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WO1995026191A1 - Injectable solutions of dirithromycin - Google Patents

Injectable solutions of dirithromycin 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
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Prior art keywords
dirithromycin
injection
solution
ethanol
water
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PCT/EP1995/001096
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German (de)
French (fr)
Inventor
Stefan Leiner
Bernhard Hassel
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Boehringer Ingelheim Vetmedica Gmbh
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Priority to EP95915148A priority Critical patent/EP0754047A1/en
Priority to JP7524954A priority patent/JPH09510722A/en
Priority to AU22141/95A priority patent/AU2214195A/en
Publication of WO1995026191A1 publication Critical patent/WO1995026191A1/en

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    • 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

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

Abstract

The invention concerns stable injectable solutions of dirithromycin.

Description

jizierbare Lösungen von Dirithromycin. jizzy solutions of dirithromycin.
Dirithromycin ist ein partialsynthetisches Antibiotikum aus der Reihe der Erythromycine. Dirithromycin, Verfahren zu seiner Herstellung und seine Verwendung als Arzneimittel wurde erstmals in der deutschen Offenlegungsschrift P 25 15 075 beschrieben. Üblicherweise wird es in Form fester oraler Zubereitung appliziert, da es in Lösungen einige problematische Eigenschaften bezüglich seiner Stabilität besitzt. In wässerigen Lösungen zersetzt es sich sehr rasch zu Erythromycylamin. Entsprechend sind wässerige Injektionslösungen nicht stabil und bisher nicht bekannt.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.
Es ist die Aufgabe der vorliegenden Erfindung, eine stabile injizierbare Lösung von Dirithromycin bereitzustellen.It is the object of the present invention to provide a stable injectable solution of dirithromycin.
Lipophile Injektionslösungen enthalten üblicherweise flüssige Fettsäureester wie beispielsweise Isopropylmyristat und Ethyloleat wie auch Triglyceride (Triacetin) und gegebenenfalls amphiphile oder hydrophile organische Solventien wie beispielsweise Ethanol, Propandiol, Benzylalkohol und Solketal.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.
Die Löslichkeit von Dirithromycin in lipophilen Medien oder lipophilen Gemischen ist nur gering, so daß eine therapeutisch notwendige wirksame Konzentration an Wirkstoff nicht erhalten werden kann. In solchen Systemen besteht zudem weiterhin die Wahrscheinlichkeit der Wirkstoffzersetzung zu noch nicht in ihrer Struktur aufgeklärten Substanzen.The solubility of dirithromycin in lipophilic media or lipophilic mixtures is only low, so that a therapeutically necessary effective concentration of active ingredient cannot be obtained. In such systems there is also still the likelihood of the active ingredient decomposing into substances that have not yet been elucidated in their structure.
