METHODS FOR MAKING AND USING ENDOXIFEN
The present disclosure provides industrially scalable methods of making (Z)-endoxifen or a salt thereof, crystalline forms of endoxifin, and compositions comprising them. The present disclosure also provides methods for treating hormone-dependent breast and hormone-dependent reproductive tract disorders.
1 . A method of treating ovarian cancer in a subject in need thereof, the method comprising administering to the subject in need thereof a composition comprising a compound of Formula (III):
or a pharmaceutically acceptable salt thereof,
thereby treating the ovarian cancer in the subject in need thereof.
2 . The method of claim 1 , wherein the compound of Formula (III) is no more than 3 wt % (E)-endoxifen or a pharmaceutically acceptable salt thereof.
3 . The method of claim 1 , wherein the compound of Formula (III) is at least 90 wt % (Z)-endoxifen.
4 . The method of claim 1 , wherein the pharmaceutically acceptable salt is selected from arecoline, besylate, bicarbonate, bitartarate, butylbromide, citrate, camysylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, mandelate, mesylate, methylbromide, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamaoate (Embonate), pantothenate, phosphate/diphosphate, polygalacuronate, salicylate, stearate, sulfate, tannate, Teoclate, triethiodide, benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc.
5 . The method of claim 1 , wherein the pharmaceutically acceptable salt of the compound of Formula (III) is a gluconate salt, a citrate salt, or a hydrochloride salt.
6 . The method of claim 3 , wherein the (Z)-endoxifen is in a crystalline form which is Form I characterized by an x-ray powder diffraction pattern comprising major peaks at 16.8±0.3°, 17.1±0.3° and 21.8±0.3° two theta.
7 . The method of claim 6 , wherein the x-ray powder diffraction pattern further comprises at least one peak selected from 16.0±0.3°, 18.8±0.3° and 26.5±0.3° two theta.
8 . The method of claim 1 , wherein the composition comprises less than 2% total impurities.
9 . The method of claim 1 , wherein the composition has one or more of the following properties:
an aerobic bacterial plate count of not more than 20,000 g/mL;
a water content of not more than 1.0% as tested by Method Ic of USP 921;
a water activity (Aw) of less than 0.9;
a residue on ignition of not more than 0.1% as tested by a method of USP 281;
a heavy metal content of not more than 20 ppm as tested by Method II of USP 231; and
a methanol content of not more than 3000 ppm, a tetrahydrofuran content of not more than 720 ppm, an isopropanol content of not more than 5000 ppm, an ethyl acetate content of not more than 5000 ppm, a n-heptane content of not more than 5000 ppm, and an ethanol content of not more than 5000 ppm, as tested by a validated HPLC method.
10 . The method of claim 1 , wherein the composition further comprises one or more pharmaceutically acceptable excipients.
11 . The method of claim 10 , wherein the one or more pharmaceutically acceptable excipients is a binder, a filler, a disintegrating agent, a lubricant, a glidant, a control release agent, an enteric coating agent, a film forming agent, a plasticizer, a sweetening agent, a flavoring agent, or a combination thereof.
12 . The method of claim 1 , wherein the composition is a modified-released composition.
13 . The method of claim 1 , wherein the composition is a delayed-released composition.
14 . The method of claim 1 , wherein the composition is formulated for oral delivery as a solid dosage form.
15 . The method of claim 1 , wherein the composition is formulated for oral delivery as a tablet, a caplet, a capsule, or a pill.
16 . The method of claim 1 , wherein the composition is formulated for oral delivery as an enteric tablet, an enteric caplet, an enteric capsule, a delayed-release tablet, a delayed-release caplet or a delayed-release capsule.
17 . The method of claim 1 , wherein the composition comprises from 0.01 mg to 200 mg of (Z)-endoxifen.
18 . The method of claim 1 , wherein the composition comprises from 1 mg to 50 mg of (Z)-endoxifen.
19 . The method of claim 1 , wherein the composition comprises 1 mg, 2 mg, 4 mg, 5 mg, 6 mg, 10 mg, 20 mg, or 40 mg of (Z)-endoxifen.
20 . The method of claim 1 , wherein the composition is administered once a day, twice a day, thrice a day, four times a day, every other day, twice a week, weekly, fortnightly, twice a month, monthly, quarterly, once every six months, or annually.
21 . The method of claim 1 , the composition is administered daily to the subject in need thereof.
22 . The method of claim 1 , wherein the subject in need thereof is tamoxifen-refractory or tamoxifen resistant.
23 . The method of claim 1 , wherein the subject in need thereof has one or more CYP2D6, CYP3A4, or CYP2C9 mutations.