Claims for Patent: 10,463,616

Summary for Patent: 10,463,616

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:	15/978,820
Patent Claims:	1. A method of increasing the bioavailability of at least one insulin in a patient, the method comprising: a. combining at least one insulin with a lipid-based particle to form a construct comprising the at least one insulin, wherein the lipid-based particle is defined by a bipolar lipid membrane comprising lipids comprising 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; 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; and b. administering the construct containing the at least one insulin to the patient. 2. The method of claim 1, wherein the construct further comprises 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. The method of claim 1, wherein the at least one 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. 4. The method of claim 1, wherein the construct further comprises cellulose acetate phthalate. 5. The method of claim 1, wherein the at least one insulin is chemically modified, thus having an isoelectric point that is distinct from the isoelectric point of the chemically unmodified insulin. 6. A method of forming a time-release composition that provides increased biodistribution of insulin in a warm-bloodied subject, the method comprising: a. contacting (i) a bulk phase medium comprising an insulin-containing construct and (ii) streptavidin agarose affinity-gel, in a system of pH equal to or greater than about 9.5, wherein the construct comprises insulin and a lipid-based particle defined by a bipolar lipid membrane comprising lipids comprising cholesterol, dicetyl phosphate, and an amphipathic lipid, 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, wherein at least one of the lipids comprises iminobiotin or an iminobiotin derivative, wherein the at least one lipid comprising iminobiotin or an iminobiotin derivative extends outward from the lipid-based particle, wherein the size of the lipid-based particle ranges from 0.0200 to 0.40 .mu.m, whereby the insulin-containing construct binds to the affinity-gel; b. separating the construct-bound affinity-gel from the bulk phase medium; and c. subjecting the construct-bound affinity-gel to a system of pH of around 4.5, whereby the insulin-containing construct is released from the affinity-gel, wherein the released construct contains insoluble insulin. 7. The method of claim 6, wherein the construct further comprises 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. 8. The method of claim 6, wherein the at least one 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. 9. The method of claim 6, wherein the construct further comprises cellulose acetate phthalate. 10. The method of claim 6, wherein the at least one insulin is chemically modified, thus having an isoelectric point that is distinct from the isoelectric point of the chemically unmodified insulin. 11. The method of claim 6, wherein administration of the released construct to the warm-bodied subject results in redissolution of the at least one insulin within the construct.

Details for Patent 10,463,616

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Eli Lilly And Company	HUMULIN R U-100	insulin human	Injection	018780	10/28/1982		2025-05-23
Eli Lilly And Company	HUMULIN R U-500	insulin human	Injection	018780	12/29/2015		2025-05-23
Eli Lilly And Company	HUMULIN R U-100	insulin human	Injection	018780	08/06/1998		2025-05-23
Eli Lilly And Company	HUMULIN R U-500	insulin human	Injection	018780	03/31/1994		2025-05-23
Eli Lilly And Company	HUMULIN R U-100	insulin human	Injection	018780	05/25/2018		2025-05-23