NZ736578B2 - Glucose-responsive insulin delivery system using hypoxia-sensitive nanocomposites - Google Patents
Glucose-responsive insulin delivery system using hypoxia-sensitive nanocompositesInfo
- Publication number
- NZ736578B2 NZ736578B2 NZ736578A NZ73657816A NZ736578B2 NZ 736578 B2 NZ736578 B2 NZ 736578B2 NZ 736578 A NZ736578 A NZ 736578A NZ 73657816 A NZ73657816 A NZ 73657816A NZ 736578 B2 NZ736578 B2 NZ 736578B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- insulin
- composition
- hypoxia
- sensitive
- glucose
- Prior art date
Links
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 title claims abstract 32
- 102000004877 Insulin Human genes 0.000 title claims abstract 15
- 108090001061 Insulin Proteins 0.000 title claims abstract 15
- 229940125396 insulin Drugs 0.000 title claims abstract 15
- 206010021143 Hypoxia Diseases 0.000 title claims abstract 14
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 title claims abstract 11
- 239000008103 glucose Substances 0.000 title claims abstract 11
- 230000007954 hypoxia Effects 0.000 title claims abstract 11
- 239000002114 nanocomposite Substances 0.000 title 1
- 239000003795 chemical substances by application Substances 0.000 claims abstract 15
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract 15
- 125000001165 hydrophobic group Chemical group 0.000 claims abstract 7
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims abstract 5
- 229920002674 hyaluronan Polymers 0.000 claims abstract 3
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract 3
- 230000001146 hypoxic effect Effects 0.000 claims abstract 3
- 229920000642 polymer Polymers 0.000 claims abstract 2
- 239000000203 mixture Substances 0.000 claims 13
- 229920001477 hydrophilic polymer Polymers 0.000 claims 11
- 238000000034 method Methods 0.000 claims 9
- 239000000463 material Substances 0.000 claims 7
- 230000000975 bioactive effect Effects 0.000 claims 5
- 108010015776 Glucose oxidase Proteins 0.000 claims 4
- 239000004366 Glucose oxidase Substances 0.000 claims 4
- 229940116332 glucose oxidase Drugs 0.000 claims 4
- 235000019420 glucose oxidase Nutrition 0.000 claims 4
- 150000004676 glycans Chemical class 0.000 claims 4
- 239000007800 oxidant agent Substances 0.000 claims 4
- 229920001282 polysaccharide Polymers 0.000 claims 4
- 239000005017 polysaccharide Substances 0.000 claims 4
- 125000003277 amino group Chemical group 0.000 claims 3
- YZEUHQHUFTYLPH-UHFFFAOYSA-N 2-nitroimidazole Chemical compound [O-][N+](=O)C1=NC=CN1 YZEUHQHUFTYLPH-UHFFFAOYSA-N 0.000 claims 2
- 239000004971 Cross linker Substances 0.000 claims 2
- 101000976075 Homo sapiens Insulin Proteins 0.000 claims 2
- 108010020346 Polyglutamic Acid Proteins 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 2
- 238000004132 cross linking Methods 0.000 claims 2
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 claims 2
- 239000004026 insulin derivative Substances 0.000 claims 2
- 229920002643 polyglutamic acid Polymers 0.000 claims 2
- 239000000126 substance Substances 0.000 claims 2
- OGNVQLDIPUXYDH-ZPKKHLQPSA-N (2R,3R,4S)-3-(2-methylpropanoylamino)-4-(4-phenyltriazol-1-yl)-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylic acid Chemical group CC(C)C(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(C(O)=O)=C[C@@H]1N1N=NC(C=2C=CC=CC=2)=C1 OGNVQLDIPUXYDH-ZPKKHLQPSA-N 0.000 claims 1
- BMVXCPBXGZKUPN-UHFFFAOYSA-N 1-hexanamine Chemical compound CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 claims 1
- 229940122254 Intermediate acting insulin Drugs 0.000 claims 1
- 108010092217 Long-Acting Insulin Proteins 0.000 claims 1
- 102000016261 Long-Acting Insulin Human genes 0.000 claims 1
- 229940100066 Long-acting insulin Drugs 0.000 claims 1
- 241001446467 Mama Species 0.000 claims 1
- 241000124008 Mammalia Species 0.000 claims 1
- 229940123452 Rapid-acting insulin Drugs 0.000 claims 1
- 108010026951 Short-Acting Insulin Proteins 0.000 claims 1
- 239000000853 adhesive Substances 0.000 claims 1
- 230000001070 adhesive effect Effects 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- 239000007864 aqueous solution Substances 0.000 claims 1
- 229920001400 block copolymer Polymers 0.000 claims 1
- 125000002843 carboxylic acid group Chemical group 0.000 claims 1
- 239000007933 dermal patch Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 238000001035 drying Methods 0.000 claims 1
- 239000000693 micelle Substances 0.000 claims 1
- 239000002105 nanoparticle Substances 0.000 claims 1
- 229920001296 polysiloxane Polymers 0.000 claims 1
- 239000002243 precursor Substances 0.000 claims 1
- 239000000243 solution Substances 0.000 claims 1
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
- 239000008280 blood Substances 0.000 abstract 1
