention have advantages over other formulations of cathepsin K inhibitors. Specifically, the formulations of the instant invention significantly improve the absorption of the cathepsin K inhibitor. The formulations of the instant invention also improve the bioavailability of the cathepsin K inhibitor and reduce the variability in exposure. Exposure can vary due to many factors, including whether the cathepsin K inhibitor is taken with or without food.
- The instant invention relates to pharmaceutical compositions containing cathepsin K inhibitors. The cathepsin K inhibitor solid dispersion formulations of the present invention are made by spray drying or hot melt extrusion processes. The cathepsin K inhibitor is combined with a polymer, thus forming an amorphous system after spray drying. The spray dried amorphous systems are made by combining 10-20% of the cathepsin K inhibitor with 80-90% polymer. The amorphous system is then combined with excipients to form tablets, or combined with water to form a suspension. Also disclosed are processes for making said pharmaceutical compositions.
- The cathepsin K inhibitor solid dispersion formulations of the present invention are made by spray drying or hot melt extrusion processes. The cathepsin K inhibitor is combined with a polymer, thus forming an amorphous system after spray drying. The spray dried amorphous systems are made by combining 10-20% of the cathepsin K inhibitor with 80-90% polymer. The amorphous system is then combined with excipients to form tablets, or combined with water to form a suspension.
- A particularly effective cathepsin K inhibitor is N1-(1-cyanocyclopropyl)-4-fluoro-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide,
- which can be prepared by procedures described in: International Publication WO03/075836, which published on Sep. 18, 2003, to Merck & Co., Inc. & Axys Pharmaceuticals; International Publication WO2006/017455, which published on Feb. 16, 2006, to Merck & Co., Inc.; U.S. Publication US2006-0052642, which published on Mar. 9, 2006; U.S. Publication US2005-0234128, which published on Oct. 20, 2005, to Merck & Co., Inc.; all of which are hereby incorporated by reference in their entirety. This compound is also known by its generic name, odanacatib.
- The invention contemplates the use of any pharmaceutically acceptable fillers/compression aids, disintegrants, super-disintegrants, lubricants, binders, surfactants, film coatings, and solvents. Examples of these components are set forth below and are described in more detail in the Handbook of Pharmaceutical Excipients, Second Edition, Ed. A. Wade and P. J. Weller, 1994, The Pharmaceutical Press, London, England.
- The instant invention comprises a pharmaceutical composition comprising from about 1% to 95% by weight of an amorphous cathepsin K inhibitor system, or a pharmaceutically acceptable salt thereof, and from about 5% to 99% by weight of excipients comprising a diluent, a glidant, a lubricant, a surfactant and a disintegrant. In a class of the instant invention, is a pharmaceutical composition comprising from about 44% to 57% by weight of an amorphous cathepsin K inhibitor system, or a pharmaceutically acceptable salt thereof, and from about 43% to 66% by weight of excipients comprising a diluent, a glidant, a lubricant, a surfactant and a disintegrant. In a class of the instant invention, is a pharmaceutical composition comprising about 50.0% by weight of an amorphous cathepsin K inhibitor system, or a pharmaceutically acceptable salt thereof, and about 50.0% by weight of excipients comprising a diluent, a polymer, a glidant, a lubricant, a surfactant and a disintegrant.
- In an embodiment of the invention, the amorphous cathepsin K inhibitor system comprises a cathepsin K inhibitor and a polymer. Examples of the amorphous cathepsin K inhibitor systems of the instant invention include the spray dried material and the hot melt extrusion material.
- In an embodiment of the invention, the cathepsin K inhibitor is N1-(1-cyanocyclopropyl)-4-fluoro-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methyl sulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide, or a pharmaceutically acceptable salt thereof.
