CA1123738A

CA1123738A - Pharmaceutical composition for rectal administration of cephalosporin

Info

Publication number: CA1123738A
Application number: CA332,022A
Authority: CA
Inventors: Hiroshi Kichijima; Junko Kidani; Mariko Tanimoto; Isamu Saikawa; Harumitsu Hiroshima
Original assignee: Toyama Chemical Co Ltd
Current assignee: Toyama Chemical Co Ltd
Priority date: 1978-07-25
Filing date: 1979-07-18
Publication date: 1982-05-18
Also published as: DK310079A; AU4919179A; SE7906340L; IL57846A0; CS268651B2; IT7949844A0; PT69969A; LU81546A1; GR69652B; PH16496A; NL7905708A; BE877831A; IN151264B; DE2929840A1; NZ191053A; IL57846A; EG15790A; GB2028655A; DE2929840C2; FR2433945B1

Abstract

ABSTRACT OF THE DISCLOSURE
A pharmaceutical composition for rectal administration comprising 7-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinylcarboxamido)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-.DELTA.3-cephem-4-carboxylic acid or its pharmaceutically acceptable salt, an oily base, and a nonionic surfactant and/or an anionic surfactant and/or a salt of bile acid is well absorbed in a living body and maintained in a high concentration in blood for a long period of time.

Description

3'~3~

1 This invention relates to a pharmaceutical composition of cephalosporin for rectal administration.
The term "cephalosporin" used herein means 7_CD(_)_ ~-(4-ethyl-2,3~dioxo-1-piperazinylcarboxamido)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetra-zolyl)thiomethyl]-~3-cephem-4-carboxylic acid repre-sented by the following structural formula and a pharmaceutically acceptable salt thereof which have been developed by Saikawa et al., Saikawa being one of the present inventors (see British Patents 1,508,071 and 1,517,o~8):

The compound represented by said structural formula is hereinafter referred to as Compound A. Compound A has a broad antibacterial spectrum against gram-positive and gram-negative bacteria and particularly exhibits an effective antibacterial activity against Pseudomonas aeruginosa, Klebsiella ~neumoniae and Proteus species which have been known as causes for clinically serious infectious deseases, and are very stable against ~.23738 l 3-lactamase produced from bacteria. Thus, Compound A is a very use~ul therapeutic drug for human infectious diseases.
When Compound A is in;ected in the form of a pharmaceutically acceptable salt (as intravenous injec-tion, intramuscular injection or drip in~usion), it is well absorbed in a living body. However, injections are difficult to use at home and the pain due to injection inspires infants with fear. This is disadvantageous.
On the other hand, oral administration or rectal administration (suppository) are advantageous in that the drug can be used relatively simply without inspiring patients with fear. However, when Compound A
or its pharmaceutically acceptable salt is administered orally, it is little absorbed in a living body, and therefore, a high concentration in blood cannot be achieved. Further, the present inventors have found that when Compound A or its pharmaceutically acceptable salt ls dispersed in an oily base or a water-soluble base according to the conventionally known method for preparing a pharmaceutical preparation for rectal administration and the preparation thus obtained is administered by rectal route, the compound is little absorbed in a living body and no effect is obtained.
The present inventors, therefore, have conducted extensive research on pharmaceutical composi-tions to be administered by rectal route which can be well absorbed in a living body and can be maintained in 1 a high concen~ration in blood for a long period of time, and as a result, have found that when a uniform disper-sion of Compound A or its pharmaceutically acceptable salt in a mixture of an oily base and a nonionic surfactant and/or an anionic surfactant and/or a salt of bile acid is administered by rectal route, Compound A is well absorbed in a living body to obtain a high concen-tration in blood.
An object of this invention is to provide a pharmaceutical composition of a cephalosporin for rectal administration.
A further object of this invention is to provide a pharmaceutical composition of a cephalosporin which can be well absorbed in a living body and can be maintained in a high concentration in blood for a long period of time when administered by rectal route.
Other objects and advantages of this invention will be apparent from the following description.
According to this invention, there is provided a pharmaceutical composition of 7-[D(-)-a~(4-ethyl-2,3-dioxo-l-piperazinylcarboxamido)-p-hydroxyphenylacet-amido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-~3-cephem-4-carboxylic acid or its pharmaceutically acceptable salt which comprises 7-[D(-)-~-(4-ethyl-2,3-dioxo-l-piperazinylcarboxamido)-p-hydroxyphenylacet-amido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-~3-cephem-4-carboxylic acid or its pharmaceutically acceptable salt, an oily base, and a nonionic surfactant-~l.t~373~3 an(l,~c)r an ar~ )nic surfc:lcc?l-lt- arl(l/o:r a scl:l.t of bi.le ~Icid.
~cc(.)l~dillg to this i.l-lV(`ntiOn, WhC'II il p}larlllaC'eUti.Cally acceptab].e salt of COT11PO~Irld ~ is usecl, a parti.cularly high concentration :in l:)lood ean be obtainec'. ~s such phclrmaceuti-eally aeeept.al)lc salts of Compound A, thcre may be exemp-lifiecl salts with alka]i metal.s such as sodium, potassium and the like; salts with a]kali.ne earth metals sueh as ealeium, magnesium and the like; ammonium salts; salts with organie bases sueh as proeain, dibenzylamine, N-benzyl-~-phenethyla-mine, 1-ephenamine, arginine, -trishydroxymethylarninomethane and the like.
As the nonionie surfactant used in this invention, there may be exemplified polyoxyethylene fatty aleohol ethers of the polyethylene glyeol type (for example Emulgen 120, Emulgen 220, Emulgen 408 and Emulgen 420, trademarks of Kao Sekken, and Nikkol BC-15TX, Nikkol BC-20TX and Nikkol BO-20, trade-marks of Nikko Chemieals); polyoxyethylene alkylaryl ethers (for example, Emulgen 920, trademarks of Kao Sekken and Nik-ko Chemicals); polyoxypropylenepolyoxyethylene alkyl ethers (for example, Pluronie L62, trademark of Asahi Denka); sugar esters of fatty aeid esters type (for example, DK rster F-140, trademark of Dai-iehi Koghy Seiyaku) and the like. In gen-eral, the nonionic surfaetants of the polyethylene glycol type having an HLB of 10 to 14 are preferred to those of the polyhydric alcohol type.
As the snionie surfactant, there may be 3o ~ ~
, . .

