JPH0684296B2 - Multi-layer suppository - Google Patents

Description

TECHNICAL FIELD The present invention relates to a multilayer suppository, and more particularly to a multilayer suppository in which a plurality of layers made of an oily base which is solid at room temperature are horizontally laminated.

[Conventional technology]

Conventionally used suppositories are single-layer suppositories in which one or more drugs are mixed in a base such as an oily base, a water-soluble base or an emulsion base and uniformly dispersed and mixed. Is common.

By the way, in recent years, various multilayer suppositories have been devised from the viewpoint of effective use of medicinal components. That is, one of the purposes in a multi-layered suppository is to combine a plurality of medicinal components into a suppository, and to include each medicinal component in the base most suitable for the manifestation of its medicinal properties, thereby producing the effect of each medicinal component. It is intended to make full use of. For this purpose, it is necessary that the layer containing a certain medicinal component and the other layer exist in separate states. Such a multi-layered suppository is filled with a heated and melted base in a suppository molding container, then cooled to a solid or semi-solid form, filled with a new base, laminated and further cooled. It was manufactured by repeating the process of coagulating and solidifying (JP-A-56-73017).

[Problems to be solved by the invention]

However, conventional multi-layer suppositories have problems such as mixing of the laminated bases depending on storage temperature and time, and migration of medicinal components to other layers. Further, such a problem has been an obstacle to development of various functions recently required for suppositories, that is, sustained-release suppositories, suppositories having a lower portion of the rectum, and the like.

[Means for solving problems]

Therefore, the present inventor has made various investigations to solve such problems, and by setting the viscosity at 40 ° C. of the oily base used as a suppository base to a certain range, a plurality of laminated layers can be preserved. The present invention has been completed by discovering that it is possible to prevent the migration of the medicinal component contained in each of the layers to the other layer without being mixed therein.

That is, the present invention is a multi-layered suppository in which a plurality of layers made of an oily suppository which are solid at room temperature are horizontally laminated, and at least one of two adjacent layers has a viscosity of 1,000 at 40 ° C.
It provides a multi-layer suppository characterized in that it is made up of layers of ~ 1 million cp.

The base used in the present invention is solid at room temperature and oily.
It is not particularly limited as long as it is, for example, cocoa butter, lanolin
Fat, isocaca (Made by Kao), Witepsol (Die
Namitsu Nobel), Sapsia (Gatsutte Otsuse
Company), SB (Made by Kanebuchi Chemical Industry), Fuamasol (Japan
For example, an external regulation hard fat such as oil and fat) can be used.

The medicinal ingredients used in the present invention include steroids such as hydrocortisone and hydrocortisone acetate for hemorrhoids; local anesthetics such as dibucaine hydrochloride, procaine hydrochloride and lidocaine; anti-inflammatory agents such as glycyrrhetinic acid, dipotassium glycyrrhizinate and allantoin; Examples include bactericides such as chlorhexidine hydrochloride and cetricid; vitamins such as retinol palmitate and dl-α-tocopherol. Examples of suppositories for antipyretic analgesia and anti-inflammatory include aspirin, sodium salicylate, indomethacin, oxyphenbutazone and the like. , Antibiotics, and suppositories for chemotherapy such as penicillin G sodium, chloramphenicol, fangizone, sulfadimethoxycin, and various sulfa drugs, but it goes without saying that they are not limited to these. Ah It

The multilayer suppository of the present invention includes, for example, a suppository molding container in which a solid oily base forming each layer is heated and melted at a normal temperature and subjected to a treatment for increasing the viscosity, and the base is melted at a temperature equal to or higher than the melting temperature. It is manufactured by continuously filling and then cooling and solidifying the whole.

To increase the viscosity, basically, by adding a thickener, the viscosity of each layer at 40 ℃ is 10 ~ 1 million cp,
It is preferably performed at 10,000 to 1,000,000 cp. When the viscosity of each layer at 40 is less than 1,000, mixing with other layers occurs during storage of suppositories, while when it exceeds 1 million, release of the medicinal component from the base is too slow, which is not preferable. In the present invention, the bases of the two adjacent layers are not necessarily required to have the viscosity within the above range.

As the thickener used, light anhydrous silicic acid, aluminum salt of stearic acid, calcium salt, barium salt or magnesium salt, 12-hydroxystearic acid, a condensate of D-sorbitol and benzaldehyde [eg, Gelol D (Nippon Rika Company)), dextrin fatty acid ester [e.g. Leopard KE (Chiba Flour Milling Co.)], styrene-ethylene-butylene-styrene polymer [e.g. SEBS (Ciel Chemical Co.)], organic bentonite and the like.