Überraschenderweise wurde gefunden, daß die Zugabe geringer Mengen an Wasser nicht nur die Löslichkeit von Dirithromycin in lipophilen (öligen) Injektionslösungen erhöht, sondern auch die Stabilität des Dirithromycins verbessert. Erfindungsgemäß beansprucht werden Dirithromycin enthaltende einphasige wasserhaltige lipophile (ölige) Injektionslösungen, die eine definierte Menge an Wasser enthalten.Surprisingly, it was found that the addition of small amounts of water not only increases the solubility of dirithromycin in lipophilic (oily) injection solutions, but also improves the stability of the dirithromycin. According to the invention, dirithromycin-containing, single-phase, water-containing lipophilic (oily) injection solutions which contain a defined amount of water are claimed.
Der maximale Anteil an Wasser ist durch die Vorgabe eines einphasigen Systems festgelegt. Untersuchungen haben gezeigt, daß sich in dem Augenblick, in dem sich durch die Wasserzugabe ein zweiphasiges System ausbildet, die Stabilität des Dirithromycins drastisch verringert. Die Bedingungen, unter denen sich bei Wasserzugabe eine zweite Phase bildet, ist von der Zusammensetzung der lipophilen Injektionslösung abhängig. Lösungen, die einen hohen Anteil an langkettigen hydrophoben oder amphiphilen Bestandteilen aufweisen, bilden bereits bei einem 3- prozentigen Wasseranteil ein zweiphasiges System, während Gemische mit kurzkettigen hydrophoben Bestandteilen, wie beispielsweise Triacetin/Ethanol enthaltende Gemische auch bei einem 20%igen Wasseranteil einphasige Systeme bilden.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 .
Erfindungsgemäß bevorzugt werden einphasige Lösungsmittelgemische, die einen maximalen Wasseranteil aufweisen, wobei als kritische Grenze der Übergang zu zweiphasigen Lösungsmittelgemischen anzusehen ist. Der maximal zusetzbare Wasseranteil ist abhängig vom Anteil des hydrophilen bzw. amphiphilen Solvents - in bevorzugter Ausführungsform Ethanol - am Lösungsmittelgemisch. Bei der Verwendung von langkettigen Fettsäureestern kann der Wasseranteil maximal ca. 10 - 12 Gew. % bezogen auf den Ethanolanteil betragen. Je größer beispielsweise der Anteil an Ethanol ist, desto höher die maximal zusetzbare Menge Wasser, bevor die kritische Grenze des Übergangs zum zweiphasigen System erreicht ist. Der Anteil an hydrophilem Lösungsmittel - beispielsweise Ethanol - ist durch zwei Faktoren begrenzt, zum einen ist Dirithromycin in reinen Ethanol/Wassersystemen instabil, zum anderen ist die Injektion von Injektionslösungen mit hohem Ethanolanteil sehr schmerzhaft. Eine noch akzeptable Obergrenze wird bei ca. 50 Gew-% Ethanol gesehen, wobei ein Bereich zwischen 30 und 40 Gew.% bevorzugt und zwischen 32 und 37 Gew.% besonders bevorzugt ist. Eine Untergrenze an hydrophilem Lösungsmittel -insbesondere an Ethanol - die im Einzelfall stark variieren kann, ergibt sich aus der Vorgabe, daß in einer bevorzugten Ausführungsform der wirkstoffhaltigen Injektionslösung die Konzentration an Dirithromycin in etwa mindestens 20 g/100 ml betragen sollte. Geringere Konzentrationen sind möglich, jedoch müssen dann größere Volumina injiziert werden, um eine therapeutisch wirksame Dosis applizieren zu können. Aufgrund dieser Randbedingungen ergebe sich beispielsweise ein Lösungsmittelgemisch aus Isopropylmyristat, Ethanol und Wasser im Verhältnis von 80:20:2, in dem 19 g Dirithromycin in 100 ml gelöst werden können. Eine besonders bevorzugte Ausführungsform wäre das eben genannte Gemisch im Verhältnis 65:35:4, in dem 32 g Dirithromycin in 100 ml gelöst werden können.According to the invention, 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. When using long-chain fatty acid esters, the water content can be a maximum of approx. 