Pharmaceutical formulations and systems for improved absorption and multistage release of active agents

• US 7,374,779 B2
• Filed: 02/11/2002
• Issued: 05/20/2008
• Est. Priority Date: 02/26/1999
• Status: Expired due to Fees

• Current Assignee: Lipocine Inc.
• Original Assignee: Lipocine Inc.
• Inventors: Krill, Steven L., Chen, Feng-Jing, Patel, Mahesh V., Venkateshwaran, Srinivasan
• Primary Examiner(s): CHANNAVAJJALA, LAKSHMI SARADA
• Application Number:
  US10/074,687
• Publication Number:
  US 20030077297A1
• Time in Patent Office: 2,290 Days
• Field of Search: 424/464, 424/451, 424/450
• US Class Current: 424/451
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/5015 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

The present invention pertains to pharmaceutical formulations and systems for delivery of active agents, wherein a first fraction of an active agent is suspended in a vehicle and a second fraction of active agent is solubilized in the vehicle, with the suspended fraction representing about 5 wt. % to about 80 wt. % of the active agent and the second fraction representing about 20 wt. % to about 95 wt. % of the active agent. One or more additional active agents, which may be fully solubilized, partially solubilized, or suspended, may also be present. The first and second fractions of the active agent may or may not have different release profiles. Generally, a significant fraction of the solubilized drug will release rapidly, providing for rapid onset, while the suspended drug may be formulated for delayed and/or sustained release.

Claims

1. A pharmaceutical formulation, comprising:

(a) fenofibrate having a first fraction and a second fraction, wherein the first fraction is comprised of a plurality of solid particles; and

(b) a pharmaceutically acceptable vehicle comprising at least one compound selected front the group consisting of a hydrophilic surfactant, a lipophilic surfactant, a triglyceride and a solubilizer, wherein said formulation is encapsulated in an exterior capsule and the first fraction and the second fraction are segregated the first fraction of the fenofibrate is suspended in the vehicle and the second fraction of the fenobibrate is solubilized in the vehicle, said first fraction representing about 5 wt. % to about 80 wt. % of the total fenofibrate and said second fraction representing about 20 wt. % to about 95 wt. % of the total fenofibrate.

2. The pharmaceutical formulation of claim 1, further including an additional active agent.

3. The pharmaceutical formulation of claim 1, wherein the first fraction represents about 30 wt. % to about 80 wt. % of the fenofibrate, and the second fraction represents about 20 wt. % to about 70 wt. % of the fenofibrate.

4. The pharmaceutical formulation of claim 3, wherein the first fraction represents about 50 wt. % to about 70 wt. % of the fenofibrate, and the second fraction represents about 30 wt. % to about 50 wt. % of the fenofibrate.

5. The pharmaceutical formulation of claim 1, wherein the solid particles are comprised of powder, granules, pellets, beads, or combinations thereof.

6. The pharmaceutical formulation of claim 1, wherein the solid particles are associated with each other to form at least one dosage unit comprised of a granule, pellet, bead or tablet suspended in the vehicle.

7. The pharmaceutical formulation of claim 1, wherein the solid particles are contained within at least one capsule suspended in the vehicle.

8. The pharmaceutical formulation of claim 1, wherein the solid particles are prepared by a process selected from melt extrusion, nanoencapsulation, lyophilization, spheronization, coacervation, cryopelletization, crystallization, antisolvent precipitation, precipitation from expanded supereritical fluid, spray drying, spray coating, spray congealing, and combinations thereof.

9. The pharmaceutical formulation of claim 8, wherein the solid particles are subjected to further processing after preparation thereof.

10. The pharmaceutical formulation of claim 9, wherein the further processing comprises size reduction.

11. The pharmaceutical formulation of claim 10, wherein the size reduction is carried out by a process selected from grinding, milling, micronization, nanosizing, and combination thereof.

12. The pharmaceutical formulation of claim 11, wherein the solid particles have a mean diameter in the range of about 0.1 μ

m to about 100 μ

m.

13. The pharmaceutical formulation of claim 10, wherein the size reduction is carried out in the presence of a surfactant, a hydrophilic polymer, a lipid, a gelatin, a saccharide, or a mixture thereof.

14. The pharmaceutical formulation of claim 10, wherein the size reduction is carried out in the presence of the vehicle.

15. The pharmaceutical formulation of claim 1, wherein the solid particles contain at least one pharmaceutically acceptable excipient.

16. The pharmaceutical formulation of claim 1, further comprising at least one pharmaceutically acceptable additive selected from the group consisting of a stabilizing agent, an antioxidant, a bufferant, an antifoaming agent, a detackifier, a preservative, a chelating agent, a viscomodulator, a tonicifier, a flavorant, a colorant, an odorant, an opacifier, a binder, a filler, a plasticizer, a taste-masking agent, a lubricant, and an enzyme inhibitor.

