MXPA06007960A - Treatment of aromatase inhibitor therapy-related osteoporosis - Google Patents

Abstract

This invention relates to the use bazedoxifene (1-[4-(2-azepan- 1-yl-ethoxy) -benzyl]-2- (4-hydroxy -phenyl)-3-methyl- 1H-indol -5-ol) in the treatment or inhibition of osteoporosis and osteopenia related to aromatase inhibitor therapy.

Description

TREATMENT OF OSTEOPOROSIS RELATED TO THERAPY WITH AROMATASE INHIBITOR BACKGROUND OF THE INVENTION This invention relates to the use of bazedoxifene (1- [4- (2-azepan-1-yl-ethoxy) -benzyl] -2- (4-hydroxy-phenyl) -3-methyl-1 H-indole-5 -ol) in the treatment or inhibition of osteoporosis and osteopenia related to therapy with aromatase inhibitor. Aromatase inhibitors, such as anostrazole and letrozole, are frequently used for the adjuvant treatment of breast cancer and for the long-term prevention of breast cancer after treatment with tamoxifen. Through their mechanism of action, these drugs induce or amplify the estrogen deficiency that develops in post-menopausal women. Estrogen deficiency induced by aromatase inhibitors is necessary to fight estrogen-dependent breast cancer, but it induces side effects in other tissues, notably bone. Aromatase inhibitors increase bone resorption, and ultimately induce osteopenia and osteoporosis. This has been demonstrated in clinical studies with an increase in biochemical markers of bone resorption, decrease in bone mineral density as measured by double X-ray absorptiometry (DXA), and an increased incidence of aromatase inhibitor-related fractures. Since aromatase inhibitors are prescribed on a long-term basis, for several years, treatment to prevent osteopenia and osteoporosis is necessary. Bazedoxifene is a selective estrogen receptor modulator (SERM) that shows an estrogen-selective receptor agonist activity in the skeleton and lipid metabolism, although it does not stimulate the uterine and breast tissues. In preclinical studies, bazedoxifene demonstrates improved compressive bone strength and a histomorphometric profile superior to that of raloxifene. This is supported by the clinical results of phase II, which reveal that bazedoxifene reduces the biochemical markers of bone resorption. These data show that bazedoxifene can potentially demonstrate: a) bone protection at a lower dose than the currently commercially available SERM, b) no uterine agonist effect, c) a low potential to induce vasomotor discharges, and d) an improvement in the lipid profile in serum. In addition, the data also show that bazedoxifene inhibits estradiol-stimulated proliferation of breast cancer cells, which suggests that bazedoxifene may also act like other SERMs that are capable of reducing the risk of developing breast cancer.

