JPS62265226A - Pharmaceutical for oral administration - Google Patents

Abstract

PURPOSE:The titled pharmaceutical containing a substance FR80482 or salt thereof and an absorption accelerator selected from free amino acids or salts thereof, bile acid or salts thereof and sucrose esters of fatty acids. CONSTITUTION:A pharmaceutical, obtained by containing a compound expressed by the formula (substance FR80482) or salt thereof, e.g. salt with an alkaline earth metal salt such as Na salt, etc., salt with an organic base such as triethylamine salt, etc., and one or two or more absorption accelerators selected from free amino acids or salts thereof, e.g. glycine, 7-aminobutyric acid, l-lysine, etc., bile acid or salts thereof, e.g. sodium glycocholate, deoxycholic acid, etc., and esters of fatty acids, e.g. monosucrose ester of fatty acid, etc., in an amount of 0.01-5 times based on the weight of the drug and capable of improving the oral absorbability of a hardly absorbable antibiotic substance. The dosage form includes pharmaceuticals, e.g. tablet, capsule, aqueous solution, etc., fine granule, granule, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] This invention relates to a preparation for oral administration, and more specifically, a combination of FR80482 substance or a salt thereof, a free amino acid or a salt thereof, a bile acid or a salt thereof, and sucrose. The present invention relates to a preparation for oral administration containing one or more absorption enhancers selected from fatty acid esters, and can be used in the medical field.

[Later's technology] There are many drugs that have poor absorption when administered orally, so-called poorly absorbed drugs.
14 fatty acids (e.g., sodium caprate, etc.), leucinic acid, N-anol amino acids having a total number of carbon atoms of 9 or more, general formula-grade Alfkyne groups, and lower alkyl groups. a compound represented by the general formula HOOCR3-COOH (wherein R3 has 8 to 14 carbon atoms);
JP-A No. 57-88126) and crude drug extracts containing saponin components (JP-A No. 57-145816, JP-A-Sho 5)
8-57400) etc. have been reported.

[Problems to be solved by the invention] Difficultly absorbed drugs have poor absorption when administered orally, so they are usually administered in the form of injections, but administration by injection only causes pain to the patient. However, there is a problem of local damage at the rheogram site. In order to solve these problems, research has been actively conducted in recent years on preparations for rectal administration that contain absorption enhancers. There is a problem of rectal mucosal damage caused by accelerators. Therefore, it is desirable to improve the oral absorption of poorly absorbed drugs by subjecting them to appropriate formulation treatments, but conventional formulation treatments (for example, adding oral absorption enhancers) do not have a sufficient effect of promoting oral absorption. The problem is that you can't get it.

[Means for Solving the Problems] As a result of intensive research aimed at improving the oral absorption of certain poorly absorbed antibiotics, the inventors of the present invention found that free amino acids or their salts, bile acids or their FR salt and sucrose fatty acid ester are one of the poorly absorbed antibiotics.
The present invention was completed based on the discovery that the present invention exhibits a remarkable effect on improving the oral absorption of substance 80487 and its salts. The substance FR80482, which is the king drug of this invention, is
It is one of the cephalosporin antibiotics with excellent antibacterial activity, and is represented by the following chemical structural formula.

Salts of the FR80482 substance that can be used in this invention include salts with inorganic bases such as alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calum salts and magnesium salts, triethylamine salts, and synchrohexyl salts. Examples include salts with organic bases such as amine salts and arginine salts.

Free amino acids and salts thereof that are absorption enhancers of the present invention include monoamine monocarboxylic acids (e.g., glycine, 2-alanine, !-valine, couroinone, 2-isoleucine, 7-aminobutyric acid, ε-amine capric acid). , 2-phenylalanine, etc.), oxymonoaminocarboxylic acids (e.g., cuhomoserine, 2-tyrosine, 2-threonine, etc.), monoaminodicarboxylic acids (e.g., couaspartic acid, !-glutamic acid, etc.), diaminomonocarboxylic acids C (column Eg!-Titrulline, 2-ornithine,
2-arginine, 2-lysine, 1-glutamine, etc.), sulfur-containing amino acids (e.g. cousistine, !-methionine,
! - cystine, etc.), cyclic imino acids (e.g. - histidine, 2-proline, 2-tryptophan, etc.), and their salts (e.g., hydrochloride, etc.), among which free amino acids having 6 or less carbon atoms and Its salts are preferred, such as glycine, 7-aminobutyric acid,! -R/R and 2-histidine hydrochloride are particularly preferred.

Bile acids and their salts include cholic acid, glyc:! Cholic acid, taurocholic acid, deoxyfuric acid, urtufuric acid, dehydrocholic acid, glycoacic/cholic acid, taurodeoxycholic acid, chenoboxyfuric acid, glycochenodeoxycholic acid, glycolidefuric acid, taurodehydrocholic acid, etc. and their salts (eg, alkali metal salts such as sodium salts), and sodium glycofulate, deoxyfuric acid, and dehydrocholic acid are particularly preferred.

Sucrose fatty acid esters include sucrose fatty acid monoesters and diesters such as sucrose laurin, sucrose myristic acid, sucrose palmitic acid, sucrose stearic acid, and sucrose oleic acid, and mixtures of two or more of these [ For example, DK ester F-160 (trademark, manufactured by Dai-Kogyo Seiyaku Co., Ltd.)] can be mentioned, and highly hydrophilic sucrose fatty acid monoester is particularly preferred.

