WO1996006631A1 - Suspensions de chlorhydrate de vancomycine a usage peroral et pour garnissage de capsules de gelatine molle - Google Patents

Suspensions de chlorhydrate de vancomycine a usage peroral et pour garnissage de capsules de gelatine molle Download PDF

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Publication number
WO1996006631A1
WO1996006631A1 PCT/SI1995/000021 SI9500021W WO9606631A1 WO 1996006631 A1 WO1996006631 A1 WO 1996006631A1 SI 9500021 W SI9500021 W SI 9500021W WO 9606631 A1 WO9606631 A1 WO 9606631A1
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WO
WIPO (PCT)
Prior art keywords
oil
soft gelatin
acid triglycerides
vancomycin
suspension
Prior art date
Application number
PCT/SI1995/000021
Other languages
English (en)
Inventor
Anton KRAMARIC^¿
Bojan Kofler
Original Assignee
Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov,
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 Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, filed Critical Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov,
Priority to AU32696/95A priority Critical patent/AU3269695A/en
Publication of WO1996006631A1 publication Critical patent/WO1996006631A1/fr

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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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • 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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds

Definitions

  • the present invention refers to novel stable and organoleptically acceptable pharma ⁇ ceutical forms of the perorally active antibiotic vancomycin hydrochloride and to processes for the preparation thereof.
  • Vancomycin is an amphoteric glycopeptide antibiotic produced by strains of species Mycropolyspora orientalis, which in earlier classification systems were named Strepto- myces orientalis and Nocardia orientalis.
  • Vancomycin was protected as substance in US patent 3,067,099 and is a very well known antibiotic for the treatment of staphylococcal infections, especially the ones caused by meticillin-resistant stapyhlococcus strains. Vancomycin is isolated from the fermentation broth in which it has been produced. It is useful for treatment in the form of hydrochloride.
  • Vancomycin hydrochloride has hitherto been available for peroral and parenteral use as a dry solid substance (in sterile bottles) obtained by freeze-drying of the water solution of vancomycin hydrochloride, which in turn was prepared from the free base of vancomycin and HC1 in a water solution. In order to shorten the time needed, it is desirable to conduct the freeze-drying in as small batches as possible and preferably directly in a vessel suitable for further use, e.g. in sterile bottles.
  • Vancomycin hydrochloride belongs to medicinal active ingredients, which are un ⁇ stable in the presence of moisture. Therefore the present invention deals with novel pharmaceutical forms, by which this problem is solved.
  • Vancomycin Peroral pharmaceutical forms of vancomycin are designed for topical intestinal ac ⁇ tion, therefore their dissolution must be good yet the absorption of vancomycin into the blood is not desired.
  • Vancomycin is one of numerous medicinal active ingredients very sensitive to mois ⁇ ture. Very frequently these active ingredients also have disagreeable organoleptic properties, particularly taste but also odor and appearance. Pharmaceutical prepara ⁇ tions for diabetics may not contain sugars. Most patients, especially older people and children, need preparations with a simple administration route.
  • the present invention is directed to vancomycin hydrochloride in novel, stable and organoleptically acceptable pharmaceutical forms for peroral use, i.e. in the form of oil suspensions with a pleasant taste and neutral odor and without sugars.
  • Such forms are very convenient for filling into plastic or glass bottles, whereby it is possible to adapt the dose to individual patients (especially important in pediatrics), and for various single dosage forms such as bags, soft gelatin capsules and such like.
  • Vancomycin hydrochloride is available on the market in the form of hard gelatin cap ⁇ sules, injections and powders.
  • EP-B- 49,909 (equivalent US 4,450,877), which generally describes hard gelatin capsules wherein the active ingredient is homogeneously dispersed in a vehicle melt e.g. in PEG, which gels or hardens and thereby loses its liquid character.
  • the process is not specifically adapted to any kind of active ingredients.
  • Vancomycin hydrochloride as an active ingredient in peroral oil suspensions or in soft gelatin capsules has hitherto not been discussed in any patent.
  • liquid suspensions for peroral use are described, wherein the pharmaceuticaly acceptable vehicles are various animal, mineral or vegetable oils and as active in ⁇ gredients various peptides, antibiotics (among them penicillin and amoxicillin) and others are used. These liquid suspensions are also filled into capsules.
  • US patent 5,114,929 (equivalent EP-A-389,117) describes pharmaceutical forms containing homogenous nonaqueous suspensions of perorally active ingredients, a pharmaceuticaly acceptable oil vehicle, an emulsifier and finely particulated sugar.
  • medicinal active ingredients there were also antibiotics, e.g. penicillin.
  • As the oil vehicle various vegetable oils, particularly fractionated coconut oil with commer ⁇ cial name Miglyol 812, are used.
  • an emulsifier and up to 40 wt.% of sugar were added.
  • Suspensions with such a composition are not suitable for general use, especially not for diabetics, and due to the danger of caries, a careful oral hygiene is necessary after every administration of such suspension.
  • the first object of the invention is a stable, organoleptically acceptable pharmaceuti ⁇ cal form containing a homogenous nonaqueous suspension of the moisture-sensitive medicinal active ingredient vancomycin hydrochloride in an oil vehicle and, option ⁇ ally, also adjuvants such as a drying agent and a protective colloid and a suitable com ⁇ bination of flavors and an artificial sweetener.
