FORMULATION OF INSULINOTROPIC PEPTIDE CONJUGATES
The present invention provides pharmaceutical formulations comprising insulinotropic peptide conjugates, particularly a conjugate of albumin to exendin-4, or a derivative thereof, and methods of administration thereof. The present invention also provides methods for treating diabetes and insulinotropic peptides related diseases or conditions by administering the pharmaceutical formulations described herein.
1 . A pharmaceutical formulation comprising: a conjugate of albumin and an insulinotropic peptide, said insulinotropic peptide comprising a sequence which has not more than 3 amino acid substitutions, deletions, or insertions relative to the native exendin-4 sequence, said conjugate being at a concentration of about 1 mg/ml to about 100 mg/ml; a buffer; a tonicity modifier, wherein the tonicity modifier is at a concentration of at least 1 mM; a stabilizer; and a surfactant, wherein said formulation has a pH from about 4 to about 8.
2 . The pharmaceutical formulation of claim 1 wherein the conjugate comprises albumin cysteine 34 thiol covalently linked to a [2-[2-[2-maleimidopropionamido(ethoxy)ethoxy]acetic acid linker covalently linked to the epsilon amino of a lysine of said peptide.
3 . The pharmaceutical formulation of claim 1 wherein the conjugate is according to the following:
(SEQ ID NO: 33)
wherein X is S, O, or NH of an amino acid of albumin.
4 . The pharmaceutical formulation of claim 2 wherein said lysine has been added to the native exendin-4 sequence.
5 . The pharmaceutical formulation of claim 2 wherein said lysine has been added to the carboxy terminus of the native exendin-4 sequence.
6 . The pharmaceutical formulation of claim 1 , wherein the albumin is human serum albumin.
7 . The pharmaceutical formulation of claim 1 wherein the albumin is recombinant serum albumin.
8 . The pharmaceutical formulation of claim 1 wherein the albumin is recombinant human serum albumin.
9 . The pharmaceutical formulation of claim 1 wherein the conjugate comprises recombinant human serum albumin cysteine 34 thiol covalently linked to a [2-[2-[2 maleimidopropionamido(ethoxy)ethoxy]acetic acid linker covalently linked to the epsilon amino of the carboxy terminal lysine of exendin-4(1-39)Lys 40 -NH 2 .
10 . The pharmaceutical formulation of claim 1 , wherein said conjugate is purified.
11 . The pharmaceutical formulation of claim 1 , wherein said conjugate is at a concentration from about 1 mg/ml to about 50 mg/ml.
12 . The pharmaceutical formulation of claim 1 , wherein said conjugate is at a concentration from about 1 mg/ml to about 15 mg/ml.
13 . The pharmaceutical formulation of claim 1 , wherein said conjugate is at a concentration from about 1 mg/ml to about 10 mg/ml.
14 . The pharmaceutical formulation of claim 1 , wherein said conjugate is at a concentration of about 10 mg/ml.
15 . The pharmaceutical formulation of claim 1 , wherein said conjugate is at a concentration of about 20 mg/ml.
16 . The pharmaceutical formulation of claim 1 , wherein the pH is between about 5 and about 7.
17 . The pharmaceutical formulation of claim 1 , wherein the pH is about 5.0.
18 . The pharmaceutical formulation of claim 1 , wherein the pH is about 7.0.
19 . The pharmaceutical formulation of claim 1 , wherein the buffer is an acetate buffer.
20 . The pharmaceutical formulation of claim 19 , wherein the acetate buffer is a sodium acetate buffer, and wherein the pH is about 4.0 to about 6.0.
21 . The pharmaceutical formulation of claim 1 , wherein the buffer is a phosphate buffer.
22 . The pharmaceutical formulation of claim 21 , wherein the phosphate buffer is a sodium phosphate buffer, and wherein the pH is about 6.0 to about 8.0.
23 . The pharmaceutical formulation of claim 1 , wherein the buffer is at a concentration from 1 mM to about 20 mM.
24 . The pharmaceutical formulation of claim 1 , wherein the buffer is at a concentration from 5 mM to about 15 mM.
25 . The pharmaceutical formulation of claim 1 , wherein the buffer is at a concentration at about 10 mM.
26 . The pharmaceutical formulation of claim 1 , wherein the tonicity modifier is sodium chloride.
27 . The pharmaceutical formulation of claim 26 , wherein the sodium chloride is at a concentration of about 135 mM to about 155 mM.
28 . The pharmaceutical formulation of claim 26 , wherein the sodium chloride is at a concentration of about 135 mM.
29 . The pharmaceutical formulation of claim 26 , wherein the sodium chloride is at a concentration of about 150 mM.
30 . The pharmaceutical formulation of claim 1 , wherein the tonicity modifier is sorbitol.
31 . The pharmaceutical formulation of claim 30 , wherein sorbitol is about 5% (w/v).
