MX2007016363A - Formulations of conjugated estrogens and bazedoxifene - Google Patents

Abstract

The present invention relates to solid dosage formulations containing conjugated estrogens and bazedoxifene, or a salt thereof. In some embodiments, the compositions include a core comprising conjugated estrogens, and at least one coating that comprises bazedoxifene, or a salt thereof.

Description

FORMULATIONS OF? STROGENS WITH UGADOS AND B & .S? DOXSE? B3Q FIELD OF THE INVENTION The present invention relates to solid dose formulations containing conjugated estrogens and bazedoxifene or a salt thereof. In some embodiments, the compositions include a core containing conjugated estrogens and a shell that includes bazedoxifene, or a salt thereof.

BACKGROUND OF THE INVENTION The use of hormone replacement therapy for the prevention of bone loss in post-menopausal women is well known above. The normal protocol seeks estrogen supplementation using such formulations containing estrone, estriol, ethinyl estradiol or conjugated estrogens isolated from natural sources (ie conjugated estrogens Premarin® <ie Wyeth-Ayerst). In some patients, therapy may be contraindicated due to the proliferative effects of unopposed estrogens (estrogens not given in combination with inas Proges) on uterine tissue. This proliferation is associated with the increased risk of endometriosis and / or breast cancer. The effects of unopposed estrogen on breast tissue are less clear, but it also carries some degree of concern. The need for estrogens that can maintain a moderate effect on the bones while minimizing the proliferative effects on the uterus and on the breasts is evident. The use of indoles as estrogen antagonists has been reported by Von Angerer, Chemical Abstracts, Vol. 99, No. 7 (1983), No. 53886u Abetract. Also, see J. Med. Chem. 1990, 33, 2635-2640; J. Med. Chem. 1987, 30, 131-136. Also see Ger. Offen., DE 3821148 Al 891228 and WO 96/03375. Most of the compounds reported in these publications fall into a class of better compounds, characterized as "pure antiestrogens". Additional reports of indole antiestrogens include: WO A 95 17383 (Kar Bio AB), WO A 93 10741, and WO 93/23374 (Otsuka Pharmaceuticals, Japan). The U.S. Patent No. 5,998,402 describes 2-phenylindole compounds which are estrogen agonists / antagonists useful for the treatment of diseases associated with estrogen deficiency. The compounds have a strong binding to the estrogen receptor. In vi tro tests, include an Ishika alkaline phosphatase test and an ERE transfection test, which show that these compounds are antiestrogens with little or no intrinsic estrogenicity and that they have been shown to be able to completely antagonize the effects of 17β-estradiol while they present little or no uterine stimulation in a rat uterine test when administered alone. In addition, some of the compounds are capable of inhibiting bone loss in a rat that underwent ovariectomy, while presenting little or no uterine stimulation. These compounds also decrease the weight gain that is normally observed in ovariectomized animals as well as reduce total cholesterol levels. One such preferred compound is bazedoxifene, which is 1-Í4- (azepan-1-yl-ethoxy) -benzyl] -2- (4-hydroxy-phenyl) -3-methyl-1H-indol-5-ol. Bazedoxifene is a selective tissue estrogen for the treatment and prevention of post-menstrual osteoporosis. It has been reported to prevent bone loss and protect the cardiovascular system and also reduce or eliminate the negative effects on the uterus and breast (potential risk of uterine cancer and breast cancer). The U.S. Patents Nos. 5,998,402 and 6,479,535 report the preparation of bazedoxifene acetate. The synthetic preparation of bazedoxifene acetate also appears in the general literature. See, for example, Miller et al., J. Med. Chem., 2001, 44, 1654-1657. There is also an additional description of the biological activity of the drug in the general literature as well as (for example, Miller, et al., Drugs of the Future, 2002, 27 (2), 117-121). Bazedoxifene acetate formulations are also reported in U.S. Patent Application Publication. No. 2002/0031548 A1. The polymorphs of bazedoxifene acetate are described in US Provisional Patent Application No. 60/560., 582 filed on April 7, 2004, and 60 / 560,584 filed on April 7, 2004. Bazedoxifene acetate dispersion formulations are described in US Provisional Patent Application No. 60 / 560,452, filed April 8. of 2004. Bazedoxifene ascorbate salt is described in US Provisional Patent Application No. 60 / 560,454, filed on April 8, 2004. There is a need for effective drug treatment for post-menopausal women that alleviates vasomotor symptoms and protect the bones without stimulating the endometrium (which can lead to endometrial hyperplasia) or breast. The present invention relates to this, as well as to other important purposes.

BRIEF DESCRIPTION OF THE INVENTION In some embodiments, the present invention provides pharmaceutical compositions that include a core and at least one coating; wherein the core comprises conjugated estrogens; and the coating comprises bazedoxifene or a pharmaceutically acceptable salt thereof.

In some embodiments, the conjugated estrogens include or consist of Premarin®.

In some embodiments, the pharmaceutical composition is a tablet. In some such embodiments, the pharmaceutical compositions include a core and at least one coating; wherein the nucleus includes conjugated estrogens; and the coating includes bazedoxifene or a pharmaceutically acceptable salt thereof. In some embodiments, the coating comprises: a) a filler component comprising from about 5% to about 30% by weight of the pharmaceutical formulation; b) a binder component comprising from about 1% to about 10% by weight of the pharmaceutical formulation; c) a wetting agent component comprising from about 0.01% to about 2% by weight of the pharmaceutical formulation; d) an optional antioxidant component comprising from 0% to about 2% by weight of the pharmaceutical formulation; e) bazedoxifene acetate, comprising from about 0.1% to about 20% by weight of the pharmaceutical formulation; and f) an optional chelating agent comprising from 0% to about 0.1% by weight of the pharmaceutical formulation. In some embodiments, the conjugated estrogens are present in an amount of about 0.10 to about 1.0 mg; or from about 0.3 to about 0.8 mg; or from about 0.4 to about 0.5 mg; or from about 0.5 to about 0.7 mg. In some embodiments, bazedoxifene is present in an amount of about 1 to about 50 mg, based on the weight of the free base of bazedoxifene; or from about 5 to about 25 mg; based on the weight of the bazedoxifene-free base; or from about 5 to about 15 mg; based on the weight of the bazedoxifene-free base; or from about 15 to about 25 mg, based on the weight of the bazedoxifene free base; or from about 35 to about 45, based on the weight of the free base of bazedoxifene. In some embodiments, the conjugated estrogens are present in an amount of about 0.10 to about 1.0 mg; and bazedoxifene is present in an amount of about 5 to about 50 mg, based on the weight of the free base of bazedoxifene. In some embodiments, conjugated estrogens are Premarin®, and bazedoxifene is bazedoxifene acetate. In some embodiments, the filling component of the coating comprises sucrose; the binder component of the coating comprises hydroxypropylmethylcellulose; the wetting agent component of the coating comprises sucrose palmitate; the optional antioxidant component of the coating, when present, comprises ascorbic acid or a salt thereof, and the optional chelating agent, when present, comprises EDTA. In some embodiments, the pharmaceutical compositions further include a color coating. In some embodiments, the color coating includes: a) an optional filler component comprising from about 0.1% to about 8% by weight of the pharmaceutical formulation; b) an optional binder component comprising from about 0.01% to about 2% by weight of the pharmaceutical formulation; and c) a coloring agent component comprising from about 0.01% to about 6% by weight of the pharmaceutical formulation. In some of these modalities, the optional filler component comprises sucrose. In some such additional embodiments, the optional binder component comprises hydroxypropylmethylcellulose. In some such additional embodiments, the coloring agent component comprises titanium dioxide. In some embodiments, the pharmaceutical compositions further include a clear coating. In some of these embodiments, the clear coating forms about 0.01% to about 2% by weight of the pharmaceutical formulation. In some such embodiments, the optional antioxidant agent, the optional chelating agent, or both the optional antioxidant agent and the optional chelating agent, being further present in the coating as described above, may also each, independent and optionally, being present in one or more of the color coating and the transparent cover. The invention further provides methods for the preparation of pharmaceutical compositions of the present invention and products of the processes.

DETAILED DESCRIPTION OF THE INVENTION In some embodiments, the present invention provides pharmaceutical compositions that include conjugated estrogens and bazedoxifene, or a salt thereof. In some embodiments, the conjugated estrogens include or consist of Premarin®. The pharmaceutical compositions of the invention include capsules and tablets in capsule formulations (TIC). In some embodiments, the pharmaceutical compositions of the invention are tablets. In some embodiments, the pharmaceutical compositions of the invention include a core and at least one coating; wherein the nucleus includes conjugated estrogens; preferably Premarin®, and the coating includes bazedoxifene, or a pharmaceutically acceptable salt thereof, preferably bazedoxifene acetate. In some embodiments, the coating comprises: a) a filler component comprising from about 5% to about 30% by weight of the pharmaceutical formulation; b) a binder component comprising from about 1% to about 10% by weight of the pharmaceutical formulation; c) a wetting agent component comprising from about 0.01% to about 2% by weight of the pharmaceutical formulation; d) an optional antioxidant component comprising from 0% to about 2% by weight of the pharmaceutical formulation; e) bazedoxifene acetate, comprising from about 0.1% to about 20% by weight of the pharmaceutical formulation, and f) an optional chelating agent comprising from 0% to about 0.1% by weight of the pharmaceutical formulation.

In some additional embodiments, the coating comprises: a) a filler component comprising from about 6% to about 12% by weight of the pharmaceutical formulation; b) a binder component comprising from about 1% to about 6% by weight of the pharmaceutical formulation; c) a wetting agent component comprising from about 0.1% to about 3% by weight of the pharmaceutical formulation; d) an optional antioxidant component comprising from 0% to about 0.5% by weight of the pharmaceutical formulation; e) bazedoxifene acetate, comprising from about 2% to about 6% by weight of the pharmaceutical formulation; and f) an optional chelating agent comprising from 0% to about 0.1% by weight of the pharmaceutical formulation.

In some embodiments, the coating comprises: a) a filler component comprising from about 12% to about 18% by weight of the pharmaceutical formulation; b) a binder component comprising from about 4% to about 8% by weight of the pharmaceutical formulation; c) a wetting agent component comprising from about 0.2% to about 0.5% by weight of the pharmaceutical formulation; d) an optional antioxidant component comprising from 0% to about 0.8% by weight of the pharmaceutical formulation; e) bazedoxifene acetate, comprising from about 4% to about 9% by weight of the pharmaceutical formulation; and f) an optional chelating agent comprising from 0% to about 0.1% by weight of the pharmaceutical formulation. In some additional embodiments, the coating comprises: a) a filler component comprising from about 20% to about 30% by weight of the pharmaceutical formulation; b) a binder component comprising from about 6% to about 10% by weight of the pharmaceutical formulation; c) a wetting agent component comprising from about 0.4% to about 0.8% by weight of the pharmaceutical formulation; d) an optional antioxidant component comprising from 0% to about 1.2% by weight of the pharmaceutical formulation; e) bazedoxifene acetate, comprising from about 7% to about 14% by weight of the pharmaceutical formulation; f) an optional chelating agent comprising from 0% to about 0.1% by weight of the pharmaceutical formulation.

