US 2007OOO3623A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0003623 A1 Chatlapalli et al. (43) Pub. Date: Jan. 4, 2007

(54) FORMULATIONS OF CONJUGATED Related U.S. Application Data ESTROGENS AND BAZEDOXFENE (60) Provisional application No. 60/694,889, filed on Jun. (75) Inventors: Ramarao S. Chatlapalli, Hopewell 29, 2005. Junction, NY (US); Arwinder S. Nagi, Thiells, NY (US); Lawrence Van Pelt, Publication Classification Garnerville, NY (US) (51) Int. Cl. Correspondence Address: A6IR 9/24 (2006.01) COZEN O' CONNOR, P. C. A6II 3/56 (2006.01) 1900 MARKET STREET (52) U.S. Cl...... 424/472: 514/171 PHILADELPHIA, PA 19103-3508 (US) (57) ABSTRACT (73) Assignee: Wyeth, Madison, NJ The present invention relates to Solid dosage formulations containing conjugated estrogens and baZedoxifene, or a salt (21) Appl. No.: 11/478,400 thereof. In some embodiments, the compositions include a core comprising conjugated estrogens, and at least one (22) Filed: Jun. 28, 2006 coating that comprises baZedoxifene, or a salt thereof. US 2007/0003623 A1 Jan. 4, 2007

FORMULATIONS OF CONUGATED ESTROGENS 0006 Bazedoxifene is a tissue selective estrogen for AND BAZEDOXFENE treatment and prevention of postmenstrual osteoporosis. It has been reported to prevent bone loss and protect the CROSS REFERENCE TO RELATED cardiovascular system and reduce or eliminate the negative APPLICATIONS effects on the uterus and breast (potential risk of uterine and 0001. This application claims priority benefit of U.S. breast cancers). Provisional application Ser. No. 60/694,889, filed Jun. 29, 0007 U.S. Pat. Nos. 5,998,402 and 6.479,535 report the 2005, the entire content of which is incorporated by refer preparation of baZedoxifene acetate. The synthetic prepara ence herein. tion of baZedoxifene acetate has also appeared in the general literature. See, for example, Miller et al., J. Med. Chem., FIELD OF THE INVENTION 2001, 44, 1654-1657. Further description of the drugs 0002 The present invention relates to solid dosage for biological activity has appeared in the general literature as mulations containing conjugated estrogens and baZedox well (e.g. Miller, et al. Drugs of the Future, 2002, 27(2), ifene, or a salt thereof. In some embodiments, the compo 117-121). Formulations of baZedoxifene acetate are also sitions include a core containing conjugated estrogens, and reported in U.S. Pat. App. Pub. No. 2002/0031548 A1. a coating that includes baZedoxifene, or a salt thereof. 0008 Bazedoxifene acetate polymorphs are described in U.S. Provisional App. Ser. Nos. 60/560,582 filed Apr. 7, BACKGROUND OF THE INVENTION 2004, and 60/560,584 filed Apr. 7, 2004. Bazedoxifene 0003. The use of hormone replacement therapy for bone acetate dispersion formulations are described in U.S. Pro loss prevention in post-menopausal women is well prece visional App. Ser. No. 60/560,452, filed Apr. 8, 2004. dented. The normal protocol calls for estrogen Supplemen BaZedoxifene ascorbate salt is described in U.S. Provisional tation using Such formulations containing estrone, estriol, App. Ser. No. 60/560,454, filed Apr. 8, 2004. ethynyl estradiol or conjugated estrogens isolated from 0009. A need exists for effective drug treatment for post natural sources (i.e. Premarin R conjugated estrogens from menopausal women to relieve vasomotor symptoms and Wyeth-Ayerst). In some patients, therapy may be contrain protect bones without stimulating the endometrium (which dicated due to the proliferative effects of unopposed estro may lead to endometrial hyperplasia) or the breast. The gens (estrogens not given in combination with progestins) present invention is directed to these, as well as other, have on uterine tissue. This proliferation is associated with important ends. increased risk for endometriosis and/or endometrial cancer. The effects of unopposed estrogens on breast tissue is less clear, but is of Some concern. The need for estrogens which SUMMARY OF THE INVENTION can maintain the bone sparing effect while minimizing the 0010. In some embodiments, the present invention pro proliferative effects in the uterus and breast is evident. vides pharmaceutical compositions including a core and at 0004 The use of indoles as estrogen antagonists has been least one coating; wherein the core comprises conjugated reported by Von Angerer, Chemical Abstracts, Vol. 99, No. estrogens; and the coating comprises baZedoxifene, or a 7 (1983), Abstract No. 53886u. Also, see, J. Med. Chem. pharmaceutically acceptable salt thereof. In some embodi 1990, 33, 2635-2640; J. Med. Chem. 1987, 30, 131-136. ments, the conjugated estrogens include or consist of Pre Also see Ger. Offen., DE 3821 148 A1 891228 and WO marinR). 96/03375. The majority of the compounds reported in these 0011. In some embodiments, the pharmaceutical compo publications fall into a class of compounds best character sition is a tablet. In some Such embodiments, the pharma ized as being “pure antiestrogens'. Additional reports of ceutical compositions include a core and at least one coat indole antiestrogens include: WOA 95 17383 (Kar Bio AB), ing; wherein the core includes conjugated estrogens; and the WOA 93 10741, and WO 93/23374 (Otsuka Pharmaceuti coating includes baZedoxifene, or a pharmaceutically cals, Japan). acceptable salt thereof. 0005 U.S. Pat. No. 5,998,402 describes 2-phenylindoles that are estrogen agonists/antagonists useful for the treat 0012) In some embodiments, the coating comprises: ment of diseases associated with estrogen deficiency. The 0013 a) a filler component comprising from about 5% to compounds show strong binding to the estrogen receptor. In about 30% by weight of the pharmaceutical formulation; vitro assays, including an Ishikawa alkaline phosphatase assay and an ERE transfection assay, show these compounds 0014 b) a binder component comprising from about 1% are antiestrogens with little to no intrinsic estrogenicity and to about 10% by weight of the pharmaceutical formulation; they have proven capable of completely antagonizing the effects of 17 B-estradiol while showing little or no uterine 0015 c) a wetting agent component comprising from stimulation in a rat uterine assay when dosed alone. Addi about 0.01% to about 2% by weight of the pharmaceutical tionally, some of the compounds are capable of inhibiting formulation; bone loss in an ovariectomized rat while showing little or no 0016 d) an optional antioxidant component comprising uterine stimulation. These compounds also decrease the from 0% to about 2% by weight of the pharmaceutical weight gain normally seen in the ovariectomized animals as formulation; well as reduce total cholesterol levels. One preferred such compound is baZedoxifene, which is 1-4-(azepan-1-yl 0017 e) baZedoxifene acetate, comprising from about ethoxy)-benzyl-2-(4-hydroxy-phenyl)-3-methyl-1H-indole 0.1% to about 20% by weight of the pharmaceutical formu 5-ol. lation; and US 2007/0003623 A1 Jan. 4, 2007

0018 f) an optional chelating component comprising 0030 The invention further provides processes for the from 0% to about 0.1% by weight of the pharmaceutical preparation of pharmaceutical compositions of the inven formulation. tion, and products of the processes. 0019. In some embodiments, the conjugated estrogens is present in an amount of from about 0.10 to about 1.0 mg; or DETAILED DESCRIPTION from about 0.3 to about 0.8 mg; or from about 0.4 to about 0031. In some embodiments, the present invention pro 0.5 mg; or from about 0.5 to about 0.7 mg. vides pharmaceutical compositions including conjugated 0020. In some embodiments, the baZedoxifene is present estrogens and baZedoxifene, or a salt thereof. In some in an amount of from about 1 to about 50 mg, based on the embodiments, the conjugated estrogens include or consist of weight of the baZedoxifene free base; or from about 5 to Premarin(R). about 25 mg, based on the weight of the baZedoxifene free 0032. The pharmaceutical compositions of the invention base; or from about 5 to about 15 mg, based on the weight include capsules and tablet in capsule (TIC) formulations. In of the baZedoxifene free base; or from about 15 to about 25 Some embodiments, the pharmaceutical compositions of the mg, based on the weight of the baZedoxifene free base; or invention are tablets. from about 35 to about 45 mg, based on the weight of the baZedoxifene free base. 0033. In some embodiments, the pharmaceutical compo sitions of the invention include a core and at least one 0021. In some embodiments, the conjugated estrogens is coating; wherein the core includes conjugated estrogens, present in an amount of from about 0.10 to about 1.0 mg; and preferably Premarin R, and the coating includes baZedox the baZedoxifene is present in an amount of from about 5 to ifene, or a pharmaceutically acceptable salt thereof, prefer about 50 mg, based on the weight of the baZedoxifene free ably baZedoxifene acetate. base. 0034) In some embodiments, the coating comprises: 0022. In some embodiments, the conjugated estrogens is 0035) a) a filler component comprising from about 5% to Premarin R, and the baZedoxifene is baZedoxifene acetate. about 30% by weight of the pharmaceutical formulation; 0023. In some embodiments, the filler component of the coating comprises Sucrose; the binder component of the 0036 b) a binder component comprising from about 1% coating comprises hydroxypropylmethylcellulose; the wet to about 10% by weight of the pharmaceutical formulation; ting agent component of the coating comprises Sucrose 0037 c) a wetting agent component comprising from palmitate; the optional antioxidant component of the coat about 0.01% to about 2% by weight of the pharmaceutical ing, when present, comprises ascorbic acid, or a salt thereof. formulation; and the optional chelating component, when present, com prises EDTA. 0038 d) an optional antioxidant component comprising from 0% to about 2% by weight of the pharmaceutical 0024. In some embodiments, the pharmaceutical compo formulation; sitions further include color coating. In some embodiments, 0039 e) baZedoxifene acetate, comprising from about the color coating includes: 0.1% to about 20% by weight of the pharmaceutical formu 0.025 a) an optional filler component comprising from lation; and about 0.01% to about 8% by weight of the pharmaceutical 0040 f) an optional chelating component comprising formulation; from 0% to about 0.1% by weight of the pharmaceutical 0026 b) an optional binder component comprising from formulation. about 0.01% to about 2% by weight of the pharmaceutical 0041) In some further embodiments, the coating com formulation; and prises: 0027 c) a coloring agent component comprising from about 0.01% to about 6% by weight of the pharmaceutical 0042 a) a filler component comprising from about 6% to formulation. In some such embodiments, the optional filler about 12% by weight of the pharmaceutical formulation; component comprises sucrose. In some further such embodi 0043 b) a binder component comprising from about 1% ments, the optional binder component comprises hydrox to about 6% by weight of the pharmaceutical formulation; ypropylmethylcellulose. In some further Such embodiments, 0044 c) a wetting agent component comprising from the coloring agent component comprises titanium dioxide. about 0.1% to about 3% by weight of the pharmaceutical 0028. In some embodiments, the pharmaceutical compo formulation; sitions further include a clear coating. In some Such embodi 0045 d) an optional antioxidant component comprising ments, the clear coating forms from about 0.01% to about from 0% to about 0.5% by weight of the pharmaceutical 2% by weight of the pharmaceutical formulation. formulation; 0029. In some embodiments, the optional antioxidant component, the optional chelating component, or both the 0046 e) baZedoxifene acetate, comprising from about 2% optional antioxidant component and the optional chelating to about 6% by weight of the pharmaceutical formulation; component, additionally being optionally present in the and coating as described above, also can each independently and 0047 f) an optional chelating component comprising optionally be present in one or more of the color coating and from 0% to about 0.1% by weight of the pharmaceutical the clear coating. formulation. US 2007/0003623 A1 Jan. 4, 2007

