WO2005020998A1

WO2005020998A1 - Pharmaceutical compositions of moxifloxacin and processes for their preparation

Info

Publication number: WO2005020998A1
Application number: PCT/IB2004/002875
Authority: WO
Inventors: Romi Barat Singh; Pananchukunnath Manoj Kumar; Vishnubhotla Nagaprasad; Sanjeev Kumar Sethi; Rajiv Malik
Original assignee: Ranbaxy Laboratories Ltd
Current assignee: Ranbaxy Laboratories Ltd
Priority date: 2003-09-03
Filing date: 2004-09-03
Publication date: 2005-03-10
Anticipated expiration: 2006-03-03
Also published as: ZA200602497B; EP1663226A1

Abstract

The present invention relates to pharmaceutical compositions of moxifloxacin. The invention also relates to processes for the preparation of such compositions.

Description

PHARMACEUTICAL COMPOSITIONS OF MOXIFLOXACIN AND PROCESSES FOR THEIR PREPARATION Field of the Invention The field of the invention relates to pharmaceutical compositions of moxifloxacin. The invention also relates to processes for the preparation of such compositions. Background of the Invention Chemically, moxifloxacin is l-cyclopropyl-7- ([S, S]-2,8-diazabicyclo [4.3. 0] non-8-yl)-6-fluoro-l, 4-dihydro-8-methoxy-4-oxo-3-quinolonecarboxylic acid. It is an antiinfective agent and is known from U.S. Patent No. 4,990,517. Moxifloxacin can be used for the treatment of various infections, like acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis and community acquired pneumonia. U.S. Patent No. 4,990,517 discloses a pharmaceutical preparation that includes the active compound, with microcrystalline cellulose, maize starch, poly- (l-vinyl)-2- pyrrolidone (insoluble), finely divided silica and magnesium stearate. U.S. Patent No. 5,286,754 discloses pharmaceutical formulations of ciprofloxacin that include binder based on cellulose, disintegrant based on starch, and a disintegrant based on cellulose derivatives and/or cross-linked polyvinylpyrrolidones. U.S. Patent No. 6,610,327 discloses pharmaceutical preparations for oral administration that includes moxifloxacin or a salt or solvate/hydrate thereof, at least one dry binder, at least one disintegrant and at least one lubricant, characterized in that the preparation contains 2.5 % to 25% of lactose. As described in more detail below, the inventors have surprisingly found that bioequivalent formulations to commercially available Avelox tablet formulations can be obtained by mtragranular and extragranular distribution of substantially water insoluble pharmaceutical excipients. Summary of the Invention In one general aspect there is provided a pharmaceutical composition that includes moxifloxacin and at least one mtragranular and extragranular substantially water insoluble excipient. Embodiments of the composition may include one or more of the following features. For example, the composition may further include other pharmaceutically accepted excipients. The other excipients may include one or more of binders, disintegerants, fillers, lubricants/glidants, and colorants. The substantially insoluble excipients may include one or more of microcrystalline cellulose, pregelatinized starch, dicalcium phosphate dibasic, corn starch, and the like. The binders may be one or more of polyvinyl pyrrolidone, hydroxypropyl cellulose and gums. The fillers may be one or more of cellulose derivatives, starch derivatives, sugars, sugar alcohols, and the like. The disintegrant may be one or more of pregelatinized starch, cross-linked polyvinylpyrrolidone and sodium croscarmellose sodium. In particular, the disintegrant maybe croscarmellose sodium. The disintegrant maybe from 0.5 to 10% by weight of the composition. More particularly, it may be from 2 to 5% by weight of the composition. The lubricant or glidant may be one or more of fatty acids and their salts, colloidal silicon dioxide and talc. In particular, the lubricant is magnesium stearate and the glidant is colloidal silicon dioxide. The lubricant may be advantageously employed in an amount of from 0.05 to 3.0% by weight of the composition. More particularly, it may be from 0.2 to 2% by weight of the composition. The composition may be formulated in the form of granules filled in capsule, tablet or other suitable oral dosage form and, in particular, may be a tablet. The tablet formulation may further be coated. In another general aspect there is provided a process for