WO2006004086A1 - Composition à base d’eau contenant de l’azithromycine qui subit une gélification thermique réversible - Google Patents

Composition à base d’eau contenant de l’azithromycine qui subit une gélification thermique réversible Download PDF

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Publication number
WO2006004086A1
WO2006004086A1 PCT/JP2005/012328 JP2005012328W WO2006004086A1 WO 2006004086 A1 WO2006004086 A1 WO 2006004086A1 JP 2005012328 W JP2005012328 W JP 2005012328W WO 2006004086 A1 WO2006004086 A1 WO 2006004086A1
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WIPO (PCT)
Prior art keywords
present
reversible
azithromycin
composition
reversible thermal
Prior art date
Application number
PCT/JP2005/012328
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English (en)
Japanese (ja)
Inventor
Hidekazu Suzuki
Kuniko Koichi
Original Assignee
Wakamoto Pharmaceutical 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 Wakamoto Pharmaceutical Co., Ltd. filed Critical Wakamoto Pharmaceutical Co., Ltd.
Publication of WO2006004086A1 publication Critical patent/WO2006004086A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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

  • Adithromycin-containing reversible thermogelling aqueous composition Adithromycin-containing reversible thermogelling aqueous composition
  • the present invention relates to a reversible thermo-gel water-repellent composition containing adithromycin.
  • Japanese Patent No. 2729859 discloses a reversible thermogel aqueous pharmaceutical composition that gels at body temperature using methylcellulose.
  • This composition is easy to administer as a liquid before administration, and after administration it gels at body temperature and increases in viscosity, improving drug retention at the administration site and improving drug bioavailability (BA).
  • BA drug bioavailability
  • Patent 3450805 discloses a reversible thermogel aqueous pharmaceutical composition containing methylcellulose as an essential component having a viscosity of 12 mPa's or less at 20 ° C of a 2 w / v% aqueous solution.
  • This reversible thermogelled aqueous pharmaceutical composition is a composition having a low gelling temperature and a rapid increase in viscosity due to heat (body temperature) compared to the composition of the above-mentioned Patent No. 2729859.
  • body temperature body temperature
  • Patent Document 1 Japanese Patent No. 2729859
  • Patent Document 2 Japanese Patent No. 3450805
  • An object of the present invention is to provide a reversible thermogelling aqueous composition that gels at a lower temperature.
  • the present invention provides the following reversibly heat-gelable aqueous composition.
  • a reversible thermal gel water-repellent composition containing methylcellulose and adisthromycin.
  • the reversible thermogel according to 1 above further comprising at least one selected from polyethylene glycol, an amino acid or a pharmaceutically acceptable salt thereof, and an oxyacid or a pharmaceutically acceptable salt force.
  • Aqueous composition containing methylcellulose and adisthromycin.
  • thermogelling aqueous composition according to any one of the above 1 to 3, further comprising a drug other than adithromycin.
  • the reversible thermal gelling hydrophobic composition of the present invention gels at a lower temperature. Therefore, when administered to a living body, there is an advantage that a higher BA of the drug can be obtained and a more effective therapeutic effect can be expected than the conventional reversible thermal gel water-repellent composition.
  • the main feature of the present invention is that it is gelled at a lower temperature than a conventional reversible thermogel aqueous pharmaceutical composition by blending methylcellulose and azithromycin.
  • the reversible thermogelable aqueous composition of the present invention has a gelling temperature of about 20 ° C to about 40 ° C because it is liquid in a cold place and desired to gel at the body temperature of mammals. It is preferred to be! / ⁇
  • azithromycin anhydride As the azithromycin used in the present invention, azithromycin anhydride, azithromycin monohydrate, azithromycin dihydrate and the like are preferable. Also suitable are pharmaceutically acceptable salts of adithromycin, for example polyvalent carboxylates such as citrate, tartrate, malate, maleate and fumarate.
  • the concentration range of adithromycin used in the present invention is not particularly limited as long as the effects of the present invention can be obtained.
  • adithromycin is generally used at 0.01 to 10 w / v%. It is preferably 0.1 to 5 w / v%, particularly preferably 0.3 to 3.0 w / v%.
  • concentration of ajithromycin is 10 w / v% or less, it is preferable because adithromycin is in a range that can be easily prepared as an aqueous solution, and when it is 0.1 w / v% or more, the gely temperature of the composition becomes lower. That's right.
  • the methylcellulose (hereinafter sometimes abbreviated as MC) used in the present invention is w / v% Any MC can be used alone or in admixture, as long as it has a viscosity in the range of 3 ⁇ 4 to 12000 millipascals.second at 20 ° C.
