EP1732518A1 - Clarithromycin extended release formulation - Google Patents
Clarithromycin extended release formulationInfo
- Publication number
- EP1732518A1 EP1732518A1 EP05764065A EP05764065A EP1732518A1 EP 1732518 A1 EP1732518 A1 EP 1732518A1 EP 05764065 A EP05764065 A EP 05764065A EP 05764065 A EP05764065 A EP 05764065A EP 1732518 A1 EP1732518 A1 EP 1732518A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- pharmaceutical composition
- extended release
- pharmaceutically acceptable
- composition according
- erythromycin
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 43
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 title claims description 25
- 238000009472 formulation Methods 0.000 title claims description 21
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims abstract description 28
- 229920000642 polymer Polymers 0.000 claims abstract description 28
- 238000013265 extended release Methods 0.000 claims abstract description 22
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 16
- 229940079593 drug Drugs 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims abstract description 14
- 229960003276 erythromycin Drugs 0.000 claims abstract description 13
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 9
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 8
- 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 abstract description 8
- 229920002125 Sokalan® Polymers 0.000 claims abstract description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims abstract description 5
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims abstract description 4
- 229920001206 natural gum Polymers 0.000 claims abstract description 4
- 229920002689 polyvinyl acetate Polymers 0.000 claims abstract description 4
- 239000011118 polyvinyl acetate Substances 0.000 claims abstract description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims abstract description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims abstract description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims abstract description 3
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims abstract description 3
- 229920000609 methyl cellulose Polymers 0.000 claims abstract description 3
- 239000001923 methylcellulose Substances 0.000 claims abstract description 3
- 235000010981 methylcellulose Nutrition 0.000 claims abstract description 3
- 229920006316 polyvinylpyrrolidine Polymers 0.000 claims abstract description 3
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims abstract 2
- 239000001856 Ethyl cellulose Substances 0.000 claims abstract 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims abstract 2
- 229920001249 ethyl cellulose Polymers 0.000 claims abstract 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims abstract 2
- 229960002626 clarithromycin Drugs 0.000 claims description 17
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 239000008187 granular material Substances 0.000 claims description 9
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 8
- 239000008101 lactose Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 239000000454 talc Substances 0.000 claims description 8
- 229910052623 talc Inorganic materials 0.000 claims description 8
- 235000012222 talc Nutrition 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000006172 buffering agent Substances 0.000 claims description 4
- 238000013270 controlled release Methods 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- 235000012239 silicon dioxide Nutrition 0.000 claims description 4
- 229920002472 Starch Polymers 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 3
- 238000011049 filling Methods 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 229910000318 alkali metal phosphate Inorganic materials 0.000 claims description 2
- 229910000316 alkaline earth metal phosphate Inorganic materials 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical class [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 2
- 150000001860 citric acid derivatives Chemical class 0.000 claims description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 150000003890 succinate salts Chemical class 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims 2
- 208000035143 Bacterial infection Diseases 0.000 claims 1
- 108010010803 Gelatin Proteins 0.000 claims 1
- 241000124008 Mammalia Species 0.000 claims 1
- 208000022362 bacterial infectious disease Diseases 0.000 claims 1
- 229920000159 gelatin Polymers 0.000 claims 1
- 239000008273 gelatin Substances 0.000 claims 1
- 235000019322 gelatine Nutrition 0.000 claims 1
- 235000011852 gelatine desserts Nutrition 0.000 claims 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 235000019359 magnesium stearate Nutrition 0.000 description 7
- 235000010443 alginic acid Nutrition 0.000 description 6
- 229920000615 alginic acid Polymers 0.000 description 6
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 5
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 3
- 229940072056 alginate Drugs 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 3
- 235000010413 sodium alginate Nutrition 0.000 description 3
- 239000000661 sodium alginate Substances 0.000 description 3
- 229940005550 sodium alginate Drugs 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 229920003091 Methocel™ Polymers 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 235000010493 xanthan gum Nutrition 0.000 description 2
- 239000000230 xanthan gum Substances 0.000 description 2
- 229920001285 xanthan gum Polymers 0.000 description 2
- 229940082509 xanthan gum Drugs 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 229920000569 Gum karaya Polymers 0.000 description 1
- 229920000161 Locust bean gum Polymers 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229940087430 biaxin Drugs 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940084436 clarithromycin 500 mg Drugs 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 235000010494 karaya gum Nutrition 0.000 description 1
- 235000010420 locust bean gum Nutrition 0.000 description 1
- 239000000711 locust bean gum Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 230000000063 preceeding effect Effects 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000007892 solid unit dosage form Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
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
- A61K9/20—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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Definitions
- the present invention relates to extended release pharmaceutical compositions of erythromycin or derivatives thereof for once daily administration.
