NZ751885A - Sustained-release formulations of colchicine and methods of using same - Google Patents
Sustained-release formulations of colchicine and methods of using same Download PDFInfo
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- NZ751885A NZ751885A NZ751885A NZ75188514A NZ751885A NZ 751885 A NZ751885 A NZ 751885A NZ 751885 A NZ751885 A NZ 751885A NZ 75188514 A NZ75188514 A NZ 75188514A NZ 751885 A NZ751885 A NZ 751885A
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- Prior art keywords
- formulation
- colchicine
- granules
- amount
- disease
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- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 title claims abstract description 60
- 239000000203 mixture Substances 0.000 title claims abstract description 51
- 238000009472 formulation Methods 0.000 title claims abstract description 48
- 229960001338 colchicine Drugs 0.000 title claims abstract description 28
- 238000013268 sustained release Methods 0.000 title claims abstract description 17
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 17
- 238000000034 method Methods 0.000 title abstract description 4
- 239000003340 retarding agent Substances 0.000 claims abstract description 10
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims abstract description 7
- 229960001021 lactose monohydrate Drugs 0.000 claims abstract description 7
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 6
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims abstract description 4
- 239000008187 granular material Substances 0.000 claims description 14
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 12
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 12
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 12
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 12
- 230000002265 prevention Effects 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 5
- 230000003143 atherosclerotic effect Effects 0.000 claims description 5
- 230000007211 cardiovascular event Effects 0.000 claims description 5
- 208000019553 vascular disease Diseases 0.000 claims description 5
- 201000005569 Gout Diseases 0.000 claims description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 208000004476 Acute Coronary Syndrome Diseases 0.000 claims description 2
- 206010016207 Familial Mediterranean fever Diseases 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- 208000032382 Ischaemic stroke Diseases 0.000 claims description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 2
- 208000004957 Out-of-Hospital Cardiac Arrest Diseases 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- 206010064930 age-related macular degeneration Diseases 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 208000029078 coronary artery disease Diseases 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- 208000002780 macular degeneration Diseases 0.000 claims description 2
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims 2
- 238000000338 in vitro Methods 0.000 claims 2
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims 1
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims 1
- 239000004372 Polyvinyl alcohol Substances 0.000 claims 1
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 claims 1
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 claims 1
- 229960005370 atorvastatin Drugs 0.000 claims 1
- 238000007906 compression Methods 0.000 claims 1
- 230000006835 compression Effects 0.000 claims 1
- 229920002451 polyvinyl alcohol Polymers 0.000 claims 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims 1
- 229960002965 pravastatin Drugs 0.000 claims 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 claims 1
- 229960000672 rosuvastatin Drugs 0.000 claims 1
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 claims 1
- 229960002855 simvastatin Drugs 0.000 claims 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 abstract description 3
- 208000024172 Cardiovascular disease Diseases 0.000 abstract description 2
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 229940002157 colcrys Drugs 0.000 description 3
- 229940084627 colchicine 0.5 mg Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 2
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 208000024963 hair loss Diseases 0.000 description 1
- 230000003676 hair loss Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000009863 secondary prevention Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
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- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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Abstract
Pharmaceutical compositions of colchicine for once-a-day oral administration are provided. The formulations comprise a sustained-release component and an optional immediate-release component, the compositions of which can be selectively adjusted, respectively, to release the active ingredient along a pre-determined or desired release profile. The formulation comprises a release-retarding agent comprising HMPC and lactose monohydrate. Methods of treating or preventing cardiovascular disease and/or inflammatory disease in mammalian subjects comprising the administration of the novel formulations disclosed herein is also provided.
Description
(93%) and statins (95%) were randomly assigned colchicine 0.5 mg/day or no colchicine and followed for a median of 3 years (Nidorf et al., JACC, 2013, 61 (4), 404-410). This study showed that colchicine 0.5 mg/day administered in addition to statins and other standard secondary prevention therapies appeared effective for the prevention of cardiovascular events in patients with stable coronary disease.
For the treatment of gout, the recommended dose of colchcine (COLCRYS®) is 1.8 mg/day in one or multiple doses in one hour. For adults with gout, treatment is initiated with a dose of 1.2 mg at the first sign of symptoms followed by 0.6 mg one hour later. (Physician's Desk Reference, 68th ed., (2014)).
COLCRYS® is an immediate release formulation. Adverse effects associated with the administration of COLCRYS® include, but are not limited to, nausea, vomiting, abdominal pain, diarrhea, hair loss, weakness, nerve irritation, severe anemia, low white blood counts, and low platelets (Physician's Desk Reference, 68th ed., (2014)).
