WO2011085303A1

WO2011085303A1 - Method for hormone ablative therapy induced osteoporosis

Info

Publication number: WO2011085303A1
Application number: PCT/US2011/020667
Authority: WO
Inventors: Mitchell S. Steiner
Original assignee: Gtx, Inc.
Priority date: 2010-01-11
Filing date: 2011-01-10
Publication date: 2011-07-14

Abstract

This invention relates to treatment, reducing the incidence, inhibition, suppression, prevention of hormone ablation therapy induced bone related disorders such as osteoporosis, osteopenia, increased bone resorption, bone fracture, bone frailty, loss of bone mineral density (BMD), or any combination thereof in women suffering from breast cancer by administering about 120 mg of toremifene citrate.

Description

METHOD FOR HORMONE ABLATIVE THERAPY INDUCED

OSTEOPOROSIS

FIELD OF THE INVENTION

[001] This invention relates to treatment, reducing the incidence, inhibition, suppression, prevention of hormone ablation therapy induced bone related disorders such as osteoporosis, osteopenia, increased bone resorption, bone fracture, bone frailty, loss of bone mineral density (BMD), or any combination thereof in women suffering from breast cancer by administering about 120 mg of toremifene citrate.

BACKGROUND OF THE INVENTION

[002] Breast cancer is one of the most common types of cancer among women in the United States. Each year in the United States, more than 192,000 women are diagnosed with breast cancer. These numbers indicate that breast cancer is one of the most dangerous diseases facing women today. Currently, a woman diagnosed with breast cancer may be treated with surgery, hormone therapy, chemotherapy, and radiation. If the patient develops metastatic disease, radiation and high dose chemotherapy are required to ablate the cancer in remote areas such as the brain, bone, and liver.

[003] Hormone ablative therapy with aromatase inhibitors is the standard treatment for women with estrogen receptor-positive breast cancer, both as adjuvant therapy and in the treatment of advanced disease. Estrogen receptor-positive (or hormone sensitive) breast cancer cells can be stimulated to grow by the hormone estradiol, its precursors or metabolites. Aromatase inhibitors block estrogen production by the body. FDA-approved aromatase inhibitors include anastrozole, exemestane, and letrozole.

[004] Different types of hormone therapy work in different ways by: a) Blocking estrogen receptors in cancer cells (e.g., selective estrogen receptor modulators [SERMs] such as tamoxifen); b) Suppressing estrogen production in the body (Aromatase inhibitors); c) Destroying ovaries, which produce estrogen (Ovarian ablation or chemotherapy).

[005] Hormone ablative therapy (i.e., treatments that stop the production of specific hormones) used for breast cancer stop the body from producing estrogens and increase the risk of fractures due to bone loss. Women treated for breast cancer develop estrogen deficiency induced by aromatase inhibitors or chemotherapy and thereby experience an increase in bone turnover, accelerated bone loss, and increased risk of fracture. The estrogen deficiency leads to bone loss because bone formation is unable to keep pace with osteoclastic bone resorption. Chemotherapy-induced early menopause also causes rapid bone loss and may increase the risk of osteoporosis later in life.

[006] Osteoporosis is a bone disease which is characterized by a decrease in bone mass and by impaired structural integrity of trabecular and/or cortical bone. Osteoporosis is often called the "silent disease" because the loss of bone can occur without symptoms. The diagnosis can be confirmed by the finding of low bone mass, evidence of fracture on x-ray, a history of osteoporotic fracture, or vertebral (spinal) fracture typically indicated by height loss or kyphosis. Although hip fractures are not as numerous as fractures of the wrist or spine, they are by far the most serious consequence of osteoporosis.

[007] The increased fracture risk associated with chemotherapy, hormone therapy and hormone ablative therapy is an increasingly important problem for women diagnosed with breast cancer. Given that more women suffering from breast cancer today are being treated by hormone ablative therapy, osteoporosis has become a clinically important side effect. Loss of bone mineral density (BMD) occurs in the majority of patients being treated by hormone ablative therapy. New innovative approaches are urgently needed at both the basic science and clinical levels to decrease the incidence of hormone ablative therapy induced osteoporosis in women suffering from breast cancer.

SUMMARY OF THE INVENTION

[008] In one embodiment this invention provides a method for treating bone-related disorders associated with hormone ablative therapy in a female subject suffering from breast cancer, said method comprising the step of administering to said subject about 80 mg of toremifene.

[009] In one embodiment this invention provides a method for treating bone-related disorders associated with hormone ablative therapy in a female subject suffering from breast cancer, said method comprising the step of administering to said subject about 120 mg of toremifene citrate.

