Fulvestrant formulations and methods of their use

Abstract

The disclosure is directed to fulvestrant formulations including suspensions of fulvestrant particles suitable for injection. The formulations can comprise fulvestrant particles having an LD Dv(10) less than about 3 microns, for example, between about 1 micron to about 3 microns, an LD Dv(50) less than about 35 microns, for example, between about 2 microns and about 35 microns, and an LD Dv(90) less than about 120 microns, for example, between about 4 microns and about 120 microns. The formulations can comprise fulvestrant particles having a CE Dv(90) less than about 200 microns, for example, between about 10 microns and about 200 microns, a CE Dv(50) less than about 60 microns, for example, between about 5 microns and about 60 microns, and a CE Dv(10) less than about 25 microns, for example, between about 1 micron and about 25 microns.

1 . A suspension comprising fulvestrant particles and a vehicle;
 wherein optionally the fulvestrant particles have
 an LD Dv(10) between about 1 micron to about 3 microns, preferably an LD Dv(10) of about 1-2 microns, 
 an LD Dv(50) between about 2 microns and about 35 microns, preferably an LD Dv(50) of about 2-4 microns, and 
 an LD Dv(90) between about 4 microns and about 120 microns, preferably an LD Dv(90) of about 6-9 microns, and; 
   wherein optionally the vehicle is a non-oil vehicle, preferably water or non-aqueous vehicle;   wherein optionally fulvestrant is at a concentration of about 100 mg/mL; and   wherein optionally the suspension is substantially oil-free.   
     
     
         2 . A suspension comprising fulvestrant and a vehicle,
 wherein the fulvestrant is at a concentration equal to or greater than about 50 mg/mL, preferably about 50 mg/mL or about 100 mg/mL;   wherein optionally the vehicle is a non-oil vehicle, preferably water or non-aqueous vehicle;   wherein optionally the suspension is substantially oil-free.   
     
     
         3 . A pharmaceutical composition comprising fulvestrant particles and a non-oil vehicle,
 wherein optionally the pharmaceutical composition further comprises at least one stabilizer selected from the group consisting of surfactants, polymers, cross-linked polymers, buffering agents, electrolytes, and non-electrolytes, preferably wherein the at least one stabilizer is a cross-linked polymer, preferably carboxymethylcellulose sodium, or the at least one stabilizer is selected from:
 the group of polyethylene oxide (PEO), a PEO derivative, polysorbate 80, polysorbate 20, poloxamer 188, poloxamer 124, poloxamer 407, polyethoxylated vegetable oils, polyethoxylated castor oil, sorbitan palmitate, lecithin, poly(vinyl alcohol), human serum albumin, and mixtures thereof, 
 the group consisting of polyvinylpyrrolidone, povidone K12, povidone K17, PLASDONE™ C-12 povidone, PLASDONE™ C-17 povidone, PLASDONE™ C-30 povidone, polyethylene glycol 3350, and mixtures thereof, 
 the group consisting of sodium chloride, calcium chloride, and mixtures thereof, or 
 the group consisting of dextrose, glycerol, mannitol, and mixtures thereof; 
   wherein optionally the pharmaceutical composition further comprises at least one buffering agent selected from the group consisting of NaH 2 PO 4 .H 2 O, NaH 2 PO 4 .2H 2 O, anhydrous NaH 2 PO 4 , sodium citrate, citric acid, Tris, sodium hydroxide, HCl, or a mixture thereof; and   wherein optionally the pharmaceutical composition further comprises solubilized fulvestrant.   
     
     
         4 . A pharmaceutical composition comprising fulvestrant particles,
 wherein the fulvestrant particles have one or more of:
 an LD Dv(10) between about 1 micron to about 3 microns, preferably between about 1 micron to about 2 microns or between about 2 microns and about 3 microns; 
 an LD Dv(50) between about 2 microns and about 35 microns, preferably between about 2 microns to about 6 microns, more preferably between about 2 microns and about 4 microns; and 
 an LD Dv(90) between about 4 microns and about 120 microns, preferably between about 7 microns to about 15 microns, more preferably between about 12 microns to about 14 microns or between about 9 microns to about 11 microns, or preferably between about 6 microns and about 9 microns, more preferably between about 6 microns and about 8 microns, most preferably between about 7 microns and about 8 microns; 
   wherein optionally the pharmaceutical composition is in the form of a suspension, preferably an aqueous suspension.   
     