32 . The pharmaceutical formulation of claim 1 , wherein the stabilizer is sodium octanoate.
33 . The pharmaceutical formulation of claim 32 , wherein the sodium octanoate is at a concentration of about 5 mM.
34 . The pharmaceutical formulation of claim 1 , wherein the surfactant is pluronic F68.
35 . The pharmaceutical formulation of claim 34 , wherein the pluronic F68 is about 0.1% (w/v).
36 . The pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation further comprises a preservative.
37 . The pharmaceutical formulation of claim 36 , wherein the preservative is selected from the group consisting of methanol, ethanol, iso-propanol, glycerol, resorcinol, 2-methyl-2,4-pentadiol, merthiolate (thimerosal), benzalkonium chloride, and sodium benzoate.
38 . The pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation is in a unit dosage form.
39 . The pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation is in a multi-use dosage form.
40 . The pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation is a liquid dosage form.
41 . The pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation is a lyophilized dosage form.
42 . The pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation is suitable for parenteral administration.
43 . The pharmaceutical formulation of claim 42 , wherein the pharmaceutical formulation is suitable for subcutaneous, intravenous, intramuscular, transdermal, intra-arterial, intra-peritoneal, pulmonary or oral administration.
44 . The pharmaceutical formulation of claim 42 , wherein the pharmaceutical formulation is suitable for subcutaneous administration.
45 . The pharmaceutical formulation of claim 1 , wherein said conjugate is at a concentration of 10 mg/ml, said buffer is sodium acetate at a concentration of 10 mM, said tonicity modifier is sodium chloride at a concentration of 150 mM, said stabilizer is sodium octanoate at a concentration of 5 mM, said surfactant is pluronic F68 at a concentration of 0.1% (w/v), and wherein said formulation has a pH of about 5.0.
46 . The pharmaceutical formulation of claim 1 , wherein said conjugate is at a concentration of 10 mg/ml, said buffer is sodium phosphate at a concentration of 10 mM, said tonicity modifier is sodium chloride at a concentration of 135 mM, said stabilizer is sodium octanoate at a concentration of 8 mM, said surfactant is polysorbate 80 at a concentration of 15 mg/L, and wherein said formulation has a pH of about 7.0.
47 . A method of treating type II diabetes mellitus in a subject, comprising administering to a subject having type II diabetes mellitus a pharmaceutical formulation comprising: a conjugate of albumin and an insulinotropic peptide, said insulinotropic peptide comprising a sequence which has not more than 3 amino acid substitutions, deletions, or insertions relative to the native exendin-4 sequence, said conjugate being at a concentration of about 1 mg/ml to about 100 mg/ml; a buffer; a tonicity modifier; a stabilizer; and a surfactant, wherein said formulation has a pH from about 4 to about 8.
48 . A method of treating type II diabetes mellitus in a subject, comprising administering to a subject having type II diabetes mellitus the pharmaceutical formulation of claim 45 .
49 . A method of treating type II diabetes mellitus in a subject, comprising administering to a subject having type II diabetes mellitus the pharmaceutical formulation of claim 46 .
50 . The method of claim 48 , which comprises administering about 1.0 to 4.0 mg of the conjugate to the subject per week.
51 . The method of claim 48 , which comprises administering about 1.5 to 2.0 mg of the conjugate to the subject per week.
52 . The method of claim 48 , which comprises administering about 3.0 to 4.0 mg of the conjugate to the subject per week.
53 . The method of claim 48 , which comprises administering 1.5 mg of the conjugate to the subject once a week.
54 . The method of claim 48 , which comprises administering 2.0 mg of the conjugate to the subject once a week.
55 . The method of claim 48 , which comprises administering 3.0 mg of the conjugate to the subject once a week.
56 . The method of claim 48 , which comprises administering 1.5 mg of the conjugate to the subject twice a week.
57 . The method of claim 48 , comprising the following steps in the order stated:
(a) administering 1.5 mg of the conjugate to the subject once a week for a first duration of time; and
(b) administering 2.0 mg of the conjugate to the subject once a week for a second duration of time.
58 . The method of claim 57 , wherein the first duration of time is 4 weeks, and wherein the second duration of time is 8 weeks.
59 . The method of claim 48 , comprising the following steps in the order stated:
(a) administering 1.5 mg of the conjugate to the subject twice a week for a first duration of time; and
(b) administering 2.0 mg of the conjugate to the subject twice a week for a second duration of time.
60 . The method of claim 59 , wherein the first duration of time is 4 weeks.
61 . The method of claim 48 , comprising the following steps in the order stated:
(a) administering 1.5 mg of the conjugate to the subject once a week for a first duration of time;
(b) administering 2.0 mg of the conjugate to the subject once a week for a second duration of time; and
(c) administering 3.0 mg of the conjugate to the subject once a week for a third duration of time.
