Patent EA-003367-B1 (EA)
Title: Stable liquid formulations of botulinum toxin
Inventor: MOYER ELIZABETH
IPC: A61P25/08
Filed: 1999-09-09
Abstract: 1. A stable liquid pharmaceutical botulinum toxin formulation, comprising a pharmaceutically acceptable buffer capable of providing a buffered pH range between about pH 5 and pH 6, and isolated botulinum toxin; wherein said formulation is stable as a liquid for at least one year at a temperature between about 0 and 10 degrees centigrade. 2. The formulation of claim 1, wherein said temperature is about 5+-3 degrees centigrade. 3. The formulation of claim 1, wherein said temperature is about 4+-2 degrees centigrade. 4. The formulation of any of claims 1-3, wherein said buffer has a pK in the range of pH 4.5-6.5. 5. The formulation of any of claims 1-4, wherein said toxin formulation is stable in liquid form for at least two years. 6. The formulation of any of claims 1-5, wherein said buffered pH range is about Ph 5.6+-0.2. 7. The formulation of any of claims 1-6, wherein said buffer is selected from the group consisting of phosphate buffer, phosphate-citrate buffer, and succinate buffer. 8. The formulation of any of claims 1-7, wherein said botulinum toxin is a botulinum toxin serotype selected from the group consisting of serotypes A, B, C1, C2, D, E, F and G. 9. The formulation of claim 8, wherein said botulinum toxin is botulinum toxin Type B present at a concentration in the range of about 100-20,000 U/ml. 10. The formulation of claim 9, wherein said botulinum toxin Type B is present at a concentration between about 1000-5000 U/ml. 11. The formulation of claim 9 or claim 10, wherein said botulinum toxin Type B is present in a high molecular weight complex of about 700 kilodaltons (kD). 12. The formulation of claim 8, wherein said botulinum toxin is botulinum toxin Type A, present at a concentration in the range of about 20-2000 U/ml. 13. The formulation of claim 12, wherein said botulinum toxin Type A is present at a concentration in the range of about 100-1000 U/ml. 14. The formulation of any of claims 1-13, which further includes an excipient protein. 15. The formulation of claim 14, wherein said excipient protein is selected from the group consisting of serum albumin, recombinant human serum albumin, and gelatin. 16. A stable liquid pharmaceutical botulinum toxin formulation, comprising a pharmaceutically acceptable liquid buffer capable of providing a buffered pH range between about pH 5 and pH 6, and isolated botulinum toxin; wherein said toxin formulation is stable as a liquid for at least about 6 months at a temperature between about 10 and 30 degrees centigrade. 17. The formulation of claim 16, wherein said temperature is about 25 degree C. 18. The formulation of any of claims 16-17, wherein said buffer has a pK in the range of pH 4.5-6.5. 19. The formulation of any of claims 16-18, wherein said buffer is selected from the group consisting of phosphate buffer, phosphate-citrate buffer, and succinate buffer. 20. The formulation of any of claims 16-19, wherein said buffered pH range is about pH 5.6+-0.2. 21. The formulation of any of claims 16-20, wherein said botulinum toxin is a botulinum toxin serotype selected from the group consisting of serotypes A, B, C1, C2, D, E, F and G. 22. The formulation of claim 21, wherein said botulinum toxin is botulinum toxin Type B present at a concentration of about 100-20,000 U/ml. 23. The formulation of claim 22, wherein said botulinum toxin Type B is present at a concentration in the range of about 1000-5000 U/ml. 24. The formulation of claim 22 or claim 23, wherein said botulinum toxin Type B is present in a high molecular weight complex of about 700 kD. 25. The formulation of claim 21, wherein said botulinum toxin is botulinum toxin Type A, present at a concentration in the range of about 20-2000 U/ml. 26. The formulation of claim 25, wherein said botulinum toxin is botulinum toxin Type A, present at a concentration in the range of about 100-1000 U/ml. 27. The formulation of any of claims 16-26, which further includes an excipient protein. 28. The formulation of claim 27, wherein said excipient protein is selected from the group consisting of serum albumin, human serum albumin, and gelatin. 29. A method of treating a patient in need of inhibition of cholinergic input to a selected muscle, muscle group, gland or organ, comprising administering to the selected muscle, muscle group, gland ar organ of the patient a pharmaceutically effective dose of a liquid botulinum toxin formulation according to any of claims 1-28. 