     
         5 . A pharmaceutical composition comprising fulvestrant,
 wherein the fulvestrant is at a concentration of about 100 mg/mL and wherein upon administration to a subject, the 90% confidence intervals (CI) of the relative mean AUC (0-t)  and AUC (0-∞)  of fulvestrant of the pharmaceutical composition is within 80% to 125% of the relative mean AUC (0-t)  and AUC (0-∞) , respectively, of fulvestrant upon administration of a reference listed fulvestrant product, for example, FASLODEX™;   wherein optionally the reference listed fulvestrant product comprises fulvestrant at a concentration of about 50 mg/mL;   wherein optionally upon administration to a subject, the 90% confidence intervals (CI) of the relative mean Cmax of fulvestrant is within 40% to 80% of the relative mean Cmax of fulvestrant after administration of the reference listed fulvestrant product.   
     
     
         6 . A pharmaceutical composition comprising fulvestrant wherein the fulvestrant is at a concentration of about 100 mg/mL and wherein after an initial administration to a subject of the pharmaceutical composition comprising 500 mg fulvestrant on day 1 and an additional administration of the pharmaceutical composition comprising 500 mg fulvestrant on day 15 to the subject provides:
 an AUC in the range of 9,120-14,250 ng·hr/mL of fulvestrant;   
       wherein optionally the pharmaceutical composition is administered as a single injection of about 5 mL or administered as two injections of about 2.5 mL. 
     
     
         7 . A pharmaceutical composition comprising fulvestrant particles wherein the fulvestrant is at a concentration of about 40 to about 125 mg/mL. 
     
     
         8 . The pharmaceutical composition of  claim 7 ,
 wherein at least about 70% of the fulvestrant is present as fulvestrant particles, preferably at least about 80% of the fulvestrant is present as fulvestrant particles, more preferably at least about 90% of the fulvestrant is present as fulvestrant particles.   
     
     
         9 . The pharmaceutical composition of  claim 7 ,
 wherein no more than about 20% of the fulvestrant is solubilized, preferably no more than about 10% of the fulvestrant is solubilized, more preferably no more than about 5% of the fulvestrant is solubilized.   
     
     
         10 . The pharmaceutical composition of  claim 6 ,
 wherein the fulvestrant particles:
 have one or more of:
 an LD Dv(10) between about 1 micron to about 3 microns; 
 an LD Dv(50) between about 2 microns and about 35 microns; and 
 an LD Dv(90) between about 4 microns and about 120 microns; 
 
 have one or more of:
 an LD Dv(10) between about 1-2 microns; 
 an LD Dv(50) between about 2-4 microns; and 
 an LD Dv(90) between about 6-9 microns; 
 
 have an LD Dv(90) of about 12-14 microns; 
 have an LD Dv(90) of about 9-11 microns; 
 have an LD Dv(90) of about 6-9 microns; 
 have an LD Dv(90) of about 6-8 microns; or 
 have an LD Dv(90) of about 7-8 microns. 
   
     
     
         11 . A method of forming an aqueous fulvestrant suspension comprising:
 mixing an aqueous medium and at least one stabilizer to form a suspension vehicle, the at least one stabilizer preferably comprising one surfactant and one polymer or one surfactant and one non-electrolyte;   adding an amount of fulvestrant to the suspension vehicle; and   dispersing the fulvestrant in the suspension vehicle to form the aqueous fulvestrant suspension, preferably performed using high shear mixing;   optionally further comprising homogenizing the aqueous fulvestrant suspension, the homogenizing preferably performed using high pressure homogenization, preferably at a pressure of about 15,000 psi to about 45,000 psi, the method preferably further comprising adding an electrolyte to the homogenized aqueous fulvestrant suspension and mixing the electrolyte into the suspension or adding a non-electrolyte to the homogenized aqueous fulvestrant suspension and mixing the non-electrolyte into the suspension;   the method optionally further comprising concentrating the fulvestrant suspension by phase separating the suspension and removing a portion of the supernatant;   the method optionally further comprising drying the aqueous suspension to form a dried pharmaceutical composition, the method preferably further comprising sterilizing the dried pharmaceutical composition using gamma irradiation, the method more preferably further comprising reconstituting the dried pharmaceutical composition into a second aqueous suspension by adding at least one of water for injection (WFI), normal saline (NS), and 5% dextrose in water (D5W).   
     
