JP3130325B2 - Vaginal or rectal composition - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

FIELD OF THE INVENTION The present invention relates to the field of pharmaceutical compositions, especially compositions for sustained release vaginal or rectal administration.

[0002]

2. Description of the Related Art A composition for vaginal or rectal administration such as a suppository or a rectal capsule has a low rate of decomposition of a drug in a living body, and can be easily administered to not only children and the elderly but also patients who cannot be orally administered. It is a dosage form that has recently been used because it is not affected by diet and the like. However, on the other hand, it has been pointed out that vaginal or rectal administration of a drug has drawbacks such as the risk of side effects due to rapid rise in plasma concentration and the difficulty of administering the drug many times a day. Various attempts have hitherto been made assuming that such disadvantages can be solved by sustained release of the preparation. In most cases, the drug is sustained-released by incorporating a specific formulation component. For example, JP-A-58-
In 140012, ethyl cellulose was added in the same manner as in 62-246.
No. 516, a surfactant, No. 62-149628, a collagen, No. 63-183523, a hydrogenated phospholipid, No. 63-14716, a hydrogenated lecithin, and JP-A-1-63512, 1-110618, and 2- 73
010, the sucrose fatty acid ester is 2-15024
Then, minerals such as montmorillonite,
In this, sodium alginate is used as a formulation component for sustained release (hereinafter sometimes referred to as a sustained release component).

[0003] However, the sustained release by these formulation components is not always satisfactory. For example, hydrogenated lecithin, which is a sustained-release component, cannot coexist with a water-soluble base, and is itself unstable or, when using sodium alginate, there is concern about the reactivity of these with the drug or base. Problem.

[0004]

The problem to be solved by the present invention is that a reliable sustained release effect can be obtained without interacting with a drug or a base, which is safe for a living body and does not irritate mucous membranes. Another object of the present invention is to find a novel sustained-release component that does not complicate the production process of the desired composition for vaginal or rectal administration.

[0005]

Means for Solving the Problems The present inventors can solve the above problems by selecting plantago plant-derived gum as a component for achieving sustained release of a composition for vaginal or rectal administration. With this knowledge, the present invention has been completed.

[0006] Plantago plants are annual plants of the predariidae cultivated mainly in India. Among the plantago plants, plantago obata (P. ovata) is the most famous, and in addition, plantago indica (P. indica), plantago arenaria (P. arenaria), plantago psyllium (P. pylllium), and the like are known. The gum substance derived from the plantago plant, especially its seed coat (husk) is a polysaccharide whose main component is D-xylol or L-arabinose, which is called psyllium (Psylium) or isapogol (Isapgol). It has various properties such as water swelling and edible but non-absorbable in vivo. Since gum from plantago plants stimulates intestinal peristalsis in the intestine when taken, it has been used as a laxative and recently as a slimming agent (health food) since ancient times. I have. However, the gum has never been used as one of the formulated components in vaginal or rectal compositions.

[0007] The present invention relates to a sustained-release vaginal or rectal composition comprising a drug, a plantago plant-derived gum and a base.

[0008] The drug in the composition of the present invention may be any of those having water-solubility, poorly water-solubility, heat instability and any other properties, and the kind thereof is not particularly limited.

The type of the base in the composition of the present invention is not particularly limited as well as the drug, and any of the conventionally used oil-based base, water-soluble base and emulsifying base can be used. Can be used. Examples of the oleaginous base include, for example, a mixture of higher fatty acid triglyceride / diglyceride / monoglyceride [for example, various witepsol (Hurz), various Novata (Henkel), various pharmazol (Nippon Yushi), isokacao (Kao), Saposire (Gatfords)], medium-chain fatty acid triglyceride (eg, Miglyol (Dynamite Nobel)), glycerin fatty acid ester, cocoa butter, hardened oil, corn oil, liquid paraffin, vaseline, and the like. Examples of the water-soluble base include polyethylene glycol, propylene glycol, glycerin, gelatin and the like. As an emulsifying base, polyoxy (40)
Stearate [eg, Nikkor MYS-40 (Nikko Chemicals)]. These bases are used alone or in the form of a mixture.

