WO2007033522A1

WO2007033522A1 - Capsule formulation containing moxifloxacin and its preparation method

Info

Publication number: WO2007033522A1
Application number: PCT/CN2005/001528
Authority: WO
Inventors: Bingqi Zhao; Bangai Zhao; Xueqi Fu
Original assignee: Shenzhen Tys R & D Co., Ltd.
Priority date: 2005-09-21
Filing date: 2005-09-21
Publication date: 2007-03-29

Abstract

A capsule formulation of Moxifloxacin or its salts and/or hydrates, comprises a hydroxpropylmethzlcellulose (HPMC) capsule containing Moxifloxacin, at least one disintegrant and at least one lubricant. Preparation of said formulation comprises : mixing or granulating Moxifloxacin blended with at least one disintegrant and at least one lubricant, then filling the mixture into HPMC capsules. The invented capsule formulation has a stable dissolution rate.

Description

Moxifloxacin capsule and preparation method thereof

The present invention relates to a pharmaceutical preparation of moxifloxacin, and in particular, to a capsule dosage form of moxifloxacin or a salt thereof and/or a hydrate thereof, and a process for the preparation thereof. Background technique

Moxifloxacin is a new generation of fluoroquinolone antibacterial. It has been marketed in tablets and injections for upper and lower respiratory tract infections caused by sensitive microorganisms, such as acute exacerbation of chronic bronchitis, community acquired pneumonia, acute Treatment of bacterial sinusitis and uncomplicated skin and soft tissue infections.

At present, the oral preparations for moxifloxacin only have moxifloxacin hydrochloride tablets, the Chinese patent "moxifloxacin pharmaceutical preparations", patent number 99813124. 5, the oral pharmaceutical tablets are disclosed, and the preparation method thereof is to treat the drugs with at least An anhydrous binder and lactose are granulated with water, which is then mixed with at least one disintegrant and at least one lubricant, and optionally tableted and coated.

In addition, the Chinese patent application "Moxifloxacin / Sodium Chloride Preparation", application number 00811427. 7, publicized moxifloxacin hydrochloride / sodium chloride infusion.

However, it has not been reported as a commonly used capsule for oral medicine. The inventors have found that the raw materials of the formulation of moxifloxacin in the prior art are filled in the gelatin capsule shell, and the dissolution performance is lowered during storage, and the medicinal requirements cannot be met.

The gelatin capsule shell is a capsule which is commonly used for capsules. The inventors filled the gelatin capsule shell with the preparation formula of moxifloxacin hydrochloride in the prior art, prepared capsules, and carried out the stability of 60 ° C for 10 days. After the test, the dissolution was measured, and it was found that the capsules were swollen and the capsules were not broken, and the contents could not be dissolved, or even if some of the capsules were broken, they could not be completely dissolved after 45 minutes, and the room was left for 15 days. That is, the dissolution rate begins to decrease as the capsule is placed for a prolonged period of time. The inventors further granulated the content of the capsule containing moxifloxacin hydrochloride by using a 5% or 5% HPMC solution, and then filling the capsule, and the capsule did not dissolve or the dissolution decreased after the stability test at 60 ° C for 10 days. phenomenon. The dosage of disintegrant was increased in the formulation of moxifloxacin hydrochloride capsules. Although the high temperature and light accelerated experiments and room temperature were observed for 20 days, 43 days, and 3 months, the dissolution behavior was improved, but room temperature was improved. After one year of standing, the observation still showed that the dissolution was unacceptable. (The above dissolution method is determined according to the first method of the Chinese Pharmacopoeia 2000 edition two appendix XC dissolution method determination method one turn blue method lOOrpm, the eluate is 0. lmol / L hydrochloric acid, the content of dissolved moxifloxacin determination method Using HPLC method).