preparing a pharmaceutical composition of moxifloxacin. The process includes a) preparing an mtragranular portion by mixing moxifloxacin and at least one substantially water insoluble excipient; b) preparing an extragranular portion by mixing at least one substantially water insoluble excipient and other pharmaceutically accepted excipients; and c) compressing said mtragranular portion and extragranular portion to a tablet or filling said mtragranular portion and extragranular portion into a capsule. Embodiments of the process may include one or more of the following features. For example, the mtragranular portion may further include other pharmaceutically accepted excipients. The other excipients may include one or more of binders, disintegerants, fillers, lubricants/glidants, and colorants. The substantially insoluble excipients may include one or more of microcrystalline cellulose, pregelatinized starch, dicalcium phosphate dibasic, corn starch, and the like. The binders may be one or more of polyvinyl pyrrolidone, hydroxypropyl cellulose and gums. The fillers may be one or more of cellulose derivatives, starch derivatives, sugars, sugar alcohols, and the like. The disintegrant may be one or more of pregelatinized starch, cross-linked polyvinylpyrrolidone and sodium croscarmellose sodium. In particular, the disintegrant maybe croscarmellose sodium. The disintegrant maybe from 0.5 to 10% by weight of the composition. More particularly, it may be from 2 to 5% by weight of the composition. The lubricant or glidant may be one or more of fatty acids and their salts, colloidal silicon dioxide and talc. In particular, the lubricant is magnesium stearate and the glidant is colloidal silicon dioxide. The lubricant may be advantageously employed in an amount of from 0.05 to 3.0% by weight of the composition. More particularly, it may be from 0.2 to 2% by weight of the composition. The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims. Detailed Description of the Invention The inventors have found that a bioequivalent formulation to commercially available Avelox tablet formulations can be obtained by mtragranular and extragranular distribution of substantially water insoluble pharmaceutical excipients, with or without the inclusion of lactose. The formulation maybe in the form of granules filled in capsule, tablet or other suitable oral dosage form. As used herein moxifloxacin refers its free base, salts, solvates, enantiomers or mixtures thereof. The salts of moxifloxacin include, for example, acid addition salts, such as salts of hydrochloric acid, sulphuric acid, acetic acid, lactic acid, etc., and also salts with bases, such as sodium hydroxide, potassium hydroxide, etc. hi particular, the acid addition salt may be moxifloxacin hydrochloride monohydrate. The term "substantially insoluble" as used herein, refers to the solubility less than that of lactose. Specific examples of substantially insoluble excipients include microcrystalline cellulose, pregelatinized starch, dicalcium phosphate dibasic, corn starch, and the like. Besides the above substantially insoluble excipients, the mtragranular and extragranular portions may also contain other pharmaceutically acceptable excipients such as binders, disintegerants, fillers, lubricants/glidants, colorants, and the like. Suitable binders may include one or more of polyvinyl pyrrolidone, hydroxypropyl cellulose, gums and the like. Suitable fillers may include one or more of cellulose derivatives, starch derivatives, sugars, sugar alcohols and the like. Suitable disintegrants include one or more of pregelatinized starch, cross-linked polyvinylpyrrolidone, sodium croscarmellose sodium and the like. In particular, the disintegrant may be croscarmellose sodium. The pharmaceutical composition may contain from 0.5 to 10%, preferably from 2 to 5%, of the disintegrant. Suitable lubricants and glidants may include one or more of fatty acids and their salts, colloidal silicon dioxide, talc and the like. In particular, the lubricant is a salt of a fatty acid, for example, magnesium stearate. In particular, the glidant is colloidal silicon dioxide. The lubricant is advantageously employed in an amount of from 0.05 to 3.0%, for example, 0.2 to 2%. The colors maybe selected from any FDA approved colors for internal use. The formulation may optionally be coated.