0048) In some embodiments, the coating comprises: mean that amount of baZedoxifene or salt thereof that 0049 a) a filler component comprising from about 12% provides the same number of molecules of baZedoxifene as to about 18% by weight of the pharmaceutical formulation; the indicated mass of baZedoxifene free base. Thus, for example, the phrase “10 mg of baZedoxifene acetate, based 0050 b) a binder component comprising from about 4% on the weight of the baZedoxifene free base' would indicate to about 8% by weight of the pharmaceutical formulation: a mass of baZedoxifene acetate Sufficient to provide a 0051 c) a wetting agent component comprising from number of molecules of baZedoxifene acetate that is the about 0.2% to about 0.5% by weight of the pharmaceutical same as the number of baZedoxifene molecules present in 10 formulation; mg of the free base form of baZedoxifene. In some embodi ments, the baZedoxifene, or pharmaceutically acceptable salt 0052 d) an optional antioxidant component comprising thereof, is present in an amount of from about 5 to about 25 from 0% to about 0.8% by weight of the pharmaceutical mg, or from about 5 to about 15 mg, or from about 15 to formulation; about 25 mg. or from about 35 to about 45 mg, based on the 0053 e) baZedoxifene acetate, comprising from about 4% weight of the baZedoxifene free base. to about 9% by weight of the pharmaceutical formulation; and 0064. In some embodiments, the baZedoxifene is present in the pharmaceutical formulation as the acetate salt. In 0054 f) an optional chelating component comprising Some Such embodiments, the baZedoxifene acetate present in from 0% to about 0.1% by weight of the pharmaceutical the coating forms from about 0.1% to about 20% by weight formulation. of the pharmaceutical formulation; or from about 2% to 0055. In some further embodiments, the coating com about 6% by weight of the pharmaceutical formulation; or prises: from about 4% to about 9% by weight of the pharmaceutical formulation; or from about 7% to about 14% by weight of 0056 a) a filler component comprising from about 20% the pharmaceutical formulation. to about 30% by weight of the pharmaceutical formulation; 0065. In addition to the baZedoxifene, or a pharmaceuti 0057 b) a binder component comprising from about 6% cally acceptable salt thereof, the coating can contain one or to about 10% by weight of the pharmaceutical formulation; more of fillers, diluents, binders, wetting agents, and/or 0058 c) a wetting agent component comprising from antioxidants. about 0.4% to about 0.8% by weight of the pharmaceutical 0066 Generally, the filler component of the coating formulation; forms from about 5% to about 30% by weight of the 0059 d) an optional antioxidant component comprising pharmaceutical formulation; or from about 6% to about 12% from 0% to about 1.2% by weight of the pharmaceutical by weight of the pharmaceutical formulation; or from about formulation; 12% to about 18% by weight of the pharmaceutical formu 0060 e) baZedoxifene acetate, comprising from about 7% lation; or from about 20% to about 30% by weight of the to about 14% by weight of the pharmaceutical formulation; pharmaceutical formulation. The filler component can include one or more fillers known to be useful in the art, for and example one or more of Sugars, for example Sucrose, man 0061 f) an optional chelating component comprising nitol, lactose, and the like, and/or other fillers such as from 0% to about 0.1% by weight of the pharmaceutical powdered cellulose, microcrystalline cellulose, malodextrin, formulation. sorbitol, starch, xylitol, carboxymethyl cellulose, carboxy 0062. In some embodiments, the core of the composition ethyl cellulose, hydroxyethyl celluloses, microcrystalline includes conjugated estrogens and one or more fillers and/or celluloses, starches, anhydrous dicalcium phosphate, binding agents. In some embodiments, the conjugated estro Sodium starch glycolates, and metal aluminosilicates. In gens include or consist of Premarin R. Generally, the core Some embodiments, the filler component of the coating includes conjugated estrogens in an amount of from about includes one or more Sugars. As used herein, the term 0.10 to about 1.0 mg, and forms from about 45% to about "Sugar refers to any type of simple carbohydrate. Such as a 80% by weight of the pharmaceutical formulation. In some mono or disaccharide, either naturally obtained, refined from embodiments, the core includes conjugated estrogens in an a natural source, or artificially produced, and includes, amount of from about 0.3 to about 0.8 mg. In some embodi without limitation, Sucrose, dextrose, maltose, glucose, fruc ments, the core includes conjugated estrogens in an amount tose, galactose, mannose, lactose, trehalose, lactulose, levu of from about 0.4 to about 0.5 mg; for example about 0.45 lose, raffinose, ribose, and Xylose. The term "sugar,” as used mg, or from about 0.5 to about 0.7 mg, for example about herein, also includes various “sugar substitutes' widely 0.625 mg. In some embodiments, the core is a filled tablet known to those of ordinary skill in the art of preparing Solid containing conjugated estrogens, preferably Premarin R. dosage forms, such as the polyhydric alcohols (sometimes referred to as "sugar alcohols' or hydrogenated saccha 0063. In some embodiments, the pharmaceutical compo rides), for example Sorbitol, mannitol. Xylitol, and erythritol, sitions of the invention include at least one coating that and the Sugar derivatives of polyhydric alcohols, such as contains baZedoxifene, or a pharmaceutically acceptable salt maltitol, lactitol, isomalt, and polyalditol. Accordingly, the thereof. In some embodiments, the baZedoxifene, or phar recitation of the term "sugar generically should be inter maceutically acceptable salt thereof, is present in an amount preted to include Such specific compounds, as well as others of from about 1 to about 50 mg, based on the weight of the not expressly recited. In certain embodiments, the Sugar is a baZedoxifene free base. As used herein, the term “based on mono- or disaccharide, for example, Sucrose, dextrose, mal the weight of the baZedoxifene free base' is intended to tose, glucose, fructose, galactose, mannose, or lactose. In US 2007/0003623 A1 Jan. 4, 2007 some preferred embodiments, the filler component of the 1.2% by weight of the pharmaceutical formulation. The coating includes or consists of Sucrose. antioxidant component, when present, can include one or more antioxidants known to be useful in the art, for example 0067 Generally, the binder component of the coating one or more of ascorbic acid or a salt thereof such as sodium forms from about 1% to about 10% by weight of the ascorbate, ascorbyl palmitate, nicotinamide ascorbate, pro pharmaceutical formulation; or from about 1% to about 6% pyl gallate, tocopherol (alpha, beta and gamma), BHA/BHT, by weight of the pharmaceutical formulation; or from about citric acid and salts thereof, for example Sodium citrate. In 4% to about 8% by weight of the pharmaceutical formula Some preferred embodiments, the antioxidant component tion; or from about 6% to about 10% by weight of the includes or consists of ascorbic acid. pharmaceutical formulation. The binder component can include one or more binders known to be useful in the art, 0071. Further examples of suitable fillers, binders, wet for example one or more of hydroxypropylmethylcellulose, ting agents and antioxidants can be found in, for example, carboxymethyl cellulose, carboxyethyl cellulose, hydroxy Remington's Pharmaceutical Sciences, 17th ed., Mack Pub ethyl celluloses, microcrystalline celluloses, starches and lishing Company, Easton, Pa., 1985, which is incorporated polyvinyl pyrrolidine (PVP). In some preferred embodi herein by reference in its entirety. ments, the filler component includes or consists of hydrox 0072 Generally, the optional chelating component forms ypropyl methylcellulose. up to about 0.1% by weight of the pharmaceutical formu 0068. It has been found in accordance with the present lation. In some embodiments, the chelating component is invention that Sucrose, although not a typical film forming present in an amount of from about 0.01% to about 0.10% agent like hydroxypropyl methylcellulose, is particularly by weight of the coating. The chelating component can advantageous when used with a lower viscosity grade of include one or more chelating agents as are known in the art hydroxypropyl methylcellulose, for example 3 cps. While for use in pharmaceutical formulations. One preferred not wishing to be bound by any particular theory, the Sucrose chelating agent is ethylenediaminetetraacetic acid (EDTA). is believed to add body to the coating, and to act as a Other suitable chelating agents can be found in, for example, soluble-filler in an active overcoat process. Generally, it is Remington's Pharmaceutical Sciences, Supra. beneficial to employ a ratio of hydroxypropyl methylcellu 0073. In some embodiments, the optional antioxidant lose to sucrose of from about 1:2 to about 1:5, or from about component, the optional chelating component, or both the 1:2 to about 1:4; or from about 1:2.5 to about 1:3.5; or about optional antioxidant component and the optional chelating 1:3. Such a ratio is believed to provide the most acceptable component, additionally being optionally present in the viscosity and sprayability characteristics of the filler sus coating as described above, also can each independently and pension at 20% w/w solids level for a continuous coating optionally be present in one or more of the color coating and process. the clear coating, as described below. In some embodiments, 0069 Generally, the wetting agent component of the the antioxidant component and the chelating component are coating is selected to increase wettability of the components both present together in one or more of the coatings. Thus, of the filler coating, and in particular, baZedoxifene, and to in Some Such embodiments, the antioxidant component and therefore aid in dispersing the baZedoxifene. Preferably, the the chelating component are both present in the coating wetting agent possesses low foaming characteristics, and containing the active agent, e.g., baZedoxifene; or in the preferably has antimicrobial activity. Generally, the wetting color coating; or in the clear coating; or in any two of the agent component of the coating forms from about 0.01% to coatings, or in all three of the coatings. about 2% by weight of the pharmaceutical formulation; or 0074. In some embodiments, the pharmaceutical compo from about 0.1% to about 3% by weight of the pharmaceu sition further includes a color coating. Generally, the color tical formulation; or from about 0.2% to about 0.5% by coating is formed over the first coating described above, and weight of the pharmaceutical formulation; or from about contains at least one coloring agent. In some embodiments, 0.4% to about 0.8% by weight of the pharmaceutical for the color coating includes: mulation. The wetting agent component can include one or more wetting agents known to be useful in the art, for 0075 a) an optional filler component including from example one or more of Sucrose fatty acid esters, such as about 0.01% to about 8% by weight of the pharmaceutical sucrose palmitate, and Poloxamer 188, metal alkyl sulfates, formulation; Sodium lauryl Sulfate, polyoxyethylene Sorbitan fatty acid 0076 b) an optional binder component including from esters, polyethylene glycols, polyoxyethylene castor oil about 0.01% to about 2% by weight of the pharmaceutical derivatives, docusate sodium, quaternary ammonium amine formulation; and compounds, Sugar esters of fatty acids and glycerides of 0077 c) a coloring agent component including from fatty acids. In some preferred embodiments, the wetting about 0.01% to about 6% by weight of the pharmaceutical agent component includes or consists of Sucrose palmitate. formulation. 0070 Generally, the optional antioxidant component of the coating forms up to about 15% by weight, e.g., from 0% 0078. The color coating can also optionally include the to about 15% by weight of the pharmaceutical formulation, aforementioned antioxidant component, or the aforemen from about 0.01% to about 5% by weight of the pharma tioned chelating component, or both, as described above. ceutical formulation; from about 0.01% to about 2% by 0079 Generally, the optional filler component of the weight of the pharmaceutical formulation; or from about color coating can include one or more fillers as described 0.1% to about 0.5% by weight of the pharmaceutical for above for the first coating. In some embodiments, the filler mulation; or from about 0.3% to about 0.8% by weight of the component of the color coating, when present, includes or pharmaceutical formulation; or from about 0.6% to about consists of Sucrose. US 2007/0003623 A1 Jan. 4, 2007