- 210000004369 blood Anatomy 0.000 abstract 1
- 230000002255 enzymatic effect Effects 0.000 abstract 1
- 230000020874 response to hypoxia Effects 0.000 abstract 1
- 230000001960 triggered effect Effects 0.000 abstract 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/44—Oxidoreductases (1)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5192—Processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0023—Drug applicators using microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0046—Solid microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2207/00—Methods of manufacture, assembly or production
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y101/00—Oxidoreductases acting on the CH-OH group of donors (1.1)
- C12Y101/03—Oxidoreductases acting on the CH-OH group of donors (1.1) with a oxygen as acceptor (1.1.3)
- C12Y101/03004—Glucose oxidase (1.1.3.4)
Abstract
closed-loop insulin delivery system is described. More particularly, the presently disclosed insulin delivery system can comprise glucose-responsive vesicles that release insulin in response to hypoxia triggered by enzymatic reduction of glucose. In addition or as an alternative to insulin, the delivery system can release other diabetes treatment agents, such as non-insulin-based diabetes treatment agents. The vesicles can be prepared from a hypoxia sensitive polymer, such as a hypoxia-sensitive hyaluronic acid (HS-HA). The HS-HA can comprise hydrophobic groups that can be reduced in hypoxic environments to form hydrophilic groups. The vesicles can be loaded into microneedles and microneedle array patches for use in the treatment of diabetes or to otherwise regulate blood glucose levels in subjects in need of such treatment.
Claims (34)
1. A composition sing: (a) an amphiphilic ric material, wherein the amphiphilic polymeric material comprises a hydrophilic polymer conjugated to a hypoxia-sensitive hydrophobic group, wherein said hypoxia-sensitive hydrophobic group comprises a hypoxia-sensitive moiety that can be reduced in the presence of a hypoxic environment to form a hydrophilic moiety; (b) a es treatment agent, optionally wherein the diabetes treatment agent is an insulin or a bioactive derivative thereof; and (c) a glucose oxidizing agent.
2. The composition of claim 1, wherein the hydrophilic polymer is biodegradable.
3. The composition of claim 1 or claim 2, wherein the hydrophilic r is a polyamino acid, such as polyglutamic acid, a synthetic block copolymer, or a polysaccharide, optionally wherein the hydrophilic r is a polysaccharide, further optionally wherein the polysaccharide is a glucosaminoglycan.
4. The composition of any one of claims 1-3, wherein the hydrophilic polymer is onic acid.
5. The composition of any one of claims 1-4, wherein the hypoxia-sensitive moiety comprises a nitroimidazole.
6. The composition of any one of claims 1-5, wherein the hydrophobic group is covalently bound to the hydrophilic polymer.
7. The composition of any one of claims 1-6, wherein said amphiphilic polymeric material comprises a hilic polymer conjugated to an amino group of an amino-substituted hydrophobic group precursor, thereby forming an amide n said amino group and a carboxylic acid group present on the hydrophilic polymer.
8. The composition of any one of claims 1-7, n the amphiphilic polymeric material comprises hyaluronic acid conjugated to 6-(2- nitroimidazole)hexylamine.
9. The composition of any one of claims 1-8, wherein the glucose oxidizing agent is glucose oxidase (GOx).
10. The composition of any one of claims 1-9, wherein the es treatment agent is an insulin or a ive derivative thereof, n the insulin or bioactive derivative thereof is ed from a human n, a recombinant human insulin, insulin from a non-human animal, a fast-acting insulin, a rapid-acting insulin analog, an intermediate-acting insulin, and/or a long-acting insulin.
11. The composition of any one of claims 1-10, wherein the diabetes treatment agent is inant human n.
12. The composition of any one of claims 1-11, wherein the amphiphilic polymeric material forms a vesicle encapsulating said diabetes ent agent and said e ing agent.
13. A nanoparticle comprising the composition of any one of claims 1-12.
14. A vesicle comprising an amphiphilic polymeric material comprising a hydrophilic polymer conjugated to a hypoxia-sensitive hydrophobic group, wherein said hypoxia-sensitive hydrophobic group comprises a a-sensitive moiety that is capable of reduction in a hypoxic environment to form a hydrophilic moiety, and further wherein (i) a diabetes treatment agent, optionally an insulin or a bioactive derivative thereof and (ii) a glucose oxidizing agent are contained within said vesicle.