  • the content of the methoxyl group is preferably in the range of 26 to 33% from the viewpoint of solubility in water.
  • MC is distinguished by the viscosity of its aqueous solution.
  • the indicated viscosity is 4, 15, 25, 100, 400, 1500, 80 00 (the numbers are in milligrams of 20 ° C viscosity of 2 w / v% aqueous solution). There are Pascal's) and are readily available.
  • MC force with a displayed viscosity of 4 to 400 is preferred because it is easy to handle.
  • the outline, specifications, usage, usage amount and product name of MC are described in detail in the Pharmaceutical Additives Dictionary (edited by the Japan Pharmaceutical Additives Association, published by Yakuji Nippo).
  • the concentration range of MC used in the present invention is not particularly limited as long as the effect of the present invention is obtained, but is preferably 0.2 to 7 w / v%, more preferably 1.0 to 6.0 w / v%, particularly preferably. Is 2.0 to 4.0 w / v%.
  • concentration power of MC is 7 w / v% or less, it is preferable because the viscosity of the composition is in a range that is easy to handle, and when the concentration of MC is 0.2 w / v% or more, gelation tends to occur at body temperature.
  • Polyethylene glycol used in the present invention (hereinafter sometimes abbreviated as PEG) is PE G-200, -300, -600, -1000, -1540, -2000, -4000, -6000,- From Wako Pure Chemical Industries, Ltd. under the trade names 20000, -50000, -50000 0, -2000000 and -4000000, also Macrogol -200, -300, -400, -600, -1000, -1540,- It is sold by Nippon Oil & Fats Co., Ltd. under the trade names of 4000, -6000, and -20000.
  • the weight average molecular weight of PEG used in the base of the present invention is preferably from 300 to 50000, particularly preferably from 1000 to 20000.
  • the weight average molecular weight is 300 or more, a liquid-gel phase transition due to body temperature occurs, and when the weight average molecular weight is 50000 or less, the viscosity in the liquid state does not become too high. It is also possible to adjust the weight average molecular weight within the above optimal range by mixing two or more PEGs.
  • the outline, specifications, application, usage, and product name of PEG are described in detail in the Pharmaceutical Additives Dictionary (edited by the Japan Pharmaceutical Additives Association, published by Yakuji Nippo).
  • the concentration range of the PEG, amino acid or pharmaceutically acceptable salt of the present invention is not particularly limited as long as the effect of the present invention is obtained.
  • the use concentration of PEG is preferably 0.1 to 13 w / v%, more preferably 1.0 to 10.0 w / v%, and particularly preferably 2.0 to 4.0 w / v%.
  • the concentration of amino acid used is preferably 0.01 to 7 w / v%, more preferably 0.05 to 4 w / v%, particularly preferably 1.0 to 2.0 w / v%.
  • oxyacid used in the present invention citrate, tartaric acid, malic acid, lactic acid and the like are preferable. Moreover, sodium salts and potassium salts are preferred as pharmaceutically acceptable salts of oxyacids.
  • the use concentration range of the oxyacid of the present invention or a pharmaceutically acceptable salt thereof is not particularly limited as long as the effect of the present invention is obtained.
  • 0.01-7 w / v% is suitable as oxyacid, more preferably 0.1-4 w / v%, and particularly preferably 1.0-4.0 w / v%.
  • thermogel containing 0.1-5 w / v% azithromycin, 0.2-7 w / v% MC, 0.1-13 w / v% PEG and 0.1-4 w / v% oxyacid.
  • An aqueous composition is one of the preferred embodiments of the present invention.
  • the azithromycin compounded in the reversible thermal gelling water-based composition of the present invention is a power that is intended to be added as a substance that lowers the gelling temperature.
  • a reversible thermogel aqueous composition can be administered.
  • the reversible thermogelable aqueous composition of the present invention can be combined with a drug other than Sarakuko and ajithromycin.
  • drugs include levofloxacin, ofloxacin, lomefloxacin, norfloxacin, tosufloxacin, gatifloxacin, cefem antibiotics such as cefmenoxime, synthetic penicillin drugs such as sulbecillin sodium, Aminoglycoside antibiotics such as nomycin, sisomycin sulfate, dibekacin sulfate, gentamicin sulfate, tobramycin, antibiotics such as chloramphee-chol, anti-viral agents such as acyclovir and iduxuridine, fluorometholone, dexamethasone, prednisolone, prednisolone acetate, Betamethasone sodium phosphate, hydrocortisone acetate, dexamethasone sodium metasulf
  • the reversible thermal gel water-repellent composition of the present invention can be used as an injection, an oral preparation, an ear drop, an nasal drop, an eye drop, a coating preparation, etc., taking advantage of its properties. it can.
  • the reversibly heat-gelable aqueous composition of the present invention is preferably adjusted to pH 4 to 10, pH 6.0 to 7.
  • pH adjusters that are usually added are used.
  • the acids include ascorbic acid, hydrochloric acid, darconic acid, acetic acid, lactic acid, phosphoric acid, sulfuric acid, citrate, and the like.
  • the base include potassium hydroxide, calcium hydroxide, sodium hydroxide, magnesium hydroxide, monoethanolamine, diethanolamine, and triethanolamine.
