HYDROMORPHONE THERAPY

• US 20100028389A1
• Filed: 10/01/2009
• Published: 02/04/2010
• Est. Priority Date: 07/07/1994
• Status: Abandoned Application

• Current Assignee: Mallinckrodt LLC (Mallinckrodt plc)
• Original Assignee: Mallinckrodt LLC (Mallinckrodt plc)
• Inventors: Kuczynski, Anthony L., Merrill, Sonya, Chadha, Navjot, Ayer, Atul D.
• Application Number:
  US12/572,106
• Publication Number:
  US 20100028389A1
• Time in Patent Office: Days
• US Class Current: 424/400
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system

Abstract

A hydromorphone composition, a hydromorphone dosage form and a method for administering hydromorphone are disclosed, indicated for the management of pain.

Claims

1-31. -31. (canceled)

32. A therapeutic composition for the relief of pain comprising:

(a) a hydromorphone formulation that on day four of once daily administration to a population of subjects provides, for a 16 mg dose of hydromorphone;

(i) a plasma concentration maximum of about 2.6 ng/mL,

(ii) a time to maximum plasma concentration of about 14.7 hours,

(iii) a plasma concentration minimum of about 1.2 ng/mL,

(iv) a time to minimum plasma concentration of about 13.1 hours following the maximum plasma concentration; and

(v) an area under the curve of 45 ng-hr/mL; and

(b) an expandable push composition, wherein the therapeutic composition is encased with a semipermeable wall with a passageway through the semipermeable wall.

33. A therapeutic composition according to claim 32, wherein the hydromorphone formulation comprises hydromorphone, a hydrogel polymer, a binder, and a lubricant.

34. A therapeutic composition according to claim 33, wherein the formulation comprises from about 1 to about 65 mg of hydromorphone or a pharmaceutically acceptable salt thereof.

35. A therapeutic composition according to claim 33, wherein the hydrogel polymer comprises a maltodextrin polymer of 500 to 1,250,000 number average molecular weight;

poly(alkylene oxide) represented by a poly(ethylene oxide) of 50,000 to 750,000 weight-average molecular weight, poly(propylene oxide) of 50,000 to 750,000 weight-average molecular weight, alkali carboxyalkylcellulose, wherein the alkali is sodium or potassium, the alkyl is methyl, ethyl, propyl, or butyl of 10,000 to 175,000 weight-average molecular weight;

or a copolymer of ethylene-acrylic acid, including methacrylic and ethacrylic acid of 10,000 to 500,000 number-average molecular weight.

36. A therapeutic composition according to claim 35, wherein the hydrogel polymer comprises poly(ethylene oxide) of 50,000 to 750,000 molecular weight.

37. A therapeutic composition according to claim 36, wherein the hydrogel polymer comprises poly(ethylene oxide) of about 200,000 molecular weight.

38. A therapeutic composition according to claim 33, wherein the binder comprises poly-n-vinylamide, poly-nvinylacetamide, poly(vinyl pyrrolidone), poly-n-vinylcaprolactone, poly-nvinyl-5-methyl-2-pyrrolidone, or poly-n-vinyl-pyrrolidone copolymers with a member selected from the group consisting of vinyl acetate, vinyl alcohol, vinyl chloride, vinyl fluoride, vinyl butyrate, vinyl laureate, or vinyl stearate.

39. A therapeutic composition according to claim 38, wherein the binder comprises poly(vinylpyrrolidone) of 38,000 to 42,000 molecular weight.

40. A therapeutic composition according to claim 39, wherein the binder comprises poly(vinylpyrrolidone) of about 40,000 molecular weight.

41. A therapeutic composition according to claim 33, wherein the lubricant is selected from the group consisting of magnesium stearate, sodium stearate, stearic acid, calcium stearate, magnesium oleate, oleic acid, potassium oleate, caprylic acid, sodium stearyl fumarate, and magnesium palmitate.

42. A therapeutic composition according to claim 41, wherein the lubricant comprises magnesium stearate.

43. A therapeutic composition according to claim 33, wherein the hydromorphone formulation is selected from the group consisting of:

(a) 8 mg of hydromorphone, 67.8 mg of poly(ethylene oxide), 4 mg of poly(vinylpyrrolidone), and 0.2 mg of magnesium stearate;

(b) 16 mg of hydromorphone, 135.6 mg of poly(ethylene oxide), 8 mg of poly(vinylpyrrolidone), and 0.4 mg of magnesium stearate;

(c) 32 mg of hydromorphone, 119.6 mg of poly(ethylene oxide), 8 mg of poly(vinylpyrrolidone), and 0.4 mg of magnesium stearate; and

(d) 64 mg of hydromorphone, 138.6 mg of poly(ethylene oxide), 10.7 mg of poly(vinylpyrrolidone), and 0.53 mg of magnesium stearate.

