System and method for uniaxial compression of an article, such as a three-dimensionally printed dosage form

• US 20030143268A1
• Filed: 10/29/2002
• Published: 07/31/2003
• Est. Priority Date: 10/29/2001
• Status: Active Grant

• Current Assignee: 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 7,931,914 B2
• Time in Patent Office: Days
• US Class Current: 424/464
• CPC Class Codes: A61J 3/10 into the form of compressed tablets tablet presses B30B11/00
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• 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: B29C 64/165 using a combination of solid and fluid materials, e.g. a powder selectively bound by a liquid binder, catalyst, inhibitor or energy absorber
• CPC Class Codes: B29L 2031/753 Medical equipment; Accessories therefor bloodbags, medical bags B29L2031/7148; artificial eyes B29L2011/0008
• CPC Class Codes: B33Y 70/00 Materials specially adapted for additive manufacturing
• CPC Class Codes: B33Y 80/00 Products made by additive manufacturing

Abstract

A uniaxially compressed dosage form manufactured by three-dimensional printing that preserves the predetermined internal architecture of the dosage form while producing an improved surface finish. The compression compacts the dosage form, eliminating at least some of the void space that remains at the end of conventional three-dimensional printing. Surface finish obtained as a result of the uniaxial compression process can be essentially equal to that obtained from conventional tablet pressing. Additionally, the internal structure or spatial variation of composition of the dosage form is preserved during the pressing operation, with geometric shrinkage occurring mostly in the direction of the axis of pressing. Further, as a result of compression, a greater quantity of API can be packed into a given final volume of dosage form.

Claims

1. A method of manufacturing a dosage form, comprising:

manufacturing a dosage form using a three-dimensional printing process; and

uniaxially compressing the dosage form.

2. The method of claim 1 wherein the uniaxial compression comprises placing the manufactured dosage form in a die assembly having confining surfaces which substantially surround the dosage form from all directions except for one direction and in that direction having an opening which defines an axis of pressing.

3. The method of claim 2 wherein the manufacturing using three-dimensional printing comprises moving a ram along the axis of pressing into the opening to uniaxially compress the dosage form.

4. The method of claim 1 further comprising, dissolving at least one Active Pharmaceutical Ingredient (API) into a binder liquid used in the three-dimensional printing process.

5. The method of claim 1 comprising, dispensing differing concentrations or different amounts of API or other substances in different places in the dosage form during the three-dimensional printing process, so as to create a spatially nonuniform composition.

6. The method of claim 5 wherein the dispensing comprises variable drop volume printing.

7. The method of claim 5 further comprising, creating an interior region in the dosage form during the three-dimensional printing process, the interior region having an interior composition surrounded by a shell having a shell composition.

8. The method of claim 7 further comprising, dispensing binder liquid during the three-dimensional printing process wherein the shell has a shell void fraction and the interior has an interior void fraction, and the shell void fraction and the interior void fraction are approximately equal to each other.

9. The method of claim 5 further comprising, dispensing binder liquid to create a plurality of regions each having an individual composition within the dosage form.

10. The method of claim 9 wherein dispensing the binder liquid further includes creating a plurality of regions that are nested within each other in the dosage form.

11. The method of claim 9 wherein each region of the dosage form has a void fraction, and all of these void fractions are approximately equal to each other.

12. The method of claim 5 further comprising, dispensing binder liquid to create a gradient of concentration of one or more substances in the dosage form.

13. The method of claim 12 wherein the dosage form has a geometric center, and wherein the binder liquid is dispensed so that the concentration of one or more substances varies as a function of distance from the geometric center of the dosage form.

14. The method of claim 12 wherein the binder liquids are dispensed so that the void fraction in the dosage form is approximately the same everywhere.

15. The method of claim 1 wherein manufacturing the dosage form by three-dimensional printing includes dispensing one or more binder liquids onto layers of powder.

16. The method of claim 15 wherein at least one binder liquid is dispensed onto a layer of powder more than one time before a next layer of powder is spread, the binder liquid containing a volatile component, the volatile component being allowed to substantially evaporate before binder liquid is re-dispensed onto the layer.

17. The method of claim 1 further comprising, applying a coating to the dosage form or enclosing the dosage form in a capsule.

18. The method of claim 1, wherein the dosage form is an implantable delivery device.

19. The method of claim 1, wherein the dosage form is an oral dosage form.

20. A dosage form having predetermined spatially nonuniform internal composition and having a void fraction less than 5%.

21. The dosage form of claim 20 wherein the dosage form is manufactured by three-dimensional printing.

22. The dosage form of claim 20 wherein the dosage form has a surface finish having a peak-to-valley dimension wherein the peak-to-valley dimension is less than or approximately equal to 3 microns.

23. The dosage form of claim 20 further comprising depressed or raised markings on one or more of its surfaces.

24. The dosage form of claim 20 wherein the dosage form has a shape selected from the group consisting of:

cylindrical with flat ends, cylindrical with curved ends, rectangular prismatic with flat ends, rectangular prismatic with curved ends, elliptical prismatic with flat ends, elliptical prismatic with curved ends, ellipsoidal, and spherical.

