NO792443L - PROCEDURE FOR THE PREPARATION OF A CEPHALOSPOR PREPARATION - Google Patents

Description

The present invention relates to the production of a pharmaceutical cephalosporin derivative for rectal administration.

The term "cephalosporin" as used herein means 7-[D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarboxamido)-p-hydroxyphenylacetamido]-3-[5-(1- methyl-1,2,3,4-tetrazolyl)-thiomethyl]-A 3-cephem-4-carboxylic acid represented by the following structural formula, and a pharmaceutically acceptable salt thereof,

which was developed by Saikawa et al, Saikawa being one of the inventors of the present application (see British patents 1,508,071 and 1,517,098):

The compound represented by the aforementioned structural formula is referred to hereafter as compound A. Compound A has a broad antibacterial spectrum against gram-positive and gram-negative bacteria and in particular has an effective antibacterial activity against Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus species which are known causes of clinically serious infectious diseases, and are very stable against (3-lactamase produced by bacteria. Compound A is thus a very useful medicine against infectious diseases in humans.

When compound A is injected in the form of a pharmaceutically acceptable salt (such as intravenous injection, intramuscular injection or drip infusion), it is well absorbed by the human body. However, injection is difficult to use at home, and the pain caused by the injection scares children. This is disadvantageous.

Oral or rectal administration (suppositories) is

on the other hand, advantageous in use, as the medicine can be used without the patient becoming afraid. However, when compound A or its pharmaceutically acceptable salt is administered orally,

is poorly absorbed in the human body, and therefore no high concentration in the blood can be achieved. Furthermore, the inventors have found that when compound A or its pharmaceutically acceptable salt is dispersed in an oil base or a water-soluble base according to the conventional, known method of preparing a pharmaceutical preparation for rectal administration, and the preparation thus prepared is administered rectally, the compound is absorbed to a small extent and no effect is achieved.

: The inventors have therefore carried out extensive research on pharmaceutical preparations for rectal administration which can be easily absorbed into the human body and can be maintained at a high concentration in the blood for longer periods of time, and as a result it has been found that when a uniform dispersion of compound A or its pharmaceutically acceptable salt in a mixture of an oil base and a nonionic surfactant and/or an anionic surfactant and/or a salt of a bile acid is administered rectally, compound A is well absorbed in the human body so that it is obtained a high concentration :in the blood.

An object of the invention is to provide a pharmaceutical preparation of cephalosporin for rectal administration.

A further object of the invention is to provide a pharmaceutical preparation of a cephalosporin which is well absorbed in a human body and can be maintained in a high blood concentration for a long time when administered rectally.

Other purposes and advantages according to the invention will be apparent from the following description.

According to the invention, a pharmaceutical preparation of 7-[D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarboxamido)-p-hydroxyphenylacetamido]-3-[5-(1-methyl) -1,2,3,4-tetrazolyl)-thiomethyl]-A 3-cephem-4-carboxylic acid or its pharmaceutically acceptable salt comprising 7- [D (-.) - a - (4-ethy 1-2 , 3 -dioxo-1-piperazinylcarboxamido)-p-hydroxyphenylacetamido]-'3- [5-(1-methyl-3 1,2,3,4-tetrazplyl)-thiomethyl]-A -cephem-4-carboxylic acid or its pharmaceutical acceptable salt, an oil base, and a nonionic and/or anionic surfactant and/or a salt of bile acid.

According to the invention, a very high blood concentration can be achieved when a pharmaceutically acceptable salt of compound A is used. As such pharmaceutically acceptable salts of. compound A can be exemplified by salts with alkali metals such as e.g. sodium, potassium and the like; salts with alkaline earth metals such as calcium, magnesium and the like; ammonium salts;

salts with organic bases such as procaine, dibenzylamine, N-benzyl-3-phenethylamine, 1-ephenamine, arginine, trishydroxymethyl-aminomethane and the like.

As non-ionic surfactants - for use - in the present invention, examples can be mentioned of polyoxyethylene fatty alcohol ethers of the polyethylene glycol type (e.g.

