JPS63267715A - suppositories - Google Patents

Abstract

PURPOSE:To obtain a suppository, containing an ester compound having a somewhat higher melting point than the body temperature as a base and an enzyme with esterase activity, having excellent sustained release effects and absorbability of a drug and wide selection range of an additive and suitable also as an antirheumatic agent, etc. CONSTITUTION:A suppository obtained by blending an ester compound as a base and an enzyme having esterase activity. An ester compound having a higher melting point than the body temperature may be used as the ester compound and the melting point is preferably within the range of 37.0-60.0 deg.C, especially <=50 deg.C. Sorbitol tetrafatty acid ester, fatty acid triglycerides, etc., are cited as specific examples. Enzymes derived from microorganisms of the genus Aspergillus, etc., enzymes derived from animals, such as lipase obtained from bovine pancreas, and enzymes derived from plants, such as lipase obtained from coconuts, are cited as the enzyme having esterase activity and preferably selected suitably according to characteristics of the base.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to suppositories. More specifically, the present invention relates to a suppository containing an enzyme having esterase activity and capable of controlling the release of a drug in the rectum for a long period of time.

[Conventional technology and its problems]

A suppository is a drug mixed into a base that gradually dissolves due to body temperature or secretions, and is molded from a small amount of the drug (usually within 10% by weight) and a large amount of the base.

The rectum, which is the administration site for suppositories, differs from the small intestine, which is a microorganism that is originally intended for absorption, in that it has a monotonous structure, has no villi, and lacks the secretion that dissolves the drug and makes it easier to absorb. The absorption from the rectum after administration is greatly influenced by the physical properties of the base, which is the continuous phase of the suppository.

Due to these physiological characteristics of the rectum, a major problem with suppositories has been how to absorb the drug through the mucous membrane surface via a small amount of secreted fluid.

Therefore, methods have been proposed to improve the absorption of drugs by adding various compounds (Japanese Patent Laid-Open No. 56-122
310 and 56-138112).

Incidentally, compounds having a melting point slightly lower than body temperature, such as oils and fats, waxes, hydrocarbons, fatty acid esters, etc., have conventionally been used as bases for suppositories. Therefore, the selection range of additives must also be limited.

Furthermore, the methods proposed so far have not necessarily resulted in sufficiently satisfactory absorption, and have also not been satisfactory in terms of sustainability (sustained release).

[Means for solving problems]

As a result of intensive research, the present inventors have found that by using an ester compound as a base with a melting point slightly higher than body temperature and containing an enzyme with esterase activity, it is possible to achieve sustained drug release and absorption. The present invention was completed by discovering that the strength can be significantly increased and that there is also a wide range of additives to choose from.

That is, the present invention provides a suppository characterized by having an ester compound as a base and containing an enzyme having esterase activity.

As the enzyme having esterase activity used in the present invention, any enzyme derived from microorganisms, animals, or plants can be used, and can be appropriately selected depending on the characteristics of the base material. Examples of enzymes derived from microorganisms include lipases derived from microorganisms such as Aspergillus, Rhizopus, Mucor, Bacillus, Campita, Colletotricium, and Sufflerotinia. Examples of animal-derived lipases include lipases obtained from cow pancreas and liver, and examples of plant-derived lipases include lipases obtained from coconuts. Lipase derived from Bacillus subtilis (molecular weight: 180,000) can also be used.

The ester compound used in the present invention is not particularly limited,
It is sufficient if the melting point is higher than body temperature.

If the melting point is too high, it will take a long time to start releasing the drug, so a melting point in the range of 37.0 to 60.0°C is preferable. More preferably it is 50°C or lower.

Specific examples of such ester compounds include the following (1
Examples include those shown in 1 to (3).

Tl) Ester alcohols of alcohol and fatty acids include glycerin, sorbitol, mannitol, polyethylene glycol, and ci! y$1! , glucose, fructose, galactose, higher alcohols, etc., and examples of fatty acids include straight chain, branched chain, saturated or unsaturated fatty acids having 6 to 30 carbon atoms.

(2) Natural oils and fats or transesterified products thereof Coconut oil, palm oil, transesterified products thereof, etc. are exemplified.

(3) Waxes In the present invention, the drugs contained in the suppositories are not particularly limited, and examples include chloral hydrate, which is a hypnotic sedative, sodium phenoparbital, acetaminophen, which is an antipyretic, analgesic, and antiinflammatory agent, aspirin, aminopyrine, Oxyphenbutacin, sulhyline, indomethacin, diclofenac nalium, butylscopolamine bromide which is an autonomic nerve blocker, diprophylline which is an antitussive expectorant, bisacodyl which is a laxative enema, betamethacin which is a hormonal agent,
Examples include chemeprost, urogenital agents econazole nitrate and miconazole nitrate, anti-malignant tumor agents tegafur, fluorouracil, and salazosulfapyridine, as well as erythromycin and thorium alginate.

