Pharmaceutical compositions of insulin drug-oligomer conjugates and methods of treating diseases therewith
First Claim
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1. A pharmaceutical composition comprising:
- an insulin drug-oligomer conjugate comprising an insulin polypeptide covalently coupled to an oligomeric moiety, wherein the insulin polypeptide is an insulin analog selected from the group consisting of GlyA21 insulin, human;
GlyA21 GlnB3 insulin, human;
AlaA21 insulin, human;
AlaA21 GlnB3 insulin, human;
GlnB3 insulin, human;
GlnB30 insulin, human;
GlyA21 GluB30 insulin, human;
GlyA21 GlnB3 GluB30 insulin, human;
GlnB3 GluB30 insulin, human;
AspB28 insulin, human;
LysB28 insulin, human;
LeuB28 insulin, human;
ValB28 insulin, human;
AlaB28 insulin, human;
AspB28 ProB29 insulin, human;
LysB28 ProB29 insulin, human;
LeuB28 ProB29 insulin, human;
ValB28 ProB29 insulin, human; and
AlaB28 ProB29 insulin, human;
a fatty acid component comprising a fatty acid; and
a bile salt component comprising a bile salt;
wherein the fatty acid component and the bile salt component are present in a weight-to-weight ratio of between 1;
5 and 5;
1, wherein the fatty acid component is present in an amount sufficient to lower the precipitation point of the bile salt compared to a precipitation point of the bile salt if the fatty acid component were not present in the pharmaceutical composition, and wherein the bile salt component is present in an amount sufficient to lower the solubility point of the fatty acid compared to a solubility point of the fatty acid if the bile salt were not present in the pharmaceutical composition.
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Abstract
Pharmaceutical compositions that include an insulin drug-oligomer conjugate, a fatty acid component, and a bile salt component are described. The insulin drug is covalently coupled to an oligomeric moiety. The fatty acid component and the bile salt component are present in a weight-to-weight ratio of between 1:5 and 5:1. Methods of treating an insulin deficiency in a subject in need of such treatment using such pharmaceutical compositions are also provided, as are methods of providing such pharmaceutical compositions.
229 Citations
133 Claims
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1. A pharmaceutical composition comprising:
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an insulin drug-oligomer conjugate comprising an insulin polypeptide covalently coupled to an oligomeric moiety, wherein the insulin polypeptide is an insulin analog selected from the group consisting of GlyA21 insulin, human;
GlyA21 GlnB3 insulin, human;
AlaA21 insulin, human;
AlaA21 GlnB3 insulin, human;
GlnB3 insulin, human;
GlnB30 insulin, human;
GlyA21 GluB30 insulin, human;
GlyA21 GlnB3 GluB30 insulin, human;
GlnB3 GluB30 insulin, human;
AspB28 insulin, human;
LysB28 insulin, human;
LeuB28 insulin, human;
ValB28 insulin, human;
AlaB28 insulin, human;
AspB28 ProB29 insulin, human;
LysB28 ProB29 insulin, human;
LeuB28 ProB29 insulin, human;
ValB28 ProB29 insulin, human; and
AlaB28 ProB29 insulin, human;
a fatty acid component comprising a fatty acid; and
a bile salt component comprising a bile salt;
wherein the fatty acid component and the bile salt component are present in a weight-to-weight ratio of between 1;
5 and 5;
1, wherein the fatty acid component is present in an amount sufficient to lower the precipitation point of the bile salt compared to a precipitation point of the bile salt if the fatty acid component were not present in the pharmaceutical composition, and wherein the bile salt component is present in an amount sufficient to lower the solubility point of the fatty acid compared to a solubility point of the fatty acid if the bile salt were not present in the pharmaceutical composition. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21)
