Details for Patent: 6,458,383

Title:	Pharmaceutical dosage form for oral administration of hydrophilic drugs, particularly low molecular weight heparin
Abstract:	A delayed release pharmaceutical dosage form for oral administration of a hydrophilic drug, e.g., a polysaccharide drug such as low molecular weight heparin, are provided. The dosage form comprises a composition of: (a) a therapeutically effective amount of low molecular weight heparin; (b) a bile salt or bile acid; (c) at least one surfactant selected from hydrophilic surfactants, lipophilic surfactants, and mixtures thereof; and a means for delaying release of the composition from the dosage form following oral administration. Osmotic drug delivery systems for oral administration of a hydrophilic drug are also provided, wherein an osmotically activated device houses the drug, a bile salt or bile acid, and at least one surfactant selected from the group consisting of hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. Methods for administering hydrophilic drugs, particularly polysaccharide drugs such as low molecular weight heparin, are also provided.
Inventor(s):	Chen; Feng-Jing (Salt Lake City, UT), Patel; Mahesh V. (Salt Lake City, UT), Fikstad; David T. (Salt Lake City, UT)
Assignee:	Lipocine, Inc. (Salt Lake City, UT)
Filing Date:	Dec 29, 2000
Application Number:	09/751,968
Claims:	1. A delayed release pharmaceutical dosage form for oral adminisitraion of low moleclar weight heparin comprising a semi-solid, substantially nonaqueous composition of: (a) a therapeutically effective amount of low molecular weight heparin; (b) a bile salt or a bile acid that is suspended in the composition (i) in amorphous form, (ii) in milled, micronized, or nanosized form, or both (i) and (ii); (c) at least one hydrophilic surfactant and at least one lipoplilic surfactant; and (d) a means for delaying release of the composition from the dosage form following oral administration, wherein the bile salt or bile acid and the surfactants are selected such that upon mixing the composition with an aqueous mediuim at 100.times. dilution, an optically clear aqucous dispersion is formed having an absorbance of less than about 0.3 at 400 nm. 2. The dosage form of claim 1, comprising a capsule containing the composition. 3. The dosage form of claim 2, wherein the capsule is a starch capsule, a cellulosic capsule, a hard gelatin capsule or a soft gelatin capsule. 4. The dosage form of claim 1, comprising a tablet or caplet. 5. The dosage form of claim 1, comprising a plurality of particles, granules, beads, pellets or mixtures thereof. 6. The dosage form of any one of claims 1 through 5, wherein the means for delaying release comprises an enteric coating on the dosage form. 7. The dosage form of claim 1, wherein the low molecular weight heparin is present as a coating. 8. The dosage form of claim 1, wherein the bile salt or bile acid is present as a coating. 9. The dosage form of claim 8, wherein the means for delaying release comprises an enteric coating on the low molecular weight heparin coating. 10. The dosage form of claim 8, wherein the means for delaying release comprises an enteric coating on the bile salt or bile acid coating. 11. The dosage form of claim 2, wherein the composition is comprised of particles, granules, beads, pellets, or mixtures thereof. 12. The dosage form of claim 11, wherein the means for delaying release comprises an enteric coating on the particles, granules, beads, pellets, or mixtures thereof. 13. The dosage form of claim 11, wherein the particles, granules, beads, pellets, or mixtures thereof are coated with a coating comprised of low molecular weight heparin. 14. The dosage form of claim 11, wherein the particles, granules, beads, pellets, powder or mixtures thereof are coated with a coating comprised of a bile salt or bile acid. 15. The dosage form of claim 13, wherein the means for delaying release comprises an enteric coating on the low molecular weight heparin coating. 16. The dosage form of claim 14, wherein the means for delaying release comprises an enteric coating on the bile salt or bile acid coating. 17. The dosage form of claim 1, further including at least one protective coating. 18. The dosage form of claim 1, wherein the at least one hydrophilic surfactant is an ionic surfactant. 19. The dosage form of claim 1, wherein the at least one hydrophilic surfactant is a non-ionic surfactant having an HLB value of or greater than about 10. 20. The dosage form of claim 1, wherein the at least one lipophilic surfactant is a non-ionic surfactant having an HLB value of or less than about 10. 21. The dosage form of claim 1, wherein the at least one lipophilic surfactant is an unionized ionizable surfactant. 22. The dosage form of claim 1, wherein the at least one hydrophilic surfactant is a non-ionic surfactant having an HLB value of or greater than about 10 and the at least one lipophilic surfactant is a non-ionic surfactant having an HLB value of or less than about 10. 