BRIEF DESCRIPTION OF THE INVENTION This invention provides the use of bazedoxifene in a mammal receiving aromatase inhibitor therapy in the treatment or inhibition of osteoporosis and osteopenia, particularly related to therapy with aromatase inhibitor. This invention also provides a combination of bazedoxifene and an aromatase inhibitor useful in the treatment of breast cancer, the inhibition of breast cancer in high-risk women, and to inhibit the reappearance of breast cancer, after an initial remission or cure. This invention also provides a product comprising a bazedoxifene and an aromatase inhibitor as a combined preparation useful in the treatment or inhibition of the conditions previously described. This invention also provides a composition for use in the treatment or inhibition of the conditions described above, comprising a bazedoxifene and an aromatase inhibitor wherein the composition is provided in an effective amount to a mammal in need thereof. This invention further provides the administration of bazedoxifene after finishing a treatment with aromatase inhibitor to improve the symptoms or side effects of the aromatase inhibitor treatment. In one aspect, the present invention provides methods for treating or inhibiting osteoporosis or osteopenia in a mammal receiving aromatase therapy., which comprises providing the mammal with an effective amount of bazedoxifene. In such embodiments, bazedoxifene is bazedoxifene acetate. In such embodiments, bazedoxifene is provided in combination with an aromatase inhibitor. In some embodiments, the bazedoxifene or the aromatase inhibitor or both are provided in subtherapeutically effective amounts. In some embodiments, the aromatase inhibitor is selected from the group consisting of exemestane, formestane, atamestane, fadrozole, letrozole, vorozole and anastrozole. In some embodiments, the aromatase inhibitor is selected from the group consisting of letrozole and anastrozole. In another aspect, the present invention provides methods for treating or inhibiting breast cancer in a mammal receiving aromatase therapy, which comprises providing the mammal with an effective amount of bazedoxifene. In such embodiments, bazedoxifene is bazedoxifene acetate. In such embodiments, bazedoxifene is provided in combination with an aromatase inhibitor. In such embodiments, the bazedoxifene or the aromatase inhibitor or both are provided in subtherapeutically effective amounts. In some embodiments, the aromatase inhibitor is selected from the group consisting of exemestane, formestane, atamestane, fadrozole, letrozole, vorozole and anastrozole. In some embodiments, the aromatase inhibitor is selected from the group consisting of letrozole and anastrozole. In a further aspect, this invention provides methods for treating or inhibiting the reappearance of breast cancer in a mammal in need thereof, which comprises providing the mammal with an effective amount of bazedoxifene. In such embodiments, bazedoxifene is bazedoxifene acetate. In some embodiments, bazedoxifene is provided in combination with an aromatase inhibitor. In such embodiment, the bazedoxifene or the aromatase inhibitor or both are provided in subtherapeutically effective amounts. In some embodiments, the aromatase inhibitor is selected from the group consisting of exemestane, formestane, atamestane, fadrozole, letrozole, vorozole and anastrozole. In some embodiments, the aromatase inhibitor is selected from the group consisting of letrozole and anastrozole. Another aspect of the invention provides methods for treating or inhibiting breast cancer in a high-risk woman, which comprises providing the woman with an effective amount of bazedoxifene. In some embodiments, bazedoxifene is bazedoxifene acetate. In such embodiments, bazedoxifene is provided in combination with an aromatase inhibitor. In some embodiments, the bazedoxifene or aromatase inhibitor or both are provided in subtherapeutically effective amounts. In some embodiments, the aromatase inhibitor is selected from the group consisting of exemestane, formestan, atamestane, fadrozole, letrozole, vorozole, and anastrozole. In some embodiments, the aromatase inhibitor is selected from the group consisting of letrozole and anastrozole. A further aspect of this invention is to provide methods for administering bazedoxifene to a mammal that has completed the aromatase inhibitor treatment to ameliorate the symptoms or side effects of the aromatase inhibitor treatment. In some modalities, the symptom or side effects are osteopenia or osteoporosis. In some embodiments, bazedoxifene is bazedoxifene acetate. In such embodiments, bazedoxifene is provided in subtherapeutically effective amounts. As used in accordance with this invention, the term "bazedoxifene" means bazedoxifene (1 - [4- (2-azepan-1-yl-ethoxy) -benzyl] -2- (4-hydroxy-phenyl) -3-methyl -1H-indol-5-ol, or a pharmaceutically acceptable salt or prodrug thereof As used in accordance with this invention, the terms "treatment" or "treating" means to cure, ameliorate, or reverse the progress of a disease or disorder, or improve or reverse one or more symptoms or side effects of said disease or disorder. As used in accordance with this invention, the term "provide" with respect to providing the combination of the aromatase inhibitor-bazedoxifene, means directly administering the combination, or administering a prodrug, derivative or analog of one or both of the components of the invention. combination that will form an effective amount of the combination within the body, and with respect to bazedoxifene, means directly administering bazedoxifene, or administering a prodrug, derivative or analogue of bazedoxifene that will form an effective amount in the body. As used in accordance with this invention, the term "high-risk woman" or "a high-risk woman" means a woman of at least 35 years with a predicted risk of 5 years of breast cancer >1.67% as calculated by Gail Model [The Lancet, 355: 18 (2000)].

