HU180740B - Process for producing sulfonamide-containing,injectable pharmaceutical composition of prolongated activity - Google Patents

Abstract

The invention relates to the preparation of a prolonged-duration injectable pharmaceutical preparation comprising from 1 to 35 parts by weight of 3- (4-aminophenylsulfonamido) -5-methylisoxazole and from 0.2 to 7 parts by weight of 2,4-diamino-5- (3,4,5 -trimethoxybenzyl) -pyrimidine in a weight ratio of 5: 1, further 50 to 97 parts by volume of N, N-Dimethylessigsaeureamid, 1 to 48 parts by volume of polyethylene glycol, 2 to 4 parts by volume Aethyloleat and 0 to 10 parts by weight of additive or additives contained. The injectable pharmaceutical preparation prepared according to the invention also has a therapeutic effect 24 hours after the administration. The ph value of the solution is close to the ph value of the blood.

Description

A process for the preparation of a sustained release sulfonamide-containing injectable pharmaceutical composition

The present invention relates to a process for the preparation of a sustained release sulfonamide-containing injectable pharmaceutical composition. More particularly, the present invention provides: - a process with a prolonged action of 3- (4-aminobenzenesulfonamido) -5-methylisoxazole (sulfamethoxazole) and 2,4-diamino-5- (3,4,5-trimethoxy) benzi]) - pyrimidine (trimethoprim) in a 5: 1 weight ratio for injection. The pharmaceutical composition can be used in the treatment of gastrointestinal diseases, respiratory diseases, urogenital infections and surgical diseases in veterinary medicine.

Trimethoprim is known to potentiate the effects of various sulfonamides, such as sulfamethoxazole [156,391]. Hungarian Patent Specification]. The cited publication describes the preparation of injectable solutions containing the sulfonamide-base salt, so that the pH of the solutions can be as high as II. Because basic chemotherapy can cause tissue damage at the injection site, the known injection solution is of limited use.

Another known method to overcome the disadvantages of using a basic solution is to adjust the pH of the pharmaceutical composition to 4-6 by adding acid [171,200 l. Hungarian Patent Specification]. However, the use of acidic pH for intravenous injection is not favorable as the pH of 4-6 is far from the physiological pH of 7.35-7.45 of the blood.

A common feature of the known injectable formulations containing sulfonamide and trimethoprim is that 6-8 hours after administration, the therapeutic effect is lost and the therapeutic level required for healing can only be achieved by another injection.

Three to four times daily injections are not beneficial in human medicine, but are particularly disadvantageous in the veterinary field.

SUMMARY OF THE INVENTION It is an object of the present invention to provide an injectable pharmaceutical formulation containing sulfamethoxazole and trime10 toprimim in a weight ratio of 5: 1, which provides a sustained therapeutic effect, is close to blood, and optionally contains active ingredients in concentrations such that solution for injection.

We have found that sustained release injectable formulations are obtained when 1 to 35 parts by weight of sulfamethoxazole and 0.2 to 7 parts by weight of trimethoprim with 50 to 97 volumes of Ν, Ν-dimethylacetamide, 1 to 48 volumes of polyethylene glycol, 2 to 4 volumes of ethyl oleate and 0 to 10 parts by weight of admixture (s) are added and the mixture is converted, in a manner known per se, into an injectable preparation.

The pharmaceutical composition according to the invention preferably contains 20 g / 100 ml of sulfamethoxazole and 4 g / 100 ml of trimethoprim.

The polyethylene glycol used may have various molecular weights. For example, PEG 200, 300, 400 30 or 600 may be used or may be present in varying proportions

Mixtures of -1I8074C. Preferably PEG 300 is used, preferably 60 volumes; amounts.

The ethyl oleate is preferably used in an amount of 3 volumes.

As additive (s), for example, antioxidants such as sodium sulfite, sodium hydrogen sulfite, sodium pyrosulfite, potassium sulfite, potassium hydrogen sulfite, potassium pyrosulfite and the like are used. Surfactants and solubilizers such as sodium dioctyl sulfosuccinate, polyvinylpyrrolidone and the like. - water, etc. It can be used. The water is taken in small amounts to dissolve the inorganic salts.

