Apparatus and method for using an intracutaneous microneedle array

• US 6,256,533 B1
• Filed: 06/09/1999
• Issued: 07/03/2001
• Est. Priority Date: 06/09/1999
• Status: Expired due to Term

• Current Assignee: Corium, Inc.
• Original Assignee: The Procter & Gamble Company
• Inventors: Gartstein, Vladimir, Sherman, Faiz Feisal, Owens, Grover David, Yuzhakov, Vadim Vladimirovich
• Primary Examiner(s): Seidel, Richard K.
• Assistant Examiner(s): Sirmons, Kevin C.
• Application Number:
  US09/329,025
• Time in Patent Office: 755 Days
• Field of Search: 604/20, 604/21, 604/501, 604/66, 604/246, 604/149, 604/152, 604/153
• US Class Current: 604/21
• CPC Class Codes: A61M 2037/0023 Drug applicators using microneedles
• CPC Class Codes: A61M 2037/003 having a lumen
• CPC Class Codes: A61M 2037/0053 Methods for producing microneedles
• CPC Class Codes: A61M 2037/0061 Methods for using microneedles
• CPC Class Codes: A61M 37/0015 by using microneedles
• CPC Class Codes: A61M 5/1723 using feedback of body parameters, e.g. blood-sugar, pressure measurement of body parameters A61B5/00
• CPC Class Codes: A61N 1/30 Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
• CPC Class Codes: B81B 2201/055 Microneedles
• CPC Class Codes: B81C 99/0085 using moulds and master templates, e.g. for hot-embossing

Abstract

A microneedle array, constructed of silicon and silicon dioxide compounds or of a molded plastic material, is provided to penetrate the stratum corneum and epidermis layers of skin, but not into the dermis. The microneedles can be used to either dispense a liquid drug, or to sample a body fluid. The delivery of drugs and sampling of fluids can be performed by way of passive diffusion (time release), instantaneous injection, or iontophoresis. A complete closed-loop system can be manufactured including active elements, such as micro-machined pumps, as well as passive elements such as sensors. A “smart patch” can thereby be fabricated that samples body fluids, performs chemistry to decide on the appropriate drug dosage, and then administers the corresponding amount of drug. An electric field may be used to increase transdermal flow rate. Such a system can be made disposable, and can be used with medical devices to dispense drugs by iontophoretic/microneedle enhancement, to sample body fluids (while providing an iontophoretically/microneedle-enhanced body-fluid sensor), and as a closed-loop drug delivery system with fluid sampling feedback using a combination of the other two devices. As a drug dispensing system, the microneedle array includes electrodes that apply an electric potential to the skin between the electrode locations. One of the electrode assemblies is filled with an ionized drug, and the charged drug molecules move into the body due to the applied electric potential. As a body-fluid sampling system, the microneedle array also includes electrodes to assist in moving fluid from the body into a receiving chamber, and which further includes a bioelectrochemical sensor to measure the concentration of a particular substance.

Claims

1. A first structure comprising:

a first base element and first plurality of microneedles formed thereon, wherein said first base element has a first side and a second side;

wherein said first plurality of microneedles comprises a plurality of hollow elements which project from the second side of said first base element along longitudinal axes that are at an angle with respect to said first base element;

wherein at least one of said longitudinal axes of said first plurality of microneedles is in alignment with one of a plurality of first openings in the second side of said first base element;

wherein said hollow elements of said first plurality of microneedles allow liquid to flow therethrough between a plurality of second openings at a distal end of said hollow elements and said first openings at the second side of said first base element; and

a first container structure comprising;

(a) a first reservoir capable of holding a liquid, (b) a first electrode proximal to said first reservoir;

a second structure comprising;

a second base element and second plurality of microneedles formed thereon, wherein said second base element has a third side and a fourth side;

wherein said second plurality of microneedles comprises a plurality of hollow elements which project from the fourth side of said second base element along a longitudinal axis that is at an angle with respect to said second base element;

wherein at least one of said longitudinal axes of said second plurality of microneedles is in alignment with one of a plurality of third openings in the fourth side of said second base element;

wherein said hollow elements of said second plurality of microneedles allow liquid to flow therethrough between a plurality of fourth openings at a distal end of said hollow elements and said third openings at the fourth side of said second base element; and

a second container structure comprising;

(a) a second reservoir capable of holding a liquid,

(b) a second electrode proximal to said second reservoir; and

an electrical power source that is in communication with said first and second electrodes.

2. The structures as recited in claim 1, further comprising an external liquid storage tank that is in fluidic communication with one of said reservoirs, and a fluid channel structure that transports liquid from said external liquid storage tank to said reservoir.

3. The structures as recited in claim 1, wherein said first and second electrodes facilitate dispensing an ionized liquid from one of said reservoirs through said plurality of microneedles into skin by iontophoresis.

