Multiple impact microprojection applicators and methods of use

1. A method of delivering a therapeutic agent to a subject, comprising:

applying to a skin site of a subject, an applicator comprising at least one plunger element, at least one microprojection retained on a distal surface of the plunger, and an actuator;

actuating the actuator to convey an external force to the at least one plunger element such that an energy required for the at least one microprojection to penetrate the skin site is delivered in multiple, discrete quanta and/or impacts at the skin site;

wherein, the multiple, discrete quanta and/or impacts are created by at least

the plunger comprising multiple energy-mass systems, each system having a different time constant, wherein each of the energy-mass systems has a progressively higher time constant such that the plunger elements impact the skin site in a defined sequence.

2. The method of claim 1 , wherein a maximum strain and/or strain rate is not exceeded by any of the multiple, discrete quanta and/or impacts.

3. The method of claim 1 , further comprising delaying between impacts at the skin site a sufficient time to allow a strain from a previous impact at the skin site to dissipate.

4. The method of claim 1 , wherein the at least one microprojection partially penetrates the skin site from a first impact, further comprising:

detaching the at least one microprojection from the plunger distal end.

5. The method of claim 1 , wherein each energy-mass system includes a spring and a mass element, further comprising

adjusting a spring constant of one or more springs in the energy-mass systems to modify a delay in impact from the plunger elements.

6. The method of claim 5 , further comprising:

adjusting a mass of the mass elements thereby to modify a delay in impact from the plunger elements.

7. The method of claim 1 , further comprising:

wherein the applicator further includes a vibration element and controlling an amplitude of the vibration element to limit an impact strain from one or more of the multiple, discrete quanta and/or impacts.

8. The method of claim 1 , further comprising:

wherein the applicator further includes a vibration element and controlling a frequency of the vibration element to limit an impact strain from one or more of the multiple, discrete quanta and/or impacts.

9. The method of claim 1 , wherein the at least one plunger element contacts a subject's skin with an energy of about 0.15-0.2 J.

10. The method of claim 1 , wherein the multiple, discrete quanta and/or impacts are further created by the applicator comprising a plurality of plunger elements and an asynchronous release mechanism such that the plunger elements are released at different time periods.

11. The method of claim 1 , wherein the multiple, discrete quanta and/or impacts are further created by the applicator comprising a plurality of plunger elements each comprising a dashpot element having a different damping coefficient.

12. The method of claim 1 , wherein the multiple, discrete quanta and/or impacts are further created by the applicator comprising a plurality of plunger elements, each having a different type of spring.

13. An applicator, comprising:

at least a first plunger element comprising a first energy-mass system, the first plunger element having a first restrained position and a second extended position, the first plunger element comprising a distal end on which at least one microprojection can be retained;

at least a second energy-mass system;

wherein the first and second energy-mass systems each has a different time constant, and each energy-mass system has a first restrained position and a second extended position;

an actuating member that can convey an external force to at least the first plunger element to release the first plunger element from the first restrained position; and

at least one microprojection attached to a distal surface of the plunger element distal end;

wherein the first energy-mass system has a faster time constant than the second energy-mass system such that the energy required for the at least one microprojection to penetrate a subject's skin at an application site is delivered by multiple, discrete impacts at the skin by the first and second energy-mass systems.

14. The applicator of claim 13 , wherein the first and second energy-mass systems each includes a mass and an energy-storing element.

15. The applicator of claim 14 , wherein the energy-storing elements are elastic energy elements each selected from a compression spring, a coil spring, a wave spring, and a slotted spring.

16. The applicator of claim 14 , wherein the mass of the first energy-mass system is different than the mass of the second energy-mass system.

17. The applicator of claim 13 , further comprising a third energy-mass system, wherein the third energy-mass system has a different time constant than the first or second energy-mass systems.

18. The applicator of claim 17 , wherein the third energy-mass system has a slower time constant than the first or second energy-mass systems.

19. The applicator of claim 13 , further comprising a housing member at least partially housing the first plunger element and actuating member.

20. The applicator of claim 13 , wherein the at least one microprojection is a microprojection array comprising a plurality of microprojections.

21. The applicator of claim 20 , wherein at least some of the plurality of microprojections are dissolvable or erodible microprojections.

22. The applicator of claim 20 , wherein at least some of the plurality of microprojections include at least one therapeutic agent selected from a drug, a small molecule, a peptide or protein, or a vaccine.

23. The applicator of claim 20 , wherein at least a portion of the plurality of microprojections are detachable from the microprojection array.

24. The applicator of claim 12 , further comprising:

a damper positioned between at least one of the energy-storing elements and a proximal surface of the first plunger element distal end.