WO1995021624A1 - Preparation sous forme de solution a base d'une forte concentration d'aureobasidine - Google Patents

Preparation sous forme de solution a base d'une forte concentration d'aureobasidine Download PDF

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Publication number
WO1995021624A1
WO1995021624A1 PCT/JP1995/000145 JP9500145W WO9521624A1 WO 1995021624 A1 WO1995021624 A1 WO 1995021624A1 JP 9500145 W JP9500145 W JP 9500145W WO 9521624 A1 WO9521624 A1 WO 9521624A1
Authority
WO
WIPO (PCT)
Prior art keywords
preparation
castor oil
aureobasidin
ethanol
wzw
Prior art date
Application number
PCT/JP1995/000145
Other languages
English (en)
Japanese (ja)
Inventor
Hironobu Hiraga
Hisae Igarashi
Takaaki Ohkuma
Original Assignee
Nippon Kayaku Kabushiki Kaisha
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 Nippon Kayaku Kabushiki Kaisha filed Critical Nippon Kayaku Kabushiki Kaisha
Publication of WO1995021624A1 publication Critical patent/WO1995021624A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K11/00—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K11/02—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof cyclic, e.g. valinomycins ; Derivatives thereof
    • 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
    • A61K38/15—Depsipeptides; Derivatives thereof
    • 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 relates to a high concentration solution preparation of aureobasidin useful as an antifungal agent for deep mycosis.
  • Deep mycosis is a fatal disease for patients with suppressed immunity, such as cancer, organ transplantation, and acquired immunodeficiency syndrome, and has been increasing in recent years.
  • the preparation of the present invention is extremely useful as a preparation for treating such diseases.
  • Aureobasidin A (same as antibiotic R106-I; hereinafter abbreviated as R106-1) is, for example, a strain belonging to the genus Aureobasidium (FERM-BP1938).
  • EP 3 is an antibiotic of cyclic peptides, and is expected to be useful as an antifungal agent.A large number of their derivatives and analogous compounds are also synthesized.
  • aureobasidins including R106-I and its derivatives or analogs are referred to as R106-1.
  • R106-Is For patients with deep mycosis, the clinical use of R106-Is, especially R106-I, depends on the infected fungus and the symptoms of the patient, but daily doses of 25 mg There is a need for a formulation of R106-1 which can easily administer 20001118 at a dose of 13 ⁇ 4106-1 and has good absorbability, especially when administered orally.
  • An object of the present invention is to provide a dosage of R 10 which is necessary for treating
  • R106-1 and ethanol and polio Completed the present invention by finding that the oral absorption of R106-I is good when a high concentration solution of R106-I containing oral kissetylene castor oil-based activator as an essential component is good. did.
  • the present invention contains R106-I, a polyoxyethylene castor oil-based activator and ethanol as essential components, and contains R106-I in an amount of at least 10 w% based on the whole preparation. 06-1 related to high concentration solution preparations.
  • polyoxyethylene castor oil-based activator used in the present invention examples include polyoxyethylene castor oil ⁇ polyoxetylene hard castor oil and the like.
  • Polyoxyethylene castor oil includes, for example, Cremophor EL (trade name, manufactured by BASF), NI KKOL CO-3. CO-10, CO-20 TX, CO-40 TX, CO-50TX, CO-60TX (trade name) ; Nikko Chemicals Co., Ltd.).
  • polyoxyethylene castor oil-based activators have an average addition monoethylene number of ethylene oxide in the range of 20 to 80, preferably 30 to 70 in view of the oral absorbability of R106-1, force preferred n and those having an HLB value in the range of 8 to 1 7
  • the amount of the polyoxyethylene castor oil-based activator used is usually at least 65 parts by weight, preferably at least 80 parts by weight, per 100 parts by weight of R106-1.
  • the upper limit is not particularly limited, and can be determined according to the volume of the preparation.
  • the amount of ethanol used is at least 30 parts by weight, preferably at least 35 parts by weight, based on 100 parts by weight of R106-I.
  • the upper limit is not particularly limited, and can be determined according to the volume of the preparation and the amount of the polyoxetylene castor oil-based active agent. Usually, it is 500 parts by weight or less.
  • the amount relative to the whole preparation is usually 10 wZw% or more for R106-Is, preferably 20 to 40 ww%, and 1% for the polyoxetylene castor oil-based active agent. 0 w / w% or more, preferably 20 to 50 wZw%, preferably ethanol? To 40 wZw%, more preferably 8 to 30 wZw%.
  • the quality of the dosage form becomes unstable due to its volatility. Inconveniences such as cracking due to losing the flexibility of the capsule occur.
  • adding a highly soluble unsaturated higher fatty acid of the R106-I class to the preparation can reduce the required amount of ethanol to be added, without increasing the capacity of the preparation.
  • a highly absorbable preparation can be obtained.
  • the unsaturated higher fatty acid is not particularly limited as long as it can be used for medicine, but preferred are unsaturated fatty acids having 18 to 20 carbon atoms. Examples of these fatty acids include oleic acid, linoleic acid, linolenic acid, arachidonic acid and the like.
  • the amount of these fatty acids to be added is usually in the range of 0 to 200 parts by weight based on 100 parts by weight of R106-I, and 10 to 60 parts by weight for the whole preparation. It is in the range of wZw%.
  • a hard gelatin capsule preparation obtained by filling a high-concentration solution formulation of the present invention into a normal hard gelatin capsule can be obtained.
  • filling the hard gelatin capsule containing polyethylene glycol (PEG) with a drug solution can cause problems such as cracking of the capsule and cracking of the capsule and leakage of the liquid content. It can prevent liquid leakage and capsule cracking.
  • PEG polyethylene glycol
  • As a hard gelatin capsule containing PEG for example, For example, those manufactured by Elanco Japan Co., Ltd. described in JP-A-3-80930 can be used. According to the above-mentioned publication, the content of the PEG slightly varies depending on the molecular weight of the PEG used. That is, for the gelatin in the gelatin capsule composition,
  • the high-concentration solution preparation of the present invention can also be used as a syrup or the like, if necessary.
  • the high-concentration solution preparation of the present invention may contain, in addition to the above-mentioned components, pharmaceutical additives such as an auxiliary agent for dissolving R106-I, an antioxidant and a preservative.
  • pharmaceutical additives such as an auxiliary agent for dissolving R106-I, an antioxidant and a preservative.
  • the compounding amount of the antioxidant is preferably from 0.01 to 10 wZw%, more preferably from 0.1 to 5 wZw%, based on the whole preparation.
  • antioxidants when fats and oils containing unsaturated bonds are incorporated into the preparations as solubilizers of R106-1 class, vitamin Es, butylhydroxytoluene, butylhydroxydisole are used to prevent oxidation of fats and oils. And the like.
  • the compounding amount of these antioxidants is in the range of 0.001 to 0.01 parts by weight based on 1 part by weight of fats and oils.
  • an inert gas such as nitrogen gas
  • a solution having the following composition is PEG-containing O 95/21624
  • R 1 06-I 15 5-40 wZw% more preferably 20-40 w / w% Polyoxyethylene 15 5-60 w / w% more preferably 20-50 ww% Castor oil-based activator
  • the preparation of the present invention can be prepared by a usual method without employing a special method. That is, for example, a polyoxyethylene castor oil-based activator and ethanol are mixed with an unsaturated higher fatty acid, an antioxidant, etc., if necessary, and then R106-I is added, followed by heating if necessary.
  • the solution can be prepared by dissolving R106-Is while mixing, and filling the resulting solution, for example, into a hard gelatin capsule, if necessary.
  • Cremophor EL brand name 0, 8 5 g (27.4 wZw%)
  • Cremophor EL 0.85 g and oleic acid (extra olein: trade name, Nippon Oil & Fat Co., Ltd.) O 95/21624
  • the hard capsules used in Examples 1, 2 and 3 and Control Examples 1 and 4 were manufactured by Nippon Elanco Co., Ltd., and PEG-containing hard capsule was PEG having a molecular weight of 4,000 with respect to the whole skin.
  • a hard gelatin capsule containing 3 wZw%, and a normal hard capsule refers to a normal hard gelatin capsule containing no PEG.