  • the selection of the oil vehicle is of great importance. It has been found that the commercially available oil ESMA-MCT 643 manufactured by the company Werner Schluter/Germany, is without taste and has a neutral odor so that there is no need for covering any oily aftertaste with sugars or emulsifiers.
  • This oil is a triglyceride of fractionated coconut oil with C 8 -C 10 fatty acids and is produced from a natural source, which may be decisive for the better taste.
  • the tastefulness of homogenous nonaqueous suspen ⁇ sions prepared with such oil vehicle is just enhanced by a suitable combination of an artificial sweetener and/or various flavors such as milk or fruit flavors.
  • the second object of the invention is a soft gelatin capsule containing a stable homogenous nonaqueous suspension of the moisture-sensitive vancomycin hydro ⁇ chloride, an edible oil vehicle and, optionally, also up to 2 wt.% of molecular sieves or other drying agents and pharmaceutically acceptable stabilizers such as anti- oxidants, preservatives, protective colloids and such like.
  • the oil vehicle is usually of vegetable origin (linseed oil, fractionated coconut oil, sunflower oil, sesame oil, palm oil, soya oil, olive oil, maize oil or peanut oil) but may also be an animal oil (North Sea fish oil).
  • the taste of the oil suspensions in soft gelatin capsules is not problematic as it is at peroral suspensions and therefore there is no need for any special selection of the oil vehicle or additives for the improvement of taste.
  • the pharmaceutical forms according to the invention need not be reconstituted before use nor stored in a cool place in order to preserve the stability of the medicinal active ingredient.
  • oil suspensions for peroral use are filled into plastic or glass bottles and similar packaging and administered by a teaspoon, or they are filled into various single dosage forms such as soft gelatin capsules, bags etc.
  • the amount of perorally active vancomycin hydrochloride in pharmaceutical forms of the invention is from 0.1 to 60 wt.%.
  • the amount of the oil vehicle ESMA-MCT 643 is from 40 to 99 wt.%.
  • homogenous nonaqueous suspensions can also contain up to 10 wt.% of protective colloids such as inorganic salts of higher fatty acids (aluminum stearate), 12-hydroxystearine (Thixcin R), silicon dioxide (Aerosil 200, Aerosil R 972), microcrystalline waxes (Lunacera M), solubilizers, wetting agents, absorption enhancers and surfactants with HLB value over 14.
  • protective colloids such as inorganic salts of higher fatty acids (aluminum stearate), 12-hydroxystearine (Thixcin R), silicon dioxide (Aerosil 200, Aerosil R 972), microcrystalline waxes (Lunacera M), solubilizers, wetting agents, absorption enhancers and surfactants with HLB value over 14.
  • molecular sieves or e.g. silicon dioxide (which can also be a protective colloid) can be added.
  • artificial sweeteners aspartame, cyclamate, saccharin or their alkali salts
  • flavors artificial milk flavor; natural flavors of orange, tangerine, lime, grapefruit, peppermint, strawberry, banana, bilberry and other fruits and com ⁇ binations thereof.
  • Daily administration doses of vancomycin hydrochloride in oil suspensions are the same as at usual administration of known commercially available preparations.
  • the doses of vancomycin hydrochloride in soft gelatin capsules are up to 0.5 g per capsule.
  • compositions according to the invention are prepared in such a way that in a pharmaceutically acceptable oil vehicle the individually necessary additives such as protective colloids are suspended at an appropriate temperature e.g. from 40 to 120°C, depending on the kind of the protective colloid used.
  • an appropriate temperature e.g. from 40 to 120°C, depending on the kind of the protective colloid used.
  • vancomycin hydrochloride, an artificial sweetener, a flavor, a drying agent and a preservative are added to obtain a homogenous product of the desired consistency.
  • the suspension can be filled into normal glass and plastic bottles or into various single dosage forms such as bags and soft gelatin capsules.
  • Aerosil 200 was suspended in the oil vehicle and heated to 70°C.
  • the colloid solution was cooled to 25°C, saccharin was dissolved in it, the flavor was added and vanco ⁇ mycin hydrochloride was suspended therein under stirring.
  • Example 2
  • Vancomycin hydrochloride was suspended in the oil vehicle under stirring at room temperature. The obtained suspension was filled into soft gelatin capsules.
  • Witepsol S 58 consists of adeps solidus, polyethyleneglycol-1000 monocetyl ether and glyceryl ricinoleate. To the oil vehicle Witepsol S 58 was added and vancomycin hydrochloride was suspended therein under stirring. The obtained homogenous suspension was filled into soft gelatin capsules.
  • Witepsol S 58 consists of adeps solidus, polyethyleneglycol-1000 monocetyl ether of the formula CH 3 -(CH 2 )i 50r i 7 -0-CH2-(CH2-0-CH 2 )i 9 - 23 -CH2-OH and glyceryl ricinoleate
  • Time soft gelatin capsules hard gelatin capsules (months) 30°C / 60% r.h.* 40°C / 75 % r.h.* 30°C / 60% r.h.* 40°C / 75% r.h.*
  • Time soft gelatin capsules hard gelatin capsules (months) 30°C / 60% r.h.* 40°C / 75% r.h.* 30°C / 60% r.h.* 40°C / 75% r.h.*
  • the test subjects took the tested drugs after going without food the night before, on an empty stomach, with 240 mL of water. Two hours after the taking of the drug the test subjects were given 200 mL of fruit juice and four hours after the taking of the drug they were given a standard lunch. No side effects were registered.
  • the plasm concentrations of vanco ⁇ mycin were determined by HPLC on a column with reverse phase and by extraction with dichloromethane. The surface of vancomycin signal in the chromatogram of the plasm extract was measured. Vancomycin concentrations (sample according to Example 7 and commercially available sample) in the plasm of five volunteers are listed in Table 4:

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne deux nouvelles formes pharmaceutiques stables et organoleptiquement acceptable de chlorhydrate de vancomycine présentant une moindre sensibilité à l'humidité du principe actif. La suspension perorale contient 250 ou 500 mg de chlorhydrate de vancomycine pour 5mL de suspension, un excipient huileux pharmaceutiquement acceptable, sans goût et d'odeur neutre, un édulcorant et des arômes artificiels, un agent colloïdal de protection, et éventuellement également un dessicant, un antioxydant et un conservateur. La suspension se conserve dans des flacons de plastique ou de verre ainsi que sous des formes galéniques individuelles telles que des sachets et autres. Les capsules de gélatine molle contiennent une suspension non aqueuse homogène et stable à 125 ou 250 mg de chlorhydrate de vancomycine, et un excipient huileux pharmaceutiquement acceptable, ainsi qu'éventuellement un dessicant, un antioxydant et un tensioactif.
PCT/SI1995/000021 1994-08-31 1995-08-30 Suspensions de chlorhydrate de vancomycine a usage peroral et pour garnissage de capsules de gelatine molle WO1996006631A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU32696/95A AU3269695A (en) 1994-08-31 1995-08-30 Vancomycin hydrochloride suspensions for peroral use and for filling into soft gelatin capsules

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SIP-9400338 1994-08-31
SI9400338A SI9400338A (en) 1994-08-31 1994-08-31 Vancomycin hydrochloride suspensions for peroral use and for filling into soft ,gelatine capsules.