0080 Generally, the optional binder component of the capacity to keep a reasonable tablet size and process times, color coating can include one or more binders as described and the limitation of the available excipients that can be used above for the first coating. In some embodiments, the binder to modify the release rate and inherent variability of the component of the color coating, when present, includes or process. consists of hydroxypropylmethylcellulose. 0094. While such intermittent processes are amenable to 0081. The coloring agent component can include one or the present formulations, it has been found in accordance more of any of the variety of coloring agents known to be with the present invention that Sugar coatings can be applied useful in the pharmaceutical arts. In some embodiments, the to tablets or other coatable dosage forms by a continuous coloring agent component includes or consists of titanium process. In the continuous Sugar coating process, active dioxide. Further preferred coloring agents include, for Suspension is applied in a “continuous manner which is example, Opadry(R) agents, for example Opadry(R) White similar to traditional film coating process from the process YS-1-182O2 A stand-point. It is known that Sugar, as such in a solution, can 0082 In some embodiments, the pharmaceutical compo not be sprayed continuously on to tablets because of its sitions of the invention further include a clear coating. In inherent physico-chemical properties, such as solubility, Some embodiments, the clear coating includes from about Viscosity, and its crystallization kinetics when dried by spray 0.01% to about 2% by weight of the pharmaceutical formu application on to tablets. However, use of the formulations lation. Generally, the clear coating is formed over the color described herein, with appropriate control of process vari coating, when present, as described above, or, alternatively, ables, produces a product of acceptable quality and stability, directly on the first coating as described above. Any of the and addresses the limitations of the intermittent Sugar coat numerous clear coatings known in the art are suitable for use ing process described above. in the pharmaceutical compositions of the invention, for 0095 Accordingly, in some embodiments, the coating of example Opadry(R) coatings, for example Opadry(R) Clear the core with the coating composition including baZedox YS-2-19114 A. ifene or a pharmaceutically acceptable salt thereof is per 0083. The clear coating can also optionally include the formed by a continuous process. aforementioned antioxidant component, or the aforemen 0096. In some embodiments, the coating composition of tioned chelating component, or both, as described above. step ii) includes: 0084. In some embodiments, the invention provides pro 0097) a) a filler component; cesses for preparing pharmaceutical compositions of the invention. In some embodiments, the processes are used to 0.098 b) a binder component; prepare pharmaceutical compositions of the invention that 0099 c) a wetting agent component; include: 0.100 d) an optional antioxidant component; 0085 a core including conjugated estrogens; and 0101 e) baZedoxifene acetate; and 0.086 a first coating including baZedoxifene or a phar maceutically acceptable salt thereof. In some embodiments, 0102) f) an optional chelating component. the processes include: 0.103 wherein the filler component, the binder compo 0087 i) providing a core including conjugated estrogens: nent, the wetting agent component, the optional antioxidant and component, and the optional chelating component are as described above. In some preferred embodiments, the filler 0088 ii) coating the core with a coating composition component of the coating comprises Sucrose; the binder including baZedoxifene or a pharmaceutically acceptable component of the coating comprises hydroxypropylmethyl salt thereof to form a coated core. cellulose; the wetting agent component of the coating com 0089. In some embodiments, the processes further prises Sucrose palmitate; the optional antioxidant component include the step of: of the coating, when present, comprises ascorbic acid, or a salt thereof, and the optional chelating component, when 0090 iii) coating the coated core with a color coating present, comprises EDTA. composition to form a color coated composition. 0104. In some embodiments, the color coating composi 0091. In some embodiments, the processes further tion includes: include the step of: an optional filler component; 0092 iv) coating the color coating composition with a 01.05 clear coating composition to form a clear coat thereon. 0106) an optional binder component; and 0093 Traditionally, sugar coatings are applied to tablet 01.07 a coloring agent component; formulations using an intermittent process. In the intermit tent active Sugar coating process, discrete amounts of the 0.108 wherein the optional filler component, the optional active Sugar coat Suspension are applied to the Surface of a binder component, and the coloring agent component are as dosage form, for example a tablet, followed by a distribution described above. The color coating can also optionally phase and drying phase, which is repeated several hundred include the aforementioned antioxidant component, or the times until the desired weight gain is achieved. Several aforementioned chelating component, or both, as described products currently sold are manufactured using this tech above. nique. This process, however, has some limitations. 0.109. In some embodiments, the optional filler compo Examples of Such limitations are the limited drug loading nent of the color coating composition includes Sucrose; the US 2007/0003623 A1 Jan. 4, 2007 optional binder component of the color coating composition 0.116) The present invention also provides products of the includes hydroxypropylmethylcellulose; and the coloring processes described herein. agent component of the color coating composition includes 0.117) It will be understood that the weight percentages titanium dioxide. In some embodiments, the optional anti set forth for each of the core, filler components, a binder oxidant component of the color coating, when present, components, wetting agent components, optional antioxi comprises ascorbic acid, or a salt thereof, and the optional dant components, optional chelating components, optional chelating component of the color coating, when present, filler components, optional binder components, coloring comprises EDTA. agent components and clear coatings of the compositions 0110. In some embodiments, the filler component of the disclosed herein are the percentages that each component coating composition of step ii) forms from about 5% to will comprise of a final pharmaceutical composition, includ about 30% by weight of the pharmaceutical formulation; the ing, if present, the clear and color coatings. binder component of the coating composition of step ii) forms from about 1% to about 10% by weight of the 0118 Oral formulations containing the present solid dis pharmaceutical formulation; the wetting agent component of persions can comprise a variety of conventionally used oral the coating composition of step ii) forms from about 0.01% forms, for example tablets and tablet-in-capsule forms. to about 2% by weight of the pharmaceutical formulation; Generally, tablets and tablet-in-capsule forms are preferred. the optional antioxidant component of the coating compo Capsules or tablets of containing the present solid dispersion sition of step ii) forms from about 0% to about 2% by weight can also be combined with mixtures of other active com of the pharmaceutical formulation; the baZedoxifene acetate pounds or inert fillers and/or diluents such as the pharma includes forms from about 0.1% to about 20% by weight of ceutically acceptable starches (e.g. corn, potato or tapioca the pharmaceutical formulation; and the optional chelating starch), Sugars, artificial Sweetening agents, powdered cel component of the coating forms from 0% to about 0.1% by luloses, such as crystalline and microcrystalline celluloses, weight of the pharmaceutical formulation. In some embodi flours, gelatins, gums, etc. In some preferred embodiments, ments, the conjugated estrogens is present in an amount of the formulations are tablets. from about 0.10 to about 1.0 mg. In some further embodi 0119) Tablet formulations can be made by conventional ments, the baZedoxifene is present in an amount of from compression, wet granulation, or dry granulation methods about 1 to about 50 mg, based on the weight of the and utilize pharmaceutically acceptable diluents (fillers), baZedoxifene free base. In some further embodiments, the binding agents, lubricants, disintegrants, Suspending or sta conjugated estrogens is present in an amount of from about bilizing agents, including those described above, as well as, 0.10 to about 1.0 mg; and the baZedoxifene is present in an without limitation, magnesium Stearate, Stearic acid, talc, amount of from about 5 to about 50 mg, based on the weight Sodium lauryl Sulfate, microcrystalline cellulose, carboxym of the baZedoxifene free base. ethylcellulose calcium, polyvinylpyrrolidone, gelatin, alg 0111. In some embodiments of each of the pharmaceuti inic acid, acacia gum, Xanthan gum, Sodium citrate, complex cal compositions and processes of the invention, the conju silicates, calcium carbonate, glycine, dextrin, Sucrose, Sor gated estrogens include or consist of Premarin R. bitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, Sodium chloride, talc, dry starches and powdered 0112 In some embodiments of each of the pharmaceuti Sugar. Oral formulations used herein may utilize standard cal compositions and processes of the invention, the conju delay or time release formulations or spansules. Suppository gated estrogens is present in the composition in an amount formulations may be made from traditional materials, of from about 0.10 to about 1.0 mg; or from about 0.3 to including cocoa butter, with or without the addition of waxes about 0.8 mg; or from about 0.4 to about 0.5 mg; or from to alter the Suppositories melting point, and glycerin. Water about 0.5 to about 0.7 mg. soluble Suppository bases, such as polyethylene glycols of 0113. In some embodiments of each of the pharmaceuti various molecular weights, may also be used. cal compositions and processes of the invention, the baZe doxifene is present in an amount of from about 1 to about 50 0120 Film coatings useful with the present formulations mg, or from about 5 to about 25 mg. or from about 5 to about are known in the art and generally consist of a polymer 15 mg. or from about 15 to about 25 mg. or from about 35 (usually a cellulosic type of polymer), a colorant and a to about 45 mg, based on the weight of the baZedoxifene free plasticizer. Additional ingredients such as wetting agents, base. Sugars, flavors, oils and lubricants can be included in film coating formulations to impart certain characteristics to the 0114. In some embodiments of each of the pharmaceuti film coat. The compositions and formulations herein may cal compositions and processes of the invention, the conju also be combined and processed as a solid, then placed in a gated estrogens is present in an amount of from about 0.10 capsule form, such as a gelatin capsule. to about 1.0 mg; and the baZedoxifene is present in an amount of from about 5 to about 50 mg, based on the weight 0.121. As will be appreciated, some components of the of the baZedoxifene free base. formulations of the invention can possess multiple func tions. For example, a given component can act as both a 0115) In some embodiments of each of the pharmaceuti binder and a filler. In some such cases, the function of a cal compositions and processes of the invention, the conju given component can be considered singular, even though its gated estrogens is present in the composition in an amount properties may allow multiple functionality. of from about 0.4 to about 0.5 mg; or from about 0.5 to about 0.7 mg; and the baZedoxifene is present in an amount of 0122) Additional numerous various excipients, dosage from about 5 to about 15 mg, or from about 15 to about 25 forms, dispersing agents and the like that are suitable for use mg, or from about 35 to about 45 mg, based on the weight in connection with the solid dispersions of the invention are of the baZedoxifene free base. known in the art and described in, for example, Remington's US 2007/0003623 A1 Jan. 4, 2007

