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US-20260124139-A1 - LIPID CONSTRUCT FOR DELIVERY OF INSULIN TO A MAMMAL

US20260124139A1US 20260124139 A1US20260124139 A1US 20260124139A1US-20260124139-A1

Abstract

The instant invention is drawn to a hepatocyte targeted composition comprising insulin associated with a lipid construct comprising an amphipathic lipid and an extended amphipathic lipid that targets the construct to a receptor displayed by an hepatocyte. The composition can comprise a mixture of free insulin and insulin associated with the complex. The composition can be modified to protect insulin and the complex from degradation. The invention also includes methods for the manufacture of the composition and loading insulin into the composition and recycling various components of the composition. Methods of treating individuals inflicted with diabetes.

Inventors

  • John R. Lau
  • W. Blair Geho

Assignees

  • DIASOME PHARMACEUTICALS, INC.

Dates

Publication Date
20260507
Application Date
20250613

Claims (14)

  1. 1 - 75 . (canceled)
  2. 76 . A method of stimulating hepatic glycogen storage in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a composition comprising a three-dimensional (3D) lipid-based particle enclosed by a bipolar lipid membrane, wherein the bipolar lipid membrane comprises cholesterol, dicetyl phosphate, an amphipathic lipid, and a biotin-containing hepatocyte receptor binding molecule, wherein the amphipathic lipid comprises at least one selected from the group consisting of 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-[3-phospho-rac-(1-glycerol)], 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl), 1,2-dimyristoyl-sn-glycero-3-phosphate; 1,2-dimyristoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphate, 1,2-dipalmitoyl-sn-glycero-3-phosphate, and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, wherein the biotin-containing hepatocyte receptor binding molecule extends outward from the 3D lipid-based particle and binds to a hepatocyte receptor; wherein the composition further comprises an insulin which is dispersed within the 3D lipid-based particle and is not covalently bound to the 3D lipid-based particle; and, wherein the size of the 3D lipid-based particle ranges from 0.0200 to 0.40 m.
  3. 77 . The method of claim 76 , wherein the insulin dispersed within the 3D lipid-based particle is selected from the group consisting of insulin lispro, insulin aspart, regular-insulin, insulin glargine, insulin zinc, extended human insulin zinc suspension, isophane insulin, human buffered regular insulin, insulin glulisine, recombinant human regular insulin, and recombinant human insulin isophane.
  4. 78 . The method of claim 76 , wherein the 3D-lipid particle is suspended in an aqueous solution, which further comprises a free dissolved insulin that is not dispersed within the 3D lipid-based particle.
  5. 79 . The method of claim 78 , wherein the insulin dispersed within the 3D lipid-based particle and the free dissolved insulin are independently selected from the group consisting of insulin lispro, insulin aspart, regular-insulin, insulin glargine, insulin zinc, extended human insulin zinc suspension, isophane insulin, human buffered regular insulin, insulin glulisine, recombinant human regular insulin, and recombinant human insulin isophane.
  6. 80 . The method of claim 76 , wherein the amphipathic lipid comprises at least one lipid selected from the group consisting of 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)], 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl).
  7. 81 . The method of claim 76 , wherein the composition further comprises cellulose acetate phthalate.
  8. 82 . The method of claim 76 , wherein the composition further comprises at least one charged organic molecule bound to the insulin dispersed within the 3D lipid-based particle, wherein the charged organic molecule is at least one selected from the group consisting of protamines, polylysine, poly(arg-pro-thr)n in a mole ratio of 1:1:1, poly (DL-Ala-poly-L-lys)n in a mole ratio of 6:1, histones, sugar polymers comprising a primary amino group, polynucleotides with primary amino groups, proteins comprising amino acid residues with carboxyl (COO − ) or sulfhydral (S − ) functional groups, acidic polymers, and sugar polymers containing carboxyl groups.
  9. 83 . The method of claim 76 , wherein the biotin-containing hepatocyte receptor binding molecule is selected from the group consisting of N-hydroxysuccinimide (NHS) biotin; sulfo-NHS-biotin; N-hydroxysuccinimide long chain biotin; sulfo-N-hydroxysuccinimide long chain biotin; D-biotin; biocytin; sulfo-N-hydroxysuccinimide-S—S-biotin; biotin-BMCC; biotin-HPDP; iodoacetyl-LC-biotin; biotin-hydrazide; biotin-LC-hydrazide; biocytin hydrazide; biotin cadaverine; carboxybiotin; photobiotin; ρ-aminobenzoyl biocytin trifluoroacetate; ρ-diazobenzoyl biocytin; biotin DUPE; biotin-X-DHPE; 12-((biotinyl)amino)dodecanoic acid; 12-((biotinyl)amino)dodecanoic acid succinimidyl ester; S-biotinyl homocysteine; biocytin-X; biocytin x-hydrazide; biotinethylenediamine; biotin-XL; biotin-X-ethylenediamine; biotin-XX hydrazide; biotin-XX-SE; biotin-XX, SSE; biotin-X-cadaverine; α-(t-BOC)biocytin; N-(biotinyl)-N′-(iodoacetyl) ethylenediamine; DNP-X-biocytin-X-SE; biotin-X-hydrazide; norbiotinamine hydrochloride; 3-(N-maleimidylpropionyl)biocytin; ARP; biotin-1-sulfoxide; biotin methyl ester; biotin-maleimide; biotin-poly(ethyleneglycol)amine; (+) biotin 4-amidobenzoic acid sodium salt; Biotin 2-N-acetylamino-2-deoxy-β-D-glucopyranoside; Biotin-α-D-N-acetylneuraminide; Biotin-α-L-fucoside; Biotin lacto-N-bioside; Biotin-Lewis-A trisaccharide; Biotin-Lewis-Y tetrasaccharide; Biotin-α-D-mannopyranoside; biotin 6-O-phospho-α-D-mannopyranoside; and polychromium-poly(bis)-N-[2,6-(diisopropylphenyl) carbamoyl methylimino]diacetic acid.
