WO2011085303A1 - Méthode de lutte contre l'ostéoporose induite par une hormonothérapie suppressive - Google Patents

Méthode de lutte contre l'ostéoporose induite par une hormonothérapie suppressive Download PDF

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WO2011085303A1
WO2011085303A1 PCT/US2011/020667 US2011020667W WO2011085303A1 WO 2011085303 A1 WO2011085303 A1 WO 2011085303A1 US 2011020667 W US2011020667 W US 2011020667W WO 2011085303 A1 WO2011085303 A1 WO 2011085303A1
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bone
toremifene
subject
administering
pharmaceutical composition
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PCT/US2011/020667
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English (en)
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Mitchell S. Steiner
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Gtx, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • Hormone ablative therapy i.e., treatments that stop the production of specific hormones
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the bone related disorder is osteoporosis, osteopenia, increased bone resorption, bone fracture, bone frailty, loss of bone mineral density (BMD), or any combination thereof.
  • 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.
  • BMD bone mineral density
  • 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 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).
  • 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).
  • 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).
  • 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).
  • 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.
  • the method comprises the step of administering to said subject toremifene citrate.
  • 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.
  • the method comprises the step of administering to said subject a dosage of about 80 mg per day of toremifene.
  • the method comprises the step of administering to said subject a dosage of about 120 mg per day of toremifene citrate.
  • 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.
  • the method comprises the step of administering to said subject toremifene citrate.
  • 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.
  • 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.
  • 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.
  • the female subject is a mammalian subject.
  • the female subject is a human subject.
  • the female is a postmenopausal woman.
  • the female is a premenopausal woman.
  • 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.
  • the female subject is a mammalian subject. In another embodiment, the female subject is a human subject.
  • 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.
  • 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.
  • BMD bone mineral density
  • DXA dual energy x-ray absorptiometry
  • 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.
  • 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.
  • 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.
  • DXA dual-energy x-ray densitometry
  • AP antero-posterior
  • lateral spine lateral spine
  • QCT Quantitative computerized tomography
  • 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.
  • SERMs selective estrogen receptor modulators
  • aromatase inhibitors aromatase inhibitors
  • estrogen receptor down-regulators luteinizing hormone-releasing hormone (LHRH) agonists or other hormonal agents, including androgens.
  • LHRH luteinizing hormone-releasing hormone
  • 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.
  • 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.
  • Anastrazole Armidex
  • Exemestane Aromatasin
  • Letrozole Femara
  • 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.
  • Drugs that inhibit steroid or estrogen production at early stages in hormone biosynthesis may also lead to bone related disorders associated with hormone ablative therapy.
  • 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.
  • LHRH luteinizing hormone-releasing hormone
  • Zoladex goserelin
  • GnRH agonists GnRH agonists
  • 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.
  • the methods of the present invention comprise administering an analog of toremifene.
  • the methods of the present invention comprise administering a derivative of toremifene.
  • 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.
  • 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.
  • 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.
  • the toremifene is an (E) isomer.
  • the toremifene is a (Z) isomer.
  • the toremifene is a mixture of (E) and (Z) isomers.
  • 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.
  • 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.
  • the "pharmaceutically acceptable salt" of toremifene is toremifene citrate.
  • the salt is toremifene acetate.
  • the salt is toremifene chloride.
  • the salt is toremifene formate.
  • the salt is toremifene mesylate.
  • the invention also includes N-oxides of the amino substituents of the compounds described herein.
  • This invention further includes derivatives of toremifene.
  • derivatives includes but is not limited to ether derivatives, acid derivatives, amide derivatives, ester derivatives and the like.
  • this invention further includes hydrates of toremifene compounds.
  • hydrate includes but is not limited to hemihydrate, monohydrate, dihydrate, trihydrate and the like.
  • 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.
  • This invention further includes pharmaceutical products of toremifene.
  • pharmaceutical product means a composition suitable for pharmaceutical use (pharmaceutical composition), as defined herein.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical compositions are administered orally, and are thus formulated in a form suitable for oral administration, i.e.
  • compositions of the present invention comprise, in addition to toremifene and the inert carrier or diluent, a hard gelatin capsule.
  • 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.
  • the pharmaceutical compositions are administered intravenously, and are thus formulated in a form suitable for intravenous administration.
  • the pharmaceutical compositions are administered intraarterially, and are thus formulated in a form suitable for intraarterial administration.
  • the pharmaceutical compositions are administered intramuscularly, and are thus formulated in a form suitable for intramuscular administration.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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
  • pharmaceutically acceptable carriers may be aqueous or nonaqueous solutions, suspensions, emulsions or oils.
  • 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.
  • 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.
  • Parenteral vehicles for subcutaneous, intravenous, intraarterial, or intramuscular injection
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like.
  • sterile liquids such as water and oils, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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).
  • the composition is an immediate-release composition, i.e. a composition in which toremifene is released immediately after administration.
  • the pharmaceutical composition can be delivered in a controlled release system.
  • the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration.
  • 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).
  • polymeric materials can be used.
  • 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).
  • 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.
  • 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.
  • particulate compositions coated with polymers e.g. poloxamers or poloxamines
  • polymers e.g. poloxamers or poloxamines
  • 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.
  • 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.
  • compositions which contain an active component are 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.
  • excipients which are pharmaceutically acceptable and compatible with the active ingredient.
  • 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.
  • 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.
  • 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.
  • 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.
  • a pharmaceutically active salt of toremifene is toremifene citrate.
  • 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.
  • 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.
  • the term “treating” includes preventative as well as disorder remitative treatment.
  • the terms “reducing”, “suppressing” and “inhibiting” have their commonly understood meaning of lessening or decreasing.
  • progression means increasing in scope or severity, advancing, growing or becoming worse.
  • recurrence means the return of a disease after a remission.
  • administering refers to bringing a subject in contact with toremifene of the present invention.
  • 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.
  • the present invention encompasses administering the compounds of the present invention to a subject.
  • the methods of the present invention comprise administering toremifene as the sole active ingredient.
  • agents for delaying the progression of hormone ablative therapy induced bone related disorder in a female subject suffering from breast cancer comprise administering toremifene of this invention in combination with one or more therapeutic agents.
  • 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.
  • the methods of the present invention include using compositions and pharmaceutical compositions comprising toremifene of this invention, in combination with an LHRH analog.
  • the methods of the present invention include using compositions and pharmaceutical compositions comprising toremifene of this invention, in combination with a reversible antiandrogen.
  • the methods of the present invention include using compositions and pharmaceutical compositions comprising toremifene of this invention, in combination with an additional anti-estrogen.
  • the methods of the present invention include using compositions and pharmaceutical compositions comprising toremifene of this invention, in combination with an anticancer drug.
  • 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.