17. The pharmaceutical formulation of claim 16, wherein said at least one pharmaceutically acceptable additive is a stabilizing agent.

18. The pharmaceutical formulation of claim 17, wherein the stabilizing agent is a suspending agent.

19. The pharmaceutical formulation of claim 18, wherein the suspending agent is selected from the group consisting of microcrystalline cellulose, sodium carboxymethylcellulose, powdered cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, ethyl methylcellulose, ethyl hydroxyethylcellulose, attapulgite, bentonite, hectorite, montmorillonita, silica gel, fumed silicon dioxide, colloidal silicon dioxide, acacia, agar, carrageenan, guar gum, locust bean gum, pectin, sodium alginate, propylene glycol alginate, tamarind gum, xanthan gum, carbomers, polyvinyl pyrrolidone, starch, sodium starch glycolate, tragacanth, magnesium aluminum silicate, aluminum silicate, magnesium silicate, gelatin, and glycyrrhizin.

20. The pharmaceutical formulation of claim 1, wherein the solid particles comprise at least one amorphous phase, at least one crystalline phase, or a mixture of at least one amorphous phase and at least one crystalline phase.

21. The pharmaceutical formulation of claim 1, wherein the solid particles further include a stabilizing agent.

22. The pharmaceutical formulation of claim 21, wherein said stabilizing agent is selected from the group consisting of synthetic hydrophilic polymers, surfactants, saccharides, gelatin, and combinations thereof.

23. The pharmaceutical formulation of claim 22, wherein the synthetic hydrophilic polymers are selected from the group consisting of polyalkylene oxides, polyalkylene oxide-substituted C₂-C₆ diols and triols, polyalkylene oxide-substituted saccharides, poly(N-vinyl lactams), and polymers of carboxyvinyl monomers.

24. The pharmaceutical formulation of claim 23, wherein the synthetic hydrophilic polymers are selected from the group consisting of polyethylene glycol, mono-poly(oxyethylene)-substituted propylene glycol, di-(polyoxyethylene)-substituted propylene glycol, mono-poly(oxyethylene)-substituted glycerol, di-(polyoxyethylene)-substit-uted glycerol, tri-(polyoxyethylene)-substituted glycerol, polyoxyethylated sorbitol, polyoxyethylated glucose, polyvinyl pyrrolidone, poly(N-vinyl caprolactam), and polymers and copolymers of acrylic acid, methacrylic acid and/or esters thereof.

25. The pharmaceutical formulation of claim 22, wherein the saccharides are cellulosic polymers.

26. The pharmaceutical formulation of claim 25, wherein the stabilizing agent is hydroxypropyl methylcellulose.

27. The pharmaceutical formulation of claim 1, wherein the vehicle is substantially free of water-indispersible wax materials.

28. The pharmaceutical formulation of claim 27, wherein the water-indispersible wax materials are selected front the group consisting of beeswax, paraffin, yellow wax, hydrogenated oils, hydrogenated vegetable oil, hydrogenated soybean oil flakes and mixtures thereof.

29. The pharmaceutical formulation of claim 1, wherein the vehicle contains less than about 20 wt. % water.

30. The pharmaceutical formulation of claim 1, wherein the vehicle contains less than about 10 wt. % water.

31. The pharmaceutical formulation of claim 1, wherein the vehicle comprises (a) at least one hydrophilic surfactant, (b) at least one lipophilic surfactant, or (c) at least one hydrophilic surfactant and at least one lipophilic surfactant.

32. The pharmaceutical formulation of claim 31, wherein the vehicle comprises at least one hydrophilic surfactant and at least one lipophilic surfactant.

33. The pharmaceutical formulation of claim 1, wherein the vehicle comprises a triglyceride, a solubilizer, or a mixture thereof.

34. The pharmaceutical formulation of claim 1, wherein said at least one compound represents about 1 wt. % to about 99 wt. % of the formulation.

35. The pharmaceutical formulation of claim 34, wherein said at least one compound represents about 10 wt. % to about 90 wt. % of the formulation.

36. The pharmaceutical formulation of claim 35, wherein said at least one compound represents about 20 wt. % to about 80 wt. % of the formulation.

37. The pharmaceutical formulation of claim 1, wherein either the first fraction of the fenofibrate, the second fraction of the fenofibrate, or both the first and second fractions of the fenofibrate are formulated for immediate release, pulsatile release, controlled release, extended release, delayed release, targeted release, or targeted delayed release of the fenofibrate.

38. The pharmaceutical formulation of claim 37, wherein the first fraction of the fenofibrate and the second fraction of the fenofibrate have different release profiles.

