JP2702938B2 - Sustained-release suppositories - Google Patents

Description

Description: FIELD OF THE INVENTION The present invention relates to sustained release suppositories. More specifically, the present invention relates to a controlled drug release suppository that can control a blood drug concentration immediately after administration and maintain a desired blood drug concentration thereafter. 2. Description of the Related Art Conventionally, many suppositories are intended for local action, such as hemorrhoids. However, in recent years, not only has it become known that some drugs can provide blood levels comparable to that of oral administration by rectal administration, and suppositories, which are one method of rectal administration, due to the advantages of rectal administration. , With emphasis on systemic effects. The advantages of rectal administration are that they are less susceptible to hepatic first-pass effects and that the drug is not degraded by acids, digestive enzymes, or microorganisms. In addition, absorption of some drugs is faster than oral administration. By the way, in recent years, a controlled release formulation by oral administration has been developed to improve compliance by reducing the number of doses of drugs with short biopharmaceutical half-life and to maintain the effective blood concentration of the drug for a long time. Have been. Here, conventional suppositories are formed by uniformly dispersing or dissolving the drug in the base, and when the base is melted by body temperature or dissolved in the secretion fluid to release the drug, the drug and the mucous membrane It is absorbed from the mucous membrane according to the transfer rate depending on the physical properties of the protein. Thus, it has been very difficult to make suppositories into sustained-release preparations by controlling release like other preparations. Attempts at sustained release of suppositories made so far
The melting rate of the base is reduced by using a high melting point fatty acid glycerin as the base. However, there were individual differences in body temperature, which caused significant differences in release and did not allow for adequate control. Problems to be Solved by the Invention It is an object of the present invention to provide a sustained-release suppository that allows a desired blood drug concentration to be maintained for a long period of time while utilizing the characteristics of the suppository. A further object of the present invention is to provide a sustained release suppository which can sufficiently control the drug release rate. Means for Solving the Problems The object of the present invention can be achieved by a sustained-release suppository in which a solid preparation is embedded in a base by dispersion or the like. More specifically, the amount of drug necessary to obtain a desired initial blood concentration is dispersed or dissolved in a base, and the amount of drug and aqueous solution necessary to maintain the desired blood concentration over a long period of time therein. This can be achieved by a sustained-release suppository in which a solid preparation comprising a hydrophilic polymer is embedded by dispersion or the like. When the suppository of the present invention is administered, the base dissolves at the body temperature after melting or secretion, and then dissolves, and the drug dispersed or dissolved in the base is transferred from the base to the mucous membrane in a short time as in the case of the conventional suppository. Transfer and be absorbed. Next, as the base is melted or dissolved, the solid preparation containing the water-soluble polymer comes into contact with secretory fluid in the rectum and gels from the surface, and the drug is gradually released from the gel portion. Here, the control of the release rate of the drug from the solid preparation is performed by controlling the size and quantity of the solid preparation, selecting the type of the water-soluble polymer,
It can be carried out by adding a disintegrant, coating the surface of the solid preparation, or the like. Among the above-mentioned various control factors, the characteristics of the water-soluble polymer greatly affect the release rate of the drug from the solid preparation. Therefore, it is necessary to select a water-soluble polymer having properties suitable for the administration schedule. The water-soluble polymer of the present invention is an alkyl cellulose having an alkyl group having 1 to 4 carbon atoms,
Celluloses such as hydroxyalkyl cellulose and its alkyl metal salt, carboxyalkyl cellulose and its alkali metal salt; carboxyalkyl starch having 1 to 4 carbon atoms in the alkyl group and its alkali metal salt, hydroxyalkyl starch, dextran, dextrin, alpha Starch such as starch and derivatives thereof; pullulan of a single polysaccharide, alginic acid and alkali metal salts thereof, and complex polysaccharides of mannan, pectin, alkali metal salts of pectic acid, agar and the like; arabia gum, karaya gum, tragacanth gum, carob gum And natural rubbers such as xanthan gum; alkali metal salts of casein; proteins such as gelatin; carboxyvinyl polymer, polyacrylic acid and its alkali metal salts, polymethacrylic acid and the like. Alkali metal salts, polyvinyl methyl ether, polyvinyl alcohol, vinyl polymers such as polyvinyl pyrrolidone may be used alone or in combination of two or more. The suppository base may be any solid that is solid at room temperature, melts at body temperature or dissolves in the secretion fluid at the administration site, and bases generally used for suppositories can be widely used. For example, as the oily base, hydrogenated local oil, fatty acid glycerin ester, higher fatty acid, higher alcohol, vegetable oil, animal oil and the like can be used alone or in combination of two or more. The melting point at this time is desirably 30 to 37 ° C. As the water-soluble base, one or more kinds of polyethylene glycol (PEG), gelatin and the like can be used alone or in combination of two or more so as to have a melting point of 30 ° C. or more. PEG 400, 100 for PEG
