Reversed liquid crystalline phases with non-paraffin hydrophobes

• US 20040022820A1
• Filed: 06/13/2003
• Published: 02/05/2004
• Est. Priority Date: 11/28/2001
• Status: Abandoned Application

• Current Assignee: Lyotropic Therapeutics Inc.
• Original Assignee: Lyotropic Therapeutics Inc.
• Inventors: Anderson, David
• Application Number:
  US10/460,659
• Publication Number:
  US 20040022820A1
• Time in Patent Office: Days
• US Class Current: 424/401
• CPC Class Codes: A61K 31/24 having an amino or nitro group
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 9/1274 Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases, cochleates; Sponge phases

Abstract

Compounds which are otherwise difficult to solubilize, such as, for example, pharmaceutical actives difficult for the body to absorb, are solubilized into a composition using a solvent system that is a structured fluid. The structured fluid is a reversed cubic phase or reversed hexagonal phase material, or a combination thereof, which includes a polar solvent, a surfactant and a non-paraffinic liquid with a high octanol-water partition coefficient which does not qualify as a surfactant. The compositions thus formed are able to enhance absorption of drugs by the induction of local, transient nanopores in biomembrane absorption barriers and particularly those in which efflux mechanisms, such as those associated with P-glycoprotein and/or cytochrome 3A4, are active. The compositions and methods that are used for solubilizing pharmaceutical actives in structured fluids can simultaneously accomplish solubilization of difficultly soluble drugs and enhancement of absorption.

Claims

1. A composition comprising:

a reversed cubic phase or reversed hexagonal phase material, or a combination thereof, comprised of a polar solvent, a surfactant, and a non-paraffinic liquid with a high octanol-water partition coefficient which does not qualify as a surfactant; and

a compound that is difficultly soluble in water solubilized in said reversed cubic phase or reversed hexagonal phase material, or a combination thereof.

2. A composition as in claim 1 wherein the reversed cubic phase or reversed hexagonal phase material is composed of pharmaceutically acceptable components.

3. A composition as in claim 1 wherein the non-paraffinic liquid comprises a polar group that is not operative as a surfactant head group.

4. A composition as in claim 3 wherein the polar group is selected from the group consisting of a hydroxy, phenolic, aldehyde, ketone, carboxylic acid (in the free acid form), isocyanate, amide, acyl cyanoguanidine, acyl guanylurea, acyl biuret, N,N-dimethylamide, nitrosoalkane, nitroalkane, nitrate ester, nitrite ester, nitrone, nitrosamine, pyridine N-oxide, nitrile, isonitrile, amine borane, amine haloborane, sulfone, phosphine sulfide, arsine sulfide, sulfonamide, sulfonamide methylimine, alcohol (monofunctional), ester (monofunctional), secondary amine, tertiary amine, mercaptan, thioether, primary phosphine, secondary phosphine, and tertiary phosphine.

5. A composition as in claim 1 wherein the non-paraffinic liquid is an essential oil or component thereof.

6. A composition as in claim 3 wherein the non-paraffinic liquid is an essential oil or component thereof.

7. A composition as in claim 1 wherein said compound is relatively more soluble in said reversed cubic phase or reversed hexagonal phase material in the presence of said non-paraffinic liquid than in the absence of said non-paraffinic liquid.