[0010] In one embodiment this invention provides a method for treating bone-related disorders associated with hormone ablative therapy in a female subject suffering from breast cancer, said method comprising the step of administering to said subject about 80 mg of toremifene or its isomer, pharmaceutically acceptable salt, ester, or N-oxide, and mixtures thereof.

[0011] In one embodiment this invention provides a method for preventing, suppressing or inhibiting bone-related disorders associated with hormone ablative therapy in a female subject suffering from breast cancer, said method comprising the step of administering to said subject about 80 mg of toremifene or its isomer, pharmaceutically acceptable salt, ester, or N-oxide, and mixtures thereof.

[0012] In one embodiment this invention is provides a method for preventing, suppressing or inhibiting bone-related disorders associated with hormone ablative therapy in a female subject suffering from breast cancer, said method comprising the step of administering to said subject about 120 mg of toremifene citrate.

[0013] In one embodiment this invention provides a method for treating and/or preventing, suppressing, or inhibiting bone-related disorders associated with hormone ablative therapy in a female subject suffering from breast cancer by administering about 80 mg of toremifene or its isomer, pharmaceutically acceptable salt, ester, or N-oxide, and mixtures thereof. In another embodiment by administering toremifene citrate.

[0014] In another embodiment, the bone related disorder is osteoporosis, osteopenia, increased bone resorption, bone fracture, bone frailty, loss of bone mineral density (BMD), or any combination thereof.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0015] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present invention.

[0016] This invention provides: 1) A method for treating bone-related disorders associated with hormone ablative therapy in a female subject suffering from breast cancer; 2) A method for treating osteoporosis associated with hormone ablative therapy in a female subject suffering from breast cancer; 3) A method for treating osteopenia associated with hormone ablative therapy in a female subject suffering from breast cancer; 4) A method for treating increased bone resorption associated with hormone ablative therapy in a female subject suffering from breast cancer; 5) A method for treating bone fracture associated with hormone ablative therapy in a female subject suffering from breast cancer; 6) A method for treating bone frailty associated with hormone ablative therapy in a female subject suffering from breast cancer; 7) A method for treating loss of bone mineral density (BMD) associated with hormone ablative therapy in a female subject suffering from breast cancer; by administering to the subject toremifene citrate, toremifene or its isomer, pharmaceutically acceptable salt, ester, orN-oxide, and mixtures thereof.

[0017] This invention provides: 1) A method for preventing, suppressing or inhibiting bone- related disorders associated with hormone ablative therapy in a female subject suffering from breast cancer; 2) A method for preventing, suppressing or inhibiting osteoporosis associated with hormone ablative therapy in a female subject suffering from breast cancer; 3) A method for preventing, suppressing or inhibiting osteopenia associated with hormone ablative therapy in a female subject suffering from breast cancer; 4) A method for preventing, suppressing or inhibiting increased bone resorption associated with hormone ablative therapy in a female subject suffering from breast cancer; 5) A method for preventing, suppressing or inhibiting bone fracture associated with hormone ablative therapy in a female subject suffering from breast cancer; 6) A method for preventing, suppressing or inhibiting bone frailty associated with hormone ablative therapy in a female subject suffering from breast cancer; 7) A method for preventing, suppressing or inhibiting loss of bone mineral density (BMD) associated with hormone ablative therapy in a female subject suffering from breast cancer; by administering to the subject toremifene citrate, toremifene or its isomer, pharmaceutically acceptable salt, ester, orN-oxide, and mixtures thereof.

[0018] In one embodiment toremifene or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof, treats, prevents, suppresses, inhibits or reduces the risk of developing bone related disorders associated with hormone ablative therapy, such as osteoporosis and/or loss of BMD and/or osteopenia and/or increased bone resorption and/or bone fracture and/or bone frailty and/or loss of bone mineral density (BMD).

[0019] In one embodiment toremifene citrate treats, prevents, suppresses, inhibits or reduces the risk of developing bone related disorders associated with hormone ablative therapy induced, such as osteoporosis and/or loss of BMD and/or osteopenia and/or increased bone resorption and/or bone fracture and/or bone frailty and/or loss of bone mineral density (BMD).