     
         12 . An aqueous fulvestrant suspension prepared according to the method of  claim 11 . 
     
     
         13 . A pharmaceutical composition comprising the aqueous fulvestrant suspension of  claim 12 ,
 wherein optionally the pharmaceutical composition comprises fulvestrant particles:
 having one or more of:
 an LD Dv(10) between about 1 micron to about 3 microns; 
 an LD Dv(50) between about 2 microns and about 35 microns; and 
 an LD Dv(90) between about 4 microns and about 120 microns; 
 
 having one or more of:
 an LD Dv(10) between about 1-2 microns; 
 an LD Dv(90) between about 6-9 microns; and 
 an LD Dv(50) between about 2-4 microns; 
 
 having one or more of:
 a CE Dv(90) between about 10 microns and about 200 microns; 
 a CE Dv(50) between about 5 microns and about 60 microns; and 
 a CE Dv(10) between about 1 microns and about 25 microns; 
 
 having a CE Dv(90) between about 10 microns and about 200 microns; 
 having a CE Dv(50) between about 5 microns and about 60 microns; or 
 having a CE Dv(10) between about 1 microns and about 25 microns. 
   
     
     
         14 . An aqueous fulvestrant suspension comprising:
 an amount of fulvestrant, preferably about 500 mg, about 450 mg, about 400 mg, about 350 mg, about 300 mg, or about 250 mg;   about 0.2 mg/mL to about 75 mg/mL of one or more stabilizers; and   an amount of aqueous medium;   wherein upon administration of the aqueous fulvestrant suspension to a subject in a single intramuscular injection, the 90% confidence intervals (CI) of the relative mean AUC(0-t) and AUC(0-∞) of fulvestrant is within 80% to 125% of the relative mean AUC(0-t) and AUC(0-∞), respectively, of fulvestrant after administration of 500 mg of fulvestrant in the form of FASLODEX™ administered intramuscularly as two 5 mL injections;   wherein optionally the suspension has a volume of about 3.0 to about 5.0 mL, preferably about 3.5 to about 4.5 mL, more preferably about 4.0 mL.   
     
     
         15 . The aqueous fulvestrant suspension of  claim 14 ,
 wherein the one or more stabilizers:
 is selected from the group consisting of surfactants, polymers, cross-linked polymers, buffering agents, electrolytes, and non-electrolytes, 
 is selected from the group consisting of polyethylene oxide (PEO), a PEO derivative, polysorbate 80, polysorbate 20, poloxamer 188, poloxamer 124, poloxamer 407, polyethoxylated vegetable oils, polyethoxylated castor oil, sorbitan palmitate, lecithin, poly(vinyl alcohol), human serum albumin, and mixtures thereof, 
 is selected from the group consisting of polyvinylpyrrolidone, povidone K12, povidone K17, PLASDONE™ C-12 povidone, PLASDONE™ C-17 povidone, PLASDONE™ C-30 povidone, polyethylene glycol 3350, and mixtures thereof, 
 is selected from the group consisting of sodium chloride, calcium chloride, and mixtures thereof, or 
 is selected from the group consisting of dextrose, glycerol, mannitol, and mixtures thereof. 
   
     
     
         16 . The aqueous fulvestrant suspension of  claim 14 , wherein the one or more stabilizers comprises a cross-linked polymer, preferably carboxymethylcellulose sodium. 
     
     
         17 . The aqueous fulvestrant suspension of  claim 14 , further comprising at least one buffering agent selected from the group consisting of NaH 2 PO 4 .H 2 O, NaH 2 PO 4 .2H 2 O, anhydrous NaH 2 PO 4 , sodium citrate, citric acid, Tris, sodium hydroxide, HCl, or mixtures thereof. 
     
     
         18 . The aqueous fulvestrant suspension of  claim 14 ,
 wherein the fulvestrant particles:
 have one or more of:
 an LD Dv(10) between about 1 micron to about 3 microns; 
 an LD Dv(50) between about 2 microns and about 35 microns; and 
 an LD Dv(90) between about 4 microns and about 120 microns; or 
 
 have one or more of:
 an LD Dv(10) between about 1-2 microns; 
 an LD Dv(50) between about 2-4 microns; and 
 an LD Dv(90) between about 6-9 microns. 
 