30. The method of claim 29, wherein said patient is suffering from a disorder selected from the group consisting of spasticity, blepharospasm, strabismus, hemifacial spasm, dystonia, otitis media, spastic colitis, anismus, urinary detrusorsphincter dyssynergia, jaw-clenching, and curvature of the spine. 31. The method of claim 30, wherein said patient is suffering from spasticity due to one or more of the group consisting of stroke, spinal cord injury, closed head trauma, cerebral palsy, multiple sclerosis, and Parkinson's disease. 32. The method of claim 30, wherein said patient is suffering from a dystonia selected from the group consisting of spasmodic torticollis (cervical dystonia), spasmodic dysphonia, limb dystonia, laryngeal dystonia, and oromandibular (Meige's) dystonia. 33. The method of claim 29, wherein said selected muscle or muscle group produces a wrinkle or a furrowed brow. 34. The method of claim 29, wherein said muscle is a perineal muscle and wherein said patient is in the process of giving birth to a child. 35. The method of claim 29, wherein said patient is suffering from a condition selected from the group consisting of myofascial pain, headache associated with migraine, vascular disturbances, neuralgia, neuropathy, arthritis pain, back pain, 32 hyperhydrosis, rhinnorhea, asthma, excessive salivation, and excessive stomach acid secretion. 36. The method of any of claims 29-35, wherein said patient is refractory to botulinum toxin serotype A and said botulinum toxin in said formulation is selected from the group consisting of botulinum toxin serotypes B, C1, C2, D, E, F and G. 37. The method of claim 36, wherein said botulinum toxin in said formulation is botulinum toxin Type B. 38. The method of any of claims 29-35, wherein said patient is refractory to botulinum toxin serotype B and said botulinum toxin in said formulation is selected from the group consisting of botulinum toxin serotypes A, C1, C2, D, E, F and G. 39. The method of claim 38, wherein said botulinum toxin in said formulation is botulinum toxin Type A. 40. The use of a stable liquid botulinum toxin formulation according to any of claims 1-28 for the manufacture of a medicament for use in treating a patient in need of inhibition of cholinergic transmission to a selected muscle, muscle group, gland or organ. 41. The use according to claim 40, wherein said patient is suffering from a disorder selected from the group consisting of spasticity, blepharospasm, strabismus, hemifacial spasm, dystonia, otitis media, spastic colitis, anismus, urinary detrusorsphincter dyssynergia, jaw-clenching, and curvature of the spine. 42. The use according to claim 41, wherein said patient is suffering from spasticity due to one or more of the group consisting of stroke, spinal cord injury, closed head trauma, cerebral palsy, multiple sclerosis, and Parkinson's disease. 43. The use according to claim 41, wherein said patient is suffering from a dystonia selected from the group consisting of spasmodic torticollis (cervical dystonia), spasmodic dysphonia, limb dystonia, laryngeal dystonia, and oromandibular (Meige's) dystonia. 44. The use according to claim 40, wherein said selected muscle or muscle group produces a wrinkle or a furrowed brow. 45. The use according to claim 40, wherein said selected muscle is a perineal muscle and wherein said patient is in the process of giving birth to a child. 46. The use according to claim 40, wherein said patient is suffering from a condition selected from the group consisting of myofascial pain, headache associated with migraine, vascular disturbances, neuralgia, neuropathy, arthritis pain, back pain, hyperhydrosis, rhinnorhea, asthma, excessive salivation, and excessive stomach acid secretion. 47. The use according to any of claims 40-46, wherein said patient is refractory to botulinum toxin Type A and said botulinum toxin in said formulation is selected from the group consisting of botulinum toxin serotypes B, C1, C2, D, E, F and G. 48. The method of claim 47, wherein said botulinum toxin in said formulation is botulinum toxin Type B. 49. The use according to any of claims 40-46, wherein said patient is refractory to botulinum toxin Type B and said botulinum toxin in said formulation is selected from the group consisting of botulinum toxin serotypes A, C1, C2, D, E, F and G. 50. The use according to claim 49, wherein said botulinum toxin in said formulation is botulinum toxin Type A.