[0020] In one embodiment, this invention provides a method for treating bone related disorders associated with hormone ablative therapy in a female subject suffering from breast cancer, said method comprising the step of administering to said subject toremifene or its isomer, pharmaceutically acceptable salt, ester, or N-oxide, and mixtures thereof. In another embodiment, the method comprises the step of administering to said subject toremifene citrate. In another embodiment, the method comprises the step of administering to said subject a dosage of about 80 mg per day of toremifene or its isomer, pharmaceutically acceptable salt, ester, or N-oxide, and mixtures thereof. In another embodiment, the method comprises the step of administering to said subject a dosage of about 80 mg per day of toremifene. In another embodiment, the method comprises the step of administering to said subject a dosage of about 120 mg per day of toremifene citrate.

[0021] In one embodiment, this invention provides a method for preventing, suppressing or inhibiting bone related disorders associated with hormone ablative therapy in a female subject suffering from breast cancer, said method comprising the step of administering to said subject toremifene or its isomer, pharmaceutically acceptable salt, ester, orN-oxide, and mixtures thereof. In another embodiment, the method comprises the step of administering to said subject toremifene citrate. In another embodiment, the method comprises the step of administering to said subject a dosage of about 80 mg per day of toremifene or its isomer, pharmaceutically acceptable salt, ester, or N-oxide, and mixtures thereof. In another embodiment, the method comprises the step of administering to said subject a dosage of about 80 mg per day of toremifene. In another embodiment, the method comprises the step of administering to said subject a dosage of about 120 mg per day of toremifene citrate.

[0022] In one embodiment, the methods of this invention are directed to treating, preventing, suppressing, inhibiting or reducing the risk of developing bone related disorders associated with hormone ablative therapy in a female subject suffering from breast cancer. In another embodiment, the female subject is a mammalian subject. In another embodiment, the female subject is a human subject. In another embodiment, the female is a postmenopausal woman. In another embodiment, the female is a premenopausal woman.

[0023]The present invention provides a safe and effective method for treating, preventing, suppressing, inhibiting or reducing the risk of developing osteoporosis and/or loss of BMD associated with hormone ablative therapy and is particularly useful for treating female subjects suffering from breast cancer having an elevated risk of developing osteoporosis and/or loss of BMD. In one embodiment, the female subject is a mammalian subject. In another embodiment, the female subject is a human subject.

[0024] Furthermore, toremifene or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof presented herein are effective at treating, suppressing or inhibiting osteopenia accompanied by bone loss that is associated with hormone ablative therapy. "Osteopenia" refers to decreased calcification or density of bone and subjects with bone mineral density (BMD) or T scores between -1 and -2.5 as determined by dual energy x-ray absorptiometry (DXA). This is a term which encompasses all skeletal systems in which such a condition is noted.

[0025] Osteoporosis is a systemic skeletal disease, characterized by low bone mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. In osteoporotic patients, bone strength is abnormal, with a resulting increase in the risk of fracture. Subjects with bone mineral density (BMD) or T scores lower than -2.5 as determined by dual energy x-ray absorptiometry (DXA) are considered to have osteoporsis. Osteoporosis depletes both the calcium and the protein collagen normally found in the bone, resulting in either abnormal bone quality or decreased bone density. Bones that are affected by osteoporosis can fracture with only a minor fall or injury that normally would not cause a bone fracture. The fracture can be either in the form of cracking (as in a hip fracture) or collapsing (as in a compression fracture of the spine). The spine, hips, and wrists are common areas of osteoporosis bone fractures, although fractures can also occur in other skeletal areas.

[0026]BMD is a measured calculation of the true mass of bone. The absolute amount of bone as measured by bone mineral density (BMD) generally correlates with bone strength and its ability to bear weight. By measuring BMD, it is possible to predict fracture risk in the same manner that measuring blood pressure can help predict the risk of stroke.

[0027] BMD in one embodiment can be measured by known bone-mineral content mapping techniques. Bone density of the hip, spine, wrist, or calcaneus may be measured by a variety of techniques. The preferred method of BMD measurement is dual-energy x-ray densitometry (DXA). BMD of the hip, antero-posterior (AP) spine, lateral spine, and wrist can be measured using this technology. Measurement at any site predicts overall risk of fracture, but information from a specific site is the best predictor of fracture at that site. Quantitative computerized tomography (QCT) is also used to measure BMD of the spine. See for example, "Nuclear Medicine: "Quantitative Procedures", by Wahner H W, Dunn W L, Thorsen H C, et al, published by Toronto Little, Brown & Co., 1983, (see pages 107-132). An article entitled "Assessment of Bone Mineral Part 1 " appeared in the Journal of Nuclear Medicine, pp 1134-1141, (1984). Another article entitled "Bone Mineral Density of The Radius" appeared in Vol. 26, No. 11, (1985) Nov. Journal of Nuclear Medicine at pp 13-39. Abstracts on the use of gamma cameras for bone- mineral content measurements are (a) S. Hoory et al, Radiology, Vol. 157(P), p. 87 (1985), and (b) C. R. Wilson et al, Radiology, Vol. 157(P), p. 88 (1985). [0028] In one embodiment, hormone ablative therapy is used in women suffering from breast cancer to prevent hormones from stimulating breast cancer cells. This may be done in a number of ways such as (a) blocking the function of hormones; which can be done with drugs; (b) suppressing the production of hormones outside of the ovary by other tissues; done with drugs; and (c) suppressing hormone production in the ovaries, which is called ovarian ablation; which can be done with drugs, radiation, or with surgery. The drugs which are known for hormone therapy include selective estrogen receptor modulators (SERMs); aromatase inhibitors, estrogen receptor down-regulators, luteinizing hormone-releasing hormone (LHRH) agonists or other hormonal agents, including androgens.

