SELF-MICROEMULSIFYING DRUG DELIVERY SYSTEMS

• US 20100331356A1
• Filed: 12/14/2007
• Published: 12/30/2010
• Est. Priority Date: 12/27/2006
• Status: Active Grant

• Current Assignee: Lek Pharmaceuticals, d.d. (Novartis Ag)
• Original Assignee: Lek Pharmaceuticals, d.d. (Novartis Ag)
• Inventors: Kerc, Janez, Jurkovic, Polona, Legen, Igor
• Granted Patent: US 8,592,490 B2
• Time in Patent Office: Days
• US Class Current: 514/291
• 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 9/1611 Inorganic compounds
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00

Abstract

Self-microemulsifying drug delivery systems and microemulsions used to enhance the solubility of pharmaceutical ingredients comprising a polyoxyethylene sorbitan fatty acid ester emulsifier; a fatty acid ester co-emulsifier and an oil.

Claims

1-34. -34. (canceled)

35. A self-microemulsifying drug delivery system comprising

(i) a polyoxyethylene sorbitan fatty acid ester emulsifier;

(ii) a co-emulsifier selected from glyceryl mono- or di-fatty acid esters of C₆-C₁₈ fatty acids; and

(iii) an oil, selected from C₆-C₁₂ fatty acid triglycerides;

wherein the polyoxyethylene sorbitan fatty acid ester emulsifier (i) and co-emulsifier (ii) are present in a ratio by weight of between 1;

1 and 4;

1 and

the emulsifier and co-emulsifier, (i)+(ii), and oil (iii) are present in a ratio by weight of between 4;

1 and 10 000;

1.

36. A self-microemulsifying drug delivery system according to claim 35, wherein the emulsifier (i) is a polysorbate.

37. The self-microemulsifying drug delivery system of claim 36, wherein the polysorbate is polysorbate 80.

38. A self-microemulsifying drug delivery system according to claim 35, wherein the ratios are selected from the group of ratios consisting of:

the polyoxyethylene sorbitan fatty acid ester emulsifier (i) and co-emulsifier (ii) are present in a ratio by weight of about 1;

1, about 2;

1, about 2.5;

1, about 3;

1, about 3.5;

1 and about 4;

1;

the ratio by weight of emulsifier and co-emulsifier, (i)+(ii), to oil (iii), is in the range selected from the group consisting of about 4;

1 to 1000;

1, about 4;

1 to 100;

1, and about 5;

1 to 40;

1; and

the ratio of coemulsifier (ii) to oil (iii) is selected from the group consisting of at least 1.5;

1, at least 2;

1, and at least 3;

1.

39. A microemulsion according to claim 35, wherein the polyoxyethylene sorbitan fatty acid ester emulsifier (i) and co-emulsifier (ii) are present in a ratio by weight of between 2.5:

1 and 3.5;

1.

40. A self-microemulsifying drug delivery system according to claim 35, wherein the co-emulsifier is selected from glyceryl mono- or di-fatty acid esters of C₆-C₁₂ fatty acids.

41. The self-microemulsifying drug delivery system according to claim 40, wherein the co-emulsifier is glyceryl caprylate.

42. A self-microemulsifying drug delivery system according to claim 35, wherein the oil is a caprylic or a capric triglyceride oil.

43. A self-microemulsifying drug delivery system according to claim 35, wherein, of the total amount of glycerides in the self-microemulsifying system, a percentage is either co-emulsifiers according to (ii) or oils according to (iii), wherein the percentage of the glycerides is at least 90%, at least 95%, at least 99% or is 100%.

44. A self-microemulsifying drug delivery system according to claim 35, wherein the system consists of (i) the polyoxyethylene sorbitan fatty acid ester emulsifier, (ii) the co-emulsifier selected from glyceryl mono- or di-fatty acid esters of C₆-C₁₈ fatty acids, and (iii), the oil, selected from C₆-C₁₂ fatty acid triglycerides.

45. A microemulsion comprising

(i) a polyoxyethylene sorbitan fatty acid ester emulsifier;

(ii) a co-emulsifier selected from glyceryl mono- or di-fatty acid esters of C₆-C₁₈ fatty acids;

(iii) an oil, selected from C₆-C₁₂ fatty acid triglycerides;

wherein the polyoxyethylene sorbitan fatty acid ester emulsifier (i) and co-emulsifier (ii) are present in a ratio by weight of between 1;

1 and 4;

1 and

wherein the emulsifier and co-emulsifier, (i)+(ii) and oil (iii) are present in a ratio by weight of between 4;

1 and 10 000;

1; and

(iv) water.

46. The microemulsion according to claim 45, wherein

the ratios are selected from the group consisting of:

the polyoxyethylene sorbitan fatty acid ester emulsifier (i) and co-emulsifier (ii) are present in a ratio by weight selected from the group consisting of about 1;

1, about 2;

1, about 2.5;

1, about 3;

1, about 3.5;

1 and about 4;

1;

wherein the ratio by weight of emulsifier and co-emulsifier, (i)+(ii), to oil (iii), is in the range selected from the group consisting of about 4;

1 to 1000;

1, about 4;

1 to 100;

1, and 5;

1 to 40;

1; and

wherein the ratio of coemulsifier (ii) to oil (iii) is selected from the group consisting of at least 1.5;

1, at least 2;

1, and at least 3;

1.

47. A microemulsion according to claim 45, wherein the polyoxyethylene sorbitan fatty acid ester emulsifier (i) and co-emulsifier (ii) are present in a ratio by weight of between 2.5:

1 and 3.5;

1.

48. A microemulsion according to claim 45, wherein the amount of water added is such that a stable microemulsion is formed.