In some embodiments, the core of the composition includes conjugated estrogens and one or more fillers and / or a binder. In some embodiments, the conjugated estrogens include or consist of Premarin®. In general, the core includes conjugated estrogens in an amount of about 0.10% to about 1.0 mg, and forms about 45% to about 80% by weight of the pharmaceutical formulation. In some embodiments, the core includes conjugated estrogens in an amount of about 0.3 to about 0.8 mg. In some embodiments, the core includes conjugated estrogens in an amount of about 0.4 to about 0.5 mg; for example about 0.45 mg, or from about 0.5 to about 0.7 mg, for example about 0.625 mg. In some embodiments, the core is a filler tablet containing conjugated estrogens, preferably Premarin®. In some embodiments, the pharmaceutical compositions of the invention include at least one coating containing bazedoxifene, or a pharmaceutically acceptable salt thereof. In some embodiments, the bazedoxifene, or a pharmaceutically acceptable salt thereof, is present in an amount of about 1 to about 50 mg, based on the weight of the free base of bazedoxifene. As used herein, the term "based on the weight of the free base of bazedoxifene" is intended to represent the amount of bazedoxifene or a salt thereof that provides the same number of bazedoxifene molecules as indicated as the mass of the free base of bazedoxifene. Thus, for example, the phrase "10 mg of bazedoxifene acetate, based on the weight of the free base of bazedoxifene" should indicate a mass of bazedoxifene acetate sufficient to provide a number of bazedoxifene acetate molecules which is the same as the number of bazedoxiferium molecules present in 10 mg of the free base form of bazedoxifene. In some embodiments, the bazedoxifene, or the pharmaceutically acceptable salt thereof, is present in an amount of about 5 to about 25 mg, or about 5 to about 15 mg, or about 15 to about 25 mg, or about 35 mg. to approximately 45 mg, based on the weight of the free base of bazedoxifene. In some embodiments, bazedoxifene is present in the pharmaceutical formulation as the acetate salt. In some such embodiments, the bazedoxifene acetate present in the coating form ranges from about 0.1% to about 20% by weight of the pharmaceutical formulation; or from about 2% to about 6% by weight of the pharmaceutical formulation; or from about 4% to about 9% by weight of the pharmaceutical formulation; or from about 7% to about 14% by weight of the pharmaceutical formulation. In addition to the bazedoxifene, or the pharmaceutically acceptable salt thereof, the coating may contain one or more fillers, diluents, binders, wetting agents and / or antioxidants. In general, the filler component of the coating forms about 5% to about 30% by weight of the pharmaceutical formulation; or from about 6% to about 12% by weight of the pharmaceutical formulation; or from about 12% to about 18% by weight of the pharmaceutical formulation; or from 20% to about 30% by weight of the pharmaceutical formulation. The filler component may include one or more fillers known to be useful in the art, for example one or more of sugars, for example sucrose, mannitol, lactose and the like, and / or other fillers such as cellulose powder, microcrystalline cellulose, maltodextrin, sorbitol, starch, xylitol, carboxymethylcellulose, carboxyethylcellulose, hydroxyethylcellulose, cellulose microcrystalline, starch, dicalcium phosphate anhydrous, sodium starch glycollates and metal aluminoeilicatoe. In some modalities, the filling component of the coating includes one or more sugars. As used in the preamble, the term "sugar" refers to any type of simple carbohydrate, such as a mono or disaccharide, whether obtained naturally, refined from a natural source, or produced artificially, and includes, without limitation, eacaroea, dextroea, maltoea, glucoea, fructoea, galactoea, mannose, lactose trehalose, lactulose, levuloea, rafinoea, ribose and xylose. The term "sugar", as used herein, also includes various "sugar substitutes" widely known to those skilled in the art to prepare forms of doeide eolide, such that polyhydric alcohols (sometimes known as "alcohols") sugar alcohols "or hydrogenated saccharides), for example, sorbitol, mannitol, xylitol, and erythritol, and the sugar derivatives of the polyhydric alcohols, such as maltitol, lactitol, isomalt, and polyalditol. Therefore, the indication of the term "sugar" in general should be interpreted as including such specific compounds, also to other, not expressly indicated. In some embodiments, the sugar is a mono- or disaccharide, for example, sucrose, dextrose, maltose, glucose, fructose, galactose, mannose, or lactose. In some preferred embodiments, the filling component of the coating includes or consists of sucrose. In general, the binder component of the coating forms about 1% to about 10% by weight of the pharmaceutical formulation; or from about 1% to about 6% by weight of the pharmaceutical formulation; or from about 4% to about 8% by weight of the pharmaceutical formulation; or from about 6% to about 10% by weight of the pharmaceutical formulation. The binder component can include one or more binders known to be useful in the art, for example one or more of hydroxypropylmethylcellulose, carboxymethylcellulose, carboxyethylcellulose, hydroxyethylcellulose, microcrystalline cellulose, starches and polyvinylpyrrolidine (PVP). In some preferred embodiments, the filler component includes or consists of hydroxypropylmethylcellulose. It has been found in accordance with the present invention that sucrose, while not being a typical film-forming agent, such as hydroxypropylmethylcellulose, is particularly advantageous when used with a low degree of hydroxypropylmethylcellulose, for example 3 cpe. While not wishing to be bound by any particular theory, it is believed that sucrose adds body to the coating, and acts as a soluble filler in an active overcoat process. In general, it is beneficial to use a ratio of hydroxypropylmethylcellulose to sucrose about 1: 2 to about 1: 5, or about 1: 2 to about 1: 4; or from about 1: 2.5 to about 1: 3.5; or around 1: 3. Such a relationship is obtained which provides the most acceptable viscosity- and ability characteristics to be applied by spraying the filling solenoid at a level of 20% w / w solids for a continuous coating process. In general, the wetting agent component of the coating is selected to increase the degree of wetting of the components of the filler coating, and particularly, the bazedoxifene, and to thereby assist in dispersing the bazedoxifene. Preferably, the wetting agent has low foaming characteristics, and preferably has antimicrobial activity. In general, the wetting agent component of the coating forms about 0.01% to about 2% by weight of the pharmaceutical formulation; or from about 0.1% to about 3% by weight of the pharmaceutical formulation; or from about 0.2% to about 0.5% by weight of the pharmaceutical formulation; or from about 0.4% to about 0.8% by weight of the pharmaceutical formulation. The wetting agent component may include one or more wetting agents known to be useful in the art, for example one or more fatty acid esters of sucrose, such as sucrose palmitate, and Poloxamer 188, alkyl metal sulfates, lauryl sulfate sodium, ester of polyoxyethylene sorbitan fatty acid, polyethylene glycols, polyoxyethylene castor oil derivatives, sodium docusate, quaternary ammonium ammonium compound, sugar esters of fatty acids and fatty acid glycerides. In some preferred embodiments, the wetting agent component includes or consists of sucrose palmitate. In general, the optional antioxidant component of the coating forms about 15% by weight, for example from about 0% to about 15% by weight of the pharmaceutical formulation, from about 0.01% to about 5% by weight of the pharmaceutical formulation; from about 0.01% to about 2% by weight of the pharmaceutical formulation; or from about 0.1% to about 0.5% by weight of the pharmaceutical formulation; or from about 0.3% to about 0.8% by weight of the pharmaceutical formulation; or from about 0.6% to about 1.2% by weight of the pharmaceutical formulation. The antioxidant component, when present, may include one or more antioxidants known to be useful in the art, for example one or more of ascorbic acid or a salt thereof such as sodium ascorbate, ascorbyl palmitate, nicotinamide ascorbate, propyl gallate, tocopherol (alpha, beta and gamma), BHA / BHT, citric acid and saltse thereof, for example sodium citrate. In some preferred embodiments, the antioxidant component includes or consists of ascorbic acid. Additional examples of suitable fillers, binders, wetting agents and antioxidants can be found in, for example, Re-ington 'e Pharmaceutical Sciences, 17th ed. , Mack Publiehing Company, Eaeton, Pa., 1985, which is incorporated herein by reference in its entirety. In general, the optional chelation component forms approximately 0.1% by weight of the pharmaceutical formulation. In some embodiments, the chelation component is present in an amount from about 0.01% to about 0.10% in coating pee. The chelation component may include one or more chelating agents as are known in the art for use in pharmaceutical formulations. A preferred chelating agent is ethylenediaminetetraacetic acid (EDTA). Other suitable chelating agents can be found, for example, in Remington'e Pharmaceutical Science, cited above. In some modality, the optional antioxidant component, the optional chelation component, or both the optional antioxidant component and the optional chelation component, being further present in the coating as described above, may also each, independently and optionally be present. in one or more of the color coating and in the transparent coating, as described below. In some embodiments, the antioxidant component and the chelation component are present together in one or more of the coatings. Therefore, in some such embodiments, the antioxidant component and the chelating component are present in the coating containing the active agent, eg, bazedoxifene; or in the color coating; or in the transparent coating; or in any of the two coatings, or in all, the three coatings. In some embodiments, the additional pharmaceutical composition includes a color coating. In general, the color is formed on the first cover described above, and contains at least one coloring agent. In some embodiments, the color coating includes: a) an optional filler component that includes from about 0.1% to about 8% by weight of the pharmaceutical formulation; b) an optional binder component that includes from about 0.01% to about 2% by weight of the pharmaceutical formulation; and c) a coloring agent component that includes from about 0.01% to about 1% by weight of the pharmaceutical formulation. The color coating may also optionally include the aforementioned antioxidant component, or the aforementioned chelation component, or both, as described above. In general, the optional filler component of the color coating may include one or more filler as previously described for the first coating. In some modality, the filling component of the color coating, when present, includes or consists of sucrose. In general, the optional binder component of the color coating may include one or more binders as described above for the first coating. In some embodiments, the binder component of the color coating, when present, includes or contains hydroxypropylmethylcellulose. The coloring agent component can include one or more of any of the variety of coloring agents known to be useful in the pharmaceutical arts. In some embodiments, the coloring agent component includes or contains titanium dioxide. Also preferred are color agents which include, for example, Opadry® agents, for example Opadry® White YS-1-18202 A. In some embodiments, the pharmaceutical compositions of the invention further include a tranepant coating. In some modality, the tranepant coating includes from about 0.01% to about 2% by weight of the pharmaceutical formulation. In general, the transparent coating is formed on the color coating, when present, as previously described, or alternatively, directly on the first cover as described above. Any of the numerous transparent coatings are known in the art and are suitable for use in the pharmaceutical compositions of this invention, for example Opadry® coatings, for example transparent Opadry® YS-2-19114 A. The tranepant coating may also include optionally to the antioxidant component mentioned above, or the chelation component mentioned above or amboe, as described above. In some embodiments, the invention provides processes for preparing the pharmaceutical compositions of the invention. In some embodiments, the processes are used to prepare pharmaceutical compositions of the invention that include: a core that includes conjugated eetrogens; and a first coating that includes bazedoxifene or a pharmaceutically acceptable salt thereof. In some embodiments, the methods include: i) providing a core that includes conjugated estrogens, and ii) coating the core with a coating composition that includes bazedoxifene or a pharmaceutically acceptable salt of the core to form a coated core. In some modality, the processes further include the step of: iii) coating the coated core with a colored covering composition to form a colored coated composition. In some embodiments, the processes further include the step of: iv) coating the color cover composition with a clear coating composition to form a tranepant coating thereon. Traditionally, the sugar coatings are applied to the tablet form using an intermittent process. In the active intermittent sugar coating process, the discrete amounts of the active sugar coating suspension are applied to the surface of a dosage form, for example a tablet, followed by a distribution phase and a drying phase, the which is repeated several hundred vecee until it achieves the desired weight gain. Varioe commonly marketed products are manufactured using this technique. This process, however, has some limitations. Examples of such limitations are the limited loading capacity of the drug to maintain a tablet size and reasonable process times, and the limitation of the available excipients that can be used to modify the rate of release and the inherent variability of the process. While intermittent procedures have been acceptable for formulations, it has been found, in accordance with the present invention, that sugar coatings can be applied to tablets or other dosage forms that can be coated by a continuous process. In continuous sugar coating processes, active euepeneion is applied in a "continuous manner" which is similar to the traditional film coating process from the process point of view. It is known that sugar, as such in a solution, can not be applied by continuous spraying on the tablet because of its inherent physicochemical properties, such as the solubility, the viscosity and its crystallization kinetics when dried by spray application. about the tablets. However, the use of the formulations described herein, with the control of the appropriate process variables, produces a product of acceptable quality and stability, and addresses the limitations of the intermittent sugar coating process described above. Accordingly, in some embodiments, coating the core with a coated composition that includes bazedoxifene or a pharmaceutically acceptable salt thereof is carried out by the continuous process. In some embodiments, the coated composition of step ii) includes: a) a filler component; b) a binder component; c) a wetting agent component; d) an optional antioxidant component; e) bazedoxifene acetate; and f) an optional chelation component, wherein the filler component, the binder component, the wetting agent component, the optional antioxidant component, and the optional chelation component as ee have described above. In some preferred embodiments, the filler component of the coating comprises eacarose; the binder component of the coating comprises hydroxypropylmethylcellulose; the wetting agent component of the coating comprises eacaroea palmitate; and the optional antioxidant component of the coating, when present, comprises aecorbic acid, or a salt thereof, and the optional chelating component, when present, comprises EDTA. In some embodiments, the color cover composition includes; an optional filler component; an optional binder component; and a coloring agent component; wherein the optional filler component, the optional binder component, and the coloring agent component are as described above. The color coating optionally may also include the aforementioned antioxidant component or the aforementioned chelation component, or both, as described above. In some embodiments, the optional filler component of the color coating composition includes sacaroea; the optional binder component of the color coating composition includes hydroxypropylmethylcellulose; and the coloring agent component of the color coating composition includes titanium dioxide. In some embodiments, the optional antioxidant component of the color coating, when present, comprises ascorbic acid, or a salt of the mole; and the optional chelation component of the color coating, when present, comprises EDTA. In some modality, the filling component of the coating composition of step ii) forms about 5% to about 30% by weight of the pharmaceutical formulation, the binder component of the coating composition of step ii) forms about 1% to about 10% by weight of the pharmaceutical formulation; the wetting agent component of the coating composition of step ii) forms about 0.01% to about 2% by weight of the pharmaceutical formulation; the optional antioxidant component of the coating composition of step ii) forms about 0% to about 2% by weight of the pharmaceutical formulation; and bazedoxifene acetate includes from about 0.1% to about 20% by weight of the pharmaceutical formulation. And the optional chelation component of the coating forms from 0% to about 0.1% by weight of the pharmaceutical formulation. In some embodiments, the conjugated estrogens are present in an amount of about 0.10 to about 1.0 mg. In some additional embodiments, bazedoxifene is present in an amount of about 1 to about 50 mg, based on the weight of the free base of bazedoxifene. In some additional embodiments, the conjugated estrogens are present in an amount of about 0.10 to about 1.0 mg; and bazedoxifene is present in an amount of about 5 to about 50 mg, based on the weight of the free base of bazedoxifene. In some embodiments of each of the pharmaceutical compositions and processes of the invention, the conjugated eetrogen includes or connects with Premarin®. In some embodiments of each of the pharmaceutical compositions and processes of the invention, the eetrogenoe conjugates eethan preends in the composition in an amount of about 0.10 to about 1.0 mg; or from about 0.3 to about 0.8 mg; or from about 0.4 to about 0.5 g; or from about 0.5 to about 0.7 mg. In some embodiments of each of the pharmaceutical compositions and processes of the invention, bazedoxifene is present in an amount of about 1 to about 50 g; or from about 5 to about 25 mg; or from about 5 to about 15 mg; or from about 15 to about 25 mg; or from about 35 to about 45, based on the weight of the free base of bazedoxifene. In some embodiments of each of the pharmaceutical compositions and processes of the invention, the conjugated estrogens are present in an amount of about 0.10 to about 1.0 mg; and bazedoxifene is present in an amount of about 5 to about 50 mg, based on the weight of the free base of bazedoxifene. In some embodiments of each of the pharmaceutical compositions and processes of the invention, the conjugated estrogens eethan preend in the composition in an amount of about 0.4 to about 0.5 mg; or from about 0.5 to about 0.7; and bazedoxifene is present in an amount of about 5 to about 15 mg; or from about 15 to about 25 mg; or from about 35 to about 45 mg, based on the weight of the free base of bazedoxifene. The present invention also provides products of the processes described herein. It will be understood that the aforementioned weight percentages for each of the filler core components, the binder components, the wetting agent components, the optional antioxidant components, the optional chelating component, the optional filler components, the binder components optional, the coloring agent components and the transparent coatings of the compositions described herein find in percentage that each component will comprise a final pharmaceutical composition, including, if present, transparent and colored coatings. Oral formulations containing the present solid dispersions can comprise a variety of oral forms conventionally used, for example tablets and tablet forms in capsules. In general, tablets and tablet formae in capsules are preferred. Lae capeulae or tablets containing the solid pre-tensor may also be combined with mixtures of other active or filler compounds inert and / or diluent, such as pharmaceutically acceptable starches (eg, corn, potato or tapioca starch), sugars , artificial sweetening agents, powdered cellulose, talee as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc. In some preferred embodiments, the formulations are tablets. Tablet formulations can be prepared by any conventional method of compression, wet granulation, or dry granulation and using pharmaceutically acceptable diluent (filler), binder, lubricants, disintegrants, stabilizing or suspending agents, including those described above, as well as without limitation magnesium stearate, ethereal acid, talc, sodium lauryl sulfate, cellulose microcrystalline, calcium carboxymethyl cellulose, polyvinyl pyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, silicate complexe, calcium carbonate, glycine , dextrin, eacaroea, eorbitol, dicalcium phosphate, calcium eulfate, lactoea, kaolin, mannitol, eodium chloride, talc, starch, and powdered sugar. The standard formulations used in the present can use standard delay or release formulations over time or spandose. The formulations of the suppositories can be prepared 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 can also be used, such as polyethylene glycols of diverse molecular structure. The coatings of films useful with the present formulations are known in the art and generally consist of a polymer (usually a type of cellulosic polymer), a colorant and plasticizer. Additional ingredients such as wetting agents, sugars, flavors, oil and lubricants may also be included in the film cover formulations to impart certain characteristics for the sheet cover. The compositions and formulations described in the preamble can also be combined and processed as a solid, then placed in a capsule form, such as a gelatin capsule.

