Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2000-06-21
2001-09-11
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C424S200100
Reexamination Certificate
active
06288113
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a new use of a prostaglandin E
1
precursor. More specifically, the present invention relates to an angiogenesis promoter and a potentiator of an angiogenic effect due to a growth factor.
BACKGROUND ART
It is known that prostaglandin E
1
(PGE
1
) exists in a trace amount in a living body, has a broad range of physiological actions and the like, but lacks chemical stability. Therefore, an improvement in the formulation of a preparation and modification of PGE
1
have been considered. In particular, a PGE
1
precursor (prodrug) has been drawing attention. It is therefore an object of the present invention to provide a new use of a PGE
1
precursor.
DISCLOSURE OF THE INVENTION
The present inventors have found that a specific PGE
1
precursor has an angiogenesis promoting effect and potentiates the angiogenic effect by a growth factor, such as basic fibloblast growth factor (hereinafter to be referred to as b-FGF), which resulted in the completion of the present invention.
Accordingly, the present invention provides an angiogenesis promoter comprising a compound of the following formula (I)
wherein R
1
is acyl, R
2
is alkyl, R
3
and R
4
are the same or different and each is hydrogen atom or hydroxy protecting group and R
5
is alkyl (hereinafter to be also referred to PGE
1
precursor), as an active ingredient. The present invention also provides a potentiator of an angiogenic effect of a drug having such effect, which contains a PGE
1
precursor as an active ingredient.
The acyl at R
1
of the formula (I) has 2 to 6, preferably 2 to 4, carbon atoms. Preferable examples thereof include alkanoyl such as acetyl, propionyl, butyryl, pivaloyl, hexanoyl and the like. The alkyl at R
2
has 1 to 30, preferably 1 to 4, carbon atoms. Examples thereof include methyl, ethyl, propyl, butyl, hexyl, octyl, decyl, icosyl, triacosyl and the like. The alkyl at R
5
has 1 to 10, preferably 5 to 7, carbon atoms. Examples thereof include the above-mentioned alkyl having the corresponding carbon atoms and the like. The hydroxy protecting group at R
3
and R
4
includes, for example, acyl (e.g., acetyl, propionyl, benzoyl and the like), aralkyl (e.g., benzyl, phenylethyl and the like), and the like.
Specific examples of the PGE
1
precursor of the formula (I) include methyl 9-acetoxy-11&agr;,15S-dihydroxyprosta-8,13E-dien-1-oate, methyl 9,11&agr;,15S-triacetoxyprosta-8,13E-dien-1-oate, methyl 9,15R-diacetoxy-11&agr;-hydroxyprosta-8,13E-dien-1-oate, methyl 9,15S-diacetoxy-11&agr;-hydroxyprosta-8,13E-dien-1-oate, butyl 9-acetoxy-11&agr;,15S-dihydroxy-17S,20-dimethylprosta-8,13E-dien-1-oate, butyl 9-acetoxy-11&agr;,15S-dihydroxyprosta-8,13E-dien-1-oate, butyl 9-butyryloxy-11&agr;,15S-dihydroxyprosta-8,13E-dien-1-oate, butyl 9,11&agr;-diacetoxy-15S-hydroxy-17S,20-dimethylprosta-8,13E-dien-1-oate and the like.
The methods for preparing the compounds of the formula (I) are disclosed in JP-A-58-39660 (corresponding U.S. Pat. No. 4,363,817, U.S. Pat. No. 4,543,421, EP-A-133450), JP-A-3-204853 (corresponding U.S. Pat. No. 5,120,870, EP-A-423697), JP-A-5-213862 (corresponding USP 5194670, EP-A-624574) and the like.
The PGE
1
precursor can be used upon preparation into a suitable dosage form by inclusion in cyclodextrin (CD), formulating into a liposome, preparing into an ethanol solution, preparing into a lipid emulsion and the like. Preferred is the form of a lipid emulsion which is superior in sustained release, duration, local cumulativeness and stability during storage.
