JPH05221862A - Medical composition for suppository - Google Patents

Abstract

PURPOSE:To provide a medicinal composition for buprenorphine suppository which develops the action in a short time and maintains the efficacy for hours. CONSTITUTION:A polymer complex from N-cyclopropylmethyl-7alpha-[(S)-1- hydroxy-1,2,2-trimethylpropyl]-6,14-endo-ethano-6,7,8,14-tetrahydronor oripavine or its pharmaceutically acceptable salt and an acidic polysaccharide is added to an oil base.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a suppository pharmaceutical composition.

[0002]

2. Description of the Related Art N-Cyclopropylmethyl-7
α-[(S) -1-hydroxy-1,2,2-trimethylpropyl] -6,14-endo-ethano-6,7,
8,14-Tetrahydronororubabine (hereinafter referred to as “buprenorphine”) has been proved in clinical trials as a potent antagonistic analgesic agent that does not exhibit the psychopathic effect generally found in narcotic antagonistic analgesics. ..

Conventionally, buprenorphine has been widely used as an injection for postoperative pain, cancer pain, anesthesia support, myocardial infarction pain and the like. However, injectables are complicated to administer in patients who have long-term use, such as in the case of intractable chronic pain such as cancer pain, and are disadvantageous in that they are painful at the time of injection and cannot be treated at home. have.

Therefore, it is desired to develop an excellent buprenorphine preparation which can be treated at home.

[0005]

In view of the present situation, the present inventor has conducted extensive research to develop a pharmaceutical composition for suppository which can be treated at home. In the process of research, we paid attention to acidic polysaccharides. Acidic polysaccharides are stabilizers, binders,
It is a compound widely used in the pharmaceutical field as a suspending agent and the like. As an example in which the drug and the acidic polysaccharide are mixed,
For example, β-lactam antibiotics, morphine, etc. have been reported. In all of these examples, the drug and the acidic polysaccharide are uniformly dispersed in the base. Therefore, the present inventor prepared a suppository pharmaceutical composition in which buprenorphine or a salt thereof and an acidic polysaccharide were simply blended in an oily base, and investigated the pharmacological effect thereof. However, in such a composition, the release of the active ingredient compound is insufficient and, as a result, the absorption of the active ingredient compound from the intestinal tract is not sufficiently carried out, so that a satisfactory analgesic effect is not obtained, and thus such a composition is obtained. It has been found that the product cannot be the desired pharmaceutical composition for suppositories. The present inventor, while continuing to carry out research, produced a polymer complex from buprenorphine or a salt thereof and an acidic polysaccharide, and when this was mixed with an oily base, the absorbability of buprenorphine from the intestinal tract was decreased. It has been found that the suppository can be excellent and the analgesic effect can be exhibited at an early stage, and the medicinal effect can be maintained for a long period of time, resulting in an extremely excellent suppository pharmaceutical composition. The present invention has been completed based on such findings.

[0006] That is, the present invention provides a suppository pharmaceutical composition characterized in that an oily base is blended with a polymer complex of buprenorphine or a pharmaceutically acceptable acid addition salt thereof and an acidic polysaccharide. Related to things.

In the present invention, examples of the acidic polysaccharide include metal alginate, metal chondroitinate, metal pectate and the like, among which metal alginate is particularly preferable. Examples of the metal salt include monovalent metal salts such as sodium salt, potassium salt and lithium salt, with sodium salt being particularly preferred.

The average molecular weight of the acidic polysaccharide used in the present invention is not particularly limited, but usually 10
It is about 100 to 10 million. Here, the average molecular weight is measured by high performance liquid chromatography (HPLC) and expressed as a weight average molecular weight. In the present invention, when an acidic polysaccharide having a low molecular weight, for example, about 1000 to 30,000 is used, a suppository pharmaceutical composition having particularly excellent durability can be obtained. High molecular weight, for example, 300,000 to 50
When about 0,000 acidic polysaccharides are used, a suppository pharmaceutical composition having particularly excellent releasability can be obtained. Therefore, in the present invention, it is also desirable to appropriately mix and use two or more types of acidic polysaccharides having different molecular weights in consideration of both releasability and sustainability. In this case, for example, the average molecular weight of 1000 to 3 is used.
About 10 parts by weight of the former and about 10 parts by weight of the latter and 100 parts by weight of the acidic polysaccharide having an average molecular weight of about 300,000-5,000,000.
It is advisable to mix them at a ratio of about 1000 parts by weight.

The polymer complex of the present invention is prepared by, for example, dissolving buprenorphine or a pharmaceutically acceptable acid addition salt thereof and an acidic polysaccharide in a suitable inert solvent, and then distilling the solvent, for example, under reduced pressure and freeze-drying. It is manufactured by removing it with a solvent removing means such as. The use ratio of buprenorphine or a pharmaceutically acceptable acid addition salt thereof and acidic polysaccharide is usually 1 to 50 parts by weight, preferably 5 to 30 parts by weight, per 100 parts by weight of the former. Good.

As the oily base, widely known ones can be widely used, for example, C _{12 to} C ₁₈ higher fatty acid glycerin esters (for example, Witepsol (Dynamic N).
Obel, West Germany, Supporters (Gattefos)
seafpf, France), Novata (Henkel)),
Semi-synthetic oil and fat bases such as Pharmasol (Nippon Yushi Co., Ltd.) and natural oil and fat bases such as cacao butter and lanolin fat are listed. Of these, Witepsol is preferable, and Type H-15 is particularly preferable.

