JPS6067413A - Composition for rectal administration - Google Patents

Abstract

PURPOSE:A composition for rectal administration that is prepared by adding 8-12C fatty acid to medicament selected from cefatriaxone, cefotetan, AC-1370, MT-141, ceftazidime and azthreonam, thus showing improved absorption of these medicament from rectum. CONSTITUTION:The objective composition for rectal administration contains (A) at least one selected from 8-12C fatty acids and their nontoxic salts and (B) at least one beta-lactam antibiotic selected from cefatriaxone, cefotetan, AC- 1370, MT-141, ceftazidime and azthreonam. The above medicaments are not rectally absorbed as such, but component A promotes absorption from rectum into blood, resulting in causing these medicaments to be rectally absorbed.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compositions for rectal administration. For more details,
The present invention relates to a composition for rectal administration that provides good drug absorption.

Drugs that are difficult to absorb into the blood when administered orally are generally administered by injection. However, injections are not always satisfactory because they are painful, inconvenient to use, and pose a risk of muscular contractures.

Also, when antibiotics are administered orally with relatively good absorption, the blood concentration decreases in an extremely short period of time, making it necessary to increase the dose or administer the drug more frequently. The resulting unabsorbed matter sterilizes or stabilizes existing bacteria in the intestines, resulting in changes in the intestinal bacterial flora, causing unfavorable clinical problems. Furthermore, many compounds are known to be degraded by digestive enzymes in the gastrointestinal tract when administered orally.

Under these circumstances, various attempts have been made to improve the absorption of drugs into living bodies. In particular, many attempts have been made to administer the drug intrarectally. .

However, conventionally known compositions for rectal administration are
Not necessarily satisfactory because absorption is insufficient, safety is unsatisfactory, absorption promotion effect is only shown for very specific pharmacologically active substances, or rectal mucosal irritation It's not worth it. In particular, a number of β-lactam antibiotics, among others Cefot 1 noaxone, Cefotecum, AC-1370, MT
-141, ceftazidine, azuthreonam, is not absorbed rectally by itself.

In view of these circumstances, the present inventors have conducted intensive research and found that non-toxic salts of fatty acids having 8 to 2 carbon atoms are
Among the drugs with poor rectal absorption in the list, cefatriaxone, cefottam, AC-1370, MT-+ 4
1. It has been found that ceftazidine and azuthreonam exhibit particularly excellent effects of promoting absorption into the blood from the rectum, and as a result of further studies, the present invention has been completed.

That is, the present invention contains at least one drug selected from fatty acids having 8 to 12 carbon atoms or non-toxic salts thereof, and at least one drug selected from cefatriaxone, cefotetam, AC-1370, MT-141, ceftazidine, and azthreonam. This is a composition for rectal administration.

The fatty acid having 8 to 12 carbon atoms used in the present invention may be obtained naturally or synthetically, but naturally obtained fatty acids are preferably used. The fatty acids include both linear and branched fatty acids, and preferably linear ones are used.

The most preferred such fatty acid is capric acid.

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

Specifically, the fatty acids and their non-toxic salts include, for example, capric 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, alkali metal salts (especially sodium salts) of capric acid and 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 amount of the fatty acid having 8 to 12 carbon atoms and its non-toxic salt is usually 0.5 to 20% by weight, preferably 2 to 5% by weight in the total preparation.

The composition of the present invention further includes a nonionic interface, a carboxymethyl cellulose salt, an alginate, a polyacrylate, a carboxyvinyl polymer, an alkali metal salt of an inorganic acid, an alkali of a carboxylic acid having two or more carboxyl groups. At least one selected from metal salts, basic amino acids, sugar amines, and organic amines represented by the general formula (in the formula, I, I, I, and R3 each represent an optionally substituted alkyl group) It is preferable to incorporate one type of auxiliary agent.

The nonionic surfactant usually has an HL B of 5 to 20.
Those with values are used. For example, polyoxyethylene alkyl ether (e.g. N1-KKOL BL
-21), polyoxyethylene sorbitan fatty acid ester (for example, NTKKOL T'0-10M>,
Polyethylene glycol fatty acid esters (e.g. N
IKKOL MYS-40), glycerin fatty acid ester (e.g. NIKKOL-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 oil derivatives (for example, NIKKOL Go-440), polyoxyethylene castor oil or castor oil derivatives (for example, NIKKOL Go-440)
KOL jlcO-60), etc. In addition, N
All TOLs 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.

Examples of alkali metal salts of inorganic acids include alkali metal salts of carbonic acid (e.g., sodium carbonate), alkali metal salts of hydrogen carbonate (e.g., sodium hydrogen carbonate), alkali metal salts of phosphoric acid (e.g., trisodium phosphate, (distrium phosphate), etc. In addition, examples of alkali metal salts of carboxylic acids having two or more carboxyl groups include alkali metal salts of citric acid (e.g., tris-1-lium citrate), alkali metal salts of tartaric acid (e.g., distartrate), Examples include oxyacids such as thorium), alkali metal salts of succinic acid (eg, disodium succinate), and the like.

