WO1995026191A1 - Solutions injectables de dirithromycine - Google Patents

Solutions injectables de dirithromycine Download PDF

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Publication number
WO1995026191A1
WO1995026191A1 PCT/EP1995/001096 EP9501096W WO9526191A1 WO 1995026191 A1 WO1995026191 A1 WO 1995026191A1 EP 9501096 W EP9501096 W EP 9501096W WO 9526191 A1 WO9526191 A1 WO 9526191A1
Authority
WO
WIPO (PCT)
Prior art keywords
dirithromycin
injection
solution
ethanol
water
Prior art date
Application number
PCT/EP1995/001096
Other languages
German (de)
English (en)
Inventor
Stefan Leiner
Bernhard Hassel
Original Assignee
Boehringer Ingelheim Vetmedica Gmbh
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 Boehringer Ingelheim Vetmedica Gmbh filed Critical Boehringer Ingelheim Vetmedica Gmbh
Priority to JP7524954A priority Critical patent/JPH09510722A/ja
Priority to AU22141/95A priority patent/AU2214195A/en
Priority to EP95915148A priority patent/EP0754047A1/fr
Publication of WO1995026191A1 publication Critical patent/WO1995026191A1/fr

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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • 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
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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

  • Dirithromycin is a partially synthetic antibiotic from the Erythromycine series. Dirithromycin, process for its preparation and its use as a medicinal product was first described in German Offenlegungsschrift P 25 15 075. It is usually applied in the form of solid oral preparation, since it has some problematic properties with regard to its stability in solutions. In aqueous solutions, it decomposes very quickly to erythromycylamine. Correspondingly, aqueous injection solutions are not stable and are not yet known.
  • Lipophilic injection solutions usually contain liquid fatty acid esters such as isopropyl myristate and ethyl oleate as well as triglycerides (triacetin) and optionally amphiphilic or hydrophilic organic solvents such as ethanol, propanediol, benzyl alcohol and solketal.
  • liquid fatty acid esters such as isopropyl myristate and ethyl oleate
  • triglycerides triacetin
  • amphiphilic or hydrophilic organic solvents such as ethanol, propanediol, benzyl alcohol and solketal.
  • dirithromycin-containing, single-phase, water-containing lipophilic (oily) injection solutions which contain a defined amount of water are claimed.
  • the maximum proportion of water is determined by the specification of a single-phase system. Studies have shown that the instant the two-phase system is formed by the addition of water, the stability of the dirithromycin is drastically reduced. The conditions under which a second phase forms when water is added depends on the composition of the lipophilic solution for injection. Solutions with a high proportion of long-chain hydrophobic or amphiphilic components already form a two-phase system with a 3% water content, while mixtures with short-chain hydrophobic components, such as triacetin / ethanol, also form single-phase systems with a 20% water content .
  • the transition to two-phase solvent mixtures preference is given to single-phase solvent mixtures which have a maximum water content, the transition to two-phase solvent mixtures to be regarded as the critical limit.
  • the maximum proportion of water that can be added depends on the proportion of the hydrophilic or amphiphilic solvent - in a preferred embodiment ethanol - in the solvent mixture.
  • the water content can be a maximum of approx. 10 - 12% by weight based on the ethanol content.
  • the greater the proportion of ethanol the higher the maximum amount of water that can be added before the critical limit of the transition to the two-phase system is reached.
  • hydrophilic solvent - for example ethanol - is limited by two factors, on the one hand, dirithromycin is unstable in pure ethanol / water systems, and on the other hand, the injection of injection solutions with a high proportion of ethanol is very painful.
  • a still acceptable upper limit is seen at approximately 50% by weight ethanol, a range between 30 and 40% by weight being preferred and between 32 and 37% by weight being particularly preferred.
  • a lower limit of hydrophilic solvent - in particular ethanol - which can vary widely in individual cases results from the stipulation that in a preferred embodiment of the active ingredient-containing injection solution, the concentration of dirithromycin should be approximately at least 20 g / 100 ml.
  • Solvent mixtures which contain, for example, triacetin as an oily component, permit a higher percentage of water with a low content of hydrophilic solvent (for example ethanol). Corresponding correlations can be found in the tables in the examples.
  • oils and fatty acid esters in oily solution mixtures are medium-chain triglycerides (e.g. Miglyol®812), soybean oil, castor oil, sunflower oil, isopropyl palmitate, isopropyl myristate, oleic acid oleate ester (Cetiol®), peanut oil and other vegetable oils. Isopropyl myristate, ethyl oleate and triacetin are preferred.
  • Preferred hydrophilic solvents are propanediol, benzyl alcohol, polyethylene glycols and solketal; ethanol is particularly preferred.
  • the solutions of dirithromycin according to the invention are stable and can be used over a longer period of at least 6-12 months, and under suitable storage conditions up to several years.
  • Triacetin / ethanol system Triacetin / ethanol system

