Claims for Patent: 10,004,686

Summary for Patent: 10,004,686

Title:	Lipid construct for delivery of insulin to a mammal
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.
Inventor(s):	Lau; John R. (Howard, OH), Geho; W. Blair (Wooster, OH)
Assignee:	SDG, Inc. (Cleveland, OH)
Application Number:	13/916,115
Patent Claims:	1. A composition comprising a lipid-based particle defined by a bipolar lipid membrane, wherein the lipids in the bipolar lipid membrane are cholesterol, dicetyl phosphate, and an amphipathic lipid, and wherein the bipolar lipid membrane further comprises a hepatocyte receptor binding molecule, wherein the amphipathic lipid is at least one selected from the group consisting of 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycerol-[3-phospho-rac-(1-glycero)], 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(succinyl),1,2-dimyris- toyl-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; and wherein the hepatocyte receptor binding molecule is the only hepatocyte receptor binder in the composition and is a biotin-containing compound selected from the group consisting of biotin DHPE (2,3-diacetoxypropyl 2-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d] imidazol-4-yl)pentanamido)ethyl phosphate); biotin-X-DHPE (2,3-diacetoxypropyl 2-(6-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanami- do)hexanamido) ethyl phosphate); and any combinations thereof; wherein the biotin-containing compound extends outward from the lipid-based particle and binds to a biotin-binding hepatocyte receptor; and, wherein the size of the lipid-based particle ranges from 0.0200 to 0.40 .mu.m. 2. The construct of claim 1, further comprising at least one charged organic molecule selected from the group consisting of protamines, polylysine, poly (arg-pro-thr).sub.n, poly (DL-Ala-poly-L-lys).sub.n, histones, sugar polymers comprising a primary amino group, polynucleotides with primary amino groups, proteins comprising amino acid residues with sulfhydral (S.sup.-) functional groups, and acidic polymers. 3. A method of manufacturing a composition comprising a lipid-based particle defined by a bipolar lipid membrane, wherein the lipids in the bipolar lipid membrane are cholesterol, dicetyl phosphate, and an amphipathic lipid, and wherein the bipolar lipid membrane further comprises a hepatocyte receptor binding molecule, wherein the amphipathic lipid is 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 hepatocyte receptor binding molecule is the only hepatocyte receptor binder in the composition and is a biotin-containing compound selected from the group consisting of biotin DHPE (2,3-diacetoxypropyl 2-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d] imidazol-4-yl)pentanamido)ethyl phosphate); biotin-X-DHPE (2,3-diacetoxypropyl 2-(6-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanami- do)hexanamido) ethyl phosphate); and any combinations thereof; wherein the biotin-containing compound extends outward from the lipid-based particle and binds to a biotin-binding hepatocyte receptor; and wherein the size of the lipid-based particle ranges from 0.0200 to 0.40 .mu.m. 4. A method of manufacturing a composition comprising a lipid-based particle defined by a bipolar lipid membrane, wherein the lipids in the bipolar lipid membrane are cholesterol, dicetyl phosphate, and an amphipathic lipid, and wherein the bipolar lipid membrane further comprises a hepatocyte receptor binding molecule, wherein the composition comprises an insulin that is dispersed within the lipid-based particle and not covalently bound to the lipid-based particle, further wherein the composition comprises a free dissolved insulin that is not dispersed within the lipid-based particle; the method comprising contacting an insulin with an aqueous media suspension of a mixture comprising lipids, which are cholesterol, dicetyl phosphate, and an amphipathic lipid, wherein the mixture further comprises a hepatocyte receptor binding molecule, whereby the composition is formed, wherein the amphipathic lipid is 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 hepatocyte receptor binding molecule is the only hepatocyte receptor binder in the composition and is a biotin-containing compound selected from the group consisting of biotin DHPE (2,3-diacetoxypropyl 2-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d] imidazol-4-yl)pentanamido)ethyl phosphate); biotin-X-DHPE (2,3-diacetoxypropyl 2-(6-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanami- do)hexanamido) ethyl phosphate); and any combinations thereof; wherein the biotin-containing compound extends outward from the lipid-based particle and binds to a biotin-binding hepatocyte receptor; and, wherein the size of the lipid-based particle ranges from 0.0200 to 0.40 .mu.m. 5. The method of claim 4, further comprising the step of separating a solution comprising the free dissolved insulin not dispersed within the lipid-based particle from the composition, wherein the composition comprises insulin dispersed within the lipid-based particle and not covalently bound to the lipid-based particle. 