As will be appreciated, some components of the formulations of the invention may possess multiple functions. For example, a delivered component that acts as a binder and a filler. In some cases, the function of a given component can be considered singular, even though its properties may allow multiple functionality. The additional excipients and the doεeεe formaεe, the dieεeεe agent and the like which are suitable for use in connection with the solid diereεeεeεe of the invention are known in the art and are described in, for example, Remington's Pharmaceutical Sciences, 17th ed. , Mack Publishing Company, Eaeton, Pa., 1985, which is incorporated herein by reference in its entirety. As described above, it has been found in accordance with the present invention, that sugar coatings can be applied to tablets or other dosage forms that can be coated by a continuous process. Accordingly, in some embodiments, the present invention provides for a process for preparing a pharmaceutical composition, wherein the composition comprises: a core comprising a therapeutic agent; and a coating optionally comprising a second therapeutic agent and at least one sugar; the procedure comprises: i) providing a core comprising the first therapeutic agent; and ii) coating the core with a coating composition comprising: a) a filler component comprising at least one sugar; b) a binder component; c) a wetting agent component; d) an optional antioxidant component; e) optionally, a second therapeutic agent; and f) an optional chelation component. wherein the coating composition of step ii) is applied by a continuous sugar coating technique. In some such embodiments: the filler component comprises one or more of sucrose, mannitol, lactose, cellulose powder, microcrystalline cellulose, maltodextrin, sorbitol, starch, xylitol, carboxymethylcellulose, carboxyethylcellulose, hydroxyethylcelluloses, microcrystalline celluloses, starch, anhydrous dicalcium phosphate, glycolates of sodium starch and alu inosilicatoe etálicoe; the binder component comprises one or more of hydroxypropylmethylcellulose, carboxymethylcellulose, carboxyethylcellulose, hydroxyethylcellulose, microcrystalline celluloses, starches; the wetting agent component comprises one or more of sucrose palmitate, and Poloxamer 188, metal alkyl sulfates, sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid ester, polyethylene glycols, polyoxyethylene castor oil derivatives, sodium docusate, ammonium of quaternary amine, sugar esters of fatty acids and glyceride of fatty acids; and the optional antioxidant component, when present, comprises one or more of ascorbic acid, citric acid, eodium ascorbate, ascorbyl palmitate, nicotinamide ascorbate, propyl gallate, alpha tocopherol, beta tocopherol, gamma tocopherol and BHA / BHT, and the optional chelation component, when present, comprises EDTA. In some additional embodiments, the filling component of the coating comprises sucrose; the binder component of the coating comprises hydroxypropylmethylcellulose; the wetting agent component of the coating comprises sucrose palmitate; and the optional antioxidant component of the coating comprises ascorbic acid, or a salt thereof, and the optional chelation component, when present, comprises EDTA. In some embodiments, the processes further comprise the step of iii) coating the coated core with a color coating composition to form a color coated composition; and in some additional embodiments, the processes further comprise the step of iv) coating the color coated composition with a transparent coating composition to form a clear layer thereon. The first therapeutic agent can be any of a variety of therapeutic agents. As used in this, the term "therapeutic agent" also refers to a substance that is capable of exerting a biological therapeutic effect in vivo. The therapeutic agents can be neutral or charged positively or negatively. Examples of pharmaceutically suitable agents include, among others, diagnostic agents, pharmaceuticals, drugs, synthetic and organic molecules, proteins, peptides, vitamins and steroids. For example, the composition may include one or more hormonal steroids, such as medroxyprogesterone acetate, levonorgestrel, gestodene, medrogestone, estradiol, estriol, ethinylestradiol, mestranol, estrone, dieneetrol, hexetrol, diethylethylbestrol, progesterone, desogeetrel, norgeetimate, hydroxyprogeeterone, norethindrone. , norethindrone acetate, norgeetrel, megestrol acetate, methyltestosterone, ethylestrerenol, methandienone, oxandrolone, trimegethone, dionogeet and eimilaree. In addition, progenytherones of eelective tissue and / or progesterone antagonists, which may or may not have the typical spheroidal functionality, may be present in the composition. This includes, but is not limited to: RU-486 <mifepristone), ZK 98 299 (onapristone), ZK-137316 (Schering AG, Berlin.}., ZK-230211. {Schering AG, Berlin), and HRP-2000 (17-acetoxy- (llß- (4- N, N-dimethylaminophenyl)] -19-norpregna-4,9-diene-3, 20-dione.) When desired, estrogenic steroids and progestogenic steroids can be used in combination. The processes of the present invention are particularly suitable for used in the coating of core materials, eg tablets, to produce a coated solid dose form The term "core material" refers to any tablet, capsule, particle, micronized particle, particulate, pellet, pill, core granule, granulate, small mass, eemilla, pequee trozoe, spheres, crystals, beads, agglomerates, mixtures of the same and eimilaree that are sufficiently stable physically and chemically to be effectively coated in a continuous sugar coating process. preferred modality rida, the core material is present in the tablet form. As used in the preamble, the term "tablet" refers to a solid pharmaceutical dosage form containing a therapeutic agent with or without suitable diluents and which is prepared either by compression or molding methods, such as are well known to those skilled in the art. Suitable methods for forming tablets as described, for example, in Edward M. Rudnick, et al., "Oral Solid Doeage Forme," in Remington: The Science and Practice of Pharmacy, 20th Ed., Chap. 45, Alfoneo R. Cennaro, ed. , Philadelphia College of Pharmacy and Science, Philadelphia, PA (2000), which is incorporated herein by reference in its entirety. In some modality, the core material is a tablet formed by compression method. Most often the core material will at least comprise a therapeutic agent, as defined above, and at least one pharmaceutically acceptable excipient. The term "pharmaceutically acceptable", as used herein, refers to materials that are generally non-toxic or harmful to a patient when used in the compositions of the present invention, including when the compositions are administered through the orally. The term "patient", as used herein, refers to animals, including mammals, preferably humans. The term "excipient", as used herein, refers to ingredients that provide volume, impart satiefactory characteristics to processing and compression, assist in the control of the rate of dissolution, and / or otherwise impart desirable additional physical characteristics. for the core material. Included within this term, for example, diluents, binders, lubricants and disintegrants well known to those skilled in the art, as described, for example, in Handbook of Pharmaceutical Excipient, American Pharmaceutical Association, Washington, D.C. and The Pharmaceutical Society of Great Britain, London, England (1986), which are incorporated herein by reference in their entirety. A wide variety of therapeutic agents can be used either in the core material (ie, as the first therapeutic agent), or in the coating (ie, as the second therapeutic agent). Specific examples of therapeutic agents include, but are not limited to: acetazolamide, acetohexamide, acrivastine, alatrofloxacin, albuterol, alclofenac, aloxiprine, alproetadyl, amodiaquine, amphotericin, amylobarbital, aspirin, atorvasta ina, atovaquone, baclofen, barbital, benazepril, bezafibrate, bro fenaco, bumetanide, butobarbital, candesartan, capsaicin, captopril, cefazolin, celecoxib, cefadrine, cephalexin, cerivastatin, cetrizin, chlorambucil, chlorothiazide, chlorpropamide, chlorthalidone, cinoxacin, ciprofloxacin, clinofibrate, cloxacillin, cromoglycate, cromolyn, dantrolene, dichlorophene, diclofenac , dicloxacillin, dicumarol, diflunisal, dimenhydrinate, divalproex, docusate, dronabinol, enoximone, enalaprila, enoxacin, enrofloxacin, epalrestat, eposartan, fatty acids, estramustine, ethacrynic acid, ethotoin, etodolac, etoposide, fenbufen, fenoprofen, xofenadine, fluconazole, flurbiprofen, fluvastatin , fosinopril, foephenytoin, fumagillin, furosemide, gabapentin, gemfibrozil, gliclazide, glipizide, glibenclamide, glyburide, glimepiride, grepafloxacin, ibufenac, ibuprofen, imipenem, indomethacin, irbesartan, isotretinoin, ketoprofen, ketorolac, lamotrigine, levofloxacin, lieinopril, 1ornefloxacin, losartan , lovaetatin, mecfenamic acid, mefenamic acid, mesalamine, methotrexate, metolazone, montelukast, nalidixic acid, naproxen, natamycin, nimesulide, nitrofurantoin, acide graeoe not eeencialee, norfloxacin, nietatin, ofloxacin, oxacillin, oxaprozin, oxifenbutazone, penicillins, pentobarbital, perfloxacin , phenobarbital, phenytoin, pioglitazone, piroxica m, pramipexole, pranlukaet, pravastatin, probenecid, probucol, propofol, propylthiouracil, quinaprila, rabeprazole, repaglinide, rifampin, rifapentine, sparfloxacin, eulfabenzamide, eulfacetamide, eulfadiazine, sulfadoxine, eulfamerazine, eulfametoxazole, sulfafurazole, sulfapyridine, sulfasalazine, sulindac, eulfaealazine, euthyma, telmieartan, teniposide, terbutaline, tetrahydrocannabinol, tirofiban, tolazamide, tolbutamide, tolcapone, tolmethine, tretinoin, troglitazone, trovafloxacin, undecenoic acid, ursodeoxycholic acid, valproic acid, valeartan, vancomycin, verteporfin, vigabatrin, vitamin KS (II) and zafirlukast . Additional therapeutic agents include abacavir, acebutolol, acrivastine, alatrofloxacin, albuterol, albendazole, alfentanil, alprazolam, alprenolol, amantadine, amiloride, inoglutethimide, amiodarone, amitriptyline, amlodipine, amodiaquine, amoxapine, amphetamine, amphotericin, amprenavir, amrinone, amsacrine, apomorphine. , astemizol, atenolol, atropine, azathioprine, azelastine, azithromycin, baclofen, benetamine, benidipine, benzhexol, benznidazole, benztropine, biperiden, bisacodyl, bisantrene, bromazepam, bromocriptine, bromperidol, brompheniramine, brotizolam, bupropion, butenafine, butoconazole, cambendazole, camptothecin , carbinoxamine, cefadrine, cephalexin, cetrizine, cinnarizine, chlorambucil, chlorpheniramine, chlorproguanil, chlordiazepoxide, chlorpromazine, chlorprothixene, chloroquine, cimetidine, ciprofloxacin, cisapride, citalopram, clarithromycin, clemastine, clemizole, clenbuterol, clofazimine, clomiphene, clonazepam, clopidogrel, clozapine , clotiazepam, clotrimazole, codeine , cyclisine, cyproheptadine, dacarbazine, darodipine, decoquinate, delavirdine, demeclo-cyclin, dexanfe amine, dexchlorpheniramine, dexfenfluramine, diamorphine, diazepam, diethylpropion, dihydrocodeine, dihydroergotamine, diltiazem, dihydrazinate, diphenhydramine, diphenoxylate, diphenyl-imidazole, diphenylpyraline, dipyridamole , disopyramide, dolasetron, domperidone, donepezil, doxazosin, doxycycline, droperidol, econazole, efavirenz, elipticin, enalaprila, enoxacin, enrofloxacin, eperisone, ephedrine, ergotamine, erythromycin, ethambutol, ethionamide, ethopropazine, etoperidone, famotidine, felodipine, fenbendazole, fenfluramine, phenoldopam, fentanyl, fexofenadine, flecainide, flucytoeine, flunarizine, flunitrazepam, fluopromazine, fluoxetine, flufenthixol, flufenthixol decanoate, flufenazine, fluphenazine decanoate, flurazepam, fluritromycin, frovatriptan, gabapentin, granieetron, grepafloxacin, guanabenzo, halofantrine, haloperidol, hyoscyamine, imipenem, indinavir, iri notecan, ieoxazol, ieradipine, itraconazole, ketoconazole, ketotifen, labetalol, lamivudine, lanzoprazole, leflunomide, 1evofloxacin, lieinopril, lomefloxacin, loperamide, loratadine, lorazepam, lormetazepam, lieuride, mepacrine, maprotiline, mazindol, mebendazole, meclizine, medazepam, mefloquine, melonicam, meptazinol, mercaptopurine, meealamine, meeoridazine, metforminmethadone, methaqualone, methylphenidate, methylphenobarbital, methysergide, metoclopramide, metoprolol, metronidazole, mianserin, miconazole, midazolam, miglitol, minoxidil, mitomycins, mitoxantrone, modafinil, molindone, montelukast, morphine, moxifloxacin, nadolol, nalbuphine, naratriptan, natamycin, nefazodone , nelfinavir, nevirapine, nicardipine, nicotine, nifedipine, nimodipine, nimorazol, nieoldipine, nitrazepam, nitrofurazone, nizatidine, norfloxacin, nortriptyline, nietatin, ofloxacin, olanzapine, omeprazole, ondansetron, omidazole, oxamniquine, oxantel, oxate ida, oxazepam, oxfendazole, oxiconazole, oxprenolol, oxybutynin, oxyphencyclimine, paroxetine, pentazocine, pentoxifyne, perchloride, perfloxacin, perphenazine, fenbenzamine, feniramine, phenoxybenzamine, phentermine, fieoetigmine, pimozide, pindolol, pizotifen, pramipexole, pranlukaet, praziquantel, prazosin, procarbazine, prochlorperazine, proguanil, propranolol, peedoephedrine, pyrantel, pyrimethamine, quetiapine, quini dina, quinine, raloxifene, ranitidine, remifentanil, repaglinide, reserpine, ricobendazole, rifabutin, rifampin, rifapentine, rimantadine, risperidone, ritonavir, rizatriptan, ropinirole, rosiglitazone, roxatidine, roxithromycin, salbutamol, saquinavir, selegiline, sertraline, sibutramine, sildenafil, sparfloxacin, eepiramicinae, etavudine, sufentanil, sulconazole, sulfaealazine, sulpiride, sumatriptan, tacrine, tamoxifen, tamsulosin, temazepam, terazosin, terbinafine, terbutaline, terconazole, terfenadine, tetramisol, thiabendazole, thioguanine, thioridazine, tiagabine, ticlopidine, timolol, tinidazole, thioconazole, tirofiban, tizanidine, tolterodine, topotecan, toremifene, tramadol, trazodone, triamterene, triazolam, trifluoperazine, trimethoprim, trimipramine, tromethamine, tropheamide, trovafloxacin, vancomycin, venlafaxine, vigabatrin, vinblastine, vincristine, vinorelbine, vitamin K5, vitamin K6, vitamin K7, zafirlukast, zolmitriptan, zolpidem and zopiclone. Of course, any of the aforementioned therapeutic agents can be included in the coating composition, as described above, and any of the therapeutic agents described with respect to the coating composition can alternatively be included in the core material. The core material can be designed to deliver therapeutic agents that are intended to be supplied over a prolonged period. The following are representative of such therapeutic agents: anti-inflammatory, antipyretic, anti-spasmodic or analgesic such as indomethacin, diclofenac, diclofenac sodium, codeine, ibuprofen, phenylbutazone, oxyphenbutazone, mepirizole, aspirin, etenzamide, acetaminophen, aminopyrine, phenacetin, bromide butylscopolamine, morphine, etomidoline, pentazocine, calcium fenoprofen, naproxen, eelecxip, valdecxip and tolamadol, anti-rheumatism drugs such as etodolac, talee anti-tuberculosis drugs such as isoniazid and ethambutol hydrochloride, cardiovascular drugs such as isosorbide dinitrate, nitroglycerin, nifedipine, barnidipine hydrochloride, nicardipine hydrochloride, dipyridamole, amrinone, indenolol hydrochloride, hydralazine hydrochloride, methyldopa, furosemide, spironolactone, guanetidine nitrate, reeerpine, amoeulalol hydrochloride, lisinopril, metoprolol, pilocarpine, and talcetin, antipsychotic drugs like clorhid time of chlorpromazine, amitriptyline hydrochloride, nemonapride, haloperidol, moperone hydrochloride, perphenazine, diazepam, lorazepam, chlorodiazepoxide, adinazolam, alprazolam, methylphenidate, mirnasipran, peroxetine, risperidone and sodium valproate, anti-emetics such as metoclopramide, lamocetron hydrochloride, granisetron hydrochloride, ondansetron hydrochloride and azacetron hydrochloride, antihistamines such as chlorpheniramine maleate and diphenhydramine hydrochloride, vitamins such as thiamine nitrate, tocopheryl acetate, cycothiamine, pyridoxal phosphate, cobarnamide, ascorbic acid, and nicotinamide, anti-gout drugs such as allopurinol, colchicine, and probenecid, anti-Parkinson's disease drugs such as levodopa and selegrina, sedantee and hypnotic talee such as amobarbital, bromuralil urea, midazolam and doral hydrate, antineoplaics such as fluorouracil, carmofur, acralvidin hydrochloride, cyclophosphamide and thiodepa, anti-allergy drugs such as pseudoephedrine and terfenadine, deecongestants such as phenylpropanolamine and efedorin, drugs for diabetes mellitus such as acetohexamide, insulin, tolbutamide, desmopressin and glipizide, diuretics such such as hydrochlorothiazide, polythiazide, triamterene, bronchodilators such as aminophylline, formoterol fumarate and theophylline, tartaric acid such as codeine foefate, noecapine, dimorphane phorphate and dextromethorphan, anti-arrhythmic drugs such as quinidine nitrate, digitoxin, propafenone hydrochloride, and procainamide, aneetéeicoe topical such as ethyl aminobenzoate, lidocaine, and dibucaine hydrochloride, anticonvulsants such as phenytoin, ethosuximide, and primidone, synthetic glucocorticoids such as hydrocortisone, prednisolone, triamcinolone, and betamethasone, anti-ulcers such as fa otidin, ranitidine hydrochloride, cimetidine, eucralfate, eulpiride, teprenone, plaunotol, 5-aminosalicylic acid, sulfasalazine, omeprazole and lansoprazole, drug for the central nervous system such as indeloxazine, idebenone, thiapride hydrochloride, bifemelane hydrochloride and calcium homopantotenate, antihyperlipoproteinidemia as sodium pravaetatin, simvaetatin, lovastatin, and atorvastatin, talee antibiotics such as ampicillin hydrochloride, phthalyleacetamide, cefotetan and joeamycin, therapeutic agents of BPH such as tamsulosin hydrochloride, doxazosin mesylate and terazoein hydrochloride, drugs that affect uterine motility talee as branilcast, zafilcast, albuterol, amb roxol, budesonide, and reproterol, improved the peripheral circulation of proleglandin I derivative, talee as erythium beraproet, anticoagulants, hypotensives, agent for the treatment of heart failure, agents used to treat divertere complications of diabetee, therapeutic agents peptic ulcer, skin ulcer therapeutic agents, agents used to treat hyperlipidemia, tocolytics, etc. The therapeutic agent can be used in its free form or as a pharmaceutically acceptable salt. In addition, one or a combination of two or more therapeutic agents may be present in the core material. In some embodiments, the therapeutic agent in the core material includes conjugated estrogens. The term "conjugated estrogens" (CE) as used herein includes both natural and synthetic conjugated estrogens, such as the compounds described in the United States Pharmacopeia (USP 23), as well as other estrogens so considered by those skilled in the art. . In addition, the "conjugated eetrogens" refer to esters of such compounds, such as the eulfate ether, the esters of such compounds, such as sodium salts and the salts of salts of such compounds, such as sodium salts of a eulfate ester, as well as other derivatives known in the art. Some specific examples include: 17-alpha and beta-dihydroequilin, equilenin, 17-alpha and beta-dihydroequilenin, estrone, 17-beta-estradiol and their sodium sulfate esters. Although ECs are usually a mixture of estrogenic components, such as eetrone and equilin, the core material can be formulated to make a mixture or to include only selected or individual estrogenic components. Eetoe CE may be of natural or synthetic origin. Examples of oestrogens produced in synthetic form include, among others, sodium estrone sulfate, sodium equilin sulfate, sodium 17a sulfate, sodium dihydroequilin sulfate, sodium 17β-dihydroequilin sulfate., sodium sulfate 17 -estradiol, sodium 17β-estradiol eulfate, equilenin sodium sulfate, sodium 17a-sulfate dihydroequilenin, sodium 17β-dihydroequilenin sulfate, eetropipate and ethinyl estradiol. The salts of etalee alkalinoe of 8,9-deehydroettrone and the alkali metal saltse of 8,9-dehydroestrone sulfate ester can also be used, as described in US Patent No. 5,210,081, which is incorporated herein by reference. reference. Loe that exist naturally in general are obtained from pregnant mare's urine and then come and can be stabilized. Examples of such processes are indicated in US Pat. Nos. 2,565,115 and 2,720,483, each of which is incorporated herein by reference. Many CE products are commercially available. The naturally-occurring EC product known as Premarin® (Wyeth, Madieon, NJ). Another commercially available CE product prepared from eetrogenoe eintéticoe ee Cenestin® (Duramed Pharmaceuticals, Inc., Cincinnati, Ohio). The specific CE doeie included in the core material can be any doeie required to achieve a specific therapeutic effect, and can vary depending on the specific treatment indicated, and the specific CE included in the tablet. In some embodiments, the first active agent comprises conjugated estrogens, and the second active agent comprises bazedoxifene or a salt thereof. It is intended that the material, methods and examples presented in the preamble be illustrative, and is not intended to limit the scope of the invention.

