Method and form of a drug delivery device, such as encapsulating a toxic core within a non-toxic region in an oral dosage form

• US 20020015728A1
• Filed: 05/18/2001
• Published: 02/07/2002
• Est. Priority Date: 05/18/2000
• Status: Active Grant

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Cima, Michael J., Sherwood, Jill K., Payumo, Francis C., Wang, Chen-Chao, Gaylo, Christopher M., Monkhouse, Donald C., Yoo, Jaedeok
• Granted Patent: US 7,276,252 B2
• Time in Patent Office: Days
• US Class Current: 424/451
• 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 9/2886 having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer of the type active core-drug layer-inactive layer A61K9/209
• CPC Class Codes: A61K 9/2893 Tablet coating processes mechanical aspects A61J3/06
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: B33Y 10/00 Processes of additive manufacturing
• 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 drug delivery device such as an oral dosage form (ODF) with a toxic or potent core encapsulated by a non-toxic region. The non-toxic region may be a region including multiple layers, coatings, shells, and combinations thereof, which provides protection to and isolation from the toxic or potent core. The drug in the toxic or potent core is incorporated into the dosage form via, for example, three-dimensional printing, as a solution, solubilization or suspension of solid particles in liquid, rather than by the more conventional handling and compressing of dry powder. This minimizes the likelihood of creating airborne particles of the toxic drug during manufacturing, hence controlling and minimizing the exposure of manufacturing personnel to the hazardous substance. Wet dispensing of the toxic or potent drug further provides greater bioavailability of the drug to the patient.

Claims

1. A pharmaceutical dosage form, comprising:

a core region containing a first toxic or potent pharmaceutical active;

a transitional region wherein the transitional region encapsulates the core region; and

a shell region wherein the shell region encapsulates the transitional region and wherein the shell region is not toxic or potent.

2. The pharmaceutical dosage form of claim 1 wherein the transitional region includes unbound powder.

3. The pharmaceutical dosage form of claim 1 wherein the first toxic or potent pharmaceutical active is dispensed as a solution or a suspension or by solubilization.

4. The pharmaceutical dosage form of claim 1, further including a second toxic or potent active contained in the core region independent from the first toxic or potent active.

5. The pharmaceutical dosage form of claim 4 wherein the second toxic or potent active encapsulates the first toxic or potent active.

6. The pharmaceutical dosage form of claim 1 wherein the first pharmaceutical active is an anti-cancer drug, a steroid, a hormone, a narcotic or another compound having a high toxicity or potency.

7. The pharmaceutical dosage form of claim 1 wherein the first pharmaceutical active is camptothecin or 9-nitrocamptothecin or triiodothyronine or tetraiodothyroxine.

8. The pharmaceutical dosage form of claim 1 wherein the shell region is pharmaceutically inert.

9. The pharmaceutical dosage form of claim 1 wherein the shell region includes one or more pharmaceutical excipients.

10. The pharmaceutical dosage form of claim 1, further comprising a capsule that completely surrounds the shell region.

11. The pharmaceutical dosage form of claim 1 wherein the shell region includes a release-controlling substance.

13. The pharmaceutical dosage form of claim 12 wherein the toxic or potent pharmaceutical is dissolved in the first liquid.

14. The pharmaceutical dosage form of claim 12 wherein the toxic or potent pharmaceutical is present in the first liquid as suspended particles.

15. The pharmaceutical dosage form of claim 14 wherein the average size of the suspended particles is approximately 0.5 micron or less.

16. The pharmaceutical dosage form of claim 14 wherein the first liquid is dispensed through an orifice having a diameter, and the maximum size of the suspended particles is less than approximately one-tenth the diameter of the orifice.

17. The pharmaceutical dosage form of claim 14 wherein the suspension further comprises a steric hindrant or a suspending agent or both.

18. The pharmaceutical dosage form of claim 12 wherein the device is made from powder that is one or more pharmaceutical excipients.

19. The pharmaceutical dosage form of claim 18 wherein the powder further comprises a gelatin agent that forms a gel when it interacts with the first liquid, whereby the migration of first liquid through the powder is slowed.

20. The pharmaceutical dosage form of claim 19 wherein the gelation agent comprises hydroxypropyl methylcellulose or other hydrophilic polymer.

21. The pharmaceutical dosage form of claim 12 wherein the shell region includes a release-controlling substance.

22. The pharmaceutical dosage form of claim 12 further comprising a capsule that completely surrounds the shell.

23. The pharmaceutical dosage form of claim 12 wherein the second liquid is a solvent for a powder in the powder bed.

24. The pharmaceutical dosage form of claim 12 wherein the second liquid comprises adhesive or plasticizer.

25. The pharmaceutical dosage form of claim 12 wherein the powder comprises solid particles of an adhesive that interacts with the first or the second liquid.

27. The method of claim 26 wherein the first or the second liquid further include a binding agent.

28. The method of claim 26 wherein the pharmaceutical active is a anti-cancer drug, a steroid, a hormone, a narcotic, or another compound having high toxicity or potency.

29. The method of claim 26 wherein the pharmaceutical active is camptothecin or 9-nitrocamptothecin or other derivatives of camtothecin or triiodothyronine or tetraiodothyroxine.

30. The method of claim 26 wherein the first liquid contains the pharmaceutical active in solution.

31. The method of claim 26 wherein the first liquid contains the pharmaceutical active as solid particles suspended in the first liquid.

12. A pharmaceutical dosage form manufactured by three-dimensional printing comprising:

a core region containing at least one toxic or potent pharmaceutical contained in a first liquid deposited on a powder bed;

a transitional region wherein the transitional region encapsulates the core region; and

a shell region wherein the shell region encapsulates the transitional region, wherein the shell region is non-toxic and wherein the shell region comprises a second liquid deposited on the powder bed.

26. A method of manufacturing a pharmaceutical delivery device comprising a core region containing a pharmaceutical active and a shell region surrounding the core region, comprising:

spreading a layer of powder;

dispensing a first fluid containing a pharmaceutical active onto the powder in selected places forming a core region;

dispensing a second fluid onto the powder in places such as to completely surround the places where the first fluid is deposited and forming a shell region; and

repeating the process as many times as needed, wherein the first liquid is dispensed only into a region that is encapsulated by the surrounding shell region formed by the second liquid.

32. A method of manufacturing a dosage form containing an encapsulated toxic or potent core, comprising:

dispensing a first binder fluid which contains neither a toxic or potent excipient onto a layer of bulk material;

dispensing a second binder fluid containing a toxic or potent active within the footprint of the first binder fluid on at least one subsequent layer of bulk material;

dispensing a binder fluid which contains neither a toxic or potent excipient around a perimeter region of the dispensed toxic binder on the at least one subsequent layer of bulk material wherein the perimeter region is bound to the adjacent layer;

dispensing a binder fluid which contains neither a toxic or potent excipient over at least one subsequent layer of bulk material thereby enclosing the toxic or potent binder region with an encapsulating region which contains neither a toxic or potent excipient.