- Erythromycin and derivatives are known for their anti-bacterial activity against a number of micro-organisms and are typically administered as immediate release (IR) compositions, two or three times a day, for a regimen of 10 to 14 days.
- IR immediate release
- 6-O-methylerythromycin A (Clarithromycin), which has been disclosed in US patent No. 4,331,803. It is currently marketed by Abbott as an immediate release formulation, for at least twice daily administration. Abbott is also marketing controlled release composition of Clarithromycin 500 mg under the brand "Biaxin XL".
- Literature discloses various approaches for therapeutic dosage forms, which are designed to deliver the drug at an extended rate to the gastrointestinal tract.
- U.S. Patent 4,842,866 discloses the development of a controlled release formulation of erythromycin derivatives using an alginate matrix comprising a water-soluble alginate and a complex salt of alginic acid, having one cation that yields a soluble alginate salt and another cation that alone yields an insoluble alginate salt.
- US patents 6,010,718, and 6,551,616 disclose formulations of extended release clarithromycin containing 5 to 50% w/w of pharmaceutically acceptable polymer.
- the specification and examples of this patent disclose preferred formulations containing 10%-
- US patent application 2003/0175341 discloses controlled release formulations containing about 0.1% to about 4.5% of one or more cellulosic ether rate controlling polymers.
- PCT application WO 03/082241 discloses clarithromycin formulations having improved bioavailability, using micronized drug.
- the patent exemplifies formulations of extended release clarithromycin containing the drug of particle size less than 35 microns. Improved dissolution relative to un-micronized drug is documented in the said patent. However, the formulation as disclosed in the patent application does not show significant improvement in bioavailability.
- U.S. Pat. No. 4,389,393 describes sustained release therapeutic composition using less than about one third of the weight of the solid unit dosage form, of hydroxypropyl methylcellulose or a mixture of hydroxypropyl methylcellulose with certain other rate controlling polymers.
- the inventors disclose that they have been able to achieve sustained release from solid dosage forms containing as little as about 5 to about 30 weight percent of these hydroxypropyl methylcelluloses. All the examples disclose compositions containing 9% or more of the rate-controlling polymer.
- compositions prepared using polymers in the range of about 50% to about 65% showed pharmacokinetic profile similar to the innovator, which has lower polymer content.
- the object of the present invention is to provide a pharmaceutical composition for extended release of erythromycin or its derivatives for once daily administration comprising about 50% to about 65% by weight of pharmaceutically acceptable polymers.
- Another object of the invention is to provide a process for preparing extended release composition of erythromycin or its derivatives comprising mixing the drug with about 50% to about 65% by weight of one or more than one of pharmaceutically acceptable polymers, granulating the blend by wet or dry means, followed by either filling the granules into capsules, sachets or compressing them into tablets.
- Yet another object of the present invention is to provide a pharmaceutical composition for extended release of Clarithromycin comprising from about 50% to about 65% of pharmaceutically acceptable polymers, wherein the T/R ratio of the geometric mean of Cmax and AUC are within acceptable limit (80-125%) with respect to the currently marketed extended release Clarithromycin formulation marketed under the trade name Biaxin XL.
- an extended release formulation of erythromycin or its derivatives suitable for once daily oral administration comprising about 50% to about 65% by weight of pharmaceutically acceptable polymers or combinations thereof.
