Novel cyclosporine analog formulations

• US 20060217309A1
• Filed: 03/13/2006
• Published: 09/28/2006
• Est. Priority Date: 10/19/2001
• Status: Active Grant

• Current Assignee: Aurinia Pharmaceuticals Inc.
• Original Assignee: Isotechnika Inc. (Endo International PLC)
• Inventors: Naicker, Selvaraj A., Foster, Robert T., Yatscoff, Randall W.
• Granted Patent: US 7,429,562 B2
• Time in Patent Office: Days
• US Class Current: 514/20.500
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 9/0095 Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 7/645 : Cyclosporins; Related peptides

Abstract

The present invention relates to formulations containing cyclosporin analogs that are structurally similar to cyclosporin A, in particular isomeric mixtures of cyclosporin analogs that are structurally similar to cyclosporin A. The formulations form stable microemulsion preconcentrates and may provide superior drug bioavailability and/or may reduce one or more adverse effects associated with the administration of cyclosporin. Also disclosed are methods for using and preparing the formulations.

Claims

1-45. -45. (canceled)

46. A pharmaceutical composition comprising:

a) a pharmaceutically effective amount of ISA_Tx247;

b) Vitamin E TPGS;

c) MCT oil;

d) an emulsifier; and

e) ethanol

47. The pharmaceutical composition of claim 46 wherein the emulsifier is selected from the group consisting of polyoxyethylene(20)sorbitanmonopalmitate and polyoxyethylene(20)sorbitanmonooleate.

48. The pharmaceutical composition of claim 46, which comprises from about 5 to about 10% by weight of ISA_Tx247, greater than 0% to about 50% by weight of Vitamin E TPGS, greater than 0% to about 50% by weight of MCT oil, greater than 0% to about 50% by weight of emulsifier and about 5 to about 15% by weight of ethanol, wherein the composition is a liquid microemulsion preconcentrate at room temperature.

49. The pharmaceutical composition of claim 48, wherein the ratio by weight of ISA_Tx247:

Vitamin E TPGS;

MCT oil;

emulsifier;

ethanol is about 0.5-1;

4;

2;

2;

1.

50. The pharmaceutical composition of claim 48 wherein the emulsifier is polyoxyethylene(20)sorbitanmonopalmitate and further wherein the preconcentrate, when mixed with an aqueous media in a ratio of about 1 part preconcentrate to about 10 to about 100 parts aqueous media, forms a clear stable microemulsion solution.

51. The pharmaceutical composition of claim 46, wherein the bioavailability of ISA_Tx247 is greater than about 30%.

52. The pharmaceutical composition of claim 46, which is adapted for oral administration.

53. The pharmaceutical composition of claim 46 which further comprises biocompatible polymers as protective colloids, suspension stabilizers or bulking agents, excipients, binders and carriers.

54. The pharmaceutical composition of claim 53, wherein the biocompatible polymer is selected from the group consisting of polyoxyethylene glycolated natural or hydrogenated vegetable oils, polyoxyl castor oils, polyoxyethylene-sorbitan-fatty acid esters, polyoxyethylene-polyoxypropylene block co-polymers, lecithins, propylene glycol mono-and di-fatty acid esters and propylene glycol caprylic-capric acid diester.

55. The pharmaceutical composition of claim 54, wherein the biocompatible polymer is selected from the group consisting of polyoxyethylene(20)sorbitanmonolaurate, polyoxyethylene(20)sorbitanmonopalmitate, polyoxyethylene(20)sorbitantrioleate, polyoxyethylene(20)sorbitanmonostearate, polyoxyethylene(20)sorbitanmonooleate, polyoxeythylene(20)sorbitantristearate, polyoxyethylene(4)sorbitanmonolaurate, polyoxyethylene(4)sorbitanmonostearate, and polyoxyethylene(5)sorbitanmonooleate.

56. A method of producing immunosuppression comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 46.

57. The method of claim 56, wherein the amount of ISA_TX247 administered is about 0.5 to 3 mg/kg of body weight of said subject per day.

58. The method of claim 56, wherein the pharmaceutical composition is administered using a schedule selected from the group consisting of once a day and twice a day.

59. The method of claim 56, wherein the pharmaceutical composition is used to treat an inflammatory or autoimmune disease or condition in said subject.

