Microscale lyophilization and drying methods for the stabilization of molecules

• US 20040043042A1
• Filed: 12/03/2002
• Published: 03/04/2004
• Est. Priority Date: 12/03/2001
• Status: Active Grant

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Johnson, Audrey M., Cima, Michael J., Langer, Robert S.
• Granted Patent: US 7,354,597 B2
• Time in Patent Office: Days
• US Class Current: 424/400
• CPC Class Codes: F26B 5/06 the process involving freezing

Abstract

Methods and systems are provided for microscale lyophilization or microscale drying of agents of interest, such as pharmaceutical agents or other molecules that are unstable or easily degraded in solution. The drying method includes (a) providing a liquid comprising an agent of interest dissolved or dispersed in a volatile liquid medium; (b) depositing a microquantity (between 1 nL and 10 μL) of the liquid onto a preselected site of a substrate; and then (c) drying the microquantity by volatilizing the volatile liquid medium to produce a dry, solid form of the agent of interest. The lyophilization method includes freezing the microquantity of liquid after step (b) and before step (c). By processing the agent of interest in microquantities in controlled contact with a substrate surface, improved heat and mass transfer is provided, yielding better process control over drying of the agent of interest compared to conventional bulk drying or lyophilization.

Claims

1. A method of obtaining a quantity of a dry, solid form of an agent of interest comprising:

(a) providing a liquid which comprises an agent of interest dissolved or dispersed in a volatile liquid medium;

(b) depositing a microquantity of the liquid onto a preselected site of a substrate; and

(c) drying the microquantity by volatilizing the volatile liquid medium to produce a dry, solid form of the agent of interest.

2. The method of claim 1, wherein the volatile liquid medium comprises a solvent for the agent of interest and the liquid of step (a) comprises a solution of the active agent dissolved in the solvent.

3. The method of claim 1, wherein the volatile liquid medium comprises a non-solvent for the agent of interest and the liquid of step (a) comprises a suspension of the active agent dispersed in the non-solvent.

4. The method of claim 1, wherein the agent of interest comprises a pharmaceutical agent.

5. The method of claim 4, wherein the pharmaceutical agent comprises a peptide or a protein.

6. The method of claim 4, wherein the pharmaceutical agent is selected from the group consisting of glycoproteins, enzymes, hormones, interferons, interleukins, and antibodies.

7. The method of claim 4, wherein the pharmaceutical agent is selected from the group consisting of vaccines, gene delivery vectors, antineoplastic agents, antibiotics, analgesic agents, and vitamins.

8. The method of claim 4, wherein the agent of interest further comprises one or more pharmaceutically acceptable excipients.

9. The method of claim 1, wherein the agent of interest comprises an amino acid, peptide, or protein.

10. The method of claim 1, wherein the agent of interest comprises an enzyme.

11. The method of claim 1, wherein the volatile liquid medium is aqueous.

12. The method of claim 1, wherein the volatile liquid medium is non-aqueous.

13. The method of claim 12, wherein the volatile liquid medium comprises an aprotic, hydrophobic, non-polar liquid which comprises biocompatible perhalohydrocarbons or unsubstituted saturated hydrocarbons.

14. The method of claim 1, wherein the volatile liquid medium comprises one or more excipients.

15. The method of claim 14, wherein the one or more excipients comprise a surfactant.

16. The method of claim 15, wherein the one or more excipients comprise a polyoxyethylene sorbitan fatty acid ester.

17. The method of claim 1, wherein the microquantity has a volume between 1 nL and 1 μ

L.

18. The method of claim 1, wherein the microquantity has a volume between 10 nL and 500 nL.

19. The method of claim 1, wherein the microquantity of liquid is frozen after the deposition of step (b) and before the drying of step (c).

20. The method of claim 19, wherein the drying of step (c) comprises reheating the frozen microquantity.

21. The method of claim 1, wherein the drying of step (c) comprises subjecting the microquantity of liquid to a sub-atmospheric pressure.

22. The method of claim 1, wherein the drying of step (c) is carried out at a temperature at or less than 10°

C. at the preselected site.

23. The method of claim 1, wherein the preselected site of the substrate is a microscale reservoir.

24. The method of claim 23, wherein the microscale reservoir has a volume between 1 nL and 100 μ

L.

25. The method of claim 1, wherein step (b) comprises depositing two or more discrete microquantities onto two or more discrete preselected sites, respectively.

26. The method of claim 25, wherein the discrete preselected sites are provided on a single substrate.

27. The method of claim 25, wherein the single substrate comprises 100 or more discrete preselected sites.

28. The method of claim 25, wherein each of the two or preselected sites is a microscale reservoir.

29. The method of claim 28, wherein the microscale reservoirs are in the substrate of a microchip device.

30. The method of claim 28, wherein the agent of interest comprises a pharmaceutical agent and the microscale reservoirs are provided in an implantable drug delivery device.

31. The method of claim 25, further comprising, after the drying of step (c), combining together the two or more microquantities of dry, solid form of the agent of interest.

32. The method of claim 25, which is conducted in a continuous process.

35. A pharmaceutical formulation comprising a dry, solid form of a pharmaceutical agent made by the method of claim 4.

36. A medical device comprising microscale reservoirs containing a dry, solid form of a pharmaceutical agent made by the method of claim 4.

33. A method of obtaining a quantity of a dry, solid form of an agent of interest comprising:

(a) providing a liquid which comprises an agent of interest dissolved or dispersed in a volatile liquid medium;

(b) depositing a microquantity of the liquid onto a preselected site of a substrate;

(c) freezing the microquantity of liquid; and

then

(d) drying the microquantity by volatilizing the volatile liquid medium to produce a dry, solid form of the agent of interest.

34. The method of claim 33, wherein the drying of step (d) comprises heating the microquantity to enhance volatilization of the volatile liquid medium.

37. An apparatus for producing a quantity of a dry, solid form of an agent of interest comprising:

supply means for providing a liquid which comprises an agent of interest dissolved or dispersed in a volatile liquid medium;

deposition means for depositing two or more discrete microquantities of the liquid onto two or more discrete preselected sites, respectively, of a substrate;

dryer means for drying the microquantity by volatilizing the volatile liquid medium to produce a dry, solid form of the agent of interest;

collection means for removing the dry, solid form of the agent of interest from the preselected sites and then combining together the two or more microquantities of dry, solid form of the agent of interest; and

conveying means for returning the preselected sites and substrate from the collection means, following the removal of the dry, solid form of the agent of interest, to the deposition means so that additional two or more discrete microquantities of the liquid can be deposited onto the two or more discrete preselected sites of the substrate.

38. The apparatus of claim 37, further comprising a cooling means for freezing the deposited two or more discrete microquantities of liquid at the two or more discrete preselected sites, before drying.

39. The apparatus of claim 38, further comprising a heating means for re-heating the frozen microquantities during the drying of the microquantities.