CS268651B2 - Method of pharmaceutical production for rectal dosage - Google Patents

Abstract

A pharmaceutical composition for rectal administration comprises 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 and is well absorbed in a living body and maintained in a high concentration in blood for a long period of time.

Description

The present invention relates to a process for the manufacture of a pharmaceutical composition for rectal administration and containing cefaloaporin.

The term cephalosporin in this case means 7'Cn - (-) - X- (4-ethyl-2,3-dihydro-1-piperazinylcarboxamido) -p-hydroxyphenylacetamido] -3-5K1-ethyl-1,2, 3,4-trazolyl) thiomethyl-4-cephem-4-carboxylic acid of the following formula

or a pharmaceutically acceptable salt thereof. These compounds have been described by Saikawa et al. 1,508,071 and 1,517,098.

The compound of the above structural formula will be hereinafter referred to as Compound A. Compound A has a broad antibacterial spectrum against both gram-positive and gram-negative bacteria and has particularly high antibacterial activity against Peeudomonas seruginoea, Klebsiella pneumoniae and Proteus species, causing clinically serious diseases and very stable against B-lactamase produced by bacteria. This means that compound A is a very valuable substance for the treatment of infectious diseases in humans.

When Compound A is administered in an injectable form or when one of its pharmaceutically acceptable salts (intravenous injection, intramuscular injection or drip infusion) is administered, these are well absorbed. However, it is very difficult to inject these substances in the home environment, and the pain of these injections is particularly a concern for children, so the use of this substance is associated with disadvantages.

Oral administration or rectal administration in the form of suppositories is advantageous because administration of the compound is simple and non-painful. However, when administered orally, Compound A or a pharmaceutically acceptable salt thereof is relatively poorly absorbed and therefore high blood circulation concentrations cannot be achieved. In addition, it has been found that when Compound A or a pharmaceutically acceptable salt thereof is dispersed in an oil or water-soluble base, it is formulated in a conventional manner into a pharmaceutical composition for rectal administration and the composition thus obtained is administered rectally, the compound is poorly absorbed and the desired effect cannot be achieved.

For this reason, efforts have been made to formulate this substance into a pharmaceutical composition for rectal administration so that it is well absorbed and can maintain a high concentration of the substance in the bloodstream for a long time. It has been found that when a dispersion of Compound A or a pharmaceutically acceptable salt thereof in oil is administered together with a non-lotion or anionic type surfactant or a bile acid salt rectally, good absorption of Compound A is achieved to achieve a sufficiently high blood concentration.

Accordingly, it is an object of the present invention to provide a pharmaceutical composition containing cephalosporin for rectal administration with good drug absorption and

CS 26Θ 651 B2 to maintain a high concentration of this substance in the bloodstream for a long time.

Further advantages of the process of the present invention will be elucidated in the following section.

A process for the manufacture of a pharmaceutical composition for rectal administration by admixing a cefem derivative β with an oil base and a wetting agent according to the present invention comprises using cephem derivative 7- [D - (-) - ic- (4-ethyl-2,3-dioxo). -1- (piperazinylcarboxamido) -β-hydroxyphenylacetamido-3- [5- (1'-methyl-1,2,3,4-teteasolyl) thiomethyl] - ^3- cephem-4-carboxylic acid or a salt thereof, which is acceptable from a pharmaceutical and non-ionic or anionic surfactants or bile salts are used as wetting agents, wherein the oil base is used in an amount of 1 to 20 times higher relative to the weight amount of cephem derivative and the total amount of nonionic type surfactant, anionic type surfactant and bile salt 20% by weight based on the total weight of the oil base

When a pharmaceutically acceptable salt of Compound A is used in a pharmaceutical composition of the present invention, a particularly high blood concentration of the compound can be obtained. Examples of pharmaceutically acceptable salts of Compound A include alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium salts, magnesium salts and the like, ammonium salts, β organic base salts such as procaine, dibenzylamine, N-benzylphenethylamine, 1-efenamine, trihydroxymethylaminomethane and the like.