The preparation for oral administration of this invention is a crude drug, FR8048.
2 substances or their salts, and one or more absorption enhancers selected from the above-mentioned free amino acids or their salts, bile acids or their salts, and sucrose fatty acid esters, and a disintegrant commonly used in this field [e.g. ECG505 (trademark, manufactured by Tsuji Nichirin Kagaku Co., Ltd.) etc., a lubricant (e.g. magnenium stearate, etc.), an organic base (e.g. sodium hydrogen carbonate, etc.), an excipient (e.g. lactose), a binder, if necessary. (for example, hydroxypropyl cellulose, etc.) and tabletted according to a conventional method, or once made into a slug, crushed and sieved, and then tableted according to a conventional method,
Or manufactured by a method such as filling into capsules,
Alternatively, by adding the above-mentioned organic base etc., an aqueous solution,
It can be manufactured by making it into a liquid preparation such as a suspension. In addition to these preparations, fine granules, granules, etc. can also be produced by conventional methods.

- The amount of absorption enhancer in the formulation is usually adjusted to zero for status drug loading.
．． The amount is 0.01 to 5 times, preferably 0.25 to 1 times, but is not limited to this and can be determined as appropriate.

[Effects of the Invention] Representative test results are listed below to show the effects of this invention.

Acquisition and excretion test Wistar male pouch/throat (appropriate age 7, weight 220 &)
Pour the aqueous solutions or suspensions obtained in Examples 1 to B and Reference Examples 1 to 3 described later to give a concentration of FR80 per kg of throat weight.
R80482 substance was orally administered at a concentration of 20 mg, urine was collected up to 24 hours after administration, and the concentration of R80482 substance in the urine was measured using high performance liquid chromatography. FR80482 substance excretion rate in the bed (calculated using the following formula).

The test results are shown in the table below. The urinary excretion rate is shown as the mean value ± standard error of the number of test samples.

From the above test results, it was found that the formulations for oral administration containing the absorption enhancer of this invention (Examples 1 to 8) had higher FR8048 compared to the formulation without the absorption enhancer (Reference Example 1).
It can be seen that the excretion rate of the two substances in the bed is about twice as high.

:ξIt can be seen that the urinary excretion rate of the FR80482 substance is high even when compared with the conventional formulations containing absorption enhancers (Reference Examples 2 and 3).

[Example] The present invention will be explained below with reference to Examples.

X mutual! YuFR80482 substance (50mg potency) and glycine (
50 mg), 0.5% sodium hydrogen carbonate aqueous solution 2.
Add 5mQ and dissolve to make an aqueous solution.

Example 2 2.5 mQ of 0.5% sodium bicarbonate aqueous solution was added to FR80482 substance (50 mg titer) and 7-aminobutyl v (50 mg) to form an aqueous solution.

J crime example 3 FR80482 substance (50mg potency) and! - Lysine (50 mg) and 0.5% sodium bicarbonate aqueous solution 2.
51 and dissolve it to form an aqueous solution.

Example 4 FR80482 substance (50 mg potency) and! - Add and dissolve 2.5 fflQ of 0.5% sodium bicarbonate aqueous solution to histidine hydrochloride (50 mg) to obtain an aqueous solution.

2.5 mQ of a 0.5% sodium bicarbonate aqueous solution is added to the FR80482 substance (50 mg titer) and sodium glycocholate (50 mg) to form an aqueous solution.

X and Encounter I 2.5 mQ of 0.5% sodium bicarbonate aqueous solution is added to FR80482 substance (50 mg titer) and deoxyfuric acid (50 mg) to form an aqueous solution.

2.5 ml of 0.5% sodium bicarbonate aqueous solution was added to FR80482 substance (50 mg titer) and dehydrocholic acid (50 mg) to dissolve it to form an aqueous solution.

1 FR80482 substance (100 mg titer) is dissolved by adding 5 mff1 of a 0.5% aqueous sodium bicarbonate solution, and then DK Nisel F-160 (25 mg) is uniformly dispersed to form a suspension.

]■Milk and FR80482 substance (10.31g), DK ester F-160 (2.5g), sodium hydrogen carbonate (2.
5g), EaJ505 (1g) and magnesium stearate 1.1g) were mixed, tableted by a conventional method, crushed, and passed through a U. The grains produced in this way (10g
) and tablet again to obtain tablets having the following composition per tablet.

DK Ester F -16025mg Sodium hydrogen carbonate 25mg ECG505 10a+g Magnesium stearate 1mg 164, 1mg Reference example I Dissolved in FR80482 substance (50mg titer) by adding 0.5% sodium hydrogencarbonate water t″# liquid 2.5 Makoto. Make an aqueous solution.

Reference Example 2 2.5 mu of 0.1% sodium bicarbonate aqueous solution is added to FR80482 substance (20 mg titer) and 20 mg of sodium caprate to form an aqueous solution.

Reference example 3 FR80482 substance (20mg potency) and saponin 2
0mg to 01% sodium bicarbonate aqueous solution 2.5ff
Add lQ and dissolve to form an aqueous solution.

Claims (1)

[Claims] (1) Contains the FR80482 substance or its salt and one or more absorption enhancers selected from free amino acids or their salts, bile acids or their salts, and sucrose fatty acid esters. (2) The oral preparation according to claim 1, wherein the absorption enhancer is a free amino acid or a salt thereof. (3) The preparation for oral administration according to claim 2, wherein the free amino acid or its salt is glycine, γ-aminobutyric acid, l-lysine, or l-histidine hydrochloride. (4) The preparation for oral administration according to claim 1, wherein the absorption enhancer is a bile acid or a salt thereof. (5) The preparation for oral administration according to claim 4, wherein the bile acid or its salt is sodium glycocholate, deoxycholic acid, or dehydrocholic acid. (6) The preparation for oral administration according to claim 1, wherein the absorption enhancer is a sucrose fatty acid ester. (7) The preparation for oral administration according to claim 6, wherein the sucrose fatty acid ester is a sucrose fatty acid monoester.