JPS5840526B2 - Composition for rectal administration of bleomycin - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to pleomycin (hereinafter abbreviated as compound (I))
Dispersed in a mixture of a nonionic surfactant and an oily or water-soluble base.

Compound (I) is a water-soluble basic peptide antitumor antibiotic, but since it is poorly absorbed when administered orally, it is usually administered as an injection before use.

The present inventors have conducted various studies in order to obtain a dosage form other than injections that can achieve high blood concentrations. It has been found that when the dispersed composition is administered as a rectal administration agent, it is rapidly absorbed into the body from the rectum and gives a high blood concentration.

Nonionic surfactants used in the composition of the present invention include, for example, polyoxyethylene sorbitan fatty acid esters (e.g., Pharmacopoeia name: Polysorbate 80; Tween 80, manufactured by Kao Atlas Co., Ltd., Nitsukol To-2, manufactured by Nikko Chemicals Co., Ltd.).
10■), polyoxyethylene fatty acid esters (e.g., Pharmacopoeia name: Polyoxyl Stearate 40; Nikko Chemicals Co., Ltd., Nikkor MMS-400), polyoxyethylene higher alcohol ethers (e.g., Pharmacopoeia name: Uromacrogol; Nikko Chemicals Co., Ltd., Nitsukol) BL-9EX■)
etc., and those with HLBIO to 18 are preferred.

The amount of this nonionic surfactant to be used is 0.01 to 0.5 times (by weight) the amount of the oil-based or water-soluble base used, and particularly preferably 0.01 to 0.1 times (by weight). .

In addition, the oil base used in the composition of the present invention includes ordinary ointments,
Bases used in the production of cross-agents, etc. Examples of natural bases include peanut oil, coconut oil, olive oil, soybean oil, rapeseed oil,
Oils and fats such as menjitsu oil, sesame oil, corn oil, bran oil, camellia oil, cacao fat, lard, wool fat, beef tallow, and those modified by hydrogenation, acetylation, fractional extraction, etc., and synthetic ones Esters of fatty acids having 6 to 20 carbon atoms and glycerol [for example, Dynamite Nobel (Dy
0DO-1 (manufactured by Nisshin Oil Co., Ltd.); esters of fatty acids with 6 to 30 carbon atoms and alcohols with 2 to 8 carbon atoms; (EX)), etc.

These fats and oils may be used alone or in combination of two or more.

Particularly suitable oily bases include corn oil, olive oil, Huitepsol (2), and the like.

In addition, the water-soluble base used is polyethylene glycol 300, 400.1000.1500°4000 and 6
000 (the above are the pharmacopeia names), methylcellulose (for example, Metrose S Mo manufactured by Shin-Etsu Chemical Co., Ltd.), sodium carboxymethyl cellulose (for example, Celogen PR@ manufactured by Daiichi Kogyo Kagaku Co., Ltd.), glycerogelatin, etc., and these water-soluble groups These agents may be used alone or in combination of two or more.

A particularly suitable water-soluble base is a mixture of polyethylene glycols 1000 and 4000.

The amount of this oil-based or water-soluble base used is determined by the amount of the compound (I
) 25 to 600 times the amount (weight), particularly preferably 50 to 600 times
It is 300 times the amount (weight).

Additionally, stabilizers, preservatives (eg, antioxidants, ethylenediaminetetraacetic acid, etc.), and the like may be added to these.

When adjusting the composition of the present invention into a preparation, the dosage form may be an anal carcass type that is solid at room temperature and melts at body temperature, or an ointment or enema liquid dispersed in liquid oil. For example, the drug may be in the form of a soft capsule for rectal administration, a syringe for rectal administration, or the like.

To produce the composition of the present invention, the above-mentioned oil base or water-soluble base and surfactant are mixed and melted, compound (I) is evenly dispersed in the melt, and then a well-known ointment or cross-linking agent is added. It can be prepared by molding according to the manufacturing method.

Next, further explanation will be given with reference to experimental examples showing the absorbability of compound (I) in the composition for rectal administration of the present invention and examples showing the manufacturing method of the composition for rectal administration of the present invention.

Experimental Examples Compound (I) dispersed in an oily base containing a nonionic surfactant (composition of the present invention), Compound (I) dispersed in a base not containing a nonionic surfactant things (
Control) was administered to domestic rabbits, and the blood concentration and urinary excretion rate were compared.

The method of rectal administration is to rabbits of body weight 3 to 9 who have fasted for 24 hours.
Approximately 3 cI from the anus using a small syringe into the rectum of a male rabbit.
It was administered deep into the rL.

To measure the blood concentration, blood was collected from the ear vein over time, and the plasma obtained by a conventional method was quantified using a biological assay.

At the same time, urine from 0 to 6 hours was collected by inserting a cannula and quantified using the above method, and the urinary excretion rate of Compound (I) was compared. The results are shown in Table 2.

As shown in Table 1, when the mixture of base and surfactant according to the present invention is used, the blood concentration is extremely high compared to when only the base is used.

Example 1 Corn oil97. Polyoxyethylene lauryl ether 3.0 in OP? Add and stir to dissolve.

0.7 P of compound (I) powder is added to this and dispersed to prepare a composition for rectal administration.

This is used by dispensing 2.2 tons each into a syringe for rectal administration.

Example 2 After melting Uitepsol W-350 (higher saturated fatty acid triglyceride) 95.3P at 45°C, polyoxyethylene stearate 4.7? Add and stir to dissolve.

1.1 liters of Compound (I) powder is added to this, and the mixture is stirred and dispersed to prepare a composition for rectal administration.

This is poured into a 1.41 suppository mold while being careful not to settle during heating, and after solidification, it is separated from the mold and used as a single agent.

Example 3 After melt-mixing polyethylene glycol (1000) 100S' and polyethylene glycol (4000) 12.42 at 50°C, polyoxyethylene stearate)5.
Add 5P and stir to dissolve.

1.3 i of Compound (I) powder is added to this, and the mixture is stirred and dispersed to prepare a composition for rectal administration.

This is poured into a 1.4z suppository mold while being careful not to settle when heated, separated from the solidified mold, and used as a single agent.

Example 4 Corn oil97. Add 3.01 liters of polyoxyethylene lauryl ether to l' and stir to dissolve.

0.7 P of compound (I) powder is added to this and dispersed to prepare a composition for rectal administration.

This is used as a capsule by filling 2.2 tons into soft capsules for rectal administration.

Example 5 Olive oil97. Of polyoxyethylene sorbitan monoole) 3. Add Or and stir to dissolve.

To this, 0.71 g of compound (I) powder is added and dispersed to prepare a composition for rectal administration.

This is used by dispensing 2.2i into a syringe for rectal administration.

Claims (1)

[Claims] 1. A composition for rectal administration, characterized in that pleomycin is dispersed in a mixture of a nonionic surfactant and an oily or water-soluble base.