LONG ACTING SULFONAMIDE INJECTABLE COMPOSITIONS

Abstract: A long acting liquid sulfonamide injectable composition comprising (a) water (b) from 5 to 25% w/v based on the total volume of the solution of a sulfonamide selected from sulfadimethoxine and sulfamethazine and (c) 40 to 65% w/v based on the total volume of the solution of a co-solvent selected from 2-pyrrolidone and N-methylpyrrolidone, the composition having a pH of from 5 to 9.5. The compositions may also include from 1 to 5% w/v based on the total volume of solution of polyvinylpyrrolidone having an m.w. of 5000-100,000.

Description: LONG ACTING SULFONAMIDE INJECTABLE COMPOSITIONS This invention relates to sulfonamide solutions suitable for pharmaceutical use. More particularly, it relates to aqueous injectable solutions of sulfadimethoxine or sulfamethazine in 2-pyrrolidone or N-methylpyrrolidone. Parenteral solutions of sulfamethoxazole and trimethoprim containing the following water-miscible solvents are disclosed in U.S. Patent No. 3,551,564: polyethyleneglycol ethers of tetrahydrofurfuryl alcohol, dimethylformamide, dimethylsulfoxide, dimethylacetamide, diethylacetamide, 1,2-propyleneglycol, di-(1,2-propyleneglycol), 1,3-butylene glycol1 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 and sulfadoxine in a mixture of 10-60% water and 30-90% organic solvents such as dimethyl and diethylacetamide, dimethyl formamide, dimethylsulfoxide, glycerol formal and various glycols. U.S. Patent No. 4,018,889 discloses oxytetracycline solutions containing from about 1 to 40% oxytetracycline in an aqueous vehicle containing from about 10 to 50% by weight of 2-pyrrolidone, about 0.8 to 1.3 molar proportions of a pharmaceutically acceptable magnesium compound soluble in the said solution, said solution having a pH value in the range of from about 7.5 to 9.5. This invention discloses a long acting liquid sulfonamide injectable composition comprising (a) water (b) from 5 to 25% w/v based on the total volume of the solution of a sulfonamide selected from sulfadimethoxine and sulfamethazine and (c) 40 to 65% w/v based on the total volume of the solution of a co-solvent selected from 2-pyrrolidone and N-methylpyrrolidone, the composition having a pH of from 5 to 9.5. The sulfonamides utilized in the compositions of this invention are sulfadimethoxine and sulfamethazine. They are present in concentrations of from 5 to 25% w/v. The preferred concentration for sulfadimethoxine is 10 to 20% w/v and 15 to 20% w/v for sulfamethazine. Sulfadimethoxine is also known as N1-(2,6-dimethoxy- 4-pyrimidinyl)sulfanilamide and sulfamethazine is also known as N1-(4,6-dimethyl-4-pyrimidinyl)sulfanilamid 2-Pyrrolidone or N-methylpyrrolidone is present as a co-solvent in a concentration of from 40 to 65% w/v. The preferred concentration for 2-pyrrolidine is from 50 to 65% w/v and 40 to 65% for N-methyl-pyrrolidine. The pH value of these compositions is adjusted if necessary to pH 5 to 9.5. The pH can be adjusted by means of a base that is pharmaceutically acceptable, such as monoethanolamine. As an optional. ingredient polyvinylpyrrolidone, having 8 molecular weight of between about ski 000 and 100,000 (K-12 to 30), may also be present in these compositions in a concentration of from 1 to 5 w/v. The polyvinylpyrrolidone most preferred for this invention is one having an average molecular weight of about 10,000-17,000 (where Value = 17). It is present in part as a co-solubilizer and may improve tissue toleration. As optional co-solvents ingredients such as propylene glycol, polyethylene glycols, benzyl alcohol, dimethylacetamide, ethyl lactate and glycerol formal may be present at concentrations of from 0.5 to 30t w/v. The stability of these solutions for therapeutic administration is still further enhanced by use of an antioxidant such as monothioglycerol at levels of from 0.1 to 1% w/v. The primary application of these sulfonamide compositions is as a parenteral composition. The sulfonamide antibiotic compositions of this invention are easy to syringe over a wide temperature range and are satisfactory from a physical and chemical stability standpoint. These solutions produce prolonged efficacious blood levels and are well tolerated in