JPH09249558A - Dopamine derivative-containing suppository - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a dopamine derivative-containing suppository, good in elution property and absorption in the body and having excellent bioavailability. SOLUTION: This suppository contains a dopamine derivative of the formula (R is methyl or 2-methylthioethyl) and a water-swelling polymeric substance in a water-soluble base material (e.g. polyethylene glycol). The content of the dopamine derivative is 1-60wt.%, the content of the water-soluble base material is 35-90wt.% and the content of the water-swelling polymeric substance is 1-30wt.%, each based on the total of the preparation. As an example of the dopamine derivative, (-)-(S)-2-acetamido-N-[3,4-bis(ethoxycarbonyloxy) phenethyl]-4-(methylthio)butylamide is cited, and as an example of the water- swelling polymeric substance, an internally crosslinked polyvinylpyrrolidone, chitosan, etc., is cited. Preferably, other various additives are adequately compounded and the mixture is formulated by a heat fusing method, and the weight of each preparation is 1-2g.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel suppository containing a dopamine derivative.

[0002]

2. Description of the Related Art Docarpamine [Chemical name: (-)-(S)]
Dopamine derivatives such as 2-acetamido-N- [3,4-bis (ethoxycarbonyloxy) phenethyl] -4- (methylthio) butyramide] are prodrugs of dopamine, and are excellent for various symptoms associated with circulatory failure. It is useful as a therapeutic drug. However, these dopamine derivatives have a problem that they are extremely low in water solubility and have strong cohesiveness, and therefore have a problem when used as a suppository.

That is, in the case of a dopamine derivative such as docarpamine, a base such as a conventional suppository (for example, a preparation in which a morphinan derivative is dispersed in polyethylene glycol or glycerin fatty acid ester (JP-A-53-101519)) is used. Simply blending the pharmaceutically active ingredient into
Sufficient bioavailability was not obtained due to deterioration of disintegration / dissolution and absorption. For example, when these dopamine derivatives (pharmaceutical active ingredients) are blended with a lipophilic base, the pharmaceutically active ingredient is covered with the lipophilic base, water wetness deteriorates, and sufficient absorbability cannot be obtained. Further, even if a water-soluble base such as macrogol (polyethylene glycol) is used, when the dose of the pharmaceutically active ingredient is large, the pharmaceutically active ingredients are likely to aggregate with each other, resulting in dispersibility in the rectal endocrine fluid. Solubility is poor and sufficient absorption cannot be obtained.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a suppository containing a dopamine derivative, which has good disintegration / dissolution properties and excellent bioavailability.

[0005]

[Means for Solving the Problems] As a result of earnest studies, the inventors of the present invention have incorporated a water-swellable polymeric substance into a water-soluble base material to contain a dopamine derivative having excellent disintegration / dissolution in the rectum and excellent absorbability. They have found that a suppository can be obtained, and completed the present invention.

That is, the present invention relates to the formula [I]:

[0007]

Embedded image

A suppository containing a dopamine derivative represented by the formula (wherein R represents a methyl group or a 2-methylthioethyl group) and a water-swellable polymer substance.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION Examples of the dopamine derivative of the present invention include docarpamine [chemical name: (-)-(S) -2].
-Acetamide-N- [3,4-bis (ethoxycarbonyloxy) phenethyl] -4- (methylthio) butyramide] and the like.

The content of the dopamine derivative may be usually 1 to 60% by weight, preferably 3 to 50% by weight, based on the total weight of the preparation.

The water-soluble base may be any substance as long as it is a substance that dissolves in the rectal endocrine fluid and can maintain the shape of a suppository at room temperature. Furthermore, a suppository prepared by a heating and melting method is more preferable because it can be easily mass-produced.

Examples of such water-soluble bases include polyethylene glycol (macrogol), polyoxypropylene polyoxyethylene glycol, glycerogelatin, etc. Of these, polyethylene glycol (macrogol) is preferred. The water-soluble bases may be used alone or in combination of two or more. In addition, those having different degrees of polymerization may be used in combination.

Polyethylene glycol (macrogol)
Have various degrees of polymerization, and those having an average molecular weight of 200 to 20,000 can be preferably used. Polyethylene glycols having different degrees of polymerization may be used in combination, and for example, the average molecular weight is 1,000.
In the case of using polyethylene glycol which is a liquid of less than 100 g, solid polyethylene glycol having an average molecular weight of 1000 or more may be added so that the suppository may be obtained at room temperature.

