US 9,867,869 B2Granted

Insulin derivatives for diabetes treatment

AssigneesMassachusetts Institute of Technology, Children's Medical Center Corporation

InventorsDaniel G. Anderson, Hung-Chieh Chou, Michael J. Webber, Benjamin C. Tang, Yair Levi, Yunlong Zhang, Rosemary Lynn Kanasty, Arturo Jose Vegas, Robert S. Langer

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Abstract

Compounds, compositions, and methods for “smart” delivery of a therapeutic, prophylactic or diagnostic agent, such as glucose-mediated delivery of insulin through glucose-sensing insulin derivatives, are provided. The insulin derivatives bind serum albumin or agglomerate in vivo. The insulin derivatives effectively dissociate to release insulin in a hyperglycemic condition, where the complexation of glucose to a glucose-sensing element alters properties of the insulin derivative leading to the dissociation. The compounds, compositions, and methods provide a delivery strategy for both self-regulated and long-term diabetes management.

Claims18

Dependent claims

An insulin conjugate having the formula:

X1-X2
wherein X1 is insulin, an insulin analog, glucagon, GLP-1, or a GLP-1 agonist,
X2 is:
(i) —CO—(CH2)1—NH—CO—CR1R2,
wherein j is an integer from 3-25
R1 is —NH—R12 or —NH—CO—CH2—CH2—CNR12—C(O)R32, where R32 is glucamine, gluconic acid, glucosamine, fructosamine, galactosamine, mannosamine, or other hexosamines,
R12 is selected from the group consisting of hydrogen, —SO2alkyl, —SO2cycloalkyl, —SO2heterocycloalkyl, —SO2aryl, —SO2heteroaryl, —COalkyl, —COcycloalkyl, —COheterocycloalkyl, —COaryl, —COheteroaryl, —CONHalkyl, —CONHcycloalkyl, —CONHheterocycloalkyl, —CONHaryl, —CONHheteroaryl,
wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are substituted or unsubstituted,
R2 is —(CH2)n—NH—CO—R11 or —(CH2)n—NH—SO2R11,
n is an integer from 3-25, and
R11 is an organic borate group;
(ii) an oligomer comprising a plurality of monomers, wherein the monomers comprise a side chain, wherein the side chain comprises one or more organic borate groups, hydrophobic groups, hydrophilic neutral groups, hydrophilic charged groups, diol groups, fluorescent groups, and combinations thereof, wherein at least one of the side chains comprises an organic borate group;
(iii) —CO—R6—R7,
wherein R6 is a linker or is not present,
wherein R7 is a diol-containing group complexed to a hydrophobic organic borate group, wherein the diol-containing group comprises one or more diols, wherein the hydrophobic organic borate group comprises one or more organic borate groups covalently linked to a hydrophobic group, wherein at least one diol and one hydrophobic organic borate group form a boronic ester;
or
(iv) —CO—R8, wherein R8 is:
(a) -alkenyl-R9, wherein R9 is a phenylboronic acid group, wherein the alkenyl group can be substituted or unsubstituted, wherein the number of carbons in the alkenyl group is from 3 to 25,
(b) —R13, wherein R13 is a bile acid, wherein one or more hydroxyls on the bile acid are derivatized with an organic borate group, or
(c) —(CH2)r—NH—CO—CHR14—NH—CO—(CH2)s, wherein r is an integer from 3-25, wherein s is an integer from 3-25, wherein R14 is an amine-containing group comprising an organic borate group.

17 more elements

An insulin conjugate having the formula:

