IMPLANTABLE-GLUCOSE RESPONSIVE INSULIN DELIVERY DEVICE

• US 20140213963A1
• Filed: 03/31/2014
• Published: 07/31/2014
• Est. Priority Date: 05/05/2010
• Status: Active Grant

• Current Assignee: The Governing Council of the University of Toronto (University of Toronto)
• Original Assignee: The Governing Council of the University of Toronto (University of Toronto)
• Inventors: Wu, Xiao Yu, Gordijo, Claudia, Zhang, Kai, Huang, Huiyu, Li, Jason Siu-Wei, Chu, Michael K.L.
• Granted Patent: US 9,387,279 B2
• Time in Patent Office: Days
• US Class Current: 604/66
• CPC Class Codes: A61L 31/041 Mixtures of macromolecular compounds
• CPC Class Codes: A61M 2205/0227 Materials having sensing or indicating function, e.g. indicating a pressure increase
• CPC Class Codes: A61M 2230/201 Glucose concentration
• CPC Class Codes: A61M 5/14276 specially adapted for implantation

Abstract

A biocompatible insulin delivery device is provided comprising an insulin reservoir sealed with a glucose-responsive plug or membrane. The plug functions to release insulin from the reservoir in response to a hyperglycemic glucose concentration and to prevent insulin release from the reservoir in response to hypoglycemic glucose concentration. In one embodiment, the plug is made of a biocompatible polymeric matrix comprising an inorganic component, a stimulus-responsive component and a catalytic component.

Claims

1. A biocompatible insulin delivery device comprising a reservoir for insulin, a glucose-responsive plug that seals the reservoir, and optionally comprising a protective microporous membrane covering the exposed surface of the glucose-responsive plug and further sealing the reservoir, wherein the plug comprises a polymeric matrix having an inorganic component and a stimulus-responsive component adapted to alter the porosity of the plug in response to a stimulus and wherein the plug functions to release insulin from the reservoir in response to a hyperglycemic glucose concentration and to prevent insulin release from the reservoir in response to a hypoglycemic glucose concentration.

2. The device of claim 1, wherein the reservoir is made of a biocompatible material selected from the group consisting of synthetic polymer, natural polymer, metal, glass, ceramic and hybrid materials formed with biocompatible metal, glass or ceramics with one or more polymers.

3. The device of claim 1, wherein the reservoir is made of a polymer selected from the group consisting of collagen, starch blends, hyaluronic acid, alginates, carrageenan, silicone rubbers, polydimethylsiloxane, polyurethanes, acrylic polymers, poly(methyl methacrylate), polyesters, cellulose derivatives, cellulose acetate, polyethylene terephthalate, polycarbonate, polysulfone, polyvinyl chloride, polyethylene, polypropylene, polymethylacrylate and nylon.

4. The device of claim 2, wherein the material is surface modified with polyethylene glycol of at least about 2-50 kDa in size.

5. The device of claim 4, wherein the polyethylene glycol is at least about 20 kDa in size.

6. The device of claim 1, wherein the protective microporous membrane comprises a polymer selected from the group consisting of polyvinyls, polyamides, polyimides, polysulphones, polyurethanes, polyolefins, polyesters, polycarbonates, polyacrylates, polysaccharides, poly(amino acids), aramids, nylons, silicone rubbers and acrylic polymers.

7. The device of claim 6, wherein the polymer is selected from the group consisting of poly(vinyl chloride), poly(vinyl acetate), poly(ethylene-co-vinyl acetate) (EVA), poly(ethylene), poly(propylene), poly(lactic-co-glycolic acid) (PLGA), poly(methyl methacrylate) (PMMA), ethylcellulose, cellulose acetate, cellulose nitrate, polybutylene and ethylene propylene rubber and poly(dimethylsiloxane) (PDMS).

8. The device of claim 1, wherein the protective membrane comprises pores ranging in size from about 5-100 μ

m.

9. The device of claim 8, wherein the pores range in size from about 10-20 μ

m.

10. The device of claim 1, wherein the protective membrane is spaced from the exposed surface of the plug surface.

11. The device of claim 1, wherein the stimulus-responsive component comprises a composite of at least one hydrogel that changes porosity when exposed to a stimulus and at least one second polymer or polymer mixture that does not change when exposed to the stimulus.

12. The device of claim 11, wherein the hydrogel is selected from the group consisting of poly(ethylene oxide), polymers of R-acrylamide, R-acrylate or R₁-acrylic acid, and R,R₁,R₂-cellulose in which R, R₁ and R₂ may be H, alkyl or —

COOH containing groups.

13. The device of claim 11, wherein the second polymer is selected from the group consisting of crosslinked proteins and derivatives thereof, ethylcellulose, methylcellulose, propylcellulose, methoxypropylcellulose, hydroxypropylmethylcellulose, cellulose nitrate, poly(vinyl alcohol), poly(vinyl chloride), polystyrene, polyethylene, polypropylene, poly(ethylene-co-vinyl acetate), polyesters, poly(hydroxybutyric acid), poly(hydroxyvalerianic acid-co-hydroxybutyric acid), poly(lactic acid), poly(glycolic acid), poly(lactic acid-co-glycolic acid), poly(ε

□

caprolactones), poly(ε

□

caprolactone-co-DL-lactic acid), polyanhydrides, poly(maleic anhydride), polyamides, albumin, gelatin, chitosan, collagen, pol(hydroxyalkyl)-L-glutamines, poly(γ

-ehtyl-L-glutaminate-co-glutamic acid), poly(L-leucine-co-L-aspartic acid), poly(proline-co-glutamic acid), poly(orthoesters), poly(alkyl 2-cyanoacrylates), polylysin, alginate, alginic acid, polyurethanes, poly(methyl methacrylate), poly(methyl methacrylate-co-methacrylic acid) and poly(methacrylate-co-hydroxypropyl methacrylate).

14. The device of claim 11, wherein the stimulus-responsive component comprises a catalytic component that catalyzes the change in porosity in the hydrogel component in response to a change in the glucose level.

15. The device of claim 14, wherein the catalytic component comprises glucose oxidase that optionally includes catalase.

16. The device of claim 1, wherein the inorganic component comprises one or more of MnO₂, Ag, Au, SiO₂, titanium, iron, magnesium, silica-based materials and non-hydrocarbon-based nanomaterials.

17. The device of claim 1, wherein the plug comprises inorganic particles in an amount in the range of about 0.01% -25% (w/w).

18. A biocompatible glucose responsive membrane comprises a polymeric matrix having an inorganic component and a stimuli-responsive component adapted to alter the porosity of the matrix in response to a change in glucose concentration.

19. The membrane of claim 18, wherein the inorganic component comprises one or more of MnO₂, Ag, Au, SiO₂, titanium, iron, magnesium, silica-based materials and non-hydrocarbon-based nanomaterials.

20. A method of preparing a membrane as defined in claim 18, comprising the steps of

i) incubating the inorganic component, at least one polymer that does not change dimension when exposed to stimulus and a stimulus-responsive component with a cross-linking agent;

and

ii) adding to the polymer mixture at least one hydrogel that changes dimensions when exposed to a stimulus and incubating to permit further crosslinking.