To date, no reports have been published on the in vitro dissolution behavior or dissolution of moxifloxacin or its salts and/or its hydrate gelatin capsules during storage and their solutions. Summary of the invention

SUMMARY OF THE INVENTION An object of the present invention is to provide a capsule dosage form of moxifloxacin or a salt thereof and/or a hydrate thereof which has high dissolution rate and stable dissolution property for a long period of time, and a preparation method of the capsule.

To achieve the above object, the present invention adopts the following technical solutions:

The invention discloses a moxifloxacin capsule containing moxifloxacin or a salt thereof and/or a hydrate thereof, wherein the capsule content further comprises at least one disintegrant and at least one lubricant And the capsule shell of the capsule is a hydroxypropyl methylcellulose capsule shell.

The moxifloxacin or a salt thereof and/or its hydrate is moxifloxacin hydrochloride. The disintegrant includes sodium carboxymethyl starch, microcrystalline cellulose, croscarmellose sodium, and crosslinked polyvinylpyrrolidone.

The disintegrant is added in an amount of 5 to 50% by weight based on the total amount of the capsule contents. Further, the amount of the disintegrant added is 25 to 35% of the total amount of the capsule contents.

The lubricant includes magnesium stearate.

- The capsule contents of the capsule may also contain one or more of other pharmaceutically acceptable amounts of pharmaceutically acceptable excipients such as diluents, binders and the like. A pharmaceutically acceptable amount specifically refers to the amount of these excipients commonly used in the prior art.

5〜1. 5。 The capsules containing 65~74% of moxifloxacin or a salt thereof and/or its hydrate, 25~34% of a disintegrant, and 1. 0~1. % of a lubricant; the disintegrant is one or more mixtures selected from the group consisting of sodium carboxymethyl starch, microcrystalline cellulose, croscarmellose sodium, and crosslinked polyvinylpyrrolidone, the lubricant It is magnesium stearate.

The above percentages are all by weight.

The invention also discloses a preparation method of the above moxifloxacin capsule, the method comprising the steps of: thoroughly mixing moxifloxacin or a salt thereof and/or a hydrate thereof with at least one disintegrant and at least one lubricant or The granules are filled with a hydroxypropyl methylcellulose capsule shell. The granules can be subjected to conventional pharmaceutics, including dry granulation or wet granulation.

The moxifloxacin or a salt thereof and/or its hydrate is moxifloxacin hydrochloride.

The disintegrant includes sodium carboxymethyl starch, microcrystalline cellulose, croscarmellose sodium, and crosslinked polyvinylpyrrolidone.

The lubricant includes magnesium stearate.

Since the above scheme is adopted, the present invention has the beneficial effects that - the moxifloxacin capsule prepared by the invention adopts a hydroxypropyl methylcellulose capsule shell, Overcoming the problem that the preparation of the existing moxifloxacin pharmaceutical preparation is added to the shell of the gelatin capsule leads to a change in the dissolution behavior of the capsule and a decrease in the dissolution rate. The invention adopts a hydroxypropylmethylcellulose capsule shell of moxifloxacin capsule, the dissolution start time is 8~12 minutes, the dissolution degree is high, both are above 90%; at least one suitable amount of disintegrant is contained When the capsule is dissolved, the contents are quickly dissolved by the action of the disintegrant. Moreover, the moxifloxacin capsules of the present invention using the hydroxypropyl methylcellulose capsule shell have stable dissolution properties, and the dissolution is basically unchanged after long-term (two years) storage, and the dissolution rate is compared with that of the fresh preparation. Significant differences are above 90%. detailed description

The structure of moxifloxacin hydrochloride used in the present invention is as follows:

Molecular formula: C21H24FN304. HC1. Molecular weight: 437. 90

Hydroxypropyl methylcellulose (HPMC) capsule shell, also known as plant capsule (VcapsTM), the main component is hydroxypropyl methylcellulose. The hydroxypropyl methylcellulose (HPMC) capsule shell used in the examples of the present invention is a product of Acting French Capsule Co., Ltd. of Suzhou Capsule Co., Ltd.