~.Z3738 1 examplified alkyl sulfates (for example, ~merl 10 powder, trade ~a of Kao Sekken); di-alkyl sulfosuccinates (for example, Rapizole B-90, trade ~ of Nippon Oil & Fats Co., Ltd.), and as the salt of bile acid, there may be examplified sodium tauroglycolate, sodium glycolate, sodium taurocholate and the like.
In this invention, at least two of the surfactants mentioned above may be used in admixture.
The total amount of the nonionic surfactant, the anionic surfactant and the salt of bile acid used in this invention may be 1 to 20% by weight based on the weight of the oily base, and an amount of 5 to 10% by weight is particularly preferable.
As the oily base used in this invention, there may be examplified bases having themselves no pharma-ceutical activity as used in the production of conven-tional ointments, suppositories and the like, for example, fats and oils such as peanut oil, sesame oil, soybean oil, corn oil, rape seed oil, cotton seed oil, oaster oil, tubaki oil, coconut oil, olive oil, poppy seed oil, cacao butter, laurin butter, beaf tallow, squalene, wool fat and the like; those fats and oils that have been modified by chemical reaction, such as hydrogeneration or the like; mineral oils such as vaselin, paraffin, silicone oil and the like; higher fatty acid esters such as isopropyl myristate, n-butyl myristate, isopropyl linolate, cetyl ricinolate, stearyl ricinolate, diethyl sebacate, diisopropyl adipate, and the like; higher 1~1.23738 1 aliphatic alcohols such as cetyl alcohol, stearyl alcohol and the like; waxes such as bleached bees wax, sper-maceti, Japan wax and the like; higher fatty acids such as stearic acid, oleic acid, palmitic acid and the like;
and mixtures of triglycerides of naturally occurring saturated fattty acids having 12 to 18 carbon atoms in which the whole of the hydroxyl groups have been esterified and triglycerides of said fatty acids in which a part of the hydroxyl groups has been esterified.
Vegetable oils are particularly preferable.
These oily bases may be used alone or in admixture of two or more. The amount of the oily base used is 1 to 20 times the weight of Compound A or its pharmaceutically acceptable salt used, and an amount of