- the invention provides for an extended release formulation of erythromycin or derivatives thereof, comprising erythromycin or derivatives thereof, pharmaceutically acceptable polymers in the range of about 50% to about 65% by weight, in addition to other pharmaceutically acceptable excipients
- the extended release formulation of the invention is prepared by following the processes of wet or dry granulation, filling the granules into capsules, sachets or compressing into tablets.
- Erythromycin or derivatives used according to the present invention comprise about 10% to about 40% of the total weight of the formulation.
- the pharmaceutically acceptable polymers are present in the range of about 50% to about 65% by weight.
- the pharmaceutically acceptable polymers according to the present invention may be selected from group of polyvinyl pyrrolidine, celluloses, polyvinyl pyrrolidone/polyvinyl acetate copolymers, polyethylene oxide polymers, acrylic acid polymers, methacrylic acid copolymers, natural gums, and derivatives and mixtures thereof.
- Celluloses used in accordance with the present invention include hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethylcellulose, methylcellulose and the like.
- the viscosity of the polymers may be in the range of 5 to 200 cps.
- Polyvinyl pyrrolidone/polyvinyl acetate copolymers according to the present invention may be such as available under the brand name Kollidon SR (BASF).
- Polyethylene oxide polymers are sold by Union Carbide.
- Acrylic acid polymers according to the present invention may be such as available under the brand name carbopol (B.F. Goodrich, USA).
- composition may contain pharmaceutically acceptable excipients such as buffering agents, binders, lubricants and fillers.
- Fillers according to the present invention may be selected from amongst those conventionally used in the art such as lactose, starches, glucose, sucrose, mannitol, silicic acid and mixtures thereof.
- composition according to the present invention may also contain pharmaceutically acceptable lubricants such as those selected from amongst talc, calcium stearate, magnesium stearate, polyethylene glycol, silicon dioxide, sodium stearyl fumarate and the like.
- pharmaceutically acceptable lubricants such as those selected from amongst talc, calcium stearate, magnesium stearate, polyethylene glycol, silicon dioxide, sodium stearyl fumarate and the like.
- the release profile of the product is evaluated using USP apparatus Type 1 (basket), at 100 rpm in 900 ml. Medium for 0 to 2h, pH 3.5 acetate buffer. The medium was then changed to pH 6.8 phosphate buffer, for the next 12 hours.
- Example 1 i) Clarithromycin 38.46 % ii) Hydroxypropyl Methylcellulose lOOcps 7.00 % iii) Hydroxypropyl Methylcellulose 5cps 48.00 % iv) Lactose 4.23 % v) Talc 1.54 % vi) Magnesium Stearate 0.77 % vii) Water qs
- Example 3 i) Clarithromycin 38.46 % ii)Hydroxypropyl Methylcellulose 5cps 46.50 % iii) Hydroxypropyl Methylcellulose lOOcps 7.00 % iv) Sodium alginate (Keltone LVCR) 1.50 % v) Lactose 4.23 % vi) Talc 1.54 % vii) Magnesium Stearate 0.77 % viii) Water qs
- Example 4 i) Clarithromycin 38.46 % ii) Hydroxypropyl Methylcellulose lOOcps 10.00 % iii) Hydroxypropyl Methylcellulose 5cps 45.00 % iv) Lactose 4.23 % v) Talc 1.54 % vi) Magnesium Stearate 0.77 % vii) Water qs
- Example 6 i) Clarithromycin 35.89 % ii)Hydroxypropyl Methylcellulose 5cps 48.50 % iii) Hydroxypropyl Methylcellulose lOOcps 7.00 % ( Methocel KlOO LN) iv) Sodium alginate (Keltone LNCR) 1.50 % v) Xanthan Gum 1.00 % vi) Lactose 3.95 % vii) Talc 1.44 % viii) Magnesium Stearate 0.72 % ix) Water qs
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A pharmaceutical composition for extended release of erythromycin or a derivative thereof. the composition comprises comprising a pharmaceutically effective amount of the drug and about 50% to about 65% by weight of one or more pharmaceutically acceptable polymer(s). The pharmaceutically acceptable polymer(s) are selected from the group comprising polyvinyl pyrrolidine, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, ethyl cellulose, polyvinyl pyrrolidone/polyvinyl acetate copolymers, polyethylene oxide polymers, acrylic acid polymers, methacrylic acid copolymers, natural gums, and derivatives and mixtures thereof.
