Pharmaceutical Formulations of Follicle Stimulating Hormone(FSH)

PHARMACEUTICAL FORMULATIONS

Recombinant FSH preparations distinguish them-selves by their high purity (at least 97%) for example from urinary FSH preparations, which typically have a purity of less than 5%. Pure proteins are, however, relatively unstable and are generally lyophilized, unless some specific stabilizing measures can be taken. FSH preparations are available in different strengths and presentation forms, both as freeze-dried products (powder, cake, lyosphere) and as solution for injection (Table 1). Lyospheres are frozen drops of aqueous solution, which are freeze-dried in bulk and subsequently put in ampoules. Compared to the traditional freeze-dried cake formulation, lyospheres have the advantage of high dose uni-formity, less adsorption to the glass walls of the

ampoule, instantaneous dissolution, and in case of FSH, improved stability. Follitropin a was originally formulated with sucrose (bulking agent, lyoprotec-tant), sodium dihydrogen phosphate/disodium hydrogen phosphate, phosphoric acid and sodium hydroxide (for pH adjustment). In 2002, L-methio-nine (antioxidant) and polysorbate 20 (to prevent adsorption losses) were added to the single dose formulation. Follitropin b is formulated with sucrose, sodium citrate (stabilizer), polysorbate 20 (lyoprotectant and agent to prevent adsorption losses), and hydrochloride/sodium hydroxide (for pH adjustment). The lyophilized preparations are to be reconstituted before use to obtain a ready-for-use solution for injection. In addition to the freeze-dried presentation form, a solution for injection with several strengths of follitropin b could be developed. To stabilize the solutions 0.25 mg of L-methionine had to be added. Furthermore, the solution in the cartridge contains benzyl alcohol as preservative. For follitropin a multidose solution for injection in a pre-filled pen became available in 2004. This solution contains poloxamer 188 instead of polysorbate 20 and m-cresol has been added as preservativeThe lyophilized formulations are registered in strengths from 37.5 to 1050 IU. The dosage is not fixed, but is individually titrated based on ovarian response. For the convenience of both patient and healthcare worker a solution presentation has been developed. The Puregon/Follistim solution for injection is avail-able in vials and is very suitable for titration because of the large range of 50 to 250 IU of available strengths. A pen injector has been developed with multidose cartridges containing solution for injection, giving the patient optimal convenience.

The shelf-life of the freeze-dried recombinant FSH products is two years when stored in the containers in which they are supplied, at temperatures below 30LC, not frozen and protected from light. The solutions for injection should be stored in the refrigerator for a maximum of three years with the container kept in the outer carton to protect the solution from light. The patient can keep the solutions at room temperature for a maximum of three months. The multidose solution of follitropin has a shelf-life of two years and can be stored for one month at room temperature.