As used in accordance with this invention, the term "subtherapeutically" means below the dose levels normally used to treat a disease, ie, a dose less than the amount required for a therapeutic effect. When used for the combination therapy of bazedoxifene and an aromatase inhibitor, it may refer to a synergistic effect between the compounds. Aromatase is an enzyme that converts androgens into estrone. Estrone can subsequently be converted to estradiol, which has been linked to increased growth or proliferation of positive estrogen receptor carcinoma. As used in accordance with this invention, the term "aromatase inhibitor" means compounds or substances that inhibit the activity of the aromatase enzyme. Thus, the goal of using aromatase inhibitors in chemotherapy is typically to reduce circulating estradiol levels, to ultimately inhibit the growth of neoplasms that are estrogen or estrogen receptor positive. There are two types of aromatase inhibitors: steroidal (type I) and non-steroidal (type II) inhibitors. Examples of steroidal aromatase inhibitors include exemestane, formestane, atamestane, and the like. Examples of non-steroidal aromatase inhibitors include fadrozole, letrozole, vorozole, anastrozole and the like. The preparation of bazedoxifene and its pharmaceutically acceptable salts is described in the patent of E.U.A. 5,998,402 which is incorporated herein by reference in its entirety. When administered for the treatment or inhibition of a particular disease state or disorder, it is understood that the effective dose may vary depending on, for example, whether bazedoxifene is used with or without an aromatase inhibitor, the particular aromatase inhibitor used. , if one is used, the mode of administration, the condition to be treated, and the severity thereof, as well as several physical factors related to the individuals to be treated. The effective administration of bazedoxifene of this invention can be in any variety of dosage regimens such as single dose, multiple dose, combination dose and dosage forms of delayed release and in time. Bazedoxifene acetate has been evaluated in clinical trials using doses of 10, 20 and 40 mg / day. Based on the results of these tests, it is anticipated that doses between about 5 and about 80 mg / day of bazedoxifene will provide an effective amount within the methods of the invention. It is expected that these projected daily doses will vary with the route of administration. The selection of the appropriate administration and dosage forms for an individual patient will be apparent to those skilled in the art. Such determinations are routine for one skilled in the art (see, for example Harrison's Principles of Internal Medicine (1998), edited by Anthony Fauci et al., 14th edition, published by McGraw Hill). In some embodiments, a combination of bazedoxifene and an aromatase inhibitor are administered according to the invention wherein the aromatase inhibitor is letrozole, and wherein both are provided orally. In such embodiments, the initial oral dose of bazedoxifene may be from about 5 to about 80 mg / day (on the days it is provided) and the initial oral dose of letrozole may be from about 1 to about 10 mg daily (in the days it is provided). In some embodiments, the initial oral dose of bazedoxifene may be from about 10 to about 60 mg / day (on the days it is provided) and the initial oral dose of letrozole may be from about 1 to about 10 mg daily (in the days it is provided). In such embodiments, the initial oral dose of bazedoxifene may be from about 10 to about 40 mg / day (on the days it is provided) and the initial oral dose of letrozole may be from about 1 to about 10 mg daily (in the days it is provided). further, in some embodiments, the initial oral dose of bazedoxifene may be from about 10 to about 30 mg / day (on the days it is provided) and the initial oral doses of letrozole may be from about 1 to about 10 mg daily ( on the days it is provided). In some embodiments, the initial oral dose of bazedoxifene may be from about 20 to about 40 mg / day (on the days it is provided) and the initial oral dose of letrozole may be from about 1 to about 10 mg daily (in the days it is provided). In some embodiments, a combination of bazedoxifene and an aromatase inhibitor are administered according to the invention wherein the aromatase inhibitor is anastrozole, and wherein both are provided orally. In such embodiments, the initial oral dose of bazedoxifene may be from about 5 to about 80 mg / day (on the days it is provided) and the initial oral dose of anastrozole may be from about 1 to about 10 mg daily (in the days it is provided). In such embodiments, the initial oral dose of bazedoxifene may be from about 10 to about 60 mg / day (on the days it is provided) and the initial oral dose of anastrozole may be from about 1 to about 10 mg daily (in the days it is provided). In some embodiments, the initial oral dose of bazedoxifene may be from about 10 to about 40 mg / day (on the days it is provided) and the initial oral dose of anastrozole may be from about 1 to about 10 mg daily (in the days it is provided). In some embodiments, the initial oral dose of bazedoxifene may be from about 10 to about 30 mg / day (on the days it is provided) and the initial oral dose of anastrozole may be from about 1 to about 10 mg daily (in the days it is provided). In some embodiments, the initial oral dose of bazedoxifene may be from about 20 to about 40 mg / day (on the days it is provided) and the initial oral dose of anastrozole may be from about 1 to about 10 mg daily (in the days it is provided). Aromatase inhibitors specifically named in this description are commercially available or can be made from methods known in the literature. This invention is not limited to the use of the specific aromatase inhibitors named in this; the preparation of other aromatase inhibitors will be apparent to one skilled in the art based on the literature. As used in this invention, the combination regimen may occur simultaneously or may occur in a spaced regime, the bazedoxifene being given at a different time to the aromatase inhibitor. This time difference can vary from several minutes, hours, days, weeks or more between the administration of the two agents. Therefore, the term "combination" does not necessarily mean administered at the same time or as a unit dose, but rather that each of the components is administered during a desired treatment period. The agents can be administered by the same routes or different routes. For example, one component can be administered orally, while the other parenterally and these combinations can be administered daily, weekly, or even once a month. Oral formulations containing the active compounds of this invention may comprise any oral form conventionally used, including tablets, capsules, buccal forms, lozenges, troches, and suspensions or oral liquid solutions. The capsules may contain mixtures of the compound (s) with inert fillers and / or diluents such as pharmaceutically acceptable starches (eg, corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, as crystalline and microcrystalline cellulose, flours, tins, gums, et cetera. Useful tablet formulations can be made by conventional compression, wet granulation or by dry granulation methods and using pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including, surfactants), suspending agents or stabilizers , including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, calcium carboxymethyl cellulose, polyvinyl pyrrolidone, tin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, carbonate calcium, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dried starches and powdered sugar. Preferred surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecyl sulfate, aluminosilicate magnesium and triethanolamine. Oral formulations herein may utilize standard delayed or delayed release formulations to alter the absorption of the active compound (s). The oral formulation may also consist of administering the active ingredient in water or a fruit juice, which contains appropriate solubilizers or emulsifiers as needed.