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22. A pharmaceutical composition comprising:
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an insulin drug-oligomer conjugate comprising an insulin polypeptide covalently coupled to an oligomeric moiety, wherein the insulin polypeptide is an insulin analog selected from the group consisting of GlyA21 insulin, human;
GlyA21 GlnB3 insulin, human;
AlaA21 insulin, human;
AlaA21 GlnB3 insulin, human;
GlnB3 insulin, human;
GlnB30 insulin, human;
GlyA21 GluB30 insulin, human;
GlyA21 GlnB3 GluB30 insulin, human;
GlnB3 GluB30 insulin, human;
AspB28 insulin, human;
LysB28 insulin, human;
LeuB28 insulin, human;
ValB28 insulin, human;
AlaB28 insulin, human;
AspB28 ProB29 insulin, human;
LysB28 ProB29 insulin, human;
LeuB28 ProB29 insulin, human;
ValB28 ProB29 insulin, human; and
AlaB28 ProB29 insulin, human;
a bile salt component comprising a bile salt; and
a fatty acid component comprising a fatty acid, wherein the fatty acid component and the bile salt component are present in a weight-to-weight ratio of between 1;
5 and 5;
1, and wherein the fatty acid component is present in a first amount such that, at the precipitation point of the bile salt, the bile salt precipitates as first bile salt particles that, upon a return to a pH above the precipitation point of the bile salt, re-solubilize more quickly than second bile salt particles that would have precipitated if the fatty acid component were not present in the composition. - View Dependent Claims (23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42)
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43. A pharmaceutical composition comprising:
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an insulin drug-oligomer conjugate comprising an insulin polypeptide and an oligomeric moiety, wherein the insulin polypeptide is an insulin analog selected from the group consisting of GlyA21 insulin, human;
GlyA21 GlnB3 insulin, human;
AlaA21 insulin, human;
AlaA21 GlnB3 insulin, human;
GlnB3 insulin, human;
GlnB30 insulin, human;
GlyA21 GluB30 insulin, human;
GlyA21 GlnB3 GluB30 insulin, human;
GlnB3 GluB30 insulin, human;
AspB28 insulin, human;
LysB28 insulin, human;
LeuB28 insulin, human;
ValB28 insulin, human;
AlaB28 insulin, human;
AspB28 ProB29 insulin, human;
LysB28 ProB29 insulin, human;
LeuB28 ProB29 insulin, human;
ValB28 ProB29 insulin, human; and
AlaB28 ProB29 insulin, human;
between 0.1 and 15% (w/v) of a fatty acid component;
wherein the fatty acid component comprises a medium-chain fatty acid and a long-chain fatty acid; and
between 0.1 and 15% (w/v) of a bile salt component;
wherein the fatty acid component and the bile salt component are present in a weight-to-weight ratio of between 1;
5 and 5;
1. - View Dependent Claims (44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60)
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61. A pharmaceutical composition comprising:
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an insulin drug-oligomer conjugate comprising the structure of Formula V;
wherein the insulin polypeptide is an insulin analog selected from the group consisting of GlyA21 insulin, human;
GlyA21 GlnB3 insulin, human;
AlaA21 insulin, human;
AlaA21 GlnB3 insulin, human;
GlnB3 insulin, human;
GlnB30 insulin, human;
GlyA21 GluB30 insulin, human;
GlyA21 GlnB3 GluB30 insulin, human;
GlnB3 GluB30 insulin, human;
AspB28 insulin, human;
LysB28 insulin, human;
LeuB28 insulin, human;
ValB28 insulin, human;
AlaB28 insulin, human and the oligomeric moiety of the conjugate is coupled to the B29 lysine of the insulin polypeptide;
between 0.1 and 15% (w/v) of a fatty acid component comprising capric acid, lauric acid, and oleic acid; and
between 0.1 and 15% (w/v) of a bile salt component comprising a pharmaceutically acceptable salt of cholic acid;
wherein the fatty acid component and the bile salt component are present in a weight-to-weight ratio of between 1;
5 and 5;
1.
