JPS6067412A - Composition for rectal administration - Google Patents

Abstract

PURPOSE:A composition for rectal administration that contains combination of 8-12C fatty acid and/or its salt with a specific alkali metal salt, basic aminoacid, glucosamine and/or a specific organic amine, thus showing improved absorption of the medicament from rectum. CONSTITUTION:The objective composition contains (A) at least one selected from 8-12C fatty acids and their salts, (B) at least one selected from alkali metal salts of inorganic acids, alkali metal salts of di- or more carboxylic acids, basic aminoacids, glucosamines, and organic amines of the formula (R1-R3 are alkyl which may be substituted) and (C) a preparation base for rectal administration. The resultant composition increases the rectal absorption of the medicaments which have been conventionally used for rectal administration and enables the medicaments to be applied which could not have been used for rectal administration, because of their poor absorption.

Description

[Detailed description of the invention] The present invention relates to compositions for rectal administration.

More specifically, the present invention relates to a composition for rectal administration for improving rectal absorption of drugs.

The applicant of the present application found that the rectal absorption of a drug is significantly improved if the drug is administered rectally together with a fatty acid having 8 to 14 carbon atoms or a salt thereof (Japanese Patent Laid-Open No. 55-1492
09), and as the research progressed further, the number of carbon atoms was 8 to 1.
2 fatty acid salt, an alkali metal salt of an inorganic acid, an alkali metal salt of a carponic acid having two or more carboxyl groups, a basic amino acid, a sugar amine, a general formula (wherein R1, R2 and R3 are each as defined above) The present inventors have found that the rectal absorption of a drug can be further improved by rectally administering the drug together with at least one organic amine selected from the following organic amines (same meaning), and have completed the present invention.

That is, the present invention provides at least one type selected from fatty acids having 8 to 12 carbon atoms and salts thereof (component A), an alkali metal salt of an inorganic acid, an alkali metal salt of a carboxylic acid having two or more carboxyl groups, and a base. amino acids, sugar amines,
The present invention relates to a composition for rectal administration, characterized in that it contains at least one type selected from organic amines represented by the general formula (1,) (component B) and a base for a preparation for rectal administration (component C).

The fatty acid having 8 to 12 carbon atoms used in the present invention may be naturally obtained or synthetically obtained, but naturally obtained fatty acids are preferably used. Both chain-like and branched forms are mentioned, and straight-chain forms are preferably used.

The most preferred such fatty acid is capric acid.

The non-toxic salt of a fatty acid having 8 to 12 carbon atoms as used in the present invention may be any pharmacologically acceptable salt.
Examples of such salts include alkali metal salts (eg, sodium salts and potassium salts), organic base salts (eg, basic amino acid salts such as arginine salts and lysine salts), and the like.

Specifically, the fatty acids and their non-toxic salts include, for example, caprylic acid, its sodium salt, potassium salt, lysine salt, arginine salt; pelargonic acid, its sodium salt, potassium salt, lysine salt, arginine salt; capric acid; , its sodium salt, potassium salt, lysine salt, and arginine salt; undecylic acid, its arginine salt; lauric acid, its sodium salt, potassium salt, lysine salt, and arginine salt. Among these, the above-mentioned alkali metal salts (especially sodium salts) of capric acid;
; Alkali metal salts (especially sodium salts) of lauric acid are preferred.

These fatty acids having 8 to 12 carbon atoms and their non-toxic salts may be used alone or in combination of two or more.

The alkali metal salts of inorganic acids used in the present invention include:
For example, alkali metal salts of carbonic acid (e.g., sodium carbonate)
, alkali metal salts of hydrogen carbonate (eg, sodium hydrogen carbonate), alkali metal salts of phosphoric acid (eg, trisodium phosphate, disodium phosphate), and the like. In addition, examples of alkali metal salts of carboxylic acids having two or more carboxyl groups include oxyacids such as alkali metal salts of citric acid (e.g., trisodium citrate), alkali metal salts of tartaric acid (e.g., disodium tartrate), Alkali metal salts of succinic acid (eg, disodium succinate, etc.).

Examples of basic amino acids include lysine and arginine.

Examples of sugar amines include glucosamine.

