System for manufacturing controlled release dosage forms, such as a zero-order release profile dosage form manufactured by three-dimensional printing

• US 20030198677A1
• Filed: 10/29/2002
• Published: 10/23/2003
• Est. Priority Date: 10/29/2001
• Status: Active Grant

• Current Assignee: Aprecia Pharmaceuticals Company, Massachusetts Institute of Technology
• Original Assignee: Therics Inc.
• Inventors: Cima, Michael J., Materna, Peter A., Pryce Lewis, Wendy E., Rowe, Charles William
• Granted Patent: US 7,300,668 B2
• Time in Patent Office: Days
• US Class Current: 424/471
• CPC Class Codes: A61J 3/10 into the form of compressed tablets tablet presses B30B11/00
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• 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 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• 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: A61K 9/2893 Tablet coating processes mechanical aspects A61J3/06
• 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 present invention includes controlled release dosage forms and methods of designing and manufacturing dosage forms to obtain specific release profiles, for example, zero-order release profiles, escalating release profiles or decreasing release profiles. The dosage forms of the present invention can include spatial variation of API concentration in the dosage form and can include nested regions. Dosage forms according to the present invention may be manufactured by any appropriate method for obtaining the internal structure as disclosed herein for producing zero-order release profiles and increasing or decreasing release profiles. The invention further includes methods of manufacturing such dosage forms, such as by three-dimensional printing, possibly also including compression of the dosage form after three-dimensional printing. The invention further includes methods of designing such dosage forms. Release profiles from non-uniform distributions of API concentration may be predicted based on simple experiments with uniform-concentration dosage forms.

Claims

1. A dosage form comprising:

an innermost region having a respective regional concentration of at least one Active Pharmaceutical Ingredient; and

one or more additional regions, wherein each additional region completely surrounds the innermost region and any other region located interiorly of the region, and wherein each additional region has a respective regional concentration of at least one Active Pharmaceutical Ingredient which is different from the regional concentration in any region adjacent to the region.

2. The dosage form of claim 1, wherein the innermost region has a zero concentration.

3. The dosage form of claim 1, wherein the dosage form has a cylindrical geometric shape having a radial direction and an axial direction, and wherein each region except the innermost region has a regional axial wall thickness and a regional radial wall thickness, and wherein upon exposure to a liquid each region has a regional rate of axial recession and a regional rate of radial recession, and wherein for each region except the innermost region the regional axial wall thickness divided by the regional rate of axial recession, and the regional radial wall thickness divided by the regional rate of radial recession, are substantially equal to each other.

4. The dosage form of claim 1, wherein the dosage form has a cylindrical geometric shape having a radial direction and an axial direction, and wherein each region except the innermost region has a regional axial wall thickness and a regional radial wall thickness, and for each region except the innermost region the regional axial wall thickness and the regional radial wall thickness are substantially equal.

5. The dosage form of claim 4, wherein the dosage form comprises planar layers having a layer thickness, and for each region the regional radial wall thickness and the regional axial wall thickness are substantially equal to an integer multiple of the layer thickness, which integer can include one.

6. The dosage form of claim 1, wherein the dosage form has a rectangular prismatic geometric shape having a lengthwise direction and a widthwise direction and a heightwise direction, and wherein each region except the innermost region has a regional lengthwise wall thickness and a regional widthwise wall thickness and a regional heightwise wall thickness, and wherein upon exposure to a liquid each region has a regional rate of lengthwise recession and a regional rate of widthwise recession and a regional rate of heightwise recession, and wherein for each region except the innermost region the regional lengthwise wall thickness divided by the regional rate of lengthwise recession, and the regional widthwise wall thickness divided by the regional rate of widthwise recession, and the regional heightwise wall thickness divided by the regional rate of heightwise recession, are all substantially equal to each other.

7. The dosage form of claim 1, wherein the dosage form has a rectangular prismatic geometric shape having a lengthwise direction and a widthwise direction and a heightwise direction, and wherein each region except the innermost region has a regional lengthwise wall thickness and a regional widthwise wall thickness and a regional heightwise wall thickness, and wherein for each region except the innermost region the regional lengthwise wall thickness and the regional widthwise wall thickness and the regional heightwise wall thickness are all substantially equal to each other.

