Claims for Patent: 6,238,888

Summary for Patent: 6,238,888

Title:	Keratinocyte growth factor-2 formulations
Abstract:	The invention is directed to liquid and lyophilized forms of Keratinocyte Growth Factor-2 (KGF-2) and derivatives thereof. This invention further relates to the formulation of KGF-2 for therapeutic use, for example, to promote or accelerate wound healing.
Inventor(s):	Gentz; Reiner L. (Rockville, MD), Chopra; Arvind (Gaithersburg, MD), Kaushal; Parveen (Silver Spring, MD), Spitznagel; Thomas (Vienna, VA), Unsworth; Edward (Kensington, MD), Khan; Fazel (Gaithersburg, MD)
Assignee:	Human Genone Sciences, Inc. (Rockville, MD)
Application Number:	09/218,444
Patent Claims:	1. A pharmaceutical composition, comprising: (a) a KGF-2 polypeptide in a concentration range of about 0.02 to about 40 mg/ml (w/v); (b) a buffer having a buffering capacity of about pH 5.0 to about pH 8.0 at a concentration range of about 5 mM to about 50 mM; and (c) a diluent to bring the composition to a designated volume; or a reaction product of (a), (b), (c) or any combination thereof formed by admixing the ingredients of said composition together. 2. The pharmaceutical composition of claim 1, further comprising: (d) a chelating agent at a concentration range of about 0.1 mM to about 10 mM; and (e) NaCl at a concentration range of about 0.01 mM to about 150 mM. 3. The pharmaceutical composition of claim 1, further comprising one of: (f) about 0.5% to about 2% w/v glycerol, (g) about 0.1% to about 1% w/v methionine, or (h) about 0.1% to about 2% w/v monothioglycerol. 4. The pharmaceutical composition of claim 1, wherein said KGF-polypeptide is present in a concentration range of about 0.05 to about 30 mg/ml (w/v). 5. The pharmaceutical composition of claim 4, wherein said KGF-polypeptide is present in a concentration range of about 0.1 to about 20 mg/ml (w/v). 6. The pharmaceutical composition of claim 5, wherein said KGF-polypeptide is present in a concentration range of about 0.2 to 4 mg/ml. 7. The pharmaceutical composition of claim 1, wherein said KGF-2 polypeptide is Ser (69)--Ser (208) of KGF-2. 8. The pharmaceutical composition of claim 1, wherein said diluent is water. 9. The pharmaceutical composition of claim 2, wherein said chelating agent is ethylenediamine tetraacetic acid at a concentration of about 1 mM, and said NaCl is present at a concentration of about 125 mM. 10. The pharmaceutical composition of claim 1, wherein said pH is from about pH 5.5 to about pH 6.5. 11. The pharmaceutical composition of claim 10, wherein said pH is about pH 6.2. 12. The pharmaceutical composition of claim 1, wherein said buffer is selected from the group consisting of phosphonic, acetic, aconitic, citric, glutaric, malic, succinic carbonic acid, and an alkali or alkaline earth salt thereof. 13. The pharmaceutical composition of claim 12, wherein said buffer is a phosphate, acetate or citrate salt. 14. The pharmaceutical composition of claim 13, wherein said buffer is a citrate salt. 15. The pharmaceutical composition of claim 1, wherein said buffer is present in a concentration range of about 5 mM to about 30 mM. 16. The pharmaceutical composition of claim 15, wherein said buffer is a citrate salt present in a concentration of from about 10 mM to about 20 mM. 17. The pharmaceutical composition of claim 1, further comprising a stabilizing amount of one or more of (a) an antioxidant or (b) a thiol-compound. 18. The pharmaceutical composition of claim 1, wherein said composition is maintained at a temperature at or below -20.degree. C. 19. The pharmaceutical composition of claim 1, comprising: (a) 2 mg/ml Ser (69)--Ser (208) of KGF-2polypeptide(w/v); (b) 20 mM sodium acetate; (c) 125 mM NaCl; (d) 1 mM ethylenediamine tetraacetic acid; and (e) water as diluent, or a reaction product of (a), (b) or (c) or any combination thereof formed by admixing the ingredients of said composition together. 20. The pharmaceutical composition of claim 19, wherein said KGF-2 polypeptide is selected from the group consisting of Ser (69)--Ser (208) of KGF-2 having an N-terminal methionine, Ser (69)--Ser (208) of KGF-2 lacking an N-terminal methionine, and a mixture thereof. 21. A pharmaceutical composition, comprising: (a) a KGF-2 polypeptide in a concentration range of about 0.02 to about 40 mg/ml (w/v); (b) a buffer having a buffering capacity of about pH 5.0 to about pH 8.0 at a concentration range of about 5 mM to about 50 mM; (c) a bulking agent; and (d) a to bring the composition to a designated volume; or a reaction product of (a), (b), (c), (d) or any combination thereof formed by admixing the ingredients of said composition together. 