JPS621370B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a well-absorbed pharmaceutical composition for rectal administration of succibuzone. Succibuzone is 1,2-diphenyl-4-(β
-carboxypropionyloxymethyl)-4-
Butyl-3,5-pyrazolidinedione with the following formula It is expressed as This compound has anti-inflammatory and analgesic effects, and its efficacy in basic oral administration and in clinical trials is almost the same as that of phenylbutazone, but its toxicity is low, and in acute toxicity tests in rats, it has approximately the same efficacy as phenylbutazone.
1/5, and gastrointestinal disorders are about 1/10. Also, in clinical trials, it has been shown to be a highly useful drug with fewer side effects than phenylbutazone. Although such suxibuzone is well absorbed when administered orally, oral administration is generally not suitable for patients who have difficulty swallowing or for infants and young children. In addition, injections cannot be used at home, and there are concerns that they may cause pain, local induration, quadriceps shortening, etc. Rectal administration, on the other hand, has the advantage of being relatively simple to use. Therefore, the present inventor dispersed succibuzone in an oily base based on the generally known manufacturing method for suppositories for rectal administration and attempted rectal administration, but the results showed that absorption was poorer with this method than with oral administration. It has been found. Therefore, the present inventor conducted various studies on methods for achieving good absorption in the body and maintaining a high blood concentration when administered rectally, and eventually arrived at the present invention. That is, the present invention comprises blending succibuzone or a pharmacologically acceptable salt thereof with starch, cellulose and at least one of their derivatives and an oily base, and further blending a nonionic surfactant with this. The present invention relates to a pharmaceutical composition for rectal administration. When administered rectally, the composition of the present invention has the remarkable effect of rapid and increased absorption. The oily base used in the present invention may be one that is used in the production of ordinary ointments, suppositories, etc., and does not itself exhibit medicinal efficacy, such as rattan oil, olive oil, coconut oil, soybean oil, Oils and fats such as rapeseed oil, menjitsu oil, corn oil, sesame oil, bran oil, camellia oil, cacao oil, lard, wool fat, beef tallow, etc., modified by hydrogenation, acetylation, fractional extraction, etc., carbon Examples include esters of 6 to 30 fatty acids and glycerol (for example, Dynamite Nobel, Witepsol, Miglyol). These oily bases may be used alone or in combination of two or more.
A particularly suitable oily base in the present invention is Witepsol. The amount of these oily bases to be used is approximately 2 to 10 times the amount of succibuzone or its pharmacologically acceptable salt.
A double amount (by weight), especially about 3 to 5 times (by weight) is preferred. When the rectal suppository composition of the present invention is administered to a living body, starch, cellulose, or a derivative thereof used in the present invention weakens the bond between succibuzone and the oily base, promotes the separation of succibuzone from the base, and improves absorption. It is added to increase the concentration of succibuzone and increase absorption efficiency. Typical examples include corn starch, potato starch, crystalline cellulose, methylcellulose,
Examples include carboxymethyl cellulose and hydroxypropyl cellulose. These starches,
Cellulose or its derivatives can be used alone or in combination of two or more, and the amount used is about 10 to 50% (by weight), particularly about 20 to 30% (by weight) of the oil base.
is preferred. The nonionic surfactant used in the present invention has the effect of increasing the absorption efficiency of succibuzone when further administered, and typical examples thereof include Tween 80 manufactured by Kao Atlas Co., Ltd. and Nitsukor TO-- manufactured by Nikko Chemicals Co., Ltd. 10. Polyoxyethylene sorbitan fatty acid esters such as Emazol 1130, Emazol 3130, and Emazol 4130 manufactured by Kao Atlas, Emulgen manufactured by Kao Atlas
Polyoxyethylene alkyl ethers such as 120, Emulgen 220, and Emulgen 109P, polyoxyethylene fatty acid esters such as Milzi 45, Milzi 52, and Milzi 53 manufactured by Kao Atlas, and Emarnon 1112 and Emarnon 3115 manufactured by Kao Atlas.
, polyoxyethylene acyl esters such as Emanon 4115, etc., and these nonionic surfactants preferably have an HLB of about 10 to 20.