49. A microemulsion according to claim 45, wherein (iv) the water is in an aqueous phase in which the percentage of water is selected from the group of percentages consisting of at least 50%, at least 70%, at least 80%, at least 90%, at least 99%, and is 100% water.

50. A solid pharmaceutical composition comprising a pharmaceutically active ingredient and either

a-1) a self-microemulsifying drug delivery system comprising

(i) a polyoxyethylene sorbitan fatty acid ester emulsifier;

(ii) a co-emulsifier selected from glyceryl mono- or di-fatty acid esters of C₆-C₁₈ fatty acids; and

(iii) an oil, selected from C₆-C₁₂ fatty acid triglycerides;

wherein the polyoxyethylene sorbitan fatty acid ester emulsifier (i) and co-emulsifier (ii) are present in a ratio by weight of between 1;

1 and 8;

1 and

the emulsifier and co-emulsifier, (i)+(ii) and oil (iii) are present in a ratio by weight of between 1;

10 and 10 0000;

1, or

a-2) a microemulsion comprising

(i) a polyoxyethylene sorbitan fatty acid ester emulsifier;

(ii) a co-emulsifier selected from glyceryl mono- or di-fatty acid esters of C₆-C₁₈ fatty acids;

(iii) an oil, selected from C₆-C₁₂ fatty acid triglycerides;

wherein the polyoxyethylene sorbitan fatty acid ester emulsifier (i) and co-emulsifier (ii) are present in a ratio by weight of between 1;

1 and 8;

1 and

wherein the emulsifier and co-emulsifier, (i)+(ii) and oil (iii) are present in a ratio by weight of between 1;

10 and 10 000;

1; and

(iv) water.

51. A solid pharmaceutical composition according to claim 50, wherein the pharmaceutically active ingredient is dissolved or dispersed in the self-microemulsifying drug delivery system or the microemulsion.

52. A solid pharmaceutical composition according to claim 50, wherein the pharmaceutically active ingredient is present in the range 5-70% by weight with respect to the self-microemulsifying drug delivery system.

53. A solid pharmaceutical composition according to claim 50, wherein the pharmaceutically active ingredient has a solubility of less than 0.1 g of pharmaceutically active ingredient in 1 ml of water at 20°

C.

54. A solid pharmaceutical composition according to claim 53, wherein the pharmaceutically active ingredient is candesartan cilexetil or celecoxib.

55. Method of treating a subject in need of a treatment by a poorly soluble pharmaceutically active ingredient which has a solubility of less than 0.1 g of pure pharmaceutically active ingredient in 1 ml of water at 37°

C., the method comprising the steps of;

providing said poorly soluble pharmaceutically active ingredient dissolved or dispersed in a self-microemulsifying drug delivery system comprising

(i) a polyoxyethylene sorbitan fatty acid ester emulsifier;

(ii) a co-emulsifier selected from glyceryl mono- or di-fatty acid esters of C₆-C₁₈ fatty acids; and

(iii) an oil, selected from C₆-C₁₂ fatty acid triglycerides;

wherein the polyoxyethylene sorbitan fatty acid ester emulsifier (i) and co-emulsifier (ii) are present in a ratio by weight of between 1;

1 and 4;

1 and,

the emulsifier and co-emulsifier, (i)+(ii) and oil (iii) are present in a ratio by weight of between 4;

1 and 10 000;

1, to enhance the solubility of said poorly soluble pharmaceutically active ingredient by a factor of three;

optionally adding water to said self-microemulsifying drug delivery system to obtain a microemulsion; and

administering the self-microemulsifying drug delivery system or said microemulsion, comprising the pharmaceutically active ingredient, to the subject.

56. The method according to claim 55, wherein the pharmaceutically active ingredient is candesartan cilexetil, celecoxib, eprosartan mesylate, sirolimus or lercanidipine HCl.

57. A method of preparing a solid oral pharmaceutical composition comprising the steps of:

a-1) forming a self-microemulsifying drug delivery system comprising

(i) a polyoxyethylene sorbitan fatty acid ester emulsifier;

(ii) a co-emulsifier selected from glyceryl mono- or di-fatty acid esters of C₆-C₁₈ fatty acids; and

(iii) an oil, selected from C₆-C₁₂ fatty acid triglycerides;

wherein the polyoxyethylene sorbitan fatty acid ester emulsifier (i) and co-emulsifier (ii) are present in a ratio by weight of between 1;

1 and 8;

1 and the emulsifier and co-emulsifier, (i)+(ii) and oil (iii) are present in a ratio by weight of between 1;

10 and 10 000;

1;

or

a-2) forming a microemulsion comprising

(i) a polyoxyethylene sorbitan fatty acid ester emulsifier;

(ii) a co-emulsifier selected from glyceryl mono- or di-fatty acid esters of C₆-C₁₈ fatty acids; and

(iii) an oil, selected from C₆-C₁₂ fatty acid triglycerides;

wherein the polyoxyethylene sorbitan fatty acid ester emulsifier (i) and co-emulsifier (ii) are present in a ratio by weight of between 1;

1 and 8;

1, and

wherein the emulsifier and co-emulsifier, (i)+(ii) and oil (iii) are present in a ratio by weight of between 1;

10 and 10 000;

1; and

(iv) water; and

b) adding a pharmaceutically active ingredient to the self-microemulsifying drug delivery system formed in step a-1) or the microemulsion formed in step a-2) to form a pharmaceutical composition; and

c) solidifying the pharmaceutical composition formed in step b) to form a solid oral pharmaceutical composition.

58. Method according to claim 57, wherein the solidifying in step c) is performed either by adsorbing the pharmaceutical composition onto a solid support;

or

by dispersing the pharmaceutical composition in polyethylene glycol;

or

by mixing the pharmaceutical composition with an aqueous solution of a solid support and spray drying or lyophilizing.