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62. A method of treating an insulin deficiency in a subject in need of such treatment, said method comprising administering to the subject a pharmaceutical composition comprising
(a) a therapeutically effective amount of an insulin drug-oligomer conjugate that comprises an insulin polypeptide covalently coupled to an oligomeric moiety, wherein the insulin polypeptide is an insulin analog selected from the group consisting of GlyA21 insulin, human; - GlyA21 GlnB3 insulin, human;
AlaA21 insulin, human;
AlaA21 GlnB3 insulin, human;
GlnB3 insulin, human;
GlnB30 insulin, human;
GlyA21 GluB30 insulin, human;
GlyA21 GlnB3 GluB30 insulin, human;
GlnB3 GluB30 insulin, human;
AspB28 insulin, human;
LysB28 insulin, human;
LeuB28 insulin, human;
ValB28 insulin, human;
AlaB28 insulin, human;
AspB28 ProB29 insulin, human;
LysB28 ProB29 insulin, human;
LeuB28 ProB29 insulin, human;
ValB28 ProB29 insulin, human; and
AlaB28 ProB29 insulin, human;
(b) a fatty acid component comprising a fatty acid; and
(c) a bile salt component comprising a bile salt, wherein the fatty acid component and the bile salt component are present in a weight ratio of between 1;
5 and 5;
1, wherein the fatty acid component is present in an amount sufficient to lower the precipitation point of the bile salt compared to a precipitation point of the bile salt if the fatty acid component were not present in the pharmaceutical composition, and wherein the fatty acid component is present in an amount sufficient to lower the solubility point of the fatty acid compared to a solubility point of the fatty acid if the bile salt were not present in the pharmaceutical composition. - View Dependent Claims (63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82)
- GlyA21 GlnB3 insulin, human;
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83. A method of treating an insulin deficiency in a subject in need of such treatment, said method comprising administering to the subject a pharmaceutical composition comprising:
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(a) a therapeutically effective amount of an insulin drug-oligomer conjugate that comprises an insulin polypeptide covalently coupled to an oligomeric moiety, wherein the insulin polypeptide is an insulin analog selected from the group consisting of GlyA21 insulin, human;
GlyA21 GlnB3 insulin, human;
AlaA21 insulin, human;
AlaA21 GlnB3 insulin, human;
GlnB3 insulin, human;
GlnB30 insulin, human;
GlyA21 GluB30 insulin, human;
GlyA21 GlnB3 GluB30 insulin, human;
GlnB3 GluB30 insulin, human;
AspB28 insulin, human;
LysB28 insulin, human;
LeuB28 insulin, human;
ValB28 insulin, human;
AlaB28 insulin, human;
AspB28 ProB29 insulin, human;
LysB28 ProB29 insulin, human;
LeuB28 ProB29 insulin, human;
ValB28 ProB29 insulin, human; and
AlaB28 ProB29 insulin, human;
(b) a bile salt component comprising a bile salt; and
(c) a fatty acid component comprising a fatty acid, wherein the fatty acid component and the bile salt component are present in a weight ratio of between 1;
5 and 5;
1, and wherein the fatty acid component is present in a first amount such that, at the precipitation point of the bile salt, the bile salt precipitates as first bile salt particles that, upon a return to a pH above the precipitation point of the bile salt, re-solubilize more quickly than second bile salt particles that would have precipitated if the fatty acid component were not present in the composition. - View Dependent Claims (84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102)
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103. A method of treating an insulin deficiency in a subject in need of such treatment, said method comprising administering to the subject a pharmaceutical composition comprising:
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(a) a therapeutically effective amount of an insulin drug-oligomer conjugate that comprises an insulin polypeptide and an oligomeric moiety, wherein the insulin polypeptide is an insulin analog selected from the group consisting of GlyA21 insulin, human;
GlyA21 GlnB3 insulin, human;
AlaA21 insulin, human;
AlaA21 GlnB3 insulin, human;
GlnB3 insulin, human;
GlnB30 insulin, human;
GlyA21 GluB30 insulin, human;