Publications (1)

Publication Number Publication Date
WO1996006631A1 true WO1996006631A1 (fr) 1996-03-07

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SI1995/000021 WO1996006631A1 (fr) 1994-08-31 1995-08-30 Suspensions de chlorhydrate de vancomycine a usage peroral et pour garnissage de capsules de gelatine molle

Country Status (3)

Country Link
AU (1) AU3269695A (fr)
SI (1) SI9400338A (fr)
WO (1) WO1996006631A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005009409A2 (fr) * 2003-07-17 2005-02-03 Banner Pharmacaps, Inc. Preparations a liberation controlee
CN101991557A (zh) * 2009-08-10 2011-03-30 杭州赛利药物研究所有限公司 一种盐酸万古霉素液体胶囊及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0295941A2 (fr) * 1987-06-19 1988-12-21 ELAN CORPORATION, Plc Dispersion liquide administrable oralement
EP0370481A2 (fr) * 1988-11-22 1990-05-30 F. Hoffmann-La Roche Ag Préparations pharmaceutiques pour une résorption augmentée de composés antibactériens
EP0389177A2 (fr) * 1989-03-21 1990-09-26 Beecham Group Plc Formulation pharmaceutique
EP0418674A1 (fr) * 1989-09-11 1991-03-27 F. Hoffmann-La Roche Ag Préparations pharmaceutiques pour l'absorption améliorée de composés anti-bactériens

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0295941A2 (fr) * 1987-06-19 1988-12-21 ELAN CORPORATION, Plc Dispersion liquide administrable oralement
EP0370481A2 (fr) * 1988-11-22 1990-05-30 F. Hoffmann-La Roche Ag Préparations pharmaceutiques pour une résorption augmentée de composés antibactériens
EP0389177A2 (fr) * 1989-03-21 1990-09-26 Beecham Group Plc Formulation pharmaceutique
EP0418674A1 (fr) * 1989-09-11 1991-03-27 F. Hoffmann-La Roche Ag Préparations pharmaceutiques pour l'absorption améliorée de composés anti-bactériens

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 109, no. 14, 3 October 1988, Columbus, Ohio, US; abstract no. 115991 *
CHEMICAL ABSTRACTS, vol. 120, no. 26, 27 June 1994, Columbus, Ohio, US; abstract no. 331024 *
H.OHKOUCHI ET AL.: "BASIC STUDIES ON PREPARATIONS AND DRUG RELEASE PROPERTIES OF W/O/W TYPE MULTIPLE EMULSIONS AS CARRIERS OF WATER-SOLUBLE DRUGS-THE USE OF LIPIODOL-SOYBEAN OIL MIXTURE FOR OILY PHASE.", DRUG DELIVERY SYST., vol. 9, no. 1, pages 31 - 36 *
W.J.BOWTLE ET AL.: "A NEW APPROACH TO VANCOMYCIN FORMULATIONS USING FILLING TECHNOLOGY FOR SEMISOLID MATRIX CAPSULES.", PHARM. TECHNOL., vol. 12, no. 6, pages 86 - 97 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005009409A2 (fr) * 2003-07-17 2005-02-03 Banner Pharmacaps, Inc. Preparations a liberation controlee
WO2005009409A3 (fr) * 2003-07-17 2005-08-11 Banner Pharmacaps Inc Preparations a liberation controlee
JP2007523872A (ja) * 2003-07-17 2007-08-23 バナー ファーマキャップス，インコーポレイティド 制御放出製剤
CN101991557A (zh) * 2009-08-10 2011-03-30 杭州赛利药物研究所有限公司 一种盐酸万古霉素液体胶囊及其制备方法
CN101991557B (zh) * 2009-08-10 2013-09-18 杭州赛利药物研究所有限公司 一种盐酸万古霉素液体胶囊及其制备方法

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Publication number Publication date
AU3269695A (en) 1996-03-22
SI9400338A (en) 1996-04-30

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