2 to 18 times is preferred.
In the preparation of the composition of this invention, the nonionic surfactant and/or the anionic surfactant and/or the salt of bile acid is first dis-persed in the oily base, and the necessary amount of Compound A or its pharmaceutically acceptable salt is added to the resulting dispersion and uniformly dis-persed in the latter. However, in this invention, the order of adding the base, the surfactants and the cephalosporin is not limited to the above-mentioned one.
The particle size of Compound A and its pharmaceutically acceptable salt is preferably 100 ~ or less.
In preparing a pharmaceutical preparation from the composition thus obtained, the composition may be l formed into a conventional anal suppository, or a sus-penslon or an ointment in which the surfactant and the cephalosporin are dispersed in the oily base may be put in a soft capsule, or said dispersion or ointment may be put in a tube, which is infused at the time of use.
To the above preparations may be added antioxidants such as tocopherol, BHA, NDGA and the likej synergists such as phosphoric acid, citric acid, ascorbic acid, malonic acid; antiseptics; concealing agents; excipients; and the like.
The effective administration amount of the composition of this invention may be varied depending upon Compound A or its pharmaceutically acceptable salt, and such an amount of the composition may be selected that said compound may be administered in an amount 1j5 to 3 times the effective administration amount in the case of an injection.
This invention is illustrated below with reference to Examples, which are merely by way of illustration and not by way of limitation.

Application Example A dispersion of Compound A or its sodium salt in a mixture of an oily base, and various surfactants and/or a salt of bile acid (the present invention); a dispersion of the sodium salt of Compound A in physiological saline solution as an injection (control);
a dispersion of the sodium salt of Compound A in water 1 (control); a dispersion of the sodium salt of Compound A
in an oily base (peanut oil) only (control); and a dispersion of the sodium salt of Compound A in a water-soluble base (propylene glycol) only (control) were administered rectally, orally or by injection, and changes of concentration in blood with the lapse of time were compared.
The method of administration of a sample was as follows:
In the case of rectal administration, each sample was administered through anus into the rectum of a male Wister rat (weight: about 350 g), which had been abstained from food for 15 hours, by using a small in-~ector or by inserting a Witepsol suppository obtained by pouring the sample into a mold for suppository and solidifying the same therein. After the administration, the anus was sewed up with surgical seaming thread Nos.
4 to 6.
In the case of oral administration, each sample was administered to the above rats by means of a sonde for rat.
The measurement of concentration in blood was conducted as follows: The neck of a rat was operated at a certain interval of time and a small amount of blood was sampled from the jugular vein, and the concentration of the compound therein was quantitatively determined by a conventional bioassay method. Bacillus subtilis ATCC
6633 was used as an examination bacterium and the ~.23738 1 culture medium was prepared by adding water to a mixture of 5 g of peptone, 3 g of meat extract and 15 g of agar in such an amount that the total volume became one liter, and ad~usting the pH thereof to 6.2. The volume of the seed layer was 8 ml.
In measuring a concentration as low as 2 ~g/ml or less, Micrococcus luteus ATCC 9341 was used as the examination bacterium, and the culture medium was prepared by adding water to a mixture of 10 g of peptone, 2.5 g of sodium chloride, 5 g of meat extract and 15 g of agar in such an amount that the total volume became one liter and adjusting the pH thereof to 6.5. The volume of the seed layer was 8 ml.
The serum was separated from the sampled blood by centrifugation at 3000 r.p.m. and cultivated at 37C
for a period of 16 to 20 hours by the paper disc method and then examined. A 1% phosphate buffer solution (pH: 6.0) was used as the solution for calibration curve. The results obtained are shown in Table l.

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373~3 1 As is clear from Table 1, w~len t~le sample of this invention was rectally admirlistered, a much higher concentration in blood was obtained than when the control samples were administered orally or rectally.

Production Example 1 In 85 g of corn oil was dispersed 5 g of a nonionic surfactant polyoxyethylene oleyl alcohol ether (Emulgen 408) and thereafter 10 g of 7-[D(-)-a-(4-ethyl-2,3-dioxo-1-piperazinylcarboxamido)-p-hydroxyphenyl-acetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-~3-cephem-4-carboxylic acid was added to the disper-sion, after which the resulting mixture was stirred to disperse the carboxylic acid uniformly in the disper-sion. A gelatine soft capsule was filled with the resulting dispersion in an amount of 1.25 g per capsule to prepare a soft capsule suppository.