0, 4000, 6000 are suitable. If necessary, a surfactant may be added to these bases. The drug may have a local effect or a systemic effect. In addition, one kind or two or more kinds may be used. At least one of the drug contained in the base and the drug contained in the solid preparation is the same, and aims to maintain the effect of the same drug. The solid preparation comprises a drug and a water-soluble polymer, and may contain an auxiliary such as a disintegrant, if necessary. The solid preparation may be in the form of tablets, granules, pellets or pills, as long as it can be applied to the anus as a suppository when covered with a base and molded. In addition, one or more solid preparations are embedded in the base. The surface of the sustained release suppository of the present invention is not different from that of a conventional suppository. Thus, the administration does not involve insertion difficulties, such as occur when administering a powdered suppository whose surface is not covered with a base. The sustained-release suppository of the present invention is obtained by embedding a solid preparation produced by a usual method when embedding a base in a suppository mold, or premixing and dispersing with a base. Can be manufactured by The sustained release suppository of the present invention can be administered not only from the anus but also from the vagina. Effect The sustained-release suppository of the present invention can obtain an effective blood concentration immediately after administration, and can maintain the effective blood concentration for a long time. Compared to oral administration, it is less susceptible to the first pass of the liver, and it is needless to say that it does not impair the effects of conventional suppositories, such as the fact that the drug is not decomposed by acids, digestive enzymes, or microorganisms. is there. Reference Example 1 For each suppository, 1,200 mg of fatty acid glycerin ester (product sold under the trademark Novata E from Henkel, Germany) and 430 mg of fatty acid glycerin ester (product sold under the trademark Novata D from Doyle Henkel) , Tween 20 as a dispersant and 70 mg of aminopyrine as a drug were weighed, melted and uniformly kneaded on a warm bath to produce a drug-containing base. Next, per suppository, 148.4 mg of CMC sodium as a water-soluble polymer, 50 mg of L-HPC (low-substituted hydroxypropylcellulose) as a disintegrant, 1.6 mg of magnesium stearate as a lubricant, and 60 mg of aminopyrine as a drug are weighed. After well mixing the components, the mixture was molded into tablets by a conventional method. Melt the base prepared in advance, pour it into a suppository molding mold, and when the part of the base in contact with the mold starts to solidify, insert one molded tablet in the center, and further Pour the molten base from the top and, when the whole is completely solidified, scrape the base overflowing onto the mold surface, take out the suppository, split the mold, and take 2,000mg per piece
Suppositories. Per prescription suppository [Drug-containing base] Fatty acid glycerin ester (Novata E) 1,200 mg Fatty acid glycerin ester (Novata D) 430 mg Tween20 70 mg aminopyrine 40 mg [Tablets] CMC sodium 148.4 mg L-HPC 50 mg Magnesium stearate 1.6 mg aminopyrine A total of 2,000 mg of the suppository produced, 60 mg, was subjected to a release test using a suppository release tester (manufactured by Toyama Sangyo). The results are shown in FIG. The mixing ratio of Novata E, Novata D and Tween 20 is shown in Reference Example 1.
A suppository weighing 2,000 mg containing 100 mg of aminopyrine was prepared. This conventional suppository was also subjected to a release test in the same manner as in Reference Example 1. The results are shown in FIG. 1 together with the results of Reference Example 1. As is clear from FIG.
The suppository of the present invention reaches 90% 3 hours after the start of the test, and 100% 5 hours after the start of the test, while maintaining the release rate 100% over 3 hours. And extremely excellent sustained release properties. Reference Example 2 Suppositories per polyethylene glycol 4000
0 mg, polyethylene glycol 1000 700 mg, polyethylene glycol 400 95 mg, indomethacin 5 mg as drug
Was weighed, melted on a warm bath and kneaded uniformly to obtain a drug-containing base. Next, per suppository, 153.8 mg of hydroxypropylcellulose (HPC-L) as a water-soluble polymer, 1.2 mg of magnesium stearate, 45 m of indomethacin as a drug
g was weighed, each component was mixed well, and formed into tablets by a conventional method. Pour the pre-melted base into a suppository mold, and when the part of the base in contact with the mold begins to solidify,
Insert one preformed tablet into the center, pour a molten base from above, and after the whole is hardened, scrape the base overflowing to the mold surface, take out the molded suppository, and remove mg suppositories were produced. Per prescription suppository [Drug-containing base] Polyethylene glycol 4000 1,000 mg Polyethylene glycol 1000 700 mg Polyethylene glycol 400 95 mg Indomethacin 5 mg [Tablets] HPC-L 153.8 mg Magnesium stearate 1.2 mg Indomethacin 45 mg Total 2,000 mg The release rate was measured in the same manner as in Reference Example 1. The results are shown in FIG. The release rate is about 95% at 6 hours and 100% at 7 hours after the start of the test.