   
     
     
         19 . The aqueous fulvestrant suspension of  claim 14 ,
 wherein the fulvestrant particles:
 have one or more of:
 a CE Dv(10) between about 4-10 microns, 
 a CE Dv(50) between about 10-35 microns, and 
 a CE Dv(90) between about 35-110 microns; 
 
 have one or more of:
 a CE Dv(10) between about 4-8 microns, 
 a CE Dv(50) between about 10-25 microns, and 
 a CE Dv(90) between about 25-60 microns; or 
 
 have one or more of:
 a CE Dv(10) between about 4-8 microns, 
 a CE Dv(50) between about 10-20 microns, and 
 a CE Dv(90) between about 20-35 microns. 
 
   
     
     
         20 . The aqueous fulvestrant suspension of  claim 14 ,
 wherein:
 the suspension comprises about 56 mg/mL to about 59 mg/mL of one or more stabilizers; and 
 the one or more stabilizers comprises:
 about 1.0 mg/mL to about 4.0 mg/mL of one or more polyvinylpyrrolidones; 
 about 5.0 mg/mL of polysorbate 80; and 
 about 50 mg/mL of mannitol; or 
 
   wherein:
 the suspension comprises about 56.6 mg/mL to about 57.4 mg/mL of one or more stabilizers; and 
 the one or more stabilizers comprises:
 about 1.6 mg/mL to about 2.4 mg/mL of one or more polyvinylpyrrolidones; 
 about 5.0 mg/mL of polysorbate 80; and 
 about 50 mg/mL of mannitol; or 
 
   wherein the suspension comprises:
 about 1.6 mg/mL to about 2.4 mg/mL of PLASDONE™ C-12 povidone, povidone K12, or a combination thereof; 
 about 5.0 mg/mL of polysorbate 80; and 
 about 50 mg/mL of mannitol; or 
   wherein the suspension comprises:
 about 100 mg/mL fulvestrant; 
 about 1.6 mg/mL of PLASDONE™ C-12 povidone, povidone K12, or a combination thereof; 
 about 5.0 mg/mL of polysorbate 80; and 
 about 50 mg/mL of mannitol; or 
   wherein the suspension comprises:
 about 100 mg/mL fulvestrant; 
 about 2.4 mg/mL of PLASDONE™ C-12 povidone, povidone K12, or a combination thereof; 
 about 5.0 mg/mL of polysorbate 80; and 
 about 50 mg/mL of mannitol. 
   
     
     
         21 . The pharmaceutical composition of  claim 6 ,
 wherein after the initial administration the additional administration provides:
 both a C max  in the range of 10.04-12.55 ng/mL of fulvestrant and an AUC in the range of 9,120-14,250 ng·hr/mL of fulvestrant; 
 both a C max  in the range of 12.55-15.06 ng/mL of fulvestrant and an AUC in the range of 9,120-14,250 ng·hr/mL of fulvestrant; 
 both a C max  in the range of 15.06-17.57 ng/mL of fulvestrant and an AUC in the range of 9,120-14,250 ng·hr/mL of fulvestrant; 
 both a C max  in the range of 17.57-20.08 ng/mL of fulvestrant and an AUC in the range of 9,120-14,250 ng·hr/mL of fulvestrant; 
 both a C max  in the range of 10.04-11.295 ng/mL of fulvestrant and an AUC in the range of 9,120-14,250 ng·hr/mL of fulvestrant; 
 both a C max  in the range of 11.295-12.55 ng/mL of fulvestrant and an AUC in the range of 9,120-14,250 ng·hr/mL of fulvestrant; 
 both a C max  in the range of 12.55-13.805 ng/mL of fulvestrant and an AUC in the range of 9,120-14,250 ng·hr/mL of fulvestrant; 
 both a C max  in the range of 13.805-15.06 ng/mL of fulvestrant and an AUC in the range of 9,120-14,250 ng·hr/mL of fulvestrant; 
 both a C max  in the range of 15.06-16.315 ng/mL of fulvestrant and an AUC in the range of 9,120-14,250 ng·hr/mL of fulvestrant; 
 both a C max  in the range of 16.315-17.57 ng/mL of fulvestrant and an AUC in the range of 9,120-14,250 ng·hr/mL of fulvestrant; 
 both a C max  in the range of 17.57-18.825 ng/mL of fulvestrant and an AUC in the range of 9,120-14,250 ng·hr/mL of fulvestrant; 
 both a C max  in the range of 18.825-20.08 ng/mL of fulvestrant and an AUC in the range of 9,120-14,250 ng·hr/mL of fulvestrant; 
 both a C max  in the range of 15.06-18.825 ng/mL of fulvestrant and an AUC in the range of 9,120-14,250 ng·hr/mL of fulvestrant; 
 both a C max  in the range of 12.55-18.825 ng/mL of fulvestrant and an AUC in the range of 9,120-14,250 ng·hr/mL of fulvestrant; or 
 both a C max  in the range of 10.04-15.06 ng/mL of fulvestrant and an AUC in the range of 9,120-14,250 ng·hr/mL of fulvestrant. 
   
