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WO2007033522A1 - Formulation de gélule contenant de la moxifloxacine et son procédé de préparation - Google Patents

Formulation de gélule contenant de la moxifloxacine et son procédé de préparation Download PDF

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Publication number
WO2007033522A1
WO2007033522A1 PCT/CN2005/001528 CN2005001528W WO2007033522A1 WO 2007033522 A1 WO2007033522 A1 WO 2007033522A1 CN 2005001528 W CN2005001528 W CN 2005001528W WO 2007033522 A1 WO2007033522 A1 WO 2007033522A1
Authority
WO
WIPO (PCT)
Prior art keywords
moxifloxacin
capsule
disintegrant
lubricant
dissolution
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.)
Ceased
Application number
PCT/CN2005/001528
Other languages
English (en)
Chinese (zh)
Inventor
Bingqi Zhao
Bangai Zhao
Xueqi Fu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenzhen Tys R & D Co Ltd
Original Assignee
Shenzhen Tys R & D Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Shenzhen Tys R & D Co Ltd filed Critical Shenzhen Tys R & D Co Ltd
Priority to PCT/CN2005/001528 priority Critical patent/WO2007033522A1/fr
Publication of WO2007033522A1 publication Critical patent/WO2007033522A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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%.
  • moxifloxacin hydrochloride used in the present invention is as follows:
  • HPMC Hydroxypropyl methylcellulose
  • VcapsTM plant capsule
  • HPMC 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.
  • 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.
  • 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.
  • magnesium stearate is a lubricant commonly used in the art.
  • the amount of the lubricant can also be added in accordance with the usual addition amount of the lubricant in the prior art.
  • 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.
  • 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. '
  • 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.
  • Example 3 Component: Moxifloxacin hydrochloride 218. 4mg
  • 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.
  • 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.
  • Example 5 Component: Moxifloxacin hydrochloride 218.1 1 ⁇ 2 g
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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)
  • Example 5 98. 1 97. 6
  • Example 6 97.2 99.8
  • Example 7 101.3 98.3 "Example 8 99.1 101.3
  • 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.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une formulation sous forme de gélule de moxifloxacine ou de ses sels et/ou hydrates, qui comprend une gélule d’hydroxpropylméthylcellulose(HPMC) contenant de la moxifloxacine, au moins un désagrégeant et au moins un lubrifiant. La présente invention concerne également la préparation de ladite formulation, qui comprend les étapes suivantes : mélange ou granulation de la moxifloxacine mélangée avec au moins un désagrégeant et au moins un lubrifiant, puis remplissage des gélules HPMC au moyen du mélange. La formulation de gélule selon cette invention présente une vitesse de dissolution stable.
PCT/CN2005/001528 2005-09-21 2005-09-21 Formulation de gélule contenant de la moxifloxacine et son procédé de préparation Ceased WO2007033522A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2005/001528 WO2007033522A1 (fr) 2005-09-21 2005-09-21 Formulation de gélule contenant de la moxifloxacine et son procédé de préparation

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2005/001528 WO2007033522A1 (fr) 2005-09-21 2005-09-21 Formulation de gélule contenant de la moxifloxacine et son procédé de préparation

Publications (1)

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WO2007033522A1 true WO2007033522A1 (fr) 2007-03-29

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1271281A (zh) * 1997-09-25 2000-10-25 拜尔公司 控释活性化合物的药物制剂
CN1325306A (zh) * 1998-11-10 2001-12-05 拜尔公司 莫西沙星药物制剂
CN1327387A (zh) * 1999-08-10 2001-12-19 法玛西雅厄普约翰公司 羟丙甲基纤维素胶囊形式的药物制剂
CN1373656A (zh) * 1999-09-13 2002-10-09 霍夫曼-拉罗奇有限公司 含有脂酶抑制剂的分散体制剂
WO2005020998A1 (fr) * 2003-09-03 2005-03-10 Ranbaxy Laboratories Limited Compositions pharmaceutiques a base de moxifloxacine et leurs procedes de preparation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1271281A (zh) * 1997-09-25 2000-10-25 拜尔公司 控释活性化合物的药物制剂
CN1325306A (zh) * 1998-11-10 2001-12-05 拜尔公司 莫西沙星药物制剂
CN1327387A (zh) * 1999-08-10 2001-12-19 法玛西雅厄普约翰公司 羟丙甲基纤维素胶囊形式的药物制剂
CN1373656A (zh) * 1999-09-13 2002-10-09 霍夫曼-拉罗奇有限公司 含有脂酶抑制剂的分散体制剂
WO2005020998A1 (fr) * 2003-09-03 2005-03-10 Ranbaxy Laboratories Limited Compositions pharmaceutiques a base de moxifloxacine et leurs procedes de preparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WANG YI. ET AL.: "New antibacterial drug, Moxifloxacin hydrochloride", QILU PHARMACOLOGICAL AFFAIRS, vol. 23, no. 9, 2004, pages 60 - 61, XP008079488 *

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