JPS60132918A - Oral cephalosporin composition - Google Patents

Abstract

PURPOSE:The titled composition obtained by incorporating a cephalosporin compound with sucrose ester of a fatty acid. CONSTITUTION:An oral cephalosporin composition, obtained by incorporating a cephalosporin compound expressed by the formula (R is 5--6-membered heterocyclic ring containing S, etc.; R1 is 1-6C straight chain alkyl, 3-6C branched alkyl, 2-6C alkoxyalkyl, etc.; R2 is H, Cl, CH3, OCH3, etc.; R3 is H, physiologically acceptable salt or protecting group of the carboxyl group) with sucrose ester of a fatty acid at 0.01-50wt. ratio between the cephalosporin compound and the sucrose ester of the fatty acid, and having improved oral absorbability. The above-mentioned composition can be administered by dissolving or suspending a cephalosporin based antibiotic substance and the sucrose ester of the fatty acid in water or phosphoric acid buffer solution. Furthermore, the dosage form may be granule, capsule or tablet, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an oral cephalosporin composition, and more specifically, an oral cephalosporin composition comprising a cephalosporin compound represented by the following general formula (I) and a sucrose fatty acid ester. The present invention relates to cephalosporin compositions.

General formula (I) [R is a di- to 6-membered heterocyclic group containing at least one heteroatom selected from S, N and 0,
or represents a heterocyclic group having an amino group as a substituent which may be protected by a heterocyclic group, R8 is a C1 to C6 straight chain alkyl group, a C3 to C6 branched alkyl group, a C2 to C6 alkoxyalkyl group, cycloalkyl group of C1 to C6, cycloalkenyl group of CS to C, aromatic group, or 3 including 1 to 4 N, S, 0 are the same or different hydrogen atoms or C;

- C4 alkyl group), R3 is -H, -C1゜-C13, -OCR,, -CB, OCR -CM =
CH, , -CH,0COCH.

t fc Fi-CH,5Het (net is 5 containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur)
or 6-membered heterocycle and substituted heterocycle)
, avian represents hydrogen or a physiologically acceptable salt or a protecting group for a carboxyl group. ] Among antibiotics, cephalosporin antibiotics have excellent safety, antibacterial properties, and antibacterial spectrum, and are the most frequently used antibiotics. However, most drugs with excellent antibacterial activity and antibacterial spectrum are injectables, and oral drugs such as cephalexin and similar compounds are commercially available, but their antibacterial activity is inferior to that of injectables. ing.

Therefore, the present invention has discovered a new composition whose oral absorbability is improved by blending a sucrose fatty acid ester with a cephalosporin antibiotic that has excellent antibacterial activity and antibacterial spectrum. This new composition is a cephalosporin antibiotic with strong antibacterial activity and a broad antibacterial spectrum that has improved oral absorption.
The significance of the present invention is great.

In Mayuki general formula (I), R is specifically represented. ) Next, % R1 is C0 to C6 straight chain alkyl, C8 to C8
represents a branched alkyl group of C2 to C6, an alkoxyalkyl group of C2 to C6, a cycloalkyl group of C1 to C.', a cycloal of C3 to C. or an alkyl group of C,%C,).

Next, examples of - include commonly used 3-position substituents, such as %+11 -H, -0CH3, -CH=CH,, -CHlOCR,
etc. 75, Sara K is NHL 8h! SNH! etc. can also be used. It is not necessary to be limited to the above-mentioned 3-substituted product.

Next, R3 is hydrogen or physiologically acceptable salts such as inorganic salts such as sodium salt, potassium salt, calcium salt, and magnesium salt, and organic salts such as lysine and arginine.

Furthermore, as a protecting group for a carboxyl group, for example, -
CH,0CHs, -CH,OCOCH3, -CH,0
Examples include CO-C(CB).

The sucrose fatty acid ester used in the present invention has a fatty acid carbon number of 81ii! 11 to 5 are preferably used, and naturally-obtained ones or synthetically-obtained ones may be used, but naturally-obtained ones are preferably used. The fatty acids include linear branched fatty acids,
Preferably, linear ones are used. Preferred fatty acids include caproic acid, capric acid, myristic acid, stearic acid, valmitic acid, lauric acid, and oleic acid. Sucrose has 5 primary alcohols, and there are 1 (monoester type), 2 (diester type), and 3 (triester type) fatty acids bonded together, but monoester, diester, It may be a mixture of triesters or a mixed ester of two or three of the above fatty acids. The higher the proportion of monoester type, the better the ability to promote oral absorption. That is, the present invention has revealed that the larger the HLB, the better the ability to promote oral absorption.

