JPS61200907A - Suppository - Google Patents

Abstract

PURPOSE:To provide a suppository having high safety, by dispersing crystalline indomethacin in a base composed mainly of polyethylene glycol and containing water, glycerol, a solid oil component and a surfactant. CONSTITUTION:The objective suppository is produced by dispersing crystalline indomethacin in a base composed mainly of polyethylene glycol and containing 1-7wt% water, 6-10% glycerol, 0.4-5% solid oil component, and 1.2-15% surfactant. Indomethacin can be maintained in the base of the suppository extremely stably without causing the lowering of the drug action for a long period. The polyethylene glycol is preferably the one having a number-average molecular weight of 1,000-6,000. The solid oil component is an oil or fat (especially hardened castor oil), was (especially beeswax), a higher alcohol (especially stearyl alcohol), a higher fatty acid (especially lauric acid), etc., and the surfactant is preferably a nonionic surfactant having an HLB of 10-20.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] This invention relates to a suppository stably containing indomethacin.

[Prior Art and its Problems] Indomethacin is a drug that is poorly soluble in water, but is well soluble in, for example, polyethylene glycol having a molecular weight of 200 to 20,000. Therefore, suppositories containing indomethacin in a base containing polyethylene glycol alone or in combination with polyethylene glycol have been conventionally formulated into a predetermined shape. In this type of conventional suppository, since indomethacin forms a solid solution with polyethylene glycol, it takes on a yellow color, that is, the color when indomethacin is dissolved.

However, although indomethacin in conventional layer agents was considered to be stable when quantitatively determined using absorbance method, it was found to be unstable when quantitatively determined using high-performance liquid chromatography, and its content decreases over time. It has been found. Stable retention of indomethacin in the layer is a basic requirement for this type of drug.

This invention has been made based on the above circumstances. That is, an object of the present invention is to provide a halving solution that can stably retain indomethacin in a base.

[Means for solving the above problems] In order to achieve the above object, the inventors first discovered that indomethacin in a base is unstable, although the reason is not necessarily clear. We speculated that this may be due to the formation of a solid solution with the polyethylene glycol contained therein, and as a result of further studies, we arrived at this invention.

That is, the outline of the present invention is a halved product characterized by dispersing crystalline indomethacin in a base containing polyethylene glycol as a main component.

In order to disperse indomethacin in crystalline form in the base,
It is preferable that the base has polyethylene glycol as a main component, and contains water, glycerin, a solid oil component, and a surfactant.

As the polyethylene glycol, those having a number average molecular weight of 200 to e, o o o can be used,
In particular, the number average molecular weight is t, o o o ~ e, o o.

The polyethylene glycol preferably used in this way is, for example, Macrogo JL/1
,000, Macrogo JL/1,500, Macrogole 1,540, Macrogole 2,000. macro goal 4
,000 and Macrogol 8,000, and one of these may be used alone, or two or more of these may be used in combination.

The water blended into the base is preferably purified water.

There are no particular restrictions on glycerin.

As the solid oil component, one or a mixture of two or more selected from the group consisting of fats and oils, waxes, higher alcohols, and higher fatty acids that are in a solid state at room temperature can be suitably used.

As the oil and fat, for example, vegetable fats such as cacao butter, Japanese oak oil, and palm oil, fish oil, gay oil, and other hydrogenated oils obtained by adding hydrogen to animal or vegetable fatty oils are preferably used. Hydrogenated castor oil is particularly preferred.

As the wax, animal waxes such as beeswax, gay wax, and wool wax, vegetable waxes such as carnauba wax, candelilla wax, and paiberry wax, and mineral waxes such as montan wax can be suitably used.

Among these, beeswax is particularly preferred.

Examples of the higher alcohol include natural alcohols such as lauryl alcohol, cetyl alcohol, stearyl alcohol, oleic alcohol, and lanolin alcohol;
hexyldecanol, isostearyl alcohol, 2-
Examples include synthetic alcohols such as octyldodecanol,
Stearyl alcohol is particularly preferred.

The higher fatty acids include lauric acid, myristic acid,
Examples include natural fatty acids such as palmitic acid, stearic acid, and oleic acid, and synthetic fatty acids such as isostearic acid. Among these, the aforementioned natural fatty acids are preferred, and lauric acid is particularly preferred.

The surfactant has an HLB of 10 or more.

Nonionic surfactants having a molecular weight of preferably 10 to 20 can be suitably used. That's what I mean.