44. A therapeutic composition according to claim 33, wherein the hydromorphone formulation is selected from the group consisting of:

(a) 10.5% hydromorphone hydrochloride, 84.23% poly(ethylene oxide), 5% poly(vinylpyrrolidone), 0.02% butylated hydroxytoluene, and 0.25% magnesium stearate for a 8 mg dose of hydromorphone;

(b) 10.5% hydromorphone hydrochloride, 84.23% poly(ethylene oxide), 5% poly(vinylpyrrolidone), 0.02% butylated hydroxytoluene, and 0.25% magnesium stearate for a 16 mg dose of hydromorphone;

(c) 20% hydromorphone hydrochloride, 74.68% poly(ethylene oxide), 5% poly(vinylpyrrolidone), 0.02% butylated hydroxytoluene, and 0.25% magnesium stearate for a 32 mg dose of hydromorphone; and

(d) 30% hydromorphone hydrochloride, 64.73% poly(ethylene oxide), 5% poly(vinylpyrrolidone), 0.02% butylated hydroxytoluene, and 0.25% magnesium stearate for a 64 mg dose of hydromorphone.

45. A therapeutic composition according to claim 32, wherein the push composition comprises an osmopolymer, an osmagent, a colorant, a lubricant, and an antioxidant.

46. A therapeutic composition according to claim 45, wherein the osmopolymer comprises polyalkylene oxide and a hydroxpropylalkyl cellulose.

47. A therapeutic composition according to claim 46, wherein the polyalkylene oxide comprises polyethylene oxide of 1,000,000 to 7,000,000 molecular weight.

48. A therapeutic composition according to claim 47, wherein the polyalkylene oxide comprises polyethylene oxide of about 2,000,000 molecular weight.

49. A therapeutic composition according to claim 46, wherein the hydroxpropylalkyl cellulose comprises hydroxypropylmethylcellulose of 9,000 to 450,000 number average molecular weight.

50. A therapeutic composition according to claim 45, wherein the osmagent is selected from the group consisting of sodium chloride, potassium chloride, magnesium sulfate, lithium phosphate, lithium chloride, sodium phosphate, potassium sulfate, sodium sulfate, potassium phosphate, glucose, fructose and maltose.

51. A therapeutic composition according to claim 50, wherein the osmagent comprises sodium chloride.

52. A therapeutic composition according to claim 45, wherein the colorant is selected from the group consisting of FD&

C No. 1 blue dye, FD&

C No. 4 red dye, red ferric oxide, yellow ferric oxide, titanium dioxide, carbon black, and indigo.

53. A therapeutic composition according to claim 45, wherein the lubricant is selected from the group consisting of magnesium stearate, sodium stearate, stearic acid, calcium stearate, magnesium oleate, oleic acid, potassium oleate, caprylic acid, sodium stearyl fumarate, and magnesium palmitate.

54. A therapeutic composition according to claim 53, wherein the lubricant comprises magnesium stearate.

55. A therapeutic composition according to claim 45, wherein the antioxidant is selected from the group consisting of ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, a mixture of 2 and 3 tertiary-butyl-4-hydroxyanisole, butylated hydroxytoluene, sodium isoascorbate, dihydroguaretic acid, potassium sorbate, sodium bisulfate, sodium metabisulfate, sorbic acid, potassium ascorbate, vitamin E, 4-chloro-2,6-ditertiary butylphenol, alphatocopherol, and propylgallate.

56. A therapeutic composition according to claim 55, wherein the antioxidant comprises butylated hydroxytoluene.

57. A therapeutic composition according to claim 45, wherein the push composition is selected from the group consisting of:

(a) 37.8 mg of poly(ethylene oxide), 18 mg of osmagent, 3 mg of hydroxypropylmethylcellulose, 0.6 mg of a colorant, 0.15 mg of a lubricant, and 0.06 mg of an antioxidant for a 8 mg dose of hydromorphone;

(b) 76.49 mg of poly(ethylene oxide), 36 mg of osmagent, 6 mg of hydroxypropylmethylcellulose, 1.2 mg of a colorant, 0.3 mg of a lubricant, and 0.12 mg of an antioxidant for a 16 mg dose of hydromorphone;

(c) 76.49 mg of poly(ethylene oxide), 36 mg of sodium chloride, 6 mg of hydroxypropylmethylcellulose, 1.2 mg of a colorant, 0.3 mg of a lubricant, and 0.012 mg of an antioxidant for a 32 mg dose of hydromorphone; and

(d) 104.53 mg of poly(ethylene oxide), 49.2 mg of sodium chloride, 8.2 mg of hydroxypropylmethylcellulose, 1.64 mg of a colorant, 0.41 mg of a lubricant, and 0.123 mg of an antioxidant for a 64 mg dose of hydromorphone.

