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WO2004087112A1 - Formulation pour forme posologique orale de clarithromycine dans laquelle l'amertume est masquee, et procede de fabrication - Google Patents

Formulation pour forme posologique orale de clarithromycine dans laquelle l'amertume est masquee, et procede de fabrication Download PDF

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Publication number
WO2004087112A1
WO2004087112A1 PCT/KR2003/000814 KR0300814W WO2004087112A1 WO 2004087112 A1 WO2004087112 A1 WO 2004087112A1 KR 0300814 W KR0300814 W KR 0300814W WO 2004087112 A1 WO2004087112 A1 WO 2004087112A1
Authority
WO
WIPO (PCT)
Prior art keywords
clarithromycin
bitter taste
water
insoluble polymer
pharmaceutical composition
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/KR2003/000814
Other languages
English (en)
Inventor
Dong-Hyun Cho
Young-Sig Gil
Seok-Cheon Hong
Chang-Hun Yu
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.)
Korea United Pharm Inc
Original Assignee
Korea United Pharm Inc
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 Korea United Pharm Inc filed Critical Korea United Pharm Inc
Priority to AU2003227373A priority Critical patent/AU2003227373A1/en
Publication of WO2004087112A1 publication Critical patent/WO2004087112A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • 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
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a clarithromycin- containing oral pharmaceutical composition where the bitter taste of clarithromycin is masked, and also to a preparing method thereof .
  • Clarithromycin used in the present invention is a macrolide antibiotic, and chemically, is 6- O-methylerythromycin. This compound has an antibiotic effect against S . pyrogenes, S. pneumoniae, S. agalactiae, viridans Streptococcus, M. catarrhalis, C. trachomatis, Legionella species, Mycoplasma pneumoniae, H. influenzae, S .
  • aureus and the like is used for the treatment of pharyngitis, tonsillitis, acute maxillary sinusitis, acute exacerbation of chronic bronchitis, pneumonia, skin infections without complications, and the like. Furthermore, it may also be used in combination with other antibiotics in order to eradicate H. pylori in gastric ulcer therapy. Moreover, unlike other macrolide antibiotics, it is stable in the gastrointestinal tract and thus has excellent therapeutic effects. Usually, clarithromycin is administered at a dosage of 250 mg twice daily for adults, and in the case of serious infections, administered at a dosage of 500 mg twice daily. Generally, clarithromycin is orally administered.
  • clarithromycin due to the bitter taste of the raw material itself of clarithromycin, patients can feel the bitter taste in the mouse not only upon oral administration of clatithromycin but also upon drug reflux caused by reflux esophagitis which is attributed to oxidative stress occurred from excessive acids caused by gastric ulcer or gastritis. For these reason, clarithromycin has the problem of low patient compliance.
  • Korean Patent Laid-Open Publication No. 2002- 0016069 discloses a method for producing a cation exchange resin complex, in which the macrolide antibiotics are reacted with a cation exchange resin in a solvent and then dried.
  • this method is carried out in a complicated operation and provides a complex having the macrolide antibiotics at a low content, so that it is difficult for this method to produce an oral preparation containing a usual dosage of macrolide antibiotics.
  • Korean Patent Laid-Open Publication No. 1999-0067265 discloses a method wherein the macrolide antibiotics are mixed with carbomer as an anionic polymer, wetted and blended, thereby producing granules.
  • this method is disadvantageous in that the process of uniform mixing of the drug with the polymer is difficult and preparation processes, including a mixing method, such as wetting, and setting of temperature in a reaction section, are complicated, so that there can be the difficulty of reproduction in preparation.
  • Korean Patent Registration No. 10-0218700 discloses a method wherein basic drugs with an unpleasant taste are mixed with a functional polymer and dispersed or dissolved in a material having a low melting point of 40-120 °C, and the resulting complex is mixed with sugar alcohol and a basic oxide.
  • this method is disadvantageous in that, since heat of a certain temperature or above needs to be applied in order to dissolve the drugs in the material having a low melting point, the macrolide drugs are liable to be broken.
  • a composition containing the macrolide antibiotics at a low content is obtained so that it is difficult to produce an oral preparation containing a. usual dosage of macrolide antibiotics .
  • the present invention has been made in view of the above-mentioned problems occurring in the prior art, and an object of the present invention is to provide a pharmaceutical composition containing clarithromycin coated with a water-insoluble polymer, and a method for producing the same, in which the bitter taste of clarithromycin is masked while the dissolution rate of clarithromycin is maintained at the same level as prior preparations.
  • Another object of the present invention is to produce a clarithromycin-containing oral preparation, which is easily produced, has an administrable size, and shows little or no bitter taste after administration, particularly in patients with reflux esophagitis.
  • the present invention provides an oral pharmaceutical composition containing clarithromycin, as an active ingredient, coated with a water-insoluble polymer, so that the dissolution pattern of clarithromycin is the same as prior preparations while the bitter taste of clarithromycin is masked.
  • the water-insoluble polymer there can be used one or more selected from the group consisting of ethylcellulose, methacrylic acid polymers and esters, polyethylene, polyamide, poly (ethylene-vinylacetate) , cellulose nitrate, silicone, and poly (lactide-co-glycolide) .