In some cases it may be convenient to administer the compounds directly to the airways in the form of an aerosol. The compounds can also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or a pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. The dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that there is an easy injection capacity. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or a dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. For the purposes of this disclosure, transdermal administrations are understood to include all administrations across the body surface and the inner linings of body passages that include epithelial and mucosal tissues. Such administrations can be carried out using the compounds of the present invention, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal). Transdermal administration can be achieved through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the bloodstream by means of of the skin. The carrier can take any number of forms such as creams and ointments, pastes, gels and occlusive devices. The creams and ointments can be a viscous liquid or semi-solid emulsions or be of the oil-in-water or water-in-oil type. Pastes comprised of absorbent powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. A variety of occlusive devices can be used to release the active ingredient into the bloodstream such as a semi-permeable membrane that covers a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature. The suppository formulations can be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the melting point of the suppository and glycerin. Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, can also be used. For bazedoxifene, solid oral formulations, such as in the form of a tablet or film-coated capsule, useful for this invention include the active pharmacological agents described herein in combination with a carrier or excipient systems having the components: a) a filler and disintegrating component comprising from about 5% to about 82% by weight of the total formulation, preferably between about 30% and about 80% of the formulation, of which from about 4% to about 40% by weight of the total formulation comprises one or more pharmaceutically acceptable disintegrants. b) optionally, a wetting agent comprising from about 0.2 to about 5% of the composition (by weight), such as that selected from the group of sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, esters of sorbitan fatty acid, polyethylene glycols, polyoxyethylene castor oil derivatives, sodium docusate, quaternary ammonium compounds, fatty acid sugar esters and fatty acid glycerides; c) a lubricant comprising from about 0.2% to about 10% of the composition (by weight) as selected from the group of magnesium stearate or other metal stearates (eg, calcium stearate or zinc stearate), esters of fatty acid (for example sodium stearyl fumarate), fatty acids, (for example, stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols, metal laurisulfates and sodium chloride; and d) optionally, a slider comprising from about 0.1% to about 10% (by weight) of the composition, the slider selected from those known in the art, including from the group of silicon dioxide, talc, metal stearates, silicate calcium or metal lauryl sulfates. Although the formulations described herein may be used in an uncoated or unencapsulated solid form, in some embodiments the final compositions are coated or encapsulated. The pharmacological compositions can optionally be coated with a film coating, for example, comprising from about 0.3% to about 8% by weight of the total composition. Film coatings useful with the formulations herein are known in the art and generally consist of a polymer (usually a cellulose type of polymer), a colorant and a plasticizer. Additional ingredients such as wetting agents, sugars, flavors, oils and lubricants can be included in the film coating formulations to impart certain characteristics to the film coating. The compositions and formulations herein may also be combined and processed as a solid, subsequently placed in a capsule form, such as a gelatin capsule. The filler component listed above can utilize the filler or binder components known in the art for solid oral formulations. The fillers or pharmaceutically acceptable binders can be selected from those known in the art such as, but not limited to, lactose, microcrystalline cellulose, sucrose, mannitol, calcium phosphate, calcium carbonate, cellulose powder, maltodextrin, sorbitol, starch, or xylitol. In conjunction with or in place of the materials listed