EXAMPLES Example 1 Process for the preparation of tablets containing estrogen conjugate / bazedoxifene acetate; 0.45 mg / 10 mg. A. Preparation of 10% w / w broth of hydroxypropylmethylcellulose solution, USP 2910, 3 cps. 1. 900 g of purified water, USP, were placed in a container equipped with a low-cut mixer < Type Lightnin). 2. 100 g of hydroxypropylmethylcellulose, USP 2910, 3 cps, were added in small increments to the vortex created in the water by means of stirring step 1. 3. Agitation was continued for a minimum of one hour, or until dissolved all the hydroxypropylmethylcellulose, USP 2910, 3 cpe. 4. If necessary, add USP purified water to achieve the total theoretical weight. Bl Preparation of the bazedoxifene acetate filler coating suspension: 1. 428.30 g of USP purified water was placed in a vessel equipped with a low cut mixer (Lightnin type) and a high cut mixer (Silverston type). 2. With the Lightnin type mixer turned on, the water was heated to 60-702C (white 652C). 3. With the Lightnin-type mixer turned on at low speed, 110.64 g of sacaroea, NF were added and the mixture was reheated to 65 ° C and kept at this temperature for 10 minutes, and the sucrose was diluted. 4. With the Lightnin type mixer turned on at low speed, 2.5523 g of sucrose palmitate were added and the mixture was continued at low speed for 10 minutes. If necessary, mixing can be carried out at high cutting speed for 2 minutes with the high cut mixer to disperse and dissolve any non-depleted palmetto of eacaroea. 5. The mixture was then cooled between 23-27SC (25SC white). When the mixture reached approximately 30 ° C, 4.0837 g of ascorbic acid USP were added slowly and mixing was continued using the Lightnin-type mixer for 10 minutes. 6. When the mixture reached 23-27 ° C (25aC white), the mixing ceased, and 46,054 g of bazedoxifene acetate were added. The low and high cut mixers were turned on, and mixing was continued for approximately 15 minutes. 7. Both mixers were turned off, the walls and shafts of the mixers were scraped and both mixers were turned on for an additional 15 minutes. 8. Both mixers were quenched and a sufficient amount of 10% of the hydroxypropylmethylcellulose solution broth, USP 2910, 3 cps from step B above, was added to provide 408.37 g of hydroxypropylmethylcellulose, USP 2910, 3 cps. The mixture was combined at low speed for 10 minutes, adjusting the speed of the mixer to prevent the generation of excess foam. 9. The euepension of the previous stage 8 was brought to the Theoretical Weight with purified USP water and the mixing was continued for 10 minutes and added with the Lightnin type mixer at low speed. 10. The mixing of the eeolution continued with the Lightnin-type mixer at low speed and intermittently with the high-cut mixer, as needed while maintaining the temperature at 23-27 SC (25SC white). Mixing continued with the low-cut mixer until the level of suspension fell under the head of the agitator.