62 . The method of claim 61 , wherein the first duration of time is 4 weeks, and wherein the second duration of time is 4 weeks.
63 . The method of claim 61 , wherein the first duration of time is 2 weeks, and wherein the second duration of time is 2 weeks.
64 . A method of treating type II diabetes mellitus in a subject, comprising administering to a subject having type II diabetes mellitus a pharmaceutical formulation comprising an insulinotropic conjugated exendin-4 derivative, the derivative comprising recombinant human serum albumin cysteine 34 thiol covalently linked to a [2-[2-[2 maleimidopropionamido(ethoxy)ethoxy]acetic acid linker covalently linked to the epsilon amino of the carboxy terminal lysine of exendin-4(1-39)Lys 40 -NH 2 , wherein the subject is administered 1.5 mg of the conjugated exendin-4 derivative once a week.
65 . A method of treating type II diabetes mellitus in a subject, comprising administering to a subject having type II diabetes mellitus a pharmaceutical formulation comprising an insulinotropic conjugated exendin-4 derivative, the derivative comprising recombinant human serum albumin cysteine 34 thiol covalently linked to a [2-[2-[2 maleimidopropionamido(ethoxy)ethoxy]acetic acid linker covalently linked to the epsilon amino of the carboxy terminal lysine of exendin-4(1-39)Lys 40 -NH 2 , wherein the subject is administered 1.5 mg of the conjugated exendin-4 derivative twice a week.
66 . A method of treating type II diabetes mellitus in a subject, comprising administering to a subject having type II diabetes mellitus a pharmaceutical formulation comprising an insulinotropic conjugated exendin-4 derivative, the derivative comprising recombinant human serum albumin cysteine 34 thiol covalently linked to a [2-[2-[2 maleimidopropionamido(ethoxy)ethoxy]acetic acid linker covalently linked to the epsilon amino of the carboxy terminal lysine of exendin-4(1-39)Lys 40 -NH 2 , wherein the subject is administered 2.0 mg of the conjugated exendin-4 derivative once a week.
67 . A method of treating type II diabetes mellitus in a subject, comprising administering to a subject having type II diabetes mellitus a pharmaceutical formulation comprising an insulinotropic conjugated exendin-4 derivative, the derivative comprising recombinant human serum albumin cysteine 34 thiol covalently linked to a [2-[2-[2 maleimidopropionamido(ethoxy)ethoxy]acetic acid linker covalently linked to the epsilon amino of the carboxy terminal lysine of exendin-4(1-39)Lys 40 -NH 2 , wherein the subject is administered 2.0 mg of the conjugated exendin-4 derivative twice a week.
68 . A method of treating type II diabetes mellitus in a subject, comprising administering to a subject having type II diabetes mellitus a pharmaceutical formulation comprising an insulinotropic conjugated exendin-4 derivative, the derivative comprising recombinant human serum albumin cysteine 34 thiol covalently linked to a [2-[2-[2 maleimidopropionamido(ethoxy)ethoxy]acetic acid linker covalently linked to the epsilon amino of the carboxy terminal lysine of exendin-4(1-39)Lys 40 -NH 2 , wherein the subject is administered 3.0 mg of the conjugated exendin-4 derivative once a week.
69 . A method of treating type II diabetes mellitus in a subject, comprising administering to a subject having type II diabetes mellitus a pharmaceutical formulation comprising an insulinotropic conjugated exendin-4 derivative, the derivative comprising recombinant human serum albumin cysteine 34 thiol covalently linked to a [2-[2-[2 maleimidopropionamido(ethoxy)ethoxy]acetic acid linker covalently linked to the epsilon amino of the carboxy terminal lysine of exendin-4(1-39)Lys 40 -NH 2 , wherein the subject is administered 1.5 mg of the conjugated exendin-4 derivative once a week for 4 weeks followed by 2.0 mg of the conjugated exendin-4 derivative once a week.
70 . A method of treating type II diabetes mellitus in a subject, comprising administering to a subject having type II diabetes mellitus a pharmaceutical formulation comprising an insulinotropic conjugated exendin-4 derivative, the derivative comprising recombinant human serum albumin cysteine 34 thiol covalently linked to a [2-[2-[2 maleimidopropionamido(ethoxy)ethoxy]acetic acid linker covalently linked to the epsilon amino of the carboxy terminal lysine of exendin-4(1-39)Lys 40 -NH 2 , wherein the subject is administered 1.5 mg of the conjugated exendin-4 derivative twice a week for 4 weeks followed by 2.0 mg of the conjugated exendin-4 derivative once a week.
