GLP-1 PHARMACEUTICAL COMPOSITIONS
The present invention is directed to peptide analogues of glucagon-like peptide-1, the pharmaceutically-acceptable salts thereof, to methods of using such analogues to treat mammals and to pharmaceutical compositions useful therefore comprising said analogues.
1 - 63 . (canceled)
64 . A pharmaceutical composition comprising an analog of glucagon-like peptide-1 according to the formula:
[Aib 8,35 ]hGLP-1(7-36)NH 2 ;
together with zinc and a pharmaceutically acceptable carrier or diluent, wherein said diluent comprises a pharmaceutically acceptable aqueous solution and said pharmaceutical composition is a clear solution when said composition is administered, said analog of glucagon-like peptide-1 is released within said subject for at least approximately 5 to approximately 7 days, with the proviso that said composition does not consist of a clear aqueous ZnCl 2 solution having pH 4 in which said [Aib 8,35 ]hGLP-1(7-36)NH 2 is present at a concentration of 4 mg/ml and said ZnCI 2 is present at a concentration of 0.5 mg/ml.
65 . The pharmaceutical composition according to claim 64 , wherein said zinc is present in a concentration from 0.0005 mg/mL to 50 mg/mL.
66 . The pharmaceutical composition according to claim 65 , wherein said zinc is present in a concentration from 0.01 mg/mL to 0.50 mg/mL.
67 . The pharmaceutical composition according to claim 64 , wherein said diluent comprises sterile water.
68 . The pharmaceutical composition according to claim 64 , wherein said pharmaceutical composition comprises an aqueous mixture, suspension or solution, and wherein said analog of glucagon-like peptide-1 is present at a concentration of approximately 0.5%-30% (w/w).
69 . The pharmaceutical composition according to claim 68 , wherein the concentration of said analog of glucagon-like peptide-1 in said aqueous mixture, suspension or solution is approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% (w/w).
70 . The pharmaceutical composition according to claim 69 , wherein the concentration of said analog of glucagon-like peptide-1 in said aqueous solution is approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 14%, 15%, 16%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 29%, or 30% (w/w).
71 . The pharmaceutical composition according to claim 70 , wherein the concentration of said analog of glucagon-like peptide-1 in said aqueous solution is approximately 1%, 2%, 3%, 4%, 5%, 6%, 9%, 10%, 11%, 22%, 23%, 24%, 25% or 26% (w/w).
72 . The pharmaceutical composition according to claim 71 , wherein the concentration of said analog of glucagon-like peptide-1 in said aqueous solution is approximately 1%, 2%, 3%, 4%, 5%, 6%, 10%, 22%, 23%, 24%, 25%, or 26% (w/w).
73 . The pharmaceutical composition according to claim 72 , wherein the concentration of said analog of glucagon-like peptide-1 in said aqueous solution is approximately 1%, 2%, 5%, 10%, 23% or 25% (w/w).
74 . The pharmaceutical composition according to claim 68 , wherein the molar ratio of said analog of glucagon-like peptide-1 to zinc in said pharmaceutical composition ranges from approximately 6:1 to approximately 1:1.
75 . The pharmaceutical composition according to claim 74 , wherein said ratio ranges from approximately 5.5:1 to approximately 1:1.
76 . The pharmaceutical composition according to claim 75 , wherein said ratio ranges from approximately 5.4:1 to approximately 1.5:1.
77 . The pharmaceutical composition according to claim 76 , wherein said ratio is approximately 5.4:1, 4.0:1, or 1.5:1.
78 . The pharmaceutical composition according to claim 77 , wherein said ratio is approximately 1.5:1.
79 . The pharmaceutical composition according to claim 68 , wherein said zinc is provided as zinc chloride or zinc acetate.
80 . The pharmaceutical composition according to claim 79 , wherein said zinc acetate is provided as ZnAc 2 .2H 2 O.
81 . The pharmaceutical composition according to claim 64 , wherein when said composition is administered to said subject in need thereof, said analog of glucagon-like peptide-1 is released within said subject for at least approximately 6 days.