B2. Alternative procedure for the preparation of bazedoxifene acetate fill-coating suspension: 1. Water, USP, purified was placed in a suitable container with a low-cut blender. { Lightnin type) and a high cut mixer (Silverston type or equivalent). 2. With the Lightnin type mixer turned on, the water was heated between 55-65aC (white 60aC). 3. The speed of the lightnin mixer was adjusted to create a vortex without extracting the air inside the water.

The eacarosa palmitate was slowly added to the vortex and mixed for approximately 20 minutes to dissolve it. The high cut mixer was used for about 5 minutes to dispene and dissolve any undissolved particles of sucrose palmitate. 4. With the Lightnin-type mixer on, the NF was added to the vortex and reheated between 55-65aC (white 60aC) and then mixed for about 15 minutes to dissolve the sacaroea NF. The temperature was then maintained at 60 ° C for about 15 minutes to ensure that all sucrose is dissolved. 5. With the Lightnin type mixer on, hydroxypropylmethylcellulose, USP 2910, 3 cps was added to the vortex and reheated between 55-65aC (white 60SC). The high cut mixer can be used during and after the addition to assist with the wetting of hydroxypropylmethylcellulose, USP 2910, 3 cps. The dispersion was mixed for approximately 15 minutes to die the hydroxypropylmethylcellulose, USP 2910, 3 cps, with the speed of the mixer being adjusted to obtain adequate mixing. The temperature was maintained at 60aC for approximately 15 minutes to ensure that all the hydroxypropylmethylcellulose, USP 2910, 3 cps had dispersed well without forming any lumps. 6. With the Lightnin type mixer on, the solution from the previous stage was cooled between 23-27 BC (white 259C). Once the temperature decreased below 30 ° C, ascorbic acid USP was slowly added and the mixture was continued by running the Lightnin-type mixer for approximately 10 minutes to dissolve the USP-acidic acid. 7. When the temperature reached 23-272C (white 25aC) the bazedoxifene acetate was added to the vortex. Once the bazedoxifene acetate was added, the high-cut mixer was turned on and the mixture was continued for approximately 10 minutes, with the energy of the high-cut mixer being shaken so as not to generate excessive foam. 8. Both mixers were turned off and the tank walls were scraped off the mixer shaft. Both mixers were fired with loe miemoe ajuetee as used in the previous stage and mixing continued for about 10 minutes to dietease the bazedoxifene acetate. 9. The suspension from the previous stage was brought to the theoretical weight with USP water, purified as necessary and mixing was continued for an additional 10 minutes with the Lightnin type mixer at low speed. 10. Mixing of a suepeneum with the mixer of type Lightnin and intermittently with the high cut mixer (as needed) continued during the apption, while maintaining the temperature between 23-27 SC (white 25SC). Mixing was carried out continuously with the high cutter mixer that the level of suspeneion fell below the head of the agitator.

