WO2011086577A2

WO2011086577A2 - Pharmaceutical composition of moxifloxacin and its pharmaceutically acceptable salts

Info

Publication number: WO2011086577A2
Application number: PCT/IN2011/000021
Authority: WO
Inventors: Manne Satyanarayana Reddy; Elevathingal Nicholas Madhu
Original assignee: Msn Laboratories Limited
Priority date: 2010-01-12
Filing date: 2011-01-11
Publication date: 2011-07-21
Also published as: WO2011086577A3

Abstract

A solid pharmaceutical composition of moxifloxacin, its pharmaceutically acceptable salts and/or hydrates thereof as well as process for its preparation are disclosed. Furthermore, a stable aqueous formulation of moxifloxacin hydrochloride and process for its preparation are also disclosed. The pharmaceutical compositions disclosed herein can be used for the treatment and/or the prevention of bacterial infections in humans and/or animals.

Description

Pharmaceutical Composition of Moxifloxacin and its pharmaceutically acceptable salts

Related Applications:

This application claims the benefit of priority of our Indian complete specification number: 80/CHE/2010, filed on 12^th January 2010, which is incorporated herein by reference.

Field of the Invention:

The present invention relates to pharmaceutical composition of moxifloxacin, its pharmaceutically acceptable salts and/or hydrates thereof and also relates to process for its preparation. Moxifloxacin is chemically known as l-cyclopropyl-7-([S,S]- 2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-l,4-dihydro-8-methoxy-4-oxo-3-quinolone carboxylic acid (formula- 1).

Formula- 1

Furthermore, the present invention relates to aqueous formulation of moxifloxacin hydrochloride and its process.

Background of the invention

Moxifloxacin is an effective anti-infective agent which can be used for the treatment of various infections, like acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis and community acquired pneumonia. It is also used in the treatment of tuberculosis. Moxifloxacin hydrochloride tablets are marketed under the brand name of Avelox by Bayer.

Moxifloxacin and its related compounds were reported in U.S. Patent No.

4,990,517. The patent also discloses a pharmaceutical preparation that includes the moxifloxacin, with microcrystalline cellulose, maize starch, poly-(l-vinyl)2-pyrrolidone

(insoluble), finely divided silica and magnesium stearate.

Moxifloxacin hydrochloride monohydrate was reported in U.S. Patent No.

5,849,752. This patent also discloses a pharmaceutical preparation that includes the moxifloxacin hydrochloride monohydrate, with microcrystalline cellulose, maize starch,

PVP-25, croscarmellose sodium and magnesium stearate. This patent does not explain specific advantages by using this composition.

U.S. Patent No. 6,610,327 discloses pharmaceutical preparations for oral administration that includes moxifloxacin or a salt or a 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. It has been disclosed that the use of 2.5 to

25% of lactose in the composition improved the hardness or breaking load of the tablet formulation. Though there was an improvement in these properties, they were not substantial enough as desired.

WO 2005/020998 discloses pharmaceutical preparation that includes moxifloxacin and at least one intragranular and extragranular substantially water insoluble excipients.

Still there is a scope for the improvement of the moxifloxacin hydrochloride composition for enhanced release properties. When the present inventor working on enhancing the release properties of moxifloxacin hydrochloride tablets, we surprisingly found that, excess concentration of lactose with or without wet binder has improved the properties like hardness of the tablets or the breaking load and release properties. The usage of wet binder further provides greater viscosity and adhesive properties improve the overall quality of the pharmaceutical composition compared to the prior art compositions, which involves dry binder.

US 6548079 disclosed an aqueous formulation comprises moxifloxacin hydrochloride and sodium chloride and process for its preparation. There is no specific disclosure found for the aqueous formulation comprising moxifloxacin free base. We the present inventor surprisingly found that the usage of moxifloxacin free base as an active ingredient along with hydrochloric acid and sodium chloride leads to highly stable formulation compared to prior art. Hence the main objective of the present invention is to provide solid pharmaceutical composition comprising moxifloxacin hydrochloride with improved release properties and stable aqueous composition of moxifloxacin hydrochloride compared to the known compositions.

Summary of the invention:

Accordingly the first aspect of the present invention provides a pharmaceutical composition of moxifloxacin, its salts and/or hydrate which comprises of lactose in a concentration of from 26% to 50%, along with at least one disintegrant, a glidant and a lubricant.

The second aspect of this invention provides a pharmaceutical composition of moxifloxacin, its salts and/or hydrate which comprises of lactose in a concentration of from 26% to 50%, along with one wet binder, at least one disintegrant, a glidant and a lubricant.

The third aspect of the present invention provides a pharmaceutical composition of moxifloxacin, its salts and/or hydrate comprising the active substance in combination with water soluble diluent especially mannitol, at least one wet binder, at least one disintegrant, a glidant and a lubricant.