[0029] Aromatase inhibitors work by inhibiting the conversion of androgens into estrogens. Aromatase inhibitors block the action of aromatase, making less estrogen available to stimulate estrogen receptors on cancer cells. Aromatase inhibitors block aromatase, an enzyme that is a major source of estrogen in many major body tissues, including the breast, muscle, liver, and fat. Aromatase inhibitors work differently than tamoxifen. Tamoxifen interferes with the ability of tumors to use estrogen by blocking the interaction of estrogen with estrogen receptors. Aromatase inhibitors reduce the overall amount of estrogen in the body by inhibiting one enzyme that is responsible for estrogen biosynthesis. The following aromatase inhibitors are approved for treating early-stage, hormone receptor-positive breast cancer in postmenopausal women: Anastrazole (Armidex) for treatment after surgery; Exemestane (Aromasin) for women who have taken tamoxifen for 2 - 3 years, and Letrozole (Femara) for treatment after surgery or for women who have completed 5 years of tamoxifen therapy. The primary side effect of aromatase inhibitors is an increased risk of osteoporosis (including bone thinning and hip fractures see: as PMID: 19833206 /. Steroid. Biochem. Mol. Biol. 2009 Oct 13. [Epub ahead of print]) and /. Clin. Endocrinol. Metab. 2003 Aug;88(8):3785-93 which are incorporated herein by reference. Drugs that inhibit steroid or estrogen production at early stages in hormone biosynthesis (e.g., lyase inhibitors like abiraterone acetate) may also lead to bone related disorders associated with hormone ablative therapy.

[0030] Ovarian ablation is a treatment that stops estrogen production from the ovaries. Medications can accomplish ovarian ablation. Destroying the ovaries with surgery or radiation can also shut down estrogen production wherein osteoporosis is one serious side effect of this approach. Drug treatment to block ovarian production of estrogen is called chemical ovarian ablation. It is often reversible. The primary drugs used are luteinizing hormone-releasing hormone (LHRH) agonists, such as goserelin (Zoladex). (They are also sometimes called GnRH agonists). These drugs block the release of the reproductive hormones LH-RH, therefore stopping ovulation and estrogen production.

[0031] As contemplated herein, the present invention relates to the use of toremifene compound and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or combinations thereof for treating, preventing, suppressing, inhibiting or reducing the risk of developing hormone ablative therapy induced bone related disorders such as is osteoporosis, osteopenia, increased bone resorption, bone fracture, bone frailty, loss of bone mineral density (BMD), or any combination thereof. Thus, in one embodiment, the methods of the present invention comprise administering an analog of toremifene. In another embodiment, the methods of the present invention comprise administering a derivative of toremifene. In another embodiment, the methods of the present invention comprise administering an isomer of toremifene. In another embodiment, the methods of the present invention comprise administering a metabolite of toremifene. In another embodiment, the methods of the present invention comprise administering a pharmaceutically acceptable salt of toremifene. In another embodiment, the methods of the present invention comprise administering a pharmaceutical product of toremifene. In another embodiment, the methods of the present invention comprise administering a hydrate of toremifene. In another embodiment, the methods of the present invention comprise administering an N-oxide of toremifene. In another embodiment, the methods of the present invention comprise administering toremifene citrate.

[0032]Toremifene is described in US. Patent Nos. 4,696,949 and 5,491 , 173 to Toivola et al., the disclosures of which are incorporated herein by reference. The parenteral and topical administration to mammalian subjects of formulations containing Toremifene is described in U.S. Patent No. 5,571 ,534 to Jalonen et al. and in U.S. Patent No. 5,605,700 to DeGregorio et al., the disclosures of which are incorporated herein by reference.