The dosage form may be in tablet or capsule form, however, the tablet form is particularly suitable. The tablet may further be coated. For coating, any formulation, which is customary in pharmaceutical technology, such as, for example, those based on hydroxypropyl methyl cellulose (HPMC) and/or polyethylene glycol of various molecular weights may be used. The invention is further illustrated by the following examples but they should not be construed as limiting the scope of the invention any way. Example 1 :

Process: 1. All the intragranular excipients except for Polyvinyl pyrrollidone K-30 were sifted and then mixed in a high shear mixer for 10 minutes. 2. Polyvinyl pyrrollidone K-30 was dissolved in a specified amount of purified water. The binder solution was added to the premix under continuous mixing in a high shear mixer till granulation is achieved. 3. The granules were dried, sifted and mixed with microcrystalline cellulose for 10- 15 minutes in a low shear blender. 4. Magnesium stearate was added to the blend of step 3 and mixed for 5 minutes. 5. The final blend was compressed at 700 mg fill weight and coated with Opadry. Example 2:

Process: 1. All the intragranular excipients except for polyvinyl pyrrollidone K-30 were sifted and then mixed in a high shear mixer for 10 minutes. 2. Polyvinyl pyrrollidone K-30 was dissolved in a specified amount of purified water. The binder solution was added to the premix under continuous mixing in a high shear mixer till granulation is achieved. 3. The granules were dried, sifted and mixed with microcrystalline cellulose and colloidal silicon dioxide for 10-15 minutes in a low shear blender. 4. Magnesium stearate was added to the blend of step 3 and mixed for 5 minutes. 5. The final blend was compressed at 700 mg fill weight and coated with Opadry dispersion. Example 3:

Process: 1. All the intragranular excipients except for polyvinyl pyrrollidone K-30 were sifted and then mixed in a high shear mixer for 10 minutes. 2. Polyvinyl pyrrollidone K-30 was dissolved in a specified amount of purified water. The binder solution was added to the premix under continuous mixing in a high shear mixer till granulation is achieved. 3. The granules were dried, sifted and mixed with microcrystalline cellulose and colloidal silicon dioxide for 10-15 minutes in a low shear blender. 4. Magnesium stearate was added to the blend of step 3 and mixed for 5 minutes. 5. The final blend was compressed at 700 mg fill weight and coated with Opadry dispersion. Example 4:

Process: 1. All the intragranular excipients except for polyvinyl pyrrollidone K-30 were sifted and then mixed in a high shear mixer for 10 minutes. 2. Polyvinyl pyrrollidone K-30 was dissolved in a specified amount of purified water. The binder solution was added to the premix under continuous mixing in a high shear mixer till granulation is achieved. 3. The granules were dried, sifted and mixed with dicalcium phosphate and colloidal silicon dioxide for 10-15 minutes in a low shear blender. 4. Magnesium stearate was added to the blend of step 3 and mixed for 5 minutes. 5. The final blend was compressed at 700 mg fill weight and coated with Opadry dispersion. Example 5:

The process similar to above examples was followed to prepare the tablet dosage form. The dissolution profiles of above examples using USP II, 0.01 N HCL, 900ml at 50 rpm is as given below.

The formulations prepared according to the present invention were found to be bioeqivalent to the Avelox tablet dosage form available in the US market by Bayer. The following data shows the phannacokinetic data of tablet formulation of present invention and Avelox tablet available in US market carried out in 12 healthy human volunteers.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.

Claims

We claim:

1. A pharmaceutical composition comprising moxifloxacin and at least one intragranular and extragranular substantially water insoluble excipient.

2. The pharmaceutical composition of claim 1 , wherein the substantially water insoluble excipient has solubility less than that of lactose.