The fourth aspect of the present invention provides an aqueous formulation of moxifloxacin hydrochloride comprises moxifloxacin free base, sodium chloride, hydrochloric acid and water for injection.

Furthermore, the present invention provides a process for preparing tablets which comprise such preparations.

Detailed Description of the invention:

Unless otherwise specified, as used herein the term "moxifloxacin" refers to its salts, solvates, enantiomers or mixtures thereof. The salts of moxifloxacin include, for example, acid addition salts, such as hydrochloric acid, sulphuric acid, acetic acid, lactic acid, etc. In particular, the acid addition salt is moxifloxacin hydrochloride monohydrate. As used herein an aqueous formulation refers to that the components of the formulation present in water.

The formulation according to the present invention preferably comprises from 50 to 80%, preferably from 60 to 75% of moxifloxacin or salts and/or hydrates thereof (all the percentages are % by weight based on the weight of the pharmaceutical preparation). Based on the individual dose, the pharmaceutical preparation comprises generally from 50 to 800 mg of moxifloxacin, preferably from 100 to 600 mg, more preferably from 200 to 400 mg of moxifloxacin.

The first aspect of the present invention provides a pharmaceutical composition of moxifloxacin, its salts and/or hydrate which comprises of lactose in a concentration of from 26 to 50%, along with at least one disintegrant, a glidant and a lubricant. The second aspect of the present invention provides a pharmaceutical composition of moxifloxacin, its salts and/or hydrate which consist of lactose in a concentration of 26% to 50%, along with wet binder, at least one disintegrant, a glidant and a lubricant.

The pharmaceutical preparation comprises, as components which are essential for achieving the object according to the invention, from 26 to 50% of lactose, preferably form 28 to 45% of lactose and more preferably from 30 to 35% of lactose. The lactose used can be intra-granular as well as inter-granular.

The main advantage of the present invention emphasizes the usage of higher percentage of lactose, which will improve the solubility of the tablet and also enhances the stability of the product.

The third aspect of the present invention provides a pharmaceutical composition of moxifloxacin, its salts and/or hydrates comprising the active substance in combination with water soluble diluent especially mannitol, at least wet binder, at least one disintegrant, a glidant and a lubricant.

The fourth aspect of the present invention provides an aqueous formulation of moxifloxacin hydrochloride comprises moxifloxacin free base, sodium chloride, hydrochloric acid and water for injection. The present invention involves the usage of highly stable moxifloxacin free base prepared as per the process disclosed in WO 2008/059521 and has been converted to hydrochloride salt during formulation process for preparing aqueous formulation of moxifloxacin hydrochloride. Where as the prior art composition involves the usage of hygroscopic moxifloxacin hydrochloride as an active ingredient, which exist in different polymorphic forms. Further the aqueous formulation of the present invention is more stable and there is no crystal formation or sedimentation of particles and no impurities were found during storage. Hence the aqueous formulation of moxifloxacin hydrochloride of the present invention is highly advantages over the known aqueous composition of moxifloxacin hydrochloride.

, According to the present invention the wet binder is selected from the group consisting of: corn starch, polyvinyl pyrrolidone (povidone), vinylpyrrolidone- vinylacetate copolymer (copovidone) and cellulose derivatives like hydroxy methylcellulose, hydroxy ethylcellulose, hydroxy propylcellulose and hydroxy propylmethylcellulose. According to the invention, the wet binder preferably used is polyvinyl pyrrolidone. This is commercially available, for example under the name povidone. The pharmaceutical preparation advantageously utilizes from 0 to 10%, preferably from 0.5% to 6%, more preferably from 1 to 2% of the wet binder.

According to the present invention the water soluble diluent is selected from polyols such as mannitol, xylitol, sorbitol; polysaccharides such as dextrates, maltodextrin and cyclodextrins. According to the invention, the water soluble diluent preferably used is mannitol. The pharmaceutical preparation advantageously utilzes from 15 to 40%, preferably from 20 to 38%, more preferably from 25 to 35% of the water soluble diluent.

According to the present invention the disintegrant is selected from the group consisting of starch, pregelatinized starch, starch glycolates, crosslinked polyvinylpyrrolidone and sodium carboxymethylcellulose (croscarmellose sodium). According to the invention, the disintegrant preferably used is croscarmellose sodium. The pharmaceutical preparation advantageously utilizes from 1 to 10%, preferably from 1.5 to 8%, more preferably from 2 to 6% of the disintegrant. According to the present invention the lubricant is selected from the group consisting of fatty acids and their salts. According to the present, the lubricant preferably used is magnesium stearate. The pharmaceutical preparation advantageously utilizes from 0.2 to 2%, preferably from 0.3 to 1.5%, more preferably from 0.4 to 1% of the lubricant.