8. A composition as in claim 1 wherein said compound is difficultly-soluble in oil.

9. A composition as in claim 1 wherein the surfactant is of low solubility in water.

10. A composition as in claim 1 wherein said compound is a pharmaceutical active.

11. A composition as in claim 10 wherein said pharmaceutical active is selected from the group consisting of Nandrolone decanoate, Fentanyl citrate, Testosterone, Albendazole, Doxorubicin, Epirubicin, Idarubicin, Valrubicin, Oxybutinin, Amphotericin B, Enalaprilat, Docetaxel, Paclitaxel, Vinblastine, Vincristine, Vinorelbine, Batimastat, Eptifibatide, Tirofiban, Droperidol, Acyclovir, Pentafuside, Saquinavir, Cromolyn, Doxapram, SN-38 (Irinotecan), Topotecan, Hemin, Daunorubicin, Teniposide, Trimetrexate, Octreotride, Leuprolide, Clyclosporin A, Milrinone lactate, Buprenorphine, Nalbuphine, Carboplatin, Cisplatin, Mitoxantrone, Estradiol, Hydroxyprogesterone, L-Thyroxine, Etanercept, Neostigmine, Epoprostenol, Enalapril, Albuterol, Sulfinalol, Nandrolone, Morphine, Aspirin, Testosterone, Hexobarbitol, Cyclexedrine, Niclosamide, Mebendazole, Amphotalide, Retinoic acid, Emetine, Nifedipine, Quinidine, Chloramphenicol, Rifamide, Ampicillin, Erythromycin A, Tetracycline, Ciprofloxacin, Sulfamoxole, Dapsone, Atropine, Warfarin, Nitrazapem, Zometapine, Glyburide, Uzarin, Aspirin, Taxol, Etiposide, Bupivicaine or local anesthetic, and Dantrolene.

12. A composition as in claim 5 wherein the non-paraffinic liquid is selected from the group consisting of benzyl benzoate, peppermint oil, orange oil, spearmint oil, essential oil of ginger, thymol, vanillin, anethole, cinnamon oil, cinnamaldehyde, clove oil, coriander oil, ylang-ylang oil, benzaldehyde, zingerone, carvone, linalool, and menthol.

13. A composition as in claim 1 wherein the polar solvent is selected from the group consisting of water, glycerol, ethylene glycol or propylene glycol, ethylammonium nitrate, acetamide, N-methyl acetamide, dimethylacetamide, and low-molecular weight polyethylene glycol (PEG).

14. A composition as in claim 1 wherein the non-paraffinic liquid has a molecular weight of about 500 or less.

15. A composition as in claim 1 wherein the non-paraffinic liquid has a molecular weight of about 250 or less.

16. A composition as in claim 1 wherein the poorly-water-soluble compound has at least 3 polar groups.

17. A composition as in claim 1 wherein the reversed hexagonal or reversed cubic phase is a component of a pill, tablet, lozenge, capsule, troche, syrup or suspension drug formulation.

18. A composition as in claim 1 wherein the surfactant is chosen from the group consisting of Pluronics, D-alpha tocopheryl polyethylene glycol succinates, sorbitan fatty acid esters, docusate salts, polyethylene glycol oleyl ethers, polyoxyethylene castor oil derivatives, and polyoxyethylene hydrogenated castor oil derivatives.

19. A composition as in claim 1 wherein the reversed hexagonal or reversed cubic phase is tunable.

39. The composition of claim 1 wherein said composition is present as a reversed bicontinuous cubic phase.

74. The composition of claim 3 wherein said non-paraffinic liquid is an essential oil or a component thereof selected from the group consisting of clove bud, ylang-ylang, santalwood, peppermint, eucalyptus, ginger, carrot seed, bay, myrrh, fir needle, patchouli, spearmint, and thyrne.

20. A composition, comprising:

a polar solvent;

a surfactant; and

a non-paraffinic liquid with a polar group that is not operative as a surfactant head group and with a high octanol-water partition coefficient which does not qualify as a surfactant,

wherein the composition is present as a reversed cubic or reversed hexagonal liquid crystalline phase, or a combination thereof.

21. The composition of claim 20 wherein said composition is formulated in internally administrable form and includes only pharmaceutically acceptable components.

22. The composition of claim 20 wherein said composition is present as a reversed bicontinuous cubic phase.

23. The composition of claim 22 wherein said composition is formulated in internally administrable form and includes only pharmaceutically acceptable components.