"Emulgen 120", "Emulgen 220", "Emulgen 408" and "Emulgen 420", trademarks of Kao Sekken, and "Nikkol BC-15TX", "Nikkol BC-20TX"

and "Nikkol BO-20", trademarks of Nikko Chemicals); polyoxyethylene alkyl aryl ethers (eg "Emulgen 920", trademark, from Kao Sekken and "Nikkol NP-7.5", trademark from Nikko Chemicals); polyoxypropylene polyoxyethylene alkyl ethers (eg "Pluronic L62", trademark of Asahi Denka); sugar esters of the fatty acid ester type

(e.g. "DK Ester F-140", trademark of Dai-ichi Kogyo Seiyaku)

and such. In general, the nonionic surfactants of the polyethylene glycol type with HLB of 10 to 14 are preferred over those of the polyhydric alcohol type.

Examples of anionic surfactants include alkyl sulfates (e.g. "Emerl" 10 powder, trademark from Kao Sekken); dialkyl sulfosuccinates (e.g. "Rapizole B-90", trademark from Nippon Oil&Fats Co., Ltd.), and as a salt of bile acid sodium tauroglycolate, sodium glycolate, sodium taurocholate and the like can be mentioned, for example.

In the present invention, at least two of the above-mentioned surfactants can be used in mixture.

The total amount of the nonionic surfactant, the anionic surfactant and the salt of the bile acid used in the present invention may be 1 to 20% by weight based on the weight of the oil base, and an amount of 5 to 10% by weight

is particularly preferred.

As an oil base for use in the present invention, for example, bases can be mentioned which in themselves have no pharmaceutical activity when they are used. production of conventional salts, suppositories and the like, e.g. fats and oils such as peanut oil, sesame oil, soybean oil, corn oil, rapeseed oil, cottonseed oil, castor oil, tubaki oil, coconut oil, olive oil, poppy seed oil, cocoa butter, "laurin" butter, beef tallow, squalene, wool fat and the like ; such fats and oils which have been modified by chemical reaction, such as e.g. hydrogenation etc.; mineral oils such as vaseline, paraffin, silicone oil etc.; higher fatty acid esters such as isopropyl myristate, n-butyl myristate, isopropyl linoleate, cetyl ricinoleate, stearyl ricinoleate, diethyl sebacate, diisopropyl adipate and the like; higher aliphatic alcohols such as cetyl alcohol, stearyl alcohol and the like; growing as e.g. bleached beeswax, sperm set, Japan wax, etc.; higher fatty acids such as stearic acid, oleic acid, palmitic acid etc.;

and mixtures of triglycerides of naturally occurring saturated fatty acids with 12 to 18 carbon atoms, in which all the hydroxyl groups are esterified and triglycerides of said fatty acids where. some of the hydroxyl groups are esterified. Vegetable oils are. especially preferred..

These oil bases can be used alone or in mixtures of two or more. The amount of the oil base used is 1 to 20 times the weight of compound A or its pharmaceutically acceptable salt, and an amount of 2 to 18 times is preferred.

When preparing the preparation according to the invention, the non-ionic and/or anionic surfactant and/or bile acid salt is first dispersed in the oil base, and the required amount of compound A or its pharmaceutically acceptable salt is added to the resulting dispersion and distributed evenly in the latter. In the present invention, however, the order of addition of base, surfactants and the cephalosporin is not limited to the above. The particle size of compound A and its pharmaceutically acceptable salt is preferably 100 µm or less.

When preparing a pharmaceutical preparation from the mixture thus obtained, the mixture can be formed into conventional anal suppositories, or a suspension or an ointment in which the surfactant and the cephalosporin dispersed in the oil base can be placed in a soft capsule, or said dispersion or ointment can placed in a tube that is entered at the time of application. Antioxidants such as e.g. tocopherol, BHA, NDGA and the like; synergistic agents such as phosphoric acid, citric acid, ascorbic acid, malonic acid; antiseptics; covering funds; binders, etc.

The effective administration amount of the preparation prepared according to the invention can be varied depending on compound A or its pharmaceutically acceptable salt, and such an amount of the preparation can be chosen that said compound can be administered in an amount of 1/5 to 3 times the effective administration amount by injection.

The invention is illustrated below with reference to the examples, which are only intended to illustrate and not limit the invention.