C. Preparation of color coating suspension: 1. 675 g of USP purified water, were placed in a container equipped with a low cut mixer (Type Lightnin) and a high cut mixer (Silverson type). 2. With the Lightnin type mixer turned on, the water was heated between 60-70aC (white 65aC). 3. The speed of the Lightnin mixer was adjusted to create a vortex without extracting the air inside the water. 300 g of sucrose, NF were added to the vortex and the mixture was reheated between 60-70aC (65SC white), mixed for about 15 minutes to dissolve the sucrose NF and then kept at this temperature for 15 minutes., making sure that all the sacaroea was dissolved. 4. With the Lightnin type mixer turned on, 10 g of hydroxypropylmethylcellulose, USP 2910, 3 cps were added to the vortex and the mixture was reheated between 60-7 BC (white 65aC). The high-cut mixer was used during and after the addition to assist with the wetting of hydroxypropylmethylcellulose, USP 2910, 3 cps. Mixing was continued for 5 minutes, with the speed of the mixer being adjusted to obtain adequate mixing. The mixture was maintained at 65 aC for 5 minutes, making sure that all the hydroxypropylmethylcellulose, USP 2910, 3 cps would disperse well without the formation of lumps. 5. With the Lightnin type mixer turned on, the mixture was cooled between 23-27eC (25aC white), bringing the mixture to the pee with purified USP water as needed. 6. No more than 2 hours before the color suspension was added to the tablet, 15 g of titanium dioxide NF were added to the mixture, which was then combined with the high-cut blender and the low-cut blender. for 10 minutes. 7. Both mixers were turned off, the walls and shafts of the mixers were scraped and both mixers were turned on for an additional 5 minutes. The mixing was continued with the low cut mixer during the application of the color.

D. Preparation of a transparent coating suspension 1. 950 g of USP purified water was placed in a stainless steel container equipped with a low-cut mixer (Lightnin type). 2. With the propeller in the center and as close to the bottom of the container as possible, the mixture was agitated to form a vortex without drawing air into the interior of the liquid. 3. 50.0 g transparent Opadry YS-2-19114 A, were added slowly, avoiding the floating of the powder on the surface of the liquid. The stirring speed was increased to maintain the required vortex.

E. Procedure for coating the tablet 1. 0.45 mg of Premarin® tablets filled with unblended talc were placed inside a perforated coating container. 2. Sufficient coating suspension of bazedoxifene acetate filler was added to achieve a total pee of 50 mg (± 2 mg) on the inert filled tablet, peeo (approximately 244.9 mg of ezepeneion coating of bazedoxifene acetate filler per tablet ). The tablets were coated with the suspension using a continuous coating technique wherein the suspension was sprayed onto the tablets in the rotary coating container, with concomitant drying by means of hot air, which reached the white weight gain. 3. Approximately 15 mg of the Color coating was applied to the tablets (approximately 36.15 mg of color coating suepeneion per tablet). 4. Approximately 3 mg of the clear coating was applied to the tablet (approximately 60 mg of the traneparent coverage euepeneion per tablet). The composition of the tablet is shown in the following Table.

Ingredient% p / p mg / tablet Core Tablet Premarin® 0.45 mg, Tablets filled with talcum powder not Crushed 77.56 235.0 mg Coating of bazedoxifene Sucrose, NF 8.94 27.10 mg Hydroxypropylmethylcellulose USP, 2910, 3 cps (Pharmacoat 603) 3.30 10.00 mg Water, Purified USP3 194.9 mg Sucrose Palmitate 0.21 0.625 mg Ascorbic acid, USP 0.33 1,000 mg Bazedoxifene acetate (88.68% free base bazedoxifene) 0 3.72 11.28 mg Coating Colorb Sucrose, NF 4.57 13.85 mg Hydroxypropyl / Methylcellulose, USP, 2910, 3 (Pharmacoat 603) 0.15 .46 mg Titanium dioxide, USP 0.23 0.69 mg Water, Purified USP9 31.15 mg Transparent Coating13 Trapeze Opadry YS-2-19114A 0.99 3.00 mg Water, USP Purified9 57.00 mg Total 100.0 303 g Removed during the process. bLae quantities of ingredient per tablet represent the theoretical amounts of coating solids applied. For a better presentation, the amount of water and coating ingredients used may vary. These must not exceed ± 10% of the theoretical values. The potency of bazedoxifene acetate may vary and the amount in the formula must be adjusted according to the corresponding adjustment in the amount of sucrose.

EXAMPLE 2 Process for the preparation of conjugated estrogen-containing tablets of bazedoxifene acetate; 0.45 mg / 20 mg. The procedure is essentially as described in Example 1, except that: a) the tranepant euepeneion coating contains: 125.00 g of Opadry Blanco YS-1-18202 A; 875.00 g of water, USP, purified; and b) the tranexentant coating suspension contains: 50.00 g transparent Opadry YS-2-19114 A; 950.00 g of water, USP, purified; and c) the following tablet coating process was used: 1. Premarin® 0.45 mg tablets filled with uncrushed talcum powder were loaded into a perforated coating container. 2. Sufficient coating suspension of bazedoxifen acetate was added to achieve a total 100 mg (± 2 mg) on the inert filled tablet, approximately 489.8 mg of coating suspension filled with bazedoxifene acetate per tablet) . The tablets They were covered with the suepeneion using the continuous sugar coating technique described in Example 1. 3. Approximately 17 mg of the color coating was applied to the tablet (approximately 136 mg of the color coating euepeneion per tablet). 4. Approximately 4 mg of the clear coating was applied to the tablets (approximately 80 mg of clear coating suspension per tablet). The composition of the ee mueetra tablets in the following Table Ingredient% p / p mg / tablet Core Tablet 0.45 mg of Premarin®, tablets filled with non-shredded talc 66.01 235.0 mg Coverage Bazedoxifeno Sucrose, NF 15.22 54.19 mg Hydroxypropylmethylcellulose USP, 2910, 3 cps. { Pharmacoat 603) 5.62 20.00 mg Water, Purified USP9 389.8 mg Sucrose Palmitate 0.35 1.250 mg Ascorbic acid, USP 0.56 2,000 mg Bazedoxifene Acetate (88.68% free base bazedoxifene) 0 6.34 22.56 mg Coating Colorb Opadry White YS-1-18202 A 4.78 17.00 mg Water, Purified USP3 119.0 mg Traneparente Coverage3 Opadry Transparent YS-2-19114A 1.12 4.00 g Water, USP Purified3 76.00 mg Total 100.0 356 mg aRemovida during the process.

The amount of ingredients per tablet repre- sents the theoretical amount of coating strengths applied. For a better presentation, the amount of water and coating ingredients may vary. These must not exceed ± 10% of the theoretical values. The potency of bazedoxifene acetate may vary and the amount in the formula must be adjusted according to the corresponding adjustment in the amount of sucrose.

EXAMPLE 3 Process for the Preparation of Tablets Containing Conjugated Estrogens of Bazedoxifene Acetate; 0.45 mg / 40 mg. The process is essentially as described in Example 1, except that: a) the coating of the transparent suspension contains: 125.00 g of Opadry White YS-1-18202 A; 875.00 g of water, USP, purified; and b) the transparent coating suspension contains: 50.00 g of Opadry Traneparente YS-2-19114 A; 950.00 g of water, USP, purified; and c) the following tablet coating process was effected: 1. Premarin® 0.45 mg tablets filled with non-shredded talc were loaded into a perforated coating container. 2. Sufficient suspension of bazedoxifene acetate filling coverage was added to achieve a total weight of 200 mg (± 2 mg) on the inert filled tablet, approximately 979.6 mg of coated euepeneion with bazedoxifene acetate per tablet) . The tablets were covered with the suepeneion using continuous sugar with the coverage technique described in Example 1. 3. Approximately 22 mg of the color coating was applied to the tablet (approximately 176 mg of the color coverage euepension per tablet). 4. Approximately 5 mg of the clear coating was applied to the tablets (approximately 176 mg of the color coverage suspension per tablet). The composition of the tablet is shown in the following Table.

Ingredient% p / p mg / tablet Core Tablet Tablets 0.45 mg Premarin® filled with non-shredded talc 50.87 235.0 mg Coating bazedoxifene Sacaroea, NF 23.46 108.38 mg Hydroxypropylmethylcellulose USP, 2910, 3 cps (Pharmacoat 603) 8.66 40.00 mg Water, Purified USP3,779.6 mg Sacaroea palmitate 0.54 2.50 g Aezobic acid, USP 0.87 4.000 mg Bazedoxifene acetate (88.68% bazedoxifene free bae) c 9.77 45.11 mg Coating Colorb Opadry White YS-1-18202 A 4.76 22.00 mg Water, Purified USP3 154.0 mg Transparent Coating 3 Transparent Opadry YS-2-19114A 1.08 5.00 mg Water, Purified USP3 95.00 mg Total 100.0 462 mg aRemoved during processing. bThe amounts of the ingredients per tablet represent the theoretical quantities of coating elastomers applied. For elegance, the amount of water and ingredients covered can vary. Aetos must not exceed ± 10% of the theoretical values. c The potency of bazedoxifene acetate may vary and the amount in the formula must be adjusted according to the corresponding adjustment in the amount of sucrose.

EXAMPLE 4 Process for the preparation of conjugated estrogen-containing tablets of bazedoxifene acetate; 0.45 mg / 10 mg.

The procedure is essentially as described for Example 1, except that the tablets to which the coating was applied were Premarin® tablets of 0. 625 mg, filled without crushed talc. The composition of the tablets is shown in the Table below. Ingredient% p / p mg / tablet Core Tablet Premarin® tablets of 0.625 mg, filled with non-shredded talcum 7756 235.0 mg Bazedoxifen coating Sacaroea, NF 8.94 27.10 mg Hydroxypropylmethylcellulose USP, 2910, 3 cpe (Pharmacoat 603) 3, .30 210.00 mg Water, Purified USP3 194.9 mg Palmitato de Sacaroea 0, .21 0.625 mg Ascorbic acid, USP 0.333 mg Bazedoxifene acetate (88.68% bazedoxifene free base) 0 3.72 11.28 mg Coating Colorb Sucrose, NF 4.57 13.85 mg Hydroxypropylmethylcellulose USP, 2910, 3 cps (Pharmacoat 603) 0. 15 0 .46 mg Titanium dioxide USP 0. 23 0 .69 mg Water, Purified USP3 31. 15 mg Transparent Coating13 Opadry Transparent YS-2-19114a 0.99 3.00 mg Water, Purified USP3 31.15 mg Total 100.0 303 mg aRemoved during the process. The quantities of the ingredient per tablet represent the theoretical quantities of the coating elastides applied. For a better presentation, the amount of water and coating ingredients used may vary. These must not exceed ± 10% of the theoretical values. The potency of bazedoxifene acetate can vary and the amount in the formula should be adjusted according to the corresponding adjustment in the amount of Sacaroea.