Description
CLARITHROMYCIN EXTENDED RELEASE FORMULATION
FIELD OF INVENTION
The present invention relates to extended release pharmaceutical compositions of erythromycin or derivatives thereof for once daily administration.
BACKGROUND OF THE INVENTION
The advantages of extended release dosage forms are well known i.e. reduced daily dosage, patient convenience and improved patient compliance. Erythromycin and derivatives are known for their anti-bacterial activity against a number of micro-organisms and are typically administered as immediate release (IR) compositions, two or three times a day, for a regimen of 10 to 14 days.
In particular the 6-O-methylerythromycin A (Clarithromycin), which has been disclosed in US patent No. 4,331,803. It is currently marketed by Abbott as an immediate release formulation, for at least twice daily administration. Abbott is also marketing controlled release composition of Clarithromycin 500 mg under the brand "Biaxin XL".
Literature discloses various approaches for therapeutic dosage forms, which are designed to deliver the drug at an extended rate to the gastrointestinal tract.
U.S. Patent 4,842,866 discloses the development of a controlled release formulation of erythromycin derivatives using an alginate matrix comprising a water-soluble alginate and a complex salt of alginic acid, having one cation that yields a soluble alginate salt and another cation that alone yields an insoluble alginate salt.
U.S. Patent 5,705,190, claims formulations using soluble alginate, a complex salt of alginic acid and an organic carboxylic acid. The said patent discloses compositions containing equimolar quantities of citric acid and clarithromycin.
US patents 6,010,718, and 6,551,616 disclose formulations of extended release clarithromycin containing 5 to 50% w/w of pharmaceutically acceptable polymer. The specification and examples of this patent disclose preferred formulations containing 10%-
30% by weight of hydroxypropyl methylcellulose, the rate-controlling polymer, in the
formulation in addition to other excipients. This patent covers Clarithromycin extended release formulation currently marketed under the trade name Biaxin XL™.
US patent application 2003/0175341 discloses controlled release formulations containing about 0.1% to about 4.5% of one or more cellulosic ether rate controlling polymers.
PCT application WO 03/082241 discloses clarithromycin formulations having improved bioavailability, using micronized drug. The patent exemplifies formulations of extended release clarithromycin containing the drug of particle size less than 35 microns. Improved dissolution relative to un-micronized drug is documented in the said patent. However, the formulation as disclosed in the patent application does not show significant improvement in bioavailability.
U.S. Pat. No. 4,389,393 describes sustained release therapeutic composition using less than about one third of the weight of the solid unit dosage form, of hydroxypropyl methylcellulose or a mixture of hydroxypropyl methylcellulose with certain other rate controlling polymers. In the specification of this patent, the inventors disclose that they have been able to achieve sustained release from solid dosage forms containing as little as about 5 to about 30 weight percent of these hydroxypropyl methylcelluloses. All the examples disclose compositions containing 9% or more of the rate-controlling polymer.
It has been surprisingly found that compositions prepared using polymers in the range of about 50% to about 65% showed pharmacokinetic profile similar to the innovator, which has lower polymer content.
OBJECT OF THE INVENTION
The object of the present invention is to provide a pharmaceutical composition for extended release of erythromycin or its derivatives for once daily administration comprising about 50% to about 65% by weight of pharmaceutically acceptable polymers.
Another object of the invention is to provide a process for preparing extended release composition of erythromycin or its derivatives comprising mixing the drug with about 50% to about 65% by weight of one or more than one of pharmaceutically acceptable polymers,
granulating the blend by wet or dry means, followed by either filling the granules into capsules, sachets or compressing them into tablets.