8. The dosage form of claim 7, wherein the dosage form comprises planar layers having a layer thickness, and for each region the regional lengthwise wall thickness and the regional widthwise wall thickness and the regional heightwise wall thickness are substantially equal to an integer multiple of the layer thickness, which integer can be one.

9. The dosage form of claim 5, wherein the layer thickness is substantially the same everywhere in the dosage form.

10. The dosage form of claim 5, wherein the layer thickness varies from place to place within the dosage form.

11. The dosage form of claim 1, wherein the dosage form is substantially spherical and the innermost region is spherical and the additional regions are concentric spherical-annular.

12. The dosage form of claim 1, wherein the dosage form everywhere has a local surface and wherein each region except the innermost region everywhere has a regional wall thickness in a direction perpendicular to the local surface of the dosage form and, upon exposure to a liquid, has a regional rate of recession in a direction perpendicular to the local surface of the dosage form, and wherein for each region the regional wall thickness divided by the regional rate of recession is substantially the same everywhere in that region.

13. The dosage form of claim 1, wherein each region everywhere has a regional wall thickness in a direction perpendicular to the local surface of the dosage form, and wherein for each region the regional wall thickness is substantially the same everywhere in the region.

14. The dosage form of claim 1, wherein each region everywhere has a regional wall thickness in a direction perpendicular to the local surface of the dosage form, and wherein for each region the regional wall thickness is not substantially the same everywhere in the region.

15. The dosage form of claim 1, wherein the dosage form has a rectangular prismatic geometric shape having a lengthwise direction and a widthwise direction and a heightwise direction, and wherein each region except the innermost region has a regional lengthwise wall thickness and a regional widthwise wall thickness and a regional heightwise wall thickness, and wherein in at least one region the lengthwise wall thickness and the widthwise wall thickness and the heightwise wall thickness are not all equal to each other.

16. The dosage form of claim 1, wherein the dosage form has a cylindrical geometric shape having a radial direction and an axial direction, and wherein each region except the innermost region has a regional axial wall thickness and a regional radial wall thickness, and wherein in at least one region the radial wall thickness and the axial wall thickness are not equal to each other.

17. The dosage form of claim 1, wherein for at least one region at least one wall thickness varies in a continuous manner.

18. The dosage form of claim 1, wherein the dosage form has a cylindrical geometric shape having a radial direction and an axial direction, and wherein each region except the innermost region has a regional axial wall thickness and a regional radial wall thickness, and wherein for at least one region the radial wall thickness is defined by an inner circle and an outer circle which are located eccentrically with respect to each other.

19. The dosage form of claim 1, wherein each region has a respective regional surface area and the regional concentration is a function of the regional surface area.

20. The dosage form of claim 1, wherein the dosage form has a geometric center and each region has a respective distance from the center of the dosage form, and the regional concentration is a function of the distance from the center of the dosage form.

21. The dosage form of claim 1, wherein the dosage form has an exterior and a geometric center, and wherein, in the direction from the exterior closer to the geometric center of the dosage form, the regional concentrations decrease monotonically.

22. The dosage form of claim 1, wherein the dosage form has an exterior and a geometric center, and wherein, in the direction from the exterior closer to the geometric center of the dosage form, the regional concentrations increase monotonically.

23. The dosage form of claim 1, wherein each region has a regional surface area and, for each region except for the innermost region, the product of the regional concentration times the regional surface area is approximately the same as the corresponding value for any other region.

24. The dosage form of claim 1, wherein each region has a regional surface area and, for each region, the product of the regional concentration times the regional surface area is approximately the same as the corresponding value for any other region.

25. The dosage form of claim 1, wherein the dosage form is substantially spherical having a geometric center, and the innermost region is spherical and the additional regions are concentric spherical-annular, and wherein the regional concentration varies as 1/r{circumflex over ( 

)}2 or as a stepwise approximation of 1/r{circumflex over ( 

)}2, where r is the radial coordinate of any region measured from the geometric center of the dosage form.