The instant invention addresses these and other needs by providing a modified formulation of colchicine characterized by a sustained release of an active ingredient. This invention additionally provides an effective, once-daily dosage form of colchicine or salts thereof, which may improve patient compliance and also may reduce some of the side effects of colchicine compared to the current or higher daily doses of immediate release colchicine formulations.
BRIEF SUMMARY OF THE INVENTION [0013a] In a first aspect there is provided a sustained release formulation of colchicine, comprising: (a) granules comprising colchicine or a pharmaceutically acceptable salt thereof in an amount of not more than 0.6 mg, and a binder comprising hydroxypropyl methylcellulose (HPMC) 6 mPa•s in an amount of 1% to 30% (w/w) of the formulation; (b) a release retarding agent admixed with, or blended with, the granules in an amount of between 25% and 30% w/w of the formulation, wherein the retarding agent comprises a combination of equal parts hydroxypropyl methylcellulose (HPMC) with a viscosity grade of 4000 mPa*s and lactose monohydrate; and (c) at least one additional pharmaceutically acceptable excipient admixed with or blended with the granules, wherein the at least one additional pharmaceutically acceptable excipient is starch, gelatin, polyvinylpyrrolidone (PVP), polyvinyl AH26(25551143_1):RTK alcohol, microcrystalline cellulose, hydroxypropyl cellulose (HPC) or a mixture thereof, wherein the sustained release formulation is in a form of a tablet, and wherein the formulation is homogeneous. [0013b] In a second aspect there is provided use of a therapeutically effective amount of a sustained release formulation of colchicine according to the first aspect in the preparation of a medicament for the treatment and/or prevention of a cardiovascular event in a subject, wherein the cardiovascular event is acute coronary syndrome, out-of-hospital cardiac arrest, or noncardioembolic ischemic stroke. [0013c] In a third aspect there is provided use of a therapeutically effective amount of a sustained release formulation of colchicine according to the first aspect in the preparation of a medicament for the treatment and/or prevention of an inflammatory disease in a subject, wherein the inflammatory disease is gout, familial Mediterranean fever, Behcet´s disease, Age- related macular degeneration, or Alzheimer´s disease. [0013d] In a fourth aspect there is provided use of a therapeutically effective amount of a sustained release formulation of colchicine according to the first aspect in the preparation of a medicament for the treatment and/or prevention of an atherosclerotic vascular disease in a subject. [0013e] In a fifth aspect there is provided use of a therapeutically effective amount of a sustained release formulation of colchicine according to the first aspect in the preparation of a medicament for the treatment and/or prevention of atherosclerotic vascular disease in a subject, wherein the formulation comprises: (a) granules comprising not more than 0.6 mg of colchicine or a pharmaceutically acceptable salt thereof; (b) a release retarding agent admixed with the colchicine granules in an amount of 25% to 30% w/w of the formulation, and wherein the release retarding agent comprises equal parts hydroxypropyl methylcellulose (HPMC) with a viscosity grade of 4000 mPa•s and lactose monohydrate; and (c) at least one pharmaceutically acceptable excipient admixed with the granules.
According to aspects of the invention illustrated herein, there is provided a sustained release formulation of colchicine as an active ingredient, the formulation comprising colchicine or a pharmaceutically acceptable salt thereof; a retarding agent; and at least one pharmaceutically acceptable excipient.
AH26(25551143_1):RTK According to aspects of the invention illustrated herein, there is provided a method for treating and/or preventing a cardiovascular disease in a subject, comprising administering to the subject a therapeutically effective amount of a sustained release formulation of colchicine.
According to aspects of the invention illustrated herein, there is provided a method for treating and/or preventing an inflammatory disease in a subject, comprising administering AH26(25551143_1):RTK WE
Claims (16)
1. A sustained release formulation of colchicine, comprising: (a) granules comprising colchicine or a pharmaceutically acceptable salt thereof in an amount of not more than 0.6 mg, and a binder comprising hydroxypropyl methylcellulose (HPMC) 6 mPa•s in an amount of 1% to 30% (w/w) of the formulation; (b) a release retarding agent admixed with, or blended with, the granules in an amount of between 25% and 30% w/w of the formulation, wherein the retarding agent comprises a combination of equal parts hydroxypropyl methylcellulose (HPMC) with a viscosity grade of 4000 mPa*s and lactose monohydrate; and (c) at least one additional pharmaceutically acceptable excipient admixed with or blended with the granules, wherein the at least one additional pharmaceutically acceptable excipient is starch, gelatin, polyvinylpyrrolidone (PVP), polyvinyl alcohol, microcrystalline cellulose, hydroxypropyl cellulose (HPC) or a mixture thereof, wherein the sustained release formulation is in a form of a tablet, and wherein the formulation is homogeneous.