- In an embodiment of the invention, the polymer is hydroxypropyl methylcellulose acetate succinate (abbreviated as “HPMCAS”), copovidone (for example, Kollidon VA64), cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinylacetatephthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, methyl acrylate-methacrylic acid copolymer, methacrylate-methacrylic or acid-octyl acrylate copolymer. The HPMCAS can be selected from HPMCAS-HF, HPMCAS-MF or HPMCAS-LF. HPMCAS-HF has an acetyl content of 10.0-14.0%, a succinoyl content of 4.0-8.0%, a methoxyl content of 22.0-26.0% and a hydroxypropoxyl content of 6.0-10.0%, with an average particle size of not more than 10 μm (available from ShinEtsu). HPMCAS-MF has an acetyl content of 7.0-11.0%, a succinoyl content of 10.0-14.0%, a methoxyl content of 21.0-25.0% and a hydroxypropoxyl content of 5.0-9.0%, with an average particle size of not more than 10 μm (available from ShinEtsu). HPMCAS-LF has an acetyl content of 5.0-9.0%, a succinoyl content of 14.0-18.0%, a methoxyl content of 20.0-24.0% and a hydroxypropoxyl content of 5.0-9.0%, with an average particle size of not more than 10 μm (available from ShinEtsu). In a class of the invention, the polymer is HPMCAS-HF.
- In an embodiment of the invention, the amorphous cathepsin K inhibitor system comprises 10-20% of the cathepsin K inhibitor and 80-90% polymer. In a class of the invention, the amorphous cathepsin K inhibitor system comprises 10% of the cathepsin K inhibitor and 90% polymer. In another class of the invention, the amorphous cathepsin K inhibitor system comprises 15% of the cathepsin K inhibitor and 85% polymer. In another class of the invention, the amorphous cathepsin K inhibitor system comprises 20% of the cathepsin K inhibitor and 80% polymer.
- In an embodiment of the invention, the cathepsin K inhibitor comprises 5.0 to 8.334% of the total tablet formulation. In a class of the invention, the cathepsin K inhibitor comprises 5.0% of the total tablet formulation. In another class of the invention, the cathepsin K inhibitor comprises 6.667% of the total tablet formulation. In another class of the invention, the cathepsin K inhibitor comprises 6.675% of the total tablet formulation. In another class of the invention, the cathepsin K inhibitor comprises 7.5% of the total tablet formulation.
- In an embodiment of the invention, the diluents are selected from the group consisting of spray-dried lactose, lactose anhydrous, lactose monohydrate, mannitol, microcrystalline cellulose, calcium phosphate, calcium carbonate, magnesium carbonate and starch. In a class of the embodiment, the diluent is spray-dried lactose.
- In an embodiment of the invention, the glidant, or flow aid, is silicone dioxide, colloidal silica, talc or starch. In a class of the invention, the glidant is silicone dioxide.
- In an embodiment of the invention, the lubricant is magnesium stearate, stearic acid or sodium stearyl fumerate. In a class of the embodiment, the lubricant is magnesium stearate.
- In an embodiment of the invention, the surfactant is sodium laurel sulfate, ammonium lauryl sulfate, another alkyl sulfate salt or poloxamer.
- In an embodiment of the invention the disintegrant is croscarmellose sodium, starch, crospovidone, sodium starch glycolate or any mixtures thereof. In a class of the embodiment, the disintegrant is croscarmellose sodium.
- The instant invention further comprises a method of improving the absorption of a cathepsin K inhibitor by combining the cathepsin K inhibitor with a polymer to form an amorphous system.
- In an embodiment of the invention, the cathepsin K inhibitor is N1-(1-cyanocyclopropyl)-4-fluoro-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide, and the polymer is HPMCAS-HF.
- The instant invention further comprises a method of reducing a food effect observed when dosing a cathepsin K inhibitor by combining the cathepsin K inhibitor with a polymer to form an amorphous system. In an embodiment of the invention, the cathepsin K inhibitor is N1-(1-cyanocyclopropyl)-4-fluoro-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide, and the polymer is HPMCAS-HF.
- The instant invention further comprises a method of reducing variation in absorption observed when dosing a cathepsin K inhibitor by combining the cathepsin K inhibitor with a polymer to form an amorphous system. In an embodiment of the invention, the cathepsin K inhibitor is N1-(1-cyanocyclopropyl)-4-fluoro-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide, and the polymer is HPMCAS-HF.
- The pharmaceutical tablet compositions of the present invention may also contain one or more additional formulation ingredients that may be selected from a wide variety of excipients known in the pharmaceutical formulation art. According to the desired properties of the tablet, any number of ingredients may be selected, alone or in combination, based upon their known uses in preparing tablet compositions. Such ingredients include, but are not limited to, diluents, binders, compression aids, disintegrants, lubricants, glidants, stabilizers (such as dessicating amorphous silica), flavors, flavor enhancers, sweeteners, preservatives, colorants and coatings.