10 - 12% by weight based on the ethanol content. For example, 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. The proportion of 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. Lower concentrations are possible, but larger volumes must then be injected in order to be able to apply a therapeutically effective dose. Because of these boundary conditions, for example, a solvent mixture of isopropyl myristate, ethanol and water in a ratio of 80: 20: 2 results, in which 19 g of dirithromycin can be dissolved in 100 ml. A particularly preferred embodiment would be the mixture just mentioned in a ratio of 65: 35: 4, in which 32 g of dirithromycin can be dissolved in 100 ml.
Lösungsmittelgemische, die beispielsweise Triacetin als öligen Bestandteil enthalten, erlauben bei geringem Gehalt an hydrophilen Solvens (beispielsweise Ethanol) einen prozentual höheren Gehalt an Wasser. Entsprechende Korrelationen sind den Tabellen der Beispiele zu entnehmen.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.
Beispiele für Öle und Fettsäureester in öligen Lösungsgemischen sind mittelkettige Triglyceride (z. B. Miglyol®812), Sojaöl, Rizinusöl, Sonnenblumenöl, Isopropylpalmitat, Isopropylmyristat, Ölsäureoleylester (Cetiol®), Erdnußöl und andere pflanzliche Öle. Bevorzugt werden Isopropylmyristat, Ethyloleat und Triacetin.Examples of 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.
Bevorzugte hydrophile Solventien sind Propandiol, Benzylalkohol, Polyethylenglykole und Solketal, besonders bevorzugt ist Ethanol.Preferred hydrophilic solvents are propanediol, benzyl alcohol, polyethylene glycols and solketal; ethanol is particularly preferred.
Die nachfolgenden Beispiele sollen die Erfindung erläutern, ohne sie jedoch auf die belegten Beispiele einzuschränken.The following examples are intended to illustrate the invention without, however, restricting it to the examples shown.
Die erfindungsgemäßen Lösungen von Dirithromycin sind stabil und können über einen längeren Zeitraum von mindestens 6 - 12 Monaten, unter geeigneten Lagerbedingungen auch bis zu mehreren Jahren verwendet werden.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.
Einfluß von Wasser auf die Lösiichkeit von Dirithromyci nInfluence of water on the solubility of Dirithromyci n
System Isopropylmyristat / Ethanol abs. / Pro pandiol (Anga ben in Gew.-Teilen):System isopropyl myristate / ethanol abs. / Per pandiol (details in parts by weight):
Lösungsmittelgemisch ausSolvent mixture
Isopropylmyristat 60 60 60 60Isopropyl myristate 60 60 60 60
Ethanol abs. 25 25 25 25Ethanol abs. 25 25 25 25
Propandiol 15 15 15 15Propanediol 15 15 15 15
Wasser 0 1 1,4 2 ca. - Löslichkeit von 15 18 20 / Dirithromycin (g pro 100 ml) 2-Phasen-Water 0 1 1.4 2 approx. - solubility of 15 18 20 / dirithromycin (g per 100 ml) 2-phase
System System Ethyloleat / Solketal:system Ethyl oleate / Solketal system:
Lösungsmittelgemisch ausSolvent mixture
Ethyloleat 80 80 80Ethyl oleate 80 80 80
Solketal 20 20 20Solketal 20 20 20
Wasser 0 0,05 0,8 ca. - Löslichkeit von 6,5 8 10 Dirithromycin (g pro 100 ml)Water 0 0.05 0.8 approx. - solubility of 6.5 8 10 dirithromycin (g per 100 ml)
