FI72651C - FOERFARANDE FOER FRAMSTAELLNING AV EN LAONGTIDSVERKANDE INJEKTIONSLOESNING AV SULFAMETAZIN. - Google Patents

Description

1 72651

Method for preparing a long-acting sulfamethazine injection solution

This invention relates to the preparation of sulfonamide solutions suitable for pharmaceutical use, and more particularly to a process for preparing injectable aqueous solutions of sulfamethazine in N-methylpyrrolidone.

U.S. Patent No. 3,551,564 discloses parenteral solutions of sulfamethoxazole and trimethoprim containing the following water-miscible solvents: polyethylene glycol ethers of tetrahydrofuryl alcohol, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, diethylacetamide, 1,2-15 propylene -propylene glycol), 1,3-butylene glycol, glycerol formal, diethylene glycol and polyethylene glycol containing 2-15 ethylene oxide groups.

U.S. Patent No. 3,985,876 discloses solutions of trimethoprim with various sulfonamides, including sulfamethoxazole-20 and a mixture of sulfadoxine containing 10-60% water and 30-90% organic solvents such as dimethyl and diethylacetamide, dimethylformamide, dimethyl sulfoxide, glycerol formal and different glycols.

U.S. Patent No. 4,018,889 discloses containing about 1-40% oxytetracycline in an aqueous binder containing about 10-50% by weight of 2-pyrrolidone, about 0.8-1.3 molar proportions of a pharmaceutically acceptable magnesium compound soluble in said solution. oxytetracycline solutions, wherein the pH of said solution is in the range of about 7.5 to 9.5.

The process of this invention provides a long acting liquid injectable sulfonamide mixture containing about 5-25% w / v of a sulfonamide which is sulfamethazine, 40-65% w / v of a co-solvent which is N-methylpyrrolidone. The preferred sulfamethazine concentration is 15-20% w / v.

2 72651

Sulfamethazine is also known as N- (4,6-dimethyl-4-pyrimidinyl) sulfanalinamide.

The pH of these mixtures is adjusted to pH 5-9.5, if necessary. The pH can be adjusted with a pharmaceutically acceptable base such as monoethanolamine.

Optionally, polyvinylpyrrolidone having a molecular weight of between about 5,000 and 100,000 (K-12-30) at a concentration of about 1-5% w / v may be present as an optional ingredient.

The preferred polyvinylpyrrolidone of this invention has an average molecular weight of about 10,000 to 17,000 (where K value = 17). It is present in part as a co-solvent and can improve tissue tolerance.

Optional co-solvents may include ingredients such as propylene glycol, polyethylene glycols, benzyl alcohol, dimethylacetamide, ethyl lactate and glycerol formal in concentrations of about 0.5-30% w / v.

The stability of these solutions for therapeutic administration is further enhanced by the use of an antioxidant such as monothioglycerol at concentrations of about 0.1-1% w / v.

The preferred use of such sulfonamide mixtures is as a parenteral mixture.

The sulfonamide antibiotic compositions 25 of this invention are easy to inject over a wide temperature range and are satisfactory from the point of view of physical and chemical stability.

These solutions produce an extended effective concentration in the blood and are well tolerated and thus differ from the highly basic aqueous solutions of sulfonamides currently in use, which are short-acting in terms of blood levels and whose use often causes tissue damage.

The compositions of this invention are preferably prepared by mixing the co-solvent with water and any other co-solvents present. Sulfamethazine is then added and stirred until the solution is clear. The pH is then adjusted to the desired range. If polyvinylpyrrolidone is included in the mixture, it is added to the water while mixing the co-solvent.

The following examples illustrate the present invention.

It should be understood, however, that the invention is not limited to the specific details of these examples.

Examples 1 and 2

The following solutions were prepared by dissolving all 10 ingredients in water, with sulfamethazine being added last.

g / 100 ml

Example 1 Example 2 Sulfamethazine 20.00 20.00 N-methylpyrrolidone 63.50 40.00

Glycerol formal - 37.50

Polyvinylpyrrolidone (K = 17) 5.00 5.00

Benzyl alcohol 0.90 0.90 2Q Monothioglycerol 0.20 0.20

Water q s gives 100 ml 100 ml PH 7.5 7.0

Viscosity mm / s at 25 ° C 18 23 25 Example 3

Preparations containing 200 mg / ml sulfamethazine in aqueous N-methylpyrrolidone solution were administered intramuscularly to pigs at a dose of 135 mg / kg. Post-injection plasma concentrations are given below. The reference solution si-30 contained 200 mg / ml sulfamethazine in water at pH 10.4.

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Post-dose Example Example Comparison time (hours) 4 102 118 109 7 91 116 97 5 24 44 60 34 48 23 22 8 72 9 12 - 96 2 g 10

As can be seen, by using N-methylpyrrolidone as a co-solvent, the plasma concentrations are prolonged compared to the results obtained by using an aqueous sodium salt solution.

Claims (5)

5 72651 A process for preparing a long-acting liquid sulfa-metazine injection solution, characterized in that sulfamethazine is dissolved in an aqueous solution of N-methylpyrrolidone containing, if desired, polyvinylpyrrolidone, propylene glycol, glycol-ethylamine and ethyl ethyl, ethyl alcohol, dimethyl alcohol, benzyl alcohol, if desired, the pH is adjusted to about 5-9.5. A process according to claim 1, characterized in that 15-20% w / v sulfamethazine is dissolved in an aqueous solution of N-methylpyrrolidone, wherein N-methylpyrrolidone is used in about 40-65% w / v of said solution. Process according to Claim 1 or 2, characterized in that polyvinylpyrrolidone with an average molecular weight of about 5,000 to 100,000 is also present in a concentration of about 1 to 5% w / v. Process according to Claim 1, 2 or 3, characterized in that propylene glycol, a polyethylene glycol, benzyl alcohol, dimethylacetamide, ethyl lactate or glycerol formal is also present in a concentration of about 0.5 to 30% w / v.