4. The structures as recited in claim 3, wherein said first reservoir contains hydrogel and an ionized drug, and said second reservoir contains hydrogel.

5. The structures as recited in claim 1, further comprising an electronic controller;

wherein said first and second electrodes facilitate body-fluid sampling of a body fluid from skin through said plurality of microneedles by reverse iontophoresis.

6. The structures as recited in claim 5, further comprising a third electrode proximal to said first reservoir at a location different than said first electrode which detects an electrical signal in the manner of a bioelectrochemical sensor.

7. The structure as recited in claim 5, wherein said electrical power source includes a battery, and said electronic controller includes a central processing circuit;

and further comprising a visual indicator.

8. The structures as recited in claim 5, wherein said first reservoir contains hydrogel filled with glucose oxidase, and said second reservoir contains hydrogel.

9. A first structure comprising:

a first base element and first plurality of microneedles formed thereon, wherein said first base element has a first side and a second side;

wherein said first plurality of microneedles comprises a plurality of projections which extend from the second side of said first base element along a longitudinal axis that is at an angle with respect to said first base element;

wherein at least one of said longitudinal axes of said first plurality of microneedles is located proximal to a plurality of first openings in the second side of said first base element;

wherein said first plurality of microneedles allows liquid to flow along their outer surfaces through said first openings at the second side of said first base element; and

a first container structure comprising;

(a) a first reservoir capable of holding a liquid,

(b) a first electrode proximal to said first reservoir;

a second structure comprising;

a second base element and second plurality of microneedles formed thereon, wherein said second base element has a third side and a fourth side;

wherein said second plurality of microneedles comprises a plurality of projections which extend from the fourth side of said second base element along a longitudinal axis that is at an angle with respect to said second base element;

wherein at least one of said longitudinal axes of said second plurality of microneedles is located proximal to a plurality of second openings in the fourth side of said second base element;

wherein said second plurality of microneedles allows liquid to flow along their outer surfaces through said second openings at the fourth side of said second base element; and

a second container structure comprising;

(a) a second reservoir capable of holding a liquid,

(b) a second electrode proximal to said second reservoir; and

an electrical power source that is in communication with said first and second electrodes.

10. The structures as recited in claim 9, further comprising an external liquid storage tank that is in fluidic communication with one of said reservoirs, and a fluid channel structure that transports liquid from said external liquid storage tank to said reservoir.

11. The structures as recited in claim 9, wherein said first and second electrodes facilitate dispensing an ionized liquid from one of said reservoirs through said plurality of microneedles into skin by iontophoresis.

12. The structures as recited in claim 11, wherein said first reservoir contains hydrogel and an ionized drug, and said second reservoir contains hydrogel.

13. The structures as recited in claim 9, further comprising an electronic controller;

wherein said first and second electrodes facilitate body-fluid sampling of a body fluid from skin through said plurality of microneedles by reverse iontophoresis.

14. The structures as recited in claim 13, further comprising a third electrode proximal to said first reservoir at a location different than said first electrode which detects an electrical signal in the manner of a bioelectrochemical sensor.

15. The structure as recited in claim 13, wherein said electrical power source includes a battery, and said electronic controller includes a central processing circuit;

and further comprising a visual indicator.

16. The structures as recited in claim 13, wherein said first reservoir contains hydrogel filled with glucose oxidase, and said second reservoir contains hydrogel.

17. A method for dispensing liquid into a body through its skin, comprising:

(a) providing a first structure comprising;

a first base element and first plurality of microneedles formed thereon, wherein said first base element has a first side and a second side;

wherein said first plurality of microneedles comprises a plurality of hollow elements which project from the second side of said first base element along a longitudinal axis that is at an angle with respect to said first base element;

wherein at least one of said longitudinal axes of said first plurality of microneedles is in alignment with one of a plurality of first openings in the second side of said first base element;

wherein said hollow elements of said first plurality of microneedles allow liquid to flow therethrough between a plurality of second openings at a distal end of said hollow elements and said first openings at the second side of said first base element; and

a first iontophoresis apparatus comprising;

(i) a first reservoir for holding a liquid that is to be dispensed, (ii) a first electrode proximal to said first reservoir;

(b) providing a second structure comprising;

a second base element and second plurality of microneedles formed thereon, wherein said second base element has a third side and a fourth side;

wherein said second plurality of microneedles comprises a plurality of hollow elements which project from the fourth side of said second base element along a longitudinal axis that is at an angle with respect to said second base element;

wherein at least one of said longitudinal axes of said second plurality of microneedles is in alignment with one of a plurality of third openings in the fourth side of said second base element;

wherein said hollow elements of said second plurality of microneedles allow liquid to flow therethrough between a plurality of fourth openings at a distal end of said hollow elements and said third openings at the fourth side of said second base element; and

a second iontophoresis apparatus comprising;

(i) a second reservoir for holding a liquid, (ii) a second electrode proximal to said second reservoir;

(c) providing an electrical power source that is in communication with said first and second electrodes;

wherein said first and second electrodes facilitate dispensing said liquid through said plurality of microneedles into skin by iontophoresis;

(d) placing said first and second structures on skin in different locations, such that at least one of said first plurality of microneedles penetrates through a stratum corneum and into an epidermis of said skin, and that at least one of said second plurality of microneedles penetrates through said stratum corneum and into said epidermis; and

(e) dispensing liquid from said first reservoir into said epidermis by applying an electrical potential between said first and second electrodes.