Regarding the organic amine (1), the alkyl group in the optionally substituted alkyl group represented by R1, R2 and R3 is preferably one having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl. Illustrated as. Furthermore, the substituent is preferably a hydroxyl group, and the substituted alkyl group is exemplified by a hydroxyethyl group.

Specific examples of the organic amine (1) include triethylamine and 1-liethanolamine.

The composition for rectal administration according to the present invention is obtained by uniformly dispersing or dissolving component A and component B in a base conventionally used as a base for preparations for rectal administration.

Examples of bases for rectal administration include those known per se, such as oil bases and water-soluble bases.
For example, cocoa butter, 1. Caustic oil, corn oil,
Gly7rin esters of fatty acids [for example, vegetable oils and fats such as Uitepsol (manufactured by Dynamite Nobel Co., Ltd.), SB-base (manufactured by Kanegafuchi Chemical Co., Ltd.), O, D, O (manufactured by Nisshin Oil Co., Ltd.), petrolatum, paraffin Mineral oils such as Examples of water-soluble bases include polyethylene glycol, propylene glycol, and glycerin.

The composition of the present invention further includes a nonionic surfactant,
It is preferable to blend at least one selected from carboxymethylcellulose salts, alginates, polyacrylates, and carboxyvinyl polymers.

As the nonionic surfactant, one having an HLB value of 5 to 2o is usually used. For example, polyoxyethylene alkyl ethers (e.g., N1-KKOL BL-
21'), polyoxyethylene sorbitan fatty acid ester (for example, NrKKOL To-L□M), polyethylene glycol fatty acid ester (for example, NI
KKOL MYS-40), glycerin fatty acid ester (e.g. NIKKO+, -MGK), sorbitan fatty acid ester (e.g. NIKKOL 5L-10)
), polyoxyethylene sorbitan fatty acid ester (
For example, NIKKOL GO-440), polyoxyethylene castor oil or castor derivatives (for example, N[K
KOL IIGO-60). In addition, N
All IKKOL products are manufactured by Nikko Chemicals.

As carboxymethylcellulose salts, alginates and polyacrylates, their respective alkali metal salts, especially sodium salts, are preferred.

Examples of carboxyvinyl polymers include Hibis Wako-130, Hibis Wako-104, and Hibis Wako-104.
105 (both manufactured by Wako Pure Chemical Industries, Ltd.) and the like are exemplified as preferred.

The composition of the present invention may further contain known antioxidants, fillers, etc.

If the composition of the present invention is administered rectally together with a drug, it will not only further enhance the rectal absorption of drugs that have conventionally been administered rectally, but also enable the rectal administration of drugs that have not traditionally been administered rectally because rectal absorption is difficult. It is what makes it possible.

Therefore, it is preferable to incorporate a drug into the composition of the present invention to form a preparation for rectal administration. Examples of such preparations include so-called rectal suppositories, and soft capsules filled with suspensions or ointments dispersed in a liquid oily base.

For example, for rectal suppositories, ingredients A and B are added to a conventional base and dispersed uniformly, then the drug is added and dispersed uniformly, and the mixture is filled into a suppository container and molded. Prepared by. The order of addition is not necessarily limited to the order described above.

The drug may be any drug that exhibits pharmacological activity when absorbed into the blood, and preferably has a molecular weight of 12,000 or less, particularly 6,000 or less. Specific examples of drugs include, for example, antibacterial agents having a β-lactam ring (e.g., β-lactam antibiotics such as penicillins and cephalosporins, clapranic acid, chenamycin, etc.) Phosphorus is a concept that includes those in which the sulfur atom in the penum ring and cephem ring is replaced with an oxygen atom.), aminoglycoside antibiotics, polysaccharide drugs, pepquid drugs, and nucleic acid drugs. Examples include drugs.

Examples of penicillins include ampicillin, cyclacillin, cloxacillin, benzylpenicillin, carbenicillin, piperagiline, mesolocillin, pirpenicillin, and ticarcillin.