contrast to the short term blood levels and tissue damage routine experienced with presently available highly alkaline aqueous sulfonamide solutions. The compositions of this invention are preferably prepared by mixing the co-solvent with water and other co-solvents, if present. The sulfonamide is then added and stirred until a clear solution results. The pH is then adjusted to the desired range. If polyvinylpyrrolidone is to be. included, it is added to the water at the tïme of mixing the co-solvent. The present invention is illustrated by the following Examples: EXAMPLE 1 gm/100 ml Sulfadimethoxine 5.00 Pyrrolidone 50.00 Dimethylacetamide 10.00 Polyvinylpyrrolidone (K=17) S.00 Ethyl lactate 10.00 gm/100 ml Benzyl alcohol 0.90 Monothioglycerol 0.20 Water q.s. to 100 ml The 2-pyrrolidone, dimethylacetamide, polyvinylpyrrolidone, ethyl lactate, benzyl alcohol and monothioglycerol were mixed and dissolved, successively, in water. The sulfadimethoxine was added and stirred until dissolved. The solution was then brought up to volume with water. The pH of the solution was 6.5 and the viscosity was 21 cts at 250 C. EXAMPLE 2 The following solution was prepared using the procedure of Example 1. gm/100 ml Sulfadimethoxine 10.00 2-Pyrrolidone 65.00 Polyvinylpyrrolidone (K=17) 5.00 Ethyl lactate 15.00 Benzyl alcohol 0.90 Monothioglycerol 0.20 Water q.s. to . 100 ml The pH of the solution was 6.8 and the viscosity was 36 cts at 250C. EXAMPLE 3 The following solution was prepared using the procedure of Example 1. gm/100 ml Sulfadimethoxine 20.00 2-Pyrrolidone 55.00 Dimethylacetamide 10.00 Polyvinylpyrrolidone (K-17) 5.00 Ethyl lactate 7.00 gm/100 ml Benzyl alcohol 0.90 Monothioglycerol 0.20 Water q.s. to 100 ml The pH of the solution was 6.7 and the viscosity was 28 cts at 250C. Raising the pH of the above solution with monoethanolamine to 9.5 produced a similar solution with a viscosity of 61 cts. Lowering the pH with hydrochloric acid to 5.0 produced a similar solution with pH 7.0 and a viscosity of 35 cts. The substitution of glycerol formal for ethyl lactate produced a similar solution with pH 7.3 and a viscosity of 44 cts. EXAMPLE 4 gm/100 ml Sulfadimethoxine 25.00 2-Pyrrolidone 60.00 Dimethylacetamide -- 10.00 Ethyl lactate 7.00 Benzyl alcohol 0.90 Monothioglycerol 0.20 Water q.s. to ' 100 ml The solution was prepared by dissolving all the ingredients in water, with the sulfadimethoxine being added last. The pH of the solution was 6.8. EXAMPLE 5 gm/100 ml Sulfadimethoxine 20.00 2-Pyrrolidone 63.50 Ethyl lactate 15.00 Polyvinylpyrrolidone (K=17) 4.20 Benzyl alcohol 0.90 Monothioglycerol 0.20 Water q.s. to 100 ml The solution was prepared using the procedure of Example 1. The pH of the solution was 6.7 and the viscosity was 35 at 25eC. The following solutions were prepared by dissolving all the ingredients in water, with the sulfamethazine being added last. gm/100 ml Example 6 Example 7 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 Monothioglycerol 0.20 0.20 Water q.s. to 100 ml 100 ml pH 7.5 7.0 Viscosity cts at 250C 18 23 EXAMPLE g Formulations containing 200 mg/ml of sulfadimethoxine in aqueous 2-pyrrolidone were administered by intramuscular injection to swine at a dose of 55 mg/kg The plasma levels after injection are given below. The control solution contained 200 mg/ml sulfadimethoxine as the sodium salt in water at pH 10.4 Time Post Example 3 Example 5 Control Dose (Hrs.) 4 47 55 94 7 49 54 103 24 37 46 24 48 22 26 6 72 15 15 3 96 8 10 120 6 8 As can be seen, by using 2-pyrrolidone as a co-solvent the plasma levels are prolonged when compared to results obtained with the aqueous sodium salt solution. EXAMPLE 9 Formulations containing 200 mg/ml of sulfamethazine in aqueous N-methypyrrolidone were administered by intramuscular injection to swine at a dose of 135 mg/kg. The plasma levels after injection are given below. The control solution contained 200 mg/ml of sulfamethazine in water, at pH 10.4. Time Post Example 6 Example 7 Control Dose (Hrs) 4 102 118 109 7 91 116 97 24 44 60 34 48 23 22 8 72 9 12 96 2 6 As can be seen by using N-methylpyrrolidone as a co-solvent the plasma levels are prolonged when compared to results obtained with the aqueous sodium salt solution.