As the gum substance derived from a plantago plant, a gum substance derived from the seed coat powder of plantago obata is mentioned as a preferred example, and a fine powder, specifically, a substance that passes through a 100-mesh sieve is suitable. In addition, auxiliary components such as a surfactant, an absorption enhancer, and a mucosal protective agent are added as necessary.

In the composition of the present invention, the gum substance derived from the plantago plant accounts for 50% by weight or less, preferably 2 to 30% by weight, particularly preferably 5 to 20% by weight, and the drug is 2% by weight.
It accounts for less than 5% by weight, with the balance being the base and other auxiliary components.

The composition of the present invention may be in the form of a suppository, a lectal capsule, or an ointment. Ointments are administered with a special syringe.

The composition of the present invention is basically produced by dissolving or dispersing a drug in a base, and dispersing a gum derived from a plantago plant. Suppositories can be produced by melting a solid base at room temperature at about 70 ° C. or lower, preferably at 40-60 ° C., blending the necessary components, pouring the mixture into a container, and cooling. In the production of lectal capsules, it is common to mix necessary components into a liquid base such as miglyol and fill the mixture into gelatin soft capsules. The preparation of an ointment-like composition is carried out by blending necessary components into a base such as liquid paraffin or petrolatum. In each case, the auxiliary component is generally combined with the drug. It is considered that the gum from plantago plants in the composition is mostly dispersed as a solid.

[0014]

The present invention will be described in more detail with reference to the following Examples and Comparative Examples. In the following Examples and Comparative Examples, 1
A gum material (hereinafter, sometimes referred to as gum material) derived from the seed coat powder of plantago obata that passed through a 00 mesh sieve was used. In the following formulations, the amount of each component to be incorporated in one suppository or one rectal capsule is indicated.

Example 1-3 Witepsol H-15 as an oily base was heated at 42-45 ° C.
, And Na valproate and gum were dispersed therein according to the formulation shown in Table 1, and this was filled in a suppository container, and cooled to obtain a suppository.

[0016]

[Table 1]

Example 4 Na valproate 00 mg 100 g of gum Novata 299 780 mg Total amount 1200 mg Novata 299 which is an oily base Was melted at 42-45 ° C., and Na valproate and gum were dispersed therein. This was filled in a suppository container, and cooled to obtain a suppository.

Example 5 Na valproate 300 mg Game 120 mg Cocoa butter 780 mg Total amount 1200 mg Cacao butter, which is an oily base, is 42 The mixture was melted at −45 ° C., and Na valproate and gum were dispersed therein. The mixture was filled in a suppository container and cooled to obtain a suppository.

Example 6 Na valproate 300 mg Game 120 mg Miglyol 810 780 mg Total amount 1200 mg In Miglyol 810 which is an oily base Valproate Na
And gum were dispersed, and the resultant was filled in a gelatin soft capsule to obtain a lectal capsule.

Example 7 Na valproate 300 mg Game 120 mg Nichol MYS-40 780 mg Total amount 1200 mg Nichol MYS as emulsifying base -40 to 50-60 ° C
, And Na valproate and gum were dispersed therein, and this was filled in a suppository container, and cooled to obtain a suppository.

Example 8-10 Polyethylene glycol 4000 and 6000 as water-soluble bases were melted at 60-70 ° C., indomethacin was dissolved in the base according to the formulation shown in Table 2, and gum was dispersed. This was filled in a suppository container and cooled to obtain a suppository.

