JPH06298667A - Sustained release suppository - Google Patents

Abstract

PURPOSE:To provide a new sustained release suppository safe to living body and free from stimulation to mucous membrane. CONSTITUTION:A sustained release suppository composed of a drug, a polyglycerol fatty acid ester having an HLB of <=8 and an oily base and a process for producing the suppository. The product is free from the localization of the polyglycerol fatty acid ester used as a sustained release component and has little interlot variation of the sustained release effect. The sustained release effect can be regulated by varying the amount of the sustained release component. The suppository is easily producible.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to the field of pharmaceutical formulations, especially sustained release suppositories.

[0002]

2. Description of the Related Art Suppositories have a low rate of drug degradation in the body due to their administration route and are not affected by diet, and are not only for children and the elderly but also for patients who have difficulty in oral administration. It is frequently used because of its relative ease of administration. However, on the other hand, it has been pointed out that, when a drug is administered rectally, there are drawbacks such as a risk of side effects due to a rapid rise in plasma concentration and a difficulty of administering the drug many times a day. Various attempts have heretofore been made to solve such drawbacks by gradually releasing suppositories. In general, suppositories are sustained-released by incorporating a specific formulation component (sometimes referred to as sustained-release component).

However, most of the sustained-release components are not melted and become dispersed when heated together with the oily base. Therefore, in the entire manufacturing process, unless care is taken to disperse the sustained-released component uniformly in the oily base, the sustained-released component will be localized, and as a result, the sustained-released component may be distributed between the production lots. Differences may occur.

[0004]

SUMMARY OF THE INVENTION The problem to be solved by the present invention is that when heated together with an oily base, they melt together to form a uniform system, which is excellent in sustained-release effect and is safe for the living body and stimulates mucous membranes. It is to find a new sustained-release ingredient that does not complicate the production process of the intended suppository.

[0005]

Means for Solving the Problems The inventors of the present invention have said that the above problems can be solved by selecting a polyglycerin fatty acid ester having an HLB of 8 or less as a component for achieving sustained release of suppositories. The present invention has been completed based on knowledge.

The present invention relates to a sustained release suppository comprising a drug, a polyglycerin fatty acid ester having an HLB of 8 or less, and an oily base.

The polyglycerin fatty acid ester is an esterified product of polyglycerin formed by dehydration condensation of glycerin and a fatty acid such as stearic acid, and has never been used as one of formulation ingredients in suppositories until now.

The polyglycerin fatty acid ester as a sustained-release component in the present invention may be any polyglycerin fatty acid ester as long as it has an HLB of 8 or less, but preferably 6 or less, particularly preferably 2 to 5 is used. When the HLB deviates from this range, sustained release cannot be achieved as shown in the test example (FIG. 1) described later.

From the structure of polyglycerin fatty acid ester, 4-10 glycerin residues and 3-10
Those composed of individual stearic acid residues are preferably used. Specifically, tetraglyceryl tristearate (HL) commercially available from Nikko Chemicals Co., Ltd.
B = about 4), tetraglyceryl pentastearate (H
LB = about 2), hexaglyceryl tristearate (H
LB = about 6), hexaglyceryl pentastearate (HLB = about 3), decaglyceryl tristearate (HLB = about 8), decaglyceryl pentastearate (HLB = about 5), decaglyceryl heptasterate (HLB =) And about 4) and decaglyceryl decasterate (HLB = about 3). Among them, tetraglyceryl pentastearate, hexaglyceryl pentastearate, decaglyceryl heptastereate, and decaglyceryl decasterate are particularly preferable. .

The drug may be water-soluble, poorly water-soluble, or any other property, and its type is not particularly limited.

The type of the oily base is not particularly limited as well as the drug, and any of the conventionally used ones can be used. As the oily base, for example, a mixture of higher fatty acid ester triglyceride / diglyceride / monoglyceride [eg, various Witepsol (Hürz), various Novata (Henkel), various Pharmasol (Nippon Yushi), isocaca (Kao)] And medium-chain fatty acid ester triglyceride [eg, Miglyol (Dynamite Nobel)], glycerin fatty acid ester, cacao butter, hydrogenated oil, corn oil, liquid paraffin, petrolatum and the like. These oily bases are used alone or in the form of a mixture.

[0012] In addition, auxiliary components such as antioxidants, absorption promoters and mucosal protective agents are blended if necessary.

The suppository of the present invention is prepared by heating a mixture of an oily base and a polyglycerin fatty acid ester having an HLB of 8 or less to obtain a uniform melt, in which the drug is dissolved or dispersed, and a predetermined container is prepared. It can be manufactured by filling the mixture into a container and cooling. Heating temperature is below 80 ℃, usually 60
~ 70 ° C. In the suppository of the present invention, the polyglycerin fatty acid ester is 50% by weight or less, preferably 5-4.
It accounts for 0% by weight, particularly preferably 10-30% by weight, the drug accounts for 25% by weight or less, and the balance is occupied by the oily base and other auxiliary components.

