JPS60116628A - Composition of pharmaceutical preparation of 7- thiaprostaglandin e1 - Google Patents

Abstract

PURPOSE:The titled composition useful as an inhibitor of blood platelet aggregation, hyptotensor, etc. having higher action than existing PG, suitable as a pharmaceutical preparation for oral medication, having extremely improved stability, obtained by dissolving a 7-thiaprostaglandin E1 in a vegetable oil. CONSTITUTION:At least one 7-thiaprostaglandin E1 shown by the formula (R<1> is H, or lower alkyl; R<2> is H, or CH3; R<3> is 5-8C alkyl, or cycloalkyl; broken line shows single bond or double bond) is dissolved in a vegetable oil, to give the titled composition having improved stability. Especially a coconut oil or fractionated coconut oil is preferable as the vegetable oil, and an amount of it used is 100-200,000 times as heavy as the compound shown by the formula. By dissolving the compound in the vegetable oil, stability to acid, alkali, light rays, heat, oxygen, etc. is extremely improved.

Description

DETAILED DESCRIPTION OF THE INVENTION Technical Field The present invention relates to a composition for a 7-chip-staglandin E1 class preparation. More specifically, the present invention provides archiab p-staglandin E, which is prepared by dissolving archiab p-staglandin E, which has excellent pharmacological effects such as anti-platelet aggregation, antihypertensive, vasodilatory, and anti-ulcer effects, in vegetable oil. This invention relates to a pharmaceutical composition with significantly improved stability.

Prior Art 7-7 Prostaglandin E. such as 7-thiaprostaglandin E, 16.17.18.

19,20-Pentanoru 15-Cyclobenru 7-
Thiaprostaglandin E, 16, 17
.

18, 19.20-pentanol-15-cyclohexyl-7-thiaprostaglandin lid,, 17.20-
Dimethyl-Δt archabstaglandin E1 or ester compounds thereof have strong antiplatelet aggregation, hypotensive, and vasodilatory effects, and are useful as pharmaceuticals. Archipelago p-staglandins have the advantage that they have a stronger medicinal effect than conventional p-stadarandins and can be administered orally.

When formulating 7-17 p-staglandin E,
If the stability is significantly enhanced by the carrier used, it can be expected that a preferable preparation for light administration of archab p-staglandin E or the like can be obtained.

On the other hand, prostaglandin El, p-staglandin E
! A method of stabilizing compounds such as by dissolving them in triglyceride of medium-chain fatty acids (Japanese Patent Application Laid-open No. 50141/1982) or a method of stabilizing them by dissolving them in vegetable oil (Japanese Patent Application Laid-Open No. 105815/1989) Are known.

However, the relationship between the above-mentioned 7-thiaprostaglandin E and triglycerides of medium chain fatty acids or vegetable oils has not been known at all.

Purpose of the present invention As a result of intensive research aimed at obtaining a pharmaceutical composition in which the stability of 7-thiaprostaglandin E□ is significantly improved, the present inventors found that The present invention was achieved by discovering that a composition prepared by dissolving the above objects in vegetable oil can achieve the above object.

Therefore, the object of the present invention is to
Class I acids, alkalis, light, and heat.

An object of the present invention is to provide a composition for 7-thiaprostaglandin E and similar preparations, which has significantly improved stability against oxygen and the like.

Structure and effects of the present invention The present invention is based on the following formula [■] 7-Thiaprostaglandin E represented by

7-Thiaprostaglandin E, a composition for use as a phlegm agent, is prepared by dissolving at least 1s of 7-thiaprostaglandin E in vegetable oil.

The 7-thi7 prostaglandin E of the present invention has the above formula (
1), and includes all optical isomers, stereoisomers, and tautomers.

Therefore, those in which the α chain and β chain are in a cis or trans relationship,
Or a mixture of these, or the hydroxyl group at the l1 position is β
- configuration, α-configuration, or a mixture thereof. In the above formula m, RI is a hydrogen atom, a lower fulkyl group, or a pharmacologically acceptable cation.