15. The vesicle of claim 14, wherein the hydrophilic polymer is a polyamino acid, such as polyglutamic acid, a synthetic block mer, or a polysaccharide, such as a glucosaminoglycan, optionally wherein the hydrophilic polymer is hyaluronic acid.
16. The vesicle of claim 14 or 15, wherein the hypoxia-sensitive moiety comprises a nitroimidazole.
17. The vesicle of any one of claims 14-16, wherein the diabetes treatment agent is inant human insulin.
18. The vesicle of any one of claims 14-17, wherein the glucose oxidizing agent is glucose oxidase (GOx).
19. A microneedle array comprising the vesicles of any one of claims 14-18, optionally wherein said microneedle array comprises a plurality of eedles wherein each of said plurality of microneedles has a length of between about 20 and about 1000 microns, further optionally n each of the plurality of microneedles has a length of about 600 microns.
20. The microneedle array of claim 19, wherein the microneedle array is provided as part of a skin patch, optionally wherein said patch comprises one or more backing layers and/or skin-compatible adhesives.
21. A closed-loop insulin ry system comprising a microneedle array of claim 19 or claim 20.
22. Use of a diabetes treatment agent in the cture of a medicament for treating diabetes in a subject in need thereof, wherein the ent is to be provided by a eedle array of claim 19 or 20, and wherein the array is to be applied to a skin surface of said subject, wherein when glucose comes into t with the microneedle array, it is ed, thereby creating a c environment that results in the reduction of the hypoxia-sensitive moiety to form a hydrophilic moiety, leading to disruption of vesicles and release of a diabetes treatment agent contained in the vesicles.
23. The use of claim 22, wherein the delivery of the diabetes treatment agent is at a rate corresponding to the glucose concentration coming into contact with the microneedle array.
24. The use of claim 22 or 23, wherein the subject is a mammal.
25. The use of any of claims 22-24, wherein the subject is diabetic.
26. The use of any one of claims 22 to 25 wherein the diabetes treatment agent is an insulin or a bioactive insulin derivative.
27. A method of preparing a microneedle array for the glucose-sensitive delivery of a diabetes treatment agent, optionally an insulin or a bioactive derivative thereof, the method comprising: (a) preparing an aqueous solution of a vesicle of any one of claims 14-18; (b) dispersing said s solution into a mold comprising a plurality of microneedle cavities, thereby providing a filled mold; (c) drying the filled mold to remove water; and (d) removing the mold to provide a microneedle array.
28. The method of claim 27, further comprising cross-linking polymeric materials in the microneedle array.
29. The method of claim 27 or claim 28, n step (b) is performed under vacuum.
30. The method of any one of claims 27-29, wherein after step (b), the mold is centrifuged to compact the micelles into the microneedle cavities.
31. The method of any one of claims 27-30, wherein prior to step (c), additional hydrophilic polymer and/or a chemical cross-linker are added to the mold, optionally wherein the mold is centrifuged after the addition of the additional hydrophilic polymer and/or chemical cross-linker, further optionally wherein the additional hydrophilic polymer is a modified hyaluronic acid, such as an alkylene-modified and/or acrylate-modified hyaluronic acid.