above for the filler component, the formulations herein use disintegrating agents. These disintegrants may be selected from those known in the art, including pregelatinized starch and sodium starch glycolate. Other useful disintegrants include croscarmellose sodium, crospovidone, starch, alginic acid, sodium alginate, clays (e.g., veegum or xanthan gum), cellulose floc, ion exchange resin or effervescent systems, such as those using food acids. (such as citric acid, tartaric acid, malic acid, fumaric acid, lactic acid, adipic acid, ascorbic acid, aspartic acid, erythorbic acid, glutamic acid and succinic acid) and an alkaline carbonate component (such as sodium bicarbonate, carbonate of calcium, magnesium carbonate, potassium carbonate, ammonium carbonate, etc). The useful disintegrant (s) herein will comprise (s) from about 4% to about 40% of the composition by weight, preferably from about 15% to about 35%, more preferably from about 20% to approximately 35%. Some components may have multiple functions in the formulations of this invention, acting for example, as a filler and a disintegrant. Said component can be mentioned as a disintegrant of the filler and its function in a specific formulation can be unique even when its properties may allow multiple functionality. The pharmaceutical formulations and carrier or excipient systems herein may also contain an antioxidant or a mixture of antioxidants., for example, ascorbic acid. Other antioxidants that may be used include sodium ascorbate and ascorbyl palmitate, which may be used in conjunction with an amount of ascorbic acid. In some embodiments, the amount of antioxidant (s) is from about 0.5% to about 15% by weight. In some embodiments, the amount of antioxidants is from about 0.5% to about 5% by weight. Among the formulations of this invention are pharmaceutical formulations containing a pharmaceutically effective amount of an active pharmacological agent and a carrier or excipient system comprising: a) a filler and a disintegrating component comprising between about 50% and about 87% of the formulation, with from about 4% to about 40% of the formulation comprising one or more disintegrating agents; b) a wetting agent comprising between about 0.5% and about 2.7% of the formulation; c) a lubricant comprising between about 0.2% and about 5.5% of the formulation; and d) a glidant comprising between about 0.1% and about 5.5% of the formulation. The percentages listed in the above formulations indicate percentages by weight of the total weight of the components listed in a) to d). The above formulations may also contain an optional antioxidant component, for example, ascorbic acid, in a concentration of about 0.5% to about 5.5% by weight of the formulation. The formulations may be contained within a pharmaceutically acceptable capsule, such as a gel capsule or coated with a film coating comprising from about 0.3% to about 8% by weight of the formulation. This invention also encompasses carrier systems and pharmaceutical excipients useful in pharmaceutical compositions that use as one active ingredient one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, as described herein. These pharmaceutical carrier or excipient systems comprise, by weight: a) a filler and disintegrating component comprising between about 54% and about 80% of the formulation, with the disintegrating agent (s) therein comprising from around from 4% to about 40% by weight of the total formulation; b) a wetting agent comprising between about 0. 55% and approximately 2.5% of the formulation; c) a lubricant comprising between about 0.2% and about 5.5% of the formulation, and d) a glidant comprising between about 0.1% and about 5.0% of the formulation. In some embodiments, the carrier systems or excipients above may also optionally contain an antioxidant component, for example, ascorbic acid, at a concentration of from about 0.1% to about 5.0% by weight. Among the carrier systems or excipients of the invention are those comprising: a) a filler and disintegrating component, as described above, comprising between about 50% and about 87% of the formulation, the disintegrant (s) the same it comprises from about 25% to about 35% of the formulation, by weight b) a wetting agent comprising between about 0.55% and about 2.7% of the formulation; c) a lubricant comprising between about 0.2% and approximately 5.5% of the formulation; d) a slider comprising between about 0.1% and approximately 5.5% of the formulation; Y e) an anti-oxidant component, for example, ascorbic acid, a a concentration of about 0.1% to about 5.5% by weight.