22. The pharmaceutical composition of claim 21, wherein said bulking agent is selected from the group consisting of sucrose, glycine, mannitol, trehalose, and mixtures of two or more of the bulking agents present in any combination thereof in any amount as long as the total amount of the components make up 100% of the bulking agent. 23. The pharmaceutical composition of claim 21, further comprising: (e) a chelating agent at a concentration range of about 0.1 mM to about 10 mM; and (f) NaCl at a concentration range of about 0.01 mM to about 125 mM. 24. The pharmaceutical composition of claim 22, wherein said bulking agent is sucrose or a mixture of sucrose and glycine present in any combination thereof in any amount as long as the total amount of sucrose and glycine make up 100% of the bulking agent. 25. The pharmaceutical composition of claim 22, wherein said bulking agent is present in a concentration of about 2% to about 10% w/v. 26. The pharmaceutical composition of claim 22, wherein said bulking agent is 5% mannitol, 7% sucrose, 8% trehalose, or 2% glycine +0.5% sucrose. 27. The pharmaceutical composition of claim 21, wherein said pH is about pH 6.2. 28. The pharmaceutical composition of claim 21, wherein said diluent is water. 29. The pharmaceutical composition of claim 21, wherein said buffer is selected from the group consisting of phosphonic, acetic, aconitic, citric, glutaric, malic, succinic carbonic acid, and an alkali or alkaline earth salt thereof. 30. The pharmaceutical composition of claim 29, wherein said buffer is a phosphate or citrate salt. 31. The pharmaceutical composition of claim 30, wherein said buffer is a citrate salt. 32. The pharmaceutical composition of claim 21, wherein said KGF polypeptide is Ser (69)--Ser (208) of KGF-2. 33. The pharmaceutical composition of claim 32, wherein said KGF-2 .DELTA.33 polypeptide is selected from the group consisting of Ser (69)--Ser (208) of KGF-2 having an N-terminal methionine, Ser (69)--Ser (208) of KGF-2 lacking an N-terminal methionine, and a mixture thereof. 34. The pharmaceutical composition of claim 21, wherein said buffer is added in a concentration from about 5 mM to about 50 mM. 35. The pharmaceutical composition of claim 34, wherein said buffer is citrate at a concentration of about 10 mM. 36. The pharmaceutical composition of claim 21, further including a stabilizing amount of one or more of (g) an antioxidant, or (h) a thiol-compound. 37. A pharmaceutical composition, comprising: (a) a KGF-2 polypeptide in a concentration range of about 0.02 to about 40 mg/ml (w/v); (b) citric acid or a pharmaceutically acceptable salt thereof, at a concentration range of about 5 mM to about 20 mM; (c) NaCl at a concentration range of about 0.01 mM to about 125 mM; (d) ethylenediamine tetraacetic acid at a concentration range of about 0.1 mM to about 10 mM; (e) one or more of sucrose, mannitol, glycine or trehalose at a concentration range of about 2% w/v to about 15% w/v; and (f) water. 38. The pharmaceutical composition of claim 37, wherein said KGF-2 polypeptide is present at a concentration of about 2 mg/ml, about 4 mg/ml, or about 10 mg/ml. 39. The pharmaceutical composition of claim 1, further comprising a thickening agent in an amount effective to raise the viscosity to about 50 to about 10,000 centipoise. 40. The pharmaceutical composition of claim 40, wherein said thickening agent is present in an amount effective to raise the viscosity to about 50 to about 1,000 centipoise. 41. The pharmaceutical composition of claim 40, wherein said thickening agent in an amount effective to raise the viscosity to about 200 to about 300 centipoise. 42. The pharmaceutical composition of claim 21, further comprising a thickening agent in an amount effective to raise the viscosity to about 50 to about 10,000 centipoise. 43. The pharmaceutical composition of claim 39, wherein said thickening agent is present in a concentration of 0 to 5% (w/w). 44. The pharmaceutical composition of claim 39, wherein said thickening agent is a water soluble etherified cellulose or a high molecular weight polymer of acrylic acid cross-linked with allylsucrose or an allyl ether of pentaerythritol. 45. The pharmaceutical composition of claim 44, wherein said etherified cellulose is an alkyl cellulose, hydroxyalkyl cellulose, carboxyalkyl cellulose or alkylhydroxyalkyl cellulose. 