  • pH adjusters include amino acids such as glycine, histidine, and ypsilon aminocaproic acid.
  • boric acid or its salt is contraindicated because it promotes the degradation of adithromycin.
  • reversible thermal gel water-repellent composition of the present invention In preparing the reversible thermal gel water-repellent composition of the present invention, pharmaceutically acceptable tonicity agents, solubilizers, preservatives, preservatives, and the like may be added as necessary. Can be added to the reversible thermal gel water-repellent composition of the present invention within a range not impairing the properties.
  • tonicity agents examples include sugars such as xylitol, mannitol, and glucose, propylene glycol, glycerin, salted sodium, and salted potassium.
  • solubilizers include polysorbate 80 and polyoxyethylene hydrogenated castor oil.
  • Preservatives include benzalkonium chloride, benzeth-chloride and chlorhexidine dalconate.
  • Inverse stone acids parabens such as methyl parahydroxybenzoate, propyl parahydroxybenzoate, and butyl hydroxyhydroxybenzoate, alcohols such as chlorobutanol, ferroethyl alcohol and benzyl alcohol, sodium dehydroacetate, sorbine Acids and organic acids such as potassium sorbate and salts thereof, and mercury compounds such as thimerosal can be used.
  • Other additives include hydroxyethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, propylene glycol, diethylene glycol or sodium polyacrylate thickeners, EDTA (ethylene diamine tetraacetic acid) and their pharmaceutically acceptable substances. Salts, tocopherols and derivatives thereof, and stabilizers such as sodium sulfite.
  • a method for producing the reversible heat-gelable aqueous composition of the present invention is illustrated.
  • Dissolve adithromycin and polyvalent carboxylic acid in water Separately, MC and PEG are dispersed in hot water of 70 ° C or higher and cooled on ice. Add the azithromycin and polyvalent carboxylic acid solution, and mix well under ice cooling. Add sardine, oxyacid or amino acid, drugs, additives, etc., dissolve and mix well.
  • the pH is adjusted with a pH adjuster and diluted with sterile purified water to prepare the reversible thermogelled aqueous composition of the present invention.
  • the prepared composition of the present invention is sterilized by filtration through a membrane filter and then filled into a container such as a plastic eye drop bottle. .
  • methylcellulose manufactured by Shin-Etsu Chemical Co., Ltd., Metrows (registered trademark) SM-4)
  • polyethylene glycol manufactured by Nippon Oil & Fats Co., Ltd.
  • 50 mL of sterilized purified water heated to 85 ° C was added and dispersed by stirring. After confirming uniform dispersion, the mixture was ice-cooled with stirring.
  • Table 1 shows the formulation and gelation temperature of the reversibly heat-gelable aqueous composition prepared.
  • the reversible thermal gel water-repellent composition of the present invention shown in the Examples is a gel compared to the reversible thermal gel water-repellent composition of Comparative Example, which does not contain azithromycin in any formulation. It was shown that the conversion temperature was low.
  • SM-4 methylcellulose
  • Microgol 4 000 polyethylene glycol
  • the previously prepared levofloxacin-azithromycin-quenic acid aqueous solution was added and stirred and mixed under ice cooling until uniform. Furthermore, after adjusting the pH to 7.0 with 1N NaOH or 1N HC1, the total volume was adjusted to 10 mL with sterilized purified water to prepare a revofloxacin-azithromycin-containing reversible thermogelled aqueous composition of the present invention.
  • the adithromycin-containing reversible thermogelable aqueous composition of the present invention prepared in Example 1 was filtered through a membrane filter, filled into a 5 mL glass ampule, and sealed to give an injection.
  • the azithromycin-containing reversible thermogelable aqueous composition of the present invention prepared in Example 5 was filtered through a membrane filter and filled into a plastic nasal drop container to give a nasal drop.
  • aqueous azithromycin-containing reversible thermogelable aqueous composition of the present invention prepared in Example 5 was filtered through a membrane filter and filled into a plastic ear container to give an ear drop.
  • the adithromycin-containing reversible thermogelable aqueous composition of the present invention prepared in Example 1 was filtered through a membrane filter and filled into a plastic container to obtain a coating agent.
  • the adithromycin-containing reversible thermogelable aqueous composition of the present invention prepared in Example 1 was filtered through a membrane filter and filled into a glass container to obtain an oral preparation.
  • the present invention provides a reversible thermo-gel water-repellent composition containing methyl cellulose and azithromycin.
  • the reversible thermal gel water-repellent composition of the present invention is more than the conventional composition. However, since the gel temperature is low, when administered to a living body, the bioavailability of the drug is improved, and a more effective therapeutic effect can be expected.