Nonionic surfactants include, in particular, polyethylene glycol polyoxyethylene ethers of fatty alcohols (e.g., Emulgen 120, Emulgen 220, Emulgen 408 and Emulgen 420, trade names Kao Sekken and Nikkol BC-15TX, Nikkol BC-20TX and Nikkol BC-20, trade names from Nikko Chemieala), polyoxyethylene alkylaryl ethers (e.g. Emulgen 920, trade names Kao Sekken and Nikkol NP-7.5, Nikko Chemicals), polyoxypropylene polyoxyethylene alkyl ethers (e.g. Pluronic L62, Asahi Denka), fatty acid sugar esters (e.g. DK Ester F-140 , Dai-ichi Kogyo Saiyaku), etc. In general, nonionic surfactants, particularly of the polyethylene glycol type having a hydrophilic-lipophilic balance (HLB, M. GHIFFIN, Atlas Powder Company, USA) in the range of 10 to 14 are more preferred than the type. polyhydric alcohols.

Anionic type surfactants include alkyl sulfates (e.g., Emerl 10 powder, Kao Sekken), dialkyl sulfosuccinates (e.g., Rapizole B-90, Nippon Oil ond Fats Co., Ltd.) and bile salts include tri-tauroglycolate, sodium glycolate , natriumurocholate, etc.

In carrying out the process according to the invention, at least two types of the aforementioned surfactants can be used. The total amount of nonionic type surfactant, anionic type surfactant and bile type salt and bile acid salt is from 1 to 20% by weight based on the weight of the oil base, preferably from 5 to 10% by weight.

As regards the oil base used in the process of the invention described above, this base has no pharmacacentic effect and is a base commonly used in the manufacture of ointments, suppositories, and the like. For example, 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, clove oil, cocoa butter, laurin oil, beef tallow, squalene, lanolin and the like; oils which have been modified by chemical reaction, for example by hydrogenation and the like; mineral oils such as petrolatum, paraffin, silicone oil and esters of higher fatty acids, such as isopropyl myristate, n-butyl myristate, isopropyllolate, cetylricinolate, stearylricinolate, diethylsebacate, diisopropyl adipate. , higher aliphatic alcohols such as cetyl alcohol, stearyl alcohol, etc. · waxes such as bleached beeswax, spermaceti, Japanese wax and the like, higher aliphatic acids, such as stearic acid, kyCS 260 651 B2 oleic oleic acid, palmitic acid and the like, and mixtures of triglycerides of naturally occurring saturated aliphatic acids of 12 to 18 carbon atoms, wherein all of the hydroxyl groups have been esterified and the triglycerides of said aliphatic acids in which part of the hydroxyl groups have been esterified. Most preferred are vegetable oils.

The oil bases may be used as such or in a mixture of two or more of these bases. The amount of oil base is 1- to 20-fold by weight of compound A or a salt thereof, which is pharmaceutically acceptable, preferably 2- to 10-fold. .

In preparing the compositions of the present invention, a nonionic or anionic type surfactant or bile salt in an oil base is first dispersed in the dispersion, and a predetermined amount of compound A or a pharmaceutically acceptable salt thereof is added to the dispersion and dispersed uniformly. However, it is not necessary to maintain this order when mixing. The particle size of the compound A or a salt thereof, which is pharmaceutically acceptable, is preferably about 100 µm. However, the particle size may be smaller.

The pharmaceutical composition is obtained from the above dispersion by treating the mixture in a conventional manner into a suppository, suspension or ointment containing a wetting agent and cephalosporins in an oil base. This mixture is optionally also filled into soft gelatin capsules or the dispersion or ointment is filled into a tube. Antioxidants such as tocopherol, 2-tert-butyl-2-hydroxyanisole of the formula

nordihydroguaiaric acid of the formula

and the like, substances with a synergistic effect, such as, for example, phosphoric acid, citric acid, ascorbic acid or malonic acid, antiseptic active agents, fillers and the like.

The amount of the composition of the invention to be administered as a single dose depends on the amount of Compound A or a salt thereof that is pharmaceutically acceptable. The compound of the invention should be administered one to three times daily.

The following examples illustrate the use of the composition according to the invention.

CS 268 651 B2

Properties of the composition according to the invention.

Dispersion of Compound A or its sodium salt in a mixture of the oily base and with various surfactants or bile salts, dispersion of sodium salt of compound A in physiological saline solution for injection (control), dispersion of sodium salt of compound A in water (control), sodium dispersion Compound A salt in peanut oil as an oily base (control) and dispersion of Compound A sodium salt in propylene glycol as a water-soluble base (control) was administered rectally, orally or by injection, comparing changes in blood circulation concentration versus time.

