Implantable devices and methods for evaluation of active agents

• US 10,183,155 B2
• Filed: 05/18/2016
• Issued: 01/22/2019
• Est. Priority Date: 12/30/2011
• Status: Active Grant

• Current Assignee: Kibur Medical Inc., Massachusetts Institute of Technology
• Original Assignee: Kibur Medical Inc., Massachusetts Institute of Technology
• Inventors: Tepper, Robert I., Fuller, Jason, Jonas, Oliver, Santini, John
• Primary Examiner(s): Osinski, Bradley J
• Application Number:
  US15/158,344
• Publication Number:
  US 20160256670A1
• Time in Patent Office: 979 Days
• CPC Class Codes: A61B 10/0233 Pointed or sharp biopsy instruments
• CPC Class Codes: A61B 10/0266 means for severing sample
• CPC Class Codes: A61B 10/0275 with sample notch, e.g. on the side of inner stylet
• CPC Class Codes: A61B 17/3468 for implanting or removing devices, e.g. prostheses, implants, seeds, wires devices for implanting seeds A61M37/0069
• CPC Class Codes: A61B 5/0084 for introduction into the body, e.g. by catheters A61B5/1459 takes precedence
• CPC Class Codes: A61B 5/145 Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissuemeasuring of blood pressure or blood flow A61B5/02; non-radiation detecting or locating of foreign bodies in blood A61B5/06
• CPC Class Codes: A61B 5/4848 Monitoring or testing the effects of treatment, e.g. of medication
• CPC Class Codes: A61B 5/6861 Capsules, e.g. for swallowing or implanting
• 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: A61M 2202/06 Solids
• CPC Class Codes: A61M 2205/04 implanted
• CPC Class Codes: A61M 2207/00 Methods of manufacture, assembly or production
• CPC Class Codes: A61M 31/002 Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time artificial gland structures or devices A61F2/022; intra-uterine contraceptive devices A61F6/14; tampons for introducing into the vagina A61F13/20, A61L15/00; suppositories or bougies for intra-vaginal or intra-uterine application A61K9/02; physical forms of medicinal preparations for sustained or differential drug release A61K9/20, A61K9/50
• CPC Class Codes: A61M 37/0069 Devices for implanting pellets, e.g. markers or solid medicaments for introducing of radioactive sources for interstitial radiation therapy, i.e. brachytherapy A61N5/1027
• CPC Class Codes: G01N 1/31 Apparatus therefor

Abstract

Devices for the local delivery of microdose amounts of one or more active agents, alone or in combination, in one or more dosages, to selected tissue of a patient are described. The devices generally include multiple microwells arranged on or within a support structure and contain one or more active agents, alone or in combination, in one or more dosages and/or release pharmacokinetics. In an exemplary embodiment, the device has a cylindrical shape, having symmetrical wells on the outside of the device, each well containing one or more drugs, at one or more concentrations, sized to permit placement using a catheter, cannula, or stylet. Optionally, the device has a guidewire, and fiber optics, sensors and/or interactive features such as remote accessibility to provide for in situ retrieval of information and modification of device release properties. In a preferred embodiment, the fiber optics and/or sensors are individually accessible to discrete wells.

Claims

1. An implantable microdevice comprising:

a cylindrical support structure having microwells on a surface of or formed within the support structure;

a microdose of one or more active agents in at least one microwell; and

compound release mechanism comprising a polymeric matrix for controlling the release of the one or more active agents from the microwell;

wherein the microdose of the one or more active agents forms a gradient of a sub-therapeutic dose of the one or more active agents in a tissue adjacent to the microwell over a distance of at least 300 micrometers from the microwell within 72 hours following implantation of the microdevice into tissue;

wherein the device is configured to permit implantation into a tissue using a catheter, cannula or biopsy needle, and

wherein the device is further configured to release the one or more active agents from the microwells to separate and discrete areas of tissue adjacent to each microwell without overlap between the discrete areas.

2. The microdevice of claim 1, wherein the compound release mechanism further comprises a mechanism selected from the group consisting of the dimensions of an opening into the microwells, a film, a membrane, and a hydrogel pad.

3. The microdevice of claim 1 further comprising one or more active agent or combinations of active agent within the microwells.

4. The microdevice of claim 3 wherein the active agent or combinations thereof are present in different amounts.

5. The microdevice of claim 3 wherein the microwells have different pharmacokinetic release profiles.

6. The microdevice of claim 3, wherein the active agent is selected from the group consisting of cancer therapeutics, anti-angiogenic agent, immunomodulator, and anti-infective agents.

7. The microdevice of claim 1 further comprising a guide wire, wherein the guidewire is mechanically coupled to the microdevice support structure.

