Aqueous pharmaceutical formulation
The invention concerns a stable aqueous pharmaceutical composition comprising 5-[(2RS)-2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-ylmethyl]-pyrimidine-2,4-diamine in form of the water soluble methanesulfonic acid salt, a physiological sodium chloride solution, ethanol and Povidone 12 PF, the liquid having a pH of over and above 4.8, but not higher than 5.2, and wherein the oxygen amount is controlled to be 0.8 ppm or less; which can be sterilized by filtration and/or by heated treatment, stored for longer time periods and which can be use for bolus injection or diluted for i.v. infusion.
1. A composition comprising a 5-[(2RS)-2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-ylmethyl]-pyrimidine-2,4-diamine (iclaprim) in a solution consisting essentially of a physiologically acceptable solvent and a 5-[(2RS)-2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-ylmethyl]-pyrimidine-2,4-diamine (iclaprim) addition salt characterized in that the oxygen concentration in the solution is 0.8 ppm or less.
2. The composition according to claim 1 , wherein the physiologically acceptable solvent is selected from the group consisting of water, alcohol, a physiological saline, an aliphatic amide, a glycol, a polyalcohol, esters of a polyalcohol, polyglycols, polyethers, and sugar alcohols or mixtures thereof.
3. The composition according to claim 2 , wherein the physiologically acceptable solvent is water or ethanol or a water/ethanol mixture.
4. The composition according to claim 3 comprising ethanol in a concentration range of between 0% and 50%.
5. The composition according to claim 3 comprising ethanol in a concentration range of between 5% and 45%.
6. The composition according to claim 3 comprising ethanol in a concentration range of between 20% and 35%.
7. The composition according to claim 1 further comprising natrium chloride (NaCl) in a concentration of between 0% and 3%.
8. The composition according to claim 1 further comprising natrium chloride (NaCl) in a concentration of between 0.1% and 1%.
9. The composition according to claim 1 , wherein the pH of the solution is in a range of between pH 4.2 and pH 5.7.
10. The composition according to claim 1 , wherein the concentration of the 5-[(2RS)-2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-ylmethyl]-pyrimidine-2,4-diamine (iclaprim) in the solution is in a range of at least 0.1% (w/w).
11. The composition according to claim 1 , wherein the concentration of the 5-[(2RS)-2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-ylmethyl]-pyrimidine-2,4-diamine (iclaprim) in the solution is in a range of at least 1% and not exceeding 2%.
12. The composition according to claim 1 further comprising a wetting agent, selected from the group consisting of N-methylpyrrolidone, polyvinylpyrrolidone, cyclodextrine, macrogol hydroxystearate, and macrogol glycerol ricinoleate in a concentration of between 0% and 20%.
13. The composition according to claim 1 further comprising a wetting agent selected from the group consisting of N-methylpyrrolidone, polyvinylpyrrolidone, cyclodextrine, macrogol hydroxystearate, and macrogol glycerol ricinoleate in a concentration of between 0.1% and 10%.
14. The composition according to claim 1 wherein the addition salt is an acid addition salt selected from the group of salts consisting of a salt with a mineral acid, an organic sulfonic acid and an organic carboxylic acid, separately and mixtures thereof.
15. The composition according to claim 1 wherein the addition salt is a methanesulfonic acid addition salt.
16. The composition according to claim 1 , further comprising a biologically active agent or compound.
17. The composition according to claim 16 , wherein the biologically active agent or compound is a sulfonamide selected from the group consisting of sulfamethoxazole, sulfisoxazole, sulfadimethoxine, dapsone.
18. A container having therein the composition according to claim 1 , wherein the container is a sealed container such as a vial or an ampoule, and wherein said composition comprises a physiologically acceptable solution and the oxygen concentration in the headspace is less than 5% (v/v).
19. The composition according to claim 1 for use in the control or prevention of infectious diseases in humans or animals.
20. The composition according to claim 19 , for use in the control or prevention of bacterial infections.
21. The composition according to claim 20 , for use in the control or prevention of Gram-positive strains, multi-drug-resistant Gram-positive strains, Gram-negative strains, pneumocystidaceae, parasites and opportunistic pathogens.