46. The pharmaceutical composition of claim 39, wherein said etherified cellulose is methylcellulose, hydroxyethyl cellulose, hydroxy propyl cellulose, hydroxy propyl methylcellulose, or carboxymethyl cellulose. 47. The pharmaceutical composition of claim 45, wherein said etherified cellulose derivative has a molecular weight of about 50,000 to about 700,000 and is present in a concentration of about 0 to about 20% by weight. 48. The pharmaceutical composition of claim 47, wherein said etherified cellulose derivative has a molecular weight of about 80,000 to about 240,000 and is present in a concentration of about 2% to about 8% by weight. 49. The pharmaceutical composition of claim 42, wherein said buffer is citrate in a concentration of about 10 mM to about 50 mM. 50. The pharmaceutical composition of claim 49, wherein said buffer is citrate in a concentration of about 10 mM to about 20 mM citrate. 51. The pharmaceutical composition of claim 49, wherein said bulking agent is sucrose in a concentration of about 0.01% to about 5% sucrose. 52. The pharmaceutical composition of claim 51, wherein said thickening agent is added directly to a liquid formulation and thereafter lyophilized. 53. The pharmaceutical composition of claim 51, wherein said thickening agent is added to a lyophilized formulation by reconstituting said formulation by adding a suitable diluent having a thickening agent dissolved therein. 54. A thickened KGF-2 polypeptide solution composition formed by mixing: (a) a KGF-2 polypeptide in a concentration range of about 0.01 .mu.g/ml to about 10 mg/ml; (b) about 10 mM to about 500 mM sodium citrate buffer; (c) about 0.01 to about 150 mM NaCl; (d) 1 mM ethylenediamine tetraacetic acid; (e) about 0.1 to about 7% sucrose; and (f) about 0.75 to about 1.5% (w/w) carboxy methyl cellulose or about 0.5 to about 1.5% hydroxy propyl methyl cellulose or about 0.25 to about 0.75% hydroxy ethyl cellulose or about 0 to 1% carbomer or any combination thereof. 55. The composition of claim 1, further comprising a gelling agent in an amount effective to raise the viscosity to about 0.1 to about 10,000 centipoise at room temperature. 56. The composition of claim 21, further comprising a gelling agent in an amount effective to raise the viscosity to about 0.1 to about 10,000 centipoise at room temperature. 57. The composition of claim 55, wherein said gel forming agent is a water-soluble polymer capable of forming a viscous aqueous solution, or non-water soluble, water-swellable polymer capable of forming a viscous solution. 58. The composition of claim 57, wherein said gel forming agent is a high molecular weight polymer selected from the group consisting of vinyl polymer, polyoxyethylene-polyoxypropylene copolymer, polysaccharide, protein, poly(ethylene oxide), acrylamide polymer or a salt thereof. 59. The composition of claim 58, wherein said gel forming agent is (1) a vinyl polymer selected from the group consisting of polyacrylic acid, polymethacrylic acid, polyvinyl pyrrolidone polyvinyl alcohol and salts and esters thereof; or (2) a polysaccharide selected from the group consisting of a cellulose derivative, a glycosaminoglycan, agar, pectin, alginic acid, dextran, .alpha.-amylose, amylopectin, chitosan, and salts esters thereof. 60. The composition of claim 58, wherein said gel forming agent is a glycosaminoglycan selected from the group consisting of hyaluronic acid, chondroitin, chondroitin-4-sulfate, heparan sulfate, heparin and salts and esters thereof. 61. The composition of claim 60, wherein said glycosaminoglycan is present in combination with collagen, gelatin, or fibronectin. 62. The composition of claim 58, wherein said gel forming agent is an acrylamide polymer selected from the group consisting of a polyacrylamide or a polymethacrylamide. 63. The composition of claim 58, wherein said gel forming agent is a polyoxyethylene-polyoxypropylene block copolymer. 64. The composition of claim 63, which comprises about 10 to about 60% by weight of a polyoxyethylene-polyoxypropylene block copolymer having an average molecular weight of about 500 to 50,000. 65. The composition of claim 64, which comprises about 14 to about 18% by weight of a polyoxyethylene-polyoxypropylene block copolymer having a molecular weight in the range 1,000 to 15,000. 66. The composition of claim 65, wherein said gel forming agent is a polyoxyethylene-polyoxypropylene block copolymer having an average molecular weight of 12,600 or 14,600. 