Examples of lower furkyl groups include methyl and ethyl.

Examples include butyl, isobutyl, t-butyl, pentyl, hexyl, and the like.

Examples of pharmacologically acceptable cations include alkali metal ions such as sodium and potassium, NH,
Atramethylammonium.

Examples include ammonium cations such as methylammonium and benzylammonium.

R1 represents a hydrogen atom or a methyl group. R3 represents a substituted or unsubstituted furkyl group having 5 to 8 carbon atoms or a substituted or unsubstituted cycloalkyl group having 5 to 8 carbon atoms.

As the unsubstituted furkyl group having 5 to 8 carbon atoms, for example, n
-pentyl, n-hexyl, 2-methylhexyl, n
Examples include -heptyl and n-octyl groups. Examples of the unsubstituted cycloalkyl group having a prime number of 5 to 8 include cyclobenzenoν.

Examples include cyclohexyl group. Substituents for such unsubstituted alkyl groups or cycloalkyl groups include:
Examples include halogen atoms such as fluorine and chlorine; alkoxy groups such as methoxy, ethoxy and butoxy; and 7-siloxy groups such as hydroxy:acetoxy and propionyloxy groups.

Specific examples of archab p-staglandin E, etc. include the following.

(1) 7-Thiaprostaglandin E.

(2) 7-thiaprostaglandin E, methyl ester (3) 7-thiaprostaglandin E. Sodium salt (4117,20-dimethyl-7-thiabrostagundin E).

(51 17, 20-dimethyl-7-thiaprostaglandin E, methyl ester (61 16, 16-dimethyl-7-thiaprostaglandin E.

(71 16, 1 6-dimethyl-7-thiaprostaglandin E, methyl ester (81 16, 1 6-dimethyl-7-thiaprostaglandin E, sodium salt + 9+ 1 6 , 1 7 , 1 g, 19
, 2 0-pentanol-15-cyclobenthyl-7
- Thiaprostaglandin E.

QllI116, 17, 18, 19.20-he7ri/
Ru 1 5-cyclopentyl-7-thiabrostadalandin E1 methyl ester aυ 16,17,18,, 19.20-pentanol-15-γchlorohexy-7-thiaprostaglandin E
.

Ring 16, 17.18, 19.20-pentanoru 15
-Cyclohexyl-7-thiaprostaglandin E, Memorihoro Yuzutyl a3 16.17.1g, 19.20-Pentanol 1
5-cyclohexyl-7-thiaprostaglandin E,
Sodium salt of (14115-methyl-archabdistaglandin E)
1 (1915-methyl-fouthi7p-staglandin E,
Methyl ester ae 17,20-dimethyl-Δfeces-7-thiaprostaglandin E.

aη 17,2'0-dimethyl- is -7-thiaprostaglandin E, methyl ester aυ 17,20-dimethyl-Δ2-7-thiaprostaglandin E% sodium salt (19 1 6 , 1 7 , 1 B, 19
, 20-pentanol-15-cyclohexyl-Δ
17-chi 7 booster tag Grandin E.

7-thiapro'staglandin E, the corresponding 2
It can be obtained by subjecting -organothio-2-cyclopente7no and an organic steel lithium compound to a conjugate addition reaction.

The vegetable oils used in the present invention include, for example, sesame oil, soybean oil, cotton seed oil, corn oil, peanut oil, :I coconut oil, fractionated Fukonut oil, and the like. Among these, sesame oil,
Soybean oil, coconut oil, and 5-fractionated fufunut oil are preferred, and coconut oil and fractionated coconut oil are particularly preferred.

In order to obtain the pharmaceutical composition of the present invention, the above-described archiab p.
It is only necessary to dissolve at least one of the Stadalandin E, family in at least one vegetable oil. Of course 7-17
It is also possible to use 281 or more types of prostadalandin E, or a combination of two or more types of vegetable oils.