Yet another object of the present invention is to provide a pharmaceutical composition for extended release of Clarithromycin comprising from about 50% to about 65% of pharmaceutically acceptable polymers, wherein the T/R ratio of the geometric mean of Cmax and AUC are within acceptable limit (80-125%) with respect to the currently marketed extended release Clarithromycin formulation marketed under the trade name Biaxin XL.
SUMMARY OF THE INVENTION
According to a basic aspect of the present invention there is provided an extended release formulation of erythromycin or its derivatives suitable for once daily oral administration, comprising about 50% to about 65% by weight of pharmaceutically acceptable polymers or combinations thereof.
According to a preferred aspect the invention provides for an extended release formulation of erythromycin or derivatives thereof, comprising erythromycin or derivatives thereof, pharmaceutically acceptable polymers in the range of about 50% to about 65% by weight, in addition to other pharmaceutically acceptable excipients
The extended release formulation of the invention is prepared by following the processes of wet or dry granulation, filling the granules into capsules, sachets or compressing into tablets.
DETAILED DESCRIPTION OF THE INVENTION
Erythromycin or derivatives used according to the present invention comprise about 10% to about 40% of the total weight of the formulation. The pharmaceutically acceptable polymers are present in the range of about 50% to about 65% by weight.
The pharmaceutically acceptable polymers according to the present invention may be selected from group of polyvinyl pyrrolidine, celluloses, polyvinyl pyrrolidone/polyvinyl
acetate copolymers, polyethylene oxide polymers, acrylic acid polymers, methacrylic acid copolymers, natural gums, and derivatives and mixtures thereof.
Celluloses used in accordance with the present invention include hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethylcellulose, methylcellulose and the like. The viscosity of the polymers may be in the range of 5 to 200 cps.
Polyvinyl pyrrolidone/polyvinyl acetate copolymers according to the present invention may be such as available under the brand name Kollidon SR (BASF).
Polyethylene oxide polymers are sold by Union Carbide.
Natural gums according to the present invention include Xanthan gum, Locust bean gum, guar gum, gum karaya, alginates and the like.
Acrylic acid polymers according to the present invention may be such as available under the brand name carbopol (B.F. Goodrich, USA).
In addition to the pharmaceutically acceptable polymers the composition may contain pharmaceutically acceptable excipients such as buffering agents, binders, lubricants and fillers.
Buffering agents may be selected from the groups comprising alkali and alkaline earth metal phosphates, citrates, succinates, and the like.
Fillers according to the present invention may be selected from amongst those conventionally used in the art such as lactose, starches, glucose, sucrose, mannitol, silicic acid and mixtures thereof.
The composition according to the present invention may also contain pharmaceutically acceptable lubricants such as those selected from amongst talc, calcium stearate,
magnesium stearate, polyethylene glycol, silicon dioxide, sodium stearyl fumarate and the like.
The release profile of the product is evaluated using USP apparatus Type 1 (basket), at 100 rpm in 900 ml. Medium for 0 to 2h, pH 3.5 acetate buffer. The medium was then changed to pH 6.8 phosphate buffer, for the next 12 hours.
EXAMPLES
The following examples illustrate the invention, without limiting it.
Example 1 i) Clarithromycin 38.46 % ii) Hydroxypropyl Methylcellulose lOOcps 7.00 % iii) Hydroxypropyl Methylcellulose 5cps 48.00 % iv) Lactose 4.23 % v) Talc 1.54 % vi) Magnesium Stearate 0.77 % vii) Water qs
Procedure: The drug and excipients were blended and granulated with water. The granules were dried, sized, lubricated and compressed into tablets of suitable size and hardness.
Example 2 i) Clarithromycin 38.46 % ii) Hydroxypropyl Methylcellulose 5cps 50.00 % iii) Kollidone SR 5.00 % iv) Lactose 4,23 % v) Talc 1.54 % vi) Magnesium Stearate 0.77 % vii) Water qs
Procedure : The drug and excipients were blended and granulated with water. The granules were dried, sized, lubricated and compressed into tablets of suitable size and hardness.