[0033]As defined herein, the term "isomer" includes, but is not limited to, stereoisomers isomers, optical isomers, structural isomers, conformational isomers, and the like. It is to be understood that the present invention encompasses any optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, which form possesses properties useful in the treatment of hormone ablative therapy induced bone related disorders described herein. In another embodiment, the toremifene is an (E) isomer. In another embodiment, the toremifene is a (Z) isomer. In another embodiment, the toremifene is a mixture of (E) and (Z) isomers. In another embodiment, the different isomers (E) or (Z) can be prepared by crystallization. U.S. Pat. No. 4,696,949 describes separation of the E or Z isomers of toremifene analogs or their salts by crystallization from solvents such as hexane-ethanol (95:5), toluene-petroleum ether (1 : 1) and toluene. US 4,696,949 and US 7,368,607 include processes for isolating pure isomers of toremifene, which are incorporated herein by reference.

[0034] The invention includes "pharmaceutically acceptable salts" of toremifene with organic and inorganic acids, for example, citric acid, hydrochloric acid, lactic acid, acetic acid, formic acid or methanesulfonic acid. In another embodiment, the "pharmaceutically acceptable salt" of toremifene is toremifene citrate. In another embodiment the salt is toremifene acetate. In another embodiment the salt is toremifene chloride. In another embodiment the salt is toremifene formate. In another embodiment the salt is toremifene mesylate.

[0035] The invention also includes N-oxides of the amino substituents of the compounds described herein.

[0036] This invention further includes derivatives of toremifene. The term "derivatives" includes but is not limited to ether derivatives, acid derivatives, amide derivatives, ester derivatives and the like.

[0037] In addition, this invention further includes hydrates of toremifene compounds. The term "hydrate" includes but is not limited to hemihydrate, monohydrate, dihydrate, trihydrate and the like.

[0038] This invention further includes metabolites of toremifene compounds. The term "metabolite" means any substance produced from another substance by metabolism or a metabolic process. N-desmethyltoremifene (4-chloro-l ,2-diphenyl-[4-[2-(N- methylamino)ethoxy-]phenyl]-l -butene), didesmethyltoremifene ((£^')-2-(4-(4-chloro-l ,2- diphenylbut- 1 -enyl)phenoxy)ethanamine), (deaminohydroxy)toremifene, 4- hydroxytoremifene (4-chloro- 1 -(4-hydroxyphenyl)-2-phenyl- 1 - [4- [2-(N,N- dimethylamino)ethoxy]phenyl] - 1 -butene) , and 4-hydroxy-N-desmethyltoremifene.

[0039] This invention further includes pharmaceutical products of toremifene. The term "pharmaceutical product" means a composition suitable for pharmaceutical use (pharmaceutical composition), as defined herein.

[0040] In one embodiment the dosages used in the subject invention are about 80 mg of toremifene. In one embodiment, the dosages used in the subject invention are about about 120 mg of toremifene citrate. The term "about" refers to a deviance of between 1 -5 % from the indicated number or range of numbers. In one embodiment, the term "about", refers to a deviance of between 1 -10 % from the indicated number or range of numbers. In one embodiment, the term "about", refers to a deviance of up to 25 % from the indicated number or range of numbers.

Pharmaceutical Compositions

[0041] In one embodiment, the methods of the present invention comprise administering a pharmaceutical composition comprising toremifene and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof; and a pharmaceutically acceptable carrier. The pharmaceutical composition is administered to a female subject suffering from breast cancer; for treating, preventing, suppressing, inhibiting and/or reducing the risk of developing bone related disorders such as osteoporosis, osteopenia, increased bone resorption, bone fracture, bone frailty, loss of bone mineral density (BMD), or any combination thereof associated with hormone ablation therapy.

[0042] As used herein, "pharmaceutical composition" means a "therapeutically effective amount" of the active ingredient, i.e. toremifene, together with a pharmaceutically acceptable carrier or diluent. A "therapeutically effective amount" as used herein refers to that amount which provides a therapeutic effect for a given condition and administration regimen.

[0043]The pharmaceutical compositions containing toremifene can be administered to a subject by any method known to a person skilled in the art, such as orally, parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intraperitoneally, intraventricularly, intracranially, intravaginally or intratumorally.