Application example

A dispersion of compound A or its sodium salt

in a mixture of an oil base, and various surfactants and/or a bile acid salt (present invention);

a dispersion of the sodium salt of compound A in physiological saline as an injection preparation (control); a dispersion of the sodium salt of compound A in water (control); a dispersion of the sodium salt of compound A in only an oil base (peanut oil) (control); and a dispersion of the sodium salt of compound A in only a water-soluble base (propylene glycol)

(control) was administered rectally, orally or by injection, and changes in blood concentration over time were compared.

The procedure for administering a sample was as

following:

For rectal administration, each sample was administered through the anus into the rectum of a male Wister rat (weight approx. 350 g), which had not been fed for 15 hours, using a small injector or by introducing a "Witepsol" suppository, which was obtained by pouring the sample into one form of suppositories and fixing it there. After administration, the anus was sutured together with surgical suture No. 4 and 6.

By oral administration, each sample was administered

to the above rats using a rat probe.

Measurement of the blood concentration was carried out as follows: A rat's neck was operated at a certain time interval, and a small amount of blood was taken from the carotid artery, and the concentration of the compound there was determined quantitatively by a conventional bioassay method. Bacillus subtilis ATCC 6633 was used as a test bacterium and the 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 a quantity that the total volume became 1 liter, and adjusting the pH of the medium to 6/ 2. > The volume of the spray layer was 8 ml.

When measuring a concentration as low as 2 µg/ml or less, Micrococcus luteus ATCC 9341 was used as the test bacterium, and the culture medium was prepared by adding water to a mixture of • 10 g peptone, 2.5 g sodium chloride, 5 g meat extract and 15 g of agar in such a quantity that the total volume was 1 litre, and adjust the pH in the medium to 6.5. The volume of the test layer was 8 ml.

Serum was separated from the drawn blood sample by centrifugation at 3000 rpm. min and cultured at 37°C for 16 to 20 hours using the paper disc method and then examined. A 1% phosphate buffer solution (pH.6.0) was used as solution for the calibration curve. The results obtained are reproduced in table 1.

As can be seen from table 1, a much higher blood concentration was obtained when the sample was administered rectally than when the control samples were administered orally or rectally.

Manufacturing example 1

In 85 g of corn oil was dispersed 5 g of a nonionic surfactant, polyoxyethylene oleyl alcohol ether ("Emulgen 408"), and then 10 g of 7-[D (-)-a-(4-ethy1-2,3- dioxo-1-piperazinylcarboxamido)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)-thiomethyl]- A 3-cephem-4-carboxylic acid added to dispersions, after which the resulting mixture was stirred to disperse the carboxylic acid evenly in the dispersion. A soft gelatin capsule was filled with the resulting dispersion in an amount of 1.25 g per capsule to produce a soft suppository capsule.

Manufacturing example 2

In a water bath at 38 to 45°C, 80 g of a triglyceride of a higher fatty acid ("Witepsol H-15", from Dynamite Nobel) was melted, and therein was dissolved 10 g of a nonionic surfactant, polyoxyethylene oleyl alcohol ether ("Nikkol BC-20 TX"), after which 10 g of 7-[D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinyl-carboxamido)-p-hydroxyphenylacetamido]-3-[ 5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-α 3-cephem-4-carboxylic acid was added to the resulting solution. The resulting mixture was stirred to form a uniform dispersion, which was then cooled to a temperature near freezing and then poured into a mold for a rectal suppository to prepare a solid suppository.

Manufacturing 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(-)- α-(4-ethyl-2,3-dioxo-1-piperazinyl-carboxamido)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-A 3 -cephem-4-carboxylate was added to the resulting dispersion. The resulting mixture was then stirred to form a uniform dispersion. In the same way as in example 1

a soft suppository capsule was produced..

Manufacturing example 4

To 80 g of corn oil was added 10 g of a nonionic surfactant ("Emulgen 408") and then 10 g of sodium 7-[D(-)-α-(4-ethyl-2,3-dioxo- 1-piperazinylcarboxamido)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)-thiomethyl]- N -cephem-4-carboxylate, and the resulting mixture was stirred for to form a uniform dispersion. In the same way as in Example 1, a soft, capsule-shaped suppository was then prepared.