Example 3 i) Clarithromycin 38.46 % ii)Hydroxypropyl Methylcellulose 5cps 46.50 % iii) Hydroxypropyl Methylcellulose lOOcps 7.00 % iv) Sodium alginate (Keltone LVCR) 1.50 % v) Lactose 4.23 % vi) Talc 1.54 % vii) Magnesium Stearate 0.77 % viii) Water qs
Procedure: The drug and excipients were blended and granulated with water. The granules were dried, sized, lubricated and compressed into tablets of suitable size and hardness.
Example 4 i) Clarithromycin 38.46 % ii) Hydroxypropyl Methylcellulose lOOcps 10.00 % iii) Hydroxypropyl Methylcellulose 5cps 45.00 % iv) Lactose 4.23 % v) Talc 1.54 % vi) Magnesium Stearate 0.77 % vii) Water qs
Procedure: The drug and excipients were blended, and granulated with water. The granules were dried, sized, lubricated and compressed into tablets of suitable size and hardness.
ample 5 i) Clarithromycin 35.89 % ii)Hydroxypropyl Methylcellulose 5cps 48.00 % iii) Hydroxypropyl Methylcellulose lOOcps 7.00 % (Methocel KlOO LN) iv) Sodium alginate (Keltone LNCR) 3.00 % v) Lactose 3.95 % vi) Talc 1.44 % vii) Magnesium Stearate 0.72 % viii) Water qs
Procedure: The drug and excipients were blended and granulated with water. The granules were dried, sized, lubricated and compressed into tablets of suitable size and hardness.
Example 6 i) Clarithromycin 35.89 % ii)Hydroxypropyl Methylcellulose 5cps 48.50 % iii) Hydroxypropyl Methylcellulose lOOcps 7.00 % ( Methocel KlOO LN) iv) Sodium alginate (Keltone LNCR) 1.50 % v) Xanthan Gum 1.00 % vi) Lactose 3.95 % vii) Talc 1.44 % viii) Magnesium Stearate 0.72 % ix) Water qs
Procedure: The drug and excipients were blended and granulated with water. The granules were dried, sized, lubricated and compressed into tablets of suitable size and hardness.
Dissolution profiles of the above examples are summarized below in Table I:
Formulation prepared according to one of the preceeding examples was subjected to a bioequivalence study against the extended release formulation of Clarithromycin marketed under the name Biaxin XL TM in the US. The T/R ratio of geometric mean of Cmax and AUC was within acceptable limits (80%-125%) as shown in Table II.
It was surprisingly found that our formulation comprising from about 50% to about 65% of pharmaceutically acceptable polymers was bio-equivalent to Biaxin XL.
Claims
1. A pharmaceutical composition for extended release of erythromycin or a derivative thereof, comprising a pharmaceutically effective amount of the drug and about 50% to about 65% by weight of one or more pharmaceutically acceptable polymer(s).
2. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable polymer(s) are selected from the group comprising polyvinyl pyrrolidine, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, ethyl cellulose, polyvinyl pyrrolidone/polyvinyl acetate copolymers, polyethylene oxide polymers, acrylic acid polymers, methacrylic acid copolymers, natural gums, and derivatives and mixtures thereof.
3. The extended release pharmaceutical composition according to claim 2, wherein the pharmaceutically acceptable polymer(s) is hydroxypropylmethyl cellulose or combinations thereof.
4. The extended release pharmaceutical composition according to claim 3, wherein the hydroxypropylmethyl cellulose with viscosity ranging from about 5 to about 200 cps.
5. The extended release pharmaceutical composition according to claim 1, wherein the composition comprises from about 30% to about 45% by weight of the erythromycin or a derivative.
6. The extended release pharmaceutical composition according to claim 1 , wherein the erythromycin derivative is clarithromycin.
7. A pharmaceutical composition prepared according to claim 1, wherein the extended release composition further comprises pharmaceutical aids such as buffering agents, fillers, binders and lubricants.
8. A pharmaceutical composition according to claim 7, wherein the buffering agents may be selected from the groups comprising alkali and alkaline earth metal phosphates, citrates, succinates, and the like.
9. A pharmaceutical composition according to claim 7, wherein the fillers may be selected from lactose, starch, glucose, sucrose, mannitol, silicic acid and mixtures thereof.