The sucrose fatty acid ester can be used in a weight ratio of 0.01 to 50 times that of the cephalosporin antibiotic, preferably o, os7. It is 20 times more than that.

The composition of the present invention can be administered by dissolving or suspending a cephalosporin antibiotic and a sucrose fatty acid ester in water or a phosphate buffer solution. Sugar fatty acid esters are mixed in powder form and made into granules using a wet granulation method or dry granulation method, or the powder is filled into capsules to form capsules, or after adding appropriate excipients, it is made into capsules. It can also be made into tablets.

Example 1 Cefmetuxime sodium salt 40 rng/kl? , sucrose fatty acid ester (bound fatty acids are approximately 50% stearic acid and approximately 70% palmitic acid, and the ester composition has a composition ratio of approximately 70% modiester and 60% ditriester) in an amount equivalent to 30In9/& The mixture mixed with pure water was orally administered to Wistar rats (7 weeks old, 8). As a control, the same amount of cefmetuxime sodium salt was lightly administered to rats as an aqueous solution without addition of sucrose fatty acid ester.

Urine was collected from each rat over a period of 24 hours, and the amount of cefmetuxime in the urine was determined by bioassay and high performance liquid chromatography.

In the bioassay method, the test bacteria are E.
Measurements were carried out using HJ-JC2, and Micro Bondervac CXS was used as an analytical column in high performance liquid chromatography.

Urinary excretion of cefmetuxime [8 (%) Cefmetuxime sodium 40~90.2% Example 2 Ceftizoxime sodium salt 40η/9, sucrose fatty acid ester (bound fatty acid is about 30% stearic acid, Palmitic acid is about 70%, ester composition is 50% hamodiester, and ditriester is 50%)
An amount equivalent to 40 ~/yu was mixed with water and administered through the mouth to Wistar rats (7 weeks old, male). As a control, the same amount of ceftizoxime sodium salt was orally administered to rats as an aqueous solution without addition of sucrose fatty acid ester.

Urinary excretion rate of ceftizoxime (T) Ceftizoxime sodium 41] Ing/kpo,
Next, using 3% sucrose fatty acid ester using the following compound under exactly the same conditions as the above experimental method, the results were as follows.

Urinary recovery rate of ceftizoxime (¥) 1) Valmitic acid approx. 70, stearic acid approx. 30%, monoester 70%, citriester 30% 25% 2) Palmitic acid approx. 30%, stearic acid approx. 04, modiester approx. 20%, Approximately 80% ditriester 10% lauric acid 50%, monoester 70%, ditriester 50% 26%□
□ Palmitic acid about 70%, stearic acid about 50 t, monoester 90%, ditriester 10% 30g6□
Example 3 7β-((Z)-2-(2-amino-4-thiazolyl)
-2-(methoxyimino)acetamide)-3-[4-
Amino-5-carboxy-N-methylimidazole-2
-kf-omethyl]-3-cephem-4-carboxylic acid compound [with]) 40m97! I, amount equivalent to sucrose fatty acid ester 40 da/) W (palmitine composition approx. 70%
, stearic acid (approximately 30%, monoester 90%, ditriester 10%) mixed in a phosphate buffer solution was orally administered to Wistar rats (7 weeks old, 8) KM. As a control, the compound [with] was orally administered to rats in a phosphate buffer solution without adding sucrose fatty acid ester.

Urinary excretion rate (%) of the compound
-2-(methoxyimino)acetamide)-3-[5-
(2-amino-2-carboxy)ethyl-1,3,4-
Thiadiazol-2-yl-thiomethyl-3-cephem-4-carbon a<rb combination th■) 40my/! 9
, an amount equivalent to 20 mg/ky of sucrose fatty acid ester (
A mixture of approximately 70% valmitic acid, 30% stearin, 70% J monoester, and 30% ditriester was orally administered to Wistar rats (7 weeks old, 8). As a control, compound ■
was orally administered to rats in the form of a phosphoric acid purpurate solution without the addition of sucrose fatty acid ester.