The amount of the water-soluble base compounded is usually 35 to 90% by weight, preferably 40 to 85% by weight, based on the total weight of the preparation.
What is necessary is just to mix.

The water-swellable polymeric substance may be any substance that absorbs water and swells, and is acceptable as an additive for pharmaceutical preparations. As the water-swellable polymer substance, those exhibiting a swelling pressure of about 0.1 kg or more per 0.5 g of the substance are preferable.

As such a water-swellable polymer substance,
For example, cellulose such as crystalline cellulose, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose (carmellose), sodium carboxymethyl cellulose (carmellose sodium), carboxymethyl cellulose calcium (carmellose calcium) and internally crosslinked sodium carboxymethyl cellulose (croscarmellose sodium). Alternatively, cellulose derivatives, saccharides such as chitosan and chitin, synthetic polymer compounds such as internally crosslinked polyvinylpyrrolidone (crospovidone),
And starch or starch derivatives such as corn starch, sodium carboxymethyl starch, pregelatinized starch, partially pregelatinized starch and hydroxypropyl starch.

Among these water-swellable polymeric substances, low-substituted hydroxypropylcellulose, cellulose or cellulose derivatives such as carboxymethylcellulose calcium (carmellose calcium) and internally crosslinked sodium carboxymethylcellulose (croscarmellose sodium), chitosan, internal Crosslinked polyvinylpyrrolidone (crospovidone), sodium carboxymethyl starch, and partially pregelatinized starch are preferred.

These water-swellable polymeric substances may be used alone or in combination of two or more.

The amount of the water-swellable polymer substance to be added is usually 1 to 30% by weight, preferably 2 to 20% by weight, based on the total weight of the preparation.

In the suppository of the present invention, in addition to the above components, for example, colorants (food blue No. 1, food red No. 102, etc.), stabilizers (citric acid, ascorbic acid, dibutylhydroxytoluene, etc.) ), Preservatives (paraoxybenzoic acid esters, etc.), surfactants (sucrose fatty acid esters, polysorbates, polyoxyethylene fatty acid esters, etc.), solubilizing agents (propylene glycol, benzyl alcohol, etc.), etc. The additives to be added can be added if necessary.

The suppository of the present invention usually has a weight of about 0.
The amount may be 5 to 3 g, but it is preferably about 1 to 2 g for ease of handling and insertion.

The suppository of the present invention can usually be produced by a heating and melting method generally used in this field. For example, a molten water-soluble base, a dopamine derivative and a water-swellable polymeric substance, and optionally a It can be manufactured by adding various additives and then cooling and molding.

Hereinafter, the present invention will be described in more detail with reference to examples.

[0024]

【Example】

Example 1 Macrogol having an average molecular weight of 1000 (trade name: PEG1
000, manufactured by NOF CORPORATION) 0.8 g and an average molecular weight of about 260
0 to 3800 macro goals (trade name: PEG400
0.8 g (produced by NOF CORPORATION) was melted and mixed at about 70 ° C. To the base thus obtained, docarpamine 0.3
g and Crospovidone (trade name: Kollidon CL, BAS
0.1 g (manufactured by F Japan Co., Ltd.) was added and dispersed, and then the mixture was filled in a suppository container and cooled to obtain a suppository of the present invention.

Example 2 According to the method described in Example 1, a suppository of the present invention was produced according to the following formulation. Prescription: Docarpamine 0.3 g Partially pregelatinized starch 0.3 g Macrogol (average molecular weight 1000) 0.7 g Macrogol (average molecular weight 2600 to 3800) 0.7 g (total 2.0 g).

Example 3 According to the method described in Example 1, the suppository of the present invention was produced according to the following formulation. Prescription: Docarpamine 0.3 g Low-substituted hydroxypropyl cellulose 0.1 g Macrogol (average molecular weight 1000) 0.8 g Macrogol (average molecular weight 2600 to 3800) 0.8 g (total 2.0 g).