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Engineering & Computer Science (AREA)
  • Oncology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des solutions injectables stables de dirithromycine.
PCT/EP1995/001096 1994-03-26 1995-03-23 Solutions injectables de dirithromycine WO1995026191A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP7524954A JPH09510722A (ja) 1994-03-26 1995-03-23 注射可能なジリスロマイシン溶液
AU22141/95A AU2214195A (en) 1994-03-26 1995-03-23 Injectable solutions of dirithromycin
EP95915148A EP0754047A1 (fr) 1994-03-26 1995-03-23 Solutions injectables de dirithromycine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4410637.8 1994-03-26
DE4410637A DE4410637C1 (de) 1994-03-26 1994-03-26 Injizierbare Lösungen von Dirithromycin

Publications (1)

Publication Number Publication Date
WO1995026191A1 true WO1995026191A1 (fr) 1995-10-05

Family

ID=6514000

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1995/001096 WO1995026191A1 (fr) 1994-03-26 1995-03-23 Solutions injectables de dirithromycine

Country Status (7)

Country Link
EP (1) EP0754047A1 (fr)
JP (1) JPH09510722A (fr)
AU (1) AU2214195A (fr)
CO (1) CO4370014A1 (fr)
DE (1) DE4410637C1 (fr)
WO (1) WO1995026191A1 (fr)
ZA (1) ZA952405B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2616047A4 (fr) * 2010-09-16 2016-04-27 Lg Life Sciences Ltd Formulation injectable huileuse non aqueuse présentant une efficacité de conservation

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19518917A1 (de) * 1995-05-23 1996-11-28 Boehringer Ingelheim Vetmed Stabile, konzentrierte lokalverträgliche Erythromycylamin-Lösungen
DE19701949A1 (de) * 1997-01-13 1998-07-16 Jenapharm Gmbh Transdermales therapeutisches System

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4048306A (en) * 1975-04-07 1977-09-13 Boehringer Ingelheim Gmbh Aldehyde-erythromycylamine condensation products
US4918108A (en) * 1982-03-16 1990-04-17 Boehringer Ingelheim Vetmedica Gmbh Method of improving the absorption of injected antibacterial substances
WO1990014094A1 (fr) * 1989-05-26 1990-11-29 Abbott Laboratories Composition de clarithromycine injectable

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3209429A1 (de) * 1982-03-16 1983-10-06 Boehringer Ingelheim Vetmed Mittel zur verbesserung der resorption von injizierten antibakteriell wirksamen substanzen und kombinationen, enthaltend ein benzyaminderivat

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4048306A (en) * 1975-04-07 1977-09-13 Boehringer Ingelheim Gmbh Aldehyde-erythromycylamine condensation products
US4918108A (en) * 1982-03-16 1990-04-17 Boehringer Ingelheim Vetmedica Gmbh Method of improving the absorption of injected antibacterial substances
WO1990014094A1 (fr) * 1989-05-26 1990-11-29 Abbott Laboratories Composition de clarithromycine injectable

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2616047A4 (fr) * 2010-09-16 2016-04-27 Lg Life Sciences Ltd Formulation injectable huileuse non aqueuse présentant une efficacité de conservation

Also Published As

Publication number Publication date
EP0754047A1 (fr) 1997-01-22
ZA952405B (en) 1995-09-26
CO4370014A1 (es) 1996-10-07
DE4410637C1 (de) 1995-09-21
AU2214195A (en) 1995-10-17
JPH09510722A (ja) 1997-10-28

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