23. The dosage form of claim 1, wherein the low molecular weight heparin has a molecular weight in the range of approximately 1000 to 10,000 D. 24. The dosage form of claim 1, wherein the bile salt or bile acid is selected from cholic acid, ursodeoxycholic acid, chenodeoxycholic acid, deoxycholic acid, taurocholic acid, taurodeoxycholic acid, taurochenodeoxycholic acid, tauroursodeoxycholic acid, glycocholic acid, glycochenodeoxycholic acid, glycoursodeoxycholic acid, glycodeoxycholic acid, lithocholic acid, salts of any of the foregoing, and combinations thereof. 25. The dosage form of claim 24, wherein the bile salt or bile acid is ursodeoxycholic acid or a salt thereof. 26. The dosage form of claim 24, wherein the bile salt or bile acid is chenodeoxycholic acid or a salt thereof. 27. A delayed release dosage form for oral administration, comprised of a capsule coated with a biocrodible, gradually hydrolyzable, and/or gradually water-soluble enteric coating, and containing a liquid or semi-solid composition of low molecular weight heparin, a bile salt or acid that is suspended in the composition (i) in amoiorhous form, (ii) in milled, micronized, or nanosized form, or both (i) and (ii), and at least one surfactant selected from hydrophilic surfactants, lipoplhilic surfactants, and mixtures thereof, wherein any water present in the composition is insuficient to form a continuous aqueous phase, and further wherein the bile salt or bile acid and the at least one surfactant are selected such that upon mixing the composition with an aqueous medium at 100.times. dilution, an optically clear aqueous dispersion is formed having an absorbance of less than about 0.3 at 400 nm. 28. The dosage form of claim 27, wherein the enteric coating is comprised of a cellulosic polymer. 29. The dosage form of claim 28, wherein the cellulosic polymer is selected from hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose succinate, carboxymethylcellulose sodium, and mixtures thereof. 30. The dosage form of claim 27, wherein the enteric coating is comprised of an acrylic acid polymer. 31. The dosage form of claim 30, wherein the acrylic acid polymer is a copolymer of acrylic acid, methacrylic acid, methyl acrylate, ammonio methylacrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate. 32. The dosage form of claim 27, wherein the enteric coating is comprised of a vinyl polymer selected from polyvinyl pyrrolidone, polyvinyl acetate, polyvinylacetate phthalate, vinylacetate crotonic acid copolymer, and ethylene-vinyl acetate copolymers. 33. A pharmaceutical composition comprised of a liquid or semi-solid composition of a therapeutically effective amount of low molecular weight heparin, a bile salt or bile acid that is suspended in the composition (i) in amorphous form, (ii) in milled, micronized, or nanosized form, or both (i) and (ii), and at least one surfactant selected from hydrophilic surfactants, lipophilic surfactants, and mixtures thereof, wherein the composition is substantially free of glycerol triesters of C.sub.6 to about C.sub.25 fatty acids. 34. The composition of claim 33, further including a solubilizer. 35. The composition of claim 34, wherein the solubilizer is selected from alcohols, polyols, ethers, amides, esters, and mixtures thereof. 36. The composition of claim 35, wherein the solubilizer is selected from water, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol, glycofurol, diethylene glycol monoethyl ether, propylene glycol, sorbitol, glycerol, ethanol, dimethyl isosorbide, and mixtures thereof. 37. The composition of claim 33, wherein the low molecular weight heparin is partially suspended in the composition. 38. The composition of claim 33, wherein the bile salt or bile acid is at least partially solubilized in the composition. 39. The composition of claim 33, wherein the bile salt or bile acid is in milled, micronized, or nanosized form. 40. The composition of claim 33, wherein the bile salt or bile acid is selected from cholic acid, ursodeoxycholic acid, chenodeoxycholic acid, deoxycholic acid, taurocholic acid, taurodeoxycholic acid, taurochenodeoxycholic acid, tauroursodeoxycholic acid, glycocholic acid, glycochenodeoxycholic acid, glycoursodeoxycholic acid, glycodeoxycholic acid, lithocholic acid, salts of any of the foregoing, and combinations thereof. 41. The composition of claim 40, wherein the bile salt or bile acid is ursodeoxycholic acid or a salt thereof. 42. The composition of claim 40, wherein the bile salt or bile acid is chenodeoxycholic acid or a salt thereof. 43. The composition of claim 33, wherein any water present in the composition is insufficient to form a continuous aqueous phase. 44. The composition of claim 33, wherein the bile salt or bile acid and the at least one surfactant are selected such that upon mixing with an aqueous medium at 100.times. dilution, an optically clear aqueous dispersion is formed having an absorbance of less than about 0.3 at 400 nm. 45. A drug delivery system for oral administration of a polysaccharide drug, comprising: a first dosage form containing a therapeutically effective amount of the polysaccharide drug; and a second dosage form containing a bile salt or bile acid, in combination with at least one surfactant selected from hydrophilic surfactants, lipophilic surfactants, and mixtures thereof, wherein at least one of the dosage forms is a delayed release dosage form. 46. The drug delivery system of claim 45, wherein the second dosage form and optionally the first dosage form are coated with an enteric coating. 