Ethyl oleate is used as a solvent in the preparation of intramuscular injectable solutions (Remington's Pharmaceutical Sciences, 15th edition, page 1241, Mack Publiching Co., Easton, Pennsylvania, 1975). It is preferably used in pharmaceutical compositions containing various hormones. Ethanol oleate as a solvent has the advantage of being well absorbed in tissues [J. pharm. Sci., 52, 918 (1963)]. There is no indication of its use in the preparation of sustained release injections.

Accordingly, it is surprising to find that only 2-4 volumes of ethyl oleate present in the presence of a solvent provide a therapeutic effect for a 5: 1 combination of sulfamethoxazole and trimethoprim.

The prolonged action was studied in the following formulations in piglets:

I. Comparative preparation not containing ethylene:

trimethoprim 4.0g sulfamethoxazole 20.0g

N, N-dimethylacetamide 63.6 ml

PEG 300 19.1ml

100 ml

II. Ethyl oleate-containing formulations according to the invention

10 daughter: trimethoprim 4.0 g gives birth to fametoxazole 20.0 g N, N-dimethyl-acetamide 60.0 ml PEG 300 19.1 ml 15 ethyloleate 3.0 ml 100 ml

Each group of animals received 30 mg / kg im. doses of ethylene-containing and ethylene-containing 20 were administered, and blood samples were taken at 1, 2, 3, 4, 6, 8, 10, and 24 hours post-dose and assayed for trimethoprim (TMP) and sulfamethoxazole (SMX). ) in the blood. Trimethoprim blood levels were determined by the method of W. F. Rehm et al., Béri. 25 Münch. Tierarztl. Wschr., 85, 228 (1972)] and the determination of sulfamethoxazole blood according to the method of C. A. Bratton et al. Biol. Chem., 128, 537 (1939)]. The results are shown in Table I.

Table I

Comparative blood test in piglets

Ϊ

Blood level after injection, μg / ml mg / kg IM. dose

administered preparation t hours 2 o'clock 3 oh ~ a 4 o'clock 6 hours 8 hours 10 am 24 hours I. Free from ethylene TMP Ί, οο 1.05 __________________. 0.63 0.35 0.20 0.10 _ SMX 31.9 26.4 19.4 15.5 6.2 1.2 - - II. ethyl oleate TMP 1.80 1.60 1.25 1.25 0.85 0.52 0.40 0.10 with SMX 26.6 27.3 24.0 22.7 14.9 8.5 6.5 2.0

From the data in the table, it appears that the concentration of sulfamethoxazole, which provides the actual therapeutic effect in the absence of ethyl oleate, decreases to such an extent that the therapeutic effect is lost by 8 hours after administration. (The therapeutic effect requires a concentration of sulfamethoxazole of at least 2.0 µg / ml.)

There is still a therapeutic effect after 24 hours of using the ethyl oleate-containing composition of the present invention. Thus, once daily injection is sufficient when treating sick piglets.

Piglets were also tested for their ability to tolerate the pharmaceutical composition of the invention. The drug was administered intramuscularly at 30 mg / kg, 90 mg / kg, 150 mg / kg and 300 mg / kg and examined for local or systemic reactions on days 1, 2 and 3 after administration.

No local or systemic reactions were observed at the therapeutic dose. At three times the therapeutic dose (90 mg / kg), a mild swelling occurred at the injection site the following day, but resolved the following day. At five times the therapeutic dose (150 mg / kg), a solid swelling was observed at the site of administration but disappeared on Day 2. Finally, there was a marked swelling at ten times the therapeutic dose, which disappeared only by day 3. No systemic reaction occurred at this extremely high dose.

Based on the above test, it can be concluded that the pharmaceutical composition of the present invention is very well tolerated by the animals.

According to the invention, the sustained release pharmaceutical composition is prepared by dissolving trimethoprim and sulfamethoxazole in about three-quarters of the total amount of dimethylacetamide with gentle heating, adding ethyl oleate and polyethylene glycol to the resulting solution, and bubbling the solution with the remainder of dimethylacetamide. The solution was filtered in a nitrogen gas and filled into glass bottles previously purged with nitrogen, air space above the liquid level in the air is stripped with nitrogen, sealed vials and sterilized for 20 minutes at 120 C. ^c.

Of course, the solution containing the components may be sterilized and filled into ampoules by any other means known in the art.

-2180740

When additives are used, it is convenient to dissolve the surfactant and solubilizing agent (s), sulfamethoxazole and trimethoprim, in dimethylacetamide, and after cooling, add a mixture of polyethylene glycol, ethyl oleate, distilled water and antioxidant (s).