Claims: CLAIMS 1. A long acting liquid sulfonamide injectable como- sition comprising (a) water (b) from 5 to 25% w/v based on the total volume of the solution of a sulfonamide selected from sulfadimethoxine and sulfamethazine and (c) 40 to 65% w/v based on the total volume of the solution of a co-solvent selected from 2-pyrrolidone and N-methylpyrrolidone, the composition having a pH of from 5 to 9.5. 2. A composition as claimed in claim 1 wherein the sulfonamide is sulfadimethoxine and the co-solvent is 2-pyrrolidone. 3. A composition as claimed in claim 1 wherein the sulfonamide is sulfamethazine and the co-solvent is N-methylpyrrolidone. 4. A composition as claimsed in any one of the previous claims which further comprises from 1 to 5% w/v based on the total volume of the solution of polyvinylpyrrolidone having an m.w. of 5000 - 100,000. 5. A long acting liquid sulfonamide injectable composition comprising (a) water (b) from 10 to 20% wv based on the total volume of the solution of sulfadimethoxine (c) from 50 to 65% w/v based on the total volume of the solution of 2-pyrrolidone and (d) from 1 to 5% w/v based on the total volume of the solution of polyvinylpyrrolidone having an m.w. of 5000 - 100,000, the composition having a pH from 5 to 9.5. 6. A long acting liquid sulfonamide injectable composition comprising (a) water (b) from 15 to 20% w/v based on the total volume of the solution of sulfamethazine (c) from 40 to 65% w/v based on the total volume of the solution of N-methylpyrrolidone and (d) from 1 to 5% w/v based on the total volume of the solution of polyvinylpyrrolidone having an m.w. of 5000 - 100,000, the comppsition having a pH from 5 to 9.5. AUSTRIAN CLAIMS 1. A process for preparing a long acting, liquid injectable solution of a sulfonamide which comprises dissolving sulfadimethoxine or sulfamethazine in aqueous 2-pyrrolidone or N-methylpyrrolidone containing if desired, polyvinylpyrrolidone, propylene glycol, a polyethylene glycol, benzyl alcohol, dimethylacetamide, ethyl lactate, or glycerol formal, and if necessary adjusting the pH to a value of from about 5 to 9.5. 2. A process according to claim 1 wherein 10 to 20E w/v sulfadimethoxine is dissolved in aqueous 2pyrrolidone, said 2-pyrrolidone being employed at a concentration of from about 50 to 65% w/v of said solution. 3. A process according to claim 1 wherein 15 to 202 w/v sulfamethazine is dissolved in aqueous N-methylpyrrolidone, said N-methylpyrrolidone being employed at a concentration of from about 40 to 65% w/v of said solution. 4. A process according to claim 1,2 or 3 wherein polyvinylpyrrolidone having an average molecular weight of about 5,000 to 100,000 is also present in a concentration of from about l'to 5% w/v. 5. A process acdording to claim 1,2,3 or 4 wherein propylene glycol, a polyethylene glycol, benzyl alcohol, dimethylacetamide, ethyl lactate or glycerol formal is also present in a concentration of from about 0.5 to 30% w/v.

Inventors: ARMSTRONG, WILLIAM WELLESLEY, DESAI, SAURABHKUMAR JAYAVANTRAI SHEELA APARTMENTS
Applicants: PFIZER INC.
Application year: 1980
Main classification: A61K9
IPC codes: A61K31, A61K47