And excellent sustained release properties were obtained. Reference Example 3 One suppository, 1,000 polyethylene glycol 4000
0 mg, polyethylene glycol 1000 700 mg, polyethylene glycol 400 80 mg, indomethacin 20m as drug
g was weighed, melted on a warm bath, and uniformly kneaded to obtain a drug-containing base. This drug-containing base differs from Reference Example 2 only in the content of the drug. Next, HPC-L is used as a water-soluble polymer per suppository.
168.8 mg, lubricant magnesium stearate 1.2 mg,
30 mg of the drug, indomethacin, was weighed, the components were mixed well, and formed into tablets by a conventional method. A suppository was produced in the same manner as in Reference Example 2, using the drug-containing base and the tablet that had been melted in advance. Prescription suppository [drug-containing base] Polyethylene glycol 4000 1,000 mg Polyethylene glycol 1000 700 mg Polyethylene glycol 400 80 mg Indomethacin 20 mg [Tablets] HPC-L 168.8 mg Magnesium stearate 1.2 mg Indomethacin 30 mg Total 2,000 mg The release rate was measured in the same manner as in Reference Example 1. The results are shown in FIG. The release rate is about 90% at 5 hours after the start of the test and about 100 at 6 hours.
% And excellent sustained release properties were obtained. In Reference Example 2, the drug content compared to Reference Example 2 was 10% in the base portion and 90% in the tablet portion.
On the other hand, in Reference Example 3, the release rate is different because the base portion is 40% and the tablet portion is 60%. That is, the initial release rate of Reference Example 3 was higher than that of Reference Example 2, but the release was slower at around 40% release rate, and conversely, the release rate of Reference Example 2 was faster. This is because the initial release takes place from the base portion and the drug contained in the tablet is released as the base melts or dissolves in the secretion. Example 1 Per suppository, 1,270 mg of Novata E and 400 of Novata D
mg, polyoxyethylene lauryl ether 100 mg as a dispersing aid, medium-chain fatty acid triglyceride 80 mg as a base hardness regulator, diazepam 1 mg as a drug, and
The mixture was melted on a warm bath and kneaded uniformly to obtain a base melt. Separately, per a suppository, 95 mg of sodium alginate, 45 mg of lactose, and 9 mg of diazepam were weighed and fluidized while spraying water with a fluidized bed granulator to produce pellets. The pellets were dispersed in a pre-melted base, the dispersion was poured into a mold, and cooled and cured to produce a suppository. Prescription per suppository [Drug-containing base] Novata E 1,270mg Novata D 400mg Polyoxyethylene lauryl ether 100mg Medium chain fatty acid triglyceride 80mg Diazepam 1mg [Pellet] Sodium alginate 95mg Lactose 45mg Diazepam 9mg Total 2,000mg Same as Reference Example 1 When the release rate was tested, good sustained release properties were obtained.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows Reference Example 1 containing aminopyrine as a drug.
FIG. 2 is a graph showing the results of a release test of a sustained release suppository of the present invention and a conventional suppository. FIG. 2 shows the results of release tests of the sustained release suppositories of Reference Examples 2 and 3 each containing indomethacin as a drug. It is a graph showing a result.

Claims (1)

(57) [Claims] A sustained-release suppository in which a plurality of solid preparations comprising a drug, a water-soluble polymer and, if necessary, a disintegrant are dispersed in a base containing a drug and no water-soluble polymer. 2. 2. The sustained-release suppository according to claim 1, wherein said water-soluble polymer is cellulose, starch and derivatives thereof, saccharide, natural rubber, protein or vinyl polymer. 3. 3. The sustained-release suppository according to claim 1, wherein the solid preparation is a tablet, a granule, a pellet, or a pill. 4. Claims 1 and 2 wherein the base is an oily base.
Item 4. The sustained release suppository according to item 3 or 3.