Pharmaceutical composition comprising botulinum, a non ionic surfactant, sodium chloride and sucrose

Abstract

The invention relates to a solid or liquid pharmaceutical composition comprising botulinum neurotoxin complex (type A, B, C, D, E, F or G) or high purity botulinum neurotoxin (type A, B, C, D, E, F or G), and a surfactant. In particular the invention relates to a solid or liquid pharmaceutical composition comprising a crystalline agent.

Claims

1. A solid or liquid pharmaceutical composition consisting of: (a) botulinum neurotoxin complex of type A, B, C, D, E, F or G, or a high purity botulinum neurotoxin of type A, B, C, D, E, F or G; (b) a non-ionic surfactant; (c) sodium chloride; (d) a buffer capable of maintaining an aqueous solution at a pH of 5.5 to 7.5; (e) a disaccharide; and (f) when the composition is liquid, water, wherein the composition does not contain albumin or polysaccharides.

2. The composition of claim 1, wherein the botulinum neurotoxin complex is type A.

3. The composition of claim 1, wherein the high purity botulinum neurotoxin is type A.

4. The composition of claim 1, wherein the botulinum neurotoxin is present at 50 to 3,000 LD50 units.

5. The composition of claim 1, wherein the non-ionic surfactant is a polysorbate.

6. The composition of claim 5, wherein the polysorbate is polyoxyethylene (20) sorbitan monooleate.

7. The composition of claim 1, wherein the disaccharide is sucrose, trehalose or lactose.

8. The composition of claim 7, wherein the disaccharide is sucrose.

9. The composition of claim 1, wherein the buffer is succinate or histidine.

10. The composition of claim 9, wherein the buffer is histidine.

11. The composition of claim 1, wherein the buffer is capable of maintaining an aqueous solution at a pH of 5.8 to 7.0.

12. The composition of claim 1, wherein the composition is a solid pharmaceutical composition.

13. The composition of claim 1, wherein the composition is a liquid pharmaceutical composition.

14. The composition of claim 13, wherein the non-ionic surfactant is present in an amount of from above critical micellar concentration to 1% v/v of the total volume of the composition.

15. The composition of claim 13, wherein the non-ionic surfactant is polysorbate 80 and is present in an amount of from 0.005% to 0.02% v/v of the total volume of the composition.

16. The composition of claim 13, wherein the concentration of sodium chloride is from 0.1 to 0.5 M.

17. The composition of claim 13, wherein the disaccharide is present in a concentration of from 5 to 50 mM.

18. The composition of claim 13, wherein the concentration of the buffer is from 1 to 50 mM.

Description

EXAMPLES

Example 1: A Liquid Pharmaceutical Composition Containing the Following Components is Prepared

(1) TABLE-US-00001 Clostridium botulinum type A1 neurotoxin complex 2,000 LD.sub.50 units/ml Sucrose 11.7 mM Histidine 10 mM Sodium chloride 0.3M Polysorbate 80 0.01% v/v pH 6.5

(2) The mixture containing nominally 2,000 LD.sub.50 units of botulinum toxin per ml is lyophilised in a sterilised vial, which is then sealed. The solid composition obtained is stable for at least 18 months when stored at a temperature between 2 and 8° C. and at least 6 months at 23 to 27° C.

Example 2: A Liquid Pharmaceutical Composition Containing the Following Components is Prepared

(3) TABLE-US-00002 Clostridium botulinum type A1 neurotoxin complex 500 LD.sub.50 units/ml Sucrose 11.7 mM Histidine 10 mM Sodium chloride 0.3M Polysorbate 80 0.01% v/v PH 6.5

(4) The liquid composition thus prepared is sealed in a syringe type device with no liquid/gaseous interface. Stored in these conditions, it is stable for at least six months at 23 to 27° C. and at least twelve months at 2-8° C.

Example 3: A Liquid Pharmaceutical Composition Containing the Following Components is Prepared

(5) TABLE-US-00003 Clostridium botulinum type A1 neurotoxin complex 500 LD.sub.50 units/ml Sucrose 11.7 mM Histidine 10 mM Sodium chloride 0.15M Polysorbate 80 0.01% v/v PH 6.5

(6) The liquid composition thus prepared is sealed in a syringe type device with no liquid/gaseous interface. Stored in these conditions, it is stable for at least six months at 23 to 27° C. and at least twelve months at 2-8° C.

(7) Analytical Methods

(8) Mouse Toxicity Assay

(9) A mouse toxicity assay can be used to measure the toxicity of botulinum neurotoxin complex (type A, B, C, D, E, F or G) or high purity botulinum neurotoxin (type A, B, C, D, E, F or G). In the assay, a standard diluent will be used to prepare a range of dilutions at or about the estimated LD.sub.50 value. The range and scale of dilutions is arranged so as to establish an accurate LD.sub.50 value.

(10) Mice are injected intraperitoneally with a known and standardised volume of diluted toxin. After 96 hours, the number of deaths and survivors in each dilution group will be recorded. The LD.sub.50 value is the median dose which kills half of the injected animals within 96 hours.

(11) A composition according to the invention is considered stable over a certain period of time if at least 70% of the initial toxicity is maintained over said period of time relative to a reference preparation.