The hydroxypropyl methylcellulose capsule shell has a slightly slower dissolution time in 0.1 ml of hydrochloric acid than the gelatin capsule shell. In order to make the preparation dissolve better in the stomach and dissolve the drug rapidly after the capsule shell is dissolved, at least one disintegrant or a combination of several disintegrants is used in the formulation of the present invention. They may be selected from the group consisting of sodium carboxymethyl starch, croscarmellose sodium, crosslinked polypyrrolidone, microcrystalline cellulose, etc., preferably sodium carboxymethyl starch and microcrystalline cellulose. Disintegrant addition amount It may be from 5 to 50% of the total amount of the capsule contents, preferably from 25 to 35%, all of which are by weight. In the present invention, a disintegrating agent is an essential component, and when the hydroxypropylmethylcellulose capsule shell is dissolved, the contents can be rapidly dissolved by the action of the disintegrant, and disintegration which can achieve the effect can be achieved. The amount of the agent can be varied within a wide range, and within this range (5 to 50 ° /.), the change in the amount of the disintegrant has little effect on the disintegration effect.

Lubricants commonly used in the art in the prior art can be used in the present invention. Among them, magnesium stearate is a lubricant commonly used in the art. In the capsule of the present invention, the amount of the lubricant can also be added in accordance with the usual addition amount of the lubricant in the prior art. In a preferred embodiment of the invention, the lubricant magnesium stearate is added in an amount of from 1.0 to 1.5% by weight of the capsule content.

The moxifloxacin capsule prepared by the present invention contains moxifloxacin or a salt thereof and/or a hydrate thereof, usually moxifloxacin hydrochloride, and the amount thereof can be determined in accordance with the unit dose required for pharmaceutical or therapeutic use. Typically, it will comprise from 30% to 75% by weight of the capsule contents. In a preferred embodiment of the invention, moxifloxacin hydrochloride is present in the capsule contents in a percentage by weight of from 65 to 74%.

The preparation method of the capsule of the present invention is basically the same as the preparation method of the capsule which is commonly used in the prior art. The raw materials and auxiliary materials in the capsule contents can be thoroughly mixed, filled with a hydroxypropyl methylcellulose capsule shell, or the raw materials and auxiliary materials can be thoroughly mixed. After the dry preparation, the hydroxypropyl methylcellulose capsules are filled. The shell is prepared by preparing a granule by a conventional wet granulation method and filling a hydroxypropyl methylcellulose capsule shell. The raw material referred to herein means the main drug moxifloxacin or a salt thereof and/or its hydrate in the contents of the capsule, the auxiliary material refers to the disintegrating agent and the lubricant used, and the wet granulation can be directly prepared by using water, and some can be added. Commonly used adhesives.

The invention is further described in detail below by way of specific examples. Example 1

Component: Moxifloxacin hydrochloride 218. 4mg

Microcrystalline cellulose 40. Omg

Sodium Carboxymethyl Starch 68. Omg

Magnesium stearate 3. 6mR

Total amount 330. Omg

Preparation method: The raw materials and auxiliary materials in the above components are thoroughly mixed and filled, and filled in a hydroxypropyl methyl cellulose capsule shell. '

The dissolution rate of the obtained capsule was measured. After the obtained capsule was allowed to stand at room temperature for two years, the dissolution was measured in the same manner, and the results are shown in Table 2 below. Example 2

Component: Moxifloxacin hydrochloride · 436. 8mg

Microcrystalline cellulose 55. Omg

Sodium Carboxymethyl Starch 100. Omg

Magnesium stearate 8. 2mR

Total 600· Omg

Preparation method: Take the raw materials and auxiliary materials in the above components and mix well; after the dry preparation, the hydroxypropyl methylcellulose capsules are filled in the shell.