[0044] In one embodiment, the methods of this invention provide administering a pharmaceutical compositions containing toremifene and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof, wherein said administering comprises intravenously, intraarterially, or intramuscularly injecting to said subject said pharmaceutical composition in liquid form; subcutaneously implanting in said subject a pellet containing said pharmaceutical composition; orally administering to said subject said pharmaceutical composition in a liquid or solid form; or topically applying to the skin surface of said subject said pharmaceutical composition. [0045]In one embodiment, the pharmaceutical compositions are administered orally, and are thus formulated in a form suitable for oral administration, i.e. as a solid or a liquid preparation. Suitable solid oral formulations include tablets, capsules, pills, granules, pellets and the like. Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, oils and the like. In one embodiment of the present invention, toremifene are formulated in a capsule. In accordance with this embodiment, the compositions of the present invention comprise, in addition to toremifene and the inert carrier or diluent, a hard gelatin capsule.

[0046] Further, in another embodiment, the pharmaceutical compositions are administered by intravenous, intraarterial, or intramuscular injection of a liquid preparation. Suitable liquid formulations include solutions, suspensions, dispersions, emulsions, oils and the like. In one embodiment, the pharmaceutical compositions are administered intravenously, and are thus formulated in a form suitable for intravenous administration. In another embodiment, the pharmaceutical compositions are administered intraarterially, and are thus formulated in a form suitable for intraarterial administration. In another embodiment, the pharmaceutical compositions are administered intramuscularly, and are thus formulated in a form suitable for intramuscular administration.

[0047] Further, in another embodiment, the pharmaceutical compositions are administered topically to body surfaces, and are thus formulated in a form suitable for topical administration. Suitable topical formulations include gels, ointments, creams, lotions, drops and the like. For topical administration, toremifene or its physiologically tolerated derivatives such as salts, esters, N-oxides, and the like are prepared and applied as solutions, suspensions, or emulsions in a physiologically acceptable diluent with or without a pharmaceutical carrier.

[0048] Further, in another embodiment, the pharmaceutical compositions are administered as a suppository, for example a rectal suppository or a urethral suppository. Further, in another embodiment, the pharmaceutical compositions are administered by subcutaneous implantation of a pellet. In a further embodiment, the pellet provides for controlled release of toremifene over a period of time.

[0049] In another embodiment, the active compound can be delivered in a vesicle, in particular a liposome (see Langer, Science 249: 1527-1533 (1990); Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez- Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid). [0050]As used herein "pharmaceutically acceptable carriers or diluents" are well known to those skilled in the art. The carrier or diluent may be a solid carrier or diluent for solid formulations, a liquid carrier or diluent for liquid formulations, or mixtures thereof.

[0051] Solid carriers/diluents include, but are not limited to, a gum, a starch (e.g. corn starch, pregeletanized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g. microcrystalline cellulose), an acrylate (e.g. polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof.

[0052] For liquid formulations, pharmaceutically acceptable carriers may be aqueous or nonaqueous solutions, suspensions, emulsions or oils. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Examples of oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, and fish- liver oil.

[0053] Parenteral vehicles (for subcutaneous, intravenous, intraarterial, or intramuscular injection) include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like. Examples are sterile liquids such as water and oils, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants. In general, water, saline, aqueous dextrose and related sugar solutions, and glycols such as propylene glycols or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions. Examples of oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, and fish-liver oil.

[0054]In addition, the compositions may further comprise binders (e.g. acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), disintegrating agents (e.g. cornstarch, potato starch, alginic acid, silicon dioxide, croscarmelose sodium, crospovidone, guar gum, sodium starch glycolate), buffers (e.g., Tris-HCL, acetate, phosphate) of various pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g. sodium lauryl sulfate), permeation enhancers, solubilizing agents (e.g., glycerol, polyethylene glycerol), antioxidants (e.g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole), stabilizers (e.g. hydroxypropyl cellulose, hyroxypropylmethyl cellulose), viscosity increasing agents (e.g. carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum), sweeteners (e.g. aspartame, citric acid), preservatives (e.g., Thimerosal, benzyl alcohol, parabens), lubricants (e.g. stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow-aids (e.g. colloidal silicon dioxide), plasticizers (e.g. diethyl phthalate, triethyl citrate), emulsifiers (e.g. carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coatings (e.g., poloxamers or poloxamines), coating and film forming agents (e.g. ethyl cellulose, acrylates, polymethacrylates) and/or adjuvants.

[0055]In one embodiment, the pharmaceutical compositions provided herein are controlled- release compositions, i.e. compositions in which the toremifene of this invention is released over a period of time after administration. Controlled- or sustained-release compositions include formulation in lipophilic depots (e.g. fatty acids, waxes, oils). In another embodiment, the composition is an immediate-release composition, i.e. a composition in which toremifene is released immediately after administration.