6. The method of claim 5, wherein the solution is separated from the composition using a process selected from the group consisting of a rapid filtration procedure, centrifugation, filter centrifugation, and chromatography using an ion-exchange resin or streptavidin agarose affinity-resin gel having affinity for biotin, or iminobiotin. 7. The method of claim 4, further comprising the step of adding cellulose acetate phthalate to the composition. 8. The method of claim 4, wherein, before the insulin is contacted with the aqueous media suspension of the mixture, at least one charged organic molecule is added to the insulin, wherein the charged organic molecule is at least one selected from the group consisting of protamines, polylysine, poly (arg-pro-thr).sub.n, poly (DL-Ala-poly-L-lys).sub.n, histones, sugar polymers comprising a primary amino group, polynucleotides with primary amino groups, proteins comprising amino acid residues with sulfhydral (S.sup.-) functional groups, and acidic polymers. 9. A method of treating a subject afflicted with diabetes, the method comprising administering to the subject in need thereof a therapeutically effective amount of a composition comprising a lipid-based particle defined by a bipolar lipid membrane, wherein the lipids in the bipolar lipid membrane are cholesterol, dicetyl phosphate, and an amphipathic lipid, and wherein the bipolar lipid membrane further comprises a hepatocyte receptor binding molecule, wherein the composition comprises an insulin that is dispersed within the lipid-based particle and not covalently bound to the lipid-based particle, further wherein the composition comprises a free dissolved insulin that is not dispersed within the lipid-based particle; wherein the amphipathic lipid is 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 hepatocyte receptor binding molecule is the only hepatocyte receptor binder in the composition and is a biotin-containing compound selected from the group consisting of biotin DHPE (2,3-diacetoxypropyl 2-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d] imidazol-4-yl)pentanamido)ethyl phosphate); biotin-X-DHPE (2,3-diacetoxypropyl 2-(6-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanami- do)hexanamido) ethyl phosphate); and any combinations thereof; wherein the biotin-containing compound extends outward from the lipid-based particle and binds to a biotin-binding hepatocyte receptor; and wherein the size of the lipid-based particle ranges from 0.0200 to 0.40 .mu.m. 10. The method of claim 9, wherein the insulin dispersed within the lipid-based particle and the free dissolved lipid are independently selected from the group consisting of insulin lispro, insulin aspart, regular insulin, insulin glargine, insulin zinc, human insulin zinc extended, isophane insulin, human buffered regular insulin, insulin glulisine, recombinant human regular insulin, and recombinant human insulin isophane. 11. The method of claim 9, wherein the composition is administered by a route selected from the group consisting of oral, parenteral, subcutaneous, pulmonary and buccal. 12. The method of claim 9, wherein the composition is administered by a route selected from the group consisting of oral and subcutaneous. 13. The method of claim 9, wherein the insulin dispersed within the lipid-based particle is bound to at least one charged organic molecule, wherein the charged organic molecule is at least one selected from the group consisting of protamines, polylysine, poly (arg-pro-thr).sub.n, poly (DL-Ala-poly-L-lys).sub.n, histones, sugar polymers comprising a primary amino group, polynucleotides with primary amino groups, proteins comprising amino acid residues with sulfhydral (S.sup.-) functional groups, and acidic polymers. 