     
     
         22 . The pharmaceutical composition of  claim 3 , wherein the fulvestrant particles:
 have one or more of:
 a CE Dv(90) between about 35 microns and about 110 microns; 
 a CE Dv(50) between about 10 microns and about 35 microns; and 
 a CE Dv(10) between about 4 microns and about 10 microns; 
   have one or more of:
 a CE Dv(90) between about 25 microns and about 60 microns; 
 a CE Dv(50) between about 10 microns and about 25 microns; and 
 a CE Dv(10) between about 4 microns and about 8 microns; 
   have one or more of:
 a CE Dv(90) between about 20 microns and about 35 microns; 
 a CE Dv(50) between about 10 microns and about 20 microns; and 
 a CE Dv(10) between about 4 microns and about 8 microns; 
   have one or more of:
 a CE Dv(90) between about 30 microns and about 100 microns; 
 a CE Dv(50) between about 10 microns and about 50 microns; and 
 a CE Dv(10) between about 4 microns and about 10 microns; 
   have one or more of:
 a CE Dv(90) between about 50 microns and about 100 microns; 
 a CE Dv(50) between about 20 microns and about 50 microns; and 
 a CE Dv(10) between about 6 microns and about 8 microns; 
   have one or more of:
 a CE Dv(90) between about 50 microns and about 75 microns; 
 a CE Dv(50) between about 30 microns and about 40 microns; and 
 a CE Dv(10) between about 8 microns and about 10 microns; 
   have one or more of:
 a CE Dv(90) between about 20 microns and about 60 microns; 
 a CE Dv(50) between about 9 microns and about 20 microns; and 
 a CE Dv(10) between about 3 microns and about 7 microns; 
   have one or more of:
 a CE Dv(90) between about 20 microns and about 50 microns; 
 a CE Dv(50) between about 9 microns and about 20 microns; and 
 a CE Dv(10) between about 3 microns and about 7 microns; 
   have one or more of:
 a CE Dv(90) between about 20 microns and about 45 microns; 
 a CE Dv(50) between about 9 microns and about 20 microns; and 
 a CE Dv(10) between about 3 microns and about 7 microns; 
   have one or more of:
 a CE Dv(90) between about 20 microns and about 40 microns; 
 a CE Dv(50) between about 9 microns and about 15 microns; and 
 a CE Dv(10) between about 3 microns and about 7 microns; 
   have one or more of:
 a CE Dv(90) between about 20 microns and about 35 microns; 
 a CE Dv(50) between about 9 microns and about 15 microns; and 
 a CE Dv(10) between about 3 microns and about 7 microns; 
   have one or more of:
 a CE Dv(90) between about 20 microns and about 45 microns; 
 a CE Dv(50) between about 9 microns and about 15 microns; and 
 a CE Dv(10) between about 3 microns and about 7 microns; 
   have a CE Dv(90) between about 10 microns and about 200 microns;   have a CE Dv(50) between about 5 microns and about 60 microns;   have a CE Dv(10) between about 1 microns and about 25 microns;   have one or more of:
 a CE Dv(90) between about 10 microns and about 200 microns; 
 a CE Dv(50) between about 5 microns and about 60 microns; and 
 a CE Dv(10) between about 1 microns and about 25 microns; 
   have one or more of:
 a CE Dv(90) between about 10 microns and about 200 microns; and 
 a CE Dv(50) between about 5 microns and about 60 microns; 
   have one or more of:
 a CE Dv(50) between about 5 microns and about 60 microns; and 
 a CE Dv(10) between about 1 microns and about 25 microns; or 
   have one or more of:
 a CE Dv(90) between about 10 microns and about 200 microns; and 
 a CE Dv(10) between about 1 microns and about 25 microns. 
   