39. The pharmaceutical formulation of claim 37, wherein the first fraction of the fenofibrate further comprises a means for controlling release of the fenofibrate from the suspended particles.

40. The pharmaceutical formulation of claim 39, wherein the second fraction of the fenofibrate comprises an immediate release composition.

41. The pharmaceutical formulation of claim 40, wherein the second fraction of the fenofibrate exhibits an immediate release profile.

42. The pharmaceutical formulation of claim 40, wherein the second fraction provides for release of at least 50% of the fenofibrate contained therein within 30 minutes at 37°

C. as evaluated using standard USP dissolution test equipment.

43. The pharmaceutical formulation of claim 42, wherein the second fraction provides for release of at least 75% of the fenofibrate contained therein within 30 minutes at 37°

C. as evaluated using standard USP dissolution test equipment.

44. The pharmaceutical formulation of claim 43, wherein the second fraction provides for release of at least 90% of the fenofibrate contained therein within 30 minutes at 37°

C. as evaluated using standard USP dissolution test equipment.

45. A dosage form comprising the pharmaceutical formulation of claim 1.

46. A pharmaceutical system for administration of an fenofibrate, comprising:

(a) fenofibrate; and

(b) a pharmaceutically acceptable vehicle comprising at least one compound selected from the group consisting of a hydrophilic surfactant, a lipophilic surfactant, a triglyceride and a sohtbilizer, wherein the relative amounts of the fenofibrate and the vehicle are such that upon admixture thereof, a first fraction of the fenofibrate is suspended in the vehicle, and a second fraction of the fenofibrate is solubilized in the vehicle, wherein said first and second fractions of are encapsulated in an exterior capsule and the first fraction and the second fraction are segregated, and wherein the second fraction represents about 20 wt. % to about 95 wt. % of the total fenofibrate in the formulation.

47. The pharmaceutical system of claim 46, wherein the first fractidn represents about 10 wt. % to about 80 wt. % of the fenofibrate, and the second fraction represents about 20 wt. % to about 90 wt. % of the fenofibrate.

48. The pharmaceutical system of claim 47, wherein the first fraction represents about 30 wt. % to about 80 wt. % of the fenofibrate, and the second fraction represents about 20 wt. % to about 70 wt. % of the fenofibrate.

49. The pharmaceutical system of claim 48, wherein the first fraction represents about 50 wt. % to about 70 wt. % of the fenofibrate, and the second fraction represents about 30 wt. % to about 50 wt. % of the fenofibrate.

50. The pharmaceutical system of claim 49, wherein the solid particles are comprised of powder, granules, pellets, beads, or combinations thereof.

51. The pharmaceutical system of claim 46, wherein the solid particles are associated with each other to form at least one dosage unit comprised of a granule, pellet, bead or tablet.

52. The pharmaceutical system of claim 51, wherein the solid particles are contained within a capsule.

53. The pharmaceutical system of claim 51, wherein the solid particles are prepared by a process selected from melt extrusion, nanoencapsulation, lyophilization, spheronization, coacervation, cryopelletization, crystallization, antisolvent precipitation, precipitation from expanded supercritical fluid, spray drying, spray coating, spray congealing, and combinations thereof.

54. The pharmaceutical system of claim 53, wherein the solid particles are subjected to further processing after preparation thereof.

55. The pharmaceutical system of claim 54, wherein the further processing comprises size reduction.

56. The pharmaceutical system of claim 55, wherein the size reduction is carried out by a process selected from grinding, milling, micronization;

nanosizing, and combination thereof.

57. The pharmaceutical system of claim 56, wherein the solid particles have a mean diameter in the range of about 0.1 μ

m to about 100 μ

m.

58. The pharmaceutical system of claim 55, wherein the size reduction is carried out in the presence of a surfactant, a hydrophilic polymer, a lipid, a gelatin, a saccharide, or a mixture thereof.

59. The pharmaceutical system of claim 55, wherein the size reduction is carried out in the presence of the vehicle.

60. The pharmaceutical system of claim 46, wherein the solid particles contain at least one pharmaceutically acceptable excipient.

61. The pharmaceutical system of claim 46, wherein the vehicle further comprises at least one pharmaceutically acceptable additive selected from the group consisting of a stabilizing agent, an antioxidant, a bufferant, an antifoaming agent, a detackifier, a preservative, a chelating agent, a viscomodulator, a tonicifier, a flavorant, a colorant, an odorant, an opacifier, a binder, a filler, a plasticizer, a taste-masking agent, a lubricant, and an enzyme inhibitor.

62. The pharmaceutical system of claim 61, wherein said at least one pharmaceutically acceptable additive is a stabilizing agent.