32. The method of any one of claims 27-31, n step (c) is performed in a vacuum desiccator.
33. The method of any one of claims 27-32, wherein the mold comprises silicone.
34. The method of any one of claims 27-33, wherein the cross-linking is med by exposure to UV irradiation. mamas-gm mama-mm {7N mam? q? S7582 [aglhmaawm? N32 HM{EH Q NE n 1 ° ERSEHN E-?ETRQIMI?AZGLHNE) 83 GEUKZGSE HGQXE E mug? W mwmcmm?m ?g” mmmmmm ERYEQRME 55% WE??? MKRGREEELE _ ‘7" u..._.o<'_ -.V . g.(? ‘ wegag? 959193359299sz iE2 I I " L 4 32912 BIAMHERMam DEAMETEM{Mm HQ 23 ?g 25 (us) as LIFETIME mwmmmwm 629523626? g/d1 GmeE mg/dLGmeE i’H?SPHGRESiE?CE 6 5 3G 35 2Q YEMEE(min) YEMEéh m2? FIG; 26 E 259 «—~————~———i 5% mum PBS g 3% mm; a??? as {E 2 4 6 26 22 24 if; YEMEEM «Ema um nag/6E, 5299 gamma mg/dL. HGSA :g§§§%;;§<{////7 9: Ema // , //,;\\\\\\\§ TIMEimin? (Lag/mi.) H?3§ i?Sij?i‘i E} Mama». —o—~ RENE ENSUEE‘E S?ii?l?? mom REiE?SEB INSHUN FRQM ?R‘is 25:3 219 2221233 249 256 26E) WAinE?G'EE-i mm) 5C, 3329? QRVS ‘5' ?R?PmnHA EEG, £3 sir ?wmgweme 3% mm: Area ER?SSHNK $3363; 4% m??N-ERQSSEENKEB ma E m—CRGSSEENKEBMN ?g 935 33.5 9.92 (3.3:; $42604 {£213 Em?! 9.:N Id C?—h H3 >32 RESPWSE M N Id m.h {mg/ail} GHEAWI msuusgs HG; 5F mmw-mmm awmmmm mammmwm {SEVERE} WEE. mam GRWE-E-n +GRWE+H+SRV€{WEE-+3} GLUCEEE ww— GR‘JE+EE+ERVEE+H —<>v SEW-f U—i—iNS?Li? (Mi/mi.)m E M 54323” mm mmma EUMAN m£373a V . €16 PWMA 9:; .52? “g; g 4 a 4 s whm 29 24 .- 3%; 55 ___a § 4 * 3% {3.5 ‘aé?? 9.4 E?m: as g 4% 3? § 3% {m E 2% $553553? Jaw HEAHEY E 933W“? g gggg + thOSEABMIE?FSRViEg—H WIN a wth?SEABME??FI?SEELI? EEG 5E
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562150622P | 2015-04-21 | 2015-04-21 | |
PCT/US2016/028605 WO2016172320A1 (en) | 2015-04-21 | 2016-04-21 | Glucose-responsive insulin delivery system using hyoxia-sensitive nanocomposites |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ736578A NZ736578A (en) | 2023-12-22 |
NZ736578B2 true NZ736578B2 (en) | 2024-03-26 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Seong et al. | A self-adherent, bullet-shaped microneedle patch for controlled transdermal delivery of insulin | |
JP7109675B2 (en) | Implantable slow-release microneedle patch and method for preparing same | |
Gao et al. | Highly porous silk fibroin scaffold packed in PEGDA/sucrose microneedles for controllable transdermal drug delivery | |
WO2020043167A1 (en) | Quick implantable slow-release microneedle patch and preparation method therefor | |
Ling et al. | Dissolving polymer microneedle patches for rapid and efficient transdermal delivery of insulin to diabetic rats | |
RU2017139931A (en) | GLUCOSULPARATIVE INSULIN DELIVERY SYSTEM USING SENSITIVE NANOCOMPOSITES FOR HYPOXIA | |
US9675789B2 (en) | Embeddable micro-needle patch for transdermal drug delivery and method of manufacturing the same | |
TWI528975B (en) | Microneedle trandermal delivery device and microneedle transdermal delivery method using the same | |
CN114146046B (en) | Coated microneedle with multilayer structure, preparation method thereof and microneedle patch comprising coated microneedle | |
TWI718576B (en) | Hyaluronic acid microstructure having excellent dissolving properties | |
Xue et al. | Flexible PEGDA-based microneedle patches with detachable PVP–CD arrowheads for transdermal drug delivery | |
CN110870943A (en) | Implantable two-section type microneedle patch and preparation method thereof | |
JP2014516080A (en) | Water-soluble pharmaceutically active organic compound formulation with controlled absorption for once-daily administration | |
WO2016013755A1 (en) | Microneedle containing retinol or retinol derivative | |
Zhang et al. | Research progress of advanced microneedle drug delivery system and its application in biomedicine | |
US20230381096A1 (en) | Core-shell microneedle patch for h2o2 and ph cascade-triggered insulin delivery | |
US20210244658A1 (en) | Microneedle-array patches with glucose-responsive matrix for closed-loop insulin delivery | |
KR20200007017A (en) | Dental Local Anesthesia Microneedle Array | |
CN111542309A (en) | Microneedle array with active substance in salt form | |
Wang et al. | Flexible monitoring, diagnosis, and therapy by microneedles with versatile materials and devices toward multifunction scope | |
CN113827544B (en) | Heat-resistant implantable polymer microneedle and preparation method and application thereof | |
KR20170000745A (en) | Soluble microneedle patch for photosensitizer delivery | |
Liu et al. | Extensible and swellable hydrogel-forming microneedles for deep point-of-care sampling and drug deployment | |
NZ736578B2 (en) | Glucose-responsive insulin delivery system using hypoxia-sensitive nanocomposites | |
JP2010540603A (en) | Patch with hydrophilic adhesive |