System Isopropylmyristat / Benzylalkohol:Isopropyl myristate / benzyl alcohol system:
Lösungsmittelgemisch ausSolvent mixture
Isopropylmyristat 80 80Isopropyl myristate 80 80
Benzylalkohol 20 20Benzyl alcohol 20 20
Wasser 0 0,06 ca. - Löslichkeit von 8,5 11 Dirithromycin (g pro 100 ml)Water 0 0.06 approx. - solubility of 8.5 11 dirithromycin (g per 100 ml)
System Triacetin / Ethanol:Triacetin / ethanol system:
Lösungsmittelgemisch ausSolvent mixture
Triacetin 20 20 20 20Triacetin 20 20 20 20
Ethanol 4 4 4 4Ethanol 4 4 4 4
Wasser 0 2 4 5,5 ca. - Löslichkeit von 11 17 22 26 Dirithromycin (g pro 100 ml)Water 0 2 4 5.5 approx. - solubility of 11 17 22 26 dirithromycin (g per 100 ml)
System Isopropylmyristat / Ethanol abs.System isopropyl myristate / ethanol abs.
Lösungsmittelgemisch ausSolvent mixture
Isopropylmyristat 80 80 80 80Isopropyl myristate 80 80 80 80
Ethanol abs. 20 20 20 20Ethanol abs. 20 20 20 20
Wasser 0 1 2 3 ca. - Löslichkeit von 7 15 19 / Dirithromycin (g pro 100 ml) 2-Phasen-Water 0 1 2 3 approx. - solubility of 7 15 19 / dirithromycin (g per 100 ml) 2-phase
Systemsystem
Lösungsmittelgemisch ausSolvent mixture
Isopropylmyristat 65 65 65 65Isopropyl myristate 65 65 65 65
Ethanol abs. 35 35 35 35Ethanol abs. 35 35 35 35
Wasser 0 1 2 3 ca. - Löslichkeit von 13 17 22 27 Dirithromycin (g pro 100 ml) Lösungsmittelgemisch ausWater 0 1 2 3 approx. - solubility of 13 17 22 27 dirithromycin (g per 100 ml) Solvent mixture
Isopropylmyristat 65 65Isopropyl myristate 65 65
Ethanol abs. 35 35Ethanol abs. 35 35
Wasser 4 6 ca. - Löslichkeit von 32 / Dirithromycin (g pro 100 ml) 2-Phasen-Water 4 6 approx. - solubility of 32 / dirithromycin (g per 100 ml) 2-phase
Systemsystem
Einfluß von Wasser auf die Stabilität von DirithromycinInfluence of water on the stability of dirithromycin
System Isopropylmyristat / Ethanol:Isopropyl myristate / ethanol system:
Figure imgf000007_0001
Figure imgf000007_0001
*Angaben in Gew. -Teilen System Ethanol/Solketol:* Figures in parts by weight Ethanol / Solketol system:
Dirithro¬ Epi-Diri¬ Zersetzungs¬ Gesamt¬ Gesamt¬ Farbe mycin thromy¬ produkt wirkstoff¬ wirkstoff¬ cin Erythromy- gehalt gehalt als cylamin (Summe % vom Dirithro¬ Soll- mycin plus Gehalt Epi- Dirithro¬ mycin)Dirithro¬ Epi-Diri¬ Decomposition¬ Total ¬ Color mycin thromy¬ product active ingredient ¬ active ingredient in cin erythromy content as cylamine (sum% of Dirithro¬ target mycin plus Epi-Dirithro¬ mycin content)
Alle Angaben zum Wirkstoffgehalt in g / 100 mlAll information on the active substance content in g / 100 ml
5 % Dirithromycin suspendiert in Ethyloleat/Solketal 8+2*5% dirithromycin suspended in ethyl oleate / Solketal 8 + 2 *
1 Woche 25°C(= 3,2 0,5 0,1 3,7 74,0% farblos Nullwert)1 week 25 ° C (= 3.2 0.5 0.1 3.7 74.0% colorless zero value)
4 Wochen 40°C 2,2 0,3 0,1 2,5 50,0% dunkelbraun4 weeks 40 ° C 2.2 0.3 0.1 2.5 50.0% dark brown
5 % Dirithromycin Ethyloleat/Solketal/ Wasser 8 + 2 + 0,5*5% dirithromycin ethyl oleate / solketal / water 8 + 2 + 0.5 *
1 Woche 25°C (= 3,5 0,6 0,1 4,1 82,0% farblos Nullwert)1 week 25 ° C (= 3.5 0.6 0.1 4.1 82.0% colorless zero value)
4 Wochen 40°C 2,6 0,4 0,1 3 60,0% hellbraun4 weeks 40 ° C 2.6 0.4 0.1 3 60.0% light brown
•Angaben in Gew. -Teilen • Figures in parts by weight

