Diffusion-controlled dosage form and method of fabrication including three dimensional printing

• US 20040005360A1
• Filed: 05/06/2003
• Published: 01/08/2004
• Est. Priority Date: 05/06/2002
• Status: Active Grant

• Current Assignee: Aprecia Pharmaceuticals Company
• Original Assignee: Therics Inc.
• Inventors: Bornancini, Esteban, Motwani, Monica Rewachand, Roach, Willie J., Wang, Chen-Chao, Yoo, Jaedeok
• Granted Patent: US 8,088,415 B2
• Time in Patent Office: Days
• US Class Current: 424/473
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 9/00 Medicinal preparations characterised by special physical form nuclear magnetic resonance contrast preparations or magnetic resonance imaging contrast preparations A61K49/18; preparations containing radioactive substances A61K51/12
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• 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
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: B29C 64/153 using layers of powder being selectively joined, e.g. by selective laser sintering or melting
• CPC Class Codes: B33Y 70/00 Materials specially adapted for additive manufacturing
• CPC Class Codes: B33Y 80/00 Products made by additive manufacturing

Abstract

The invention includes a core-and-shell dosage form or unit in which the core contains API and in which the shell substantially governs the release such as by controlling diffusion of API through the shell. The shell may comprise a release-blocking polymer, and particles of a release-regulating polymer. The shell may be substantially impervious but the release-regulating polymer may become suitable to allow diffusion through it when activated. The core may include a buffer region between the shell and the API-containing portion of the core. The dosage form may include multiple units. The dosage form of the invention is capable of providing a release profile whose time scale can be adjusted by adjusting powder composition, and which may be approximately zero-order release. The invention further includes methods of manufacturing such a dosage form, such as three-dimensional printing.

Claims

1. A dosage form having at least one unit, the unit further comprises:

a core comprising at least one Active Pharmaceutical Ingredient; and

a shell that surrounds the core, the shell further including a release-blocking polymer that is substantially insoluble in water but is soluble at room temperature in a solvent other than water, and a release-regulating polymer.

2. The dosage form of claim 1 wherein at least some of the release-regulating polymer in the shell exists in the form of individual particles, which may touch other particles.

3. The dosage form of claim 1 wherein at least some of the release-regulating polymer in the shell exists in the form of tortuous continuous paths, which may include wider parts and narrower parts.

4. The dosage form of claim 1 wherein at least some of the release-regulating polymer in the shell exists in the form of a three-dimensionally interconnected network.

5. The dosage form of claim 1 wherein the shell is substantially free of microscopic defects.

6. The dosage form of claim 1 wherein the shell has a thickness of at least 100 microns.

7. The dosage form of claim 1 wherein the shell has a thickness of approximately 800 microns.

8. The dosage form of claim 1 wherein at least some of the release-regulating polymer in the shell exists in the form of individual particles having an average particle size dimension, and the shell has a thickness of at least 3 times the average particle size dimension.

9. The dosage form of claim 1 wherein the release-blocking polymer and the release-regulating polymer are present in the shell in a proportion that is determined by a desired time scale of a release profile of the Active Pharmaceutical Ingredient from the dosage form.

10. The dosage form of claim 1 wherein the release-regulating polymer in the shell is in the range of 20% to 60% by volume of the combined total of release-regulating polymer and release-blocking polymer in the shell.

11. The dosage form of claim 1 wherein the release-blocking polymer is substantially unaffected by body fluids.

12. The dosage form of claim 1 wherein the release-blocking polymer is substantially impermeable to water.

13. The dosage form of claim 1 wherein the release-blocking polymer is hydrophobic.

14. The dosage form of claim 1 wherein the release-blocking polymer has at least one component that is soluble in at least one non-aqueous solvent.

15. The dosage form of claim 14 wherein the release-blocking polymer has at least one component that is soluble in ethanol.

16. The dosage form of claim 1 wherein the release-blocking polymer is selected from the group consisting of:

a mixture of approximately 80% polyvinyl acetate;

approximately 19% poylvinyl pyrrolidone; and

less than approximately 1% of sodium lauryl sulfate and silica, other polyvinyl acetates, ethyl celluloses, and poly(ethyl acrylate, methyl methacrylate) trimethylammonioethyl methacrylate chloride.

17. The dosage form of claim 1 wherein the release-blocking polymer has at least one component that has a glass transition temperature in an unplasticized state that is less than a temperature that the Active Pharmaceutical Ingredient suffers thermal damage.