  • Suitable examples of the methacrylic acid esters include EudragitTM L12.5P, L12.5, LlOO, L100-55, L30 D55, S12.5P, S12.5, S100, RL12.5, RL100, RL PO, RL30D, RS12.5, RS100, RS PO, RS30D, NE30D, and the like.
  • a fluidized bed processor of a GPCG type was used, the temperature of air introduced into a chamber was adjusted to 60 °C, and the spray velocity of the water- insoluble polymer was adjusted to 5g/minute (pressure: 1.5 bar) by flow fluctuation of a peristaltic pump provided with a silicon tube (inner diameter: 6.0 mm). The chamber sprayed with an air stream was pre-warmed. Clarithromycin was introduced and an air flap was adjusted to 5 m/sec. The temperature of products was 40 ⁇ 2 °C .
  • clarithromycin was coated with a coating solution consisting of ethylcellulose dissolved in a mixed solution of methylene chloride and ethanol, according to the conditions given in Table 1 above, by means of a fluidized bed coater, thereby obtaining granules coated with ethylcellulose.
  • Composition of each of Examples 1-5 is given in Table 2 below.
  • the weight ratios between clarithromycin and ethylcellulose as a water- insoluble polymer in Examples 1-5 was 99:1, 96:4, 90:10, 80:20, and 70:30, respectively, and the weight ratio between ethylcellulose, methylene chloride and ethanol used in the water-insoluble coating layer was 1:20:20.
  • the coating process was carried out under the conditions as described above .
  • Examples 6-10 clarithromycin was coated with a coating solution consisting of hydroxypropylmethylcellulose phthalate (HP55) dissolved in a mixed solution of methylene chloride and ethanol, according to the conditions given in Table 1 above, by means of a fluidized bed coater, thereby obtaining granules coated with hydroxypropylmethylcellulose phthalate (HP55) .
  • HP55 hydroxypropylmethylcellulose phthalate
  • HP55 is a water-insoluble polymer, which starts to dissolve at a pH near 5.5.
  • Composition of each of Examples 6-10 is given in Table 3 below. The weight ratios between clarithromycin and hydroxypropylmethylcellulose phthalate
  • Examples 11-15 clarithromycin was coated with a coating solution consisting of hydroxypropylmethylcellulose phthalate (HP50) dissolved in a mixed solution of methylene chloride and ethanol, according to the conditions given in Table 1 above, by means of a fluidized bed coater, thereby obtaining granules coated with hydroxypropylmethylcellulose phthalate (HP50) .
  • HP50 hydroxypropylmethylcellulose phthalate
  • HP50 is a water-insoluble polymer, which starts to dissolve at a pH near 5.0.
  • 11-15 is given in Table 4 below.
  • the weight ratios between clarithromycin and hydroxypropylmethylcellulose phthalate (HP50) as a water-insoluble polymer in Examples 11-15 were 99:1, 96:4, 90:10, 80:20, and 70:30, respectively, and the weight ratio between hydroxypropylmethylcellulose phthalate (HP50) , methylene chloride and ethanol used in the water- insoluble coating layer was 1:20:20.
  • the coating process was carried out under the conditions as described above. '
  • Examples 16-20 clarithromycin was coated with a coating solution consisting of EudragitTM L 100-55 dissolved in a mixed solution of methylene chloride and ethanol, according to the conditions given in Table 1 above, by means of a fluidized bed coater, thereby obtaining granules coated with EudragitTM L 100-55.
  • EudragitTM L 100-55 Composition of each of Examples 16-20 is given in Table 5 below.
  • the weight ratios of clarithromycin and EudragitTM L 100-55 as a water-insoluble polymer in Examples 16-20 were 99:1, 96:4, 90:10, 80:20, and 70:30, respectively, and the weight ratio between EudragitTM L 100-55, methylene chloride and ethanol used in the water-insoluble coating layer was 1:20:20.
  • the coating process was carried out under the conditions as described above.
  • Test Example 2 Rating of Bitter Taste according to Amount of Water-Insoluble Polymer Used in Coating of Clarithromycin
  • Tablets which had been made from the granules of Examples 1-20 and Comparative Example 1 according to the above formulation example, were orally administered to 10 healthy adults, and 5 minutes after administration, were rated for their bitter taste on a scale of 0-5 as described below.
  • the results are given in Table 9. feel no bitter taste; feel a very little bitter taste; feel a slightly bitter taste; feel a bitter taste; feel a bearable bitter taste; and feel an unbearable bitter taste.
  • the present invention provides the clarithromycin-containing oral preparation where the bitter taste of clarithromycin is masked.
  • the preparation of the present invention is easily produced, has an administrable size, and shows little or no bitter taste after administration, particularly in patients with reflux esophagitis ' . Accordingly, it is a greatly useful preparation, which shows increased patient compliance and thus an increased therapeutic effect.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique pour l'administration orale contenant de la clarithromycine et un procédé de préparation de cette dernière, dans laquelle est masquée l'amertume de la clarithromycine, qui est un antibiotique macrolide d'une saveur amère désagréable lorsqu'il est administré par voie orale. Dans la composition pharmaceutique orale de l'invention, la clarithromycine, qui constitue le principe actif, est enrobée d'un polymère non soluble dans l'eau, de façon que la vitesse de dissolution de la clarithromycine est maintenue au même niveau que dans les préparations de l'état antérieur de la technique, mais que le goût amer de la clarithromycine est masqué.
PCT/KR2003/000814 2003-03-31 2003-04-22 Formulation pour forme posologique orale de clarithromycine dans laquelle l'amertume est masquee, et procede de fabrication Ceased WO2004087112A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003227373A AU2003227373A1 (en) 2003-03-31 2003-04-22 Manufacturing method and formulation for bitter taste masked oral dosage form of clarithromycin