Pharmaceutical Sciences, 17th ed., Mack Publishing Com the coating comprises hydroxypropylmethylcellulose; the pany, Easton, Pa., 1985, which is incorporated herein by wetting agent component of the coating comprises Sucrose reference in its entirety. palmitate; the optional antioxidant component of the coating 0123. As discussed above, it has been found in accor comprises ascorbic acid, or a salt thereof, and the optional dance with the present invention that Sugar coatings can be chelatin component, when present, comprises EDTA. applied to tablets or other coatable dosage forms by a 0.143. In some further embodiments, the processes further continuous process. Accordingly, in some embodiments, the comprising the step of iii) coating the coated core with a present invention provides processes for preparing a phar color coating composition to form a color coated composi maceutical composition, the composition comprising: tion; and in Some further embodiments, the processes further a core comprising a therapeutic agent; and comprising the step of iv) coating the color coated compo 0124 sition with a clear coating composition to form a clear coat 0.125 a coating optionally comprising a second therapeu thereon. tic agent and at least one Sugar, 0144. The first therapeutic agent can be any of a wide 0126) the process comprising: variety of therapeutic agents. As used herein, the term 0127 i) providing a core comprising the first therapeutic “therapeutic agent” also refers to a substance which is agent; and capable of exerting a therapeutic biological effect in vivo. The therapeutic agents may be neutral or positively or 0128 ii) coating the core with a coating composition negatively charged. Examples of Suitable pharmaceutical comprising: agents include, inter alia, diagnostic agents, pharmaceuti 0129 a) a filler component that comprises at least one cals, drugs, synthetic organic molecules, proteins, peptides, Sugar, Vitamins, and steroids. For example, the composition may include one or more hormonal steroids, such as medroX 0.130) b) a binder component; yprogesterone acetate, levonorgestrel, gestodene, medroge c) a wetting agent component; stone, estradiol, estriol, ethinylestradiol, mestranol, estrone, 0131) dienestrol, hexestrol, diethylstilbestrol, progesterone, 0132) d) an optional antioxidant component; desogestrel, norgestimate, hydroxyprogesterone, norethin drone, norethindone acetate, norgestrel, megestrol acetate, 0133) e) optionally, a second therapeutic agent; and methyltestosterone, ethylestrenol, methandienone, oxan 0134) f) an optional chelating component; drolone, trimegestone, dionogest, and the like. Additionally, tissue selective progesterones and/or progesterone antago 0135 wherein the coating composition of step ii) is nists, which may or may not have the typical steroidal applied by a continuous Sugar coating technique. functionality, may be present in the composition. These In some such embodiments: include, but are not limited to: RU-486 (mifepristone), ZK 0136 98 299 (onapristone), ZK-1373.16 (Schering AG, Berlin), 0137 the filler component comprises one or more of ZK-230211 (Schering AG, Berlin), and HRP-2000 (17 Sucrose, mannitol, lactose, powdered cellulose, microcrys acetoxy-11 B-(4-N,N-dimethylaminophenyl)-19-norpre talline cellulose, malodextrin, Sorbitol, starch, Xylitol, car gna-4,9-diene-320-dione). Where desired, estrogenic ste boxymethyl cellulose, carboxyethyl cellulose, hydroxyethyl roids and progestogenic steroids may be used in celluloses, microcrystalline celluloses, starches, anhydrous combination. dicalcium phosphate, sodium starch glycolates, and metal aluminosilicates; 0145 The processes of the present invention are particu larly Suitable for use in coating core materials, for example 0138 the binder component comprises one or more of tablets, to produce a coated Solid dosage form. The term hydroxypropylmethylcellulose, carboxymethyl cellulose, “core material' refers to any tablet, caplet, particle, micron carboxyethyl cellulose, hydroxyethyl celluloses, microcrys ized particle, particulate, pellet, pill, core, granule, granu talline celluloses, starches; late, Small mass, seed, specks, spheres, crystals, beads, 0139 the wetting agent component comprises one or agglomerates, mixtures thereof and the like that are Sufi more of sucrose palmitate, Poloxamer 188, metal alkyl ciently stable physically and chemically to be effectively Sulfates, sodium lauryl Sulfate, polyoxyethylene Sorbitan coated in a continuous Sugar coating process. fatty acid esters, polyethylene glycols, polyoxyethylene cas 0146 In a preferred embodiment, the core material is tor oil derivatives, docusate sodium, quaternary ammonium present in the form of a tablet. As used herein, the term amine compounds, Sugar esters of fatty acids and glycerides “tablet' refers to a solid pharmaceutical dosage form con of fatty acids; and taining a therapeutic agent with or without Suitable diluents 0140 the optional antioxidant component, when present, and prepared by either compression or molding methods, comprises one or more of ascorbic acid citric acid, sodium such as are well known to those of ordinary skill in the art. ascorbate, ascorbyl palmitate, nicotinamide ascorbate, pro Suitable methods of forming tablets are described, for pyl gallate, alpha tocopherol, beta tocopherol, gamma toco example, in Edward M. Rudnick, et al., “Oral Solid Dosage pherol, and BHA/BHT; and Forms, in Remington. The Science and Practice of Phar macy, 20" Ed., Chap. 45, Alfonso R. Gennaro, ed., Phila 0141 the optional chelating component, when present, delphia College of Pharmacy and Science, Philadelphia, Pa. comprises EDTA. (2000), herein incorporated by reference in its entirety. In 0142. In some further embodiments, the filler component some embodiments, the core material is a tablet formed by of the coating comprises Sucrose; the binder component of compression methods. US 2007/0003623 A1 Jan. 4, 2007