X1-X2
wherein X1 is insulin, an insulin analog, glucagon, GLP-1, or a GLP-1 agonist,
X2 is:
(i) —CO—(CH2)j—NH—CO—CR1R2,
wherein j is an integer from 3-25
R1 is —NH—R12 or —NH—CO—CH2—CH2—CNR12—C(O)R32, where R32 is glucamine, gluconic acid, glucosamine, fructosamine, galactosamine, mannosamine, or other hexosamines,
R12 is selected from the group consisting of hydrogen, —SO2alkyl, —SO2cycloalkyl, —SO2heterocycloalkyl, —SO2aryl, —SO2heteroaryl, —COalkyl, —COcycloalkyl, —COheterocycloalkyl, —COaryl, —COheteroaryl, —CONHalkyl, —CONHcycloalkyl, —CONHheterocycloalkyl, —CONHaryl, —CONHheteroaryl,
wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are substituted or unsubstituted,
R2 is —(CH2)n—NH—CO—R11 or —(CH2)n—NH—SO2R11,
n is an integer from 3-25, and
R11 is an organic borate group;
(ii) an oligomer comprising a plurality of monomers, wherein the monomers comprise a side chain, wherein the side chain comprises one or more organic borate groups, hydrophobic groups, hydrophilic neutral groups, hydrophilic charged groups, diol groups, fluorescent groups, and combinations thereof, wherein at least one of the side chains comprises an organic borate group;
(iii) —CO—R6—R7,
wherein R6 is a linker or is not present,
wherein R7 is a diol-containing group complexed to a hydrophobic organic borate group, wherein the diol-containing group comprises one or more diols, wherein the hydrophobic organic borate group comprises one or more organic borate groups covalently linked to a hydrophobic group, wherein at least one diol and one hydrophobic organic borate group form a boronic ester;
or
(iv) —CO—R8, wherein R8 is:
(a) -alkenyl-R9, wherein R9 is a phenylboronic acid group, wherein the alkenyl group can be substituted or unsubstituted, wherein the number of carbons in the alkenyl group is from 3 to 25,
(b) —R13, wherein R13 is a bile acid, wherein one or more hydroxyls on the bile acid are derivatized with an organic borate group, or
(c) —(CH2)r—NH—CO—CHR14—NH—CO—(CH2)s, wherein r is an integer from 3-25, wherein s is an integer from 3-25, wherein R14 is an amine-containing group comprising an organic borate group,
wherein the diol-containing group is -(DOPA-Gly)i—NH2, wherein i is an integer from 1-5.

18 more elements

An insulin conjugate having the formula:

X1-X2
wherein X1 is insulin, an insulin analog, glucagon, GLP-1, or a GLP-1 agonist,
X2 is:
(i) —CO—(CH2)j—NH—CO—CR1R2,
wherein j is an integer from 3-25
R1 is —NH—R12 or —NH—CO—CH2—CH2—CNR12—C(O)R32, where R32 is glucamine, gluconic acid, glucosamine, fructosamine, galactosamine, mannosamine, or other hexosamines,
R12 is selected from the group consisting of hydrogen, —SO2alkyl, —SO2cycloalkyl, —SO2heterocycloalkyl, —SO2aryl, —SO2heteroaryl, —COalkyl, —COcycloalkyl, —COheterocycloalkyl, —COaryl, —COheteroaryl, —CONHalkyl, —CONHcycloalkyl, —CONHheterocycloalkyl, —CONHaryl, —CONHheteroaryl,
wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are substituted or unsubstituted,
R2 is —(CH2)n—NH—CO—R11 or —(CH2)n—NH—SO2R11,
n is an integer from 3-25, and
R11 is an organic borate group;
(ii) an oligomer comprising a plurality of monomers, wherein the monomers comprise a side chain, wherein the side chain comprises one or more organic borate groups, hydrophobic groups, hydrophilic neutral groups, hydrophilic charged groups, diol groups, fluorescent groups, and combinations thereof, wherein at least one of the side chains comprises an organic borate group;
(iii) —CO—R6—R7,
wherein R6 is a linker or is not present,
wherein R7 is a diol-containing group complexed to a hydrophobic organic borate group, wherein the diol-containing group comprises one or more diols, wherein the hydrophobic organic borate group comprises one or more organic borate groups covalently linked to a hydrophobic group, wherein at least one diol and one hydrophobic organic borate group form a boronic ester;
or
(iv) —CO—R8, wherein R8 is:
(a) -alkenyl-R9, wherein R9 is a phenylboronic acid group, wherein the alkenyl group can be substituted or unsubstituted, wherein the number of carbons in the alkenyl group is from 3 to 25,
(b) —R13, wherein R13 is a bile acid, wherein one or more hydroxyls on the bile acid are derivatized with an organic borate group, or
(c) —(CH2)r—NH—CO—CHR14—NH—CO—(CH2)s, wherein r is an integer from 3-25, wherein s is an integer from 3-25, wherein R14 is an amine-containing group comprising an organic borate group,
wherein R6 is —(CH2)h—R31—, wherein h is an integer from 3-25, wherein R31 is O-triazole- or CO—NH—CH2—CO-dibenzo-cyclocta-triazole-.