82 . The pharmaceutical composition according to claim 64 , wherein when said composition is administered to said subject in need thereof, the analog of glucagon-like peptide-1 is released within said subject for at least approximately 7 days.
83 . The pharmaceutical composition according to claim 75 , wherein when said composition is administered to said subject in need thereof, said analog of glucagon-like peptide-1 is released within said subject for at least approximately 6 days.
84 . The pharmaceutical composition according to claim 75 , wherein when said composition is administered to said subject in need thereof, the analog of glucagon-like peptide-1 is released within said subject for at least approximately 7 days.
85 . The pharmaceutical composition according to anyone of claim 81 , 82 , 83 or 84 , wherein said subject is a mammal.
86 . The pharmaceutical composition according to anyone of claim 64 , wherein said subject is a mammal.
87 . The composition according to claim 78 , wherein the concentration of [Aib 8,35 ]hGLP-1(7-36)NH 2 in said composition is about 1% (weight/volume).
88 . The composition according to claim 78 , wherein the concentration of [Aib 8,35 ]hGLP-1(7-36)NH 2 in said composition is about 2% (weight/volume).
89 . The composition according to claim 78 , wherein the concentration of [Aib 8,35 ]hGLP-1(7-36)NH 2 in said composition is about 10% (weight/volume).
90 . The composition according to claim 78 , wherein the concentration of [Aib 8,35 ]hGLP-1(7-36)NH 2 in said composition is about 25% (weight/volume);
91 . The composition according to claim 77 , wherein the concentration of [Aib 8,35 ]hGLP-1(7-36)NH 2 in said composition is about 5% (weight/volume) and said ratio is approximately 5.4:1.
92 . The composition according to claim 77 , wherein the concentration of [Aib 8,35 ]hGLP-1(7-36)NH 2 in said composition is about 5% (weight/volume) and said ratio is approximately 4.0:1.
93 . The composition according to claim 77 , wherein the concentration [Aib 8,35 ]hGLP-1(7-36)NH 2 in said composition is about 10% (weight/volume) and said ratio is approximately 5.4:1.
94 . The composition according to claim 77 , wherein the concentration of [Aib 8,35 ]hGLP-1(7-36)NH 2 in said composition is about 23% (weight/volume) and said ratio is approximately 4.0:1.
95 . The composition according to claim 78 , wherein the concentration of [Aib 8,35 ]hGLP-1(7-36)NH 2 in said composition is about 23% (weight/volume).
96 . The pharmaceutical composition according to claim 85 , wherein said subject is a human.
97 . The pharmaceutical composition according to claim 86 , wherein said subject is a human.
98 . The composition according to claim 78 , wherein the concentration of [Aib 8,35 ]hGLP-1(7-36)NH 2 in said pharmaceutical composition is about 10% (weight/volume) and the molar ratio of [Aib 8,35 ]hGLP-1(7-36)NH 2 to zinc is about 1.5:1.
99 . A method of treating a subject afflicted with Type I diabetes, Type II diabetes or gestational diabetes comprising administering to said subject the pharmaceutical composition according to claim 64 .
100 . The method according to claim 99 , wherein said subject is a human being.
101 . The method according to claim 100 , wherein said disease is Type I diabetes or Type II diabetes.
102 . A method of stimulating beta-cell proliferation or reducing beta-cell deterioration comprising administering to a subject in need thereof the pharmaceutical composition according to claim 64 .
103 . The method according to claim 102 , wherein said subject is a human being.
104 . A method of treating a subject afflicted with Type I diabetes, Type II diabetes or gestational diabetes comprising administering to said subject the pharmaceutical composition according to claim 68 .
105 . The method according to claim 104 , wherein said subject is a human being.
106 . The method according to claim 105 , wherein said disease is Type I diabetes or Type II diabetes.
107 . A method of stimulating beta-cell proliferation or reducing beta-cell deterioration comprising administering to a subject in need thereof the pharmaceutical composition according to claim 68 .
108 . The method according to claim 107 , wherein said subject is a human being.