0147 Most frequently, the core material will comprise at Zole, alfentanil, alprazolam, alprenolol, amantadine, least one therapeutic agent, as defined previously, and at amiloride, aminoglutethimide, amiodarone, amitriptyline, least one pharmaceutically acceptable excipient. The term amlodipine, amodiaquine, amoxapine, amphetamine, “pharmaceutically acceptable,” as used herein, refers to amphotericin, amprenavir, amrinone, amsacrine, apomor materials that are generally not toxic or injurious to a patient phine, astemizole, atenolol, atropine, azathioprine, azelas when used in the compositions of the present invention, tine, azithromycin, baclofen, benethamine, benidipine, ben including when the compositions are administered by the Zhexol, benznidazole, benztropine, biperiden, bisacodyl, oral route. The term “patient, as used herein, refers to bisanthrene, bromazepam, bromocriptine, bromperidol, bro animals, including mammals, preferably humans. "Excipi mpheniramine, brotizolam, bupropion, butenafine, buto ents, as that term is used herein, refers to ingredients that provide bulk, impart satisfactory processing and compres conazole, cambendazole, camptothecin, carbinoxamine, sion characteristics, help control the dissolution rate, and/or cephadrine, cephalexin, cetrizine, cinnarizine, chlorambucil, otherwise give additional desirable physical characteristics chlorpheniramine, chlorproguanil, chlordiazepoxide, chlor to the core material. Included within this term, for example, promazine, chlorprothixene, chloroquine, cimetidine, cipro are diluents, binders, lubricants and disintegrants well floxacin, cisapride, citalopram, clarithromycin, clemastine, known to those of ordinary skill in the art, as described, for clemizole, clenbuterol, clofazimine, clomiphene, clon example, in the Handbook of Pharmaceutical Excipients, azepam, clopidogrel, clozapine, clotiazepam, clotrimazole, American Pharmaceutical Association, Washington, D.C. codeine, cyclizine, cyproheptadine, dacarbazine, darodipine, and The Pharmaceutical Society of Great Britain, London, decoquinate, delavirdine, demeclo-cycline, dexamphet England (1986), herein incorporated by reference in its amine, dexchlorpheniramine, dexfenfluramine, diamor entirety. phine, diazepam, diethylpropion, dihydrocodeine, dihydro ergotamine, diltiazem, dimenhydrinate, diphenhydramine, 0148. A wide variety of therapeutic agents may be uti diphenoxylate, diphenyl-imidazole, diphenylpyraline, dipy lized in either the core material i.e., as the first therapeutic ridamole, dirithromycin, disopyramide, dolasetron, domp agent), or in the coating (i.e., as the second therapeutic eridone, donepezil, doxazosin, doxycycline, droperidol. agent). Specific examples of therapeutic agents include, but econazole, efavirenz, ellipticine, enalapril, enoxacin, enro are not limited to: acetazolamide, acetohexamide, acrivas floxacin, eperisone, ephedrine, ergotamine, erythromycin, tine, alatrofloxacin, albuterol, alclofenac, aloxiprin, alpros ethambutol, ethionamide, ethopropazine, etoperidone, tadil, amodiaquine, amphotericin, amylobarbital, aspirin, famotidine, felodipine, fenbendazole, fenfluramine, atorvastatin, atovaquone, baclofen, barbital, benazepril, fenoldopam, fentanyl, fexofenadine, flecainide, flucytosine, bezafibrate, bromfenac, bumetanide, butobarbital, cande flunarizine, flunitrazepam, fluopromazine, fluoxetine, Sartan, capsaicin, captopril, cefazolin, celecoxib, ceph fluphenthixol, fluphenthixol decanoate, fluphenazine, adrine, cephalexin, cerivastatin, cetrizine, chlorambucil, fluphenazine decanoate, flurazepam, flurithromycin, fro chlorothiazide, chlorpropamide, chlorthalidone, cinoxacin, Vatriptan, gabapentin, granisetron, grepafloxacin, guana ciprofloxacin, clinofibrate, cloxacillin, cromoglicate, cro benZ, halofantrine, haloperidol, hyoscyamine, imipenem, molyn, dantrolene, dichlorophen, diclofenac, dicloxacillin, indinavir, irinotecan, isoxazole, isradipine, itraconazole, dicumarol, diflunisal, dimenhydrinate, divalproex, docusate, ketoconazole, ketotifen, labetalol, lamivudine, lanosprazole, dronabinol, enoXimone, enalapril, enoxacin, enrofloxacin, leflunomide, levofloxacin, lisinopril, lomefloxacin, lopera epalrestat, eposartan, essential fatty acids, estramustine, mide, loratadine, lorazepam, lormetazepam, lysuride, mepa ethacrynic acid, ethotoin, etodolac, etoposide, fenbufen, crine, maprotiline, mazindol, mebendazole, meclizine, fenoprofen, fexofenadine, fluconazole, flurbiprofen, fluvas medazepam, mefloquine, melonicam, meptazinol, mercap tatin, fosinopril, fosphenyloin, fumagillin, furosemide, topurine, mesalamine, mesoridazine, metformin, metha gabapentin, gemfibrozil, gliclazide, glipizide, glybencla done, methaqualone, methylphenidate, methylphenobar mide, glyburide, glimepiride, grepafloxacin, ibufenac, ibu bital, methysergide, metoclopramide, metoprolol. profen, imipenem, indomethacin, irbesartan, isotretinoin, metronidazole, mianserin, miconazole, midazolam, miglitol, ketoprofen, ketorolac, lamotrigine, levofloxacin, lisinopril, minoxidil, mitomycins, mitoxantrone, modafinil, molin lomefloxacin, losartan, lovastatin, meclofenamic acid, mefe done, montelukast, morphine, moxifloxacin, nadolol, nalbu namic acid, mesalamine, methotrexate, metolaZone, mon phine, naratriptan, natamycin, nefazodone, nelfinavir, nevi telukast, nalidixic acid, naproxen, natamycin, nimeSulide, rapine, nicardipine, nicotine, nifedipine, nimodipine, nitrofurantoin, non-essential fatty acids, norfloxacin, nysta nimorazole, nisoldipine, nitrazepam, nitrofuraZone, nizati tin, ofloxacin, oxacillin, oxaprozin, oxyphenbutaZone, peni dine, norfloxacin, nortriptyline, nystatin, ofloxacin, olanza cillins, pentobarbital, perfloxacin, phenobarbital, phenyloin, pine, omeprazole, ondansetron, omidazole, oxaminiquine, pioglitaZone, piroXicam, pramipexol, pranlukast, pravasta oxantel, oxatomide, oxazepam, Oxfendazole, oxiconazole, tin, probenecid, probucol, propofol, propylthiouracil, oXprenolol, oxybutynin, oxyphencyclimine, paroxetine, quinapril, rabeprazole, repaglinide, rifampin, rifapentine, pentazocine, pentoxifylline, perchlorperazine, perfloxacin, sparfloxacin, Sulfabenzamide, Sulfacetamide, Sulfadiazine, perphenazine, phenbenzamine, pheniramine, phenoxyben Sulfadoxine, Sulfamerazine, Sulfamethoxazole, Sulfafura Zamine, phentermine, physostigmine, pimozide, pindolol. Zole, Sulfapyridine, Sulfasalazine, Sulindac, SulphaSalazine, pizotifen, pramipexol, pranlukast, praziquantel, praZosin, Sulthiame, telmisartan, teniposide, terbutaline, tetrahydro procarbazine, prochlorperazine, proguanil, propranolol. cannabinol, tirofiban, tolaZamide, tolbutamide, tolcapone, pseudoephedrine, pyrantel, pyrimethamine, quetiapine, qui tolimetin, tretinoin, troglitaZone, trovafloxacin, undecenoic nidine, quinine, raloxifene, ranitidine, remifentanil, repa acid, urSodeoxycholic acid, valproic acid, Valsartan, Vanco glinide, reserpine, ricobendazole, rifabutin, rifampin, rifap mycin, verteporfin, vigabatrin, vitamin K-S (II) and entine, rimantadine, risperidone, ritonavir, rizatriptan, Zafirlukast. Additional therapeutic agents include abacavir, ropinirole, rosiglitaZone, roXatidine, roXithromycin, Salbuta acebutolol, acrivastine, alatrofloxacin, albuterol, albenda mol, saquinavir, selegiline, Sertraline, Sibutramine, sildena US 2007/0003623 A1 Jan. 4, 2007 fil, sparfloxacin, spiramycins, stavudine, Sufentanil, Sulcona sants such as phenyloin, ethoSuximide, and primidone, Syn Zole, SulphaSalazine, Sulpiride, Sumatriptan, tacrine, thetic glucocorticoids such as hydrocortisone, prednisolone, tamoxifen, tamsulosin, temazepam, teraZosin, terbinafine, triamcinolone, and betamethasone, antiulceratives such as terbutaline, terconazole, terfenadine, tetramisole, thiabenda famotidine, ranitidine hydrochloride, cimetidine, Sucralfate, Zole, thioguanine, thioridazine, tiagabine, ticlopidine, Sulpiride, teprenone, plaunotol. 5-aminosalicylic acid, Sul timolol, tinidazole, tioconazole, tirofiban, tizanidine, toltero fasalazine, omeprazole, and lansoprazol, central nervous dine, topotecan, toremifene, tramadol, traZodone, triam system drugs such as indeloxazine, idebenone, thiapride terene, triazolam, trifluoperazine, trimethoprim, trimi hydrochloride, bifemelane hydrocide, and calcium pramine, tromethamine, tropicamide, trovafloxacin, homopantothenate, antihyperlipoproteinemics such as prav Vancomycin, Venlafaxine, vigabatrin, vinblastine, Vincris astatin Sodium, simvastatin, lovastatin, and atorvastatin, tine, Vinorelbine, vitamin Ks, vitamin K. vitamin K7. antibiotics such as ampicillin hydrochloride, phthalylsulfac Zafirlukast, Zolmitriptan, Zolpidem and Zopiclone. Of course, etamide, cefotetan, and josamycin, BPH therapeutic agents any of the foregoing therapeutic agents may be included in Such as tamsulosin hydrochloride, doxazosin meSylate, and the coating composition, as discussed previously, and any of teraZosin hydrochloride, drugs affecting uterine motility the therapeutic agents discussed with regard to the coating Such as branylcast, Zafylcast, albuterol, ambroXol, budes composition alternatively may be included in the core mate onide, and reproterol, peripheral circulation improvers of rial. prostaglandin I derivatives such as beraprost sodium, anti coagulants, hypotensives, agents for treatment of cardiac 014.9 The core material may be designed for delivering insufficiency, agents used to treat the various complications therapeutic agents intended to be delivered over a Sustained of diabetes, peptic ulcer therapeutic agents, skin ulcer thera period of time. The following are representative of such peutic agents, agents used to treat hyperlipemia, tocolytics, therapeutic agents: anti-inflammatory, antipyretic, anti-spas etc. The therapeutic agent can be used in its free form or as modics or analgesics Such as indomethacin, diclofenac, diclofenac sodium, codeine, ibuprofen, phenylbutaZone, a pharmaceutically acceptable salt. Moreover, one or a oxyphenbutaZone, mepirizole, aspirin, ethenZamide, combination of two or more therapeutic agents may be acetaminophen, aminopyrine, phenacetin, butylscopolamine present in the core material. bromide, morphine, etomidoline, pentazocine, fenoprofen 0150. In some embodiments, the therapeutic agent in the calcium, naproxen, selecxip, Valdecxip, and tolamadol, anti core material includes conjugated estrogens. “Conjugated rheumatism drugs such as etodolac, anti-tuberculoses drugs estrogens' (CE) as used herein includes both natural and such as isoniazide and ethambutol hydrochloride, cardio Synthetic conjugated estrogens. Such as the compounds vascular drugs such as isosorbide dinitrate, nitroglycerin, described in the United States Pharmacopia (USP 23), as nifedipine, barnidipine hydrochloride, nicardipine hydro well as other estrogens so considered by those skilled in the chloride, dipyridamole, amrinone, indenolol hydrochloride, art. Further, "conjugated estrogens' refers to esters of Such hydralazine hydrochloride, methyldopa, furosemide, compounds, such as the Sulfate esters, salts of Such com spironolactone, guanethidine nitrate, reserpine, amoSulalol pounds. Such as Sodium salts, and esters of the salts of Such hydrochloride, lisinopril, metoprolol, pilocarpine, and talce compounds, Such as sodium salts of a Sulfate ester, as well tin, antipsychotic drugs such as chlorpromazine hydrochlo as other derivatives known in the art. Some specific ride, amitriptyline hydrochloride, nemonapride, haloperidol. examples include: 17-alpha and beta-dihydroequilin, equile moperone hydrochloride, perphenazine, diazepam, nin, 17-alpha and beta-dihydroequilenin, estrone, 17-beta lorazepam, chlorodiazepoxide, adinazolam, alprazolam, estradiol, and their sodium Sulfate esters. methylphenidate, myrnasipran, peroxetin, risperidone, and 0151. Although CE are typically a mixture of estrogenic Sodium valproate, anti-emetics such as metoclopramide, components, such as estrone and equilin, the core material lamocetron hydrochloride, granisetron hydrochloride, may be formulated to either utilize such a mixture, or to ondansetron hydrochloride, and azacetron hydrochloride, include only selected or individual estrogenic components. antihistamines Such as chlorpheniramine maleate and These CE may be of synthetic or natural origin. Examples of diphenhydramine hydrochloride, Vitamins such as thiamine synthetically produced estrogens include, interalia, Sodium nitrate, tocopherol acetate, cycothiamine, pyridoxal phos estrone Sulfate, Sodium equilin Sulfate, Sodium 17C.-dihy phate, cobarnamide, ascortic acid, and nicotinamide, anti droequilin sulfate, sodium 17 B-dihydroequilin sulfate, gout drugs such as allopurinol, colchicine, and probenecide, sodium 17C.-estradiol sulfate, sodium 17 B-estradiol sulfate, anti-Parkinson's disease drugs such as levodopa and sele Sodium equilenin Sulfate, sodium 17C.-dihydroequileninsul grine, sedatives and hypnotics such as amobarbital, bromu fate, sodium 173-dihydroequilenin Sulfate, estropipate and ralyl urea, midazolam, and chloral hydrate, antineoplastics ethinyl estradiol. The alkali metal salts of 8,9-dehy Such as fluorouracil, carmofur, acralvidine hydrochloride, droestrone and the alkali metal salts of 8.9-dehydroestrone cyclophosphamide, and thiodepa, anti-allergy drugs such as sulfate ester, as described in U.S. Pat. No. 5,210,081, which pseudoephedrine and terfenadine, decongestants such as is herein incorporated by reference, also may be used. phenylpropanolamine and ephedorine, diabetes mellitus Naturally occurring CE are usually obtained from pregnant drugs such as acetohexamide, insulin, tolbutamide, desmo pressin, and glipizide, diuretics such as hydrochlorothiazide, mare urine and then are processed and may be stabilized. polythiazide, and triamterene, bronchodilators such as ami Examples of such processes are set forth in U.S. Pat. Nos. nophylline, formoterol fumarate, and theophylline, antitus 2,565,115 and 2,720,483, each of which are herein incor sives such as codeine phosphate, noscapine, dimorfan phos porated by reference. phate, and dextromethorphan, anti-arrhythmics such as 0152 Many CE products are commercially available. quinidine nitrate, digitoxin, propafenone hydrochloride, and Preferred among these is the naturally occurring CE product procainamide, topical anesthetics such as ethyl aminoben known as Premarin R (Wyeth, Madison, N.J.). Another com Zoate, lidocaine, and dibucaine hydrochloride, anti-convul mercially available CE product prepared from synthetic US 2007/0003623 A1 Jan. 4, 2007 10 estrogens is Cenestin R. (Duramed Pharmaceuticals, Inc., 0166 6. When the mixture reached 23-27 C. (target Cincinnati, Ohio). The specific CE dose included in the core 25°C.), mixing was ceased, and 46.054 g of baZedox material may be any dosage required to achieve a specific ifene acetate was added. The low shear and high shear therapeutic effect, and may vary depending on the specific mixers were both turned on, and mixing was continued treatment indicated, and on the specific CE included in the for approximately 15 minutes. tablet. 0167 7. Both mixers were then turned off, the walls 0153. In some embodiments, the first active agent com and shaft of the mixer were scraped, and both mixers prises conjugated estrogens, and the second active agent were then turned on for an additional 15 minutes. comprises baZedoxifene or a salt thereof. 0168 8. Both mixers were then turned off, and a 0154) The materials, methods, and examples presented sufficient amount of the 10% w/w stock solution of herein are intended to be illustrative, and are not intended to Hydroxypropyl Methylcellulose, USP. 2910, 3 cps. limit the scope of the invention. from Step B above was added to provide 408.37 g of Hydroxypropyl Methylcellulose, USP, 2910, 3 cps. The EXAMPLES mixture was mixed at low speed for 10 minutes, adjusting the speed of the mixer to prevent generation Example 1 of excessive foam. Procedure for Preparation of Tablets Containing 0169. 9. The slurry from Step 8 above was brought to Conjugated Estrogens/Bazedoxifene Acetate, 0.45 Theoretical Weight with water, purified, USP, and mix mg/10 mg ing was continued for an additional 10 minutes with the Lightnin type mixer at low speed. 0155 A. Preparation of 10% w/w Stock Solution of Hydroxypropyl Methylcellulose, USP. 2910, 3 cps. 0170 10. Mixing of the suspension was continued with the Lightnin type mixer at low speed, and intermittently 0156 1.900 g of water, purified, USP, was placed in a with the high shear mixer, as needed, while maintaining vessel equipped with a low shear (Lightnin type) mixer. the temperature at 23-27 C. (target 25° C.). Mixing was continued with the low shear mixer until the level O157 2. 100 g of Hydroxypropyl Methylcellulose, of the suspension fell below the agitator head. USP. 2910, 3 cps., was added in small increments to the vortex created in the water by the moderate agitation of 0171 B2. Alternate Procedure for Preparation of Baze step 1. doxifene Acetate Filler Coat Suspension: 0158. 3. Agitation was continued for am minimum of 0172 1. Water, USP. purified was placed in a suitable one hour, or until all the Hydroxypropyl Methylcellu vessel equipped with a low shear (Lightnin type) and lose, USP. 2910, 3 cps., is dissolved. high shear (Silverson type or equivalent) mixers. 0159. 4. If necessary, add water, purified USP to 0173 2. With the Lightnin type mixer turned on, the achieve the total theoretical weight. water was heated to 55-65° C. (target 60° C.). 0.174 3. The speed of the Lightnin mixer was adjusted 0160 B1. Preparation of Bazedoxifene Acetate Filler to create a vortex without drawing air into the water. Coat Suspension: The sucrose palmitate was slowly added to the vortex 0.161 1. 428.30 g of water, purified, USP was placed in and mixed for approximately 20 minutes to dissolve it. a vessel equipped with a low shear (Lightnin type) and The high shear mixer was used for approximately 5 minutes to disperse and dissolve any undissolved par high shear (Silverson type) mixer. ticles of Sucrose palmitate. 0162 2. With the Lightnin type mixer turned on, the 0.175 4. With the Lightnin type mixer turned on, water was heated to 60-70° C. (target 65° C.). Sucrose, NF was added to the vortex and reheated to 0163. 3. With the Lightnin type mixer turned on at 55-65° C. (target 60° C.), and then mixed for approxi slow speed, 110.64 g of sucrose, NF was added, and the mately 15 minutes to dissolve the sucrose NF. The mixture was reheated to 65° C. and held at that tem temperature was then held at 60° C. for approximately perature for 10 minutes, until the sucrose dissolved. 15 minutes, to ensure all the sucrose had dissolved. 0164. 4. With the Lightnin type mixer turned on at 0176 5. With the Lightnin type mixer turned on, slow speed, 2.5523 g of Sucrose palmitate was added, Hydroxypropyl Methylcellulose, USP. 2910, 3 cps was and mixing was continued at slow speed for 10 min added to the vortex and reheated to 55-65° C. (target utes. If necessary, mixing can be performed at high 60° C.). The high shear mixer could be used during and shear for 2 minutes with the high shear mixer to after the addition to aid the wetting of the Hydroxypro disperse and dissolve any undissolved Sucrose palmi pyl Methylcellulose, USP. 2910, 3 cps. The dispersion was mixed for approximately 15 minutes to disperse tate. Hydroxypropyl Methylcellulose, USP. 2910, 3 cps, 0.165 5. The mixture was then cooled to 23-27 C. with the speed of the mixer being adjusted to obtain (target 25° C.). When the mixture was about 30° C., adequate mixing. The temperature was held at 60° C. 4.0837 g of ascorbic acid, USP was slowly added, and for approximately 15 minutes to ensure all the Hydrox mixing was continued using the Lightnin type mixer for ypropyl Methylcellulose, USP, 2910, 3 cps was well 10 minutes. dispersed without forming any clumps. US 2007/0003623 A1 Jan. 4, 2007 11