GlyA21 GlnB3 GluB30 insulin, human;
GlnB3 GluB30 insulin, human;
AspB28 insulin, human;
LysB28 insulin, human;
LeuB28 insulin, human;
ValB28 insulin, human;
AlaB28 insulin, human;
AspB28 ProB29 insulin, human;
LysB28 ProB29 insulin, human;
LeuB28 ProB29 insulin, human;
ValB28 ProB29 insulin, human; and
AlaB28 ProB29 insulin, human;
(b) between 0.1 and 15% (w/v) of a fatty acid component comprises a medium-chain fatty acid and a long-chain fatty acid; and
(c) between 0.1 and 15% (w/v) of a bile salt component, wherein the fatty acid component and the bile salt component are present in a weight to weight ratio of between 1;
5 and 5;
1. - View Dependent Claims (104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119)
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120. A pharmaceutical composition comprising:
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an insulin drug-oligomer conjugate comprising an insulin polypeptide and an oligomeric moiety, wherein the insulin polypeptide is an insulin analog selected from the group consisting of GlyA21 insulin, human;
GlyA21 GlnB3 insulin, human;
AlaA21 insulin, human;
AlaA21 GlnB3 insulin, human;
GlnB3 insulin, human;
GlnB30 insulin, human;
GlyA21 GluB30 insulin, human;
GlyA21 GlnB3 GluB30 insulin, human;
GlnB3 GluB30 insulin, human;
AspB28 insulin, human;
LysB28 insulin, human;
LeuB28 insulin, human;
ValB28 insulin, human;
AlaB28 insulin, human;
AspB28 ProB29 insulin, human;
LysB28 ProB29 insulin, human;
LeuB28 ProB29 insulin, human;
ValB28 ProB29 insulin, human; and
AlaB28 ProB29 insulin, human;
between 0.1 and 15% (w/v) of a fatty acid component; and
between 0.1 and 15% (w/v) of a bile salt component;
wherein the fatty acid component and the bile salt component are present in a weight-to-weight ratio of between 1;
5 and 5;
1, and wherein the pharmaceutical composition comprises a buffering component that comprises tris-base or trolamine. - View Dependent Claims (121, 122, 123)
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124. A pharmaceutical composition comprising:
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an insulin drug-oligomer conjugate comprising an insulin polypeptide and an oligomeric moiety, wherein the insulin polypeptide is an insulin analog selected from the group consisting of GlyA21 insulin, human;
GlyA21 GlnB3 insulin, human;
AlaA21 insulin, human;
AlaA21 GlnB3 insulin, human;
GlnB3 insulin, human;
GlnB30 insulin, human;
GlyA21 GluB30 insulin, human;
GlyA21 GlnB3 GluB30 insulin, human;
GlnB3 GluB30 insulin, human;
AspB28 insulin, human;
LysB28 insulin, human;
LeuB28 insulin, human;
ValB28 insulin, human;
AlaB28 insulin, human;
AspB28 ProB29 insulin, human;
LysB28 ProB29 insulin, human;
LeuB28 ProB29 insulin, human;
ValB28 ProB29 insulin, human; and
AlaB28 ProB29 insulin, human;
between 0.1 and 15% (w/v) of a fatty acid component; and
between 0.1 and 15% (w/v) of a bile salt component;
wherein the fatty acid component and the bile salt component are present in a weight-to-weight ratio of between 1;
5 and 5;
1, and wherein the insulin drug-oligomer conjugate is present as a monodispersed mixture.
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125. A pharmaceutical composition comprising:
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an insulin drug-oligomer conjugate comprising an insulin polypeptide and an oligomeric moiety, wherein the insulin polypeptide is an insulin analog selected from the group consisting of GlyA21 insulin, human;
GlyA21 GlnB3 insulin, human;
AlaA21 insulin, human;
AlaA21 GlnB3 insulin, human;
GlnB3 insulin, human;
GlnB30 insulin, human;
GlyA21 GluB30 insulin, human;
GlyA21 GlnB3 GluB30 insulin, human;
GlnB3 GluB30 insulin, human;
AspB28 insulin, human;
LysB28 insulin, human;
LeuB28 insulin, human;
ValB28 insulin, human;
AlaB28 insulin, human;
AspB28 ProB29 insulin, human;
LysB28 ProB29 insulin, human;
LeuB28 ProB29 insulin, human;
ValB28 ProB29 insulin, human; and
AlaB28 ProB29 insulin, human;
between 0.1 and 15% (w/v) of a fatty acid component; and
between 0.1 and 15% (w/v) of a bile salt component;
wherein the fatty acid component and the bile salt component are present in a weight-to-weight ratio of between 1;
5 and 5;
1, and wherein the insulin drug-oligomer conjugate is present as a monodispersed mixture.