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  • Health & Medical Sciences (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
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  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

Composition à base d’eau subissant une gélification thermique réversible qui contient de la méthyle cellulose et de l’azithromycine. La composition a une température de gélification inférieure par rapport aux compositions à base d’eau conventionnelles qui subissent une gélification thermique réversible et, par conséquent, elle présente l’avantage d’atteindre une meilleure biodisponibilité du médicament lorsqu’elle est administrée au corps vivant. Un effet thérapeutique plus efficace peut être envisagé.
PCT/JP2005/012328 2004-07-02 2005-07-04 Composition à base d’eau contenant de l’azithromycine qui subit une gélification thermique réversible WO2006004086A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2004-196515 2004-07-02
JP2004196515A JP2007277095A (ja) 2004-07-02 2004-07-02 アジスロマイシン含有可逆性熱ゲル化水性組成物

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WO2006004086A1 true WO2006004086A1 (fr) 2006-01-12

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8106111B2 (en) 2009-05-15 2012-01-31 Eastman Chemical Company Antimicrobial effect of cycloaliphatic diol antimicrobial agents in coating compositions
CN111214437A (zh) * 2018-11-27 2020-06-02 武汉武药科技有限公司 一种阿奇霉素微乳凝胶剂及其制备方法和应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994023750A1 (fr) * 1993-04-16 1994-10-27 Wakamoto Pharmaceutical Co., Ltd. Composition medicamenteuse se tranformant en gel thermiquement de façon reversible
JP2001089378A (ja) * 1999-08-09 2001-04-03 Sifi Soc Industria Farmaceutica It Spa 眼科用水性薬剤の製造方法
WO2002011734A1 (fr) * 2000-08-08 2002-02-14 Wakamoto Pharmaceutical Co., Ltd. Compositions pharmaceutiques aqueuses
JP2003502431A (ja) * 1999-06-19 2003-01-21 ザ・ビクトリア・ユニバーシテイ・オブ・マンチエスター 抗生物質
JP2003040782A (ja) * 2001-05-31 2003-02-13 Pfizer Prod Inc アザリド抗生物質組成物
WO2005042026A1 (fr) * 2003-10-31 2005-05-12 Wakamoto Pharmaceutical Co., Ltd. Composition a base d'eau soumise a une thermoregulation reversible

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994023750A1 (fr) * 1993-04-16 1994-10-27 Wakamoto Pharmaceutical Co., Ltd. Composition medicamenteuse se tranformant en gel thermiquement de façon reversible
JP2003502431A (ja) * 1999-06-19 2003-01-21 ザ・ビクトリア・ユニバーシテイ・オブ・マンチエスター 抗生物質
JP2001089378A (ja) * 1999-08-09 2001-04-03 Sifi Soc Industria Farmaceutica It Spa 眼科用水性薬剤の製造方法
WO2002011734A1 (fr) * 2000-08-08 2002-02-14 Wakamoto Pharmaceutical Co., Ltd. Compositions pharmaceutiques aqueuses
JP2003040782A (ja) * 2001-05-31 2003-02-13 Pfizer Prod Inc アザリド抗生物質組成物
WO2005042026A1 (fr) * 2003-10-31 2005-05-12 Wakamoto Pharmaceutical Co., Ltd. Composition a base d'eau soumise a une thermoregulation reversible

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8106111B2 (en) 2009-05-15 2012-01-31 Eastman Chemical Company Antimicrobial effect of cycloaliphatic diol antimicrobial agents in coating compositions
CN111214437A (zh) * 2018-11-27 2020-06-02 武汉武药科技有限公司 一种阿奇霉素微乳凝胶剂及其制备方法和应用

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