0.177 6. With the Lightnin type mixer turned on, the 0188 6. No more than 2 hours before the color sus solution from the preceding step was cooled to 23-27 pension was to be applied to the tablets, 15 g of C. (target 25°C.). Once the temperature was decreased titanium dioxide, NF was added to the mixture, which below 30°C., the ascorbic acid, USP was slowly added, was then mixed with the high shear mixer and low and mixing was continued using the Lightnin type shear mixer for 10 minutes. mixer for approximately 10 minutes to dissolve ascor 0189 7. Both mixers were then turned off, the walls bic acid, USP. and shaft of the mixer were scraped, and both mixers 0.178 7. When the temperature reached 23-27 C. were then turned on for an additional 5 minutes. Mixing (target 25°C.), the baZedoxifene acetate was added to was continued with the low shear mixer during color the vortex. Once all the baZedoxifene acetate had been application. added, the high shear mixer was turned on and mixing was continued for approximately 10 minutes, with the 0.190) D. Preparation of Clear Coat Suspension: power of the high shear mixer being adjusted not to 0191) 1.950 g of water, purified, USP, was placed in a generate excessive foaming. stainless steel container equipped with a low shear 0179 8. Both the mixers were then turned off, and the (Lightnin type) mixer. tank walls and mixer shaft were scraped. Both mixers 0.192 2. With the propeller in the center and as close to were then turned on at the same settings as were used the bottom of the vessel as possible, the mixture was in the previous step, and mixing continued for approxi stirred to form a vortex without drawing air into the mately 10 minutes to disperse the baZedoxifene acetate. liquid. 0180 9. The suspension from the previous step was 0193 3. 50.0 g of Opadry clear, YS-2-19114A, was brought to theoretical Weight with water, USP, Purified, added slowly, avoiding powder floatation on the liquid as necessary, and mixing was continued for an addi Surface. The stirrer speed was increased to maintain the tional 10 minutes with the Lightnin type mixer at slow Vortex as required. speed. 0194 E. Tablet Coating Procedure: 0181 10. Mixing of the suspension with the Lightnin type mixer and intermittently with the high shear mixer 0.195 1. Premarin(R) 0.45 mg No Talc Triturate Filled (as needed) was continued during application, while tablets were loaded into a perforated coating pan. maintaining temperature at 23-27 C. (target 25°C.). 0196. 2. Sufficient Bazedoxifene Acetate Filler Coat Sus Mixing was performed continuously with the low shear pension from Step C above was added to achieve a total mixer until the level of the suspension fell below the weight of 50 mg (+2 mg) above the inert tablet filled weight agitator head. (approximately 244.9 mg of Bazedoxifene Acetate Filler 0182 C. Preparation of Color Coat Suspension: Coat Suspension per tablet). The tablets were coated with the Suspension using a continuous coating technique, 0183 1. 675g of water, purified, USP was placed in a wherein the Suspension is sprayed on to the tablets in the vessel equipped with a low shear (Lightnin type) and rotating coating pan, with concomitant drying by hot air, high shear (Silverson type) mixer. until the target weight gain is achieved. 0.184 2. With the Lightnin type mixer turned on, the 0.197 3. Approximately 15 mg of the Color Coat was water was heated to 60-70° C. (target 65° C.). applied to the tablets (approximately 46.15 mg of color coat 0185 3. The speed of the Lightnin type mixer was Suspension per tablet). adjusted to create a Vortex without drawing air into the 0198 4. Approximately 3 mg of the Clear Coat was water. 300 g of sucrose, NF was added to the vortex, applied to the tablets (approximately 60 mg of clear coat and the mixture was reheated to 60-70° C. (target 65° Suspension per tablet). C.), mixed approximately 15 minutes to dissolve the sucrose, NF, and then held at that temperature for 15 0199 The composition of the tablets is shown in the minutes, making Sure that all the Sucrose was dissolved. Table below. 0186 4. With the Lightnin type mixer turned on, 10 g of Hydroxypropyl Methylcellulose, USP 2910, 3 cps. was added to the vortex, and the mixture was reheated ngredient 96 WTWT mg tablet to 60-70° C. (target 65° C.). The high shear mixer was Tablet Core used during and after the addition to aid the wetting of the Hydroxypropyl Methylcellulose, USP, 2910, 3 cps. Premarin (R) 0.45 mg, No Talc Triturate, 77.56 235.0 mg Mixing was continued for 5 minutes, adjusting the Filled Tablets speed of the mixer to obtain adequate mixing. The Balzedoxifene Coat mixture is held at 65° C. for 5 minutes, making sure that Sucrose, NF 8.94 27.10 mg all the Hydroxypropyl Methylcellulose, USP. 2910, 3 Hydroxypropyl Methylcellulose, 3.30 10.00 mg USP. 2910, 3 cps (Pharmacoat 603) cps was well dispersed without forming clumps. Water, USP Purified 194.9 mg Sucrose Palmitate O.21 0.625 mg 0187 5. With the Lightnin type mixer turned on, the Ascorbic Acid, USP O.33 1.000 mg mixture was cooled to 23-27 C. (target 25° C.), BaZedoxifene Acetate (88.68% 3.72 11.28 mg bringing the mixture to weight with water, purified, baZedoxifene free base) USP as needed. US 2007/0003623 A1 Jan. 4, 2007

-continued Ingredient 96 WTWT mg tablet ngredient 96 WTWT mg tablet Color Coat Tablet Core Sucrose, NF 4.57 13.85 mg Premarin (R) 0.45 mg, No Talc Triturate, 66.01 235.0 mg Hydroxypropyl Methylcellulose, O.15 0.46 mg Filled Tablets USP. 2910, 3 cps (Pharmacoat 603) Balzedoxifene Coat Titanium Dioxide, USP O.23 0.69 mg Water, USP Purified 31.15 mg Sucrose, NF 15.22 54.19 mg Clear Coat Hydroxypropyl Methylcellulose, S.62 20.00 mg USP. 2910, 3 cps (Pharmacoat 603) Opadry Clear YS-2-19114A O.99 3.00 mg Water, USP Purified 389.8 mg Water, USP Purified 57.00 mg Sucrose Palmitate O.35 1.250 mg Ascorbic Acid, USP O.S6 2.000 mg TOTAL 100.00 303 mg BaZedoxifene Acetate (88.68% 6.34 22.56 mg baZedoxifene free base) "Removed during processing. Color Coat The quantities of the ingredients per tablet represent theoretical amounts of coating solids applied. For elegance, the amount of water and coating Opadry White YS-1-18202 A 4.78 17.00 mg ingredients used may vary. These should not exceed +/-10% of the theo Water, USP Purified 119.0 mg retical values. Clear Coat The potency of baZedoxifene acetate may vary, and the amount in the formula must be adjusted accordingly with a corresponding adjustment in Opadry Clear YS-2-19114A 1.12 4.00 mg the amount of Sucrose. Water, USP Purified 76.00 mg TOTAL 100.00 356 mg Example 2 "Removed during processing. The quantities of the ingredients per tablet represent theoretical amounts Procedure for Preparation of Tablets Containing of coating solids applied. For elegance, the amount of water and coating Conjugated Estrogens/Bazedoxifene Acetate, 0.45 ingredients used may vary. These should not exceed +/-10% of the theo retical values. mg/20 mg The potency of baZedoxifene acetate may vary, and the amount in the formula must be adjusted accordingly with a corresponding adjustment in 0200. The procedure is essentially as described for the amount of Sucrose. Example 1, except that: 0201 a) the Color Coat Suspension contained: Example 3 0202 125.00 g of Opadry White YS-1-18202 A: Procedure for Preparation of Tablets Containing Conjugated Estrogens/Bazedoxifene Acetate, 0.45 0203 875.00 g of water, USP purified; and mg/40 mg 0204 b) the Clear Coat Suspension contained: 0213 The procedure is essentially as described for Example 1, except that: 0205 50.00 g of Opadry Clear YS-2-19114 A: 0214) a) the Color Coat Suspension contained: 0206 950.00 g of water, USP purified; and 0215) 125.00 g of Opadry White YS-1-18202 A: 0207 c) the following tablet coating procedure was used: 0216) 875.00 g of water, USP purified; and 0208 1. Premarin(R) 0.45 mg No Talc Triturate Filled tablets were loaded into a perforated coating pan. 0217 b) the Clear Coat Suspension contained: 0218 50.00 g of Opadry Clear YS-2-19114 A: 0209 2. Sufficient Bazedoxifene Acetate Filler Coat Sus pension was added to achieve a total weight of 100 mg (+2 0219) 950.00 g of water, USP purified; and mg) above the inert tablet filled weight (approximately 489.8 mg of Bazedoxifene Acetate Filler Coat Suspension 0220, c) the following tablet coating procedure was used: per tablet). The tablets were coated with the suspension 0221 1. Premarin(R) 0.45 mg No Talc Triturate Filled using the continuous Sugar coating technique as described in tablets were loaded into a perforated coating pan. Example 1. 0222 2. Sufficient Bazedoxifene Acetate Filler Coat Sus 0210 3. Approximately 17 mg of the Color Coat was pension was added to achieve a total weight of 200 mg (+2 applied to the tablets (approximately 136 mg of color coat mg) above the inert tablet filled weight (approximately Suspension per tablet). 979.6 mg of Bazedoxifene Acetate Filler Coat Suspension per tablet). The tablets were coated with the suspension 02.11 4. Approximately 4 mg of the Clear Coat was using the continuous Sugar coating technique as described in applied to the tablets (approximately 80 mg of clear coat Example 1. Suspension per tablet). 0223 3. Approximately 22 mg of the Color Coat was 0212. The composition of the tablets is shown in the applied to the tablets (approximately 176 mg of color coat Table below. Suspension per tablet). US 2007/0003623 A1 Jan. 4, 2007 13