28. The dosage form of claim 20 comprising an API which is selected from the group consisting of pain-relievers for cancer;

pain-relievers for arthritis;

pain-relievers for other diseases;

hormones;

API to combat hypertension;

API to combat Parkinson'"'"'s disease;

API to combat Attention Deficit Disorder;

API to combat asthma; and

API to combat other diseases.

29. The dosage form of claim 20 wherein the dosage form comprises predetermined compositional nonuniformity on a size scale larger than the size of the powder particles.

30. The dosage form of claim 20 wherein the dosage form comprises an interior region having an interior composition surrounded by a shell having a shell composition.

31. The dosage form of claim 30 wherein the shell comprises a substance selected to influence the release characteristics of the API.

32. The dosage form of claim 30 wherein the shell has a shell non-powder fraction and the interior has an interior non-powder fraction, and the shell non-powder fraction and the interior non-powder fraction are approximately equal to each other.

33. The dosage form of claim 29 comprising, a plurality of regions each having its own composition.

34. The dosage form of claim 33 wherein the regions are nested within each other.

35. The dosage form of claim 32 wherein each region of the dosage form has a respective non-powder fraction, and all of these non-powder fractions are approximately equal to each other.

36. The dosage form of claim 30 wherein the dosage form comprises a gradient in the composition of one or more ingredients, on a size scale greater than the powder particle size.

37. The dosage form of claim 36 wherein the dosage form has a geometric center, and wherein the concentration of one or more substances varies as a function of distance from the geometric center of the dosage form.

38. The dosage form of claim 36 wherein each local place in the dosage form has a respective non-powder fraction, and all of these non-powder fractions are approximately equal to each other.

39. The dosage form of claim 20 further comprising a coating covering the dosage form or a capsule enclosing the dosage form.

40. The dosage form of claim 20 wherein the dosage form is an implantable API delivery device.

41. The dosage form of claim 20 wherein the dosage form is an oral dosage form.

25. The dosage form of claim 25 wherein the dosage form comprises powder particles bound together by a binding substance.

26. The dosage form of claim 25 wherein the powder comprises one or more substances selected from the group consisting of a methacrylic acid copolymer, microcrystalline cellulose, hydroxypropylmethylcellulose, mannitol, xylitol, sorbitol, dicalcium phosphate, lactose, glucose, dextrose, fructose and other sugars.

27. The dosage form of claim 25 wherein the binding substance is one or more substances selected from the group consisting of hydroxypropylmethylcellulose, Eudragit L-100, Eudragit E-100, Eudragit RSPO, Eudragit RLPO, and polyvinyl pyrrolidone.

42. A uniaxially compressed dosage form manufactured by three-dimensional printing.

43. The dosage form of claim 42 wherein the dosage form has a void fraction chosen to produce a desired release characteristic of an API.

44. The dosage form of claim 42 wherein the dosage form is uniaxially compressed by a die assembly comprising a lower die having a lower die outside geometry, and a sleeve having a sleeve inside geometry, and wherein a ram having a ram outside geometry, and wherein the lower die outside geometry and the ram outside geometry are both closely fitting with respect to the sleeve inside geometry.

45. The dosage form of claim 44 wherein the ram outside geometry, the lower die outside geometry and the sleeve inside geometry are all cylindrical.

46. The dosage form of claim 44 wherein the lower die has a lower die surface facing the dosage form and the ram has a ram surface facing the dosage form, and the lower die surface or the ram surface or both are generally curved.

47. The dosage form of claim 44 wherein the lower die has a lower die surface facing the dosage form and the ram has a ram surface facing the dosage form, and the lower die surface or the ram surface or both are generally flat.

48. The dosage form of claim 44 wherein the lower die surface and the sleeve inner surface and the ram have surface finishes which are smoother than or approximately equal to 2 microns rms.

49. The dosage form of claim 44 further comprising depressed or raised markings on the lower die surface or ram surface or both.

50. The dosage form of claim 44 wherein the dosage form has a shape selected from the group consisting of:

cylindrical with flat ends, cylindrical with curved ends, rectangular prismatic with flat ends, rectangular prismatic with curved ends, elliptical prismatic with flat ends, elliptical prismatic with curved ends, ellipsoidal, spherical.

51. The dosage form of claim 44 wherein the die and the ram and the sleeve all have respective hardnesses, and the dosage form has a hardness, and the hardnesses of the die and the ram and the sleeve are all greater than the hardness of the dosage form.

52. The dosage form of claim 44 wherein the lower die has a lower die surface and the ram has a ram surface, and the dosage form has an dosage form top surface and an dosage form bottom surface, and the lower die surface approximately matches the dosage form bottom surface, and the ram surface approximately matches the dosage form top surface.

53. The dosage form of claim 44 wherein the lower die and the sleeve are integral components.