3. The pharmaceutical composition of claim 1 , wherein the substantially water insoluble excipient comprises one or more of microcrystalline cellulose, pregelatinized starch, com starch and dicalcium phosphate dihydrate.

4. The pharmaceutical composition of claim 1 , wherein the substantially water insoluble excipient is microcrystalline cellulose.

5. The pharmaceutical composition of claim 1 , wherein the substantially water insoluble excipient is dicalcium phosphate dihydrate.

6. The pharmaceutical composition of claim 1, wherein the composition further comprises one or more other pharmaceutically acceptable excipients.

7. The pharmaceutical composition of claim 6, wherein the pharmaceutically acceptable excipients comprise one or more of binders, disintegerants, fillers, lubricants/glidants, and colorants.

8. The pharmaceutical composition of claim 7, wherein the binder comprises one or more of polyvinyl pyrrolidone, hydroxypropyl cellulose and gums.

9. The pharmaceutical composition of claim 7, wherein the disintegrant comprises one or more of pregelatinized starch, cross-linked polyvinylpyrrolidone and croscarmellose sodium.

10. The pharmaceutical composition of claim 9, wherein the disintegrant is croscarmellose sodium.

11. The pharmaceutical composition of claim 7, wherein the filler comprises one or more of cellulose derivatives, starch derivatives, sugars, and sugar alcohols.

12. The pharmaceutical composition of claim 7, wherein the lubricant or glidant comprises one or more of fatty acids and their salts, colloidal silicon dioxide and talc.

13. The pharmaceutical composition of claim 12, wherein the lubricant is magnesium stearate.

14. The pharmaceutical composition of claim 1, wherein the composition is a tablet, capsule or granules.

15. The pharmaceutical composition of claim 14, wherein the composition is a tablet.

16. The pharmaceutical composition of claim 15, wherein the tablet is coated.

17. A process for preparing a pharmaceutical composition of moxifloxacin, the process comprising: a) preparing an intragranular portion by mixing moxifloxacin and at least one substantially water insoluble excipient; b) preparing an extragranular portion by mixing at least one substantially water insoluble excipient and other pharmaceutically accepted excipients; and c) compressing said intragranular portion and extragranular portion to a tablet or filling said intragranular portion and extragranular portion into a capsule.

18. The process of claim 17, wherein the substantially water insoluble excipient has water solubility less than that of lactose.

19. The process of claim 17, wherein the substantially water insoluble excipient comprises one or more of microcrystalline cellulose, pregelatinized starch, com starch and dicalcium phosphate dihydrate.

20. The process of claim 19, wherein the substantially water insoluble excipient is microcrystalline cellulose.

21. The process of claim 19, wherein the substantially water insoluble excipient is dicalcium phosphate dihydrate.

22. The process of claim 17, wherein the moxifloxacin is moxifloxacin hydrochloride monohydrate.

23. The process of claim 17, wherein the pharmaceutically acceptable excipients comprise one or more of binders, disintegerants, fillers, lubricants/glidants, and colorants.

24. The process of claim 23, wherein the binder comprises one or more of polyvinyl pyπolidone, hydroxypropyl cellulose and gums.

25. The process of claim 23, wherein the disintegrant comprises one or more of pregelatinized starch, cross-linked polyvinylpyrrolidone and croscarmellose sodium.

26. The process of claim 25, wherein the disintegrant is croscarmellose sodium.

27. The process of claim 23, wherein the filler comprises one or more of cellulose derivatives, starch derivatives, sugars, and sugar alcohols.

28. The process of claim 23, wherein the lubricant or glidant comprises one or more of fatty acids and their salts, colloidal silicon dioxide and talc.

29. The process of claim 28, wherein the lubricant is magnesium stearate.

30. The process of claim 28, wherein the glidant is colloidal silicon dioxide.

31. The process of claim 17, wherein the composition is a tablet.

32. The process of claim 31 further comprising coating the tablet.