EXAMPLES EXAMPLE 1 Bazedoxifene acetate-rapid dissolution formulation * The amount in the formula is adjusted for real potency of bazedoxifene as a free base. The corresponding adjustment made with lactose.

The formulations given above in Table 1 are prepared by incorporating a portion of the excipients in the granulation and a portion is also added in the final combination steps as dry powders. A dissolution profile generated for the formulations showed almost 90% release of the drug in 30 minutes. Thus, the unique combination of disintegrants and soluble diluents plus the incorporation of granulated and powdered solids into the composition ensures faster release of the drug. The wet granulation of the formulations as described in Table 1 can be carried out by mixing the drug and ascorbic acid with a portion of lactose, microcrystalline cellulose, pregelatinized starch and sodium starch glycolate. Sodium lauryl sulfate is dissolved in water and used to granulate the powder mixture in a high shear mixer. The granulation is dried in a fluidized bed dryer at a humidity of 2-3%. The particular size of the dry granulation is controlled by passing through a laminator equipped with knife blades and using a 20- or 30- mesh screen. The remaining silicon dioxide and lactose, microcrystalline cellulose, pregelatinized starch, and sodium starch glycolate are mixed with the laminated granulation in a drum type mixer. The final mixture is prepared by adding magnesium stearate to the drum-type mixer and mixing. The compression is carried out on a rotary tablet press using a machining of appropriate size. The coating is done in conventional coating trays and by applying the coating suspension to achieve a suitable film coating.

EXAMPLE 2 Formulation of modified bazedoxifene acetate The amount in the formula is adjusted for actual potency of bazedoxifene acetate as the free base. The corresponding adjustment made with lactose b Used in a procedure but does not appear in the final product.