Samples were administered as follows:

For rectal administration, the sample was administered rectally to male Wistar rats weighing approximately 350 g after 15 hours of fasting with a small syringe or suppository based on Witepsol, a suppository was obtained by pouring the sample into a small suppository form. After administration, the rectum was sutured using surgical material, silk number 4-6.

For oral administration, each of the samples was administered to rats of the same type and under the same conditions by gavage.

The measurement of circulating concentration was performed as follows. A small amount of blood was drawn from the rat's jugular vein at certain time intervals and the concentration of Compound A was quantitated by a biological method. For this purpose, Bacillue subtilis ATCC 6633 was used, the broth was prepared by adding water to a mixture of 5 g peptone, 3 g meat extract and 15 g agar in a quantity such that the total volume was 1 liter, then the pH was adjusted to 6, 2. The volume of one layer was 8 ml.

Micrococcua luteus ATCC 9341 was used to measure concentrations of 2 µg / ml and below 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 agar to a total volume of 1 liter at adjusting the pH to 6.5. Total layer volume is 8 ml ·

The serum is separated from the blood sample by centrifugation at 3000 rpm and then cultured at 37 ° C for 16-20 hours using paper discs, and the result is read. 1% phosphate buffer pH 6.0 was used as the solution for the calibration curve. The results are shown in Table I below.

CS 268 651 B2

The amount of Compound A or its sodium salt was 100 mg / kg

Table 1

Route of administration Sample composition Blood concentration (µg / ml) Compound A or its sodium salt and base Wetting agent or bile acid salt 15 Dec 30 60 120 240 Name Quantity (%) min. min. min. min. min

rectally rectally sodium salt of compound A 5% - water 95% sodium salt of the compound A 5% - peanut oil 95% - - 0.1 0.2 0.1 0.2 0.1 0.2 0.1 0.2 0.1 0.2 control rectally compound A 5% peanut oil 95% - - 0.8 0.3 0.2 0.1 0.1 orally Compound A 5% Water 95% - - <0.1 <0.1 <0.1 <0.1 <0.1 orally sodium salt of the compound A 5% - water 95% - - 0.2 <0.1 <o, i <0.1 <0.1 rectally compound A 5% peanut oil 95% Nikkol ВС-20 TX 5 31.0 39.0 8.7 1.7 0.5 Way rectally Compound A 10% Corn oil 85% Emulgen 408 5 8.4 8.3 5.3 2.2 0.7 according to the invention rectally Compound A 10% Witepsol H-15 Nikkol ВС-20 TX 10 20.0 30.0 20.0 7.2 1.7 rectally Compound A 20% Witepsol H-15 7% Emulgen 408 10 18.0 30.0 33.0 14.0 6.4 rectally sodium salt of the compound And 5% - peanut Emerl 10 5 10.5 2.6 1,2 0.2 <0.1 oil 90% powder rectally Compound A 5% Peanut Oil 90% Peanut Oil Nikkol 5 36.0 32.0 10.0 1.5 0.3 rectally Compound A sodium 10% - maize Emulgen 10 11.5 12.8 7.2 1.6 0.3 oil 80% 408 rectally Compound A sodium 10% - soybean oil 80% Nikkol 10 13.0 16.7 15.4 8.0 3.4 rectally Stabbing salt of compound And 20% - peanut Emulgen 10 21.5 27.0 12.2 1,2 <0.1 oil 70% 408 rectally sodium salt of compound A 10% - Miglyol 812 DK Ester 10 12.4 8.3 2.3 0.9 0.4 80% F-140

CS 268 651 B2

Table 1 - Continued rectally sodium salt of compound

And 20% - Witepsol H-15 Emulge n 10 18.0 30.0 33.0 14.0 6., 4 rectally Compound A sodium 5% - Peanut oil 90% sodium taurocholate 5 12.0 6.4 1.5 0.3 <0.1 rectally Arginine 8 Compound A 5% - Peanut Oil 90% Nikkol 5 6.4 3.3 0.7 <0.1 <0.1 rectally arginine salt of compound A 10% Pluronic 10 5.3 4.6 1.9 0.7 o, 3

soybean oil 80% L-62

As can be seen from Table 1, a much higher blood concentration can be achieved with the composition of the invention than with the oral or rectal administration of the control samples.