47. The drug delivery system of claim 45, wherein the polysaccharide drug is selected from glucosamine, glycosaminoglycans, dextran, xylan, pentasaccharide, polygalacturonic acid, polymannuronic acid, chitin, pharmaceutically acceptable salts, esters or other derivatives thereof, and combinations of any of the foregoing. 48. The drug delivery system of claim 47, wherein the polysaccharide drug is a glycosaminoglycan. 49. The drug delivery system of claim 48, wherein the glycosaminoglycan is selected from heparin, heparan, chondroitin, dermatan, hyaluronic acid and pharmaceutically acceptable salts thereof. 50. The drug delivery system of claim 48, wherein the glycosaminoglycan is selected from heparin, low molecular weight heparin, heparin sodium, heparan sulfate, and pharmaceutically acceptable salts of any of the foregoing formed with metallic cations or organic bases. 51. The drug delivery system of claim 50, wherein the polysaccharide drug is low molecular weight heparin. 52. The drug delivery system of claim 50, wherein the polysaccharide drug is heparin sodium. 53. The drug delivery system of claim 50, wherein the polysaccharide drug is heparan. 54. The drug delivery system of claim 50, wherein the polysaccharide drug is heparan sulfate. 55. In a method for administering low molecular weight heparin to a patient, the improvement comprising orally administering the low molecular weight heparin to the patient in the delayed release pharmaceutical dosage form of claim 1. 56. A method for administering a polysaccharide drug to a patient, comprising orally administering to the patient: a first dosage form containing a therapeutically effective amount of the polysaccharide drug; and a second dosage form containing a bile salt or bile acid, in combination with at least one surfactant selected from hydrophilic surfactants, lipophilic surfactants, and mixtures thereof, wherein at least one of the dosage forms is a delayed release dosage form. 57. The method of claim 56, wherein the two dosage forms are administered simultaneously. 58. The method of claim 56, wherein the first dosage form is administered before the second dosage form is administered. 59. The method of claim 56, wherein the first dosage form is administered after the second dosage form is administered. 60. A pharmaceutical dosage form for oral administration, comprising: an osmotically activated device coated with a bioerodible, gradually hydrolyzable, and/or gradually water-soluble enteric coating, and housing a composition containing a therapeutically effective amount of a hydrophilic drug, a bile salt or bile acid that is in amorphous form, is at least partially solubilized in the composition, and/or has been milled, micronized, or nanosized, and at least one surfactant selected from hydrophilic surfactants, lipophilic surfactants, and mixtures thereof, wherein the bile salt or bile acid and the at least one surfactant are selected such that upon mixing the composition with an aqueous medium at 100.times. dilution, an optically clear aqueous dispersion is formed having an absorbance of less than about 0.3 at 400 nm. 61. A delayed release pharmaceutical dosage form for oral administration of a polysaecharide drug, comprising a semi-solid, substantially nonaqueous composition of: (a) a therapeutically effective amount of a polysaecharide drug; (b) a bile salt or bile acid that is suspended in the composition (i) in amorphous form, (ii) in milled, micronized, or nanosized form, or both (i) and (ii); (c) at least one hydrophilic surfactant and at least one lipophilic surfactant; and (d) a means for delaying release of the composition of the dosage form following oral administration, wherein the bile salt or bile acid and the surfactants are selected such that upon mixing the composition with an aqueous medium at 100.times. dilution, an optically clear aqueous dispersion is formed having an absorbance of less than about 0.3 at 400 nm. 62. The dosage form of claim 61, wherein the polysaccharide drug is selected from glucosamine, glycosaminoglycans, dextran, xylan, pentasaccharide, polygalacturonic acid, polymannuronic acid, chitin, pharmaceutically acceptable salts, esters or other derivatives thereof, and combinations of any of the foregoing. 63. The dosage form of claim 62, wherein the polysaccharide drug is a glycosaminoglycan. 64. The dosage form of claim 63, wherein the glycosaminoglycan is selected from heparin, heparan, chondroitin, dermatan, hyaluronic acid and pharmaceutically acceptable salts thereof. 65. The dosage form of claim 63, wherein the glycosaminoglycan is selected from heparin, low molecular weight heparin, heparin sodium, heparan sulfate, and pharmaceutically acceptable salts of any of the foregoing formed with metallic cations or organic bases. 