- The term “tablet” as used herein is intended to encompass compressed pharmaceutical dosage formulations of all shapes and sizes, whether uncoated or coated. Substances which may be used for coating include hydroxypropylmethylcellulose, hydroxypropylcellulose, titanium dioxide, talc, sweeteners and colorants.
- The pharmaceutical compositions of the present invention are useful in the therapeutic or prophylactic treatment of disorders associated with cathepsin K functioning. Such disorders include: osteoporosis, glucocorticoid induced osteoporosis, Paget's disease, abnormal bone disease, tooth loss, bone fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, atherosclerosis, obesity, glaucoma, chronic obstructive pulmonary disease and cancer, including metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma.
- The following examples are given for the purpose of illustrating the present invention and shall not be construed as being limitations on the scope of the invention.
-
-
Amount (mg)/ Ingredient [%] tablet 15% N1-(1-cyanocyclopropyl)-4-fluoro-N2- 50.0 333.33 {(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)- 1,1′-biphenyl-4-yl]ethyl}-L-leucinamide 85% HPMC-AS-HF Lactose, spray dried 45.5 303.33 Croscarmellose sodium 3.0 20.00 Cab-o-sil 0.5 3.33 Magnesium stearate 1.0 6.67 % Total 100.0 666.67 - The tablets were prepared by a dry granulation process. The N1-(1-cyanocyclopropyl)-4-fluoro-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide is combined with HPMC-AS-HF to form the spray dried material. The spray dried material was then blended with lactose, Croscarmellose sodium, cab-O-Sil and ½ of magnesium stearate and then dry granulated using a roller compaction equipment. The ribbon from the compaction was milled through a 1 mm screen. The milled granulation was blended for five minutes with the remaining of magnesium stearate. The 50 mg tablets were prepared using a tablet machine.
-
-
Amount (mg)/ Ingredient [%] tablet 15% N1-(1-cyanocyclopropyl)-4-fluoro-N2- 44.44 333.33 {(1,S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)- 1,1′-biphenyl-4-yl]ethyl}-L-leucinamide 85% HPMCAS-HF Lactose, spray dried 45.31 339.79 Croscarmellose sodium 6.00 45.00 SLS 2.00 15.00 Cab-o-Sil 1.00 7.50 Magnesium stearate 1.25 9.38 % Total 100.0 750.00 - The tablets were prepared by a dry granulation process. The N1-(1-cyanocyclopropyl)-4-fluoro-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide is combined with HPMCAS-HF to form the spray dried material. The spray dried material was then blended with lactose, Croscarmellose sodium, sodium laurel sulfate, cab-O-Sil and ½ of magnesium stearate and then dry granulated using a roller compaction equipment. The ribbon from the compaction was milled through a 1 mm screen. The milled granulation was blended for five minutes with the remaining of magnesium stearate. The 50 mg tablets were prepared using a tablet machine.
-
-
Amount (mg)/ Ingredient [%] tablet 10% N1-(1-cyanocyclopropyl)-4-fluoro-N2- 50.0 500.00 {(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)- 1,1′-biphenyl-4-yl]ethyl}-L-leucinamide 90% HPMCAS-HF Lactose, spray dried 20.125 201.25 Avicel PH 102 20.125 201.25 Croscarmellose sodium 6.0 60,00 SLS 2.0 20.00 Cab-o-Sil 0.75 7.50 Magnesium stearate 1.0 10.00 % Total 100.0 1000 - The tablets were prepared by a dry granulation process. The N1-(1-cyanocyclopropyl)-4-fluoro-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide is combined with/HPMCAS-HF to form the spray dried material. The spray dried material was then blended with lactose, Croscarmellose sodium, cab-O-Sil and ½ of magnesium stearate and then dry granulated using a roller compaction equipment. The ribbon from the compaction was milled through a 1 mm screen. The milled granulation was blended for five minutes with the remaining of magnesium stearate. The 50 mg tablets were prepared using a tablet machine.