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2003-0019890A KR100508992B1 (ko) 2003-03-31 2003-03-31 쓴 맛을 개선한 클래리스로마이신 경구용 약제 조성물 및 그의 제조 방법
KR10-2003-0019890 2003-03-31

Publications (1)

Publication Number Publication Date
WO2004087112A1 true WO2004087112A1 (fr) 2004-10-14

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PCT/KR2003/000814 Ceased WO2004087112A1 (fr) 2003-03-31 2003-04-22 Formulation pour forme posologique orale de clarithromycine dans laquelle l'amertume est masquee, et procede de fabrication

Country Status (3)

Country Link
KR (1) KR100508992B1 (fr)
AU (1) AU2003227373A1 (fr)
WO (1) WO2004087112A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005082331A3 (fr) * 2004-02-26 2006-03-30 Ranbaxy Lab Ltd Comprimes a liberation prolongee de clarithromycine
WO2009014372A3 (fr) * 2007-07-23 2009-03-19 Amorepacific Corp Comprimé dispersible comprenant des particules enrobées contenant un médicament et procédé de préparation correspondant
CN101502492B (zh) * 2009-03-13 2013-11-27 上海微丸医药开发有限公司 一种克拉霉素去苦味颗粒的制备方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100676075B1 (ko) 2005-02-17 2007-02-01 한국유나이티드제약 주식회사 경구투여용 클래리스로마이신 함유 펠렛 제제

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5605909A (en) * 1994-11-04 1997-02-25 American Home Products Corporation Substituted N-heteroaryl-1,2-diaminocyclobutene-3,4-dione compounds
US5707646A (en) * 1992-03-12 1998-01-13 Taisho Pharmaceutical Co., Ltd. Taste masking pharmaceutical composition
WO1998047493A1 (fr) * 1997-04-23 1998-10-29 F.H. Faulding & Co. Limited Compositions pharmaceutiques a gout masque
US5972373A (en) * 1995-05-02 1999-10-26 Taisho Pharmaceutical Co., Ltd. Taste masking pharmaceutical composition for oral administration
US6350398B1 (en) * 1998-09-03 2002-02-26 Basf Aktiengesellschaft Process for producing coated solid dosage forms

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5707646A (en) * 1992-03-12 1998-01-13 Taisho Pharmaceutical Co., Ltd. Taste masking pharmaceutical composition
US5605909A (en) * 1994-11-04 1997-02-25 American Home Products Corporation Substituted N-heteroaryl-1,2-diaminocyclobutene-3,4-dione compounds
US5972373A (en) * 1995-05-02 1999-10-26 Taisho Pharmaceutical Co., Ltd. Taste masking pharmaceutical composition for oral administration
WO1998047493A1 (fr) * 1997-04-23 1998-10-29 F.H. Faulding & Co. Limited Compositions pharmaceutiques a gout masque
US6350398B1 (en) * 1998-09-03 2002-02-26 Basf Aktiengesellschaft Process for producing coated solid dosage forms

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005082331A3 (fr) * 2004-02-26 2006-03-30 Ranbaxy Lab Ltd Comprimes a liberation prolongee de clarithromycine
WO2009014372A3 (fr) * 2007-07-23 2009-03-19 Amorepacific Corp Comprimé dispersible comprenant des particules enrobées contenant un médicament et procédé de préparation correspondant
KR101436516B1 (ko) * 2007-07-23 2014-09-02 주식회사태평양제약 코팅된 펠렛을 함유하는 현탁정 및 이의 제조방법
CN101502492B (zh) * 2009-03-13 2013-11-27 上海微丸医药开发有限公司 一种克拉霉素去苦味颗粒的制备方法

Also Published As

Publication number Publication date
AU2003227373A1 (en) 2004-10-25
KR100508992B1 (ko) 2005-08-17
KR20040085256A (ko) 2004-10-08

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