  10. 84 . The method of claim 76 , wherein the biotin-containing hepatocyte receptor binding molecule is selected from the group consisting of biotin DUPE (2,3-diacetoxypropyl 2-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)ethyl phosphate); and biotin-X-DHPE (2,3-diacetoxypropyl 2-(6-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)hexanamido)ethyl phosphate).
  11. 85 . The method of claim 76 , wherein the subject suffers from Type I or Type II diabetes.
  12. 86 . The method of claim 76 , wherein the route of administration is selected from the group consisting of oral, parenteral, subcutaneous, pulmonary and buccal.
  13. 87 . The method of claim 76 , wherein the route of administration is oral or subcutaneous.
  14. 88 . The method of claim 76 , wherein the subject is human.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of, and claims priority to, U.S. patent application Ser. No. 18/941,230, filed Nov. 8, 2024, which is a continuation of, and claims priority to, U.S. patent application Ser. No. 18/430,256 filed Feb. 1, 2024, now abandoned, which is a continuation of, and claims priority to, U.S. patent application Ser. No. 17/230,089 filed Apr. 14, 2021, now abandoned, which is a continuation of, and claims priority to, U.S. patent application Ser. No. 16/585,347 filed Sep. 27, 2019, now abandoned, which is a continuation of, and claims priority to, U.S. patent application Ser. No. 15/978,820 filed May 14, 2018, now issued as U.S. Pat. No. 10,463,616, which is a continuation of, and claims priority to, U.S. patent application Ser. No. 13/916,115 filed Jun. 12, 2013, now issued as U.S. Pat. No. 10,004,686, which is a continuation of, and claims priority to, U.S. patent application Ser. No. 11/920,905 filed Nov. 18, 2009, now abandoned, which is a U.S. national phase application filed under 35 U.S.C. § 371 claiming priority to International Patent Application No. PCT/US2006/019119, filed May 16, 2006, which is a continuation-in-part of, and claims priority to, U.S. patent application Ser. No. 11/384,728 filed Mar. 20, 2006, now issued as U.S. Pat. No. 7,871,641, and is a continuation-in-part of, and claims priority to, U.S. patent application Ser. No. 11/384,659 filed Mar. 20, 2006, now issued as U.S. Pat. No. 7,858,116, and claims priority pursuant to 35 U.S.C. § 119(e) of U.S. Provisional Application No. 60/683,878, filed May 23, 2005, all of which applications are hereby incorporated herein by reference in their entireties. INCORPORATION-BY-REFERENCE OF SEQUENCE LISTING The contents of the file named “047589-5009US7 Sequence Listing ST_26.xml”, which was created Feb. 1, 2024, and is 7.35 KB in size, are hereby incorporated by reference in their entireties. BACKGROUND OF THE INVENTION Diabetes is a disorder affecting large numbers of people worldwide. Management approaches to control Type I and Type II diabetes aim primarily at normalizing blood glucose levels to prevent short- and long-term complications. Many patients require multiple daily injections of an insulin to control their diabetes. Several insulin products have been produced that control blood sugar levels over differing time intervals. Several products combine various forms of insulin in an attempt to provide a preparation which controls glucose levels over a wider period of time. Previous attempts to normalize blood glucose levels in Type I and Type II diabetic patients have centered on the subcutaneous administration of insulin in various time-released formulations, such as ultralente and humulin NPH insulin pharmaceutical products. These formulations have attempted to delay and subsequently control the bio-distribution of insulin by regulating release of insulin to peripheral tissues with the expectation that sustained management of insulin bio-availability will lead to better glucose control. Glargine insulin is a long-acting form of insulin in which insulin is released from the subcutaneous tissue around the site of injection into the bloodstream at a relatively constant rate throughout the day. Although glargine insulin is released at a constant rate throughout the day, the released insulin reaches a wide range of systems within the body rather than being delivered to targeted areas of the body. What is needed is a composition of insulin where a portion of the dosed insulin is released at a relatively constant rate throughout the day and another portion of insulin that is time released from the site of administration and targeted for delivery to the liver to better control glucose production. There is, therefore, an unmet need in the art for compositions and methods of managing blood glucose levels in Type I and Type II diabetic patients. The present invention meets these needs by providing a long-acting composition comprising insulin that is free and insulin that is associated with a lipid construct targeted for delivery to hepatocytes. A lipid construct is a lipid/phospholipid particle in which individual lipid molecules cooperatively interact to create a bipolar lipid membrane which encloses and isolates a portion of the medium in which it was formed. The lipid construct releases free insulin over time as well as targets a portion of the remaining insulin to the hepatocytes in the liver to better control glucose storage and production. BRIEF SUMMARY OF THE INVENTION In one aspect, the present invention includes a lipid construct comprising an amphipathic lipid and an extended amphipathic lipid, wherein the extended amphipathic lipid comprises proximal, medial and distal moieties, wherein the proximal moiety connects the extended amphipathic lipid to the construct, the distal moiety targets the construct to a receptor displayed by a hepatocyte, and the medial moiety connects the