US2016108125A1PendingUtilityA1
Formulations with reduced oxidation
Est. expiryMar 13, 2033(~6.6 yrs left)· nominal 20-yr term from priority
C07K 2317/52G01N 33/6854C07K 16/241C07K 16/2878C07K 2317/55A61K 31/405A61K 39/39533C12Q 1/28A61K 2039/505A61K 39/39591
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Claims
Abstract
The invention provides formulations comprising a protein in combination with a compound that prevents oxidation of the protein. The invention also provides methods for making such formulations and methods of using such formulations. The invention further provides methods of screening for compounds that prevent oxidation of a protein in a protein composition and methods of preventing oxidation of a protein in a formulation.
Claims
exact text as granted — not AI-modified1 . A liquid formulation comprising a protein and a compound which prevents oxidation of the protein in the liquid formulation, wherein the compound is of formula:
wherein R 2 is selected from hydrogen, hydroxyl, —COOH, and —CH 2 COOH;
R 3 is selected from hydrogen, hydroxyl, —COOH, —CH 2 COOH, and —CH 2 CHR 3a (NH 2 ); wherein R 3a is COOH or hydrogen;
R 4 , R 5 , R 6 , and R 7 are independently selected from hydrogen and hydroxyl;
provided that one of R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is hydroxyl;
or a pharmaceutically acceptable salt thereof.
2 . The formulation of claim 1 , wherein the compound is a compound of formula:
wherein R 2 and R 3 are independently selected from hydrogen, hydroxyl, —COOH, and —CH 2 COOH; and
R 4 , R 5 , R 6 , and R 7 are independently selected from hydrogen and hydroxyl;
provided that one of R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is hydroxyl;
or a pharmaceutically acceptable salt thereof.
3 . The formulation of claim 1 , wherein the compound is a compound of formula:
wherein R 3a is COOH or hydrogen;
R 2 , R 4 , R 5 , R 6 , and R 7 are independently selected from hydrogen and hydroxyl, provided that one of R 2 , R 4 , R 5 , R 6 , and R 7 is hydroxyl;
or a pharmaceutically acceptable salt thereof.
4 . The formulation of claim 1 , wherein R 4 , R 5 or R 7 is hydroxyl.
5 . The formulation of claim 1 , wherein the compound is selected from the group consisting of 5-hydroxy-tryptophan, 5-hydroxy indole, 7-hydroxy indole, and serotonin.
6 . The formulation of claim 1 which is a pharmaceutical formulation suitable for administration to a subject.
7 . The formulation of claim 1 which is aqueous.
8 . The formulation of claim 1 , wherein the compound in the formulation is from about 0.3 mM to about 1 mM.
9 . The formulation of claim 1 , wherein the compound prevents oxidation of tryptophan, cysteine, histidine, tyrosine, and/or methionine in the protein.
10 . The formulation of claim 1 , wherein the compound prevents oxidation of the protein by a reactive oxygen species.
11 . The formulation of claim 10 , wherein the reactive oxygen species is selected from the group consisting of singlet oxygen, hydrogen peroxide, a hydroxyl radical, and an alkyl peroxide.
12 . The formulation of claim 1 , wherein the protein is susceptible to oxidation.
13 . The formulation of claim 1 , wherein tryptophan in the protein is susceptible to oxidation.
14 . The formulation of claim 1 , wherein the protein is an antibody.
15 . The formulation of claim 14 , wherein the antibody is a polyclonal antibody, a monoclonal antibody, a humanized antibody, a human antibody, a chimeric antibody, or antibody fragment.
16 . The formulation of claim 1 , wherein the protein concentration in the formulation is about 1 mg/mL to about 250 mg/mL.
17 . The formulation of claim 1 , which further comprises one or more excipients selected from the group consisting of a stabilizer, a buffer, a surfactant, and a tonicity agent.
18 . The formulation of claim 6 , wherein the formulation has a pH of about 4.5 to about 7.0.
19 . A method of making a protein formulation comprising adding an amount of a compound that prevents oxidation of a protein to the protein formulation, wherein the compound is of formula:
wherein R 2 is selected from hydrogen, hydroxyl, —COOH, and —CH 2 COOH;
R 3 is selected from hydrogen, hydroxyl, —COOH, —CH 2 COOH, and —CH 2 CHR 3a (NH 2 ); wherein R 3a is COOH or hydrogen;
R 4 , R 5 , R 6 , and R 7 are independently selected from hydrogen and hydroxyl;
provided that one of R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is hydroxyl;
or a pharmaceutically acceptable salt thereof.