0224. 4. Approximately 5 mg of the Clear Coat was applied to the tablets (approximately 100 mg of clear coat -continued Suspension per tablet). Ingredient 96 WTWT mg tablet 0225. The composition of the tablets is shown in the Table below. Water, USP Purified 194.9 mg Sucrose Palmitate O.21 0.625 mg Ascorbic Acid, USP O.33 1.000 mg BaZedoxifene Acetate (88.68% 3.72 11.28 mg baZedoxifene free base) ngredient 96 WTWT mg tablet Color Coat Tablet Core Sucrose, NF 4.57 13.85 mg Premarin (R) 0.45 mg, No Talc Triturate, 50.87 235.0 mg Hydroxypropyl Methylcellulose, O.15 0.46 mg Filled Tablets USP. 2910, 3 cps (Pharmacoat 603) Bazedoxifene Coat Titanium Dioxide, USP O.23 0.69 mg Sucrose, NF 23.46 108.38 mg Water, USP Purified 31.15 mg Hydroxypropyl Methylcellulose, 8.66 40.00 mg Clear Coat USP. 2910, 3 cps (Pharmacoat 603) Water, USP Purified 779.6 mg Opadry Clear YS-2-19114A O.99 3.00 mg Sucrose Palmitate O.S4 2.50 mg Water, USP Purified 57.00 mg Ascorbic Acid, USP O.87 4.000 mg BaZedoxifene Acetate (88.68% 9.77 45.11 mg baZedoxifene free base) TOTAL 100.00 303 mg Color Coat Removed during processing. Opadry White YS-1-18202 A 4.76 22.00 mg The quantities of the ingredients per tablet represent theoretical amounts Water, USP Purified 154.0 mg of coating solids applied. For elegance, the amount of water and coating Clear Coat ingredients used may vary. These should not exceed +/-10% of the theo retical values. Opadry Clear YS-2-19114A 1.08 5.00 mg The potency of baZedoxifene acetate may vary, and the amount in the Water, USP Purified 95.00 mg formula must be adjusted accordingly with a corresponding adjustment in the amount of Sucrose. TOTAL 1OO.OO 462 mg Removed during processing. The quantities of the ingredients per tablet represent theoretical amounts Example 5 of coating solids applied. For elegance, the amount of water and coating ingredients used may vary. These should not exceed +/-10% of the theo retical values. Procedure for Preparation of Tablets Containing The potency of baZedoxifene acetate may vary, and the amount in the Conjugated Estrogens/BaZedoxifene Acetate, 0.625 formula must be adjusted accordingly with a corresponding adjustment in mg/20 mg the amount of Sucrose. 0228. The procedure is essentially as described for Example 4 Example 2, except that tablets to which the coatings were applied were Premarin R. 0.625 mg. No Talc Triturate, Filled Procedure for Preparation of Tablets Containing Tablets. Conjugated Estrogens/Bazedoxifene Acetate, 0.625 0229. The composition of the tablets is shown in the mg/10 mg Table below. 0226. The procedure is essentially as described for Example 1, except that tablets to which the coatings were applied were Premarin R. 0.625 mg. No Talc Triturate, Filled ngredient 96 WTWT mg tablet Tablets. Tablet Core 0227. The composition of the tablets is shown in the Table below. Premarin (R) 0.625 mg, No Talc 66.01 235.0 mg Triturate, Filled Tablets Balzedoxifene Coat Ingredient 96 WTWT mg tablet Sucrose, NF 15.22 54.19 mg Hydroxypropyl Methylcellulose, S.62 20.00 mg Tablet Core USP. 2910, 3 cps (Pharmacoat 603) Water, USP Purified 389.8 mg Premarin (R) 0.625 mg. No Talc 77.56 235.0 mg Sucrose Palmitate O.35 1.250 mg Triturate, Ascorbic Acid, USP O.S6 2.000 mg Filled Tablets BaZedoxifene Acetate (88.68% 6.34 22.56 mg Bazedoxifene Coat baZedoxifene free base) Color Coat Sucrose, NF 8.94 27.10 mg Hydroxypropyl Methylcellulose, 3.30 10.00 mg Opadry White YS-1-18202 A 4.78 17.00 mg USP. 2910, 3 cps (Pharmacoat 603) Water, USP Purified 119.0 mg US 2007/0003623 A1 Jan. 4, 2007

0233. As those skilled in the art will appreciate, numer -continued ous changes and modifications may be made to the preferred embodiments of the invention without departing from the Ingredient 96 WTWT mg tablet spirit of the invention. It is intended that all such variations Clear Coat fall within the scope of the invention. Opadry Clear YS-2-19114A 1.12 4.00 mg What is claimed is: Water, USP Purified 76.00 mg 1. A pharmaceutical composition comprising a core and at TOTAL 1OOOO 356 mg least one coating; wherein the core comprises conjugated estrogens; and the coating comprises baZedoxifene, or a Removed during processing. pharmaceutically acceptable salt thereof. The quantities of the ingredients per tablet represent theoretical amounts of coating solids applied. For elegance, the amount of water and coating 2. The pharmaceutical composition of claim 1, wherein ingredients used may vary. These should not exceed +/-10% of the theo the pharmaceutical composition is a tablet. retical values. 3. The pharmaceutical composition of claim 2, wherein The potency of baZedoxifene acetate may vary, and the amount in the formula must be adjusted accordingly with a corresponding adjustment in the conjugated estrogens comprise Premarin R. the amount of Sucrose. 4. The pharmaceutical composition of claim 2, wherein the conjugated estrogens is present in an amount of from Example 6 about 0.10 to about 1.0 mg. 5. The pharmaceutical composition of claim 2 wherein the Procedure for Preparation of Tablets Containing conjugated estrogens is present in an amount of from about Conjugated Estrogens/Bazedoxifene Acetate, 0.625 0.3 to about 0.8 mg. mg/40 mg 6. The pharmaceutical composition of claim 2 wherein the 0230. The procedure is essentially as described for conjugated estrogens is present in an amount of from about Example 3, except that tablets to which the coatings were 0.4 to about 0.5 mg. applied were Premarin R. 0.625 mg. No Talc Triturate, Filled 7. The pharmaceutical composition of claim 2 wherein the Tablets. conjugated estrogens is present in an amount of from about 0231. The composition of the tablets is shown in the 0.5 to about 0.7 mg. Table below. 8. The pharmaceutical composition of claim 2 wherein the baZedoxifene is present in an amount of from about 1 to about 50 mg, based on the weight of the baZedoxifene free base. ngredient 96 WTWT mg tablet 9. The pharmaceutical composition of claim 2 wherein the Tablet Core baZedoxifene is present in an amount of from about 5 to about 25 mg, based on the weight of the baZedoxifene free Premarin (R) 0.625 mg, No Talc 50.87 235.0 mg base. Triturate, Filled Tablets 10. The pharmaceutical composition of claim 2 wherein Bazedoxifene Coat the baZedoxifene is present in an amount of from about 5 to about 15 mg, based on the weight of the baZedoxifene free Sucrose, NF 23.46 108.38 mg base. Hydroxypropyl Methylcellulose, 8.66 40.00 mg USP. 2910, 3 cps (Pharmacoat 603) 11. The pharmaceutical composition of claim 2 wherein Water, USP Purified 779.6 mg the baZedoxifene is present in an amount of from about 15 Sucrose Palmitate O.S4 2.50 mg to about 25 mg, based on the weight of the baZedoxifene free Ascorbic Acid, USP O.87 4.000 mg base. BaZedoxifene Acetate (88.68% 9.77 45.11 mg baZedoxifene free base) 12. The pharmaceutical composition of claim 2 wherein Color Coat the baZedoxifene is present in an amount of from about 35 to about 45 mg, based on the weight of the baZedoxifene free Opadry White YS-1-18202 A 4.76 22.00 mg base. Water, USP Purified 154.0 mg Clear Coat 13. The pharmaceutical composition of claim 2 wherein the conjugated estrogens is present in an amount of from Opadry Clear YS-2-19114A 1.08 5.00 mg about 0.10 to about 1.0 mg; and the baZedoxifene is present Water, USP Purified 95.00 mg in an amount of from about 5 to about 50 mg, based on the TOTAL 100.00 462 mg weight of the baZedoxifene free base. 14. The pharmaceutical composition of claim 10 wherein Removed during processing. the conjugated estrogens is present in an amount of from The quantities of the ingredients per tablet represent theoretical amounts of coating solids applied. For elegance, the amount of water and coating about 0.4 to about 0.5 mg. ingredients used may vary. These should not exceed +/-10% of the theo 15. The pharmaceutical composition of claim 10 wherein retical values. the conjugated estrogens is present in an amount of from The potency of baZedoxifene acetate may vary, and the amount in the formula must be adjusted accordingly with a corresponding adjustment in about 0.5 to about 0.7 mg. the amount of Sucrose. 16. The pharmaceutical composition of claim 11 wherein the conjugated estrogens is present in an amount of from 0232. It is intended that each of the patents, applications, about 0.4 to about 0.5 mg. and printed publications including books mentioned in this 17. The pharmaceutical composition of claim 11 wherein patent document be hereby incorporated by reference in the conjugated estrogens is present in an amount of from their entirety. about 0.5 to about 0.7 mg. US 2007/0003623 A1 Jan. 4, 2007

18. The pharmaceutical composition of claim 12 wherein b) a binder component comprising from about 1% to the conjugated estrogens is present in an amount of from about 6% by weight of the pharmaceutical formulation; about 0.4 to about 0.5 mg. 19. The pharmaceutical composition of claim 12 wherein c) a wetting agent component comprising from about the conjugated estrogens is present in an amount of from 0.1% to about 3% by weight of the pharmaceutical about 0.5 to about 0.7 mg. formulation; 20. The pharmaceutical composition of claim 12 wherein d) an optional antioxidant component comprising from the conjugated estrogens is Premarin R, and the baZedox 0% to about 0.5% by weight of the pharmaceutical ifene is baZedoxifene acetate. formulation; 21. A pharmaceutical composition of claim 2 wherein the e) baZedoxifene acetate, comprising from about 2% to coating comprises: about 6% by weight of the pharmaceutical formulation; a) a filler component comprising from about 5% to about and 30% by weight of the pharmaceutical formulation; f) an optional chelating component comprising from 0% b) a binder component comprising from about 1% to to about 0.1% by weight of the pharmaceutical formu about 10% by weight of the pharmaceutical formula lation. tion; 31. The pharmaceutical composition of claim 30 wherein the composition contains from about 0.3 mg to about 0.8 mg c) a wetting agent component comprising from about of conjugated estrogens. 0.01% to about 2% by weight of the pharmaceutical 32. The pharmaceutical composition of claim 30 wherein formulation; the composition contains from about 0.4 mg to about 0.5 mg d) an optional antioxidant component comprising from of conjugated estrogens. 0% to about 2% by weight of the pharmaceutical 33. The pharmaceutical composition of claim 21 wherein formulation; the coating comprises: e) baZedoxifene acetate, comprising from about 0.1% to a) a filler component comprising from about 12% to about about 20% by weight of the pharmaceutical formula 18% by weight of the pharmaceutical formulation: tion; and b) a binder component comprising from about 4% to f) an optional chelating component comprising from 0% about 8% by weight of the pharmaceutical formulation; to about 0.1% by weight of the pharmaceutical formu c) a wetting agent component comprising from about lation. 0.2% to about 0.5% by weight of the pharmaceutical 22. The pharmaceutical composition of claim 21 wherein formulation; the core comprises from about 45% to about 80% by weight of the pharmaceutical formulation. d) an optional antioxidant component comprising, when 23. The pharmaceutical composition of claim 21 wherein present, from about 0.3% to about 0.8% by weight of the core comprises conjugated estrogens in an amount of the pharmaceutical formulation; from about 0.10 to about 1.0 mg. e) baZedoxifene acetate, comprising from about 4% to 24. The pharmaceutical composition of claim 21 wherein about 9% by weight of the pharmaceutical formulation; the composition contains from about 1 mg to about 50 mg and of baZedoxifene, based on the weight of the baZedoxifene free base. f) an optional chelating component comprising from 0% 25. The pharmaceutical composition of claim 21 wherein to about 0.1% by weight of the pharmaceutical formu the composition contains from about 5 mg to about 25 mg lation. of baZedoxifene, based on the weight of the baZedoxifene 34. The pharmaceutical composition of claim 33 wherein free base. the composition contains from about 0.3 mg to about 0.8 mg 26. The pharmaceutical composition of claim 21 wherein of conjugated estrogens. the composition contains from about 0.3 mg to about 0.8 mg 35. The pharmaceutical composition of claim 33 wherein of conjugated estrogens. the composition contains from about 0.4 mg to about 0.5 mg 27. The pharmaceutical composition of claim 21 wherein of conjugated estrogens. the composition contains from about 0.4 mg to about 0.5 mg 36. The pharmaceutical composition of claim 2 wherein of conjugated estrogens. the coating comprises: 28. The pharmaceutical composition of claim 21 wherein a) a filler component comprising from about 20% to about the composition contains from about 0.5 mg to about 0.7 mg 30% by weight of the pharmaceutical formulation; of conjugated estrogens. 29. The pharmaceutical composition of claim 21 wherein b) a binder component comprising from about 6% to the conjugated estrogens is present in an amount of from about 10% by weight of the pharmaceutical formula about 0.10 to about 1.0 mg; and the baZedoxifene is present tion; in an amount of from about 5 to about 25 mg, based on the c) a wetting agent component comprising from about weight of the baZedoxifene free base. 0.4% to about 0.8% by weight of the pharmaceutical 30. The pharmaceutical composition of claim 2 wherein formulation; the coating comprises: d) an optional antioxidant component comprising from a) a filler component comprising from about 6% to about 0% to about 1.2% by weight of the pharmaceutical 12% by weight of the pharmaceutical formulation; formulation; US 2007/0003623 A1 Jan. 4, 2007 16