60. A method of increasing the immunosuppressive effects of ISA_TX247 by preparing the pharmaceutical composition of claim 46.

61. The pharmaceutical composition of claim 46 which is a microemulsion preconcentrate.

62. The pharmaceutical composition of claim 61, which is mixed with an aqueous media in a ratio of about 1 part preconcentrate to about 10 to about 100 parts aqueous media.

63. The pharmaceutical composition of claim 62, wherein the aqueous media is selected from the group consisting of water, fruit juice, tea, milk and cocoa, wherein the fruit juice is not grapefruit juice.

64. The pharmaceutical composition of claim 63, wherein the fruit juice is apple juice.

65. The pharmaceutical composition of claim 52, wherein the oral formulation is encapsulated in a soft gelatin capsule.

66. A method of preparing the pharmaceutical composition of claim 46 comprising mixing the MCT oil, the emulsifier, the ethanol, the Vitamin E TPGS, and the pharmaceutically effective amount of ISA_TX247 until the ISA_TX247 is completely dissolved, wherein the composition is a liquid at room temperature.

67. The pharmaceutical composition of claim 46, wherein the pharmaceutical composition comprises from about 5% to about 10% by weight of ISA_TX247, from about 20% to about 50% by weight of Vitamin E TPGS, from about 5% to about 20% by weight of MCT oil, from about 5% to about 50% by weight of polyoxyethylene(20)sorbitanmonopalmitate and about 5% to about 15% by weight of ethanol.

68. The pharmaceutical composition of claim 67, wherein the ratio by weight of ISA_Tx247:

Vitamin E TPGS;

MCT oil;

emulsifier;

ethanol is about 0.5-1;

4;

2;

2;

1.

69. The pharmaceutical composition of claim 46, wherein the pharmaceutical composition-comprises from about 5% to about 10% by weight of ISA_TX247, from about 20% to about 50% by weight of Vitamin E TPGS, from about 5% to about 20% by weight of MCT oil, from about 5% to about 50% by weight of polyoxyethylene(20)sorbitanmonooleate and about 5% to about 15% by weight of ethanol.

70. The pharmaceutical composition of claim 69, wherein the ratio by weight of ISA_Tx247:

Vitamin E TPGS;

MCT oil;

emulsifier;

ethanol is about 0.5-1;

2;

4;

2;

1.

71. The pharmaceutical composition of claim 46 wherein the emulsifier is polyoxyethylene(20)sorbitanmonopalmitate and further wherein the pharmaceutical composition is suitable for subcutaneous or intramuscular administration.

72. The pharmaceutical formulation of claim 46 wherein the pharmaceutical formulation is an emulsion or a microemulsion.

73. The pharmaceutical formulation of claim 46 wherein the pharmaceutical formulation is an emulsion or a microemulsion preconcentrate.

74. A method of preparing the pharmaceutical composition of claim 46, comprising mixing the MCT oil, the emulsifier, the ethanol, the Vitamin E TPGS, and the pharmaceutically effective amount of ISA_TX247 until the ISA_TX247 is completely dissolved.

75. The pharmaceutical composition of claim 46 which is used as a preconcentrate, wherein the preconcentrate when mixed with an aqueous media forms a clear stable microemulsion solution.

76. The pharmaceutical composition preconcentrate of claim 75, wherein the pharmaceutical composition comprises from about 5% to about 10% by weight of ISA_TX247, from about 20% to about 50% by weight of Vitamin E TPGS, from about 5% to about 20% by weight of MCT oil, from about 5% to about 50% by weight of polyoxyethylene(20)sorbitanmonopalmitate and about 5% to about 15% by weight of ethanol.

77. The pharmaceutical composition preconcentrate of claim 76, wherein the ratio by weight of ISA_Tx247:

Vitamin E TPGS;

MCT oil;

emulsifier;

ethanol is about 0.5-1;

4;

2;

2;

1.

78. A method of preparing the pharmaceutical composition preconcentrate of claim 75, comprising mixing the MCT oil, polyoxyeihylene(20)sorbitanmonopalmitate, the ethanol, the Vitamin E TPGS, and the pharmaceutically effective amount of ISA_TX247 until the ISA_TX247 is completely dissolved then mixing the composition into an aqueous medium until a microemulsion preconcentrate solution is formed.