In carrying out the present invention, liquid paraffin, microcrystal wax, vaseline, or fatty acids such as behenic acid and stearic acid can be added to the base as necessary.
For sustained release purposes, cyclodextrin, lecithin, sodium alginate, sodium carboxymethylcellulose, sodium polyacrylate, gum arabic, guar gum, etc. can be added. Furthermore, highly safe polyoxyethylene sorbitan fatty acid ester, polyionide diethylene sorbitol fatty acid ester, etc. can be used.

[For production]

The reason why the suppositories of the present invention have sustained release properties is that enzymes act in the rectum in the presence of intestinal fluid to decompose the base ester compound.
This is because the drug elutes, and although it is not necessarily clear why the absorption is high, it is thought to be due to the action of fatty acids and alcohol produced by decomposition of the ester compound.

〔Effect of the invention〕

The most important feature of the suppositories provided by the present invention is that by containing an enzyme having esterase activity, it is possible to use an ester compound with a melting point higher than body temperature as a base for the suppositories. For this reason, it has become possible to sustainably release crude drug ingredients from crude drug formulations, and it has become possible to use crude drugs for antibiotics and rheumatism drugs as well.

〔Example〕

EXAMPLES Hereinafter, the present invention will be explained in detail with reference to Examples, but the present invention is not limited thereto.

In addition, in the Examples and Comparative Examples, the crude drug preparations were prepared by the method shown below.

Preparation of crude drug preparations All crude drugs were prepared by the melting method. That is, the crude drug base was heated and melted at 45 to 47°C, the drug and enzyme were added, and after thorough stirring, the mixture was poured into a suppository molder and molded. The weight of one of these suppositories is 1 g.

1- Indomethacin 50mg as crude drug substance, fatty acid triglyceride 900mg as agent A (melting point 42°C, fat MMi composition (stearic acid 35%, valmitic acid 20%)
, myristic acid 11%, lauric acid 34%), Colletotrichiem lagenarium (Colle
A crude drug preparation was prepared using 50 mg of lipase powder derived from Totrichum lagenariu+++.

Implementation ■1 Indomethacin 50a+g as the crude drug substance, sorbitol tetra fatty acid ester 900mg (melting point 4) as the base
0℃, fatty acid composition (behenic acid 10%, stearic acid 15%)
%, valmitic acid 15%, myristic acid 15%, lauric acid 45%), Bacillus subtilis (B
A crude drug preparation was prepared using 50 mg of lipase powder derived from A. acillus 5ubtilis.

Propranolol hydrochloride IOImg as the crude drug substance, fatty acid diglyceride 920s+g as the base (melting point 42
°C, fatty acid composition (behenic acid 19%, stearic acid 15%
, valmitic acid 15%, myristic acid 11%, lauric acid 40%), Candida cylindriacchie (
A crude drug preparation was prepared using 70 mg of lipase powder derived from Candida cylindracea.

MJIL A crude drug formulation was prepared using 50+sg of indomethacin as the crude drug substance and 950 mg of fatty acid triglyceride (the same as that used in Example 1) as the G agent.

Charcoal 1 50 mg of indomethacin as the crude drug substance, 95 g of fatty acid diglyceride as the base (melting point 36.5°C, 10% stearic acid, 12% valmitic acid, 1 ml of myristic acid)
5%, lauric acid 63%) to prepare a crude drug preparation.

le comparison yu 10 mg of propranolol hydrochloride as a crude drug substance.

Monoesterified product of lauryl alcohol and fatty acid as a base (melting point 36.9℃, fatty acid composition (valmitic acid 22
%, myristic acid 16%, and lauric acid 62%) to prepare a crude drug preparation.

For the crude drug preparations obtained in Examples 1 to 3 and Comparative Examples 1 to 3, drug release tests from the crude drug preparations and rectal absorption tests in rabbits were conducted by the methods shown below.

Table 1 shows the results of drug release tests from crude drug preparations, and Table 2 shows the results of rectal absorption tests in rabbits.

Test method for drug release from crude drug preparations> The test was carried out using a release test device manufactured by Muranishi (Yakkyoku, 18.69 (1967)).

Note that the drug was quantified using a spectrophotometer.

<Rectal absorption test in rabbits> White male domestic rabbits fasted for 48 hours (body weight 2.5-3.5
kg) A cross-over method was used with 12 birds in one group.

After administering the crude drug preparation, the anus was placed with a plastic clip to prevent leakage of the drug.

Blood was measured at 0.5.1°2, 4 immediately before and after administration of herbal medicine preparations.
．． 6.8. Collected from the ear vein at 12 hours and immediately
The serum was centrifuged at 0 rpm for 10 minutes and used as a sample for drug quantification. The numerical value is the active ingredient content in serum l-p
It was expressed as 9.

- 1: Herbal medicine = drug from drug I U test results in the case of propranolol hydrochloride> 2: In rabbits - B eradication 'As a result, by using a high melting point base together with an enzyme with esterase activity. It became clear that the drug had a sustained release effect.

Claims (1)

[Scope of Claims] 1. A suppository characterized by being based on an ester compound and containing an enzyme having esterase activity. 2. The suppository according to claim 1, wherein the ester compound has a melting point higher than body temperature.