Lyophilized composition comprising (s)-isopropyl 2-((s)-2-acetamido-3-(1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate for intravenous administration and the use thereof
The present disclosure provides lyophilates comprising (S)-isopropyl 2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate: and pharmaceutical compositions, pharmaceutical formulations, and uses thereof.
1 . A lyophilate comprising(S)-isopropyl 2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate, a stabilizing agent, and a buffering agent, wherein the (S)-isopropyl 2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate/buffering agent weight ratio is about 6.5.
2 . The lyophilate of claim 1 , wherein the (S)-isopropyl 2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate/stabilizing agent weight ratio is about 0.67.
3 . The lyophilate of claim 1 , wherein the stabilizing agent is polyvinylpyrrolidone.
4 . The lyophilate of claim 1 , wherein buffering agent is L-histidine.
5 . The lyophilate of claim 1 comprising about 42 mg of (S)-isopropyl 2-((S) -2-acetamido-3-(1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate.
6 . The lyophilate of claim 3 comprising about 63 mg of polyvinylpyrrolidone.
7 . A pharmaceutical composition comprising (S)-isopropyl 2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate, a stabilizing agent, and a solvent comprising about 45% vol/vol to about 55% vol/vol ethanol and about 55% vol/vol to about 45% vol/vol water.
8 . The pharmaceutical composition of claim 7 , wherein the (S)-isopropyl 2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate concentration is about 10 mg/mL.
9 . A pharmaceutical formulation comprising the pharmaceutical composition of claim 7 and a diluent.
10 . The pharmaceutical formulation of claim 9 , wherein the (S)-isopropyl 2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate concentration is about 0.012 to about 0.24 mg/mL.
11 . A method for treating cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of the pharmaceutical formulation of claim 10 to the subject.
12 . The method of claim 11 , wherein the pharmaceutical formulation is administered intravenously to the subject.
13 . A method of making the lyophilate of claim 1 , the method comprising:
(i) dissolving (S)-isopropyl 2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate in a mixture of a stabilizing agent, a buffering agent, t-butanol, ethanol, and water at a temperature of about 25° C. to about 35° C. to give a pre-lyophilization solution;
(ii) cooling the pre-lyophilization solution until it is frozen or partially frozen; and
(iii) applying a vacuum to the frozen or partially frozen pre-lyophilization solution to give the lyophilate.
14 . The method of claim 13 , wherein the stabilizing agent comprises polyvinylpyrrolidone and the buffering agent comprises L-histidine.
15 . The method of claim 13 , wherein the concentration of (S)-isopropyl 2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate in the pre-lyophilization solution is about 10 mg/mL.
16 . A kit comprising the lyophilate of claim 1 packaged as single unit dose in a vial.
17 . The method of claim 11 , wherein the cancer is hepatocellular carcinoma, glioblastoma, lung cancer, breast cancer, head and neck cancer, prostate cancer, melanoma, or colorectal cancer.