[0056] In yet another embodiment, the pharmaceutical composition can be delivered in a controlled release system. For example, the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In one embodiment, a pump may be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321 :574 (1989). In another embodiment, polymeric materials can be used. In yet another embodiment, a controlled release system can be placed in proximity to the therapeutic target, i.e., the brain, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984). Other controlled-release systems are discussed in the review by Langer (Science 249: 1527-1533 (1990).

[0057]The compositions may also include incorporation of the active material into or onto particulate preparations of polymeric compounds such as polylactic acid, polglycolic acid, hydrogels, etc, or onto liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts. Such compositions will influence the physical state, solubility, stability, rate of in vivo release, and rate of in vivo clearance.

[0058] Also comprehended by the invention are particulate compositions coated with polymers (e.g. poloxamers or poloxamines) and the compound coupled to antibodies directed against tissue-specific receptors, ligands or antigens or coupled to ligands of tissue-specific receptors.

[0059] Also comprehended by the invention are compounds modified by the covalent attachment of water-soluble polymers such as polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone or polyproline. The modified compounds are known to exhibit substantially longer half-lives in blood following intravenous injection than do the corresponding unmodified compounds (Abuchowski et al., 1981 ; Newmark et al., 1982; and Katre et al., 1987). Such modifications may also increase the compound's solubility in aqueous solution, eliminate aggregation, enhance the physical and chemical stability of the compound, and greatly reduce the immunogenicity and reactivity of the compound. As a result, the desired in vivo biological activity may be achieved by the administration of such polymer-compound abducts less frequently or in lower doses than with the unmodified compound.

[0060] The preparation of pharmaceutical compositions which contain an active component is well understood in the art, for example by mixing, granulating, or tablet-forming processes. The active therapeutic ingredient is often mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient. For oral administration, toremifene of this invention or its physiologically tolerated derivatives such as salts, esters, N-oxides, and the like are mixed with additives customary for this purpose, such as vehicles, stabilizers, or inert diluents, and converted by customary methods into suitable forms for administration, such as tablets, coated tablets, hard or soft gelatin capsules, aqueous, alcoholic or oily solutions. For parenteral administration, toremifene or its physiologically tolerated derivatives such as salts, esters, N-oxides, and the like are converted into a solution, suspension, or emulsion, if desired with the substances customary and suitable for this purpose, for example, solubilizers or other.

[0061] An active component can be formulated into the composition as neutralized pharmaceutically acceptable salt forms. Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the polypeptide or antibody molecule), which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, citric and the like. Salts formed from the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.

[0062]For use in medicine, the salts of toremifene are pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, lactic acid, acetic acid, formic acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. In another embodiment a pharmaceutically active salt of toremifene is toremifene citrate.

[0063]As defined herein, "contacting" means that toremifene of this invention is introduced into a sample containing the enzyme in a test tube, flask, tissue culture, chip, array, plate, microplate, capillary, or the like, and incubated at a temperature and time sufficient to permit binding of the toremifene of this invention to the enzyme. Methods for contacting the samples with toremifene or other specific binding components are known to those skilled in the art and may be selected depending on the type of assay protocol to be run. Incubation methods are also standard and are known to those skilled in the art.

[0064] In another embodiment, the term "contacting" means that the toremifene of the present invention is introduced into a subject receiving treatment, and the toremifene compound is allowed to interact with the estrogen receptor in vivo.

[0065]As used herein, the term "treating" includes preventative as well as disorder remitative treatment. As used herein, the terms "reducing", "suppressing" and "inhibiting" have their commonly understood meaning of lessening or decreasing. As used herein, the term "progression" means increasing in scope or severity, advancing, growing or becoming worse. As used herein, the term "recurrence" means the return of a disease after a remission.

[0066]As used herein, the term "administering" refers to bringing a subject in contact with toremifene of the present invention. As used herein, administration can be accomplished in vitro, i.e. in a test tube, or in vivo, i.e. in cells or tissues of living organisms, for example humans. In one embodiment, the present invention encompasses administering the compounds of the present invention to a subject. [0067] In one embodiment, the methods of the present invention comprise administering toremifene as the sole active ingredient. However, also encompassed within the scope of the present invention are methods for delaying the progression of hormone ablative therapy induced bone related disorder in a female subject suffering from breast cancer, and for preventing and/or treating the recurrence of hormone ablative therapy induced bone related disorder in a female subject suffering from breast cancer, which comprise administering toremifene of this invention in combination with one or more therapeutic agents. These agents include, but are not limited to: LHRH analogs, reversible antiandrogens (such as bicalutamide or flutamide), additional anti-estrogens, anticancer drugs, aromatase inhibitors, progestins, selective androgen receptor modulators (SARMS), or agents acting through other nuclear hormone receptors.