The pH of the composition of the invention is close to the physiological pH of the blood, generally between 7.5 and 8. Because the method of the present invention also allows for the preparation of a relatively concentrated formulation, even when used in veterinary medicine, even the treatment of animals with a high body weight can be achieved by injecting a relatively small amount of solution.

The following examples illustrate the process of the invention in detail:

Example 1

Trimethoprim (4.0 g) and sulfamethoxazole (20.0 g) were dissolved in dimethylacetamide (45.0 ml), ethyl oleate (3.0 ml) and polyethylene glycol (PEG 300) (19.1 ml) were added, followed by addition of dimethylacetamide (15.6 ml). ml. The solution is filtered under nitrogen, filled into an ampoule, sealed and sterilized.

Example 2

Example 1 was prepared as described in Example 1 below. bi-pharmaceutical composition: trimethoprim 4.0 g sulfamethoxazole 20.0 g ethyloleate 2.5 ml PEG 200 19.1 ml dimethylacetamide 61.1 ml 100.0 mi

Example 3

Example 1 was prepared as described in Example 1 below. bi-pharmaceutical composition: trimethoprim 4.0 g sulfamethoxazole 20.0 g ethyloleate 3.5 ml PEG 600 19.1 ml dimethylacetamide 60.1 ml 100.0 ml

Example 4

Example 1 was prepared as described in Example 1 below.

bi-pharmaceutical composition: trimethoprim 4.0 g sulfamethoxazole 20.0 g ethyloleate 3.0 g PEG 400 17.7 ml dimethylacetamide 62.0 ml 100.0 ml

Example 5

Example 1 was prepared as described in Example 1 below.

bi-pharmaceutical composition: 5 trimethoprim 4.0 g sulfamethoxazole 20.0 g ethyloleate 3.0 ml Mixtures of PEG 300 and 400 20.5 ml dimethylacetamide 59.2 ml 10 100.0 ml

EXAMPLE 6 Polyvinylpyrrolidone g, 0.2 g sodium dioctylsulfo 15 succinate, 20.0 g sulfamethoxazole and 4.0 g trimethoprin were dissolved in 63.0 mL dimethylacetamide at about 40 ° C. To the resulting liquid was added PEG-300 (10.0 mL), a solution of sodium bisulfite (0.1 g) in water (1 mL), and ethyl oleate (2.3 mL). The resulting solution was made up to 100.0 mL with dimethylacetamide, filtered under nitrogen, filled into an ampoule, sealed and sterilized at 100 ° C for 30 minutes.

Claims (4)

Patent claims A process for the preparation of 3- (4-aminobenzenesulfonamido) -5-methylisoxazole and 2,4-diamino-5- (3,4,5-tri- For the preparation of an injectable pharmaceutical composition containing 30 methoxybenzyl) pyrimidine in a ratio of 5: 1, characterized in that 1-35 parts by weight of 3- (4-aminobenzenesulfonamido) -5-methylisoxazole and 0.2-7 parts by weight of 2 , 4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine 50-97 35 volumes of Ν, dimet-dimethylacetamide, 1 to 48 volumes of polyethylene glycol, 2 to 4 volumes of ethyl oleate, and 0 to 40 parts by weight of additive (s) are made into injectable formulations in a manner known per se. (First Edition: 21/21/1980) 2. A process comprising a 5: 1 weight ratio of sustained release 3- (4-aminobenzenesulfonamido) -5-methylisoxazole and 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine. for the preparation of an injectable pharmaceutical composition Characterized in that 1-35 parts by weight of 3- (4-aminobenzenesulfonamido) -5-methylisoxazole and 0.2-7 parts by weight of 2,4-diamino-5- (3,4,5-trimethoxybenzyl) ) pyrimidine is mixed with 50-97 volumes of Ν, Ν-dimethylacetamide, 1-48 volumes of polyethylene glycol and 2-4 volumes of ethyl oleate, and the mixture is converted, as is known per se, into an injectable preparation. (Priority: 27 February 1979) 3. The process of claim 2 wherein the 3- (4-aminobenzenesulfone) 55 amido) -5-methylisoxazole is added in 20 parts by weight and 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine is used in 4 parts by weight. (Priority: 27 February 1979) 4. The process of claim 2 wherein the ethyl oleate is 3 parts by volume