71 . A method of treating type II diabetes mellitus in a subject, comprising administering to a subject having type II diabetes mellitus a pharmaceutical formulation comprising an insulinotropic conjugated exendin-4 derivative, the derivative comprising recombinant human serum albumin cysteine 34 thiol covalently linked to a [2-[2-[2 maleimidopropionamido(ethoxy)ethoxy]acetic acid linker covalently linked to the epsilon amino of the carboxy terminal lysine of exendin-4(1-39)Lys 40 -NH 2 , wherein the subject is administered 1.5 mg of the conjugated exendin-4 derivative twice a week for 4 weeks followed by 2.0 mg of the conjugated exendin-4 derivative twice a week.
72 . A method of treating type II diabetes mellitus in a subject, comprising administering to a subject having type II diabetes mellitus a pharmaceutical formulation comprising an insulinotropic conjugated exendin-4 derivative, the derivative comprising recombinant human serum albumin cysteine 34 thiol covalently linked to a [2-[2-[2 maleimidopropionamido(ethoxy)ethoxy]acetic acid linker covalently linked to the epsilon amino of the carboxy terminal lysine of exendin-4(1-39)Lys 40 -NH 2 , wherein the subject is administered 1.5 mg of the conjugated exendin-4 derivative once a week for 4 weeks, followed by 2.0 mg of the conjugated exendin-4 derivative once a week for 4 weeks, followed by 3.0 mg of the conjugated exendin-4 derivative once a week.
73 . A method of treating type II diabetes mellitus in a subject, comprising administering to a subject having type II diabetes mellitus a pharmaceutical formulation comprising an insulinotropic conjugated exendin-4 derivative, the derivative comprising recombinant human serum albumin cysteine 34 thiol covalently linked to a [2-[2-[2 maleimidopropionamido(ethoxy)ethoxy]acetic acid linker covalently linked to the epsilon amino of the carboxy terminal lysine of exendin-4(1-39)Lys 40 -NH 2 , wherein the subject is administered 1.5 mg of the conjugated exendin-4 derivative once a week for 2 weeks, followed by 2.0 mg of the conjugated exendin-4 derivative once a week for 2 weeks, followed by 3.0 mg of the conjugated exendin-4 derivative once a week.
74 . A kit for the treatment of type II diabetes mellitus in a subject, comprising one or more containers comprising the pharmaceutical formulation of claim 1 .
75 . The kit of claim 74 , wherein said one or more containers each comprise a unit dosage form of the pharmaceutical formulation.
76 . The kit of claim 74 , wherein the pharmaceutical formulation is lyophilized.
77 . The kit of claim 74 , wherein the lyophilized pharmaceutical formulation is produced by lyophilizing in the presence of a non-reducing sugar.
78 . The kit of claim 74 , wherein the non-reducing sugar is sucrose or trehalose.
79 . The kit of claim 76 , further comprising one or more containers comprising a sterile diluent for reconstituting the lyophilized pharmaceutical formulation.
80 . The method of claim 47 , wherein the subject is on a stable dose of ≧1000 mg metformin daily for at least 3 months.
81 . A pharmaceutical formulation consisting of a conjugate of albumin and an insulinotropic peptide, said insulinotropic peptide comprising a sequence which has not more than 3 amino acid substitutions, deletions, or insertions relative to the native exendin-4 sequence, said conjugate being at a concentration of about 1 mg/ml to about 100 mg/ml; a buffer; a tonicity modifier; a stabilizer; and a surfactant, wherein said formulation has a pH has a pH from about 4.0 to about 8.0.
82 . A pharmaceutical formulation consisting of
(a) conjugate according to the following:
(SEQ ID NO: 33) wherein X is S of cysteine 34 of albumin, said conjugate being at a concentration of 10 mg/ml;
(b) a buffer, wherein said buffer is sodium acetate at a concentration of 10 mM;
(c) a tonicity modifier, wherein said tonicity modifier is sodium chloride at a concentration of 150 mM;
(d) a stabilizer, wherein said stabilizer is sodium octanoate at a concentration of 5 mM; and
(e) a surfactant, wherein said surfactant is pluronic F68 at a concentration of 0.1% (w/v),
wherein said formulation has a pH has a pH of about 5.0.
83 . A pharmaceutical formulation consisting of:
(a) conjugate according to the following:
(SEQ ID NO: 33) wherein X is S of cysteine 34 of albumin, said conjugate being at a concentration of 10 mg/ml;
(b) a buffer, wherein said buffer is sodium phosphate at a concentration of 10 mM;
(c) a tonicity modifier, wherein said tonicity modifier is sodium chloride at a concentration of 135 mM;
(d) a stabilizer, wherein said stabilizer is sodium octanoate at a concentration of 8 mM; and
(e) a surfactant, wherein said surfactant is polysorbate 80 at a concentration of 15 mg/L,
wherein said formulation has a pH of about 7.0.
84 . The method of any one of claims 47 , wherein the albumin is human serum albumin.
85 . The method of any one of claims 47 , wherein the subject is a human.