[0014]

EXAMPLES The present invention will be described in more detail with reference to Examples and Comparative Examples.

Example 1 : Formulation-; Diclofenac sodium 25 mg Hexaglyceryl pentastearate (HLB = about 3) 175 mg Witepsol H-15 875 mg ────────────────── ────────────── Total 1000 mg Manufacturing method; Polyglycerin fatty acid ester and oil base 6
It was melted at 0 to 70 ° C, diclofenac sodium was dispersed, and this was filled in a suppository container and cooled to obtain a suppository.

Example 2 : Formulation-; Diclofenac sodium 25 mg Hexaglyceryl pentastearate (HLB = about 3) 250 mg Witepsol H-15 725 mg ────────────────── —————————————————————————————−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−.

Example 3 : Formulation-; Diclofenac sodium 25 mg Hexaglyceryl pentastearate (HLB = about 3) 300 mg Witepsol H-15 675 mg ────────────────── —————————————————————————————−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−.

Example 4 : Formulation-; Diclofenac sodium 25 mg Tetraglyceryl pentastearate (HLB = about 2) 150 mg Witepsol W-35 825 mg ────────────────── —————————————————————————————−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−.

Example 5 : Formulation-; Diclofenac sodium 25 mg Decaglyceryl decastearate (HLB = about 3) 200 mg Witepsol S-55 775 mg ────────────────── —————————————————————————————−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−.

Example 6 : Formulation-; Diclofenac sodium 25 mg Decaglyceryl heptostearate (HLB = about 4) 100 mg Witepsol H-15 875 mg ────────────────── —————————————————————————————−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−.

Example 7 : Formulation-; Diclofenac sodium 25 mg Decaglyceryl heptastearate (HLB = about 4) 150 mg Witepsol H-15 825 mg ────────────────── —————————————————————————————−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−.

Comparative Example A : Formulation-; Diclofenac sodium 25 mg Witepsol H-15 975 mg ─────────────────────────────── -Total 1000 mg Production method-; A suppository was obtained in the same manner as in Example 1.

Comparative Example B : Formulation-; Diclofenac sodium 25 mg Hexaglyceryl monostearate (HLB = about 11) 150 mg Witepsol H-15 875 mg ────────────────── —————————————————————————————−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−.

Comparative Example C : Formulation-; Diclofenac sodium 25 mg Decaglyceryl monostearate (HLB = about 14) 150 mg Witepsol H-15 875 mg ────────────────── —————————————————————————————−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−.

[0025]

INDUSTRIAL APPLICABILITY The suppository of the present invention does not show localization of polyglycerin fatty acid ester, which is a sustained-release component, has little variation in the sustained-release effect between production lots, and is safe for living organisms and mucous membranes. Further, the degree of sustained release can be adjusted by changing the amount of the sustained release component added. The suppository production method of the present invention is simple and does not complicate the production process by adopting a specific sustained-release component. The sustained release effect of the suppository of the present invention will be described below with reference to experimental examples.

Test Example : Examples 1 to 3 and Comparative Examples A and B
The release test of diclofenac sodium from C and S suppositories was conducted using a PTSW type suppository release tester (rotating cell method). The release phase solution is 0.02M phosphate buffer (pH
Using 900 ml of 7.4), the rotation speed of the cell is 25 rp
m and the temperature was 37 ° C. The result is shown in FIG. As is clear from FIG. 1, the release of the drug from the suppository was suppressed by the addition of the polyglycerin fatty acid ester having an HLB of 8 or less (Examples 1 to 3). on the other hand,
The suppositories of Comparative Example A containing no polyglycerin fatty acid ester and the suppositories of Comparative Examples B and C containing polyglycerin fatty acid ester having HLB of 8 or more were not sustained-released.

[0027]

[Brief description of drawings]

FIG. 1 shows the dissolution pattern of diclofenac sodium from suppositories.

Claims (4)

[Claims] 1. A sustained-release suppository comprising a drug, a polyglycerin fatty acid ester having an HLB of 8 or less, and an oily base. 2. The suppository according to claim 1, wherein the polyglycerin fatty acid ester is a stearic acid ester. 3. The polyglycerin fatty acid ester is 4 to 1
The suppository according to claim 1 or 2, which comprises 0 glycerin residues and 3 to 10 stearic acid residues. 4. A mixture comprising an oily base and a polyglycerin fatty acid ester having an HLB of 8 or less is heated to obtain a uniform melt, and the drug is dissolved or dispersed in the melt.
A method for producing a sustained-release suppository, which comprises filling a predetermined container and cooling.