14. A method of increasing delivery of an insulin to hepatocytes in the liver of a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a composition comprising a lipid-based particle defined by a bipolar lipid membrane, herein the lipids in the bipolar lipid membrane are cholesterol, dicetyl phosphate, and an amphipathic lipid, and wherein the bipolar lipid membrane further comprises a hepatocyte receptor binding molecule, wherein the composition comprises an insulin that is dispersed within the lipid-based particle and not covalently bound to the lipid-based particle, further wherein the composition comprises a free dissolved insulin that is not dispersed within the lipid-based particle; wherein the amphipathic lipid is 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 hepatocyte receptor binding molecule is the only hepatocyte receptor binder in the composition and is a biotin-containing compound selected from the group consisting of biotin DHPE (2,3-diacetoxypropyl 2-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d] imidazol-4-yl)pentanamido)ethyl phosphate); biotin-X-DHPE (2,3-diacetoxypropyl 2-(6-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanami- do)hexanamido) ethyl phosphate); and any combinations thereof; wherein the biotin-containing compound extends outward from the lipid-based particle and binds to a biotin-binding hepatocyte receptor; and wherein the size of the lipid-based particle ranges from 0.0200 to 0.40 .mu.m. 15. The method of claim 14, wherein the subject is afflicted with diabetes. 16. The method of claim 14, wherein the insulin dispersed within the lipid-based particle and the free dissolved lipid are independently selected from the group consisting of insulin lispro, insulin aspart, regular insulin, insulin glargine, insulin zinc, human insulin zinc extended, isophane insulin, human buffered regular insulin, insulin glulisine, recombinant human regular insulin, and recombinant human insulin isophane. 17. The method of claim 14, wherein the composition further comprises cellulose acetate phthalate. 18. A method of treating a subject afflicted with Type I or Type II diabetes, the method comprising administering to the subject in need thereof a therapeutically effective amount of a composition comprising a lipid-based particle defined by a bipolar lipid membrane, wherein the lipids in the bipolar lipid membrane are cholesterol, dicetyl phosphate, and an amphipathic lipid, and wherein the bipolar lipid membrane further comprises a hepatocyte receptor binding molecule, wherein the composition comprises an insulin that is dispersed within the lipid-based particle and not covalently bound to the lipid-based particle, further wherein the composition comprises a free dissolved insulin that is not dispersed within the lipid-based particle; wherein the amphipathic lipid is 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 hepatocyte receptor binding molecule is the only hepatocyte receptor binder in the composition and is a biotin-containing compound selected from the group consisting of biotin DHPE (2,3-diacetoxypropyl 2-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d] imidazol-4-yl)pentanamido)ethyl phosphate); biotin-X-DHPE (2,3-diacetoxypropyl 2-(6-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanami- do)hexanamido) ethyl phosphate); and any combinations thereof; and, wherein the combination of the insulin dispersed within the lipid-based particle and the free dissolved insulin comprises glargine insulin and at least one non-glargine insulin; wherein the at least one non-glargine insulin is at least one selected from the group consisting of insulin lispro, insulin aspart, regular insulin, insulin glargine, insulin zinc, human insulin zinc extended, isophane insulin, human buffered regular insulin, insulin glulisine, recombinant human regular insulin, and recombinant human insulin isophane; wherein the biotin-containing compound extends outward from the lipid-based particle and binds to a biotin-binding hepatocyte receptor; and wherein the size of the lipid-based particle ranges from 0.0200 to 0.40 .mu.m. 19. A method of treating a subject afflicted with Type I or Type II diabetes, the method comprising administering to the subject in need thereof a therapeutically effective amount of a composition comprising a lipid-based particle defined by a bipolar lipid membrane, wherein the lipids in the bipolar lipid membrane are cholesterol, dicetyl phosphate, and an amphipathic lipid, and wherein the bipolar lipid membrane further comprises a hepatocyte receptor binding molecule, wherein the composition comprises an insulin that is dispersed within the