The dissolution rate of the obtained capsule was measured. After the obtained capsule was allowed to stand at room temperature for two years, the dissolution was measured in the same manner, and the results are shown in Table 2 below. Example 3 Component: Moxifloxacin hydrochloride 218. 4mg

Microcrystalline cellulose 30. Omg

Sodium Carboxymethyl Starch 68. Omg

Croscarmellose sodium 10. Omg

Magnesium stearate 3. 6mR

Total amount 330. Omg

Preparation method: The raw materials and auxiliary materials in the above components are thoroughly mixed and filled in a shell of a hydroxypropyl cellulose capsule.

The dissolution rate of the obtained capsule was measured. After the obtained capsule was allowed to stand at room temperature for two years, the dissolution was measured in the same manner, and the results are shown in Table 2 below. Example 4

Component: Moxifloxacin hydrochloride 436. 8mg

Crosslinked polyvinylpyrrolidone 30. Omg

Carboxymethyl starch sodium 125. Omg

Magnesium stearate 8. 2mR

600. Omg

Preparation method: Take the raw materials and auxiliary materials in the above components, thoroughly mix and evenly, and dry-process the particles, and then fill the shell of hydroxypropyl methylcellulose capsules.

The dissolution rate of the obtained capsule was measured. After the obtained capsule was allowed to stand at room temperature for two years, the dissolution was measured in the same manner, and the results are shown in Table 2 below. Example 5 Component: Moxifloxacin hydrochloride 218.1 1⁄2 _g

Sodium Carboxymethyl Starch 108. Omg

Magnesium stearate 3. 6mg

Total amount 330. Omg

Preparation method: The raw materials and auxiliary materials in the above components are thoroughly mixed and filled, and filled in a hydroxypropyl methyl cellulose capsule shell.

The dissolution rate of the obtained capsule was measured. After the obtained capsule was allowed to stand at room temperature for two years, the dissolution was measured in the same manner, and the results are shown in Table 2 below. Example 6

Component: Moxifloxacin hydrochloride 218. 4m _g

Microcrystalline cellulose 180. 6mg

Magnesium stearate 3· Omg

Total amount 402. Omg

The dissolution rate of the obtained capsule was measured. After the obtained capsule was allowed to stand at room temperature for two years, the dissolution was measured in the same manner, and the results are shown in Table 2 below.

Example 7 Preparation method: The raw materials and auxiliary materials in the above components are thoroughly mixed and filled, and filled in a hydroxypropyl methylcellulose capsule shell.

EXAMPLES 8-13 The components of the formulations of the following examples in Table 1 (except magnesium stearate) were mixed, and then an appropriate amount of water was added to prepare suitable soft materials, and granules were prepared, and after drying, stearic acid was added. Mix the magnesium and fill it with a hydroxypropyl methylcellulose capsule.

Table 1. (Unit of weight: mg)

Remarks (1): The particle formulations of Examples 8, 10, 11, and 13 are respectively Chinese patent 99813124. 5 Examples 1, 3,

4, 6 uncoated core formula.

Remarks (2): In the publication of the uncoated core formulation of the example in the Chinese patent (Patent No. 99813124. 5, Publication No. CN1325306A), sodium carboxymethylcellulose should be croscarmellose sodium, It is translated from croscarmellose soldium, see page 2 of the original patent specification, correctly translated as croscarmellose sodium (disintegrant). Comparative Example 1 The components described in Example 1 were uniformly mixed and filled into a capsule. The dissolution was measured immediately after preparation and room temperature for two years. The results are shown in Table 2 below. Comparative Example 2 The components of the formulation described in Example 8 (except magnesium stearate) were mixed, and then an appropriate amount of water was added to prepare a suitable soft material. After drying, the magnesium stearate was added and mixed. Into the capsule shell. (The particle preparation method is basically the same as the uncoated core particle preparation method of the Chinese Patent No. 99813124. 5 embodiment). The dissolution rate of the obtained capsule was measured. After the obtained capsule was allowed to stand at room temperature for two years, the dissolution was measured in the same manner, and the results are shown in Table 2 below. Comparative Example 3 The components of the formulation described in Example 9 (except magnesium stearate) were mixed, and then an appropriate amount of water was added to prepare a suitable soft material, and after drying, magnesium stearate was added and mixed. Into the capsule shell. The dissolution rate of the obtained capsule was measured. After the obtained capsule was allowed to stand at room temperature for two years, the dissolution was measured in the same manner, and the results are shown in Table 2 below. Table 2. Comparison of Dissolution (%) (Inspected at the time of preparation and at room temperature for two years)