Urinary excretion rate (l) Compound ■ 40m9/9 23% Example 5 7β-C(Z)-2-(2-amino-4-thiazolyl)
-2-(methoxyimino)acetamide]-3-[(2
-Amino-2-carboxy)ethylimidazole-2-
ilthiomethyl]-5-cephem-4-carboxylic acid (
Compound ■) 20 Da/9, sucrose fatty acid ester 2Gr
An amount equivalent to n9/9 (valmitic acid about 70%, stearic acid about 30%, monoester 90%, ditriester 10-) was mixed in a phosphate buffer solution,
Oral administration was performed to cynomolgus monkeys (approximately 4 to 8 years old). As a control, compound (1) was orally administered to cynomolgus monkeys in a phosphate buffer solution without the addition of sucrose fatty acid ester.

Urinary excretion rate (%) Compound ■ 2 o my/in 1 24% Example 6 Ceftizoxime sodium salt 10~/U, sucrose fatty acid ester (bound fatty acids are about 30 units of stearic acid, about 70 units of palmitic acid) and the ester composition is monoester 7
IJ ester having a composition ratio of 30 g/kliJ) is filled into a capsule in an amount equivalent to 10 g/kliJ, and the amount of peagle dog (approximately 10 g/kliJ) is filled into a capsule.

It was administered orally to a male (male). As a control, the same amount of ceftizoxime sodium salt 10 l/kli+ was filled into capsules as an aqueous solution without adding sucrose fatty acid ester, and orally administered to pegle dogs.

Urinary excretion rate of ceftizoxime (%) Ceftizoxime 10~/yu 0.3%Example 7 Cefotaxime sodium salt 20~/yu, sucrose fatty acid ester (bound fatty acids are about 30% stearic acid, about 70% valmitin) The ester composition is approximately 50% of modiester and approximately 50% of ditriester) and mixed with water in an amount equivalent to 101%'/& was given to Wistar rats (7 weeks old, male). Oral administration was performed. As a control, the same amount of cefotaxime sodium was orally administered to rats as an aqueous solution without addition of sucrose fatty acid ester.

Urinary excretion rate of cefmetuxime (俤) Cefotaxime sodium salt 20 l/kli + 0.2%
Example 8 Cefatriaquinone 20q fuester (bound fatty acid is about 30% stearic acid, about 70% palmitin, ester composition is monoester 9%)
(composition ratio of approximately 10% ditriester)
Add an amount equivalent to 2 to 10 Ing/ phosphate buffer (
fC4 suspended or dissolved in water (pH 7) was orally administered to Wistar rats (7 weeks old, 8).

As a control, the same amount of cefatriaxone was orally administered to rats as an aqueous phosphate buffer solution without addition of sucrose fatty acid ester.

Urinary excretion rate (%) of cefatriaxone Cefatriaquine 20~/ky 0.5% Example 9 Compound 3oη/kli+ in which the 4-position carboxyl group of cefmetuxime was ratioed to acetoxymethyl ester.

Sucrose fatty acid ester (bound fatty acid is stearin (['
+7'0%, palmitin 60%, monoester 70
H, D) IJ ester 30%) An amount equivalent to 50/'l/kg was suspended in a 5% aqueous solution of carboxymethyl cellulose, and the suspension was orally administered to peagle-sized (approximately 10 kg, male). As a control, the same amount of a compound obtained by converting the 4-position carboxyl group of cefmetuxime to acetoxymethyl ester was administered as an aqueous solution of carboxymethyl cellulose without adding sucrose fatty acid ester.

Urinary excretion rate of cefmetuxime (%)

Claims (1)

[Claims] General formula (I) [R is a 5- to 6-membered heterocyclic group containing at least one heteroatom selected from S, N, and O, or
or represents a heterocyclic group having an amine group as a substituent which may be protected by a heterocyclic group, R, is a C1-C6 straight chain alkyl group, a C8-C6 branched alkyl group, a C8-C6 alkoxyalkyl group , C1-C6 cycloalkyl group, C8-C6 cycloalkenyl C, -C4 alkyl group), R8 is -H, -C1°-CH,, -0C
H,, -CH,0CR8, -CH=CH,, -CH,0
C.O.C.R. or -CH,5Het (Het represents a 5- or 6-membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, sulfur and a substituted heterocycle), R3 is hydrogen or a physiological represents a salt acceptable to or a carboxyl group-conserving group. ] An oral cephalosporin composition comprising a cephalosporin compound represented by the following formula mixed with a sucrose fatty acid ester.