18. The method as recited in claim 17, wherein said first reservoir contains hydrogel and an ionized drug, and said second reservoir contains hydrogel.

19. A method for sampling body-fluid of an organism through its skin, comprising:

(a) providing a first structure comprising;

a first base element and first plurality of microneedles formed thereon, wherein said first base element has a first side and a second side;

wherein said first plurality of microneedles comprises a plurality of hollow elements which project from the second side of said first base element along a longitudinal axis that is at an angle with respect to said first base element;

wherein at least one of said longitudinal axes of said first plurality of microneedles is in alignment with one of a plurality of first openings in the second side of said first base element;

wherein said hollow elements of said first plurality of microneedles allow liquid to flow therethrough between a plurality of second openings at a distal end of said hollow elements and said first openings at the second side of said first base element; and

a sensing apparatus comprising;

(i) a first reservoir for holding a liquid that is to be sampled, (ii) a first electrode proximal to said reservoir at a first location, (iii) a second electrode proximal to said reservoir at a second location which detects an electrical signal in the manner of a bioelectrochemical sensor;

(b) providing a second structure comprising;

a second base element and second plurality of microneedles formed thereon, wherein said second base element has a third side and a fourth side;

wherein said second plurality of microneedles comprises a plurality of hollow elements which project from the fourth side of said second base element along a longitudinal axis that is at an angle with respect to said second base element;

wherein at least one of said longitudinal axes of said second plurality of microneedles is in alignment with one of a plurality of third openings in the fourth side of said second base element;

wherein said hollow elements of said second plurality of microneedles allow liquid to flow therethrough between a plurality of fourth openings at a distal end of said hollow elements and said third openings at the fourth side of said second base element; and

a reverse iontophoresis apparatus comprising;

(i) a second reservoir for holding a liquid, (ii) a third electrode proximal to said second reservoir;

(c) providing an electrical power source that is in communication with said first and third electrodes;

an electronic controller;

wherein said first and third electrodes facilitate body-fluid sampling of a body fluid from skin through said plurality of microneedles by reverse iontophoresis;

(d) placing said first and second structures on skin in different locations, such that at least one of said first plurality of microneedles penetrates through a stratum corneum and into an epidermis of said skin, and that at least one of said second plurality of microneedles penetrates through said stratum corneum and into said epidermis; and

(e) withdrawing liquid from said epidermis into said first reservoir by applying an electrical potential between said first and third electrodes.

20. The method as recited in claim 19, wherein said first reservoir contains hydrogel filled with glucose oxidase, and said second reservoir contains hydrogel.

21. A method for dispensing liquid into a body through its skin, comprising:

(a) providing a first structure comprising;

a first base element and first plurality of microneedles formed thereon, wherein said first base element has a first side and second side;

wherein said first plurality of microneedles comprises a plurality of projections which extend from the second side of said first base element along a longitudinal axis that is at an angle with respect to said first base element;

wherein at least one of said longitudinal axes of said plurality of microneedles is located proximal to a plurality of first openings in the second side of said first base element;

wherein said first plurality of microneedles allows liquid to flow along their outer surfaces through said first openings at the second side of said first base element; and

a first iontophoresis apparatus comprising;

(i) a first reservoir for holding liquid to be dispensed, (ii) a first electrode proximal to said first reservoir;

(b) providing a second structure comprising;

a second base element and second plurality of microneedles formed thereon, wherein said second base element has a third side and a fourth side;

wherein said second plurality of microneedles comprises of plurality of projections which extend from the fourth side of said second base element along a longitudinal axis that is at an angle with respect to said second base element;

wherein at least one of said longitudinal axes of said second plurality of microneedles is located proximal to a plurality of second openings in the fourth side of said second base element;

wherein said second plurality of microneedles allows liquid to flow along their outer surfaces through said second openings at the fourth side of said second base element; and

a second iontophoresis apparatus comprising;

(i) a second reservoir for holding a liquid, (ii) a second electrode proximal to said second reservoir;

(c) providing an electrical power source that is in communication with said first and second electrodes;

wherein first and second electrodes facilitate dispensing said liquid along outer surfaces of said first plurality of microneedles through said second openings into skin by iontophoresis;

(d) placing said first and second structures on skin in different locations, such that at least one of said first plurality of microneedles penetrates through a stratum corneum and into an epidermis of said skin, and at least one of said second plurality of microneedles penetrates through said stratum corneum and into said epidermis; and

(e) dispensing liquid from said first reservoir into said epidermis by applying an electrical potential between said first and second electrodes.