67. The composition of claim 1, wherein said KGF-2 polypeptide is present in a concentration of about 0.01 mg/ml to about 10 mg/ml. 68. The composition of claim 55, wherein said composition is formed by mixing: (a) a KGF-2 polypeptide, in a final calculated concentration of 0.01 mg/ml to about 10 mg/ml; (b) an effective amount of a buffering agent; (c) about 10% to about 60% by weight of a polyoxyethylene-polyoxypropylene block copolymer having an average molecular weight of about 500 to 50,000; and (d) a diluent. 69. The composition of claim 68, wherein polyoxyethylene-polyoxypropylene block copolymer is present at a concentration of about 14% to about 18%. 70. A KGF-2 gel formulation, comprising: (a) a KGF-2 polypeptide in a concentration range of about 0.01 mg/ml to about 10 mg/ml; (b) about 10 mM to about 500 mM sodium citrate; (c) about 0.01 mM to about 150 mM NaCl; (d) about 1 mM ethylenediamine tetraacetic acid; (e) about 0.1% to about 7% sucrose; and (f) about 14% to about 18% of a polyoxypropylene-polyoxyethylene block copolymer having an average molecular weight of 12,600; wherein the pH of said formulation is about pH 6.2. 71. A KGF-2 gel formulation, comprising: (a) a KGF-2 polypeptide at a concentration range of about 0.01 mg/ml to about 10 mg/ml (w/v), (b) sodium citrate at a concentration range of about 5 mM to about 20 mM; (c) about 10% to about 25% (w/v), of a polyoxyethylene polyoxypropylene copolymer having an average molecular weight of 12,600; and (d) water to volume. 72. The gel formulation of claim 71, further comprising: (a) ethylenediamine tetraacetic acid at a concentration range of about 0.1 mM to about 10 mM; and (b) NaCl at a concentration range of about 0.01 mM to about 125 mM. 73. The pharmaceutical composition of claim 1, wherein said KGF-2 polypeptide is a N-terminal deletion selected from the group consisting of Ala (63)--Ser (208) and Ser (69)--Ser (208). 74. The pharmaceutical composition of claim 73, wherein said KGF-2 polypeptide has an N-terminal methionine, lacks an N-terminal methionine, or is a mixture thereof. 75. The pharmaceutical composition of claim 1, wherein said KGF-2 polypeptide is a N-terminal or C-terminal deletion mutant selected from the group consisting of Ala (39)--Ser (208); Pro (47)--Ser (208); Val (77)--Ser (208); Glu (93)--Ser (208); Glu (104)--Ser (208); Val (123)--Ser (208); Gly (138)--Ser (208); Met (1), Thr (36); and Cys (37)--Lys (153). 76. The pharmaceutical composition of claim 75, wherein said KGF-2 polypeptide has an N-terminal methionine, lacks an N-terminal methionine, or is a mixture thereof. 77. The pharmaceutical composition of claim 7, wherein said polypeptide is selected from the group consisting of Ser (69)--Ser (208) of KGF-2 having an N-terminal methionine, Ser (69)--Ser (208) of KGF-2 lacking an N-terminal methionine, and a mixture thereof. 78. A pharmaceutical composition produced by removing, by lyophilization, over 90% of the water from a mixture comprising: (a) a KGF-2 polypeptide in a concentration range of about 0.02 to about 40 mg/ml (w/v); (b) a buffer having a buffering capacity of about pH 5.0 to about pH 8.0 at a concentration range of about 5 mM to about 50 mM; (c) a bulking agent; and (d) water to bring the composition to a designated volume; or a reaction product of (a), (b), (c), (d) or any combination thereof formed by admixing the ingredients of said composition together. 79. A pharmaceutical composition, produced by removing, by lyophilization, over 90% of the water from a mixture comprising: (a) a KGF-2 polypeptide in a concentration range of about 0.02 to about 40 mg/ml (w/v); (b) citric acid or a pharmaceutically acceptable salt thereof, at a concentration range of about 5 mM to about 20 mM; (c) NaCl at a concentration range of about 0.01 mM to about 125 mM; (d) ethylenediamine tetraacetic acid at a concentration range of about 0.1 mM to about 10 mM; (e) one or more of sucrose, mannitol, glycine or trehalose at a concentration range of about 2% w/v to about 15% w/v; and (f) water. 80. The pharmaceutical composition of claim 78, which is reconstituted with an amount of sterile water effective to maintain isotonic conditions of about 290 mOsm. 81. The pharmaceutical composition of claim 32, wherein said composition is reconstituted in sterile water containing a stabilizing amount of an antioxidant selected from the group consisting of: a) about 0.01% to about 2% w/v monothioglycerol, b) about 0.01% to about 2% w/v ascorbic acid, c) about 0.01% to about 2% w/v methionine or d) combinations thereof.

Details for Patent 6,238,888

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Corp.	ZOSTAVAX	zoster vaccine live	For Injection	125123	05/25/2006		2017-12-22