Production Example 2 On a water bath at 38 to 45C, 80 g of a tri-glyceride of a higher fatty acid (Witepsol H-15, trade name of Dynamite Nobel) was melted, and thereto was dissolved 10 g of a nonionic surfactant polyoxyethylene oleyl alcohol ether (Nikkol BC - 20 TX), after which 10 g of 7-[D(-)-~-(4-ethyl-2,3-dioxo-1-piperazinyl-carboxamido)-p-hydroxyphenylacetamido] 3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-~3-cephem-4-carboxylic acid was added to the resulting solution. The resulting ~.23738 1 mixture was stirred to form a uniform dispersion, ~hich was then cooled to a ternperature near the freezing point and thereafter poured into a mold for rectal suppository to prepare a solid suppository.

Production Example 3 To 80 g of soybean oil was added 10 g of a nonionic surfactant polyoxyethylene nonylphenyl ether (Nikkol NP 7.5)~ and the latter was dispersed in the former, after which 10 g of sodium 7-[D(~ -(4-ethyl-2,3-dioxo-1-piperazinylcarboxamido)-p-hydroxyphenyacet-amido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-~3-cephem-4-carboxylate was added to the resulting disper-sion. The resulting mixture was then stirred to form a uniform dispersion. In the same manner as in Production Example 1, a soft capsule suppository was prepared.

Production Example 4 To 80 g of corn oil were added 10 g of a nonionic surfactant (Emulgen 408) and then 10 g of sodium 7-[D(-)-~-(4-ethyl-2,3-dioxo-1-piperazinylcarbox-amido)--p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-~3-cephem-4-carboxylate, and the resulting mixture was stirred to form a uniform dis-persion. In the same manner as in Production Example 1, a soft capsule suppository was subsequently prepared.

_ lL~ _ ~23738 1 Production Example 5 To 80 g of corn oil were added 10 g of a nonionic surfactant (Emulgen 408) and then 10 g of sodium 7~[D(~ -(4-ethyl-2,3-dioxo-1-piperazinylcarbox-amido)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-~3-cephem-4-carboxylate~ and the resulting mixture was stirred to form a uniform disper-sion. This dispersion was put in a suppository tube.

Production Example 6 To 90 g of peanut oil were added 5 g of an anionic surfactant sodium laurylsulfate (Emerl 10 powder), and then 10 g of sodium 7-[D(-)-~-(4-ethyl-2,3-dioxo-1-piperazinylcarboxamido)-p-hydroxyphenyl acetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-Q3-cephem-4-carboxylate, and the resulting mixture was stirred to ~orm a uniform dispersion, which was then put in a suppository tube.

Production Example 7 On a water bath at 38 to 45C, 70 g of a triglyceride of a higher saturated fatty acid (Witepsol H - 15) was melted, and therein was dissolved 10 g of a nonionic surfactant polyoxyethylene oleyl alcohol ether (Emulgen 408). To the resulting solution was added 20 g of sodium 7-[D(-)-~-(4-ethyl-2,3-dioxo-1-pipera-zinylcarboxamido)-p-hydroxyphenylacetamido]-3-[5-( methyl-1,2,3,4-tetrazolyl)thiomethyl]-~3-cephem-4-1~.23738 1 carboxylate, and the resulting mixture was stirred to form a uniform dispersion. In the same manner as in Production Example 2, a solid suppository was prepared.

Production Example 8 In 80 g of peanut oil were dispersed 8 g of polyoxyethylene oleyl alcohol ether (Emulgen 408) and 2 g of sodium taurocholate, after which 10 g of sodium 7-[D(-)-a-(4-ethyl-2,3-dioxo-1-piperazinylcarboxamido)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetra-zolyl)thiomethyl]-~3-cephem-4-carboxylate, and the resulting mixture was stirred to form a uniform disper-tion. A suppository tube was filled with this dispersion.

Production Example 9 On a water bath at 38 to 45C, 80 g of a triglyceride of a higher saturated fatty acid (Witepsol H-15) was melted, and therein were dissolved 7 g of a nonionic surfactant polyoxyethylene oleyl alcohol ether (Nikkol BC - 20 TX) and 3 g of sodium laury sulfate (Emerl 10 powder). To the resulting solution was added 10 g of sodium 7-[D(-)-a-(4-ethyl-2,3-dioxo-l-piperazinylcarboxamido)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-~3-cephem-

4-carboxylate, and the resulting mixture was stirred to form a uniform dispersion. In the same manner as in ~roduction ~xample 2, a solid suppository was prepared.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A pharmaceutical composition for rectal administration which comprises 7-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-l-piperazinylcarboxamido)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-.DELTA.3-cephem-4-carboxylic acid or its pharmaceutically acceptable salt, an oily base, and a nonionic surfactant and/or an anionic surfactant and/or a salt of bile acid.