8. The microdevice of claim 1, wherein the microwells are separated by walls or include recessions which limit release of active agents into areas of release from adjacent microwells.

9. The microdevice of claim 1, wherein the microdevice comprises biodegradable polymers.

10. The microdevice of claim 1 wherein the one or more active agents are released from the microwells as a bolus, sustained release, delayed release, bolus followed by sustained release, and/or pulsatile release.

11. The microdevice of claim 1 wherein the active agent is present in solid form in the microwell.

12. The microdevice of claim 1 wherein the microdevice does not comprise needles or a fluid reservoir.

13. The microdevice of claim 1 formed of a plastic selected from the group consisting of polyether-ether-ketone, polysulfone and polyphenylsulfone.

14. The microdevice of claim 1 formed by methods selected from the group consisting of deep ion etching, nano imprint lithography, micromachining, laser etching, three dimensional printing and stereolithography.

15. A kit comprising the microdevice of claim 1 and means for implantation and removal selected from the group consisting of a catheter, cannula and biopsy needle having an inner diameter slightly larger than the outer diameter of the microdevice.

16. The microdevice of claim 1, wherein the release controlling polymer is poly(ethylene-glycol) (PEG).

17. The microdevice of claim 1, comprising integrated optical fibers.

18. The microdevice of claim 1 having a length of at least 2.5 mm and a diameter between about 0.5 mm and 2 mm.

19. The microdevice of claim 1, wherein edges of the neighboring microwells are separated by a distance of at least about 50 micrometers.

20. The microdevice of claim 1, wherein the microwells have a diameter between 130 micrometers and 600 micrometers, and a depth between 50 micrometers and 600 micrometers.

21. The microdevice of claim 1, wherein the microwells have a volume between about 1.25×

10⁵ cubic micrometers and about 1.25×

10⁸ cubic micrometers.

22. A method for determining efficacy of a compound in vivo or in situ comprising implanting using a catheter, cannula or biopsy needle inserted into a tissue within an organism an implantable microdevice comprising:

a cylindrical support structure having microwells on a surface of or formed within the support structure,

the microwells each containing and releasing after implantation a microdose of one or more active agents selected from the group consisting of therapeutic, prophylactic and diagnostic agents,

a microdose of one or more active agents in at least one microwell; and

compound release mechanism comprising a polymeric matrix for controlling the release of the one or more active agents from the microwell;

wherein the microdose of the one or more active agents forms a gradient of a sub-therapeutic dose of the one or more active agents in a tissue adjacent to the microwell over a distance of at least 300 micrometers from the microwell within 72 hours following implantation of the microdevice into tissue;

wherein the device is configured to permit implantation into a tissue using a catheter, cannula or biopsy needle, and

wherein the device is further configured to release the one or more active agents from the microwells to separate and discrete areas of tissue adjacent to each microwell without overlap between the discrete areas.

23. The method of claim 22, wherein the compound release mechanism further comprises a mechanism selected from the group consisting of a film, a membrane, and a hydrogel pad.

24. The method of claim 22 wherein the microdevice comprises two or more active agents, dosages of active agents or combinations of active agent within the microwells.

25. The method of claim 22 wherein the microdevice has microwells releasing active agent with different pharmacokinetic release profiles.

26. The method of claim 22 wherein the microdevice is implanted using a catheter and a guide wire, wherein the guidewire is mechanically coupled to the support structure of the microdevice.

27. The method of claim 22 wherein the microwells of the microdevice are separated by walls or include recessions which limit release of active agents into areas of release from adjacent microwells.

28. The method of claim 22 wherein active agent is released from the microwells as a bolus, sustained release, delayed release, bolus followed by sustained release, and/or pulsatile release.

29. The method of claim 22 wherein the active agent is present in solid form in the microwell or the device does not comprise needles or a fluid reservoir.

30. The method of claim 22 wherein the microdevice is formed by methods selected from the group consisting of deep ion etching, nano imprint lithography, micromachining, laser etching, three dimensional printing and stereolithoraphy.

31. The method of claim 22 further comprising evaluating drug efficacy in vivo or in situ by removing the microdevice and an amount of surrounding tissue after an amount of time.

32. The method of claim 31 further comprising cutting the surrounding tissue along an axis parallel to a length of the microdevice to form a slab of tissue to be analyzed.

33. The method of claim 31, wherein the microdevice is removed using a coring needle.

34. The method of claim 31, wherein the thickness of the removed tissue is approximately 500 μ

m.

35. The method of claim 31, wherein the assay is performed in vivo without removal of the tissue adjacent to the microdevice.

36. The method of claim 31, wherein the assay is performed in situ after removing the device and adjacent tissue from the organism.

37. The method of claim 22, wherein the tissue is a tumor.