This is because the surfactant of HLBIO-20 promotes disintegration and dispersion in the rectal fluid of the half portion. Examples of such surfactants include polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene rubitan monostearate, polyoxyethylene glyceryl monofatty acid esters, polyoxyethylene propylene glycol monofatty acid esters, and polyoxyethylene sorbitan monostearate. Bitol fatty acid ester, polyoxyethylene fatty acid ester such as polyoxyethylene monostearate, polyhydric alcohol ester, polyoxyethylene alkyl ether such as polyoxyethylene cetyl ether, polyoxyethylene alkyl allyl ether, polyoxyethylene hardened castor Oil-like hydrogenated castor oil derivative.

Polyoxyethylene polyoxypropylene copolymers, etc. can be suitably used, and among these, polyoxyethylene hydrogenated castor oil, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monostearate, polyoxyethylene Polyoxypropylene copolymers and the like are preferred.

These are commercially available. For example, polyoxyethylene sorbitan monostearate is available as "Niracol TSIOJ" [manufactured by Nikko Chemicals Co., Ltd.], and polyoxyethylene monostearate is available as "Niracol MYS40J [Nikko Chemicals Co., Ltd.]". ), polyoxyethylene cetyl ether is manufactured by Nilacol B.
As C30TXJ [manufactured by Nikko Chemicals Co., Ltd.], polyoxyethylene hydrogenated castor oil is [Niracol HC]
060J [manufactured by Nikko Chemicals Co., Ltd.] and polyoxyethylene polyoxypropylene copolymer can be obtained commercially as [Pluminik F68JE manufactured by Asahi Denka Kogyo Co., Ltd.].

The reason for blending the water and glycerin into polyethylene glycol is to reduce the solubility of indomethacin in polyethylene glycol and to disperse indomethacin in a crystalline state in the base. However, if a large amount of water and glycerin are simply mixed with polyethylene glycol, the solubility of indomethacin in polyethylene glycol will decrease and the indomethacin will precipitate, but it will not be able to maintain its halved shape. Therefore, it becomes necessary to blend a solid oil component in order to impart half-split moldability. However, if the solid oil component is too large, it becomes difficult to break the molded halves.

Therefore, the above-mentioned surfactant is blended in order to make the halves disintegrate in the rectal fluid and to facilitate the dispersion of the ingredients in the suppository into the rectal fluid. Therefore, in this invention, indomethacin has good dispersibility in a crystalline state. In order to obtain a halved product with good moldability, disintegration and dispersibility, the blending amount of the ingredients should be polyethylene glycol as the main component, water in an amount of 1 to 7% by weight, preferably 1 to 5% by weight, and glycerin in an amount of 1 to 5% by weight. 6-10% by weight, preferably 6-8% by weight, solid oil component 0.4-5% by weight, preferably 0.4-Zf% by weight
, 1.2 to 15% by weight of surfactant, preferably 2 to 5% by weight.
It is preferable to express it in weight%.

If the water content is less than 1% by weight and the glycerin content is less than 6% by weight, indomethacin may dissolve in the polyethylene glycol, making it difficult to crystallize indomethacin. Furthermore, if the blending ratio of water exceeds 7% by weight and the blending ratio of glycerin exceeds 10% by weight, it will not be possible to maintain the halved shape even if solid oil components and surfactants are blended. Sometimes. When the blending ratio of solid oil components exceeds 5% by weight,
Even if a surfactant is added, half of the product may not disintegrate, or even if it does disintegrate, it may take a long time. If the blending ratio of the solid oil component is less than 0.4% by weight, the moldability of the halved product may be poor, and if the blending ratio of the surfactant is less than 1.2% by weight, , the disintegration property of the halved portion may decrease, and the blending ratio is 15%.
Exceeding the weight may cause the halves to collapse too easily.

In the half portion according to the present invention, when the total amount is 1500 mg, the appropriate amount of indomethacin to be blended is 25 to 100 mg.

The halved portion can be produced by mixing and molding each of the components and indomethacin in a conventional manner. For example, polyethylene glycol, a solid oil component, and a surfactant are melt-mixed under heating. , add indomethacin to this molten mixture, then add and mix glycerin and water.

Preferably, the resulting composition is processed into a mold.

[Operation] Next, the operation of the present invention will be specifically explained with reference to test examples.

(Test example) 0.5g glycerin monostearate, 59.5g macrogol 1,540.85.0g macrogol 4
,000 were heated to 70-80° C. and melt-mixed, and 5.0 g of indomethacin was added and dissolved in the molten mixture. After confirming that indomethacin was completely dissolved, the mixture was cooled to 50 to 55°C, filled into a suppository container, and molded to obtain a suppository. This suppository was yellow and translucent because the indomethacin was dissolved in polyethylene glycol. This suppository was used as a control.