10. A pharmaceutical composition according to claim 7, wherein the binder is selected from starch, polyvinyl pyrrolidone, gelatin, gums and the like.
11. A pharmaceutical composition according to claim 7 wherein the lubricants are selected from talc, stearates, polyethylene glycol, silicon dioxide, sodium stearyl fumarate and the like.
12. A method of using an extended release composition comprising erythromycin or its derivatives and about 50% to about 65% by weight of pharmaceutically acceptable polymer(s), for the treatment of bacterial infections in a mammal.
13. A process for preparing extended release composition of erythromycin or its derivatives, comprising mixing the drug with about 50% to about 65% by weight of one or more than one of pharmaceutically acceptable polymers, granulating the blend by wet or dry means, followed by either filling the granules into capsules or sachets or compressing them into tablets.
14. A pharmaceutical composition for extended release according to claim 1, wherein the T/R ratio of geometric means of C max and AUC are within the acceptable limits(80% - 125%) in comparison with Clarithromycin controlled release formulation as shown in Table II.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN356MU2004 | 2004-03-24 | ||
| PCT/IN2005/000085 WO2005102289A1 (en) | 2004-03-24 | 2005-03-17 | Clarithromycin extended release formulation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1732518A1 true EP1732518A1 (en) | 2006-12-20 |
Family
ID=34979410
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP05764065A Withdrawn EP1732518A1 (en) | 2004-03-24 | 2005-03-17 | Clarithromycin extended release formulation |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1732518A1 (en) |
| AU (1) | AU2005235237A1 (en) |
| BR (1) | BRPI0508743A (en) |
| MX (1) | MXPA06010805A (en) |
| WO (1) | WO2005102289A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1638529B1 (en) * | 2003-06-16 | 2016-08-10 | ANDRX Pharmaceuticals, LLC. | Oral extended-release composition |
| US20070141148A1 (en) * | 2005-11-30 | 2007-06-21 | Merz Pharma Gmbh & Co. Kgaa | Neramexane MR matrix tablet |
| EP2005946B1 (en) * | 2006-04-12 | 2015-11-18 | Nippon Soda Co., Ltd. | Method for producing extended release tablet |
| WO2008114143A1 (en) * | 2007-03-22 | 2008-09-25 | Aurobindo Pharma Limited | Extended release formulations of macrolide antibiotic |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8723896D0 (en) * | 1987-10-12 | 1987-11-18 | Aps Research Ltd | Controlled-release formulation |
| US6010718A (en) * | 1997-04-11 | 2000-01-04 | Abbott Laboratories | Extended release formulations of erythromycin derivatives |
| SI20150A (en) * | 1999-02-19 | 2000-08-31 | Lek, Tovarna Farmacevtskih In | Directly compressible matrix for controlled release of the daily dose of clarytomicyne |
| CA2405918A1 (en) * | 2001-10-01 | 2003-04-01 | Ind-Swift Limited | Controlled release macrolide pharmaceutical formulations |
| EP1638529B1 (en) * | 2003-06-16 | 2016-08-10 | ANDRX Pharmaceuticals, LLC. | Oral extended-release composition |
| US7943585B2 (en) * | 2003-12-22 | 2011-05-17 | Sandoz, Inc. | Extended release antibiotic composition |
-
2005
- 2005-03-17 WO PCT/IN2005/000085 patent/WO2005102289A1/en not_active Ceased
- 2005-03-17 MX MXPA06010805A patent/MXPA06010805A/en unknown
- 2005-03-17 AU AU2005235237A patent/AU2005235237A1/en not_active Abandoned
- 2005-03-17 EP EP05764065A patent/EP1732518A1/en not_active Withdrawn
- 2005-03-17 BR BRPI0508743-0A patent/BRPI0508743A/en not_active IP Right Cessation
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2005102289A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| BRPI0508743A (en) | 2008-01-22 |
| AU2005235237A1 (en) | 2005-11-03 |
| MXPA06010805A (en) | 2006-12-19 |
| WO2005102289A1 (en) | 2005-11-03 |
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