AQUEOUS PHARMACEUTICAL COMPOSITION COMPRISING A P2Y12 RECEPTOR ANTAGONIST
The present invention relates to an aqueous pharmaceutical composition comprising the P2Y12 receptor antagonist 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester and a pharmaceutically acceptable buffer and its use as a medicament by parenteral administration.
1 . An aqueous pharmaceutical composition comprising:
4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester;
a pharmaceutically acceptable buffer; and
water;
wherein the aqueous pharmaceutical composition has a pH value between 8.2 and 12.0.
2 . An aqueous pharmaceutical composition according to claim 1 , wherein the sum of the amount of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester, of the amount of the pharmaceutically acceptable buffer and of the amount of water is at least 95 ww % of the aqueous pharmaceutical composition.
3 . An aqueous pharmaceutical composition according to claim 1 , consisting essentially of:
4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester in an amount between 0.7 to 7.0 ww %;
a pharmaceutically acceptable buffer selected from a boric acid buffer and an arginine buffer;
water; and
optionally an inorganic salt of an alkali metal or an alkaline earth metal;
wherein the aqueous pharmaceutical composition has a pH value between 8.7 and 9.5.
4 . An aqueous pharmaceutical composition according to claim 1 , wherein the mass concentration of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester in the aqueous pharmaceutical composition is between 6 mg/mL and 60 mg/mL.
5 . An aqueous pharmaceutical composition according to claim 1 , wherein the pharmaceutically acceptable buffer is selected from ammonium buffer, boric acid buffer, carbonate buffer, phosphate buffer, arginine buffer, glycine buffer, histidine buffer, meglumine buffer, and tris(hydroxymethyl)aminomethane buffer.
6 . An aqueous pharmaceutical composition according to claim 1 , wherein the aqueous pharmaceutical composition has a pH value between 8.7 and 9.5.
7 . An aqueous pharmaceutical composition according to claim 1 , wherein the aqueous pharmaceutical composition comprises sodium chloride.
8 . An aqueous pharmaceutical composition according to claim 1 , wherein the osmolality of the aqueous pharmaceutical composition is between 230 mOsm/kg and 1000 mOsm/kg.
9 . An aqueous pharmaceutical composition according to claim 1 , wherein the aqueous pharmaceutical composition is in a container and wherein the container is selected from a vial, an ampoule, a cartridge, and a syringe.
10 . An aqueous pharmaceutical composition according to claim 1 , wherein the amount of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester in the aqueous pharmaceutical composition after storage for 1 year at 25° C. is at least 80% of the amount of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester in the aqueous pharmaceutical composition immediately after final preparation of the aqueous pharmaceutical composition.
11 . A container comprising an aqueous pharmaceutical composition according to claim 1 , wherein the container is selected from a vial, an ampoule, a cartridge, and a syringe.
12 . A method for the preparation of a container according to claim 11 , wherein the aqueous pharmaceutical composition is filled in the container using aseptic processing.
13 . A method for prevention or treatment of a disease or disorder in a subject in need thereof, wherein the disease or disorder is selected from acute arterial thromboses and acute venous thromboses, wherein the method comprises administering to the subject a pharmaceutically active amount of a pharmaceutical composition according to claim 1 .
14 . A method for prevention or treatment of acute myocardial infarction in a subject in need thereof, wherein the method comprises administering to the subject a pharmaceutically active amount of a pharmaceutical composition according to claim 1 .
15 . A method for emergency treatment of suspected acute myocardial infarction by patient self-administration, wherein the method comprises patient self-administration of a pharmaceutically active amount of a pharmaceutical composition according to claim 1 prior to hospitalization.
16 . A method according to claim 14 , wherein the aqueous pharmaceutical composition is administered and/or is to be administered by subcutaneous administration.
17 . A method according to claim 15 , wherein the aqueous pharmaceutical composition is administered and/or is to be administered by subcutaneous administration.