2. A pharmaceutical composition for rectal administration according to Claim 1, which consists essentially of 7-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinylcarboxamido)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-.DELTA.3-cephem-4-carboxylic acid or its pharmaceutically acceptable salt, an oily base and a nonionic surfactant.

3. A pharmaceutical composition for rectal administration according to Claim 1, which consists essentially of 7-[D(-)-.alpha.-4-ethyl-2,3-dioxo-1-piperazinylcarboxamido)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-.DELTA.3-cephem-4-carboxylic acid or its pharmaceutically acceptable salt, an oily base and an anionic surfactant.

4. A pharmaceutical composition for rectal administration according to Claim 1, which consists essentially of 7-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinylcarboxamido)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-.DELTA.3-cephem-4-carboxylic acid or its pharmaceutically acceptable salt, an oily base and a salt of bile acid.

5. A pharmaceutical composition for rectal administration according to Claim 1, wherein the oily base is at least one member selected from the group consisting of fats and oils; hydro-genated fats and oils; mineral oils, higher aliphatic alcohols; higher fatty acid esters; higher fatty acids;
waxes; and triglycerids of naturally occuring saturated fatty acids having 12 to 18 carbon atoms.

6. A pharmaceutical composition for rectal administration according to any one of Claims 1 to 1 wherein the oily base is at least one vegetable oil.

7. A pharmaceutical composition for rectal administration according to Claim 5, wherein the oily base is at least one member selected from the group consisting of peanut oil, sesame oil, soybean oil, corn oil, rape seed oil, cotton seed oil, castor oil, tubaki oil, coconut oil, olive oil, poppy seed oil, cacao butter, laurin butter, beef tallow, squalene, wool fat, vaselin, paraffin, silicone oil, isopropyl myristate, n-butyl myristate, isopropyl linolate, cetyl ricinolate, stearyl ricinolate, diethyl sebacate, diisopropyl adipate, cetyl alcohol, stearyl alcohol, bleached bees wax, spermaceti, Japan wax, stearic acid, oleic acid, palmitic acid and a mixture of a triglyceride of a naturally occurring higher saturated fatty acid having 12 to 18 carbon atoms in which the whole of the hydroxyl groups have been esterified and a triglyceride of` a naturally occurring higher saturated fatty acid having 12 to 18 carbon atoms in which a part of the hydroxyl groups have been esterified.

8. A pharmaceutical composition for rectal administration according to Claim 5, wherein the base oil is peanut oil, corn oil, a triglyceride of a higher fatty acid, or soybean oil.

9. A pharmaceutical composition for rectal administration according to Claim 1 or 2, wherein the nonionic surfactant is a polyoxyethylene higher alcohol ether, a polyoxyethylene alkylaryl ether, a polyoxypropylene-polyoxyethylene alkyl ether or a fatty acid ester of sucrose.

10. A pharmaceutical composition for rectal administration according to Claim 1 or 2, wherein the nonionic surfactant is a polyethylene glycol type one having an HLB of 10 to 14.

11. A pharmaceutical composition for rectal administration according to Claim 1 or 3, wherein the anionic surfactant is an alkyl sulfate or a di-alkyl sulfosuccinate.

12. A pharmaceutical composition for rectal administration according to Claim l or 4, wherein the salt of bile acid is sodium tauroglycolate, sodium glycolate or sodium taurocholate.

13. A pharmaceutical composition for rectal administration according to Claim l, wherein the amount of the oily base is 1 to 20 times the weight of the cephalosporanic acid or its salt and the total amount of the nonionic surfactant, the anionic surfactant and the salt of bile acid is 1 to 20% by weight based on the weight of the oily base.

14. A pharmaceutical composition for rectal administration according to Claim 13, wherein the amount of the oily base is 2 to 18 times the weight of the cephalosporanic acid or its salt and the total amount of the nonionic surfactant, the anionic surfactant and the salt of bile acid is 5 to 10% by weight of the weight of the oily base.

15. A pharmaceutical composition for rectal administration according to Claim 1, 2 or 3, wherein the salt of cephalosporanic acid is an alkali metal salt, an alkaline earth metal salt, an ammonium salt, or a salt with an organic base.

16. A pharmaceutical composition for rectal administration according to Claim 1, 2 or 3, wherein the salt of cephalosporanic acid is a sodium, potassium, calcium, magnesium, ammonium, procain, dibenzylamine, N-benzyl-8-phenethylamine, 1-ephenamine, arginine or trishydroxymethylamine salt.