Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Patent
1998-10-06
2000-05-16
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
514943, A61F 1300
Patent
active
060633948
DESCRIPTION:
BRIEF SUMMARY
The invention relates to new injection formulations of avermectins and milbemycins in animals, based on castor oil.
Injection formulations of ivermectin are disclosed in EP-A 146 414. The formulations contain a solvent mixture of propylene glycol and glycerol formal in the ratio 60:40 v/v. It is known of propylene glycol that in certain concentrations it can cause local intolerabilities (see review: B. Kruss, Acta Pharm. Technol. 35(4) (1989) 187-196). The precipitation of the water-insoluble active compound ivermectin can also occur in the tissue around the administration site. Thus when using corresponding formulations marked swellings and tissue incompatibilities were observed at the injection sites, some of which only receded after several weeks.
Injection formulations of specific avermectins are disclosed in EP-A 393 890. They are oil formulations based on sesame oil and ethyl oleate in the ratio 90:10 v/v. These formulations are tolerable, but have the disadvantage that on storage in a refrigerator at 4.degree. C. a flocculent precipitate is formed even after a few days.
Further injection formulations of avermectins are disclosed in EP-A 45 655. The formulations described there contain comparatively high amounts of emulsifiers and in some cases are not very tolerable.
Injection formulations of avermnectins which contain triacetin (glycerol triacetate) are described in EP-A 413 538. In EP-A 535 734, injection formulations of avermectins based on triacetin and hydrogenated castor oil are described.
Further formulations for the injection of milbemycins and avermectins are described in EP-A 525 307. The formulations are prepared by fusing glycerol tristearate with the active compound and mixing with an oily neutral triglyceride and emulsifying using, for example, methylcellulose and salts. The average particle size in the microemulsion thus obtained should be between 25 and 300 .mu.m.
The present invention relates to injection formulations of avermectins and milbemycins based on castor oil.
The formulations preferably contain synthetic fatty acid esters of mono- or polyhydric alcohols, aliphatic or aromatic alcohols, cyclic carbonates in concentrations of 30 to 85% by weight
The formulations according to the invention have an outstanding solubility for the active compounds.
The high viscosity of castor oil can be adjusted to a desired lower value by addition of medium-chain triglycerides or propylene glycol octanoate/decanoate or ethyl oleate. Additionally, the solubility of the active compound can be improved, the viscosity further reduced and the bioavailability of the active compound improved by addition of relatively small volumes of hydrophilic solvents such as benzyl alcohol, propylene glycol or propylene carbonate with retention of a single-phase system. The new formulations are extremely highly tolerable and have a high bioavailability.
The active compounds employed in the formulations according to the invention are known.
Avermectins were isolated from the microorganism Streptomyces avermitilis as microbial metabolites (U.S. Pat. No. 4,310,519) and can occur essentially as a mixture consisting of the eight components A.sub.1a, A.sub.1b, A.sub.2a, A.sub.2b, B.sub.1a, B.sub.1b, B.sub.2a, and B.sub.2b (I. Putter et al., Experentia 37 (1981) p. 963, Birkhauser Verlag (Switzerland)). In addition, the synthetic derivatives, in particular 22,23-dihydroavermectin B.sub.1 (ivermectin), are also of interest (U.S. Pat. No. 4,199,569). Milbemycin B-41 D was isolated from Streptomyces hygroscopicus by fermentation (cf. "Milbemycin: Discovery and Development", I. Junya et al., Annu. Rep. Sankyo Res. Lab. 45 (1993), pp.1-98; JP Pat. 8,378,549; GB 1,390,336).
The use of the avermectins, e.g. 22,23-dihydroavermectins B.sub.1, (ivermectin) and milbemycins as endoparasiticides is known and is the subject of numerous patent applications and review articles (e.g. biological actions in: "Ivermectin and Abamectin", W. C. Campbell, Ed., Springer Verlag, New York, N.Y., 1989; "Avermectins and Milbemycins Part II" H. G.
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B. Kruss, Acta Pharm. Technol. 35 (4) (month unavailable) 1989, pp. 187-196.
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Grosse-Bley Michael
Kujanek Richard
Akorli Godfried R.
Bayer Aktiengesellschaft
Gil Joseph C.
Page Thurman K.
Ware Todd D
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