LIQUID FORMULATION OF FSH
The present invention relates to a liquid pharmaceutical composition comprising a follicle stimulating hormone polypeptide and benzalkonium chloride and benzyl alcohol as preservatives. The composition further comprises optionally one or more other pharmaceutically acceptable excipients. In one embodiment, the composition contains methionine as an antioxidant. The composition shows a good storage stability and is especially useful for the prophylaxis and treatment of disorders and medical indications where follicle stimulating hormone preparations are considered as useful remedies.
1 . A liquid pharmaceutical composition comprising follicle-stimulating hormone (FSH) or a variant thereof, and both benzalkonium chloride and benzyl alcohol as preservatives.
2 . Liquid pharmaceutical composition according to claim 1 , wherein benzalkonium chloride is present in a concentration of 0.005-0.03 mg/ml and benzyl alcohol is present in a concentration of 5.0 to 12.0 mg/ml.
3 . Liquid pharmaceutical composition according to claim 1 , wherein FSH or a variant thereof is present in a concentration of 10 to 200 μg/ml.
4 . Liquid pharmaceutical composition according to claim 1 , further comprising methionine as an antioxidant.
5 . Liquid pharmaceutical composition according to claim 4 , wherein methionine is present in a concentration of 0.1 to 1.0 mg/ml.
6 . Liquid pharmaceutical composition according to claim 1 , further comprising a surfactant.
7 . Liquid pharmaceutical composition according to claim 6 , wherein the surfactant is a polyoxy ethylene sorbitan alkyl ester.
8 . Liquid pharmaceutical composition according to claim 7 , wherein the polyoxy ethylene sorbitan alkyl ester is Polysorbate 20 or Polysorbate 80.
9 . Liquid pharmaceutical composition according to claim 8 , wherein Polysorbate 20 or Polysorbate 80 is present in a concentration of 0.05 to 0.5 mg/ml.
10 . Liquid pharmaceutical composition according to claim 1 , further comprising a tonicity modifying agent.
11 . Liquid pharmaceutical composition according to claim 10 , wherein the tonicity modifying agent is sugar alcohol or sugar.
12 . Liquid pharmaceutical composition according to claim 11 , wherein the tonicity modifying agent is mannitol.
13 . Liquid pharmaceutical composition according to claim 12 , wherein mannitol is present in a concentration of 1.0 to 10 mg/ml.
14 . Liquid pharmaceutical composition according to claim 1 having a pH in the range of 6.5 to 7.5.
15 . Liquid pharmaceutical composition according to claim 14 , wherein the pH is in the range of 6.8 to 7.2.
16 . Liquid pharmaceutical composition according to claim 14 , wherein the pH is adjusted using NaOH.
17 . Liquid pharmaceutical composition according to claim 1 , further comprising a physiologically acceptable buffering agent.
18 . Liquid pharmaceutical composition according to claim 17 , wherein the buffering agent is phosphate.
19 . Liquid pharmaceutical composition according to claim 17 , wherein the buffering agent is present in a concentration of 10-100 mmol/l.
20 . Liquid pharmaceutical composition according to claim 1 , wherein the composition contains FSH or a variant thereof as active agent, Polysorbate 20 and/or Polysorbate 80 as surfactant, mannitol as tonicity modifier, phosphate as buffer, methionine as stabilising agent and benzyl alcohol and benzalkonium chloride as preservatives, and no further excipients.
21 . A pharmaceutical container containing a liquid pharmaceutical composition according to claim 1 .
22 . Pharmaceutical container according to claim 21 , wherein the container is a syringe, vial, infusion bottle, ampoule or carpoule.
23 . Pharmaceutical container according to claim 21 , wherein the container is a carpoule within an injection pen.
24 . Method for preparing a liquid pharmaceutical composition according to claim 1 , wherein FSH or a variant thereof as the active agent is formulated in an aqueous preparation comprising both benzalkonium chloride and benzyl alcohol as preservatives and further pharmaceutical excipients.
25 . Method for manufacturing a packaged pharmaceutical composition comprising placing a solution comprising FSH or a variant thereof, and benzalkonium chloride and benzyl alcohol in a vial, ampoule, carpoule or cartridge.
26 . Use of a liquid pharmaceutical composition according to claim 1 for multi-dose administration.