In particular, those having an HLB of about 12 to 15 are preferred. The amount of nonionic surfactant used is approximately 1 part of the oil base used.
~20% (by weight), particularly about 2-5% (by weight) is preferred. In the present invention, two or more arbitrarily selected nonionic surfactants may be used in combination. Examples of pharmacologically acceptable salts of succibuzone of the present invention include salts of alkali metals such as potassium and sodium, and alkaline earth metal salts such as calcium and magnesium. The pharmaceutical composition for rectal administration of the present invention may be in the form of a rectal suppository, which is solid at room temperature and melts at body temperature, or may be in the form of an ointment or enema liquid dispersed in liquid oil, for example, in a soft capsule or for rectal administration. It may also be in a dosage form to be administered using a syringe or the like. In carrying out the present invention, at least one of starch, cellulose, and their derivatives, and optionally a nonionic surfactant are added to the oily base, mixed and melted, and then succibuzone is added to the melt. or a pharmaceutically acceptable salt thereof, evenly dispersed therein. Thereafter, it can be manufactured by molding according to known manufacturing methods for suppositories and the like. Note that the particle size of succibuzone and its pharmacologically acceptable salt is preferably about 100 μm or less. The amount of succibuzone or a pharmacologically acceptable salt thereof to be incorporated into the pharmaceutical composition for rectal administration of the present invention is not particularly limited, but is usually about 50 ml in a dosage unit form such as a suppository or capsule. ~1000
mg/piece, preferably about 100 to 500 mg/piece. The daily dosage also varies depending on the symptoms, etc., and cannot be specifically limited, but it is usually about 50
~1000mg, preferably about 100-750mg. Next, examples of the present invention will be shown. Example 1 60 g of Witepsol W-35 (manufactured by Dynamite Nobel Co., Ltd., higher saturated fatty acid glyceride) was melted at about 45°, then 20 g of Avicel PH101 (manufactured by Asahi Kasei Co., Ltd., crystalline cellulose) and 20 g of succibuzone were added and stirred well. Distribute evenly. Pour into suppository molds each containing 1.6 g, being careful not to settle. Example 2 68.2 g of Witepsol W35 was melted at about 45°, and then 1.8 g of Tween 80 (manufactured by Kao Atlas Co., Ltd., polyoxyethylene sorbitan monooleate) was melted.
Add and stir. Add 10g of Avicel PH101 to this.
Add 20 g of suxibuzone and stir to uniformly disperse. While paying attention to sedimentation, the content of one piece is
Inject into a 1.6g suppository mold. Example 3 Add 2.5 g of Tween 80 to 67.5 g of Miglyol (manufactured by Dynamite Nobel, saturated fatty acid glyceride)
Add g and 10 g of corn starch and disperse, then add 20 g of succibuzone and stir well to disperse uniformly. This was filled into soft gelatin capsules to obtain soft capsule suppositories. Next, the effects of the pharmaceutical composition for rectal administration of the present invention will be shown by experimental examples. Experimental Example The rectal administration formulation composition of the present invention and a control (suxibuzone dispersion molded in an oily base) were administered rectally, and blood concentrations over time were compared. The sample was administered using a beagle dog that had been fasted for 16 hours. One hour before administration, residual feces in the rectum were removed with 300 ml of warm water, and excess water was also thoroughly removed. after that,
A molded suppository was administered and the anal region was pressed for 10 minutes to prevent leakage of the suppository. The dosage was 20 mg/Kg body weight for both suxibuzone and its sodium salt. To measure the blood concentration, blood was collected from the forelimb vein over time, and phenylbutazone, the main metabolite of succibuzone, was quantified using gas chromatography on plasma obtained by a conventional method. The results are shown in Table 1. 【table】

Claims (1)

[Scope of Claims] 1. A pharmaceutical composition for rectal administration, characterized in that succibuzone or a pharmacologically acceptable salt thereof is blended with at least one of starch, cellulose, and their derivatives, and an oily base. 2. A pharmaceutical composition for rectal administration, characterized in that succibuzone or a pharmacologically acceptable salt thereof is blended with at least one of starch, cellulose, and their derivatives, a nonionic surfactant, and an oily base.