24. A composition as in claim 20 wherein the polar group is selected from the group consisting of a hydroxy, phenolic, aldehyde, ketone, carboxylic acid (in the free acid form), isocyanate, amide, acyl cyanoguanidine, acyl guanylurea, acyl biuret, N,N-dimethylamide, nitrosoalkane, nitroalkane, nitrate ester, nitrite ester, nitrone, nitrosamine, pyridine N-oxide, nitrile, isonitrile, amine borane, amine haloborane, sulfone, phosphine sulfide, arsine sulfide, sulfonamide, sulfonamide methylimine, alcohol (monofunctional), ester (monofunctional), secondary amine, tertiary amine, mercaptan, thioether, primary phosphine, secondary phosphine, and tertiary phosphine.

25. A composition as in claim 20 wherein the non-paraffinic liquid is an essential oil or component thereof.

26. A composition as in claim 23 wherein the non-paraffinic liquid is an essential oil or component thereof.

27. A composition as in claim 20 wherein the surfactant is of low solubility in water.

28. A composition as in claim 25 wherein the non-paraffinic liquid is selected from the group consisting of benzyl benzoate, peppermint oil, orange oil, spearmint oil, essential oil of ginger, thymol, vanillin, anethole, cinnamon oil, cinnamaldehyde, clove oil, coriander oil, ylang-ylang oil, benzaldehyde, zingerone, carvone, linalool, and menthol.

29. A composition as in claim 20 wherein the polar solvent is selected from the group consisting of water, glycerol, ethylene glycol or propylene glycol, ethylammonium nitrate, acetamide, N-methyl acetamide, dimethylacetamide, and low-molecular weight polyethylene glycol (PEG).

30. A composition as in claim 20 wherein the non-paraffinic liquid has a molecular weight of about 500 or less.

31. A composition as in claim 20 wherein the non-paraffinic liquid has a molecular weight of about 250 or less.

32. A composition as in claim 20 wherein the reversed hexagonal or reversed cubic phase is a component of a pill, tablet, lozenge, capsule, troche, syrup or suspension drug formulation.

33. A composition as in claim 20 wherein the surfactant is chosen from the group consisting of Pluronics, D-alpha tocopheryl polyethylene glycol succinates, sorbitan fatty acid esters, docusate salts, polyethylene glycol oleyl ethers, polyoxyethylene castor oil derivatives, and polyoxyethylene hydrogenated castor oil derivatives.

34. A composition as in claim 20 wherein the reversed hexagonal or reversed cubic phase is tunable.

35. A composition, comprising:

a reversed cubic phase or reversed hexagonal phase material composed of pharmaceutically acceptable components, or a combination thereof, comprised of a polar solvent, a surfactant, and a non-paraffinic liquid having a polar group that is not operative as a surfactant head group, and with a high octanol-water partition coefficient which does not qualify as a surfactant; and

a compound that is difficultly soluble in water solubilized in said reversed cubic phase or reversed hexagonal phase material, or a combination thereof.

36. The composition of claim 35 wherein said composition is present as a reversed bicontinuous cubic phase.

37. The composition of claim 35 wherein said compound is difficultly soluble in oil.

38. The composition of claim 35 wherein said compound is a pharmaceutically active.

75. The composition of claim 35 wherein said non-paraffinic liquid is an essential oil or a component thereof selected from the group consisting of clove bud, ylang-ylang, santalwood, peppermint, eucalyptus, ginger, carrot seed, bay, myrrh, fir needle, patchouli, spearmint, and thyme.

40. A method for solubilizing a difficultly soluble compound comprising the step of incorporating said difficultly soluble compound into a matrix comprised of a reversed cubic or reversed hexagonal liquid crystalline phase material, or a combination thereof, wherein the reversed cubic or reversed hexagonal liquid crystalline phase material comprises a polar solvent, a surfactant, and a non-paraffinic liquid with a high octanol-water partition coefficient which does not qualify as a surfactant.