58. A therapeutic composition according to claim 45, wherein the push composition is selected from the group consisting of:

(a) 64.3% of poly(ethylene oxide), 30% of osmagent, 5% of hydroxypropylmethylcellulose, 0.4% of a colorant, 0.25% of a lubricant, and 0.05% of an antioxidant for a 8 mg dose of hydromorphone;

(b) 64.3% of poly(ethylene oxide), 30% of osmagent, 5% of hydroxypropylmethylcellulose, 0.4% of a colorant, 0.25% of a lubricant, and 0.05% of an antioxidant for a 16 mg dose of hydromorphone;

(c) 63.672% of poly(ethylene oxide), 30% of osmagent, 5% of hydroxypropylmethylcellulose, 1% of a colorant, 0.25% of a lubricant, and 0.05% of an antioxidant for a 32 mg dose of hydromorphone; and

(d) 64.3% of poly(ethylene oxide), 30% of osmagent, 5% of hydroxypropylmethylcellulose, 0.4% of a colorant, 0.25% of a lubricant, and 0.05% of an antioxidant for a 64 mg dose of hydromorphone.

59. A therapeutic composition according to claim 32, wherein the semipermeable wall comprises a member selected from the group consisting of a cellulose ester polymer, a cellulose ether polymer and a cellulose ester-ether polymer.

60. A therapeutic composition according to claim 59, wherein the semipermeable wall comprises cellulose acetate having a DS of 2 to 3 and an acetyl content of 35 to 44.8%.

61. A therapeutic composition according to claim 60, wherein the semipermeable wall comprises cellulose acetate having a DS of 2 to 3 and an acetyl content of 39.8%.

62. A therapeutic composition according to claim 59, wherein the semipermeable wall comprises 99 weight % cellulose acetate having a DS of 2 to 3 and an acetyl content of 39.8% and 1 weight % poly(ethylene glycol).

63. A therapeutic composition according to claim 59, wherein the semipermeable wall is selected from the group consisting of:

(a) 27.2 mg of cellulose acetate and 0.275 mg of polyethylene glycol for a 8 mg dose of hydromorphone;

(b) 27.52 mg of cellulose acetate and 0.27 mg of polyethylene glycol for a 16 mg dose of hydromorphone;

(c) 29.6 mg of cellulose acetate and 0.29 mg of polyethylene glycol for a 32 mg dose of hydromorphone; and

(d) 38.61 mg of cellulose acetate and 0.39 mg of polyethylene glycol for a 64 mg dose of hydromorphone.

64. An osmotically controlled-release dosage form comprising:

(a) a hydromorphone formulation;

(b) a push composition comprising an osmagent, and

(c) a semipermeable wall with a passageway through the semipermeable wall, the semipermeable wall encasing the hydromorphone formulation and the push composition,

wherein the osmotically controlled-release dosage form provides, for a 16 mg dose of hydromorphone on day four of once daily administration to a population of subjects;

(i) a plasma concentration maximum of about 2.6 ng/mL,

(ii) a time to maximum plasma concentration of about 14.7 hours,

(iii) a plasma concentration minimum of about 1.2 ng/mL,

(iv) a time to minimum plasma concentration of about 13.1 hours, and

(v) an area under the curve of 44.8 ng-hr/ml.

65. A therapeutic composition for the relief of pain comprising hydromorphone that on day four of once daily administration to a population of subjects, provides, for a 16 mg dose of hydromorphone:

(a) a plasma concentration maximum of about 2.6 ng/mL,

(b) a time to maximum plasma concentration of about 14.7 hours,

(c) a plasma concentration minimum of about 1.2 ng/mL,

(d) a time to minimum plasma concentration of about 13.1 hours, and

(e) an area under the curve of 44.8 ng-hr/ml,

in an osmotically control-release dosage form comprising;

(i) a hydromorphone formulation;

(ii) an expandable push composition, and

(iii) a semipermeable wall with a passageway through the semipermeable wall, the semipermeable wall encasing the hydromorphone formulation and the push composition.