18. The dosage form of claim 1 wherein the release-blocking polymer has at least one component that has a glass transition temperature in a plasticized state that is less than a temperature that the Active Pharmaceutical Ingredient suffers thermal damage.

19. The dosage form of claim 1 wherein the release-regulating polymer, upon exposure to water, allows diffusion of aqueous solutions therethrough.

20. The dosage form of claim 1 wherein the release-regulating polymer is capable of forming a gel upon exposure to water.

21. The dosage form of claim 1 wherein the release-regulating polymer absorbs water in a manner which is approximately unaffected by the pH of the water.

22. The dosage form of claim 1 wherein the release-regulating polymer is hydrophilic.

23. The dosage form of claim 1 wherein the release-regulating polymer degrades or dissolves at least slightly upon exposure to body fluids.

24. The dosage form of claim 1 wherein the release-regulating polymer is selected from the group consisting of:

hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, acrylate-methacrylate copolymers, polyethylene glycols, xanthan gum, gellan gum, locust bean gum, guar gum, tragacanth, and sodium alginate.

25. The dosage form of claim 1 wherein the shell has a uniform shell wall thickness.

26. The dosage form of claim 1 wherein the shell has a variable shell wall thickness.

27. The dosage form of claim 1 wherein the shell contains non-pharmaceutical materials.

28. The dosage form of claim 1 wherein the dosage form is made by three-dimensional printing, the three-dimensionally printed dosage form has dimensional increments of a drop-to-drop-spacing and a line-to-line spacing and a powder layer thickness, and wherein the shell has a thickness of at least one drop-to-drop-spacing or one line-to-line spacing or one powder layer thickness.

29. The dosage form of claim 1 wherein the dosage form is made by three-dimensional printing, the three-dimensionally printed dosage form has dimensional increments of a drop-to-drop-spacing and a line-to-line spacing and a powder layer thickness, and wherein the shell has a thickness of at least two drop-to-drop-spacings or two line-to-line spacings or two powder layer thicknesses.

30. The dosage form of claim 1 wherein the shell further includes a plasticizer.

31. The dosage form of claim 30 wherein the plasticizer and the release-blocking polymer are soluble in the same solvent.

32. The dosage form of claim 30 wherein the plasticizer is soluble in ethanol.

33. The dosage form of claim 30 wherein the plasticizer is selected from the group consisting of:

triethyl citrate, triacetin, diethyl phthalate, acetyltriethyl citrate, acetyltributyl citrate, carboxylic acid esters, and phosphoric acid esters.

34. The dosage form of claim 30 wherein the plasticizer is present in the shell in the form of micelles dispersed in the release-blocking polymer.

35. The dosage form of claim 1 wherein the core includes the release-blocking polymer and the release-regulating polymer as contained in the shell.

36. The dosage form of claim 1 wherein the core includes the release-blocking polymer and the release-regulating polymer as contained in the shell, and wherein the core has a core ratio of release-blocking polymer to release-regulating polymer in the core and the shell has a shell ratio of release-blocking polymer to release-regulating polymer in the shell, and the core ratio is substantially the same as the shell ratio.

37. The dosage form of claim 1 wherein the core includes unbound powder particles.

38. The dosage form of claim 1 wherein the core comprises powder particles bound to each other by Active Pharmaceutical Ingredient.

39. The dosage form of claim 1 wherein at least a portion of the core further includes a core binder substance.

40. The dosage form of claim 1 wherein, in the core, particles of the release-regulating polymer comprise API absorbed within them.

41. The dosage form of claim 1 wherein the core contains more Active Pharmaceutical Ingredient than can be contained in solution at body temperature in a volume of water equal to the void volume in the core.

42. The dosage form of claim 1 wherein the core contains less than or equal to the amount of Active Pharmaceutical Ingredient that can be contained in solution at body temperature in a volume of water equal to the void volume in the core.

43. The dosage form of claim 1 wherein the core contains less than or approximately equal to 0.34 milligrams of Active Pharmaceutical Ingredient per cubic millimeter of core region.

44. The dosage form of claim 1 wherein the Active Pharmaceutical Ingredient is water-soluble.

45. The dosage form of claim 1 wherein the Active Pharmaceutical Ingredient comprises at least one substance from the group consisting of pseudoephedrine hydrochloride, metoprolol, d-chlorpheniramine maleate, chlorpheniramine maleate, diphenhydramine hydrochloride, caffeine, d-brompheniramine maleate, brompheniramine maleate, aminophylline, and orphenadrine citrate.