7-17 A solution of prostadalandin E, and vegetable oil is:
Dissolve 7-thiaprostaglandin E directly in vegetable oil, or if it is difficult to dissolve them, dissolve them in advance in a solution that can dissolve both, such as ethyl acetate or ethanol, and mix them well. A method may be adopted in which the solvent is removed under reduced pressure after mixing.

The amount of vegetable oil to be used for 7-+7 prostaglandin E, can be arbitrarily selected within a wide range, and is generally 100 to 2 for 7-thiaprostaglandin E1.
00,000 times the weight range.

The thus obtained composition of 7-thiaprostaglandin E may be mixed with other substances, if necessary. Such substances include commonly known pharmaceutical additives, such as preservatives such as paraoxybenzoic acid ester, sodium benzoate, salicylic acid, sorbic acid, and boric acid; butylated hydroxyanisole, dibutylated hydroxytoluene, and toco7 ale. Antioxidants such as etc. may also be added.

The pharmaceutical composition of the present invention can be disposed of as an oral preparation, a suppository, a transdermal preparation, an injection, etc. by generally known formulation means.

In particular, the composition of the present invention is suitable for oral administration. Suitable preparations for oral administration include gelatin soft capsules.

The thus obtained preparations of 7-thiaprostaglandin E have, for example, antiplatelet aggregation activity.

It is used as a medicine that exhibits antihypertensive, vasodilatory, and antiulcer effects.

The present invention will be explained in more detail below with reference to Examples.

Example 7 - Thiaprostaglandin E, etc. was dissolved in vegetable oil (fractionated coconut oil) at a concentration of 10μ/ml and then 1 m
7-thiaprostaglandin E (4))
was measured over time using the high performance liquid chroma dog 87 method.

The results are shown in Tables 1 and 2.

Note that high performance liquid chromatography was performed as follows.

Take an amount of vegetable oil containing 10 #S of 7-thiaprostaglandin E, dissolve it by adding 10 times the amount of cyclohexane, and perform high performance liquid column chromatography (manufactured by Takashi Co., Ltd.) using a normal-phase power column. LC-3A) and quantitatively analyzed 7-thiaprostaglandins EI using a UV detector (5PD-2A, manufactured by Takashi Co., Ltd.) and a data processor (C-RIB, manufactured by Takashi Co., Ltd.). .

Table 1 Table 2 15-Methyl-archab p-staglandin E1 methyl ester residual rate (%) Results of Tables 1 and 2 and Ic 16, 17, 18
,19,20-pentanol-15-cyclohexyl-7
- Thiap p-staglandin E1 methyl ester and 15
Considering that the half-life of methyl-7-thousand p-stadalandin E, methyl ester in methanol is about 7 days, it is possible to dissolve archip-stadalandin E, etc. in vegetable oil according to the method of the present invention. It can be seen that the stability of archab p-staglandin E is significantly improved. In the above experimental example, 7-thiaprostaglandin E, 16.17.18, 19
．． 20-penta/15-cyclohexyl-7-thiabrostadalandin E, methyl ester and 15-methyl-7-thiaprostaglandin E, methyl ester were used, but other 7-thiaprostaglandin E , such as 16,17.1B, 19.20-pentanol-15
-cyclopentyl-7-thiaprostaglandin E,
, 17.20-X dimethyl-h-7-thiaprostaglandin E1 or an ester compound thereof, a similarly stable composition was obtained. Furthermore, in the above examples, 11eJ oil was used (fractionated coconut oil was used, but similar good stabilizing effects were obtained when coconut oil and refined sesame oil were used).

Claims (1)

[Scope of Claims] A 7-thiaprostaglandin E1 type preparation comprising at least one type of 7-thiaprostaglandin E represented by the following formula [■] dissolved in vegetable oil.