These thickeners generally have a viscosity of 1 to
It is preferably used in an amount of 50% by weight, particularly 5 to 10% by weight.

Further, in the multilayer suppository of the present invention, in addition to the thickener, a swelling agent is added to the oily base forming at least a part of the layer.
1 to 90% by weight, in particular 10 to 80% by weight, can be added. Examples of the swelling agent used here include various dietary fibers such as plantago ovata seed coat (ispagra seed coat), glucomannan, sodium alginate, agar, carrageenan, guar gum, locust bean gum, tamarind gum, gum arabic, karaya gum, tragacanth gum, and pectin. And natural water-soluble polymers; synthetic water-soluble polymers such as carboxymethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose, sodium polyacrylate, polyvinyl alcohol, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, etc. .

Among these, plantago ovata seed coat, sodium alginate, sodium carboxymethyl cellulose, and carboxymethyl cellulose are particularly preferable.

〔The invention's effect〕

The multi-layered suppository of the present invention is an excellent suppository in which mixing with other layers during storage and migration of the medicinal components to other layers are prevented.
Therefore, it becomes possible to include a plurality of medicinal components in a base most suitable for exhibiting their medicinal properties, and various functions required for recent suppositories, such as sustained-release suppositories and subrectal suppositories. It has become possible to have functions such as agents.

〔Example〕

Next, the present invention will be described with reference to examples, but the present invention is not limited thereto.

Example 1 A multilayer suppository consisting of a first layer and a second layer was prepared using the formulation shown in Table 1, and the migration of the drug from the second layer to the first layer of the obtained suppository Tests were conducted on the miscibility of the agents.

(1) Preparation method of suppository In the product of the present invention, a colorant and light anhydrous silicic acid are added to a molten base, and a sufficiently mixed mixture is filled in a suppository molding container, and then the molten base is added. The mixture to which prednisolone acetate was added and mixed was filled and laminated, and the whole was cooled.

In the comparative product, a suppository molding container was filled with a colorant added to and mixed with a molten base, and cooled and solidified. Next, the melted base material was added and mixed with prednisolone acetate to be laminated, and the whole was cooled and solidified.

(2) Test method Suppositories were stored in a thermostatic chamber at 35 ° C, and the following tests were conducted on the 10th, 20th, and 30th days.

Drug Transfer The prednisolone acetate content in the first layer base was measured by high performance liquid chromatography. The quantitative value (mg) is shown in Table 2. Note that nd indicates that the peak of prednisolone acetate was not observed.

Miscibility of the base material The first layer base material and the second layer base material are used with the colorant in the first layer base material as a guide.
Whether or not the layer base was mixed was judged with the naked eye according to the following criteria. The results are shown in Table 2.

-: No mixture of bases is recognized +: Some bases are mixed: All bases were mixed uniformly.

Example 2 Using the formulation shown in Table 3, a multi-layer suppository was prepared in the same manner as in Example 1, and the retention of the lower rectum of the obtained suppository was examined.

Test Method One suppository was administered into the rectum of a rabbit, and 1 hour later, the suppository was dissected and the section from the rectum to the colon was excised and incised. Then, it was cut into 2 cm pieces, and the amount of brilliant blue dye that had penetrated into each part was measured to evaluate the retention in the lower part of the rectum.

Results As shown in FIG. 1, it can be seen that the products A and B of the present invention are superior to the comparative product in retention in the lower rectum.

Example 3 A multilayer suppository was prepared in the same manner as in Example 1 using the formulations shown in Table 4, and its release characteristics were evaluated.

For the release test, a suppository release tester (Toyama Sangyo Co., Ltd.) was used. As the release phase liquid, pH 7.4 phosphate buffer solution 500 ml, liquid temperature 37
Performed at ± 0.1 ° C.

The results are shown in FIG.

[Brief description of drawings]

FIG. 1 is a drawing showing the relationship between the length from the lower part of the rectum and the permeation amount of brilliant blue in Example 2 one hour after the administration of suppositories. FIG. 2 is a drawing showing the release properties of prednisolone acetate from suppositories in Example 3.

Claims (3)

[Claims] 1. A multi-layered suppository in which a plurality of layers made of an oily base which are solid at room temperature are horizontally laminated, and at least one of two adjacent layers has a viscosity at 40 ° C. of 1,000 to 1,000,000.
A multilayer suppository characterized in that it is composed of layers that are cp. 2. The viscosity of at least one of the adjacent layers at 40 ° C. is 10,000 to 1,000,000 cp.
The multilayer suppository according to the item. 3. The multilayer suppository according to claim 1, wherein the viscosity of at least one of the adjacent layers is adjusted at 40 ° C. by adding a thickener.