Example 1

5 g of a nonionic type of wetting agent, namely polyoxyethylene oleyl alcohol ether (Emulgen 408) and 10 g of 7-rD (-) - N - (4-ethyl-2,3-dioxo-1-piperazinylcarboxamido) acid, are dispersed in 85% of corn oil. -? - hydroxyphenylation of tamido-3- [5- (1-methyl-1,2,3,4-tetrazolyl) -thiomethyl] - N -cephem-4-carboxylic acid, then the resulting mixture is treated to be carboxylic acid the acid is uniformly dispersed. The resulting dispersion was filled with soft gelatin capsules by placing 1.25 g of dispersion in each capsule. Soft gelatin capsules are administered rectally.

Example 2

80 g of higher aliphatic acid triglyceride (Witepsol H-15, Dynamite Nobel) is melted in a water bath at 38 to 45 ° C, then 10 g of a nonionic surfactant, polyoxyethylene oleyl alcohol ether (Nikkol ВС-20 TX), are added. 10 g of 7- (D (-) - <1- (4-ethyl-2,3-dioxo-1-piperazinylcarboxamido) -p-hydroxyphenylacetamido) -3- [5- (1-methyl-1,2) -acetic acid] was added to the resulting solution. (3,4-Tetrazolyl) -thiomethyl] - N -cephem-4-carboxylic acid The resulting mixture was thoroughly mixed to give a uniform dispersion which was then cooled to a temperature near the freezing point and then poured into a suppository mold to form a suppository. they get suppositories.

Example 3

To 80 g of soybean oil, 10 g of a nonionic surfactant is added, namely polyoxyethylene nonylphenyl ether (Nikkol NP 7.5)> this ether is dispersed in soybean oil and 10 g of 7-fD (-) - <K- (4) are added to the resulting dispersion. -ethyl-2,3-dioxo-1-piperazinylcarboxamido) -p-hydroxyphenylacetamido] -3-5- (1-methyl-1,2,3,4- (tetrazolyl) thiomethyl) - N -cephem-4- The resulting mixture is mixed until a uniform dispersion is obtained, and soft gelatin capsules are prepared in the same manner as in Example 1.

Example 4

To 80 g of corn oil was added 10 g of a nonionic type surfactant (Emulgen 408), followed by 10 g of 7-fD (-) - * - (4-ethyl-2,3-dioxo-1-piperazinylcarboxamido) -p-hydroxyphenylacetamido Sodium] -3- [5- (1-methyl-1,2,3,4-tetraazolyl) -thiomethyl] - N -cephem-4-carboxylate and the resulting mixture was stirred until a uniform dispersion was obtained. A soft capsule is then prepared as in Example 1. This capsule is used as a suppository for rectal administration.

С $ 268,651 B2

Example 5

To 80 g of corn oil, 10 g of a nonionic type surfactant (Emulgan 408) is added, followed by 10 g of 7- [(>) - << - (4-ethyl-2,3-dioxo-1-piperazinylcarboxamido) - p-hydroxyphenylacetamido] -3-5- (1-methyl-2,3 _F 4-tetrazolyl) thiomethyl - Δ-cephem-4-кагboxylátu solution. The resulting mixture is stirred to form a uniform dispersion which is placed in a suppository mold.

Example 6

5 g of sodium lauryl sulphate (Emerl 10 powder) are added to 90 g of radion oil as anionic type wetting agent and then 10 g of 7- [1) (-) - << - (4-ethyl-2,3-dioxo-1 - benzamido) -p-hydroxyfenylacetamidq} -3- 5- (l-methyl-2,3 _F 4-tetrazolyl) thiomethyl] -Д ¹ cephem-4-carboxylate. The resulting mixture is stirred to form a uniform dispersion which is then placed in a suppository mold.