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Abstract

La présente invention concerne le traitement, la réduction de l'incidence, l'inhibition, la suppression et la prévention d'affections osseuses induites par une hormonothérapie suppressive, comme l'ostéoporose, l'ostéopénie, une augmentation de la résorption osseuse, les fractures osseuses, la fragilité osseuse, la perte de densité minérale osseuse ou une quelconque association de ces affections chez des femmes souffrant d'un cancer du sein, grâce à l'administration d'environ 120 mg de citrate de torémifène.
PCT/US2011/020667 2010-01-11 2011-01-10 Méthode de lutte contre l'ostéoporose induite par une hormonothérapie suppressive WO2011085303A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5605700A (en) * 1992-04-03 1997-02-25 Orion-Yhtyma Oy Topical administration of toremifene and its metabolites
US6352970B1 (en) * 1998-02-23 2002-03-05 Pfizer Inc. Treatment of skeletal disorders
US7507704B1 (en) * 2002-11-15 2009-03-24 Mark Zamoyski Receptor modulated cancer protocols

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5605700A (en) * 1992-04-03 1997-02-25 Orion-Yhtyma Oy Topical administration of toremifene and its metabolites
US6352970B1 (en) * 1998-02-23 2002-03-05 Pfizer Inc. Treatment of skeletal disorders
US7507704B1 (en) * 2002-11-15 2009-03-24 Mark Zamoyski Receptor modulated cancer protocols

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