Abstract

Préparation sous forme de solution à base d'une forte concentration d'auréobasidine A (R106-I) et à absorbabilité perorale excellente. La préparation renferme, à titre d'ingrédients essentiels, la R106-I utilisée comme antimycosique, un tensioactif constitué de polyoxyéthylène et d'huile de ricin, et de l'éthanol, de préférence selon des quantités respectivement de 100, d'au moins 65 et d'au moins 30 parties en poids. La concentration de R106-I dans la préparation est comprise entre 20 et 40 % en poids. Une préparation encapsulée obtenue par introduction de ladite préparation dans une capsule de gélatine dure renfermant du polyéthylène-glycol (P.E.G.) est une préparation excellente en ce qu'elle est incassable et toute fuite de son contenu est impossible.
PCT/JP1995/000145 1994-02-08 1995-02-03 Preparation sous forme de solution a base d'une forte concentration d'aureobasidine WO1995021624A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP3427794 1994-02-08
JP6/34277 1994-02-08

Publications (1)

Publication Number Publication Date
WO1995021624A1 true WO1995021624A1 (fr) 1995-08-17

Family

ID=12409676

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1995/000145 WO1995021624A1 (fr) 1994-02-08 1995-02-03 Preparation sous forme de solution a base d'une forte concentration d'aureobasidine

Country Status (1)

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WO (1) WO1995021624A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001062268A1 (fr) * 2000-02-22 2001-08-30 Bayer Aktiengesellschaft Agents endoparasiticides

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04305534A (ja) * 1991-04-02 1992-10-28 Takara Shuzo Co Ltd オーレオバシジン類製剤
WO1994000142A1 (fr) * 1992-06-26 1994-01-06 Nippon Kayaku Kabushiki Kaisha Preparation emulsifiee d'aureobasidine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04305534A (ja) * 1991-04-02 1992-10-28 Takara Shuzo Co Ltd オーレオバシジン類製剤
WO1994000142A1 (fr) * 1992-06-26 1994-01-06 Nippon Kayaku Kabushiki Kaisha Preparation emulsifiee d'aureobasidine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001062268A1 (fr) * 2000-02-22 2001-08-30 Bayer Aktiengesellschaft Agents endoparasiticides

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