-
-
Amount (mg)/ Ingredient [%] tablet 15% N1-(1-cyanocyclopropyl)-4-fluoro-N2- 44.5 333.33 {(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)- 1,1′-biphenyl-4-yl]ethyl}-L-leucinamide 10% Cremophor EL 75% Kollidon VA64 Lactose, spray dried 12.0 89.89 Avicel PH 102 36.0 269.67 Croscarmellose sodium 6.0 44.94 Cab-o-Sil 0.5 3.75 Magnesium stearate 1.0 7.49 % Total 100.0 750.00 - The tablets were prepared by a dry granulation process. The N1-(1-cyanocyclopropyl)-4-fluoro-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide, Cremophor EL and Kollidon VA64 were combined to form the hot melt extrudet. The hot melt extrudet was then blended with lactose, Avicel PH102, Croscarmellose sodium, cab-O-Sil and ½ of magnesium stearate and then dry granulated using a roller compaction equipment. The ribbon from the compaction was milled through a 1 mm screen. The milled granulation was blended for five minutes with the remaining of magnesium stearate. The 50 mg tablets were prepared using a tablet machine.
-
-
Amount (mg)/ Ingredient [%] tablet 15% N1-(1-cyanocyclopropyl)-4-fluoro-N2- 55.56 333.33 {(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)- 1,1′-biphenyl-4-yl]ethyl}-L-leucinamide 85% HPMCAS-HF Lactose, spray dried 20.22 121.33 Avicel PH 102 20.22 121.33 Croscarmellose sodium 3.00 18.00 Magnesium stearate 1.00 6.00 % Total 100.0 600.00 - The tablets were prepared by a dry granulation process. The N1-(1-cyanocyclopropyl)-4-fluoro-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide was combined with HPMC-AS-HF to form the spray dried material. The spray dried material was then blended with lactose, Avicel PH102, Croscarmellose sodium, cab-O-Sil and ½ of magnesium stearate and then dry granulated using a roller compaction equipment. The ribbon from the compaction was milled through a 1 mm screen. The milled granulation was blended for five minutes with the remaining of magnesium stearate. The 50 mg tablets were prepared using a tablet machine.
-
-
Amount (mg)/ Ingredient [%] tablet 15% N1-(1-cyanocyclopropyl)-4-fluoro-N2- 55.56 333.33 {(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)- 1,1′-biphenyl-4-yl]ethyl}-L-leucinamide 85% HPMCAS-HF Lactose, spray dried 39.94 239.66 Croscarmellose sodium 3.00 18.00 Cab-o-sil 0.50 3.00 Magnesium stearate 1.00 6.00 % Total 100.0 600.00 - The tablets were prepared by a dry granulation process. The N1-(1-cyanocyclopropyl)-4-fluoro-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide was combined with HPMC-AS-HF to form the spray dried material. The spray dried material was then blended with lactose, Croscarmellose sodium, cab-O-Sil and ½ magnesium stearate and then dry granulated using a roller compaction equipment. The ribbon from the compaction was milled through a 1 mm screen. The milled granulation was blended for five minutes with the remaining of magnesium stearate. The 50 mg tablets were prepared using a tablet machine.
-
-
Component Amount 15% N1-(1-cyanocyclopropyl)-4-fluoro-N2- 15.0 g {(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)- 1,1′-biphenyl-4-yl]ethyl}-L-leucinamide 85% HPMCAS-HF Water 60.0 g -
-
- 1. Weigh 15.0 g of N1-(1-cyanocyclopropyl)-4-fluoro-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide and HPMCAS-HF in a defoamer container (size: 150 or 250 ml).
- 2. Add 60.0 g of water into the container; Shake gently to wet all the SD material.
- 3. Mix for 5 min using a defoamer and defoam for additional 5 min; Make sure a homogeneous suspension is formed.
-
-
Component Amount 15% N1-(1-cyanocyclopropyl)-4-fluoro-N2- 10.0 g {(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)- 1,1′-biphenyl-4-yl]ethyl}-L-leucinamide 85% HPMCAS-HF Water 65.0 g -
-
- 1. Weigh 10.0 g of N1-(1-cyanocyclopropyl)-4-fluoro-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide and HPMCAS-HF in a defoamer container (size: 150 or 250 ml).
- 2. Add 65.0 g of water into the container; Shake gently to wet all the SD material.
- 3. Mix for 5 min using a defoamer and defoam for additional 5 min; Make sure a homogeneous suspension is formed.