Manufacturing example 5

To 80 g of corn oil was added 10 g of a nonionic surfactant ("Emulgen 408") and then 10 g of sodium 7-[D(-)-α-(4-ethyl-2,3-dioxo-1 -piperazinylcarboxamido)-p-hydroxyphenyl-acetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)-thiomethyl]-A 3'-cephem-4-carboxylate, and the resulting mixture was stirred to form a uniform dispersion. This dispersion was placed in a suppository tube.

Manufacturing example 6

To 90 g of peanut oil was added 5 g of an anionic surfactant, sodium lauryl sulfate ("Emerl 10" powder), and then 10 g of sodium 7-[D(-)-a-(4-ethy 1-2,3- dioxo-1-piperazinyl-carbdxamido.).-p-hydroxyphenylacetamido]-3-[5- (1-methyl-1-1,2,3,4-tetrazolyl)thiomethyl]-A 3-cephem-4-carboxylate , and the resulting mixture was stirred to form a uniform dispersion, which was then placed in a suppository tube.

Manufacturing example 7

In a water bath at 38 to 45°C, 70 g of a triglyceride of a higher, saturated fatty acid ("Witepsol 11-15") was melted, and therein was dissolved 10 g of a nonionic surfactant, polyoxyethylene oleyl alcohol ether (" The emulsion 408"). To the resulting solution was added 20 g of sodium 7-[D (-)-ot-(4-ethyl 1-2,3-dioxo-1-piperazinylcarboxamido)-p-hydroxyphenylacetamido]-3-[5-(1- methyl 1-1,2,3,4-tetrazolyl)thiomethyl]-A 3-cephem-4-carboxylate, and the resulting mixture was stirred to form a uniform dispersion. In the same way as in example 2, a solid suppository was prepared.

Manufacturing example 8

In 80 g of peanut oil, 8 g of polyoxyethylene-oleyl alcohol ether ("Emulgen 408") and 2 g of sodium taurocholate were dispersed, after which 10 g of sodium 7-[D(-)-a-(4-ethyl-2,3-dioxo-l -piperazinylcarboxamido)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-3 1,2,3,4-tetrazolyl)thiomethyl]-A -cephem-4-carboxylate, and the

the resulting mixture was stirred to form a uniform dispersion. A suppository tube was filled with this dispersion.

Manufacturing example 9

In a water bath at 38 to 45°C, 80 g of a triglyceride of a higher saturated fatty acid ("Witepsol H-15") was melted, and therein was dissolved 7 g of a nonionic surfactant, polyoxyethylene oleyl alcohol ether (" Nikkol BC-20.TX") and 3 g sodium lauryl sulfate ("Emerl 10" powder). To the resulting solution was added 10 g of sodium 7-[D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarboxamido)-p-hydroxyphenylacetamido]-3-[5-(1- methyl 1,2,3,4-tetrazolyl)-thiomethyl]-A 3-cephem-4-carboxylate, and the resulting mixture was stirred to form a uniform dispersion. In the same way as in example 2, a solid suppository was prepared.

Claims (17)