Claims

PatentansprücheClaims
1) Injektionslösung enthaltend Dirithromycin als Wirkstoff in einem lipophilen wasserhaltigen einphasigen pharmakologisch verträglichem Lösungsmittelgemisch.1) Injection solution containing dirithromycin as an active ingredient in a lipophilic, water-containing, single-phase, pharmacologically acceptable solvent mixture.
2) Injektionslösung nach Anspruch 1 , dadurch gekennzeichnet, daß das lipophile Lösungsmittelgemisch aus einer lipophilen Komponente und einem amphiphilen oder hydrophilen organischen Solvens besteht.2) Injection solution according to claim 1, characterized in that the lipophilic solvent mixture consists of a lipophilic component and an amphiphilic or hydrophilic organic solvent.
3) Injektionslösung nach Anspruch 2, dadurch gekennzeichnet, daß die lipophile Komponente aus einem pharmakologisch verträglichen Fettsäureester oder einem Triglycerid besteht.3) solution for injection according to claim 2, characterized in that the lipophilic component consists of a pharmacologically acceptable fatty acid ester or a triglyceride.
4) Injektionslösung nach Anspruch 2 oder 3, dadurch gekennzeichnet, daß die lipophile Komponente aus der Gruppe mittelkettige Triglyceride, Sojaöl, Rizinusöl, Sonnenblumenöl, Isopropylpalmitat, Ölsäureoleylester, Erdnußöl, Isopropymyristat, Triacetin oder Ethyloleat ausgewählt ist.4) solution for injection according to claim 2 or 3, characterized in that the lipophilic component is selected from the group consisting of medium-chain triglycerides, soybean oil, castor oil, sunflower oil, isopropyl palmitate, oleic acid oleyl ester, peanut oil, isopropymyristate, triacetin or ethyl oleate.
5) Injektionslösung nach Anspruch, dadurch gekennzeichnet, daß das hydrophile organische Solvents aus der Gruppe Ethanol, Propandiol, Propylenglykol, Benzylalkohol oder Solketal ausgewählt ist.5) Injection solution according to claim, characterized in that the hydrophilic organic solvent is selected from the group consisting of ethanol, propanediol, propylene glycol, benzyl alcohol or solketal.
6) Injektionslösung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß sie Isopropylmyristat als lipophile Komponente und Ethanol als hydrophiles Solvents enthält.6) Injection solution according to one of the preceding claims, characterized in that it contains isopropyl myristate as a lipophilic component and ethanol as a hydrophilic solvent.
7) Injektionslösung nach Anspruch 6, dadurch gekennzeichnet, daß sie zwischen 65 und 80 Gew.% Isopropylmyristat, zwischen 20 und 35 Gew.% Ethanol und zwischen 1 und 4 % Wasser enthält.7) Injection solution according to claim 6, characterized in that it contains between 65 and 80 wt.% Isopropyl myristate, between 20 and 35 wt.% Ethanol and between 1 and 4% water.
8) Injektionslösung nach einem der vorhergehenden Patentansprüche, dadurch gekennzeichnet, daß die Konzentration an Dirithromycin mindestens 20 g pro 100 ml Lösung beträgt. 9) Injektionslösung nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß die Injektionslösung zusätzlich einen oder mehrere pharmazeutische(n) Hilfsstoff(e) enthält.8) solution for injection according to one of the preceding claims, characterized in that the concentration of dirithromycin is at least 20 g per 100 ml of solution. 9) Injection solution according to one of the preceding claims, characterized in that the injection solution additionally contains one or more pharmaceutical (s) excipient (s).
10) Injektionslösung, dadurch gekennzeichnet, daß die Konzentration an Dirithromycin zwischen 20 und 40 g/100 ml Lösungsmittel beträgt.10) solution for injection, characterized in that the concentration of dirithromycin is between 20 and 40 g / 100 ml of solvent.
11) Stabile verträgliche Lösungen von Dirithromycin. 11) Stable compatible solutions of dirithromycin.
PCT/EP1995/001096 1994-03-26 1995-03-23 Injectable solutions of dirithromycin WO1995026191A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP95915148A EP0754047A1 (en) 1994-03-26 1995-03-23 Injectable solutions of dirithromycin
JP7524954A JPH09510722A (en) 1994-03-26 1995-03-23 Injectable dilithromycin solution
AU22141/95A AU2214195A (en) 1994-03-26 1995-03-23 Injectable solutions of dirithromycin

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4410637.8 1994-03-26
DE4410637A DE4410637C1 (en) 1994-03-26 1994-03-26 Injectable solutions of dirithromycin

Publications (1)

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WO1995026191A1 true WO1995026191A1 (en) 1995-10-05

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Country Status (7)

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

Cited By (1)

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Publication number Priority date Publication date Assignee Title
EP2616047A4 (en) * 2010-09-16 2016-04-27 Lg Life Sciences Ltd Non-aqueous oily injectable formulation exhibiting preservative efficacy

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Publication number Priority date Publication date Assignee Title
DE19518917A1 (en) * 1995-05-23 1996-11-28 Boehringer Ingelheim Vetmed Stable, concentrated, locally tolerated erythromycylamine solutions
DE19701949A1 (en) * 1997-01-13 1998-07-16 Jenapharm Gmbh Transdermal therapeutic system

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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 (en) * 1989-05-26 1990-11-29 Abbott Laboratories Injectable clarithromycin composition

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DE3209429A1 (en) * 1982-03-16 1983-10-06 Boehringer Ingelheim Vetmed AGENT FOR IMPROVING THE RESORPTION OF INJECTED ANTIBACTERIAL EFFECTIVE SUBSTANCES AND COMBINATIONS CONTAINING A BENZYAMINE DERIVATIVE

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 (en) * 1989-05-26 1990-11-29 Abbott Laboratories Injectable clarithromycin composition

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2616047A4 (en) * 2010-09-16 2016-04-27 Lg Life Sciences Ltd Non-aqueous oily injectable formulation exhibiting preservative efficacy

Also Published As

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

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