EXAMPLE 3 Bazedoxifene acetate at 5% granulation A preferred carrier or excipient system for formulating a granulation of from about 2 to about 8% by weight of one of the active pharmacological agents of this invention, for example, of about 5%, can be produced using the carrier or excipient components in a percentage by weight; lactose from about 32% to about 38%, macrocrystalline cellulose from about 32% to about 38%, pregelatinized starch from about 12% to about 16%, ascorbic acid from about 1% to about 2%, lauryl sulfate sodium from about 1% to about 2%, sodium starch glycolate from about 4% to about 8%, silicon dioxide from about 0.1% to about 0.2%, and magnesium stearate from about 0.3% to about 0.7 %.

A formulation of this invention that uses bazedoxifene As the active ingredient to a 5% granulation is prepared using the components listed below in a granulation part and in a Dry part of the components.

Item no. Ingredients Mg / unit Part of granulation 1 Bazedoxifene acetate 5.00 2 Lactose NF 26.60 3 Microcrystalline cellulose NF 25.00 4 Pregelatinized starch NF 10.00 Ascorbic acid USP 1.50 6 Sodium lauryl sulfate 1.50 7 Sodium starch glycolate NF 4.00 8 Water, purified USP C.N. 73.60 Dry Part: 9 Lactose NF (Rapid Flow) 9.75 10 Microcrystalline Cellulose NF 10.00 11 Pregelatinized starch NF 4.00 12 Sodium starch glycolate 0.15 13 Silicon dioxide NF 0.15 14 Magnesium stearate 0.50 100.00 A film coating of White Opadry I (YS-1-18027-A) was applied to the tablets, which were compressed as follows: Dosage of bazedoxifene Weight of the tablet, mq mq of the applied film coating / tablet mg 100 6.0 10 mg 200 8.0 20 mg 400 13.0 EXAMPLE 4 Bazedoxifene in the treatment of osteopenia or osteoporosis Mice, rats or monkeys can be treated daily with a aromatase inhibitor and combination of bazedoxifene. The administration of both components of the combination can be subcutaneous, intraperitoneal or oral during periods ranging from 2 weeks to 1 year. Bone mineral density can be measured by standard methods, eg, double-energy X-ray absorptiometry (Wickman, S. et al., J. Clin. Endocrin. &Metab. (88 (8): 3785-3793 (2003)). Vanderschueren, D. et al., Endocrin, 138 (8): 2310-2307 (1997).) Uterine weights can be measured as is described by Schieweck, K. et al in J. Steroid Biochem. Mol Biol. 44 (4-6): 633-6 (1993). A decrease in uterine weight is a positive control, ensuring aromatase functional activity. An improvement in the loss of Bone mass after co-treatment with bazedoxifene can demonstrate that bazedoxifene is effective in treating bone loss by maintaining bone mass without stimulating the uterus or breast tissues. Those skilled in the art will recognize that various changes and / or modifications may be made to aspects or embodiments of the invention and that such changes and / or modifications may be made without departing from the spirit of this invention. Therefore, it is intended that the appended claims cover such equivalent variations that fall within the spirit and scope of this invention. Each reference cited in the present application, including references to literature, books, patents, and patent applications, is hereby incorporated by reference herein in its entirety. This application claims the priority benefit of the provisional application of E.U.A. Serial No. 60 / 536,035 filed 01/13/04, which is incorporated by reference herein in its entirety.

Claims (32)

NOVELTY OF THE INVENTION CLAIMS

1. - The use of bazedoxifene, in the preparation of a medicament for treating or inhibiting osteoporosis or osteopenia in a mammal.

2. The use as claimed in claim 1, wherein the bazedoxifene is provided in combination with an aromatase inhibitor.

3. The use as claimed in claim 1 or claim 2, wherein the aromatase inhibitor is selected from the group consisting of exemestane, formestane, atamestane, fadrozole, letrozole, vorozole, and anastrozole.

4. The use as claimed in claim 3, wherein the aromatase inhibitor is letrozole or anastrozole.

5. The use as claimed in any of claims 1 to 4, wherein the bazedoxifene or the aromatase inhibitor or both are provided in subtherapeutically effective amounts.

