Microarray for delivery of therapeutic agent, methods of use, and methods of making
Devices and methods for manufacturing and using microstructure arrays are described. In the methods, formulation is introduced into cavities of a microprojection array mold by means that include a vacuum to achieve a more efficient and uniform filling of the cavities and/or reduce bubble formation in the cavities.
1. A method of making an array of microstructures employing a continuous conveyor system, said system comprising a movable mold having an array of microstructure cavities, a soluble gas dispensing section, a vacuum application section, a formulation dispensing section and a drying section, the method comprising:
(a) dissolving or suspending at least one therapeutic agent in a first solvent to form a therapeutic agent solution or therapeutic agent suspension;
(b) dissolving at least one polymer in a second solvent to form a polymer solution or polymer suspension;
(c) mixing
(i) the therapeutic agent solution or therapeutic agent suspension and
(ii) the polymer solution or polymer suspension to form a casting solution or casting formulation;
(d) exposing the movable mold having an array of microstructure cavities to at least one of carbon dioxide (CO 2 ) gas or methane (CH 4 ) gas in the soluble gas dispensing section, where solubility and diffusivity of the CO 2 gas or CH 4 gas is greater in the mold compared to solubility and diffusivity of the CO 2 gas or CH 4 gas in air;
(e) applying a low vacuum to the movable mold having an array of microstructure cavities in the vacuum application section, wherein at least 90% of air in the cavities is removed by application of the low vacuum prior to dispensing the casting solution or casting formulation;
(f) dispensing the casting solution or casting formulation onto the mold in the formulation dispensing section;
(g) filling the microstructure cavities in the mold with the casting solution or casting formulation; and
(h) drying the casting solution or casting formulation to form the array of microstructures in the drying section.
2. The method of claim 1 , wherein the low vacuum is applied to achieve a vacuum pressure of about 1×10 −3 to less than about 760 Torr.
3. The method of claim 1 , wherein the low vacuum is applied to achieve a vacuum pressure of about 25 to less than about 760 Torr.
4. The method of claim 1 , further comprising:
after step (g), removing excess casting solution or casting formulation on the mold surface.
5. The method of claim 1 , wherein the drying of step (h) comprises drying at a temperature of about 5-50° C.
6. The method of claim 1 , wherein the drying of step (h) comprises drying for at least about 30-60 minutes.
7. The method of claim 1 , further comprising after step (h):
dispensing a basement or backing layer formulation on the mold surface; and
drying the basement or backing layer formulation, thereby forming a basement or backing layer on the array of microstructures.
8. The method of claim 7 , wherein the basement or backing layer is comprised of at least one non-biodegradable polymer.
9. The method of claim 7 , wherein drying the basement or backing layer formulation comprises drying at about 5-50° C.
10. The method of claim 7 , further comprising:
affixing the basement or backing layer to a substrate.
11. The method of claim 10 , wherein the substrate is selected from a pressure sensitive adhesive and a UV cured adhesive.
12. The method of claim 1 , wherein at least one of the first or second solvent is water or an aqueous solution.
13. The method of claim 1 , further comprising after step (h):
demolding the microstructure array.
14. The method of claim 7 , further comprising:
demolding the microstructure array after drying the basement or backing layer formulation.
15. The method of claim 1 , further comprising:
dissolving at least one of a sugar, a surfactant, or an antioxidant in at least one of the first or the second solvent prior to step (c).
16. The method of claim 15 , wherein the sugar is selected from sorbitol, sucrose, trehalose, fructose, or dextrose.
17. The method of claim 15 , wherein the surfactant is selected from polyoxyethylene ( 20 ) sorbitan monolaurate or polyoxyethylene ( 20 ) sorbitan monooleate.
18. The method of claim 15 , wherein the antioxidant is selected from methionine, cysteine, D-alpha tocopherol acetate, EDTA, or vitamin E.
19. The method of claim 1 , further comprising:
dissolving a sugar in the casting solution or casting formulation prior to step (f).
20. The method of claim 1 , wherein the therapeutic agent is selected from a drug, a small molecule, a peptide or protein, or a vaccine.
21. The method of claim 1 , wherein the microstructure cavities in the movable mold comprising the casting solution or casting formulation are pressurized for a period of time between steps (g) and (h).
22. A method for making an array of microstructures employing a continuous conveyor system, said system comprising a movable mold having an array of microstructure cavities, a soluble gas dispensing section, a vacuum application section, a formulation dispensing section and a drying section, the method comprising:
(a) providing a casting formulation, said formulation comprising:
(i) a solvent or combination of solvents,
(ii) at least one polymer dissolved in said solvent or combination of solvents, and
(iii) at least one therapeutic agent dissolved or suspended in said solvent or combination of solvents;
(b) exposing the movable mold having an array of microstructure cavities to at least one of carbon dioxide (CO 2 ) gas or methane (CH 4 ) gas in the soluble gas dispensing section, where solubility and diffusivity of the CO 2 gas or CH 4 gas is greater in the mold compared to solubility and diffusivity of the CO 2 gas or CH 4 gas in air;
(c) applying a low vacuum to the movable mold having an array of microstructure cavities in the vacuum application section, thereby removing at least 90% of the air from the microstructure cavities;
(d) dispensing the casting formulation onto the mold in the formulation dispensing section;
(e) filling the microstructure cavities in the mold with the casting formulation; and
(f) drying the casting formulation to form the array of microstructures in the drying section.
23. The method of claim 21 , wherein the microstructure cavities in the movable mold comprising the casting solution or casting formulation are pressurized for a period of time between steps (e) and (f).