Sample 0 months 24 months

Example 1 99. 5 99. 2

Example 2 98. 2 98. 3

Example 3 99. 2 98. 9

Example 4 98. 4 98. 2

Example 5 98. 1 97. 6 Example 6 97.2 99.8

Example 7 101.3 98.3 "Example 8 99.1 101.3

Example 9 98.7 100.4

Example 10 102.5 99.6

Example 11 100.2 99.1

Example 12 97.2 99.3

Example 13 98.8 100.1

Comparative example 1 97.0 0

Comparative example 2 94.0 0

Comparative example 3 95.3 0

Note: Dissolution method: According to the first method of the Chinese Pharmacopoeia 2000 edition two appendix XC dissolution method, the dissolution medium is 0.1M hydrochloric acid solution, the rotation speed is lOOrpm, and the dissolution value is measured for 45 minutes.

Claims

Rights request

A moxifloxacin capsule containing moxifloxacin or a salt thereof and/or a hydrate thereof, wherein the capsule content further comprises at least one disintegrant and at least one A lubricant, and the capsule shell of the capsule is a hydroxypropyl methylcellulose capsule shell.

The moxifloxacin capsule according to claim 1, wherein the moxifloxacin or a salt thereof and/or a hydrate thereof is moxifloxacin hydrochloride.

3. A moxifloxacin capsule according to claim 1 or 2, wherein: the disintegrant comprises sodium carboxymethyl starch, microcrystalline cellulose, croscarmellose sodium, cross-linking Polyvinylpyrrolidone.

The moxifloxacin capsule according to claim 3, wherein the disintegrant is added in an amount of 5 to 50% by weight based on the total amount of the capsule contents.

The moxifloxacin capsule according to claim 4, wherein the disintegrant is added in an amount of 25 to 35% by weight based on the total amount of the capsule contents.

6. A moxifloxacin capsule according to claim 1 or 2, wherein: said lubricant comprises magnesium stearate.

The moxifloxacin capsule according to claim 1 or 2, wherein the capsule contains

65 to 74% by weight of moxifloxacin or a salt thereof and/or a hydrate thereof,

25 to 34% by weight of disintegrant, and

The weight percentage is 1. 0~1. 5% of the lubricant;

The disintegrant is one or more mixtures selected from the group consisting of sodium carboxymethyl starch, microcrystalline cellulose, croscarmellose sodium, and crosslinked polyvinylpyrrolidone, and the lubricant is magnesium stearate. .

8. The method for preparing a moxifloxacin capsule according to claim 1, wherein the method comprises Steps: The moxifloxacin capsule shell is filled with or mixed with moxifloxacin or a salt thereof and/or its hydrate with at least one disintegrant and at least one lubricant.

The method for producing a moxifloxacin capsule according to claim 8, wherein the moxifloxacin or a salt thereof and/or a hydrate thereof is moxifloxacin hydrochloride.

The method for preparing a moxifloxacin capsule according to claim 8 or 9, wherein the disintegrant comprises sodium carboxymethyl starch, microcrystalline cellulose, and croscarmellose sodium. , cross-linked polyvinylpyrrolidone.

A method of producing a moxifloxacin capsule according to claim 8 or 9, wherein the lubricant comprises magnesium stearate.