The preferable form of lipid emulsion is explained in the following. In the present invention, a lipid emulsion containing a PGE
1
precursor (hereinafter to be also referred to as PGE
1
precursor-containing lipid emulsion) is a preparation containing a PGE
1
precursor and an oil component dispersed in a dispersing medium as liquid drops.
The oil component is exemplified by vegetable oil, middle chain fatty acid triglyceride (so-called MCT), fish oil and the like. These may be used alone or in combination. Examples of the vegetable oil include soybean oil, sesame oil, castor oil, cottonseed oil, olive oil and the like. These need only purified by a known method to a level permitting clinically safe use. Preferred is purified soybean oil having high purity, more preferably purified soybean oil having high purity (purity: containing 99.9% or above as triglyceride, diglyceride and monoglyceride) obtained by further purifying the purified soybean oil by, for example, steam distillation method.
To disperse the oil component in a dispersing medium, phospholipid and the like are used as emulsifiers. Examples of the phospholipid include egg yolk phospholipid, soybean phospholipid and the like, and purified phospholipids thereof are particularly preferably used. The purified phospholipid can be prepared by a conventional method using fractionation with an organic solvent. The purified phospholipid mainly consists of phosphatidylcholine, phosphatidylethanolamine, and, as a phospholipid other than these, phosphatidylinositol, phosphatidylserine, sphingomyelin and the like. In addition, a phospholipid obtained by substantially removing phosphatidylethanolamine from purified phospholipid, to, for example, the content of not more than about 1 w/w%, may be used. This phospholipid can be obtained by using the phospholipid of egg yolk, soybean and the like and subjecting same to fractionation in organic solvent by a conventional method, and purifying with an inorganic adsorbent such as silica gel, alumina and the like. The thus-obtained phospholipid consists mainly of phosphatidylcholine [[(JP-A-60-149524 (corresponding U.S. Pat. No. 4,684,633, EP-A-150732)]. Alternatively, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine or phosphatidylinositol itself can be used. The dispersing medium may be water and the like, with preference given to purified water. This PGE
1
precursor-containing lipid emulsion mainly comprises a vegetable oil (5-50% w/v), phospholipid (1-300, preferably 5-100, more preferably 10-50, parts by weight, compared with 100 parts by weight of the vegetable oil), and a suitable amount of water.
The PGE
1
precursor-containing lipid emulsion according to the present invention can contain, in addition to the above-mentioned ingredients, emulsifier, preservative, stabilizer, high molecular weight substance, isotonizing agent and the like, where necessary.
The emulsifier is exemplified by a fatty acid having 6 to 22, preferably 12 to 20, carbon atoms, a pharmacologically acceptable salt thereof, an aliphatic amine having 2 to 22 carbon atoms and the like. The fatty acid is free of particular limitation as long as it can be added to a pharmaceutical product, and may be linear or branched. To be specific, linear stearic acid, oleic acid, linoleic acid, palmitic acid, linolenic acid, myristic acid and the like are preferably used. The pharmacologically acceptable salts of these fatty acids may be, for example, alkali metal salt (e.g., sodium salt, potassium salt and the like), alkaline earth metal salt (e.g., calcium salt, magnesium salt and the like) and the like. Moreover, the aliphatic amine is free of particular limitation as long as it can be added to a pharmaceutical product and may be linear or branched primary amine having 2 to 22 carbon atoms, secondary amine having 2 to 22 carbon atoms, and the like. Specifically, ethanolamine, propylamine, octylamine, stearylamine, oleylamine and the like can be used. The content of the emulsifier when it is a fatty acid or a salt thereof is preferably not more than 0.3% (w/v). When it is an aliphatic amine and the like, the content is preferably not more than 0.1% (w/v).
The stabilizer is free of particular limitation as long as it can be used for pharmaceuticals, and may be cholesterol, phosphatidic acid and the like. The content thereof when it is cholesterol is preferably not more than 0.5% (w/v), more preferably not more than 0.1% (w/v). When it is phosphatidic acid, the content is preferably not more than 5% (w
Egi Yasuhiro
Hayashi Kazutaka
Inoue Satoru
Kido Hideaki
Kubo Yoshiji
Reamer James H.
Welfide Corporation
Wenderoth , Lind & Ponack, L.L.P.
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