According to the present invention the glidant is selected from the group consisting of colloidal silicon dioxide, calcium silicate, magnesium silicate, silicon hydrogel, talc. According to the invention, the glidant preferably used is colloidal silicon dioxide. The pharmaceutical preparation advantageously utilizes from 0 to 0.5%, preferably from 0.1 to 0.4%, more preferably from 0.2 to 0.35% of the glidant. The colors may be selected from any FDA approved colors for internal use. The formulation may optionally be coated.

The pharmaceutical composition of this invention may be administered to a subject in need of treatment by a variety of conventional routes of administration, preferably oral and intravenous administrations.

The pharmaceutical composition of this invention may be present in several product forms, but not limited to tablet, capsule or granule, preferably tablet or capsule. An aqueous formulation of moxifloxacin hydrochloride of this invention present in the form of intravenous injections.

The dosage form may be in tablet or capsule form, however, the tablet form is particularly suitable for the present formulation which may optionally be coated. For coating, any formulation, which is customary in pharmaceutical technology, such as, for example, those based on hydroxy methyl cellulose and/or polyethylene glycol of various molecular weights may be used.

The pharmaceutical preparation according to the invention is preferably used for the treatment and/or the prevention of bacterial infections in humans and/or animals.

The Active Pharmaceutical Ingredient Moxifloxacin and its pharmaceutically acceptable salts or its hydrates prepared by the process disclosed in US 5,849,752 & US 4,990,517 or by the process known in the art. The invention is further illustrated by the following examples but they should not be construed as limiting the scope of the invention any way.

Examples:

Example 1:

TABLE- 1

Process:

Compound-I and lactose were mixed in Shizona mixer to form a partial granulating mixture. This partial granulating mixture was granulated with purified water until coagulate mass obtained. The obtained granules were dried. The dried granules were screened and then the resulting granules were mixed in blender with lactose, croscarmellose sodium and colloidal silicon dioxide and magnesium stearate for 10 minutes. The blend was then subjected to compression on a machine to make tablets.

The cores were coated in a coating pan with hydroxypropyl cellulose and with colouring agents used as titanium dioxide and yellow oxide of iron.

Example 2:

TABLE-2

Process:

Compound-I and mannitol were mixed in Shizona mixer to form a partial granulating mixture. Added binder solution of povidone to the above partial granulating mixture and mixed until coagulate mass was obtained. The obtained granules were dried. The dried granules were screened and then the resulting granules were mixed in blender with mannitol, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate for 10 minutes. The blend was then subjected to compression on a machine to make tablets.

The cores were coated in a coating pan with hydroxypropyl cellulose and with coloring agents used as titanium dioxide and yellow oxide of iron.

Example 3:

TABLE-3

Moxifloxacin hydrochloride tablet formulation

Ingredients Amount mg/ tablet

Moxifloxacin hydrochloride monohydrate equivalent to 436.40 Moxifloxacin [compound-I]

Lactose 235.10

Povidone 11.00

Crosscarmellose sodium 16.50

Colloidal silicon dioxide 2.00

Magnesium stearate 4.00

Total weight 705.00

Process:

Compound-I and lactose were mixed in Shizona mixer to form a partial granulating mixture. Added binder solution of povidone to the above partial granulating mixture and mixed until coagulate mass was obtained. The obtained mass was dried. The dried granules were screened and then the resultihg granules were mixed in blender with lactose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate for 10 minutes. The blend was then subjected to compression on a machine to make tablets.

Example 4;

TABLE-4

Process:

Moxifloxacin was added to warm water for injection under nitrogen atmosphere. Sodium chloride was added to the above solution and mixed well. Adjusted the solution pH~3.5- 4.6 by using dilute hydrochloride. The solution was filtered through 0.22 micron nylon and filled in USP type 1 glass vials. Dissolution tests with Moxifloxacin Pharmaceutical Tablet Dosage forms:

Dissolution tests of the moxifloxacin pharmaceutical tablet formulation prepared according to the examples 1 to 3 were performed and compared with the dissolution of the reference tablet formulation, i.e., Avelox, marketed by Bayer. These in vitro dissolution tests were conducted using an Apparatus-II (Paddle Method). The comparative dissolution tests were conducted under the following conditions.

Avelox tablets and moxifloxacin tablets of examples 1 to. 3 were dissolved in a USP type II apparatus at paddle speed of 50 rpm, at temperature 37° C, in 900 ml of 0.1 N HC1. The results of these dissolution tests are presented in Table-4

TABLE-4

Avelox tablets and moxifloxacin tablets of examples 1 to 3 were dissolved in a USP type II apparatus at paddle speed of 50 rpm, at temperature 37° C, in 900 ml of a buffer at pH 6.8. The results of these dissolution tests are presented in Table-5

TABLE-5

Avelox tablets and moxifloxacin tablets of examples 1 to 3 were dissolved in a USP type II apparatus at paddle speed of 50 rpm, at temperature 37° C, in 900 ml of a buffer at pH 4.5. The results of these dissolution tests are presented in Table-6 TABLE-6

Stability tests for Pharmaceutical composition of Moxifloxacin:

Stability tests for the moxifloxacin formulation was tested for different time periods and the resulting tested data was tabulated below in Table-7.