[0068] Thus, in one embodiment, the methods of the present invention include using compositions and pharmaceutical compositions comprising toremifene of this invention, in combination with an LHRH analog. In another embodiment, the methods of the present invention include using compositions and pharmaceutical compositions comprising toremifene of this invention, in combination with a reversible antiandrogen. In another embodiment, the methods of the present invention include using compositions and pharmaceutical compositions comprising toremifene of this invention, in combination with an additional anti-estrogen. In another embodiment, the methods of the present invention include using compositions and pharmaceutical compositions comprising toremifene of this invention, in combination with an anticancer drug. In another embodiment, the methods of the present invention include using compositions and pharmaceutical compositions comprising toremifene of this invention, in combination with an aromatase inhibitor. In another embodiment, the methods of the present invention include using compositions and pharmaceutical compositions comprising toremifene of this invention, in combination with a progestin. In another embodiment, the methods of the present invention include using compositions and pharmaceutical compositions comprising toremifene of this invention, in combination with a SARM. In another embodiment, the methods of the present invention include using compositions and pharmaceutical compositions comprising toremifene of this invention, in combination with an agent acting through other nuclear hormone receptors.

[0069] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.

Claims

CLAIMS What is claimed is:

1. A method for treating bone related disorders associated with hormone ablative therapy in a female subject suffering from breast cancer, said method comprising the step of administering to said subject about 80 mg of toremifene or its isomer, pharmaceutically acceptable salt, ester, or N-oxide, and mixtures thereof.

2. A method for treating bone related disorders associated with hormone ablative therapy in a female subject suffering from breast cancer, said method comprising the step of administering to said subject about 120 mg of toremifene citrate..

3. The method of claims 1 or 2 wherein said female is a postmenopausal or premenopausal woman.

4. The method of claims 1 or 2 wherein said bone related disorders consist of osteoporosis, osteopenia, increased bone resorption, bone fracture, bone frailty, loss of bone mineral density (BMD), or any combination thereof.

5. The method of claims 1 or 2, wherein said administering comprises administering a pharmaceutical composition comprising said toremifene citrate, toremifene or its isomer, pharmaceutically acceptable salt, ester, or N-oxide, or any combination thereof; and a pharmaceutically acceptable carrier.

6. The method of claim 5, wherein said administering comprises intravenously, intraarterially, or intramuscularly injecting to said subject said pharmaceutical composition in liquid form; subcutaneously implanting in said subject a pellet containing said pharmaceutical composition; orally administering to said subject said pharmaceutical composition in a liquid or solid form; or topically applying to the skin surface of said subject said pharmaceutical composition.

7. The method according to claim 6 wherein said pharmaceutical composition is a pellet, a tablet, a capsule, a solution, a suspension, an emulsion, an elixir, a gel, a cream, a suppository or a parenteral formulation

8. A method for preventing, suppressing or inhibiting bone related disorders associated with hormone ablative therapy in a female subject suffering from breast cancer, said method comprising the step of administering to said subject about 80 mg of toremifene or its isomer, pharmaceutically acceptable salt, ester, or N-oxide, and mixtures thereof.

9. A method for preventing, suppressing or inhibiting bone related disorders associated with hormone ablative therapy in a female subject suffering from breast cancer, said method comprising the step of administering to said subject about 120 mg of toremifene citrate.

10. The method of claims 8 or 9 wherein said female is a postmenopausal or premenopausal woman.

11. The method of claims 8 or 9 wherein said bone related disorders consist of osteoporosis, osteopenia, increased bone resorption, bone fracture, bone frailty, loss of bone mineral density (BMD), or any combination thereof.

12. The method of claims 8 or 9 wherein said administering comprises administering a pharmaceutical composition comprising said toremifene or its isomer, pharmaceutically acceptable salt, ester, or N-oxide, or any combination thereof; and a pharmaceutically acceptable carrier.

13. The method of claim 12, wherein said administering comprises intravenously, intraarterially, or intramuscularly injecting to said subject said pharmaceutical composition in liquid form; subcutaneously implanting in said subject a pellet containing said pharmaceutical composition; orally administering to said subject said pharmaceutical composition in a liquid or solid form; or topically applying to the skin surface of said subject said pharmaceutical composition.

14. The method according to claim 12 wherein said pharmaceutical composition is a pellet, a tablet, a capsule, a solution, a suspension, an emulsion, an elixir, a gel, a cream, a suppository or a parenteral formulation.