Microchip devices for delivery of molecules and methods of fabrication thereof

• US 6,808,522 B2
• Filed: 12/01/2000
• Issued: 10/26/2004
• Est. Priority Date: 12/10/1999
• Status: Expired due to Term

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Richards, Amy C., Cima, Michael J., Santini, John T. Jr., Langer, Robert S.
• Primary Examiner(s): BENNETT, HENRY A
• Application Number:
  US09/727,858
• Publication Number:
  US 20020107470A1
• Time in Patent Office: 1,425 Days
• Field of Search: 604/890.1, 604/891.1, 604/93.01, 128/899, 216/2, 216/39
• US Class Current: 604/890.1
• CPC Class Codes: A61K 9/0009 involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis microelectromechanical systems A61K9/0097
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/0097 Micromachined devices; Microelectromechanical systems [MEMS]; Devices obtained by lithographic treatment of silicon; Devices comprising chips intradermal microneedle arrays A61K9/0021; MEMS in general B81B7/02
• CPC Class Codes: Y10T 436/25 including sample preparation

Abstract

Methods of manufacturing microchip devices are provided for controlled release of molecules, such as drugs. Methods include compression molding and casting, alone or in combination with microfabrication techniques. In preferred embodiments, devices are made by (1) filling a die with a polymer powder; (2) compressing the powder to form a polymer preform; (3) thermal compression molding the preform to form a substrate in a mold having a plurality of protrusions that form reservoirs in the substrate; and (4) filling the reservoirs with a release system comprising the molecules to be released. Alternatively, ceramic devices are formed by casting the substrate from a ceramic powder or a slurry using a mold having protrusions that form reservoirs in the substrate. Control over the release rate and time of the molecules from the reservoirs of the microchip device is provided by incorporating release systems and/or reservoir caps.

Claims

1. A method of fabricating an implantable microchip device for the controlled release of drug molecules, the method comprising:

molding or casting a material in a mold to form a substrate for use in an implantable drug delivery device, wherein a surface of the mold has a plurality of protrusions which form reservoirs in the substrate;

microinjecting or inkjet printing a fluid to form a reservoir can at one end of each of said reservoirs, said fluid being a solution comprising a cap material in a solvent, a suspension comprising a cap material in a nonsolvent, or a liquefied cap material; and

filling the reservoirs with a release system comprising drug molecules to be released.

2. The method of claim 1 wherein the material is a metal or polymer preform and the molding is compression molding.

3. The method of claim 1 wherein the material comprises a ceramic powder which is cast in the mold.

4. The method of claim 3 further comprising firing the substrate to densify it.

5. The method of claim 1 further comprising exposing the ends of the reservoirs to the surface of the substrate by cutting the substrate, planarizing a surface of the substrate, or a combination thereof.

6. The method of claim 5 wherein the planarization is performed by a method selected from the group consisting of polishing, chemical etching, and plasma etching.

7. The method of claim 5 wherein the cutting is conducted using a laser, water jet, or saw.

8. The method of claim 1 further comprising capping the reservoirs caps with an outer reservoir cap material.

9. The method of claim 5 further comprising sealing the other end of the reservoirs.

14. A microchip device made by the method of claim 1.

16. The method of claim 1, wherein the substrate comprises a polymer.

17. The method of claim 16, wherein the polymer is biodegradable.

18. The method of claim 1, wherein the release system further comprises a polymeric matrix.

19. The method of claim 1, wherein the reservoir cap material comprises a polymer.

20. The method of claim 8, wherein the outer reservoir cap material comprises a metal.

21. The method of claim 1, wherein the reservoir cap material comprises a resorbable biological material or biodegradable polymer.

22. The method of claim 1, wherein the release of molecules is passively controlled.

10. A method of fabricating an implantable microchip device for the controlled release of drug molecules, the method comprising:

providing a substrate for use in an implantable drug delivery device;

forming a plurality of reservoirs in the substrate;

microinjecting or inkjet printing a fluid to form a reservoir cap at one end of each of said reservoirs, said fluid being a solution comprising a cap material in a solvent, a suspension comprising a cap material in a nonsolvent, or a liquefied cap material; and

depositing a thin film of conductive material on one or more surfaces of the substrate to form electrodes near, in, or partially covering the reservoirs; and

filling the reservoirs with a release system comprising drug molecules to be released.

11. The method of claim 10 wherein the release system, upon application of an electric potential or current across the electrodes, (a) disintegrates or becomes permeable to the molecules due to a local pH change, or (b) exchanges ions in solution with an ionically bound active substance, thereby releasing the molecules.

12. The method of claim 11, wherein the release system further comprises a polymeric matrix.

13. The method of claim 10, wherein the reservoir caps, upon application of an electric potential or current across the electrodes, (a) disintegrate or becomes permeable to the molecules due to a local pH change, or (b) exchange ions in solution with an ionically bound active substance, thereby releasing the molecules.

15. A microchip device made by the method of claim 10.

23. The method of claim 10, wherein the substrate is made by molding or casting a material in a mold having a surface from which a plurality of protrusions extend, the protrusions forming said reservoirs in the substrate.

24. The method of claim 10, wherein the substrate comprises a polymer.

25. A method of fabricating an implantable drug delivery device for the controlled release of drug molecules, the method comprising:

molding or casting a material in a mold to form a substrate, wherein a surface of the mold has a plurality of protrusions which form reservoirs in the substrate, and the material comprises a biodegradeable polymer selected from the group consisting of poly(anhydrides), polyphosphazenes, pseudo poly(amino acids), and poly(esters);

microinjecting or inkjet printing a fluid to form a reservoir cap at one end of each of said reservoirs, said fluid being a solution comprising a cap material in a solvent, a suspension comprising a cap material in a nonsolvent, or a liquefied cap material; and

filling the reservoirs with a release system comprising drug molecules to be released.

26. The method of claim 25, wherein the reservoirs cap comprises a biodegradable polymer or a resorbable biological material.

27. The method of claim 26, wherein the biodegradable polymer comprises a poly(lactide-co-glycolide) or poly(lactone) copolymer.

28. The method of claim 26, wherein the resorbable biological material comprises a cholesterol or another lipid.

29. The method of claim 25, wherein the release of the drug molecules is passively controlled.