18 more elements

An insulin conjugate having the formula:

X1-X2
wherein X1 is insulin, an insulin analog, glucagon, GLP-1, or a GLP-1 agonist,
X2 is:
—CO—(CH2)j—NH—CO—CR1R2,
wherein j is an integer from 3-25
R1 is —NH—R12 or —NH—CO—CH2—CH2—CNR12—C(O)R32, where R32 is glucamine, gluconic acid, glucosamine, fructosamine, galactosamine, mannosamine, or other hexosamines,
R12 is selected from the group consisting of hydrogen, —SO2alkyl, —SO2cycloalkyl, —SO2heterocycloalkyl, —SO2aryl, —SO2heteroaryl, —COalkyl, —COcycloalkyl, —COheterocycloalkyl, —COaryl, —COheteroaryl, —CONHalkyl, —CONHcycloalkyl, —CONHheterocycloalkyl, —CONHaryl, —CONHheteroaryl,
wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are substituted or unsubstituted,
R2 is —(CH2)n—NH—CO—R11 or —(CH2)n—NH—SO2R11,
n is an integer from 3-25, and
R11 is an organic borate group;
(ii) an oligomer comprising a plurality of monomers, wherein the monomers comprise a side chain, wherein the side chain comprises one or more organic borate groups, hydrophobic groups, hydrophilic neutral groups, hydrophilic charged groups, diol groups, fluorescent groups, and combinations thereof, wherein at least one of the side chains comprises an organic borate group;
(iii) —CO—R6—R7
wherein R6 is a linker or is not present,
wherein R7 is a diol-containing group complexed to a hydrophobic organic borate group, wherein the diol-containing group comprises one or more diols, wherein the hydrophobic organic borate group comprises one or more organic borate groups covalently linked to a hydrophobic group, wherein at least one diol and one hydrophobic organic borate group form a boronic ester, or
(iv) —CO—R8, wherein R8 is:
(a) -alkenyl-R9, wherein R9 is a phenylboronic acid group, wherein the alkenyl group can be substituted or unsubstituted, wherein the number of carbons in the alkenyl group is from 3 to 25,
(b) —R13, wherein R13 is a bile acid, wherein one or more hydroxyls on the bile acid are derivatized with an organic borate group, or
(c) —(CH2)r—NH—CO—CHR14—NH—CO—(CH2)s, wherein r is an integer from 3-25, wherein s is an integer from 3-25, wherein R14 is an amine-containing group comprising an organic borate group,
wherein the hydrophobic group is —(CH2)k—CH3, wherein k is an integer from 3-25.

17 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/652,011Filed 12 Dec 2013 · us provisional application
Priority: 12 Dec 2012
Published: US 2015/0320837 A112 Nov 2015
Granted: 16 Jan 2018
Term ends: Not estimatedThe source records don’t support an estimate.

Classification13 codes

A61K 38/28
Hormones: insulins
A61K 47/54
The non-active ingredient being a modifying agent: the modifying agent being an organic compound
A61K 47/542
The modifying agent being an organic compound: carboxylic acids, e.g. a fatty acid or an amino acid
A61K 47/543
The modifying agent being an organic compound: lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine

Family

Application61/736,079Us provisional application · filed 12 Dec 2012
Application61/736,092Us provisional application · filed 12 Dec 2012
Application61/736,109Us provisional application · filed 12 Dec 2012
US 2015/0320837 A1Pre-grant publication · published 12 Nov 2015
US 9,867,869 B2This patent

From the US filing history. Foreign family members aren’t listed.