Examples of basic amino acids include lysine and arginine.

Examples of sugar amines include glucosamine.

Regarding the organic amine (T), 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 hydroxy-ethyl group.

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

The blending amount of these is about 0.5 to 20% by weight as one kind or a mixture of two or more kinds.

Among the drugs used in the present invention, AC-1370 is 1--
((6R,7R)-2-carboxy-7-[(R)-
(2-(5-carboxy-L H-imidazole-4-
Carboxamide)-2-phenyl] Acetamide]
-8-oxo5-thia-1-azabicyclo(4,2,
O) oct-2-en-3-yl]methyl-4-(2-
sulfoethyl)pyridinium hydroxide (its inner salt, monosodium salt)
1 is (6R,7S) 7 ((2S) 2-amino-2
-carboxyethylthioacetamide]-7-medoxy1-(((1-methyl-IH-tetrazol-5-yl)thio]methyl)-8-oxo5-thia-1-azabicyclo(4,2,O ) Oct-2-ene-2-carboxylene 1-(heptahydrate, sodium salt).

The drug is usually incorporated into the composition for rectal administration of the present invention in a proportion corresponding to 20 to 500 μ, preferably 60 to 250 μ per 1 g of the total preparation.

When formulating the composition of the present invention, it can be formulated into a conventional rectal suppository, or a suspension or ointment dispersed in a liquid oily base and filled into soft capsules, or a tube. Such formulations are prepared by methods known per se.

Examples of the base include oil bases, water-soluble bases, and other known bases. For example, oil bases include cassava oil, olive oil, corn oil, castor oil, cocoa butter, glycerin esters of fatty acids, etc. , vegetable oils and fats such as Uitepsol (manufactured by Dynamite Nobel Co., Ltd., SB-base (Kanegafuchi Chemical Co., Ltd.), O, D, O (manufactured by Nisshin Oil Co., Ltd.); mineral oils such as vaseline, paraffin, etc.). Examples of water-soluble bases include polyethylene glycol and glycerin.

The composition of the present invention is generally prepared by adding a fatty acid having 8 to 12 carbon atoms or a non-toxic salt thereof to a base, uniformly dispersing it, and then
Manufactured by adding drugs and uniformly dispersing them. The order of addition is not necessarily limited to the above order,
Can be selected arbitrarily.

Furthermore, antioxidants, preservatives, masking agents, excipients, etc. may be added to these.

According to the composition of the present invention, the dose of the drug is usually about 125 mg to 2 g titer per adult, and the amount of the fatty acid and its non-toxic salt is usually 1 mg to 2001' per adult.
mg will be administered.

Example 1 Witepsol H-15 (manufactured by Dynamite Nobel)
224g and 1g of sodium carbonate at about 60-70℃
After melting, dihecasin sulfate 315
Add g and disperse evenly. 125 g of this was filled into a suppository container and molded to obtain a suppository of dihecasin sulfate.

Example 2 In the same manner as in Example 1, rectal suppositories having the compositions shown in Tables 1 and 2 were administered through the anus of dogs or rabbits that had been fasted for 24,114 days. After administration, collect blood or urine over time,
Each time the active concentration was determined by a biological assay, the blood concentration or urinary excretion rate of the drug was measured, and the results are shown in Tables 1 and 2.

In addition, as a test bacterium, Bacillus subtilis ATcc
'6633 was used.

Margin Table 1 Below: Procedural amendment (self-effective 1980, 1 Swordsmith 1, 1, Indication of the case, 1982 Patent Application No. 176629 2, Name of the invention: Composition for rectal administration' 3. Person making the amendment) Related Patent applicant name Kyoto Yakuhin Kogyo Co., Ltd. 4, Agent 541 Address New Life Hirano-cho 406, 4-53-3 Hirano-cho, Higashi-ku, Osaka Telephone: (06) 227-1156 6. Increased due to amendment Number of inventions (none) 7, "Detailed explanation of the invention" column 8 of the specification to be amended, contents of the amendment/home! ・ -- 1'j"2"f (1) Meiji G11l No. 10 Ding T, line 16 (7) r
Correct 2001mgj to l-2(] On+gJ.

(2) Replace r224gj on page 10, line 19 with “22
．． 4 g-1, rllgJ is corrected to ``1.1g1.

(3) Dokichi page 11, line 1, ro 84 g”
, 84 [Corrected to J.

(4) "Same", page 11, line 3, r315 gJ to r3
．． Corrected to 15gj.

(5) r125g, I in the same book, page 11, line 4, r 1
．． Corrected to 25' g-1.

that's all

Claims (1)

[Claims] Number of carbons is 8~! at least one selected from the group consisting of fatty acids and non-toxic salts thereof;
Composition for rectal administration containing at least one drug selected from azureonam