1. Process for the production of a pharmaceutical preparation for rectal administration, characterized in that 7-[D(-)-a-(4-ethyl-2,3-dioxo-1-piperazinylcarboxamido)-p-hydroxyphenylacetamido]-3-[5 -(1-methyl-1,2,3,4-tetrazolyl)-thiomethyl]-A 3-cephem-4-carboxylic acid or its pharmaceutically acceptable salt is mixed with an oil base, and a nonionic and/or anionic surfactant and /or a bile acid salt. 2. Process according to claim 1, characterized in that 7-[D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarboxamido)-p-hydroxyphenylacetamido]-3-[5-(1-methyl- 1,2,3,4-tetrazolyl)-thiomethyl]-α 3-cephem-4-carboxylic acid or its pharmaceutically acceptable salt is mixed with an oil base and a nonionic surfactant. 3. Process according to claim 1, characterized in that 7-[D(-)-a-(4-ethyl-2,3-dioxo-1-piperazinylcarboxamido)-p-hydroxyphenylacetamido]-3-[5-(1-methyl- 1,2,3,4-tetrazolyl)-thiomethyl]-α 3-cephem-4-carboxylic acid or its pharmaceutically acceptable salt is mixed with an oil base and an anionic surfactant. 4. Process according to claim 1, characterized in that 7-[D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarboxamido)-p-hydroxyphenylacetamido]-3-[5-(1-methyl- 1,2,3,4-tetrazolyl)-thiomethyl]-α 3-cephem-4-carboxylic acid or its pharmaceutically acceptable salt is mixed with an oil base and a bile acid salt. 5. Method according to one of claims 1 to 4, characterized in that at least one fat or oil is used as an oil base; hydrogenated fat or oil; mineral oil; higher aliphatic alcohol; higher fatty acid esters; higher fatty acid; wax; or triglyceride of naturally occurring fatty acid with 12 to 18 carbon atoms. 6. Method according to one of claims 1 to 4, characterized in that at least one vegetable oil is used as the oil base. 7. Method according to claim 5, characterized in that at least peanut oil, sesame oil, soybean oil, corn oil, rapeseed oil, cottonseed oil, castor oil, tobacco oil, coconut oil, olive oil, poppy seed oil, cocoa butter, lauric butter, beef tallow, squalene, wool fat, vaseline, paraffin are used as the oil base. , silicone oil, isopropyl myristate, n-butyl myristate, isopropyl linoleate, cety lricinoleate, steary l.ri c inoleate, ' diety lsebacate, diisopropyl adipate, cetyl alcohol, stearyl alcohol, bleached beeswax, spermacetate, Japan wax, stearic acid, oleic acid, palmitic acid or a mixture of a naturally occurring, higher saturated fatty acid with 12 to 18 carbon atoms in which all the hydroxyl groups are. esterified and a triglyceride of a naturally occurring, higher, saturated fatty acid with 12 to 18 carbon atoms in which part of the hydroxyl groups is esterified. 8. Method according to claim 5, characterized in that peanut oil, corn oil, a triglyceride of a higher fatty acid or soya oil is used as the oil base. 9. Method according to claim 1 or 2, characterized in that a polyoxyethylene higher alcohol ether, a polyoxyethylene alkyl aryl ether, a polyoxypropylene polyoxyethylene alkyl ether or a sucrose fatty acid is used as a non-ionic surfactant. 10. Method according to claim 1 or 2, characterized in that a polyethylene glycol with HLB of 10 to 14 is used as non-ionic surfactant. 11. Method according to claim 1 or 3, characterized in that an alkyl sulfate or a dialkyl sulfosuccinate is used as anionic surfactant. 12. Method according to claim 1 or 4, characterized in that the bile acid salt used is sodium tauroglycolate, sodium glycolate or sodium taurocholate. 13. Method according to claim 1, characterized in that an amount of oil base is used which is 1 to 20 times the weight of the cephalosporanic acid or its salt, and a total amount of the non-ionic surfactant, the anionic surfactant and the bile acid salt which is 1 to 20% by weight based on the weight of the oil base. 14. Method according to claim 13, characterized in that an amount of oil base is used which is 2 to 18 times the weight of the cephalosporanic acid or its salt, and a total amount of the non-ionic surfactant, the anionic surfactant and the bile acid salt which is 5 to 10% by weight of the weight of the oil base. 15.. Method according to claim 1, 2, 3 or 4, characterized by. that as a salt of cephalosporan the acid is used an alkali metal salt, et. alkaline earth metal salt, an ammonium salt or a salt with an organic base. 16. Method according to claim 1,2,3 or 4, characterized in that as a salt of cephalo- ammonium, sporanic acid is used as a sodium, potassium, calcium, magnesium, / procaine, dibenzylamine, N-benzyl-B-phenethylamine, 1-ephenamine, arginine or trishydroxymethylamine salt. 17. Method according to claim 1, 2, 3 or 4, characterized in that the non-ionic and/or anionic surfactant and/or the bile acid salt is first dispersed in the oil base and that the cephalosporanic acid or its pharmaceutically acceptable salt is then added to the resulting dispersion and dispersed uniformly in the latter.