Charge-switchable polymeric depot for glucose-triggered insulin delivery with ultrafast response
A composition comprising a glucose-responsive charge-switchable polymer is described. In the absence of glucose or under normoglycemic conditions, the positively charged polymer can be complexed with negatively charged therapeutic agents, such as insulin. Under hyperglycemic conditions, the positive charge of the polymer is reduced, and the polymer/therapeutic agent complex can disassemble, allowing the therapeutic agent to be released. Pharmaceutical compositions, nanoparticles, and microneedle arrays of the polymer and/or polymer/therapeutic agent complex and methods of treating diabetes are also described.
1. A composition comprising:
(a) a positively-charged polymer, wherein the positively-charge, polymer has a polyacrylamide backbone comprising a plurality of side chains comprising an ammonium group and a plurality of side chains comprising a glucose-binding group, wherein the glucose-binding croup is a halophenylboronic acid group; and
(b) insulin or a bioactive derivative thereof.
2. The composition of claim 1 , wherein the halophenylboronic acid group is a fluorophenylboronic acid group.
3. The composition of claim 1 , wherein the polymer has a structure of formula (I):
wherein
x and y are each integers greater than 1, wherein the sum of integers x and y is at least about 10; and wherein the ratio of x to y is between about 7:3 and about 1:5;
R is H or alkyl;
R 1 is a protonated aminoalkyl group; and
R 2 is a group comprising a halophenylboronic acid.
4. The composition of claim 3 , wherein R 1 has the structure -L-NH 3 + , wherein L is a C 1 -C 6 straight or branched, substituted or unsubstituted alkylene group.
5. The composition of claim 3 , wherein R 2 has the structure -L 1 -NH—C(═O)—R 3 , wherein L 1 is a C 1 -C 6 straight or branched, substituted or unsubstituted alkylene group and wherein R 3 is a fluorophenylboronic acid group or other halophenylboronic acid group.
6. The composition of claim 3 , wherein the ratio of x to y is about 2:3.
7. The composition of claim 1 , wherein the composition comprises a weight ratio of positively-charged polymer (a) to insulin or bioactive derivative thereof (b) of between about 2:1 and about 1:4.
8. The composition of claim 7 , wherein the weight ratio of (a) to (b) is about 1:1.
9. A nanoparticle or microparticle comprising the composition of claim 1 .
10. The nanoparticle or microparticle of claim 9 , wherein the nanoparticle or microparticle has a diameter of between about 0.1 micrometers (μm) and about 1000 μm.
11. A microneedle array comprising the nanoparticle or microparticle of claim 9 , wherein said microneedle array comprises a plurality of microneedles, wherein each of said plurality of microneedles has a length of between about 20 and about 1000 micrometers.
12. A skin patch comprising the microneedle array of claim 11 .
13. A pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a composition of claim 1 .
14. A method of delivering insulin or a bioactive derivative thereof to a subject in need thereof, the method comprising administering a skin patch of claim 12 .
15. The method of claim 14 , wherein the subject is a mammal.
16. The method of claim 14 , wherein the subject has Type 1 or Type 2 diabetes.
17. The method of claim 14 , wherein the skin patch or pharmaceutical formulation releases insulin at a rate that corresponds directly to blood glucose levels of the subject.
18. A method of treating diabetes in a subject in need thereof, wherein the method comprises administering a skin patch of claim 12 to the subject.
19. The method of claim 18 , wherein the administration is performed once a day.
20. A pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a nanoparticle or microparticle of claim 9 .
21. A method of delivering insulin or a bioactive derivative thereof to a subject in need thereof, the method comprising administering a pharmaceutical formulation of claim 13 to the subject.
22. A method of treating diabetes in a subject in need thereof, wherein the method comprises administering a pharmaceutical formulation of claim 13 to the subject.
23. The composition of claim 1 , wherein the insulin or bioactive derivative thereof is recombinant human insulin.
24. The composition of claim 3 , wherein R is C 1 -C 6 alkyl.
25. The composition of claim 4 , wherein L is —CH 2 CH 2 —.
26. The composition of claim 5 , wherein L 1 is —CH 2 CH 2 —.
27. The nanoparticle or microparticle of claim 10 , wherein the nanoparticle or microparticle has a diameter of about 50 μm.
28. The microneedle array of claim 11 , wherein each of the plurality of microneedles has a length of about 600 micrometers.
29. The skin patch of claim 12 , wherein said skin patch comprises one or more backing layers and/or skin compatible adhesives.
30. The method of claim 15 , wherein the subject is a human.