2. The formulation of claim 1, wherein less than about 70% of the colchicine is released in vitro within 2 hours at 37 °C.
3. The formulation of claims 1 or 2, wherein the formulation releases at least about 20% of the colchicine in vitro within the first 30 minutes.
4. The formulation of any one of claims 1 to 3, wherein the granules in part (a) further comprise a first filling agent comprising lactose monohydrate in an amount of 10% to 80 % (w/w) of the formulation.
5. The formulation of any one of claims 1 to 4, further comprising a second filling agent admixed or blended with the granules comprising lactose monohydrate in an amount of 10% to 30% (w/w) of the formulation.
6. The formulation of any one of claims 1 to 5, wherein the formulation comprises no immediate release component or layer. AH26(25551143_1):RTK
7. The formulation of any one of claims 1 to 6, wherein the formulation is formulated for once daily administration.
8. The formulation of any one of claims 1 to 7, wherein the compression strength of the tablet is between 30N and 130N.
9. The formulation of any one of claims 1 to 8, wherein the formulation further comprises a statin.
10. The formulation of claim 9, wherein the statin is admixed with the formulation.
11. The formulation of claim 9 or claim 10, wherein the statin is one or more of atorvastatin, rosuvastatin, simvastatin, and pravastatin, or a salt thereof.
12. Use of a therapeutically effective amount of a sustained release formulation of colchicine according to any one of claims 1 to 11 in the preparation of a medicament for the treatment and/or prevention of a cardiovascular event in a subject, wherein the cardiovascular event is acute coronary syndrome, out-of-hospital cardiac arrest, or noncardioembolic ischemic stroke.
13. Use of a therapeutically effective amount of a sustained release formulation of colchicine according to any one of claims 1 to 11 in the preparation of a medicament for the treatment and/or prevention of an inflammatory disease in a subject, wherein the inflammatory disease is gout, familial Mediterranean fever, Behcet´s disease, Age-related macular degeneration, or Alzheimer´s disease.
14. Use of a therapeutically effective amount of a sustained release formulation of colchicine according to any one of claims 1 to 11 in the preparation of a medicament for the treatment and/or prevention of an atherosclerotic vascular disease in a subject.
15. Use of a therapeutically effective amount of a sustained release formulation of colchicine according to any one of claims 1 to 11 in the preparation of a medicament for the treatment and/or prevention of atherosclerotic vascular disease in a subject, wherein the formulation comprises: (a) granules comprising not more than 0.6 mg of colchicine or a pharmaceutically acceptable salt thereof; AH26(25551143_1):RTK (b) a release retarding agent admixed with the colchicine granules in an amount of 25% to 30% w/w of the formulation, and wherein the release retarding agent comprises equal parts hydroxypropyl methylcellulose (HPMC) with a viscosity grade of 4000 mPa•s and lactose monohydrate; and (c) at least one pharmaceutically acceptable excipient admixed with the granules.
16. The use of claim 14 or claim 15, wherein the atherosclerotic vascular disease is a coronary disease. Murray and Poole Enterprises Limited By the Attorneys for the Applicant SPRUSON & FERGUSON Per: AH26(25551143_1):RTK
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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US201361812514P | 2013-04-16 | 2013-04-16 | |
US61/812,514 | 2013-04-16 | ||
EPEP13194505.7 | 2013-11-26 | ||
EP13194505 | 2013-11-26 | ||
NZ713151A NZ713151B2 (en) | 2013-04-16 | 2014-04-16 | Sustained-release formulations of colchicine and methods of using same |
Publications (2)
Publication Number | Publication Date |
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NZ751885A true NZ751885A (en) | 2021-01-29 |
NZ751885B2 NZ751885B2 (en) | 2021-04-30 |
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JP6887043B2 (en) | 2021-06-16 |
NZ713151A (en) | 2021-01-29 |
HRP20210963T1 (en) | 2021-09-17 |
JP2020125335A (en) | 2020-08-20 |
ES2870718T3 (en) | 2021-10-27 |
IL242001B (en) | 2021-07-29 |
HUE054663T2 (en) | 2021-09-28 |
LT2986280T (en) | 2021-06-25 |
DK2986280T3 (en) | 2021-06-14 |
JP2019065032A (en) | 2019-04-25 |
JP6697539B2 (en) | 2020-05-20 |
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