63. The pharmaceutical system of claim 62, wherein the stabilizing agent is a suspending agent.

64. The pharmaceutical system of claim 63, wherein the suspending agent is selected from the group consisting of microcrystalline cellulose, sodium carboxymethylcellulose, powdered cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, ethyl methylcellulose ethyl hydroxyethylcellulose, attapulgite, bentonire, hectorite, montmorillonite, silica gel, fumed silicon dioxide, colloidal silicon dioxide, acacia, agar, carrageenan, guar gum, locust bean gum, pectin, sodium alginate, propylene glycol alginate, tamarind gum, xanthan gum, carbomers, polyvinyl pyrrolidone, starch, sodium starch glycolate, tragacanth, magnesium aluminum silicate, aluminum silicate, magnesium silicate, gelatin, and glycyrrhizin.

65. The pharmaceutical system of claim 46, wherein the solid particles comprise at least one amorphous phase, at least one crystalline phase, or a mixture of at least one amorphous phase and at least one crystalline phase.

66. The pharmaceutical system of claim 65, wherein the solid particles further include a stabilizing agent.

67. The pharmaceutical system of claim 66, wherein said stabilizing agent is selected from the group consisting of synthetic hydrophilic polymers, surfactans, saccharides, gelatin, and combinations thereof.

68. The pharmaceutical system of claim 67, wherein the synthetic hydrophilic polymers are selected from the group consisting of polyalkylene oxides, polyalkylene oxide-substituted C₂-C₆ diols and triols, polyalkylene oxide-substituted saccharides, poly(N-vinyl lactams), and polymers of carboxyvinyl monomers.

69. The pharmaceutical system of claim 68, wherein the synthetic hydrophilic polymers are selected from the group consisting of polyethylene glycol, mono-poly(oxyethylene)-substituted propylene glycol, di-(polyoxyethylene)-substituted propylene glycol, mono-poly(oxyethylene)-substituted glycerol, di-(polyoxyethylene)-substit-uted glycerol, tri-(polyoxyethylene)-substituted glycerol, polyoxyethylated sorbitol, polyoxyethylated glucose, polyvinyl pyrrolidone, poly(N-vinyl caprolactam), and polymers and copolymers of acrylic acid, methacrylic acid and/or esters thereof.

70. The pharmaceutical system of claim 69, wherein the saccharides are cellulosic polymers.

71. The pharmaceutical system of claim 70, wherein the stabilizing agent is hydroxypropyl methylcellulose.

72. The pharmaceutical system of claim 46, wherein the vehicle is substantially free of water-indispersible wax materials.

73. The pharmaceutical system of claim 72, wherein the water-indispersible wax materials are selected from the group consisting of beeswax, paraffin, yellow wax, hydrogenated oils, hydrogenated vegetable oil, hydrogenated soybean oil flakes and mixtures thereof.

74. The pharmaceutical system of claim 46, wherein the vehicle contains less than about 20 wt. % water.

75. The pharmaceutical system of claim 74, wherein the vehicle contains less than about 10 wt. % water.

76. The pharmaceutical system of claim 46, wherein the vehicle comprises (a) at least one hydrophilic surfactant, (b) at least one lipophilic surfactant, or (c) at least one hydrophilic surfactant and at least one lipophilic surfactant.

77. The pharmaceutical system of claim 76, wherein the vehicle comprises at least one hydrophilic surfactant and at least one lipophilic surfactant.

78. The pharmaceutical system of claim 46, wherein the vehicle comprises a triglyceride, a solubilizer, or a mixture thereof.

79. The pharmaceutical system of claim 46, wherein either the first fraction of the fenofibrate, the second fraction of the fenofibrate, or both the first and second fractions of the fenofibrate are formulated for immediate release, pulsatile release, controlled release, extended release, delayed release, targeted release, or targeted delayed release of the fenofibrate.

80. The pharmaceutical system of claim 79, wherein the first fraction of the agent and the second fraction of the fenofibrate have different release profiles.

81. The pharmaceutical system of claim 79, wherein the first fraction of the fenofibrate further comprises a means for controlling release of the fenofibrate from the suspended particles.

82. The pharmaceutical system of claim 81, wherein the second fraction of the fenofibrate comprises an immediate release composition.

83. The pharmaceutical system of claim 81, wherein the second fraction of the fenofibrate exhibits an immediate release profile.

84. The pharmaceutical system of claim 83, wherein the second fraction provides for release of at least 50% of the fenofibrate contained therein within 30 minutes at 37°

C. as evaluated using standard USP dissolution test equipment.

85. The pharmaceutical system of claim 84, wherein the second fraction provides for release of at least 75% of the fenofibrate contained therein within 30 minutes at 37°

C. as evaluated using standard USP dissolution test equipment.

86. The pharmaceutical system of claim 85, wherein the second fraction provides for release of at least 90% of the fenofibrate contained therein within 30 minutes at 37°

C. as evaluated using standard USP dissolution test equipment.