66. The dosage form of claim 65, wherein the polysaccharide drug is low molecular weight heparin. 67. The dosage form of claim 65, wherein the polysaccharide drug is heparin sodium. 68. The dosage form of claim 65, wherein the polysaccharide drug is heparan. 69. The dosage form of claim 65, wherein the polysaccharide drug is heparan sulfate. 70. A delayed release pharmaceutical dosage form comprising: (a) a therapeutically effective amount of low molecular weight heparin, and (b) at least one hydrophilic surfactant and at least one lipophilic surfactant, wherein the dosage form is coated with (c) a coating comprised of a bile salt or bile acid that is in amorphous form, and/or has been milled, micronized, or nanosized, and (d) an outermost layer of an enteric coating thereon. 71. A delayed release pharmaceutical dosage form comprising: (a) a bile salt or acid that is in amorphous form, and/or has been milled, micronized, or nanosized, and (b) at least one hydrophilic surfactant and at least one lipophilic surfactant, wherein the dosage form is coated with (c) a coating comprised of low molecular weight heparin, and (d) an outermost layer of an enteric coating thereon. 72. The dosage form of claim 1, wherein the bile salt or acid is in amorphous form. 73. The dosage form of claim 72, wherein the amorphous bile salt or acid is in milled, micronized, or nanosized form. 74. The dosage form of claim 27, wherein the bile salt or acid is in amorphous form. 75. The dosage form of claim 74, wherein the amorphous bile salt or acid is in milled, micronized, or nanosized form. 76. The composition of claim 33, wherein the bile salt or acid is in amorphous form. 77. The composition of claim 76, wherein the amorphous bile salt or acid is in milled, micronized, or nanosized form. 78. The dosage form of claim 60, wherein the bile salt or acid is in amorphous form. 79. The dosage form of claim 78, wherein the amorphous bile salt or acid is in milled, micronized, or nanosized form. 80. The dosage form of claim 61, wherein the bile salt or acid is in amorphous form. 81. The dosage form of claim 80, wherein the amorphous bile salt or acid is in milled, micronized, or nanosized form. 82. The dosage form of claim 70, wherein the bile salt or acid is in amorphous form. 83. The dosage form of claim 82, wherein the amorphous bile salt or acid is in milled, micronized, or nanosized form. 84. The dosage form of claim 71, wherein the bile salt or acid is in amorphous form. 85. The dosage form of claim 84, wherein the amorphous bile salt or acid is in milled, micronized, or nanosized form. 86. In a method for administering low molecular weight heparin to a patient, the improvement comprising orally administering the low molecular weight heparin to the patient in the delayed release pharmaceutical dosage form of claim 27. 87. In a method for administering low molecular weight heparin to a patient, the improvement comprising orally administering the low molecular weight heparin to the patient in the composition of claim 33. 88. In a method for administering low molecular weight heparin to a patient, the improvement comprising orally administering the low molecular weight heparin to the patient in the delayed release pharmaceutical dosage form of claim 70. 89. In a method for administering low molecular weight heparin to a patient, the improvement comprising orally administering the low molecular weight heparin to the patient in the delayed release pharmaceutical dosage form of claim 71. 90. A delayed release pharmaceutical dosage form for oral administration of low molecular weight heparin comprising a solid composition of: (a) a therapeutically effective amount of low molecular weight heparin; (b) a bile salt or a bile acid in amorphous form and/or milled, micronized, or nanosized form; (c) at least one surfactant selected from hydrophilic surfactants, lipophilic surfactants, and mixtures thereof; and (d) a means for delaying release of the composition from the dosage form following oral administration. 91. The dosage form of claim 1, wherein the composition further includes an additional quantity of the bile salt or acid that is in solubilized form, such that the bile salt or acid is partially solubilized and partially suspended in the composition. 92. The dosage form of claim 27, wherein the composition further includes an additional quantity of the bile salt or acid in solubilized form, such that the bile salt or acid is partially soltubilized and partially suspended in the composition. 93. The composition of claim 33, further including an additional quantity of the bile salt or acid in solubilized form, such that the bile salt or acid is partially solubilized and partially suspended in the composition. 94. The dosage form of claim 61, wherein the composition further includes an additional quantity of the bile salt or acid in solubilized form, such that the bile salt or acid is partially solubilized and partially suspended in the composition.