     
     
         23 . The aqueous fulvestrant suspension of  claim 14 ,
 wherein:
 upon administration of the aqueous fulvestrant suspension to a subject in a single intramuscular injection, the 90% confidence intervals (CI) of the relative mean Cmax of fulvestrant is within 40% to 80% of the relative mean Cmax of fulvestrant after administration of 500 mg of fulvestrant in the form of FASLODEX™ administered intramuscularly as two 5 mL injections; 
 upon administration of the aqueous fulvestrant suspension to a subject in a single intramuscular injection, the 90% confidence intervals (CI) of the relative mean Cmax of fulvestrant is within 60% to 80% of the relative mean Cmax of fulvestrant after administration of 500 mg of fulvestrant in the form of FASLODEX™ administered intramuscularly as two 5 mL injections; 
 upon administration of the aqueous fulvestrant suspension to a subject in a single intramuscular injection, the 90% confidence intervals (CI) of the relative mean Cmax of fulvestrant is within 50% to 75% of the relative mean Cmax of fulvestrant after administration of 500 mg of fulvestrant in the form of FASLODEX™ administered intramuscularly as two 5 mL injections; 
 upon administration of the aqueous fulvestrant suspension to a subject in a single intramuscular injection, the 90% confidence intervals (CI) of the relative mean Cmax of fulvestrant is within 40% to 50% of the relative mean Cmax of fulvestrant after administration of 500 mg of fulvestrant in the form of FASLODEX™ administered intramuscularly as two 5 mL injections; 
 upon administration of the aqueous fulvestrant suspension to a subject in a single intramuscular injection, the 90% confidence intervals (CI) of the relative mean Cmax of fulvestrant is within 50% to 60% of the relative mean Cmax of fulvestrant after administration of 500 mg of fulvestrant in the form of FASLODEX™ administered intramuscularly as two 5 mL injections; 
 upon administration of the aqueous fulvestrant suspension to a subject in a single intramuscular injection, the 90% confidence intervals (CI) of the relative mean Cmax of fulvestrant is within 60% to 70% of the relative mean Cmax of fulvestrant after administration of 500 mg of fulvestrant in the form of FASLODEX™ administered intramuscularly as two 5 mL injections; 
 upon administration of the aqueous fulvestrant suspension to a subject in a single intramuscular injection, the 90% confidence intervals (CI) of the relative mean Cmax of fulvestrant is within 70% to 80% of the relative mean Cmax of fulvestrant after administration of 500 mg of fulvestrant in the form of FASLODEX™ administered intramuscularly as two 5 mL injections; or 
 upon administration of the aqueous fulvestrant suspension to a subject in a single intramuscular injection, the 90% confidence intervals (CI) of the relative mean Cmax of fulvestrant is within 70% to 80% of the relative mean Cmax of fulvestrant after administration of 500 mg of fulvestrant in the form of FASLODEX™ administered intramuscularly as two 5 mL injections. 
   
     
     
         24 . A method of treating a subject having breast cancer, comprising administering to the subject
 the suspension of  claim 1 ;   wherein optionally the suspension, pharmaceutical composition, or aqueous fulvestrant suspension comprises about 50 mg/mL or about 100 mg/mL fulvestrant;   wherein optionally the suspension, pharmaceutical composition, or aqueous fulvestrant suspension is administered in combination with one or more additional therapeutic agents, preferably palbociclib.   
     
     
         25 . The method of  claim 24 , wherein the breast cancer is hormone receptor (HR)-positive breast cancer. 
     
     
         26 . The method of  claim 24 , wherein the subject is a post-menopausal human woman with disease progression following antiestrogen therapy. 
     
     
         27 . The method of  claim 24 , wherein the breast cancer is HR-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. 
     
     
         28 . The method of  claim 24 , wherein the subject is a human woman with disease progression after endocrine therapy.