22. The method as recited in claim 21, wherein said first reservoir contains hydrogel and ionized drug, and said second reservoir contains hydrogel.

23. A method for sampling body fluid of an organism through its skin, comprising:

(a) providing a first structure comprising;

a first base element and first plurality of microneedles formed thereon, wherein said first base element has a first side and second side;

wherein said first plurality of microneedles comprises a plurality of projections which extend from the second side of said first base element along a longitudinal axis that is at an angle with respect to said first base element;

wherein at least one of said longitudinal axes of said plurality of microneedles is located proximal to a plurality of first openings in the second side of said first base element;

wherein said first plurality of microneedles allows liquid to flow along their outer surfaces through said first openings at the second side of said first base element; and

a sensing apparatus comprising;

(i) a first reservoir for holding a liquid that is to be sampled, (ii) a first electrode proximal to said reservoir at a first location (iii) a second electrode proximal to said reservoir at a second location which detects an electrical signal in the manner of a bioelectrochemical sensor;

(b) providing a second structure comprising;

a second base element and second plurality of microneedles formed thereon, wherein said second base element has a third side and a fourth side;

wherein said second plurality of microneedles comprises of plurality of projections which extend from the fourth side of said second base element along a longitudinal axis that is at an angle with respect to said second base element;

wherein at least one of said longitudinal axes of said second plurality of microneedles is located proximal to a plurality of second openings in the fourth side of said second base element;

wherein said second plurality of microneedles allows liquid to flow along their outer surfaces through said second openings at the fourth side of said second base element; and

a reverse iontophoresis apparatus comprising;

(i) a second reservoir for holding a liquid, (ii) a third electrode proximal to said second reservoir;

(c) providing an electrical power source that is in communication with said first and third electrodes;

an electronic controller;

wherein first and third electrodes facilitate body-fluid sampling of a body fluid along outer surfaces of said first plurality of microneedles through said second openings from skin by reverse iontophoresis;

(d) placing said first and second structures on skin in different locations, such that at least one of said first plurality of microneedles penetrates through a stratum corneum and into an epidermis of said skin, and at least one of said second plurality of microneedles penetrates through said stratum corneum and into said epidermis; and

(e) withdrawing liquid from said epidermis into said first reservoir by applying an electrical potential between said first and third electrodes.

24. The method as recited in claim 23, wherein said first reservoir contains hydrogel filled with glucose oxidase, and said second reservoir contains hydrogel.

25. A method for real-time control of drug delivery into a body while sampling body-fluid, comprising:

(a) providing a first plurality of microneedles formed on a first base element, said first plurality of microneedles being in fluidic communication with a first reservoir containing a liquid drug that is to be dispensed;

(b) providing a second plurality of microneedles formed on a second base element, said second plurality of microneedles being in fluidic communication with a second reservoir for holding a liquid;

(c) placing said first and second structures on skin in different locations, such that at least one of said first plurality of microneedles penetrates through a stratum corneum and into an epidermis of said skin, and that at least one of said second plurality of microneedles penetrates through said stratum corneum and into said epidermis;

(d) withdrawing body-fluid through said second plurality of microneedles, and storing the body-fluid in said second reservoir;

(e) measuring in real time a concentration of a predetermined substance of said body fluid contained within said second reservoir;

(f) based upon the concentration of said predetermined substance, determining a correct dosage level of said drug contained within said first reservoir; and

(g) dispensing said liquid drug from said first reservoir into said epidermis.

26. The method as recited in claim 25, wherein said liquid drug passes from said first reservoir through said first plurality of microneedles into said skin, by way of diffusion.

27. The method as recited in claim 25, wherein said first and second plurality of microneedles are hollow.

28. The method as recited in claim 25, wherein said first and second plurality of microneedles are solid.

29. The method as recited in claim 25, further comprising:

providing a first electrode proximal to said first reservoir, a second electrode proximal to said second reservoir, and an electrical power source that is in communication with said first and second electrodes;

wherein said first and second electrodes facilitate dispensing said liquid drug through said first plurality of microneedles into skin by iontophoresis; and

wherein said first and second electrodes facilitate sampling said body-fluid through said second plurality of microneedles from said skin by reverse iontophoresis.

30. The method as recited in claim 29, wherein said first and second base elements comprise a single base structure;

and wherein an electronic controller is provided to control the application of an electrical potential between said first and second electrodes in one direction or the other, to measure the concentration of said body-fluid, and to determine a correct dosage of said liquid drug.