46. The dosage form of claim 1 wherein the core comprises a central region comprising Active Pharmaceutical Ingredient, and comprises a buffer region, surrounding the central region, wherein the buffer region has at least some porosity and contains non-pharmaceutical ingredients.

47. The dosage form of claim 46 wherein the buffer region is sized so as to provide a desired delay time in a release of the Active Pharmaceutical Ingredient from the dosage form.

48. The dosage form of claim 46 wherein the buffer region is sized so as to prevent an initial burst release of the Active Pharmaceutical Ingredient.

49. The dosage form of claim 46 wherein the buffer region has a thickness of at least 200 micrometers.

50. The dosage form of claim 46 wherein the buffer region comprises the same release-blocking polymer and the same release-regulating polymer as are contained in the shell, and wherein the buffer region has a buffer region ratio of release-blocking polymer to release-regulating polymer in the buffer region and the shell has a shell ratio of release-blocking polymer to release-regulating polymer in the shell, and the buffer region ratio is substantially the same as the shell ratio.

51. The dosage form of claim 46 wherein the dosage form is made by three-dimensional printing, the three-dimensionally printed dosage form has dimensional increments of a drop-to-drop-spacing and a line-to-line spacing and a powder layer thickness, and wherein the buffer region has a thickness of at least one drop-to-drop-spacing or one line-to-line spacing or one powder layer thickness.

52. The dosage form of claim 1 wherein the unit has a rectangular prismatic shape.

53. The dosage form of claim 1 wherein the unit has a cylindrical shape.

54. The dosage form of claim 1, further comprising at least one additional unit.

55. The dosage form of claim 54 wherein the additional unit or units are joined to the unit by a joining structure that comprises an inter-unit binding substance.

56. The dosage form of claim 55 wherein the inter-unit binding substance is soluble in water.

57. The dosage form of claim 55 wherein the inter-unit binding substance is soluble in aqueous solutions of a specified pH.

58. The dosage form of claim 54 wherein the additional unit or units are substantially identical to the first unit.

59. The dosage form of claim 54 wherein at least one additional unit differs from the first unit.

60. The dosage form of claim 54 wherein at least one additional unit does not comprise a shell.

61. The dosage form of claim 1, further including a capsule that encloses the unit or units.

62. The dosage form of claim 1 wherein the core has a void fraction of greater than 20%.

63. The dosage form of claim 1 wherein the unit or the dosage form has a void fraction less than 5%.

98. The dosage form of claim 1 wherein the dosage form is manufactured by methods that include three-dimensional printing.

64. A method of making a dosage form, comprising:

depositing a layer of a powder comprising particles of a release-blocking polymer which is substantially insoluble in water but soluble in another solvent, and particles of a release-regulating polymer;

depositing onto the powder in selected places a pattern of a shell binder liquid which comprises a solvent for the release-blocking polymer;

depositing onto the powder in selected places a pattern of an API-containing liquid;

repeating the above steps enough times to manufacture a desired shape, wherein the shell binder liquid and the API-containing liquid differ from layer to layer;

allowing the dosage form to dry; and

separating unbound powder from the dosage form.

65. The method of claim 64 wherein the patterns of selected places in various layers are such that there is a region which received API-containing liquid, and that region is completely surrounded by a region which received shell binder liquid.

66. The method of claim 64 wherein the shell binder liquid is a solvent in which the release-blocking polymer is soluble.

67. The method of claim 64 wherein the shell binder liquid is a solvent in which both the release-blocking polymer and a plasticizer are soluble.

68. The method of claim 64 wherein the shell binder liquid is ethanol.

69. The method of claim 64 wherein the shell binder liquid further includes a plasticizer.

70. The method of claim 69 wherein the plasticizer is selected from the group consisting of:

triethyl citrate, triacetin, diethyl phthalate, acetyltriethyl citrate, acetyltributyl citrate, carboxylic acid esters, and phosphoric acid esters.

71. The method of claim 64 wherein the shell binder liquid comprises approximately 15 wt % triethyl citrate, together with approximately 85 wt % of an ethanol-water mixture, wherein the ethanol-water mixture comprising approximately 25 wt % water and approximately 75 wt % ethanol.

72. The method of claim 64 wherein the shell binder liquid further includes a thickening agent suitable to increase the viscosity of the shell binder liquid to a desired value.

