JPS58140012A - Gradually releasing imdomethacin suppository - Google Patents

Abstract

PURPOSE:The titled suppository that is made by adding cyclodextrin, ethylcellulose, glycerol fatty acid ester and oily base to indomethacin (a nonsteroid anti-inflammatory) and forming the mixture, thus being stable and good in gradually releasing action with no side-effects. CONSTITUTION:The objective gradually releasing indomethacin suppository is prepared by adding (a) cyclodextrin, (b) ethylcellulose, (c) glycerol fatty acid ester and (d) an oily base such as triglyceride of higher fatty acid to indomethacin, which shows outstanding anti-inflammatory and analgesic actions among nonsteroidal anti-inflammatory agents at weight ratios to the indomethacin of 1/(8-5), preferably 1/(2-4) in (a), 1/(8-10), preferably 1/(4-5) in (b), and 1/(8-5), preferably 1/(2-3) in (c). Thus, the resultant suppository causes no side-effects such as dizzy feeling, keeps its medicinal effect for hours and shows high stability on storage.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to sustained release indomethacin semi-release. More specifically, the present invention relates to sustained-release indomethacin, which does not cause side effects, maintains its efficacy for a long time, and is stable during storage.

Indomethacin is the best anti-inflammatory drug among the currently used non-steroidal anti-inflammatory drugs! ill! It has an effect. However, there is experience that indomethacin causes gastrointestinal disturbances as a therapeutically unfavorable side effect.

In order to eliminate this side effect, sustained-release oral drugs have been developed in recent years, but these oral drugs do not sufficiently solve the problem of indomethacin directly irritating the gastrointestinal tract.

One way to resolve this problem of gastrointestinal disorders is to use indomethacin in the form of suppositories, but since suppositories are administered after defecation, they can be administered as frequently as oral medications. , 7, the drug is released gradually and the medicinal effect lasts for a long time (i.e., it must be sustained release). However, in the currently available indomethacin suppositories, the release of the drug (indomethacin) from the base is too fast, resulting in a rapid increase in the concentration of indomethacin in the blood and a very short duration of drug efficacy. There's a problem.

Moreover, indomethacin alllF in the blood suddenly! j
There is a serious problem that when L increases, side effects such as light-headedness often occur. Furthermore, since commercially available indomethacin suppositories use a water-soluble base, they are irritating because they absorb mucus in the intestinal tract when dissolved, and some patients often have the urge to defecate, which is not desirable from a therapeutic perspective.

The present inventors have conducted extensive research to resolve the above problem, and have found that by blending indomethacin with cyclodextrin, ethyl cellulose, glycerin fatty acid ester, and an oil-based base and molding it, the release of the drug is stabilized. The inventors have discovered that an excellent sustained-release indomethacin half-release that lasts for a long time and does not cause side effects such as a light-headed feeling can be obtained, and the present invention has been completed.

In the present invention, the meaning of the combination of the above components is as follows.

First, the reason for replacing the water-soluble base with an oil-based base in the present invention is to reduce irritation to the intestinal tract and to suppress release of the drug into the living body. As the oleaginous base, for example, triglycerides of higher fatty acids can be used.

However, when an oil-based base is used, indomethacin is not dissolved in the base but suspended, and absorption into the body becomes too slow. In order to solve this problem, the present inventors have conventionally tried adding various interfacial C-occupying agents in a half-open manner, but in all cases, f+ and yll I! In addition, many surfactants could not be used because they did not have any systemic adverse effects on living organisms. On the other hand, according to the present invention, by combining an oleaginous base and each component described below, it is possible to obtain an excellent sustained release half-release.

Cyclodextrin has the effect of promoting the release of indomethacin from the half-open. In other words, when an oil-based base is used, indomethacin is not dissolved in the base and exists in a suspended state as described in the previous step, and as it is, the release of the drug is hindered, so it is not fully absorbed into the body. cannot be absorbed into. On the other hand, if indomethacin is mixed with cyclodextrin in an oily base, absorption of the drug into the living body will be improved due to the surface activation effect of cyclodextrin. Note that, as described above, such good effects cannot be obtained by using other surfactants.

Furthermore, cyclodextrin allows water to easily enter when it is half-open, and together with the drug release inhibiting effect of ethyl cellulose and glycerin fatty acid ester, which will be described later, it maintains drug release and absorption into the body at an appropriate rate for a long time. It has the role of Moreover, unlike other surfactants, cyclodextrin does not have an adverse effect on the intestinal wall, so it is suitable for repeated local administration over a long period of time as a crude drug.

The cyclodextrin used may be α, β, or γ, but β-cyclodextrin is convenient because it is easily available.