Examples of cephalosporins include cephalothin,
Cefoxitin, cefazolin, cephaloridine, cefacedryl, cefothiam, ceforanide, cephanone,
Cefaclor, cefadroxil 1. Cefatridine, cefrazine, cephaloglyzine, ceftriaquinone,
Examples include cefotechn, latamoxef, cefpyramite, cefbuperazone, cefmetuxime, cefmetuxime, cefodazidine, and cefmetuxime. Examples of aminoglycosides include aminoglycoside antibiotics such as streptomycin, kanamycin, fradiomycin, paromomycin, bekanamycin, ribostamycin, gentamicin, tobramycin, dihekacin, sisomicin, micronomycin, netilmicin, amikacin, and fortimidine. etc.

Examples of pepquid drugs include insulin, angiotensin, ACTH, TRH and their analogs,
Enkephalin, LH-RHL peptide antibiotic (
Examples include polymyxin B, colistin, gramicidin, bacitracin, etc.). Examples of nucleic acid drugs include citicoline.

The amount of component A and component B blended in the composition of the present invention is an amount sufficient to promote rectal absorption of the drug to be incorporated later, although it varies depending on the type of base, the type of drug intended to promote absorption, etc. , 0405 to 20% by weight, preferably 0.1 to 15% by weight as the total amount of component A and component B.
, preferably 0.2 to 10% by weight.

The mixing ratio of component A and component B is usually 1 to 300 parts by weight, preferably 5 parts by weight of component B to 1.00 parts by weight of component A.
~200 parts by weight.

When a drug is added to the composition of the present invention, the amount of the drug to be added may be sufficient as long as it has a medicinal effect.The amount varies depending on the type of drug, the subject to be administered, the symptoms, etc., and can be determined in each case by a person skilled in the art. Bye. For example, in the case of antibiotics, an amount corresponding to a one-time dose of 10 to 500 μl may be added.

Example 1 Witepsol H-5- (manufactured by Dynamite Nobel)
224g and 1.1g of sodium carbonate at about 60-70g
After melting at .degree. C., 0.84 g of sodium caprate was added at a temperature below about 50.degree. C. and uniformly dispersed to obtain a composition.

3.1'5 g of dibekacin sulfate was added to the composition thus obtained.
and disperse it evenly. 1.25 g of this was filled into a suppository container and molded to obtain a suppository of dibekacin sulfate.

Example 2 Recal suppositories having the compositions shown in Tables 1 and 2 were obtained in the same manner as in Example 1, and administered through the anus of dogs or rabbits that had been fasted for 24 hours. After administration, blood or urine was collected over time, and the active concentration was determined using a biological assay to measure the blood concentration or urinary excretion rate of the drug, and the results are shown in Tables 1-
Shown in 2.

The test bacteria used is Bacillus subtilis ATCC.
6633 was used.

(Margin) Table 17 Blood concentration of minoglycoside antibiotics (dogs) Table 2 Note) ☆: 100 mg titer Na: Sodium salt procedural amendment (own ship January 11, 1980), Indication: 1982 Patent Application No. 176628 2, Name of the invention: Composition for rectal administration 3, Relationship with the amended person's case Name of patent applicant: Kyoto Yakuhin Kogyo Co., Ltd. 4, Agent ■541 Address: Osaka 4-53-3 New Life Hirano-cho, Higashi-ku, Ishigashi-ku Tel: (06) 227-1156 6. Number of inventions increased by amendment (none) 7. Detailed explanation of 1 invention in the specification to be amended Column 8, Contents of amendment (1) “Rysine” on page 4, line 5 of the specification was changed to “lysine”
Correct.

(2) “-lysine” on page 4, line 6 of the same book is “lysine”
Correct.

(3) In the same book, page 5, line 4, line 10, ``base-kake'' is corrected to ``basic.''

(4) “Made from plants” on page 6, line 15 of the same book is “vegetable-based”
Correct.

(5) r224 gJ on page 12, line 4 of the same book as r2
2.4 g Correct to J.

that's all

Claims (1)

[Scope of Claims] At least one selected from fatty acids having 8 to 12 carbon atoms and their salts, alkali metal salts of inorganic acids, alkali metal salts of carboxylic acids having two or more carboxyl groups, basic amino acids, sugars amine, at least one selected from organic amines represented by the general formula (wherein R1, R2 and R3 each represent an optionally substituted alkyl group) and a base for rectal administration preparations. A composition for rectal administration, characterized in that: