Claims for Patent: 9,994,615

Summary for Patent: 9,994,615

Title:	Self-regulated peptide hydrogel for insulin delivery
Abstract:	A glucose binding amphiphilic peptide hydrogel insulin delivery system that is responsive to glucose concentrations under physiological conditions is provided. Insulin is encapsulated in a glucose binding hydrogel, made from self-assembling amphiphilic peptides including a hydrophobic domain including a beta sheet forming region coupled to a charged hydrophilic domain modified to contain a glucose binding segment. The formulations are designed to release insulin as a function of blood glucose level, maintaining the patients\' blood glucose level in an optimum range and avoiding both hyper- and hypoglycemia.
Inventor(s):	Langer; Robert S. (Newton, MA), Anderson; Daniel G. (Sudbiry, MA), Gu; Zhen (Cambridge, MA), Aimetti; Alex Arthur (Waltham, MA)
Assignee:	Massachusetts Institute of Technology (Cambridge, MA) The Children\'s Medical Center Corporation (Boston, MA)
Application Number:	14/379,477
Patent Claims:	1. Self-assembling glucose binding peptides comprising (a) a hydrophilic region comprising a charged segment which enhances solubility of the self-assembling peptide in an aqueous environment, (b) a hydrophobic region, (c) a beta-sheet forming region, and (d) an organic borate glucose binding moiety, wherein the hydrophilic and hydrophobic regions, present in distinct regions, sequentially along the backbone of the self-assembling peptide, are covalently linked via the beta-sheet forming region, wherein the self-assembling peptides are between six and about 200 .alpha.-amino acid residues, wherein the self-assembling peptides self-assemble under physiological conditions, of pH of approximately 7-7.5, to form a hydrogel, and wherein binding of glucose to the glucose binding moiety increases the permeability of the hydrogel. 2. The self-assembling glucose binding peptides of claim 1, wherein the hydrophilic region comprises charged amino acid residues. 3. The self-assembling glucose binding peptides of claim 1, wherein the hydrophobic region comprises side chains or amino acids forming a beta sheet structure. 4. The self-assembling glucose binding peptides of claim 1, wherein the organic borate is a phenyl borate. 5. The self-assembling glucose binding peptides of claim 1, wherein the glucose binding moiety is attached to the hydrophobic region. 6. The self-assembling glucose binding peptides of claim 1, wherein the beta-sheet forming regions of individual self-assembling peptides associate to form nanofibers. 7. The self-assembling glucose binding peptides of claim 1, wherein the beta-sheet forming region has about four to ten amino acid residues. 8. The self-assembling glucose binding peptides of claim 7, wherein the hydrophilic region has about two to seven amino acid residues. 9. The self-assembling glucose binding peptides of claim 8, the self-assembling peptide comprising between eight and about twenty-four .alpha.-amino acid residues. 10. A self-assembling glucose binding peptide having the chemical structure: ##STR00001## 11. A hydrogel composition for delivering insulin or an insulin analog, comprising Insulin or an insulin analog; and self-assembling peptides comprising (a) a hydrophilic region comprising a charged segment which enhances solubility of the self-assembling peptide in an aqueous environment, (b) a hydrophobic region, (c) a beta-sheet forming region, (d) an organic borate glucose binding moiety, wherein the hydrophilic and hydrophobic regions, present in distinct regions, sequentially along the backbone of the self-assembling peptide, are covalently linked via the beta-sheet forming region, wherein the self-assembling peptides are between six and about 200 .alpha.-amino acid residues and wherein the self-assembling peptides self-assemble under physiological conditions, of pH of approximately 7-7.5, forming a hydrogel, wherein binding of glucose to the glucose binding moiety increases the permeability of the hydrogel, and wherein the insulin or insulin analog is released. 12. The composition of claim 11, wherein the composition comprises insulin. 13. The composition of claim 11, wherein the insulin is selected from the group consisting of insulin lispro, insulin glulisine, insulin aspart, and insulin detemir. 14. The composition of claim 11, wherein the permeability of the hydrogel to insulin is increased when tissue glucose levels at physiological pH are increased. 15. The composition of claim 11, wherein the insulin or insulin analog is entrapped within the hydrogel. 16. A method for making a formulation for delivering insulin comprising self-assembling glucose binding peptides, wherein the self-assembling peptides each comprise: (a) a hydrophilic region comprising a charged segment which enhances solubility of the self-assembling peptide in an aqueous environment, (b) a hydrophobic region, (c) a beta-sheet forming region, and (d) an organic borate glucose binding moiety, wherein the hydrophilic and hydrophobic regions, present in distinct regions, sequentially along the backbone of the self-assembling peptide, are covalently linked via the beta-sheet forming region, wherein the self-assembling peptide comprises between six and about 200 .alpha.-amino acid residues, and wherein the self-assembling peptides self-assemble under physiological conditions, of pH of approximately 7-7.5, to form a hydrogel, and wherein binding of glucose to the glucose binding moiety increases the permeability of the hydrogel, comprising adding insulin or insulin analog to a solution of the self-assembling peptides and adding ions or changing pH to cause the self-assembling peptides to form a hydrogel entrapping the insulin or insulin analog in the hydrogel. 17. The method of claim 16, wherein the hydrophilic region has about two to seven amino acid residues. 18. The method of claim 17, the self-assembling peptide comprising between eight and about twenty-four .alpha.-amino acid residues. 19. A method of alleviating one or more symptoms of diabetes comprising administering to a diabetic individual an effective amount of the formulation of claim 11. 20. The method of claim 19 wherein the formulation is administered by subcutaneous injection. 21. The method of claim 16, wherein the insulin or insulin analog is entrapped within the hydrogel. 22. The method of claim 16, wherein the beta-sheet forming regions of individual self-assembling peptides associate to form nanofibers.

Details for Patent 9,994,615

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Eli Lilly And Company	HUMALOG	insulin lispro	Injection	020563	06/14/1996		2032-02-17
Eli Lilly And Company	HUMALOG	insulin lispro	Injection	020563	08/06/1998		2032-02-17
Eli Lilly And Company	HUMALOG	insulin lispro	Injection	020563	09/06/2007		2032-02-17
Eli Lilly And Company	HUMALOG	insulin lispro	Injection	020563	06/06/2017		2032-02-17
Eli Lilly And Company	HUMALOG	insulin lispro	Injection	020563	11/15/2019		2032-02-17
Novo Nordisk Inc.	NOVOLOG	insulin aspart	Injection	020986	06/07/2000		2032-02-17