[0022]

[Table 2]

Example 11 Indomethacin 50 mg Game 120 mg Polyethylene glycol 400 530 mg Propylene glycol 500 mg Total amount 1200 mg Water-soluble group Polyethylene glycol 400 and propylene glycol, which are agents, were mixed, indomethacin was dissolved therein, and gum was further dispersed. This was filled in a gelatin soft capsule to obtain a rectal capsule.

[0024]

The composition for vaginal or rectal administration of the present invention contains a gum substance derived from a plantago plant as a sustained-release component, and this gum substance interacts with a drug or a base. It is intended to provide a sustained release of the drug without matching and is safe for the living body and does not irritate the mucous membrane. In addition, by adopting such gum as a sustained-release component, the method for producing the composition does not become complicated. Therefore, the type of drug and base used in the composition of the present invention is not limited. Hereinafter, the sustained release effect of the composition of the present invention will be described with reference to experimental examples.

Experimental Example 1 The release experiment of sodium valproate from the suppository obtained in Example 1-3 and the suppository of Comparative Example 1 was carried out by the dissolution test method (rotating basket method) described in the 11th edition of the Japanese Pharmacopoeia. I went according to. The release phase solution was prepared by adding 0.02 M phosphate buffer (pH 7.4) to 9
The rotation speed of the basket was 50 rpm, and the temperature was 37 ° C. The result is shown in FIG. As is clear from FIG. 1, the release of Na valproate from the suppository was suppressed by the addition of plantago obata seed coat powder in accordance with the amount added.

Experimental Example 2 Release of indomethacin from the suppositories obtained in Examples 8-10 and Comparative Example 2 was performed in accordance with Experimental Example 1. The result is shown in FIG. As apparent from FIG. 2, the release of indomethacin from the suppository was suppressed by the amount of plantago obata seed coat powder added, and the effect was remarkable especially when added at 10% or more.

Experimental Example 3 The suppository obtained in Example 2 and the suppository of Comparative Example 1 were administered into the rectum of a rabbit, and after administration, the valproic acid concentration in plasma was measured with time. The result is shown in FIG. As is clear from FIG. 3, a rapid increase in the plasma valproic acid concentration after administration of the suppository was suppressed, and the plasma concentration was sustained.

Experimental Example 4 The suppository obtained in Example 9 and the suppository of Comparative Example 2 were administered into the rectum of a rabbit, and after administration, the concentration of indomethacin in plasma was measured over time. FIG. 4 shows the results. As is clear from FIG. 4, a rapid increase in the plasma indomethacin concentration was suppressed, and the plasma concentration was sustained.

[0029]

[Brief description of the drawings]

FIG. 1 shows the elution pattern of Na valproate from suppositories.

[0030]

FIG. 2 shows the elution pattern of indomethacin from suppositories.

[0031]

FIG. 3 shows the relationship between the plasma concentration of valproic acid and the elapsed time when a suppository was administered to the rectum of a rabbit.

[0032]

FIG. 4 shows the relationship between the plasma concentration of indomethacin and the elapsed time when a suppository was administered to the rectum of a rabbit.

Continuation of the front page (72) Inventor Hirokazu Makita 5-5-4 Ukyo, Nara City, Nara Prefecture (56) References JP-A-1-93522 (JP, A) JP-A-60-174728 (JP, A) ( 58) Field surveyed (Int. Cl. ⁷ , DB name) A61K 9/02, 9/48, 47/36

Claims (5)

(57) [Claims] 1. passing the drug and a 100 mesh sieve
Do from gum and base derived from Plantago plant was Ri, based on
That plant gum derived from plantago is dispersed in
Characterized sustained release vaginal or rectal administration compositions. 2. The composition according to claim 1, wherein the plantago plant is plantago obata. 3. The composition according to claim 1, wherein the gum is derived from the seed coat powder of plantago obata. 4. The composition according to claim 1, wherein the gum substance content derived from the seed coat powder of plantagoobata is 50% by weight or less. 5. The composition according to claim 1, wherein the composition is in the form of a suppository or a lectal capsule.