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126. A pharmaceutical composition comprising:
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an insulin drug-oligomer conjugate comprising an insulin polypeptide and an oligomeric moiety, wherein the insulin polypeptide is an insulin analog selected from the group consisting of GlyA21 insulin, human;
GlyA21 GlnB3 insulin, human;
AlaA21 insulin, human;
AlaA21 GlnB3 insulin, human;
GlnB3 insulin, human;
GlnB30 insulin, human;
GlyA21 GluB30 insulin, human;
GlyA21 GlnB3 GluB30 insulin, human;
GlnB3 GluB30 insulin, human;
AspB28 insulin, human;
LysB28 insulin, human;
LeuB28 insulin, human;
ValB28 insulin, human;
AlaB28 insulin, human;
AspB28 ProB29 insulin, human;
LysB28 ProB29 insulin, human;
LeuB28 ProB29 insulin, human;
ValB28 ProB29 insulin, human; and
AlaB28 ProB29 insulin, human;
between 0.1 and 15% (w/v) of a fatty acid component; and
between 0.1 and 15% (w/v) of a bile salt component;
wherein the fatty acid component and the bile salt component are present in a weight-to-weight ratio of between 1;
5 and 5;
1, and wherein the insulin drug-oligomer conjugate comprises the structure of Formula V;
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127. A method of treating an insulin deficiency in a subject in need of such treatment, said method comprising administering to the subject a pharmaceutical composition comprising:
- (a) a therapeutically effective amount of an insulin drug-oligomer conjugate that comprises an insulin polypeptide and an oligomeric moiety, wherein the insulin polypeptide is an insulin analog selected from the group consisting of GlyA21 insulin, human;
GlyA21 GlnB3 insulin, human;
AlaA21 insulin, human;
AlaA21 GlnB3 insulin, human;
GlnB3 insulin, human;
GlnB30 insulin, human;
GlyA21 GluB30 insulin, human;
GlyA21 GlnB3 GluB30 insulin, human;
GlnB3 GluB30 insulin, human;
AspB28 insulin, human;
LysB28 insulin, human;
LeuB28 insulin, human;
ValB28 insulin, human;
AlaB28 insulin, human;
AspB28 ProB29 insulin, human;
LysB28 ProB29 insulin, human;
LeuB28 ProB29 insulin, human;
ValB28 ProB29 insulin, human; and
AlaB28 ProB29 insulin, human;between 0.1 and 15% (w/v) of a fatty acid component; and
(c) between 0.1 and 15% (w/v) of a bile salt component, wherein the fatty acid component and the bile salt component are present in a weight to weight ratio of between 1;
5 and 5;
1, and wherein the pharmaceutical composition comprises a buffering component that comprises tris-base or trolamine. - View Dependent Claims (128, 129, 130)
- (a) a therapeutically effective amount of an insulin drug-oligomer conjugate that comprises an insulin polypeptide and an oligomeric moiety, wherein the insulin polypeptide is an insulin analog selected from the group consisting of GlyA21 insulin, human;
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131. A method of treating an insulin deficiency in a subject in need of such treatment, said method comprising administering to the subject a pharmaceutical composition comprising:
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(a) a therapeutically effective amount of an insulin drug-oligomer conjugate that comprises an insulin polypeptide and an oligomeric moiety, wherein the insulin polypeptide is an insulin analog selected from the group consisting of GlyA21 insulin, human;
GlyA21 GlnB3 insulin, human;
AlaA21 insulin, human;
AlaA21 GlnB3 insulin, human;
GlnB3 insulin, human;
GlnB30 insulin, human;
GlyA21 GluB30 insulin, human;
GlyA21 GlnB3 GluB30 insulin, human;
GlnB3 GluB30 insulin, human;
AspB28 insulin, human;
LysB28 insulin, human;
LeuB28 insulin, human;
ValB28 insulin, human;
AlaB28 insulin, human;
AspB28 ProB29 insulin, human;
LysB28 ProB29 insulin, human;
LeuB28 ProB29 insulin, human;
ValB28 ProB29 insulin, human; and
AlaB28 ProB29 insulin, human;
(b) between 0.1 and 15% (w/v) of a fatty acid component; and
(c) between 0.1 and 15% (w/v) of a bile salt component, wherein the fatty acid component and the bile salt component are present in a weight-to-weight ratio of between 1;
5 and 5;
1, and wherein the insulin drug-oligomer conjugate is present as a substantially monodispersed mixture.