6. The use as claimed in any of claims 1 to 5, wherein the bazedoxifene is bazedoxifene acetate.

7. The use of bazedoxifene in the preparation of a medicament for use in combination with an aromatase inhibitor to treat or inhibit osteoporosis, osteopenia or breast cancer in a mammal.

8. - The use as claimed in claim 7, wherein the aromatase inhibitor is selected from the group consisting of exemestane, formestane, atamestane, fadrozole, letrozole, vorozole, and anastrozole.

9. The use as claimed in claim 8, wherein the aromatase inhibitor is letrozole or anastrozole.

10. The use as claimed in any of claims 7 to 9, wherein the bazedoxifene or the aromatase inhibitor or both are provided in subtherapeutically effective amounts.

11. The use as claimed in any of claims 7 to 10, wherein the bazedoxifene is bazedoxifene acetate.

12. The use of bazedoxifene in the preparation of a medicament for use in combination with an aromatase inhibitor to inhibit the reappearance of breast cancer in a mammal.

13. The use as claimed in claim 12, wherein the aromatase inhibitor is selected from the group consisting of exemestane, formestane, atamestane, fadrozole, letrozole, vorozole, and anastrozole.

14. The use as claimed in claim 13, wherein the aromatase inhibitor is letrozole or anastrozole.

15. The use as claimed in any of claims 12 to 14, wherein the bazedoxifene or the aromatase inhibitor or both are provided in subtherapeutically effective amounts.

16. - The use as claimed in any of claims 12 to 15, wherein the bazedoxifene is bazedoxifene acetate.

17. The use of bazedoxifene in the preparation of a drug for use in combination with an aromatase inhibitor to inhibit breast cancer in a high-risk woman.

18. The use as claimed in claim 17, wherein the aromatase inhibitor is selected from the group consisting of exemestane, formestane, atamestane, fadrozole, letrozole, vorozole, and anastrozole.

19. The use as claimed in claim 18, wherein the aromatase inhibitor is letrozole or anastrozole.

20. The use as claimed in any of claims 17 to 19, wherein the bazedoxifene or the aromatase inhibitor or both are provided in subtherapeutically effective amounts.

21. The use as claimed in any of claims 17 to 20, wherein the bazedoxifene is bazedoxifene acetate

22. The use as claimed in any of claims 1 to 21, wherein the amount Effectiveness of bazedoxifene is around 5 to about 80 mg / day.

23. - The use as claimed in claim 22, wherein the effective amount of bazedoxifene is from about 10 to about 60 mg / day. 24.- The use as claimed in claim 23, wherein the effective amount of bazedoxifene is from about 10 to about 40 mg / day. 25. The use as claimed in claim 24, wherein the effective amount of bazedoxifene is from about 10 to about 30 mg / day. 26. The use as claimed in claim 24, wherein the effective amount of bazedoxifene is from about 20 to about 40 mg / day. 27. A product comprising a bazedoxifene and an aromatase inhibitor as a combined preparation for simultaneous separate or sequential use in the treatment or inhibition of osteoporosis, osteopenia or breast cancer in a mammal. 28. A product comprising a bazedoxifene and an aromatase inhibitor as a combined preparation for simultaneous separate or sequential use for inhibition of breast cancer in a woman at high risk or inhibition of the reappearance of breast cancer in a mammal. 29. A composition for use in a method for treating or inhibiting osteoporosis or osteopenia in a mammal, said composition comprising a bazedoxifene and an aromatase inhibitor and said method comprising providing said mammal with an effective amount of said composition. 30. A composition for use in the treatment or inhibition of osteoporosis or osteopenia or breast cancer in a mammal comprising a bazedoxifene and an aromatase inhibitor. 31.- A composition for use in the inhibition of breast cancer in a high risk woman comprising a bazedoxifene and an aromatase inhibitor. 32. A composition for use in the inhibition of the reappearance of breast cancer in a mammal comprising a bazedoxifene and an aromatase inhibitor.