73. The method of claim 64 wherein the depositing of the shell binder liquid is done at a drop volume per voxel volume of at least 0.5 milliliters of shell binder liquid per milliliter of overall volume of a voxel which receives shell binder liquid.

74. The method of claim 64 wherein the depositing of the shell binder liquid is done at a drop volume per voxel volume of approximately 0.55 milliliters of shell binder liquid per milliliter of overall volume of a voxel which receives shell binder liquid.

75. The method of claim 64 wherein the depositing of the shell binder liquid is done such that at least some of the shell comprises at least two adjacent drops.

76. The method of claim 64 wherein the depositing of the shell binder liquid is done such that at least some of the shell comprises at least two adjacent lines.

77. The method of claim 64 wherein the depositing of the shell binder liquid is done such that at least some of the shell includes at least two adjacent powder layers.

78. The method of claim 64 wherein the depositing of the shell binder liquid is done such that the shell includes at least two adjacent drops or two adjacent lines or two adjacent powder layers.

79. The method of claim 64 wherein the release-blocking polymer in the shell has a glass transition temperature, and further including heating the dosage form to a temperature higher than the glass transition temperature.

80. The method of claim 64 wherein the release-blocking polymer with plasticizer in the shell has a glass transition temperature, and further including heating the dosage form to a temperature higher than the glass transition temperature.

81. The method of claim 64 wherein the depositing of the shell binder liquid is done at a drop volume per voxel volume of at least 0.5 milliliters of shell binder liquid per milliliter of overall volume of a voxel which receives shell binder liquid, and wherein dispensing of the shell binder liquid is done such that the shell includes at least two adjacent drops or at least two adjacent lines or at least two adjacent powder layers.

82. The method of claim 81, further including heating the dosage form to a temperature higher than a glass transition temperature of the release-blocking polymer in the shell.

83. The method of claim 64 wherein the API-containing liquid includes a binder substance capable of adhering particles to each other.

84. The method of claim 64 wherein the API-containing liquid does not include a binder substance.

85. The method of claim 64 wherein the API-containing liquid is pseudoephedrine hydrochloride and water.

86. The method of claim 64 wherein the API-containing liquid is approximately 50 wt % pseudoephedrine hydrochloride, approximately 5 wt % polyvinyl pyrrolidone, approximately 0.01 wt % surfactant, balance water.

87. The method of claim 64 wherein the API-containing liquid includes at least one substance from the group consisting of pseudoephedrine hydrochloride, metoprolol, d-chlorpheniramine maleate, chlorpheniramine maleate, diphenhydramine hydrochloride, caffeine, d-brompheniramine maleate, brompheniramine maleate, aminophylline, and orphenadrine citrate.

88. The method of claim 64, further including allowing the API-containing liquid to at least partially dry, and again depositing API-containing liquid onto the powder before deposition of another layer of powder.

89. The method of claim 64 wherein the release-regulating polymer is selected from the group consisting of:

hydroxypropylmethylcellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, acrylate-methacrylate copolymers, polyethylene glycols, xanthan gum, gellan gum, locust bean gum, guar gum, tragacanth, and sodium alginate.

90. The method of claim 64 wherein the release-blocking polymer is selected from the group consisting of:

a mixture of approximately 80% polyvinyl acetate with approximately 19% poylvinyl pyrrolidone and less than approximately 1% of sodium lauryl sulfate and silica, other polyvinyl acetates, ethyl celluloses, and poly(ethyl acrylate, methyl methacrylate) trimethylammonioethyl methacrylate chloride.

91. The method of claim 64 wherein the release-blocking polymer is a mixture of approximately 80% polyvinyl acetate with approximately 19% poylvinyl pyrrolidone and less than approximately 1% of sodium lauryl sulfate and silica, and the release-regulating polymer is hydroxypropylmethyl cellulose.

92. The method of claim 64 wherein the powder comprises a volumetric ratio of release-blocking polymer to release regulating polymer in the range of approximately 80:

20 to approximately 40;

60.

93. The method of claim 64, further comprising leaving some powder between the core and the shell that receives neither API-containing liquid nor shell binder liquid.

94. The method of claim 64, further including compressing the dosage form.

95. The method of claim 64, further including enclosing one or more units in a capsule.

97. A dosage form made by the method of claim 64.

96. A method of forming a dosage form, comprising forming a core and coating it with a shell which comprises a release-blocking polymer and particles of a release-regulating polymer.