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132. A method of treating an insulin deficiency in a subject in need of such treatment, said method comprising administering to the subject a pharmaceutical composition comprising:
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(a) a therapeutically effective amount of an insulin drug-oligomer conjugate that comprises an insulin polypeptide and an oligomeric moiety, wherein the insulin polypeptide is an insulin analog selected from the group consisting of GlyA21 insulin, human;
GlyA21 GlnB3 insulin, human;
AlaA21 insulin, human;
AlaA21 GlnB3 insulin, human;
GlnB3 insulin, human;
GlnB30 insulin, human;
GlyA21 GluB30 insulin, human;
GlyA21 GlnB3 GluB30 insulin, human;
GlnB3 GluB30 insulin, human;
AspB28 insulin, human;
LysB28 insulin, human;
LeuB28 insulin, human;
ValB28 insulin, human;
AlaB28 insulin, human;
AspB28 ProB29 insulin, human;
LysB28 ProB29 insulin, human;
LeuB28 ProB29 insulin, human;
ValB28 ProB29 insulin, human; and
AlaB28 ProB29 insulin, human;
(b) between 0.1 and 15% (w/v) of a fatty acid component; and
(c) between 0.1 and 15% (w/v) of a bile salt component, wherein the fatty acid component and the bile salt component are present in a weight-to-weight ratio of between 1;
5 and 5;
1, and wherein the insulin drug-oligomer conjugate is present as a monodispersed mixture.
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133. A method of treating an insulin deficiency in a subject in need of such treatment, said method comprising administering to the subject a pharmaceutical composition comprising:
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(a) a therapeutically effective amount of an insulin drug-oligomer conjugate that comprises an insulin polypeptide and an oligomeric moiety, wherein the insulin polypeptide is an insulin analog selected from the group consisting of GlyA21 insulin, human;
GlyA21 GlnB3 insulin, human;
AlaA21 insulin, human;
AlaA21 GlnB3 insulin, human;
GlnB3 insulin, human;
GlnB30 insulin, human;
GlyA21 GluB30 insulin, human;
GlyA21 GlnB3 GluB30 insulin, human;
GlnB3 GluB30 insulin, human;
AspB28 insulin, human;
LysB28 insulin, human;
LeuB28 insulin, human;
ValB28 insulin, human;
AlaB28 insulin, human;
AspB28 ProB29 insulin, human;
LysB28 ProB29 insulin, human;
LeuB28 ProB29 insulin, human;
ValB28 ProB29 insulin, human; and
AlaB28 ProB29 insulin, human;
(b) between 0.1 and 15% (w/v) of a fatty acid component; and
(c) between 0.1 and 15% (w/v) of a bile salt component, wherein the fatty acid component and the bile salt component are present in a weight to weight ratio of between 1;
5 and 5;
1, and wherein the insulin drug-oligomer conjugate comprises the structure of Formula V;
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Specification