41. A method for administering a pharmaceutical active compound to a patient, comprising the steps of:

providing said patient with said pharmaceutical active compound associated with a reversed cubic phase or reversed hexagonal phase material, or a combination thereof, and

inducing nanopores in biomembrane absorption barriers in cells or tissues or organs of said patient using said reversed cubic phase or reversed hexagonal phase material, or a combination thereof, wherein said nanopores permit said pharmaceutical active compound to pass therethrough.

42. The method of claim 41 wherein said reversed cubic phase or reversed hexagonal phase material, or a combination thereof is present as a reversed bicontinuous cubic phase.

43. The method of claim 41 wherein nanopores formed in said inducing step are transient.

44. The method of claim 41 wherein said pharmaceutical active compound is difficultly soluble in water.

45. The method of claim 41 wherein said pharmaceutical active compound is difficulty soluble in oil.

46. The method of claim 41 wherein said reversed cubic phase or reversed hexagonal phase material, or a combination thereof, is comprised of a polar solvent, a surfactant, and a non-paraffinic liquid with a high octanol-water partition coefficient which does not qualify as a surfactant.

47. The method of claim 41 wherein said pharmaceutical active compound is selected from the group consisting of Nandrolone decanoate, Fentanyl citrate, Testosterone, Albendazole, Doxorubicin, Epirubicin, Idarubicin, Valrubicin, Oxybutinin, Amphotericin B, Enalaprilat, Docetaxel, Paclitaxel, Vinblastine, Vincristine, Vinorelbine, Batimastat, Eptifibatide, Tirofiban, Droperidol, Acyclovir, Pentafuside, Saquinavir, Cromolyn, Doxapram, SN-38 (Irinotecan), Topotecan, Hemin, Daunorubicin, Teniposide, Trimetrexate, Octreotride, Leuprolide, Clyclosporin A, Milrinone lactate, Buprenorphine, Nalbuphine, Carboplatin, Cisplatin, Mitoxantrone, Estradiol, Hydroxyprogesterone, L-Thyroxine, Etanercept, Neostigmine, Epoprostenol, Enalapril, Albuterol, Sulfinalol, Nandrolone, Morphine, Aspirin, Testosterone, Hexobarbitol, Cyclexedrine, Niclosamide, Mebendazole, Amphotalide, Retinoic acid, Emetine, Nifedipine, Quinidine, Chloramphenicol, Rifamide, Arnpicillin, Erythromycin A, Tetracycline, Ciprofloxacin, Sulfamoxole, Dapsone, Atropine, Warfarin, Nitrazapem, Zometapine, Glyburide, Uzarin, Aspirin, Taxol, Etiposide, Bupivicaine or local anesthetic, and Dantrolene.

76. The method of claim 46 wherein said non-paraffinic liquid is an essential oil or a component thereof selected from the group consisting of clove bud, ylang-ylang, santalwood, peppermint, eucalyptus, ginger, carrot seed, bay, myrrh, fir needle, patchouli, spearmint, and thyme.

48. A method for transporting a compound through a biomembrane absorption barrier, comprising the steps of:

inducing nanopores in said biomembrane absorption barrier using a reversed cubic phase or reversed hexagonal phase material, or a combination thereof, which is associated with said compound; and

passing said compound through said nanopores.

49. The method of claim 48 wherein said compound is difficultly soluble in water.

50. The method of claim 48 wherein said compound is difficulty soluble in oil.

51. The method of claim 48 wherein said reversed cubic phase or reversed hexagonal phase material, or a combination thereof, is comprised of a polar solvent, a surfactant, and a non-paraffinic liquid with a high octanol-water partition coefficient which does not qualify as a surfactant.

