Microscale lyophilization and drying methods for the stabilization of molecules
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.
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 at a preselected site of a substrate; and
(c) drying the microquantity of the liquid by volatilizing the volatile liquid medium to produce a dry, solid form of the agent of interest,
wherein the volatile liquid medium comprises an aprotic, hydrophobic, non-polar liquid which comprises biocompatible perhalohydrocarbons or unsubstituted saturated hydrocarbons.
2. 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 at a preselected site of a substrate; and
(c) drying the microquantity of the liquid by volatilizing the volatile liquid medium to produce a dry, solid form of the agent of interest,
wherein the volatile liquid medium comprises one or more excipients, which comprise a surfactant.
3. The method of claim 2 , wherein the surfactant comprises a polyoxyethylene sorbitan fatty acid ester.
4. The method of claim 2 , wherein the microquantity of the liquid has a volume between 1 nL and 1 μL.
5. 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 at a preselected site of a substrate; and
(c) drying the microquantity of the liquid by volatilizing the volatile liquid medium to produce a dry, solid form of the agent of interest,
wherein the microquantity of the liquid has a volume between 10 nL and 500 nL, and wherein the agent of interest comprises an amino acid, a peptide, or a protein.
6. 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 at a preselected site of a substrate; and
(c) drying the microquantity of the liquid by volatilizing the volatile liquid medium to produce a dry, solid form of the agent of interest,
wherein the microquantity of the liquid is frozen after the deposition of step (b) and before the drying of step (c).
7. The method of claim 6 , wherein the drying of step (c) comprises reheating the frozen microquantity.
8. 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 at a preselected site of a substrate; and
(c) drying the microquantity of the liquid by volatilizing the volatile liquid medium to produce a dry, solid form of the agent of interest,
wherein the drying of step (c) comprises subjecting the microquantity of the liquid to a sub-atmospheric pressure.
9. 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.
10. 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 two or more discrete microquantities of the liquid at two or more discrete preselected sites of at least one substrate;
(c) drying the discrete microquantities of the liquid by volatilizing the volatile liquid medium to produce two or more microquantities of the dry, solid form of the agent of interest; and
(d) combining together the two or more microquantities of the dry, solid form of the agent of interest to form a single collection of the dry, solid form of the agent of interest,
wherein the agent of interest comprises insulin.
11. The method of claim 5 , wherein step (b) comprises depositing two or more discrete microquantities at two or more discrete, preselected sites, respectively.
12. The method of claim 11 , wherein each of the discrete, preselected sites is a microscale reservoir.
13. The method of claim 12 , wherein the microscale reservoir is in the substrate of a microchip device.
14. The method of claim 12 , wherein the microscale reservoir is located in a medical stent.
15. The method of claim 5 , wherein the agent of interest comprises a pharmaceutical agent.
16. The method of claim 15 , wherein the agent of interest further comprises one or more pharmaceutically acceptable excipients.
17. The method of claim 12 , wherein the agent of interest comprises a pharmaceutical agent and the microscale reservoirs are provided in an implantable drug delivery device.
18. The method of claim 6 , wherein step (b) comprises depositing two or more discrete microquantities at two or more discrete, preselected sites, respectively.
19. The method of claim 18 , wherein each of the discrete, preselected sites is a microscale reservoir.
20. The method of claim 19 , wherein the microscale reservoir is in the substrate of a microchip device.
21. The method of claim 19 , wherein the microscale reservoir is located in a medical stent.
22. The method of claim 6 , wherein the agent of interest comprises an amino acid, a peptide, or a protein.
23. The method of claim 6 , wherein the agent of interest comprises a pharmaceutical agent.
24. The method of claim 23 , wherein the agent of interest further comprises one or more pharmaceutically acceptable excipients.
25. The method of claim 19 , wherein the agent of interest comprises a pharmaceutical agent and the microscale reservoirs are provided in an implantable drug delivery device.
26. The method of claim 19 , wherein the microscale reservoir has a volume between 1 nL and 100 μL.
27. The method of claim 8 wherein step (b) comprises depositing two or more discrete microquantities at two or more discrete, preselected sites, respectively.
28. The method of claim 27 , wherein each of the discrete, preselected sites is a microscale reservoir.
29. The method of claim 28 , wherein the microscale reservoir is in the substrate of a microchip device.
30. The method of claim 28 , wherein the microscale reservoir is located in a medical stent.
31. The method of claim 8 , wherein the agent of interest comprises an amino acid, a peptide, or a protein.
32. The method of claim 8 , wherein the agent of interest comprises a pharmaceutical agent.
33. The method of claim 32 , wherein the agent of interest further comprises one or more pharmaceutically acceptable excipients.
34. 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.
35. The method of claim 28 , wherein the microscale reservoir has a volume between 1 nL and 100 μL.
36. A method comprising:
(a) providing a liquid which comprises a pharmaceutical agent dissolved or dispersed in a volatile liquid medium;
(b) depositing two or more discrete microquantities of the liquid into two or more respective, discrete microreservoirs located in a medical stent; and
(c) drying the two or more microquantities of the liquid by volatilizing the volatile liquid medium to produce dry, solid forms of the pharmaceutical agent in the microreservoirs of the medical stent.
37. The method of claim 36 , wherein the liquid in step (a) further comprises one or more pharmaceutically acceptable excipients.
38. The method of claim 37 , wherein the agent of interest comprises an amino acid, a peptide, or a protein.
39. The method of claim 36 , wherein the microquantities of liquid are frozen after the deposition of step (b) and before the drying of step (c).
40. The method of claim 36 , wherein the discrete microreservoirs are apertures extending through the medical stent.