Example 7

70 g of a higher saturated aliphatic acid triglyceride (Witepsol H-15) is melted in a water bath at 38-45 ° C, and 10 g of a nonionic surfactant, polyoxyethylenoleyl alcohol ether (Emulgen 408), is dissolved in this material. To the resulting solution is added 20 g of 7-fb (-) - * - (4-ethyl-2,3-dioxo-1-piperazinylcarboxamido) -p-hydroxyphenylacetamido] - [5- (1-methyl-1,2, Sodium 3,4-tetrazolyl) thiomethyl-β-cephem-4-carboxylate. Then, the resulting mixture is mixed until a uniform dispersion is formed and the suppositories are prepared as in Example 2.

Example 8

8 g of polyoxyethylenoleyl alcohol ether (Emulgen 408) and 2 g of sodium taurocholate and then 10 g of 7-fD (-) - * - (4 * ethyl-2,3-dioxo-1-piperazinylcarboxamido) -p are dispersed in 80 g of peanut oil. -hydroxyfenylacetamidq] -3-F5 "(L" 1 _1-methyl 2,3,4-tetrazolyl) methyl -thiome - ^^ - ce'fem-4-carboxylate, and the resulting mixture was stirred to form a uniform dispersion and filled into suppository molds.

Example 9

80 g triglyceride of higher saturated aliphatic acid (Witepsol H-15) is melted in a water bath at 38-45 ° C and 7 g of non-ionic surfactant, polyoxyethylenoleylalcohol alcohol (Nikkol ВС-20 TX) and 3 g of sodium lauryl sulphate ( Emerl 10 Powder). To the resulting solution was added 10 g of 7-fD - (-) - 4- (4-ethyl-2,3-dioxo-1-piperazinylcarboxamido) -p-hydroxyphenylacetamido] -3- [5- (1-methyl-1-methylphenyl) acetamide], Sodium 2,3,4-tetrazolyl) thiomethyl] -2- (4-carboxylate) sodium, and the resulting mixture is stirred until a uniform dispersion is obtained, the suppositories being prepared as in Example 2.

Claims (9)

A process for the preparation of a pharmaceutical composition for rectal administration by admixing a cephem derivative with an oil base and a wetting agent, wherein the cephem derivative is 7-fl - (-) - * - (4-ethyl-2,3-dioxo acid). -1-piperazinylcarboxamido) -p-hydroxyphenylacetamido] -3- [5- (1-methyl-1,2,3,4-tetrazolyl) -thiomethyl] -4-cephem-4-carboxylic acid or a salt thereof, which is acceptable from a pharmaceutical point of view, a nonionic or anionic surfactant or bile salt is used as a wetting agent, wherein the oil base is used in an amount of 1 to 20 times the weight of the cephem derivative and the total amount of nonionic surfactant, anionic surfactant and bile salt 1 to 20% by weight, based on the total weight of the oil base. 2. The process of claim 1 wherein the weight of the oil base is 2 to 18 times the weight of the cefemcarboxylic acid or salt thereof, and the total amount of the cefemcarboxylic acid. Non-ionic surfactants, anionic type wetting agents, and bile acid salts are 5-10% by weight based on the total weight of the oil base. 3. The method of claim 1 wherein the nonionic surfactant is polyoxyethylene ethers of higher alcohols, polyoxyethylene alkyl aryl ethers, polyoxypropylene-polyoxyethylene alkylsters or sucrose fatty acid esters. 4. The process of claim 1 wherein the nonionic surfactant is a polyethylene glycol having a hydrophilic-lipophilic balance of 10-14. 5. The process of claim 1 wherein the anionic surfactant is an alkyl sulfate or dialkyl sulfosuccinate. 6. A process according to claim 1, wherein the bile acid salt is sodium tauroglycolate, sodium glycolate or sodium taurocholate. 7. A process according to claim 1, wherein the alkali metal salt, the alkaline earth metal salt, the ammonium salt or the salt and the organic base are used as the cephemarboxylic acid salt. 8. The process of claim 1, wherein the salts of cephalosporic acid are sodium, potassium, calcium, magnesium, ammonium, procaine, dibenzylamine, N-benzyl-B-phenethylamine, 1-efenamine, arginine or trishydroxyme salts. thylamine. 9. A process according to claim 1, wherein a nonionic or anionic type surfactant or a bile salt is first dispersed in the oil base and cephalosporanic acid is added to the obtained dispersion and the mixture is uniformly dispersed.