-
-
Component Amount 15% N1-(1-cyanocyclopropyl)-4-fluoro-N2- 1.00 g {(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)- 1,1′-biphenyl-4-yl]ethyl}-L-leucinamide 85% HPMCAS-HF Water 74.0 g -
-
- 1. Weigh 1.00 g of N1-(1-cyanocyclopropyl)-4-fluoro-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide and HPMCAS-HF in a defoamer container (size: 150 or 250 ml).
- 2. Add 74.0 g of water into the container; Shake gently to wet all the SD material.
- 3. Mix for 5 min using a defoamer and defoam for additional 5 min; Make sure a homogeneous suspension is formed.
-
-
Ingredient % Mg/Tablet N1-(1-cyanocyclopropyl)-4-fluoro-N2- 12.5 50.00 {(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)- 1,1′-biphenyl-4-yl]ethyl}-L-leucinamide Microcrystalline Cellulose 40 160.00 Lactose Monohydrate 40 160.000 Croscarmellose Sodium 4 16.00 Hydroxypropyl cellulose 3 12.00 Magnesium Stearate 0.5 2.00 Purified Water* [35] [140.00] Total 100 400.00 *removed during the during process - N1-(1-cyanocyclopropyl)-4-fluoro-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide, 4% (wt./wt.) croscarmellose sodium, and a 1:1 (wt./wt.) mixture of microcrystalline cellulose and lactose monohydrate are dry blended in a high shear mixer, and then a 3% (wt./wt.) hydroxypropyl cellulose solution is sprayed onto the mixing powders to effect granulation. The wet granulate is dried in a fluid bed dryer, the dried granulate is then milled, and finally lubricated with 0.5% (wt./wt.) magnesium stearate in a blender. Tablets were then compressed on a rotary tablet press.
-
-
Dose AUC0-72 hr AUC0-24 hr Cmax Tmax Formulation (mg) (μM*hr) (μM *hr) (μM) (hr) Example 10 10 N/A 7.3 (3.6) 0.46 (0.14) 4 (0.5, 4) Example 2 10 N/A 59.6 (5.2) 3.93 (0.10) 4 (4, 4) Example 3 10 178.0 (38.2) 70.6 (16.2) 4.0 (0.8) 2 (2, 8) Example 4 10 41.8 (11.8) 16.8 (4.0) 0.9 (0.2) 8 (8, 24) - Animal studies in beagle dogs were conducted to evaluate the formulations. In general, the formulations containing the spray dried material (Examples 2 and 3) provided ˜8-10 fold higher exposures compared to the formulation that does not contain the spray dried material or hot melt extrusion and ˜5 folds higher than the hot melt extrusion (Example 4). Similarly, the formulation containing the hot melt extrusion material (Example 4) increased the exposure by about 2.3 folds higher exposure compared to the standard formulation (Example 10).
-
-
Feeding conditions AUC0-24 hr Cmax Tmax Formulation (10 mg dose) (μM *hr) (μM) (hr) AUCFed/Fasted Example 10 Fasted 7.3 (3.6) 0.46 (0.14) 4 (0.5, 4) 4.3 Fed (high fat) 31.4 (6.1) 1.77 (0.40) 8 (8, 8) Example 2 Fasted 59.6 (5.2) 3.93 (0.10) 4 (4, 4) 1.2 Fed (high fat) 73.0 (8.3) 4.27 (0.41) 6 (6, 8) - A significant food effect was observed with the formulation that does not contain the spray dried material. The formulation containing the spray dried material (Example 2) helped to minimize the variability in exposure.