The amount of the above-mentioned oily base to be used is not particularly limited and can be appropriately selected within the range usually used for suppositories, but is 10 to 300 relative to buprenorphine or its salt. It is preferable to use it in a ratio that is about twice the weight.

If necessary, water, stabilizers, preservatives, preservatives, antioxidants, thickeners, molding aids, colorants, fragrances, etc. may be appropriately added to the composition of the present invention. You can

Examples of the dosage form of the composition of the present invention include rectal suppositories, soft capsules for rectal administration, ointment-like or enema liquid dosage forms for administration using an injector for rectal administration. Each of these various dosage forms is prepared according to a conventional method. A preferred dosage form is rectal suppository, which usually has a weight of 0.5 to 3 g per one and contains buprenorphine or its salt as an active ingredient compound in an amount of 0.05 to 1.
It is desirable to contain 2 mg.

[0014]

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a pharmaceutical composition for buprenorphine suppository which has extremely weak side effects such as mucous membrane irritation, a short onset time of action, and a long-lasting drug effect.

[0015]

EXAMPLES The present invention will be further clarified with reference to the following examples.

Reference Example 1 1.5 g (3 mmol) of buprenorphine hydrochloride and 0.38 g of sodium alginate (average molecular weight of about 3.7 million)
(2 mmol) was dissolved in 1000 ml of distilled water and freeze-dried to produce a polymer complex of buprenorphine of the present invention and sodium alginate.

Reference Example 2 1.5 g (3 mmol) of buprenorphine hydrochloride and 0.7 g of sodium alginate (average molecular weight of about 3.7 million)
(3 mmol) was dissolved in 1000 ml of distilled water and freeze-dried to prepare a polymer complex of buprenorphine of the present invention and sodium alginate.

Reference Example 3 1.5 g (3 mmol) of buprenorphine hydrochloride and sodium alginate (with an average molecular weight of about 4000 and about 3
It is used by mixing with 700,000 one in a weight ratio of 1: 1).
38 g (2 mmol) was dissolved in 1000 ml of distilled water and freeze-dried to prepare a polymer complex of buprenorphine of the present invention and sodium alginate.

Example 1 7 g of an oily base (Witepsol H-15) was melted at 45 ° C., 9.4 mg of the polymer composite prepared in Reference Example 1 was added thereto, and an ultrasonic cleaner (branson,
It was treated with 220j) for 10 minutes and dispersed uniformly. This base solution is kept at about 40 ° C and poured into a metal suppository mold,
It was solidified at room temperature and then in a refrigerator to prepare 1.38 g of each suppository of the present invention.

Example 2 In the same manner as in Example 1 except that 11.0 mg of the polymer composite prepared in Reference Example 2 was used, 1.
38 g of the suppository of the invention was produced.

Example 3 In the same manner as in Example 1 except that 9.4 mg of the polymer composite prepared in Reference Example 3 was used, 1.3 per unit was obtained.
8 g of the suppository of the invention was produced.

Comparative Example 1 Instead of the polymer composite prepared in Reference Example 1, 2
Suppository g of 1.38 g per piece was produced in the same manner as in Example 1 except that 7.5 mg of buprenorphine hydrochloride powder (crystal form) that had been sieved through 00 mesh was used.

Comparative Example 2 Instead of the polymer composite prepared in Reference Example 1, 2
Buprenorphine hydrochloride powder (crystal form) 7.5 mg and sodium alginate 1.9 mg passed through a 00 mesh sieve.
1.38 g of suppository per tablet was produced in the same manner as in Example 1 except that

Comparative Example 3 Instead of the polymer composite prepared in Reference Example 1, 2
Buprenorphine hydrochloride powder (crystal form) 7.5 mg and sodium alginate 3.5 mg passed through a 00 mesh sieve
1.38 g of suppository per tablet was produced in the same manner as in Example 1 except that

Test Example 1 With respect to each suppository obtained in Examples 1 to 2 and Comparative Examples 1 to 3, the release behavior of the active ingredient compound (buprenorphine hydrochloride) in vitro was examined.

This test is performed by a suppository release tester (Toyama Sangyo,
TMS-103). 300 ml of physiological saline was added to the release phase, the mixture was stirred at 100 rpm using a magnetic stirrer, and the temperature was adjusted to 37 ± 0.1 ° C. The inside of the suppository release cell (with a 3 μm membrane filter) was filled with 3 ml of physiological saline, and each suppository was added, and then stirred at 50 rpm. After that, 1 ml of the release phase was collected with time, and the release rate of buprenorphine hydrochloride was examined. The results are shown in FIGS. 1 and 2.

As is apparent from FIGS. 1 and 2, the release rate and release rate of buprenorphine hydrochloride could be remarkably improved by using the polymer composite.

[Brief description of drawings]

FIG. 1 is a graph showing the release behavior of buprenorphine hydrochloride from each suppository obtained in Example 1 and Example 2.

FIG. 2 is a graph showing the release behavior of buprenorphine hydrochloride from each suppository obtained in Comparative Example 1, Comparative Example 2 and Comparative Example 3.

Claims (1)

[Claims] 1. An oily base material having N-cyclopropylmethyl-7α-[(S) -1-hydroxy-1,2,2-trimethylpropyl] -6,14-endo-ethano-6.
A pharmaceutical composition for suppositories, which comprises a polymer complex of 7,8,14-tetrahydronororubabine or a pharmaceutically acceptable acid addition salt thereof and an acidic polysaccharide.