26. The dosage form of claim 1, wherein the regional concentrations in respective regions are selected so that one of the regions has a smallest non-zero regional concentration, and the regional concentrations in all of the regions having non-zero concentration are integer multiples of the smallest non-zero regional concentration, which integers can include one.

27. The dosage form of claim 1, wherein the regional concentrations in respective regions have arbitrary numerical relationship to each other.

28. The dosage form of claim 1 wherein each non-innermost region has at least one wall thickness and an overall dimension in the same direction as each wall thickness, and wherein for each region the wall thickness is no more than approximately one-third of the corresponding overall dimension of the region in the same direction as the wall thickness.

29. The dosage form of claim 1, wherein the innermost region has substantially no content of at least one Active Pharmaceutical Ingredient.

30. The dosage form of claim 1, wherein the innermost region has substantially no content of any Active Pharmaceutical Ingredient.

31. The dosage form of claim 1, wherein the respective regional concentrations are selected so that the at least one Active Pharmaceutical Ingredient is released in a desired release profile.

32. The dosage form of claim 1, wherein the respective regional concentrations are selected so that the at least one Active Pharmaceutical Ingredient is released in approximately a zero-order release.

33. The dosage form of claim 1, wherein the respective regional concentrations, progressing inwardly into the dosage form, increase more rapidly than the concentration distribution for zero-order release.

34. The dosage form of claim 1, wherein the respective regional concentrations are selected so that the at least one Active Pharmaceutical Ingredient is released in an escalating release.

35. The dosage form of claim 1, wherein the respective regional concentrations, progressing inwardly into the dosage form, increase less rapidly than the concentration distribution for zero-order release or decreases.

36. The dosage form of claim 1, wherein the respective regional concentrations are selected so that the at least one Active Pharmaceutical Ingredient is released in a decreasing release.

37. A dosage form, having a geometric center, wherein:

at an outer point there is a non-zero outer-point concentration of at least one Active Pharmaceutical Ingredient and at an inner point there is a non-zero inner-point concentration of at least one Active Pharmaceutical Ingredient, the outer point being further from the geometric center than the inner point, and the outer-point concentration being different from the inner-point concentration.

38. The dosage form of claim 37, wherein between the outer point and the inner point the concentration varies in a continuous manner.

39. The dosage form of claim 37, wherein between the outer point and the inner point there is a variation of concentration between the outer-point concentration and the inner-point concentration that is monotonically increasing.

40. The dosage form of claim 37, wherein between the outer point and the inner point there is a variation of concentration between the outer-point concentration and the inner-point concentration that is monotonically decreasing.

41. The dosage form of claim 37, wherein the dosage form is an oral dosage form.

42. The dosage form of claim 37, wherein the dosage form is an implantable dosage form.

43. The dosage form of claim 37, wherein the dosage form has a shape selected from the group consisting of:

cylindrical of any aspect ratio with flat ends;

cylindrical of any aspect ratio with rounded ends;

rectangular prismatic;

substantially spherical; and

substantially ellipsoidal.

44. The dosage form of claim 37, wherein the dosage form comprises a pharmaceutical excipient and the at least one Active Pharmaceutical Ingredients.

45. The dosage form of claim 44, wherein the pharmaceutical excipient forms a gel upon exposure to water.

46. The dosage form of claim 44, wherein the pharmaceutical excipient is hydroxypropyl methylcellulose.

47. The dosage form of claim 44, further comprising a water-soluble adjuvant.

48. The dosage form of claim 47, wherein the adjuvant is selected from the group consisting of lactose, other sugars, sodium chloride, other water-soluble salts, and other water-soluble substances.

49. The dosage form of claim 37, wherein the dosage form has a void fraction less than 5%.

50. The dosage form of claim 37, further comprising a surround-region having a wall thickness selected in accordance with the behavior of the dosage form during an initial period of dissolution of the dosage form.