20 . A method of preventing oxidation of a protein in a protein formulation comprising adding an amount of a compound that prevents oxidation of the protein to the formulation, wherein the compound is of formula:
wherein R 2 is selected from hydrogen, hydroxyl, —COOH, and —CH 2 COOH;
R 3 is selected from hydrogen, hydroxyl, —COOH, —CH 2 COOH, and —CH 2 CHR 3a (NH 2 ); wherein R 3a is COOH or hydrogen;
R 4 , R 5 , R 6 , and R 7 are independently selected from hydrogen and hydroxyl;
provided that one of R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is hydroxyl;
or a pharmaceutically acceptable salt thereof.
21 . The method of claim 19 , wherein the compound is a compound of formula:
wherein R 2 and R 3 are independently selected from hydrogen, hydroxyl, —COOH, and —CH 2 COOH; and
R 4 , R 5 , R 6 , and R 7 are independently selected from hydrogen and hydroxyl;
provided that one of R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is hydroxyl;
or a pharmaceutically acceptable salt thereof.
22 . The method of claim 19 , wherein the compound is a compound of formula:
wherein R 3a is COOH or hydrogen;
R 2 , R 4 , R 5 , R 6 , and R 7 are independently selected from hydrogen and hydroxyl, provided that one of R 2 , R 4 , R 5 , R 6 , and R 7 is hydroxyl;
or a pharmaceutically acceptable salt thereof.
23 . The method of claim 19 , wherein R 4 , R 5 or R 7 is hydroxyl.
24 . The method of claim 19 , wherein the compound is selected from the group consisting of 5-hydroxy-tryptophan, 5-hydroxy indole, 7-hydroxy indole, and serotonin.
25 . The method of claim 19 which is a pharmaceutical formulation suitable for administration to a subject.
26 . The method of claim 19 which is aqueous.
27 . The method of claim 19 , wherein the compound in the formulation is from about 0.3 mM to about 1 mM.
28 . The method of claim 19 , wherein the compound prevents oxidation of tryptophan, cysteine, histidine, tyrosine, and/or methionine in the protein.
29 . The method of claim 19 , wherein the compound prevents oxidation of the protein by a reactive oxygen species.
30 . The method of claim 29 , wherein the reactive oxygen species is selected from the group consisting of singlet oxygen, hydrogen peroxide, a hydroxyl radical, and an alkyl peroxide.
31 . The method of claim 19 , wherein the protein is susceptible to oxidation.
32 . The method of claim 19 , wherein tryptophan in the protein is susceptible to oxidation.
33 . The method of claim 19 , wherein the protein is an antibody.
34 . The method of claim 33 , wherein the antibody is a polyclonal antibody, a monoclonal antibody, a humanized antibody, a human antibody, a chimeric antibody, or antibody fragment.
35 . The method of claim 19 , wherein the protein concentration in the formulation is about 1 mg/mL to about 250 mg/mL.
36 . The method of claim 19 , wherein the formulation further comprises one or more excipients selected from the group consisting of a stabilizer, a buffer, a surfactant, and a tonicity agent.
37 . The method of claim 26 , wherein the formulation has a pH of about 4.5 to about 7.0.
38 . A method of screening a compound that prevents oxidation of a protein in a protein composition, comprising selecting a compound that has lower oxidation potential and less photosensitivity as compared to L-tryptophan, and testing the effect of the selected compound on preventing oxidation of the protein.
39 . The method of claim 38 , wherein the photosensitivity is measured based on the amount of H 2 O 2 produced by the compound upon light exposure.
40 . The method of claim 39 , wherein the compound that produces less than about 10% of the amount of H 2 O 2 produced by L-tryptophan is selected.
41 . The method of claim 38 , wherein the oxidation potential is measured by cyclic voltammetry.
42 . The method of claim 38 , wherein the selected compound is tested for the effect on preventing oxidation of the protein by reactive oxygen species generated by 2,2′-azobis(2-amidinopropane)dihydrochloride (AAPH), light, and/or a Fenton reagent.Join the waitlist — get patent alerts
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