Fulvestrant Injection for intramuscular administration is an estrogen receptor antagonist without known agonist effects and is marketed by Astra-Zeneca under trade name Faslodex®. The chemical name is 7-alpha-[9-(4,4,5,5,5-penta fluoropentylsulphinyl) nonyl]estra-1,3,5-(10)-triene-3,17-beta-diol. The molecular formula is C32H47F5O3S and its structural formula is:

Fulvestrant is a white powder with a molecular weight of 606.77. The solution for injection (as currently marketed) is a clear, colorless to yellow, viscous liquid. Each injection of the currently marketed FASLODEX contains as inactive ingredients: Alcohol, USP; Benzyl Alcohol, NF; and Benzyl Benzoate, USP, as co-solvents; and Castor Oil, USP as a co-solvent and release rate modifier. Its manufacture and general use are disclosed in U.S. Pat. No. 4,659,516, which is incorporated herein by reference in its entirety.
FASLODEX is supplied in sterile single patient pre-filled syringes containing 50 mg/ml fulvestrant either as a single 5 ml or two concurrent 2.5 ml injections to deliver the required monthly dose. Fulvestrant is currently labeled in the currently marketed FASLODEX product to be administered as an intramuscular injection of 250 mg once monthly.
A formulation of fulvestrant for intramuscular injection is disclosed in U.S. Pat. No. 6,774,122, which is incorporated herein by reference in its entirety. The formulation claimed in that patent is a fulvestrant solution in a ricinoleate vehicle that additionally has at least one alcohol and a non-aqueous solvent which is miscible with the ricinoleate vehicle. The currently marketed FASLODEX injection product contains, in addition to the fulvestrant; alcohol USP; benzyl alcohol; benzyl benzoate; and castor oil. Castor oil administration by injection has been associated with potential side effects. In fulvestrant formulations having castor oil, injection site irritation is one of the most common side effects. Ricinoleate (the major component of castor oil) is an intestinal secretogogue. Zinc ricinoleate has been found to be a sensitizer in deodorants in which it has been incorporated. Sodium ricinoleate has been found to have membrane disruptive effects. Type IV dermal sensitization response in those previously sensitized to ricinoleate have been attributed to ricinoleate administration. U.S. Pat. No. 5,462,726 is directed to a method of reducing, inhibiting, or treating the unwanted side effects of castor oil in a solvent in a drug formulation by administering a thromboxane A2 receptor antagonist. Thus, it is clear that the art recognizes there are concerns about administering castor oil and castor oil derivatives as pharmaceutical excipients, especially by injection or transdermal routes. And, while these side effects may have to be accepted when there is no other material which is suitable for administering a drug in an appropriate manner, the search for a suitable alternative without these side effects, or lesser degree of these side effects, continues, and the discovery of such an appropriate alternative would meet a long felt unmet need in the art.
In addition, there has been increasing interest in administration of fulvestrant at doses in excess of the currently labeled amounts, up to and including as much as 1 gram per month. To do so with current formulations, would currently require considerably larger volumes than could be injected intramuscularly at any one time (5 ml being about the most possible), use of multiple injection sites, or administration at multiple times throughout the month. Ideally, one would like to administer the full desired dose at one time and at one injection site. With the currently marketed fulvestrant products, this is currently impossible. Thus the search for injectable formulations of fulvestrant that can deliver more than 250 mg in less than 5 ml of formulation is a sought after end in the art.
USPTO Backgrounds
USPTO Backgrounds