EXAMPLE 5 Process for the preparation of conjugated estrogen-containing tablets of bazedoxifene acetate; 0.625 mg / 20 mg.

The procedure is essentially as described for Example 2, except that the tablet to which the coatings were applied was 0.625 mg of Premarin® tablet without the talcum powder. The composition of the tablets is shown in the following Table. Ingredient% p / p mg / tablet Core Tablet 0.625 mg Premarin® tablets filled with non-shredded talc 66.01 235.0 mg Coating of bazedoxifene Sucrose, NF 15.22 54.19 mg Hydroxypropylmethylcellulose USP, 2910, 3 cps (Pharmacoat 603) 5.62 20.00 mg Water, Purified USP3 389.8 mg Sucrose Palmitate 0.35 1.250 mg Ascorbic acid, USP 0.56 2,000 mg Bazedoxifene Acetate (88.68% free base bazedoxifene) 0 6.34 22.56 mg Coating of Colorb Opadry Transparent YS-2-19114A 4.78 17.00 mg Water, Purified USP3 119.0 mg Transparent Coating13 Opadry Transparent YS-2-19114A 1.12 4.00 mg Water, USP Purified3 76.00 mg Total 100.0 356 mg aRemoved during the process. The quantities of the ingredients per tablet represent the theoretical quantities of coating powder applied. For a better presentation, the amount of water and coverage ingredients used may vary. These must not exceed ± 10% of the theoretical values. The potency of bazedoxifene acetate can vary and the amount in the formula should be adjusted according to the corresponding adjustment in the amount of Sacaroea.

EXAMPLE 6 Process for the preparation of conjugated estrogen-containing tablets of bazedoxifene acetate; 0.625 mg / 40 mg. The process is essentially as described by Example 3, except that the tablets to which the coatings were applied were Premarin® tablets of 0.625 mg, filled without ground talcum powder. The composition of the tablets is shown in the following Table.

Ingredient% p / p mg / tablet Core Tablet Premarin® tablets of 0.625 mg, filled with non-shredded talcum 50.87 235.0 mg Coating of Bazedoxifene Sucrose, NF 23.46 108.38 mg Hydroxypropylmethylcellulose USP, 2910, 3 cpe (Pharmacoat 603) 866 40.00 mg Water, Purified USP3,779.6 mg Palmitato de Sacaroea 0.54 2.50 mg Ascorbic acid, USP 087 4,000 mg Bazedoxifene Acetate (88.68% free base bazedoxifene) 0 977 45.11 mg Colorb Opadry Transparent Coating YS-1-18202A 4.76 22.00 mg Water, Purified USP3 154.0 mg Coating Transparent13 Opadry Transparent YS-2-19114A 1.08 5.00 mg Water, Purified USP3 95.00 mg Total 100.0 462 g 3Removed during the process. bThe amounts of the ingredients per tablet represent the theoretical quantities of the coating solids applied. For a better presentation, the amount of water and coating ingredients used may vary. They should not exceed ± 10% of theoretical values. The potency of bazedoxifene acetate may vary and the amount in the formula must be adjusted according to the corresponding adjustment in the amount of sucrose. It is intended that each of the patents, applications and publications printed including the books mentioned in this patent document are incorporated herein by reference in their entirety. As experienced in the art they will be able to appreciate the numerous changes and modifications that can be made to the modalities of the preference of the present invention without departing from the scope of the present invention. It is thought that modifications will fall within the scope of the present invention. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the clear one of the present description of the invention.

Claims (51)