Meanwhile, 0.8g hydrogenated castor oil, 3.0g polyoxyl stearate 40 and 1.3g macrogol 1.54
0 and 120.1g macro goals 4,000 and 6.5g
Macrogol e and ooo were melt-mixed while heating to 70-80°C, 5.0 g of indomethacin was added and mixed to this molten mixture, and further 12.0 g of glycerin and 1.
5 g of purified water was added and mixed and stirred to form an apparently homogeneous mixture.Then, this mixture was cooled to 50 to 55°C, filled into a suppository container, further cooled and molded, and the present invention A suppository was obtained. This suppository does not contain indomethacin dissolved in polyethylene glycol.
It was white. This suppository was used as a specimen.

The control sample and the sample were stored for a long period of time while being heated to 35°C, and the content of indomethacin in the halves was determined by liquid chromatography. The results are shown in Table 1. The liquid chromatography measurement described above is based on the National Institutes of Health's quantitative method for "indomethacin skewers" [Monthly Yakuji, 2
6(3).

153 (1984)], the measurement conditions in this test example are shown below.

(Liquid chromatography measurement conditions) Detector: Ultraviolet photometer (measurement wavelength 254 nm) Column: Internal diameter 4.0-8.0 mm, length 100-3
00 stainless steel tube or plastic tube was filled with 5 to 10 pm of octadecylsilylated silica gel as a filler.

Column temperature: Constant temperature from room temperature to 40°C Mobile phase: Methanol 71,000 times diluted phosphoric acid mixture (70:30) Flow rate: Adjusted so that the retention time of indomethacin was approximately 8 minutes Recording paper speed: per minute 2 to 5 mm (hereinafter referred to as margin) From the results shown in Table 1, it was found that indomethacin is extremely stable in suppositories made by dispersing indomethacin in a crystalline state in polyethylene glycol. ] According to the present invention, it is possible to provide a halved product containing indomethacin extremely stably in a base mainly composed of polyethylene glycol. Therefore, since the content of indomethacin does not decrease over a long period of time, the halved product according to the present invention can withstand long-term storage and can be useful without decreasing its medicinal efficacy.

[Example] Next, an example of this invention will be shown. It goes without saying that this invention is not limited to this example.

(Example 1) 1.0g lauric acid and 5.0g Nilacol BC40
TX and 117. Og's -yyo goal 4,000 and 7.
0 g of macrogol s, ooo were melt-mixed while heating to 70 to 80°C, 5.0 g of indomethacin was added and mixed to this molten mixture, and further 9.0 g of glycerin and 6
．． Add and mix with 0g of purified water and stir to give an apparently uniform
Then, this mixture was cooled to 50 to 55°C, filled into a suppository container, and further cooled and molded to obtain a half according to the present invention. This half is because indomethacin is not dissolved in polyethylene glycol.

(Example 2) 2. Og of beeswax, 6.0g of Niracol TSIO, 101.5g of Macrogol 4,000 and 20.0g of Macrogol S,ooo were heated to 70-80°C. 2.5 g of indomethacin was added to the molten mixture, and further 10.0 g of glycerin and 8.0 g of glycerin were added.
g of purified water was added and mixed and stirred to form an apparently homogeneous mixture.Then, this mixture was cooled to 50 to 55°C, filled into a suppository container, further cooled and molded,
I got half a percent according to this invention. This half was white because the indomethacin was not dissolved in the polyethylene glycol.

(Example 3) 0.8 g of stearyl alcohol, 12.0 g of Pluronic F68, and 7.0 g of Macrogol 1,540 and 1
09.2g of macrogol e, o o o and 70-8
Melt and mix while heating to 0°C, and add lO, O to this molten mixture.
Add and mix g of indomethacin.

Furthermore, 9.5 g of glycerin and 1.5 g of purified water were added and mixed, and stirred to form an apparently homogeneous mixture.Next, this mixture was cooled to 50 to 55°C, and then filled into suppository containers. It was further cooled and molded to obtain a half-split according to the present invention. This half was white because the indomethacin was not dissolved in the polyethylene glycol.

Claims (5)

[Claims] (1) A suppository comprising crystalline indomethacin dispersed in a base mainly composed of polyethylene glycol. (2) The suppository according to claim 1, wherein the base containing polyethylene glycol as a main component contains water, glycerin, a solid oil component, and a surfactant. (3) The base mainly composed of polyethylene glycol contains 1 to 7% by weight of water, 6 to 10% by weight of glycerin,
Solid oil component: 0.4-5% by weight, surfactant: 1.2%
Suppositories according to claim 2, containing in a proportion of ~15% by weight. (4) Claims 2 and 3 above, wherein the solid oil component is one or a mixture of two or more selected from the group consisting of fats and oils, waxes, higher alcohols, and higher fatty acids. The suppository described in any of the above. (5) Claim 2, wherein the surfactant is a nonionic surfactant and has an HLB of 10 to 20.
The suppository according to any one of Items 1 to 4.