51. The dosage form of claim 50, wherein the surround-region does not comprise any Active Pharmaceutical Ingredient.

52. The dosage form of claim 50, wherein the surround-region has a concentration of surround-region Active Pharmaceutical Ingredient that is selected in accordance with the behavior of the dosage form during an initial period of exposure of the dosage form to a bodily fluid.

53. The dosage form of claim 37, further comprising, external of all the regions and attached to the outside of the dosage form, at least one cap-region, at least one of the cap-regions comprising at least one cap-region Active Pharmaceutical Ingredient.

54. The dosage form of claim 37, wherein the dosage form is manufactured by three-dimensional printing.

55. A dosage form comprising:

a first end cap;

a second end cap spaced apart from the first end cap; and

a first region extending from the first end cap to the second end cap, comprising a first regional concentration of at least one Active Pharmaceutical Ingredient, which concentration may be zero; and

one or more additional regions extending from the first end cap to the second end cap and surrounding the first region and any other region located interiorly of it, at least one of the additional regions having a respective non-zero regional concentration of at least one Active Pharmaceutical Ingredient which is different from the regional concentration in any region adjacent to the region,

wherein, upon exposure to a liquid, the regions have respective regional recession rates and the end caps have an end cap recession rate which is substantially slower than any of the regional recession rates.

56. The dosage form of claim 55, wherein the respective concentrations are selected so that the at least one Active Pharmaceutical Ingredient is released in an escalating release profile.

57. The dosage form of claim 55, wherein the respective concentrations are selected so that the at least one Active Pharmaceutical Ingredient is released in a decreasing release profile.

58. The dosage form of claim 55, wherein the respective concentrations are selected so that the at least one Active Pharmaceutical Ingredient is released in approximately a zero-order release profile.

59. The dosage form of claim 55, wherein each region except the innermost region is annular and has a respective radial distance from a central axis of the dosage form, and the respective regional concentrations are approximately proportional to the inverse of the respective radial distance of the region from the axis.

60. The dosage form of claim 55, wherein each region except the innermost region is annular and has a respective radial distance from a central axis of the dosage form, and the respective regional concentrations are approximately proportional to the inverse of the square of the respective radial distance of the region from the axis.

61. The dosage form of claim 55, wherein the innermost region has the shape of a rectangular prism and each region except the innermost region has a shape of a rectangular shell.

62. The dosage form of claim 55, wherein the innermost region has substantially no content of at least one Active Pharmaceutical Ingredient.

63. The dosage form of claim 55 wherein the innermost region has substantially no content of any Active Pharmaceutical Ingredient.

64. The dosage form of claim 55 wherein the end caps are made of pure hydroxypropyl methylcellulose and the regions comprise hydroxypropyl methylcellulose and an adjuvant.

65. The dosage form of claim 55, wherein the dosage form has a shape selected from the group consisting of:

cylindrical of any aspect ratio with flat ends;

cylindrical of any aspect ratio with rounded ends;

rectangular prismatic;

substantially spherical; and

substantially ellipsoidal.

66. The dosage form of claim 55, wherein the dosage form has a void fraction less than 5%.

67. The dosage form of claim 55, further comprising a surround-region, which surrounds the regions, having a wall thickness selected in accordance with the behavior of the dosage form during an initial period of exposure of the dosage form to a bodily fluid.

68. The dosage form of claim 67, wherein the surround-region does not comprise any Active Pharmaceutical Ingredient.

69. The dosage form of claim 67, wherein the surround-region has a concentration of a surround-region Active Pharmaceutical Ingredient that is selected in accordance with the behavior of the dosage form during an initial period of exposure of the dosage form to a bodily fluid.

70. The dosage form of claim 55, wherein the dosage form is manufactured by three-dimensional printing.

71. A dosage form having a plurality of concentric regions of varying size, wherein each region contains an Active Pharmaceutical Ingredient concentration and wherein regions of a larger size contain lower the API concentrations as compared to regions of a smaller size such that an approximately zero-order release profile is achieved.