TABLE-7

Quinolonic ethyl ester

ND ND ND ND

impurity

Major unknown

ND 0.001% 0.001% 0.005% individual impurity

Total Impurities 0.022% 0.021% 0.021% 0.036%

Water by KF (% w/w) 4.43% 3.89%

Disintegration Time

10Ί5" 6^*18" 6'30" 8'33" (min)

BQL: Below Quality Level,

ND: Non Detected The formulations prepared according to the present invention were in-vitro and in- vivo studies equivalent to the Avelox tablets of Bayer.

Claims

We claim:

1. A pharmaceutical composition for oral administration which comprises:

a) moxifioxacin hydrochloride and /or hydrate thereof,

b) lactose in an amount from 26 to 50% by weight of the composition,

c) at least one wet binder in an amount from 0.5 to 10% by weight of the composition,

d) at least one disintegrant,

e) at least one lubricant and/ or

f) a glidant.

2. A pharmaceutical composition for oral administration which comprises:

a) moxifioxacin hydrochloride and /or hydrate thereof,

b) lactose in an amount from 26 to 50% by weight of the composition,

c) at least one disintegrant,

d) at least one lubricant and/ or

e) a glidant.

3. The pharmaceutical composition according to claim 1 and 2, wherein lactose present in an amount from 30 to 35% by weight of the composition.

4. A pharmaceutical composition for oral administration which comprises:

a) moxifioxacin hydrochloride and /or hydrate thereof,

b) water soluble diluent such as mannitol,

c) at least one wet binder,

d) at least one disintegrant,

e) at least one lubricant and/ or

f) a glidant.

5. The pharmaceutical composition according to claims 1, 2 and 4, characterized in that the wet binder used is povidone.

6. The pharmaceutical composition according to any of the preceding claims, wherein the disintegrant is croscarmellose sodium, lubricant is magnesium stearate, and glidant is colloidal silicon dioxide.

7. The pharmaceutical composition for oral administration according to any of the preceding claims, wherein the composition is in the form of a tablet, a capsule or granules.

8. The pharmaceutical composition for oral administration according to claims 1-7, the composition is in the form of a tablet, which is optionally coated with coating agents and coloring agents.

9. Process for the preparation of the pharmaceutical composition for oral administration according to claims 1 to 8, comprises of the following steps:

a) mixing the moxifloxacin hydrochloride, with lactose and binder solution to obtain homogeneous mixture,

b) drying the obtained granules,

c) mixing of granules with a lactose, a disintegrant, a glidant and a lubricant, d) compressing the granules obtained in preceding step into tablets,

e) coating of tablets obtained in preceding step.

10. The pharmaceutical composition for oral administration according to any of the preceding claims, wherein the composition comprises of 50 to 800 mg of moxifloxacin hydrochloride and/or hydrates thereof, based on an individual dosage.

11. Stable pharmaceutical composition of moxifloxacin hydrochloride for oral administration which comprises:

a) moxifloxacin hydrochloride monohydrate,

b) lactose in an amount from 26 to 50% by weight of the composition,

c) povidone in an amount from 0.5 to 10% by weight of composition.

d) croscarmellose sodium,

e) magnesium stearate and

f) colloidal silicon dioxide.

12. Stable pharmaceutical composition for oral administration which comprises:

a) moxifloxacin hydrochloride monohydrate,

b) lactose in an amount of from 26 to 50% by weight of the composition,

c) croscarmellose sodium, d) magnesium stearate and

e) colloidal silicon dioxide.

13. Stable pharmaceutical composition according to claims 11 and 12, wherein the lactose presents in an amount from 26 to 50%, preferably 30 to 35% by weight of the composition.

14. The stable aqueous formulation of moxifloxacin hydrochloride comprises of:

a) Moxifloxacin free base,

b) sodium chloride,

c) hydrochloric acid,

d) water for injection.

15. Process for the preparation of aqueous formulation moxifloxacin hydrochloride comprises the following steps:

a) Adding moxifloxacin free base to the warm water for injection,

b) adding sodium chloride to the step-a,

c) acidifying the above solution with hydrochloric acid,

d) filtering the above solution and

e) filling the filtrate in a suitable vial.

16. The aqueous formulation according to claims 14 & 15, the formulation is in the form of injections.

17. According to any preceding claims, the pharmaceutical composition of moxifloxacin hydrochloride useful for the treatment and/or the prevention of bacterial infections in humans and/or animals.