Pamidronate solution

A stable injectable solution containing pamidronate and a method for preparing a therapeutic aqueous disodium pamidronate solution. The method comprises preparing a slurry of pamidronic acid in water, combining aqueous sodium hydroxide with the slurry in an amount about 2:1 molar ratio of sodium hydroxide to pamidronic acid to yield a solution of disodium pamidronate having visual clarity and a pH of about 6.5, and packaging the solution in sealed containers. A unit dosage form including the solution and a vial or ampule comprising the unit dosage form are also described.

EXAMPLE 1 In this example the product solution was composed of the following: 1 pamidronic acid 2.53 mg mannitol 47.0 mg sodium hydroxide 0.43 mg pH qs to 6.3-6.7 using 1.0 N sodium hydroxide WFI qs to 1.0 mL The solution was formulated using standard manufacturing processes and filled into 10 mL siliconised, low aluminium, type 1 glass vials, supplied by SGD. Each vial was enclosed by a 20 mm, S10-F451, D777-1, B2-40, Fluorotec stopper supplied by Daikyo/West. Table 1 shows the test results measured over a 18 month period while being stored inverted at 25° C., relative humidity (RH) 60%. 2 TABLE 1 Initial (0 Months) 6 months 12 months 18 months Appearance N N N N Potency 97.5% 99.5% 100.8% 99.9% pH 6.4 6.2 6.4 6.4 Metal ions silicon ppm 0.23 2.2 calcium ppm <0.04 <0.04 aluminium ppm <0.04 0.1 N - Clear colorless solution, free from visible particles. 
 EXAMPLE 2 In this example the product solution was composed of the following: 3 pamidronic acid 7.58 mg mannitol 37.5 mg sodium hydroxide 1.29 mg pH qs to 6.3-6.7 using 1.0 N sodium hydroxide WFI qs to 1.0 mL The solution was formulated using standard manufacturing processes and filled into 10 mL siliconised, low aluminium, type 1 glass vials, supplied by SGD. Each vial was enclosed by a 20 mm, S10-F451, D777- 1, B2-40, Fluorotec stopper supplied by Daikyo/West. Table 2 shows the test results measured over a 18 month period while being stored inverted at 25° C., relative humidity (RH) 60%. 4 TABLE 2 Initial (0 Months) 6 months 12 months 18 months Appearance N N N N Potency 105.1% 106.0% 105.9% 107.2% pH 6.4 6.2 6.4 6.3 Metal ions silicon ppm .4 5.9 calcium ppm 0.06 0.1 aluminium ppm 0.04 .29 N - Clear colourless solution, free from visible particles. 
 EXAMPLE 3 In this example the product solution was composed of the following: 5 pamidronic acid 2.53 mg mannitol 47.0 mg sodium hydroxide 0.86 mg pH qs to 6.3-6.7 using 1.0 N sodium hydroxide or 1.0 N phosphoric acid. WFI qs to 1.0 mL The solution was formulated using standard manufacturing processes and filled, into 10 mL siliconised, low aluminium, type 1 glass vials, supplied by SGD. Each vial was enclosed by a 20 mm, S10-F451, D777-1, B2-40, Fluorotec stopper supplied by Daikyo/West. Table 3 shows the test results measured over a 12 month period while being stored inverted at 25° C., relative humidity (RH) 60%. 6 TABLE 3 Initial (0 Months) 6 months 12 months Appearance N N N Potency 103.6% 103.5% 104.0% pH 6.5 6.4 6.5 Metal ions silicon ppm 0.31 0.2 0.47 calcium ppm 0.06 <0.04 <0.04 aluminium ppm 0.17 <0.04 <0.04 N - Clear colorless solution, free from visible particles. 
 EXAMPLE 4 In this example the product solution was composed of the following: 7 pamidronic acid 7.58 mg mannitol 37.5 mg sodium hydroxide 2.58 mg pH qs to 6.3-6.7 using 1.0 N sodium hydroxide or 1.0 N phosphoric acid. WFI qs to 1.0 mL The solution was formulated using standard manufacturing processes and filled, into 10 mL siliconised, low aluminium, type 1 glass vials, supplied by SGD. Each vial was enclosed by a 20 mm, S10-F451, D777-1, B2-40, Fluorotec stopper supplied by Daikyo/West. Table 4 shows the test results measured over a 12 month period while being stored inverted at 25° C., relative humidity (RH) 60%. 8 TABLE 4 Initial (0 Months) 6 months 12 months Appearance N N N Potency 98.9% 99.2% 100.0% pH 6.5 6.4 6.5 Metal ions silicon ppm 0.29 0.3 0.65 calcium ppm 0.18 0.10 0.13 aluminium ppm 0.12 <0.04 0.07 N - Clear colorless solution, free from visible particles. It is understood that various modifications, alternatives and/or additions may be made to the product specifically described herein without departing from the spirit and ambit of the invention.