lipid-based particle and not covalently bound to the lipid-based particle, further wherein the composition comprises a free dissolved insulin that is not dispersed within the lipid-based particle; wherein the amphipathic lipid is 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 hepatocyte receptor binding molecule is the only hepatocyte receptor binder in the composition and is a biotin-containing compound selected from the group consisting of biotin DHPE (2,3-diacetoxypropyl 2-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d] imidazol-4-yl)pentanamido)ethyl phosphate); biotin-X-DHPE (2,3-diacetoxypropyl 2-(6-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanami- do)hexanamido) ethyl phosphate); and any combinations thereof; and, wherein the combination of the insulin dispersed within the lipid-based particle and the free dissolved insulin comprises recombinant human insulin isophane and at least one insulin that is not recombinant human insulin isophane; wherein the at least one insulin that is not recombinant human insulin isophane is at least one selected from the group consisting of insulin lispro, insulin aspart, regular insulin, insulin glargine, insulin zinc, human insulin zinc extended, isophane insulin, human buffered regular insulin, insulin glulisine, recombinant human regular insulin, and glargine insulin; wherein the biotin-containing compound extends outward from the lipid-based particle and binds to a biotin-binding hepatocyte receptor; and wherein the size of the lipid-based particle ranges from 0.0200 to 0.40 .mu.m. 20. A kit for use in treating a mammal inflicted with diabetes, the kit comprising a composition, a physiological buffer solution, an applicator, and an instructional material for the use thereof, wherein the composition comprises a lipid-based particle defined by a bipolar lipid membrane, wherein the lipids in the bipolar lipid membrane are cholesterol, dicetyl phosphate, and an amphipathic lipid, and wherein the bipolar lipid membrane further comprises a hepatocyte receptor binding molecule; wherein the amphipathic lipid is at least one selected from the group consisting of 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycerol-[3-phospho-rac-(1-glycero)], 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; and wherein the hepatocyte receptor binding molecule is the only hepatocyte receptor binder in the composition and is one biotin-containing compound selected from the group consisting of biotin DHPE (2,3-diacetoxypropyl 2-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d] imidazol-4-yl)pentanamido)ethyl phosphate); biotin-X-DHPE (2,3-diacetoxypropyl 2-(6-(5-((3aS,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanami- do)hexanamido) ethyl phosphate); and any combinations thereof; wherein the biotin-containing compound extends outward from the lipid-based particle and binds to a biotin-binding hepatocyte receptor; and, wherein the size of the lipid-based particle ranges from 0.0200 to 0.40 .mu.m. 21. The kit of claim 20, wherein the kit further comprises an insulin. 22. The kit of claim 21, wherein the insulin is in contact with the composition, wherein the composition comprises an insulin that is dispersed within the lipid-based particle and not covalently bound to the lipid-based particle, and a free dissolved insulin that is not dispersed within the lipid-based particle. 23. The kit of claim 21, wherein the insulin dispersed within the lipid-based particle and the free dissolved insulin are independently selected from the group consisting of glargine insulin and recombinant human insulin isophane. 24. The kit of claim 20, wherein the composition is formulated for administration by a route selected from the group consisting of oral, parenteral, subcutaneous, pulmonary and buccal.

Details for Patent 10,004,686

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Eli Lilly And Company	HUMULIN R U-100	insulin human	Injection	018780	October 28, 1982	10,004,686	2025-05-23
Eli Lilly And Company	HUMULIN R U-500	insulin human	Injection	018780	December 29, 2015	10,004,686	2025-05-23
Eli Lilly And Company	HUMULIN R U-100	insulin human	Injection	018780	August 06, 1998	10,004,686	2025-05-23
Eli Lilly And Company	HUMULIN R U-500	insulin human	Injection	018780	March 31, 1994	10,004,686	2025-05-23
Eli Lilly And Company	HUMULIN R U-100	insulin human	Injection	018780	May 25, 2018	10,004,686	2025-05-23
Novo Nordisk Inc.	NOVOLIN R	insulin human	Injection	019938	June 25, 1991	10,004,686	2025-05-23