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

spreading a layer of powder;

depositing at least one binder liquid onto the powder in specified places, which binder liquid may contain at least one Active Pharmaceutical Ingredient; and

repeating, the above steps as many times as needed;

wherein the repeated depositing is performed so as to create an innermost region, the innermost region having a concentration of at least one Active Pharmaceutical Ingredient, which concentration may be zero, and at least one additional region, each additional region surrounding the innermost region and any other regions interiorly of the region, each additional region having a respective concentration of at least one Active Pharmaceutical Ingredient which is different from the concentration in adjacent regions.

74. The method of claim 72, further comprising compressing the dosage form.

75. The method of claim 72, wherein depositing at least one binder liquid comprises depositing multiple passes of a single binder liquid.

76. The method of claim 72, wherein depositing at least one binder liquid comprises depositing different binder liquids, each binder liquid having its respective concentration of at least one Active Pharmaceutical Ingredient.

77. The method of claim 72, wherein depositing is done by one or more printheads or types of printheads selected from the group consisting of:

a continuous jet with deflection printhead;

a microvalve printhead; and

a piezoelectric printhead.

78. The method of claim 72, wherein at least some of the depositing is done to a saturation parameter of greater than 1.

79. An oral dosage form manufactured by the method of claim 72.

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

spreading a layer of a first powder;

depositing an end cap binder liquid onto the first powder;

repeating the above steps as many times as needed to make an end cap;

spreading a layer of a second powder;

depositing at least one binder liquid onto the powder in specified places, which binder liquid may contain at least one Active Pharmaceutical Ingredient;

repeating, the above steps as many times as needed;

spreading a layer of the first powder;

depositing end cap binder liquid onto the first powder;

repeating the above steps as many times as needed to make an end cap; and

harvesting the dosage form;

wherein the repeated depositing of binder liquids is performed so as to create an innermost region, the innermost region having a concentration of at least one Active Pharmaceutical Ingredient, which concentration may be zero, and at least one additional region, each additional region surrounding the innermost region and any other regions interiorly of the region, each region having a respective non-zero concentration of at least one Active Pharmaceutical Ingredient which is different from the concentration in adjacent regions.

80. A method of designing a dosage form to provide release of at least one Active Pharmaceutical Ingredient in a desired release profile, comprising:

selecting a material set;

determining a surface recession rate or Active Pharmaceutical Ingredient release rate for the selected material set when exposed to a liquid;

estimating a design of regions, each region having respective dimensions and having a respective regional concentration of the at least one Active Pharmaceutical Ingredient;

calculating a predicted release profile of the at least one Active Pharmaceutical Ingredient;

comparing the predicted release profile to the desired release profile; and

adjusting a dimension or concentration or both in some layers to obtain a predicted release profile which matches the desired release profile to a desired closeness.

81. The method of claim 80, further comprising manufacturing trial dosage forms having the estimated dimensions and concentration distribution, dissolving the trial dosage forms under controlled conditions to obtain a measured release profile, and comparing the measured release profile to the desired release profile.

82. The method of claim 81, further comprising adjusting the Active Pharmaceutical Ingredient concentration distribution or dimensions based on the measured release profile, calculating a modified predicted release profile if desired, manufacturing new trial dosage forms and dissolving the new trial dosage forms under controlled conditions to obtain a new measured release profile.

83. The method of claim 80, wherein determining the surface recession rate or Active Pharmaceutical Ingredient release rate for the selected material system comprises manufacturing uniform-composition dosage forms, dissolving the uniform-composition dosage forms under controlled conditions to obtain release data as a function of time, and fitting a best-fit curve to the release data.

84. The method of claim 83, wherein manufacturing uniform-composition tablets comprises pressing powder to form a tablet.

85. The method of claim 83, wherein manufacturing uniform-composition tablets comprises three-dimensionally printing a dosage form followed by compressing the dosage form.

86. The method of claim 80, wherein the desired release profile is approximately zero-order.

87. The method of claim 80, wherein the desired release profile is escalating as a function of time.

88. The method of claim 80, wherein the desired release profile is decreasing as a function of time.