Ethylcellulose suppresses the rapid release of indomethacin in the living body, especially lowering its maximum blood concentration)
It has the role of maintaining blood indomethacin concentration at an appropriate level for a long period of time. Usually viscosity 7-250c
ps is used, but for actual production the viscosity is 10 to 100.
Glycerin fatty acid esters, preferably those of cps, do not have the effect of suppressing the rapid release of indomethacin, or have the role of delaying the time for indomethacin to reach its peak in the blood * i pc +−,r in vivo. For example, if you add 6 times as much glycerin fatty acid ester to indomethacin, the time it takes for indomethacin to reach its maximum level in the blood will be delayed by about 1 hour. This means that by combining glycerin fatty acid ester with the ethyl cellulose, the blood concentration of indomethacin can be kept constant over a long period of time. Therefore, the use of these two components in this book is particularly conservative.

The above ingredients should be blended in a weight ratio of T to 5 times, preferably + to 4 times the amount of cyclodextrin to indomethacin.
twice the amount, ethyl cellulose is + to 10 times the amount, preferably +
-5 times the amount, glycerin fatty acid ester is + to 5 times the amount, preferably -+ to 6 times the amount. By changing the violet of each component within the above range H according to the membership fee, the blood concentration pattern of indomethacin when administered to a living body can be adjusted as appropriate.

The halved product of the present invention is produced by thoroughly mixing the ingredients blended as described above, and pouring the mixture into a halved mold using the usual half-opening manufacturing method, or by filling it into gelatin capsules.

The indomethacin suppository of the present invention obtained in this manner consists of cyclodextrin, which acts to promote the release of indomethacin, ethylcellulose, which suppresses excessive release of indomethacin and maintains its blood concentration at a constant value, and subtly controls the release of indomethacin. It is a carefully formulated combination of three regulating glycerin fatty acid ester components, and is a sustained release half-release that releases indomethacin well from the beginning of the moth and lasts for a long time. Therefore, the half of the present invention does not have the risk of side effects caused by a sudden increase in blood indomethacin concentration, can reduce the number of administrations, exhibits anti-inflammatory and analgesic effects immediately after administration, and has a constant effect over a long period of time. 5. By adding cyclodextrin, the halved product of the present invention has a great advantage of being long-lasting. Unlike the halved product using a general oil-based base, the crystalline form of the base material changes depending on the storage temperature. Even if the change was made, the release rate of the drug did not change, and according to an accelerated test, it was found that the change in the book quality of the halved books was also prevented.

Next, we will show examples of the present invention and test examples in which the changes in the blood concentration of idomethacin were investigated when half of these Daijichi were administered to domestic rabbits.

Example t Indomethacin 2! i0F, high-grade fat dispersion triglyceride [Witep sol: Dynamit INobe
597, 5 F, glycerin fatty acid ester [Nikkol/l/ (Nikkol) -MGS]
: Manufactured by Jow Chemical Co.] 25, Ql,
Z5J' and β-cyclodextrin [Celdex -N: J3hon Shokuhin Kogyo Co., Ltd.
) 1 ouo/(z) were weighed, stirred and mixed in a dissolution tank on a water bath at 80° C., and filled into a half mold and solidified to form a half containing indomethacin 5αos!P.

Example 2 Indomethacin 25.0/, Lytep Sol 59zO1
1 Nitsukor-1VQs5α0/, Etcel 5. ．． 01
Then, halves were molded in the same manner as in Example 1 using Seldex-N75.01.

Example 5 Indomethacin 25. Op, Leitep Sol 592
511 Nikkor-MGS7al, Etself, 5! and 7 Ludex-N5 [LOJ' were used to mold the halves in the same manner as in Example 1.

Test Example Using 10 healthy domestic rabbits weighing between 2-5 and 50, blood indomethacin levels were measured when half of the doses of Examples 1 to 5 were administered. The rabbits were previously fasted for 42 hours but were given water ad libitum. The rabbit was fixed in the dorsal position, and a blood collection cannula was inserted into the large depressive vein. A half-split was inserted into the anus of this domestic rabbit, and the anus was sandwiched with a clip to prevent leakage of the half-opened component. Blood was administered “2” after half-open administration, 1.1.5.2.
4. At 6 and 8 hours, blood was collected through each 3d Caniere and centrifuged into 7 tubes (H, B, 1 lu-cker).
) Indomethacin in plasma was quantified according to the method of

The results are shown in the figure. In the figure, the dotted line, the dotted line, and the dashed-dotted line represent the time course of the blood indomethacin level when half of Example 1, Example 2, and Example 5 were administered. The line represents the change over time in blood indomethacin #ffl when a commercially available half dose containing 50 doses of indomethacin using a water-soluble base was administered as a comparative test. Note that the width of each point on the graph represents the standard deviation.

As is clear from the figure, all of the halves of the present invention are better at starting the transfer of indomethacin into the blood than the commercially available halves, and have a sustained effect due to sustained release.

[Brief explanation of the drawing]

The figure is a graph showing the time course of blood indomethacin concentration due to half-open administration. (1 other person)

Claims (2)

[Claims] (1) A sustained-release indomethacin half-open product prepared by blending indomethacin with cyclodextrin, ethyl cellulose, glycerin fatty acid ester, and an oil base. (2) The suppository according to claim 1, wherein the base is a higher fatty acid triglyceride.