1. REIVIB? DSCACXOmg Having ascribed the invention as above, the claim contained in the following claims is claimed as property: 1. a pharmaceutical composition comprising a core and at least one coating, characterized in that the core comprises estrogen conjugates and the coating comprises bazedoxifene or a pharmaceutically eal acceptable of them.
2. 2. The pharmaceutical composition according to claim 1, characterized in that it is a tablet.
3. 3. The pharmaceutical composition according to claim 1 or 2, characterized in that the conjugated estrogens are present in an amount of about 0.10 to about 1.0 mg.
4. 4. The pharmaceutical composition according to claim 1 or 2, characterized in that conjugated estrogens are present in an amount from about 0.3 to about 0.8 mg.
5. 5. The pharmaceutical composition according to claim 1 or 2, characterized in that the conjugated estrogen eethan is present in an amount of about 0.4 to about 0.5 mg.
6. 6. The pharmaceutical composition according to claim 1 or 2, characterized in that the conjugated estrogens eethan preend in an amount of about 0.5 to about 0.7 mg.
7. 7. The pharmaceutical composition according to any of claims 1 to 6, characterized in that the bazedoxifene is present in an amount of about 1 to about 50 mg, based on the weight of the free base bazedoxifene.
8. 8. The pharmaceutical composition according to any of claims 1 to 6, characterized in that the bazedoxifene is present in an amount of about 5 to about 25 mg, based on the weight of the free base bazedoxifene.
9. 9. The pharmaceutical composition according to any of claims 1 to 6, characterized in that the bazedoxifene is present in an amount of about 5 to about 15 mg, based on the weight of the free base bazedoxifene.
10. 10. The pharmaceutical composition according to any of claims 1 to 6, characterized in that the bazedoxifene is present in an amount of about 15 to about 25 mg, based on the weight of the free base bazedoxifene.
11. 11. The pharmaceutical composition according to any of claims 1 to 6, characterized in that the bazedoxifene is present in an amount of about 35 to about 45 mg, based on the weight of the free base bazedoxifene.
12. 12. The pharmaceutical composition according to claim 1 or 2, characterized in that the conjugated estrogens are present in an amount of about 0.10 to about 1.0 mg and the bazedoxifene is present in an amount of about 5 to about 50 mg, based on the bazedoxifene weight of free baee.
13. 13. The pharmaceutical composition according to any of claims 1 to 12, characterized in that the bazedoxifene is a bazedoxifene acetate.
14. The pharmaceutical composition according to any of claims 1 to 13, characterized in that the coating comprises: a) a filler component comprising about 5% to about 30% by weight of the pharmaceutical formulation; b) a binder component comprising about 1% to about 10% by weight of the pharmaceutical formulation; c) a wetting agent component comprising about 0.01% to about 2% by weight of the pharmaceutical formulation; d) an optional antioxidant component comprising from 0 to about 2% by weight of the pharmaceutical formulation; e) bazedoxifene acetate, comprising from about 0.1% to about 20% by weight of the pharmaceutical formulation; and f) an optional chelation component comprises from 0% to about 0.1% by weight of the pharmaceutical formulation.
15. 15. The pharmaceutical composition according to claim 14, characterized in that the core comprises from about 45% to about 80% by weight of the pharmaceutical formulation.
16. 16. The pharmaceutical composition according to claim 14 or 15, characterized in that the conjugated estrogens are present in an amount of about 0.10 to about 1.0 mg.; and bazedoxifene is present in an amount of about 5 to about 25 mg, based on the weight of the bazedoxif not of free base.
17. 17. The pharmaceutical composition according to any of claims 1 to 13, characterized in that the coating comprises: a) a filler component comprising from about 6% to about 12% by weight of the pharmaceutical formulation; b) a binder component comprising from about 1% to about 6% by weight of the pharmaceutical formulation; c) a wetting component agent comprising from about 0.01% to about 3% by weight of the pharmaceutical formulation; d) an optional antioxidant component comprising from 0 to about 0.5% by weight of the pharmaceutical formulation; e) bazedoxifene acetate, comprising from about 2% to about 6% by weight of the pharmaceutical formulation; and f) a chelating component comprising from 0% to about 0.1% by weight of the pharmaceutical formulation.
18. 18. The pharmaceutical composition according to any of claims 1 to 15, characterized in that the coating comprises: a) a filler component comprising from about 12% to about 18% by weight of the pharmaceutical formulation; b) a binder component comprising from about 4% to about 8% by weight of the pharmaceutical formulation; c) a wetting agent component comprising from about 0.2% to about 0.5% by weight of the pharmaceutical formulation; d) an optional antioxidant component comprising when present from about 0.3% to about 0.8% by weight of the formulation; e) bazedoxifene acetate, comprising from about 4% to about 9% by weight of the pharmaceutical formulation; and f) a chelating component comprising from 0% to about 0.1% by weight of the pharmaceutical formulation.
19. 19. The pharmaceutical composition according to any of claims 1 to 15, characterized in that the coating comprises: a) a filler component comprising from about 20% to about 30% by weight of the pharmaceutical formulation; b) a binder component comprising from about 6% to about 10% by weight of the pharmaceutical formulation; c) a wetting agent component comprising from about 0.4% to about 0.8% by weight of the pharmaceutical formulation; d) an optional antioxidant component comprising from 0% to about 1.2% by weight of the pharmaceutical formulation; e) bazedoxifene acetate, comprising from about 7% to about 14% by weight of the pharmaceutical formulation; and f) a chelating component comprising from 0% to about 0.1% by weight of the pharmaceutical formulation.
20. 20. The pharmaceutical composition according to any of claims 14 to 19, characterized in that: the filling component of the coating comprises one or more sucrose, mannitol, lactoea, cellulose powder, microcrystalline cellulose, maltodextrin, sorbitol, starch, xylitol, carboxymethylcellulose, carboxyethylcellulose, hydroxyethylcellulose, cellulose microcrystallins, starches, anhydrous dicalcium phosphate, eolic starch glycollates and metallic aluminoeilicates; the binder component of the coating comprises one or more of hydroxypropylmethylcellulose, carboxymethylcellulose, carboxyethylcellulose, hydroxyethylcellulose, microcrystalline cellulose, starches and polyvinylpyrrolodines; the wetting agent component of the coating comprises one or more sucrose palmitate, poloxamer 188, metal alkyl sulfates, sodium lauryl sulfate, polyoxyethylene sorbitan esters of fatty acids, polyethylene glycols, polyoxyethylene castor oil derivatives, docusate sodium, quaternary ammonium amine, sugar esters of fatty acids and glycerides of graeoe acids; and the optional antioxidant component when present comprises one or more of ascorbic acid or an eal thereof, sodium ascorbate, citric acid and ascorbyl palmitate, nicotinamide ascorbate, propyl gallate, alpha tocopherol, beta tocopherol, tocopherol range and BHA / BHT and the optional chelation component of the coating, when present, comprises EDTA.
21. 21. The pharmaceutical composition according to any of claims 14 to 19, characterized in that: the filler component of the coating comprises eacaroea; the binder component of the coating comprises hydroxypropylmethylcellulose; the wetting agent component of the coating comprises eacaroea palmitate; and the antioxidant component of the coating when present comprises ascorbic acid, or a salt thereof; and the optional chelation component of the coating, when present, comprises EDTA.
22. 22. The pharmaceutical composition according to any of claims 14 to 21, characterized in that it also comprises a colored coating.
23. 23. The pharmaceutical composition according to claim 22, characterized in that the color coating comprises: a) an optional filler component comprising from about 0.01% to about 8% by weight of the pharmaceutical composition; b) an optional filler component comprising from about 0.01% to about 2% by weight of the pharmaceutical composition; c) a coloring agent component comprising from about 0.01% to about 6% by weight of the pharmaceutical composition. d) an optional antioxidant component comprising from 0% to about 2% by weight of the pharmaceutical formulation; and e) an optional chelation component comprising from 0% to about 0.1% by weight of the pharmaceutical formulation.
24. 24. The pharmaceutical composition according to claim 23, characterized in that: the optional filler component comprises sucrose; the optional binder component comprises hydroxypropylmethylcellulose; and the coloring agent component comprises titanium dioxide; the optional antioxidant component comprises ascorbic acid or an ether salt; and the optional chelation component comprises EDTA.
25. 25. The pharmaceutical composition according to any of claims 14 to 24, characterized in that it also comprises a transparent coating.
26. 26. The pharmaceutical composition according to claim 25, characterized in that the tranepant coating comprises from about 0.01% to about 2% by weight of the pharmaceutical composition.
27. 27. A pharmaceutical composition, characterized in that it comprises: a core comprising conjugated eetrogens in an amount of about 0.10 mg to about 1.0 mg; a first coating; a color coating; and a transparent coating; wherein the core comprises from about 45% to about 80% by weight of the pharmaceutical composition; the first coating comprises; a) a filler component comprising from about 5% to about 30% by weight of the pharmaceutical composition; b) a binder component comprising from about 1% to about 10% by weight of the pharmaceutical formulation; c) a wetting agent component comprising from about 0.01% to about 2% by weight of the pharmaceutical formulation; d) an optional antioxidant component comprising from 0% to about 2% by weight of the pharmaceutical composition; e) bazedoxifene acetate, comprising from about 0.1% to about 20% by weight of the pharmaceutical composition; and f) an optional chelation component comprising from 0% to about 0.1% by weight of the pharmaceutical formulation; the color coating comprises; g) an optional filler component comprising from about 0.01% to about 8% by weight of the pharmaceutical composition; h) an optional binder component comprising from about 0.01% to about 2% by weight of the pharmaceutical composition; i) a coloring agent component comprising from about 0.01% to about 6% by weight of the pharmaceutical composition; j) an optional antioxidant component comprising from 0% to about 2% by weight of the pharmaceutical formulation; k) an optional chelation component comprises from 0% to about 0.1% by weight of the pharmaceutical composition; And the clear coat comprises from about 0.01% to about 2% by weight of the pharmaceutical composition, the clear coat comprises an optional antioxidant component comprising from 0% to about 2% by weight of the pharmaceutical composition; and an optional chelation component comprising from 0% to about 0.1% by weight of the pharmaceutical composition.
28. 28. The pharmaceutical composition according to claim 27, characterized in that the composition contains from about 1 to about 50 mg of bazedoxifene, based on the weight of the free base bazedoxifene.
29. 29. The pharmaceutical composition according to claim 27 or 28, characterized in that: the filling component of the coating comprises eacaroea; the binder component of the first coating comprises hydroxypropylmethylcellulose; the wetting agent component of the first coat comprises eacaroea palmitate; the optional antioxidant component of the first coating, when present, comprises an azobic acid, or a salt thereof; the optional chelation component of the coating, when present, comprises EDTA, the optional filler component of the color coating when present, comprises eucarose; the optional binder component of the color coating when present, comprises hydroxypropylmethylcellulose; the optional antioxidant component of the color coating, when present, comprises ascorbic acid or a salt thereof; the optional chelation component of the color coating, when present, comprises EDTA; and the coloring agent component of the color coating comprises titanium dioxide.
30. The pharmaceutical composition according to any of claims 1 to 29, characterized in that the conjugated estrogens comprise Premarin®.
31. 31. Process for the preparation of a pharmaceutical composition, characterized in that it comprises: a nucleus comprising conjugated estrogens; and a first bazedoxifene coating or a pharmaceutically acceptable salt thereof; the process comprises: i) providing a core comprising conjugated estrogens; and ii) covering the core with a composition comprising bazedoxifene or a pharmaceutically acceptable salt thereof to form a coated core.
32. 32. Process according to claim 31, characterized in that it also comprises the step of; iii) covering the coated core with a color coating composition to form a color coated composition.
33. 33. A process according to claim 32, characterized in that it further comprises the step of; iv) coating the color coated composition with a clear cover composition to form a clear coating thereon.
34. 34. Process according to any of claims 31 to 33, characterized in that the cover composition of step ii) comprises: a) a filling component; b) a binder component; c) a wetting agent component; d) an optional antioxidant component; and e) bazedoxifene acetate; and f) an optional chelation component.
35. 35. Process according to claim 34, characterized in that; the filling component of the coating comprises one or more of sucrose, mannitol, lactose, cellulose powder, microcrystalline cellulose, maltodextrin, sorbitol, starch, xylitol, carboxymethylcellulose, carboxyethylcellulose, hydroxyethylcellulose, microcrystalline celluloses, starches, anhydrous dicalcium phosphate, starch glycollates sodium and metallic aluminoeilicatoe; the binder component of the coating comprises one or more of hydroxypropylmethylcellulose, carboxymethylcellulose, carboxyethylcellulose, hydroxyethylcellulose, microcrystalline celluloses, starches and polyvinylpyrrolodines; the humectant component of the coating comprises one or more palmitate of sacaroea, poloxamer 188, eulfatoe of alkylmetallic, eodium lauryl eulfate, ethers of polyoxyethylene eorbitan of fatty acids, polyoxyethylene castor oil derivative, sodium docueate, quaternary ammonium amine compounds , sugar esters of fatty acids and glyceride of fatty acid; and the optional antioxidant component when present, comprises one or more ascorbic acid or a salt of éete, sodium ascorbate, citric acid, ascorbyl palmitate, nicotinamide ascorbate, propyl gallate, alpha tocopherol, beta tocopherol, tocopherol range and BHA /B HT; and the optional chelation component, when present, comprises EDTA.
36. 36. Process according to claim 34, characterized in that; the filler component of the coating comprises eacarose; the binder component of the coating comprises hydroxypropylmethylcellulose; the wetting agent component of the coating comprises saccharoea palmitate; the antioxidant component of the coating when present, comprises ascorbic acid, or a salt thereof; and the optional chelation component of the coating, when present, comprises EDTA.
37. 37. Process according to claim 36, characterized in that the coating composition of step ii) is applied by means of a continuous sugar coating technique.
38. 38. Proceed in accordance with claim 32, characterized in that the color coating composition comprises; an optional filler component; an optional binder component; a coloring agent component; an optional antioxidant component; and an optional chelation component.
39. 39. Proceed according to claim 38, characterized in that: the optional filler component of the color coating comprises eacaroea; the optional binder component of the color coating comprises hydroxypropylmethylcellulose; the coloring agent component of the color coating comprises titanium dioxide; the optional antioxidant component of the color coating comprises aecorbic acid or an eal of eete; and the optional chelation component of the color coating comprises EDTA.
40. 40. Proceed according to claim 36, characterized in that: a) the filling component of the coating composition of step ii) comprises about 5% to about 30% by weight of the pharmaceutical formulation; b) the binder component of the coating composition of step ii) comprises about 1% to about 10% by weight of the pharmaceutical formulation; c) a wetting component agent of the coating composition of step ii) comprises about 0.01% to about 2% by weight of the pharmaceutical formulation; d) an optional antioxidant component of the coating composition of step ii) comprises from 0% to about 2% by weight of the pharmaceutical formulation; e) bazedoxifene acetate, comprises about 0.1% to about 20% by weight of the pharmaceutical formulation; and f) the optional chelation component of the coating composition comprises from 0% to about 0.1% by weight of the pharmaceutical formulation.
41. 41. Proceed in accordance with any of the claims 31 to 40, characterized in that the conjugated eetrogens eethan are present in an amount of about 0.10 to about 1.0 mg.
42. 42. Process according to any of claims 31 to 41, characterized in that the bazedoxifene is present in an amount of about 1 to about 50 mg, based on the weight of bazedoxifene free bae.
43. 43. Proceed according to any of claims 31 to 41, characterized in that the conjugated estrogens are present in an amount of about 0.10 to about 1.0 mg.; and bazedoxifene is present in an amount of about 5 to about 50 mg, based on the weight of the free base bazedoxifene.
44. 44. Process according to any of claims 31 to 43, characterized in that the conjugated eetrogen comprises Premarin®.
45. 45. Process product characterized in that it conforms to any of claims 31 and 44.
46. 46. Proceed to prepare a pharmaceutical composition, characterized in that the composition comprises: a core comprising a therapeutic agent; and an optional coating comprising a second therapeutic agent and at least one sugar; the process comprises: i) providing a core comprising the first active agent; And ii) covering the core with a coating composition comprising: a) a filling component comprising at least one sugar; b) a binder component; c) a binder component; d) an optional antioxidant component; and e) optionally, a second therapeutic agent; and f) an optional chelation component; wherein the coating composition of step ii) is applied by means of a continuous sugar coating technique.
47. 47. Process according to claim 46, characterized in that; the filling component of the coating comprises one or more of sucrose, mannitol, lactose, cellulose powder, microcrystalline cellulose, maltodextrin, sorbitol, starch, xylitol, carboxymethyl cellulose, carboxyethyl cellulose, hydroxyethyl cellulose, microcrystalline cellulose, starches, anhydrous dicalcium phosphate, starch glycollates sodium and metal aluminosilicates; the binder component of the coating comprises one or more of hydroxypropylmethylcellulose, carboxymethylcellulose, carboxyethylcellulose, hydroxyethylcellulose, microcrystalline celluloses, starches and polyvinylpyrrolodinae; the wetting agent component of the coating comprises one or more eacarose palmitate, poloxamer 188, alkyl metal sulfatee, sodium lauryl eulfate, polyoxyethylene sorbitan ethers of fatty acids, polyethylene glycols, polyoxyethylene castor oil derivatives, docusate sodium, quaternary ammonium amine, sugar esters of fatty acids and fatty acid glycerides; and the optional antioxidant component when present comprises one or more aecorbic acid or an eal of ete, eodic ascorbate, citric acid, ascorbyl palmitate, nicotinamide ascorbate, propyl gallate, alpha tocopherol, beta tocopherol, tocopherol range and BHA / BHT.; and the optional chelation component, when present, comprises EDTA.
48. 48. Proceed in accordance with claim 46, characterized in that; the filling component of the coating comprises eacaroea; the binder component of the coating comprises hydroxypropylmethylcellulose; the wetting agent component of the coating comprises eacaroea palmitate; the antioxidant component of the coating when present comprises aecorbic acid, or an etal of ethers; and the optional chelation component of the coating, when present, comprises EDTA.
49. 49. Proceed according to any one of claims 46 or 48, characterized in that it further comprises the steps of: iii) covering the covered core with a color covering composition to form a color covered composition.
50. 50. Process according to claim 49, characterized in that it further comprises the step of: iv) coating the color coated composition with a tranepant cover composition to form a tranepant coating in the eeta.
51. 51. Proceed according to any of claims 46 to 50, characterized in that the first therapeutic agent comprises conjugated eetrogens and the second therapeutic agent comprises a bazedoxifene or an eal of eete.