Claims (9)
Priority Applications (1)
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US12/992,124 US20110065800A1 (en) | 2008-05-14 | 2009-05-06 | Formulations for cathepsin k inhibitors |
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US12763008P | 2008-05-14 | 2008-05-14 | |
US12/992,124 US20110065800A1 (en) | 2008-05-14 | 2009-05-06 | Formulations for cathepsin k inhibitors |
PCT/US2009/042924 WO2009140105A2 (en) | 2008-05-14 | 2009-05-06 | Formulations for cathepsin k inhibitors |
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US13/847,794 Continuation US8975296B2 (en) | 2008-05-14 | 2013-03-20 | Formulations for cathepsin K inhibitors |
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US12/992,124 Abandoned US20110065800A1 (en) | 2008-05-14 | 2009-05-06 | Formulations for cathepsin k inhibitors |
US13/847,794 Active US8975296B2 (en) | 2008-05-14 | 2013-03-20 | Formulations for cathepsin K inhibitors |
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CN103732216A (en) * | 2011-08-16 | 2014-04-16 | 默沙东公司 | Use of inorganic matrix and organic polymer combinations for preparing stable amorphous dispersions |
US20160106679A1 (en) * | 2013-05-16 | 2016-04-21 | Sandoz Ag | Tablet with increased drug load of odanacatib |
EP2808012A1 (en) * | 2013-05-29 | 2014-12-03 | ratiopharm GmbH | Method for producing dosage form comprising odanacatib |
WO2016059192A1 (en) * | 2014-10-17 | 2016-04-21 | Ratiopharm Gmbh | Composition comprising odanacatib |
WO2016075184A1 (en) * | 2014-11-11 | 2016-05-19 | Hexal Ag | Tablet with an increased drug load of stable amorphous odanacatib |
WO2017196712A1 (en) * | 2016-05-09 | 2017-11-16 | Dispersol Technologies, Llc | Improved drug formulations |
US11766467B2 (en) * | 2017-09-01 | 2023-09-26 | University Of Wyoming | Methods of treating wounds using cathepsin K inhibitors |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4983593A (en) * | 1988-05-30 | 1991-01-08 | Zeria Pharmaceutical Co | Pharmaceutical composition of dihydropyridine compound |
US20030232863A1 (en) * | 2002-03-05 | 2003-12-18 | Bayly Christopher I. | Cathepsin cysteine protease inhibitors |
US20060009433A1 (en) * | 2003-03-14 | 2006-01-12 | Zhi-Xing Yao | Neuroprotective spirostenol pharmaceutical compositions |
US20070237818A1 (en) * | 2005-06-02 | 2007-10-11 | Malcolm Bruce A | Controlled-release formulation of HCV protease inhibitor and methods using the same |
US20090318560A1 (en) * | 2007-02-26 | 2009-12-24 | Wayne Parent | Formulations for cathepsin k inhibitors |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
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TW487582B (en) | 1995-08-11 | 2002-05-21 | Nissan Chemical Ind Ltd | Method for converting sparingly water-soluble medical substance to amorphous state |
ES2287971T3 (en) | 1997-08-11 | 2007-12-16 | Pfizer Products Inc. | SOLID PHARMACEUTICAL DISPERSIONS WITH INCREASED BIODISPONIBILITY. |
AU2006302797B2 (en) * | 2005-03-02 | 2012-02-02 | Merck Canada Inc. | Composition for inhibition of cathepsin K |
-
2009
- 2009-05-06 US US12/992,124 patent/US20110065800A1/en not_active Abandoned
- 2009-05-06 WO PCT/US2009/042924 patent/WO2009140105A2/en active Application Filing
- 2009-05-06 EP EP09747191.6A patent/EP2291079B1/en active Active
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2013
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Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4983593A (en) * | 1988-05-30 | 1991-01-08 | Zeria Pharmaceutical Co | Pharmaceutical composition of dihydropyridine compound |
US20030232863A1 (en) * | 2002-03-05 | 2003-12-18 | Bayly Christopher I. | Cathepsin cysteine protease inhibitors |
US7375134B2 (en) * | 2002-03-05 | 2008-05-20 | Axys Pharmaceuticals, Inc. | Cathepsin cysteine protease inhibitors |
US20060009433A1 (en) * | 2003-03-14 | 2006-01-12 | Zhi-Xing Yao | Neuroprotective spirostenol pharmaceutical compositions |
US20070237818A1 (en) * | 2005-06-02 | 2007-10-11 | Malcolm Bruce A | Controlled-release formulation of HCV protease inhibitor and methods using the same |
US20090318560A1 (en) * | 2007-02-26 | 2009-12-24 | Wayne Parent | Formulations for cathepsin k inhibitors |
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EP2291079A4 (en) | 2011-06-22 |
EP2291079A2 (en) | 2011-03-09 |
US20130217766A1 (en) | 2013-08-22 |
US8975296B2 (en) | 2015-03-10 |
WO2009140105A2 (en) | 2009-11-19 |
EP2291079B1 (en) | 2013-04-24 |
WO2009140105A3 (en) | 2010-01-07 |
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