52. The method of claim 48 wherein said pharmaceutical active compound is selected from the group consisting of Nandrolone decanoate, Fentanyl citrate, Testosterone, Albendazole, Doxorubicin, Epirubicin, Idarubicin, Valrubicin, Oxybutinin, Amphotericin B, Enalaprilat, Docetaxel, Paclitaxel, Vinblastine, Vincristine, Vinorelbine, Batimastat, Eptifibatide, Tirofiban, Droperidol, Acyclovir, Pentafuside, Saquinavir, Cromolyn, Doxapram, SN-38 (Irinotecan), Topotecan, Hemin, Daunorubicin, Teniposide, Trimetrexate, Octreotride, Leuprolide, Clyclosporin A, Milrinone lactate, Buprenorphine, Nalbuphine, Carboplatin, Cisplatin, Mitoxantrone, Estradiol, Hydroxyprogesterone, L-Thyroxine, Etanercept, Neostigmine, Epoprostenol, Enalapril, Albuterol, Sulfinalol, Nandrolone, Morphine, Aspirin, Testosterone, Hexobarbitol, Cyclexedrine, Niclosamide, Mebendazole, Amphotalide, Retinoic acid, Emetine, Nifedipine, Quinidine, Chloramphenicol, Rifamide, Ampicillin, Erythromycin A, Tetracycline, Ciprofloxacin, Sulfamoxole, Dapsone, Atropine, Warfarin, Nitrazapem, Zometapine, Glyburide, Uzarin, Aspirin, Taxol, Etiposide, Bupivicaine or local anesthetic, and Dantrolene.

53. The method of claim 48 wherein said reversed cubic phase or reversed hexagonal phase material, or a combination thereof is present as a reversed bicontinuous cubic phase.

54. The method of claim 48 wherein nanopores formed in said inducing step are transient.

77. The method of claim 51 wherein said non-paraffinic liquid is an essential oil or a component thereof selected from the group consisting of clove bud, ylang-ylang, santalwood, peppermint, eucalyptus, ginger, carrot seed, bay, myrrh, fir needle, patchouli, spearmint, and thyme.

55. A method for administering a pharmaceutical active compound to a patient, comprising the steps of:

providing said patient with said pharmaceutical active compound;

providing said patient with a reversed cubic phase or reversed hexagonal phase material, or a combination thereof; and

inducing nanopores in biomembrane absorption barriers in cells or tissues or organs of said patient using said reversed cubic phase or reversed hexagonal phase material, or a combination thereof, wherein said nanopores permit said pharmaceutical active compound to pass therethrough.

56. The method of claim 55 wherein said two providing steps are performed together.

57. The method of claim 56 wherein said compound and said reversed cubic phase or reversed hexagonal phase material, or a combination thereof, are associated with each other.

58. The method of claim 55 wherein said two providing steps are performed sequentially.

59. The method of claim 55 wherein said reversed cubic phase or reversed hexagonal phase material, or a combination thereof is present as a reversed bicontinuous cubic phase.

60. The method of claim 55 wherein nanopores formed in said inducing step are transient.

61. The method of claim 55 wherein said pharmaceutical active compound is difficultly soluble in water.

62. The method of claim 55 wherein said pharmaceutical active compound is difficulty soluble in oil.

63. The method of claim 55 wherein said reversed cubic phase or reversed hexagonal phase material, or a combination thereof, is comprised of a polar solvent, a surfactant, and a non-paraffinic liquid with a high octanol-water partition coefficient which does not qualify as a surfactant.

64. The method of claim 55 wherein said pharmaceutical active compound is selected from the group consisting of Nandrolone decanoate, Fentanyl citrate, Testosterone, Albendazole, Doxorubicin, Epirubicin, Idarubicin, Valrubicin, Oxybutinin, Amphotericin B, Enalaprilat, Docetaxel, Paclitaxel, Vinblastine, Vincristine, Vinorelbine, Batimastat, Eptifibatide, Tirofiban, Droperidol, Acyclovir, Pentafuside, Saquinavir, Cromolyn, Doxapram, SN-38 (Irinotecan), Topotecan, Hemin, Daunorubicin, Teniposide, Trimetrexate, Octreotride, Leuprolide, Clyclosporin A, Milrinone lactate, Buprenorphine, Nalbuphine, Carboplatin, Cisplatin, Mitoxantrone, Estradiol, Hydroxyprogesterone, L-Thyroxine, Etanercept, Neostigmine, Epoprostenol, Enalapril, Albuterol, Sulfinalol, Nandrolone, Morphine, Aspirin, Testosterone, Hexobarbitol, Cyclexedrine, Niclosamide, Mebendazole, Amphotalide, Retinoic acid, Emetine, Nifedipine, Quinidine, Chloramphenicol, Rifamide, Ampicillin, Erythromycin A, Tetracycline, Ciprofloxacin, Sulfamoxole, Dapsone, Atropine, Warfarin, Nitrazapem, Zometapine, Glyburide, Uzarin, Aspirin, Taxol, Etiposide, Bupivicaine or local anesthetic, and Dantrolene.