Example 4 According to the method described in Example 1, the suppository of the present invention was produced according to the following formulation. Prescription: Docarpamine 0.3 g Chitosan 0.1 g Macrogol (average molecular weight 1000) 0.8 g Macrogol (average molecular weight 2600 to 3800) 0.8 g (total 2.0 g).

Comparative Example 1 According to the method described in Example 1, a suppository for comparison was obtained according to the following formulation. Prescription: Docarpamine 0.3 g Macrogol (average molecular weight 1000) 0.85 g Macrogol (average molecular weight 2600 to 3800) 0.85 g (total 2.0 g).

Comparative Example 2 Suppository as a comparative control according to the method described in Example 1 according to the following formulation using Hardfat (trade name: Witepsol H-35, component: triacylated glycerin, manufactured by Huls) as a base according to the method described in Example 1. Got Prescription: Docarpamine 0.3 g Hard fat 1.7 g (total 2.0 g).

Comparative Example 3 A comparative suppository according to the method described in Example 1 according to the following formulation using Hardfat (trade name: Witepsol H-35, component: triacylated glycerin, manufactured by Huls) as a base according to the method described in Example 1. Got Prescription: Docarpamine 0.3 g Crospovidone 0.1 g Hard fat 1.6 g (total 2.0 g).

Experimental Example 1 For the suppositories of Examples 1 to 4 and Comparative Examples 1 to 3, PTS was used.
1000m water as eluent in W type suppository dissolution tester
Using l, the dissolution test of the pharmaceutically active ingredient (docalpamine) was carried out under the conditions of 37 ° C. and 25 rpm. As a result, as shown in FIGS. 1 and 2, the suppository of the present invention (Example 1
4) showed excellent dissolution properties as compared with the control suppositories (Comparative Examples 1 to 3).

Experimental Example 2 The suppositories of Example 1, Example 2 and Comparative Example 1 were administered to the rectum of dogs, and the concentration of dopamine (active substance of docarpamine) in plasma was measured with time. The suppository was administered to 3 dogs each, and the average plasma concentration was calculated. As a result, as shown in FIG. 2, the suppositories of the present invention (Examples 1 and 2) exhibited remarkably excellent absorbability as compared with the control suppositories (Comparative Example 1).

[0033]

EFFECTS OF THE INVENTION The suppositories containing the dopamine derivative of the present invention have good dissolution properties, good absorbability in vivo, and excellent bioavailability.

[Brief description of drawings]

FIG. 1 shows the dissolution curve of docarpamine from the suppository of the present invention.

FIG. 2 shows the dissolution curve of docarpamine from the suppositories of Comparative Examples.

FIG. 3 shows changes with time in plasma dopamine concentration when a suppository of the present invention and a suppository of a comparative example were administered to dogs.

Claims (10)

[Claims] 1. In a water-soluble base material, the compound of formula [I]: (In the formula, R represents a methyl group or a 2-methylthioethyl group.) A suppository containing a dopamine derivative and a water-swellable polymer substance. 2. The dopamine derivative is docarpamine [chemical name: (−)-(S) -2-acetamide-N- [3,4-
Bis (ethoxycarbonyloxy) phenethyl] -4-
(Methylthio) butyramide]. 3. The suppository according to claim 1, wherein the water-soluble base is polyethylene glycol. 4. The water-swellable polymer is a cellulose or cellulose derivative selected from the group consisting of crystalline cellulose, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and internally crosslinked sodium carboxymethyl cellulose. The suppository according to claim 1. 5. The suppository according to claim 1, wherein the water-swellable polymeric substance is a saccharide selected from the group consisting of chitosan and chitin. 6. The suppository according to claim 1, wherein the water-swellable polymeric substance is internally crosslinked polyvinylpyrrolidone. 7. The water-swellable polymeric substance is a starch or starch derivative selected from the group consisting of corn starch, sodium carboxymethyl starch, pregelatinized starch, partially pregelatinized starch and hydroxypropyl starch. Suppository. 8. The suppository according to claim 1, wherein the content of the dopamine derivative is 1 to 60% by weight based on the total weight of the preparation. 9. The suppository according to claim 1, wherein the content of the water-soluble base is 35 to 90% by weight based on the total weight of the preparation. 10. The suppository according to claim 1, wherein the content of the water-swellable polymer substance is 1 to 30% by weight based on the total weight of the preparation.