78. The method of claim 63 wherein said non-paraffinic liquid is an essential oil or a component thereof selected from the group consisting of clove bud, ylang-ylang, santalwood, peppermint, eucalyptus, ginger, carrot seed, bay, myrrh, fir needle, patchouli, spearmint, and thyme.

65. A method for transporting a compound through a biomembrane absorption barrier, comprising the steps of:

inducing nanopores in said biomembrane absorption barrier using a reversed cubic phase or reversed hexagonal phase material, or a combination thereof; and

passing said compound through said nanopores.

66. The method of claim 65 wherein said compound and said reversed cubic phase or reversed hexagonal phase material, or a combination thereof, are associated with each other.

67. The method of claim 65 wherein said compound and said reversed cubic phase or reversed hexagonal phase material, or a combination thereof, are separate from each other.

68. The method of claim 65 wherein said compound is difficultly soluble in water.

69. The method of claim 65 wherein said compound is difficulty soluble in oil.

70. The method of claim 65 wherein said reversed cubic phase or reversed hexagonal phase material, or a combination thereof, is comprised of a polar solvent, a surfactant, and a non-paraffinic liquid with a high octanol-water partition coefficient which does not qualify as a surfactant.

71. The method of claim 65 wherein said pharmaceutical active compound is selected from the group consisting of Nandrolone decanoate, Fentanyl citrate, Testosterone, Albendazole, Doxorubicin, Epirubicin, Idarubicin, Valrubicin, Oxybutinin, Amphotericin B, Enalaprilat, Docetaxel, Paclitaxel, Vinblastine, Vincristine, Vinorelbine, Batimastat, Eptifibatide, Tirofiban, Droperidol, Acyclovir, Pentafuside, Saquinavir, Cromolyn, Doxapram, SN-38 (Irinotecan), Topotecan, Hemin, Daunorubicin, Teniposide, Trimetrexate, Octreotride, Leuprolide, Clyclosporin A, Milrinone lactate, Buprenorphine, Nalbuphine, Carboplatin, Cisplatin, Mitoxantrone, Estradiol, Hydroxyprogesterone, L-Thyroxine, Etanercept, Neostigmine, Epoprostenol, Enalapril, Albuterol, Sulfinalol, Nandrolone, Morphine, Aspirin, Testosterone, Hexobarbitol, Cyclexedrine, Niclosamide, Mebendazole, Amphotalide, Retinoic acid, Emetine, Nifedipine, Quinidine, Chloramphenicol, Rifamide, Ampicillin, Erythromycin A, Tetracycline, Ciprofloxacin, Sulfamoxole, Dapsone, Atropine, Warfarin, Nitrazapem, Zometapine, Glyburide, Uzarin, Aspirin, Taxol, Etiposide, Bupivicaine or a local anesthetic, and Dantrolene.

72. The method of claim 65 wherein said reversed cubic phase or reversed hexagonal phase material, or a combination thereof is present as a reversed bicontinuous cubic phase.

73. The method of claim 65 wherein nanopores formed in said inducing step are transient.

79. The method of claim 70 wherein said non-paraffinic liquid is an essential oil or a component thereof selected from the group consisting of clove bud, ylang-ylang, santalwood, peppermint, eucalyptus, ginger, carrot seed, bay, myrrh, fir needle, patchouli, spearmint, and thyme.