e) baZedoxifene acetate, comprising from about 7% to b) an optional binder component comprising from about about 14% by weight of the pharmaceutical formula 0.01% to about 2% by weight of the pharmaceutical tion; and formulation; f) an optional chelating component comprising from 0% c) a coloring agent component comprising from about to about 0.1% by weight of the pharmaceutical formu 0.01% to about 6% by weight of the pharmaceutical lation. formulation; 37. The pharmaceutical composition of claim 36 wherein the composition contains from about 0.3 mg to about 0.8 mg d) an optional antioxidant component comprising from of conjugated estrogens. 0% to about 2% by weight of the pharmaceutical 38. The pharmaceutical composition of claim 36 wherein formulation; and the composition contains from about 0.4 mg to about 0.5 mg e) an optional chelating component comprising from 0% of conjugated estrogens. to about 0.1% by weight of the pharmaceutical formu 39. The pharmaceutical composition of claim 21 wherein: lation. the filler component of the coating comprises one or more 43. The pharmaceutical composition of claim 42 wherein: of Sucrose, mannitol, lactose, powdered cellulose, the optional filler component comprises Sucrose; microcrystalline cellulose, malodextrin, Sorbitol, starch, xylitol, carboxymethyl cellulose, carboxyethyl the optional binder component comprises hydroxypropy cellulose, hydroxyethyl celluloses, microcrystalline lmethylcellulose; and celluloses, starches, anhydrous dicalcium phosphate, the coloring agent component comprises titanium diox Sodium starch glycolates, and metal aluminosilicates; ide; the binder component of the coating comprises one or the optional antioxidant component comprises ascorbic more of hydroxypropylmethylcellulose, carboxym acid or a salt thereof, and ethyl cellulose, carboxyethyl cellulose, hydroxyethyl celluloses, microcrystalline celluloses, starches and the optional chelating component comprises EDTA. polyvinyl pyrrolidine; 44. The pharmaceutical composition of claim 21 further comprising a clear coating. the wetting agent component of the coating comprises one 45. The pharmaceutical composition of claim 42 further or more of sucrose palmitate, Poloxamer 188, metal comprising a clear coating. alkyl Sulfates, sodium lauryl Sulfate, polyoxyethylene 46. The pharmaceutical composition of claim 44 wherein Sorbitan fatty acid esters, polyethylene glycols, poly the clear coating comprises from about 0.01% to about 2% oxyethylene castor oil derivatives, docusate Sodium, by weight of the pharmaceutical formulation. quaternary ammonium amine compounds, Sugar esters 47. The pharmaceutical composition of claim 35 wherein of fatty acids and glycerides of fatty acids; and the clear coating comprises from about 0.01% to about 2% the optional antioxidant component of the coating, when by weight of the pharmaceutical formulation. present, comprises one or more of ascorbic acid or a 48. A pharmaceutical composition comprising: salt thereof, sodium ascorbate, citric acid, ascorbyl palmitate, nicotinamide ascorbate, propyl gallate, alpha a core comprising conjugated estrogens in an amount of tocopherol, beta tocopherol, gamma tocopherol, and from about 0.10 mg to about 1.0 mg: BHA/BHT; and a first coating: the optional chelating component of the coating, when a color coating; and present, comprises EDTA. 40. The pharmaceutical composition of claim 21 wherein: a clear coating: the filler component of the coating comprises Sucrose; wherein: the binder component of the coating comprises hydrox the core comprises from about 45% to about 80% by ypropylmethylcellulose; weight of the pharmaceutical formulation; the wetting agent component of the coating comprises the first coating comprises: Sucrose palmitate; a) a filler component comprising from about 5% to the optional antioxidant component of the coating, when about 30% by weight of the pharmaceutical formu present, comprises ascorbic acid, or a salt thereof, and lation; the optional chelating component of the coating, when b) a binder component comprising from about 1% to present, comprises EDTA. about 10% by weight of the pharmaceutical formu 41. The pharmaceutical composition of claim 21 further lation; comprising a color coating. c) a wetting agent component comprising from about 42. The pharmaceutical composition of claim 41 wherein 0.01% to about 2% by weight of the pharmaceutical the color coating comprises: formulation; a) an optional filler component comprising from about d) an optional antioxidant component comprising from 0.01% to about 8% by weight of the pharmaceutical 0% to about 2% by weight of the pharmaceutical formulation; formulation; US 2007/0003623 A1 Jan. 4, 2007

e) baZedoxifene acetate, comprising from about 0.1% 51. A process for preparing a pharmaceutical composition, to about 20% by weight of the pharmaceutical for the composition comprising: mulation; and a core comprising conjugated estrogens; and f) an optional chelating component comprising from 0% to about 0.1% by weight of the pharmaceutical a first coating comprising baZedoxifene or a pharmaceu formulation; tically acceptable salt thereof; the color coating comprises: the process comprising: g) an optional filler component comprising from about i) providing a core comprising conjugated estrogens; and 0.01% to about 8% by weight of the pharmaceutical ii) coating the core with a coating composition comprising formulation; baZedoxifene or a pharmaceutically acceptable salt h) an optional binder component comprising from thereof to form a coated core. about 0.01% to about 2% by weight of the pharma 52. A process of claim 51 further comprising the step of: ceutical formulation; iii) coating the coated core with a color coating compo i) a coloring agent component comprising from about sition to form a color coated composition. 0.01% to about 6% by weight of the pharmaceutical 53. A process of claim 52 further comprising the step of: formulation; iv) coating the color coated composition with a clear j) an optional antioxidant component comprising from coating composition to form a clear coat thereon. 0% to about 2% by weight of the pharmaceutical 54. A process of claim 51 wherein the coating composi formulation; tion of step i comprises: k) an optional chelating component comprising from a) a filler component; 0% to about 0.1% by weight of the pharmaceutical formulation; b) a binder component; the clear coating comprising from about 0.01% to about c) a wetting agent component; 2% by weight of the pharmaceutical formulation; said d) an optional antioxidant component; clear coating comprising an optional antioxidant com ponent comprising from 0% to about 2% by weight of e) baZedoxifene acetate; and the pharmaceutical formulation; and an optional chelat f) an optional chelating component. ing component comprising from 0% to about 0.1% by weight of the pharmaceutical formulation. 55. A process of claim 54 wherein: 49. The pharmaceutical composition of claim 48 wherein the filler component comprises one or more of Sucrose, the composition contains from about 1 mg to about 50 mg mannitol, lactose, powdered cellulose, microcrystalline of baZedoxifene, based on the weight of the baZedoxifene cellulose, malodextrin, Sorbitol, starch, Xylitol, car free base. boxymethyl cellulose, carboxyethyl cellulose, 50. The pharmaceutical composition of claim 49 wherein: hydroxyethyl celluloses, microcrystalline celluloses, starches, anhydrous dicalcium phosphate, Sodium the filler component of the first coating comprises starch glycolates, and metal aluminosilicates; Sucrose; the binder component comprises one or more of hydrox the binder component of the first coating comprises ypropylmethylcellulose, carboxymethyl cellulose, car hydroxypropylmethylcellulose; boxyethyl cellulose, hydroxyethyl celluloses, microc the wetting agent component of the first coating com rystalline celluloses, starches and polyvinyl prises Sucrose palmitate; pyrrolidine; the optional antioxidant component of the first coating, the wetting agent component comprises one or more of when present, comprises ascorbic acid or a salt thereof; sucrose palmitate, Poloxamer 188, metal alkyl sulfates, sodium lauryl sulfate, polyoxyethylene sorbitan fatty the optional chelating component of the first coating, acid esters, polyethylene glycols, polyoxyethylene cas when present, comprises EDTA; tor oil derivatives, docusate sodium, quaternary ammo the optional filler component of the color coating, when nium amine compounds, Sugar esters of fatty acids and present, comprises Sucrose; glycerides of fatty acids; and the optional binder component of the color coating, when the optional antioxidant component, when present, com present, comprises hydroxypropylmethylcellulose; prises one or more of ascorbic acid, Sodium ascorbate, citric acid, ascorbyl palmitate, nicotinamide ascorbate, the optional antioxidant component of the color coating, propyl gallate, alpha tocopherol, beta tocopherol, when present, comprises ascorbic acid or a salt thereof; gamma tocopherol and BHA/BHT; and the optional chelating component of the color coating, the optional chelating component, when present, com when present, comprises EDTA; and prises EDTA. the coloring agent component of the color coating com 56. A process of claim 54 wherein: prises titanium dioxide. the filler component of the coating comprises sucrose; US 2007/0003623 A1 Jan. 4, 2007

the binder component of the coating comprises hydrox 63. A process of claim 60 wherein the conjugated estro ypropylmethylcellulose; gens is present in an amount of from about 0.10 to about 1.0 mg; and the baZedoxifene is present in an amount of from the wetting agent component of the coating comprises about 5 to about 50 mg, based on the weight of the Sucrose palmitate; baZedoxifene free base. the optional antioxidant component of the coating, when 64. A pharmaceutical composition of any of claims 13, 21. present, comprises ascorbic acid, or a salt thereof, and and 48 wherein the conjugated estrogens comprise Pre the optional chelating component of the coating, when marinR). present, comprises EDTA. 65. A process of any of claims 51, 54, 56, 57 and 60 57. A process of claim 56 wherein the coating composi wherein the conjugated estrogens comprise Premarin R. tion of step ii is applied by a continuous Sugar coating 66. A product of the process of any of claims 51 and 57. technique. 67. A process for preparing a pharmaceutical composition, 58. A process of claim 52 wherein the color coating the composition comprising: composition comprises: a core comprising a therapeutic agent; and an optional filler component; a coating optionally comprising a second therapeutic an optional binder component; agent and at least one Sugar, a coloring agent component; the process comprising: an optional antioxidant component; and i) providing a core comprising the first active agent; and an optional chelating component. ii) coating the core with a coating composition compris 59. A process of claim 58 wherein: ing: the optional filler component of the color coating com a) a filler component that comprises at least one Sugar, position comprises sucrose; b) a binder component; the optional binder component of the color coating com c) a wetting agent component; position comprises hydroxypropylmethylcellulose; d) an optional antioxidant component; the coloring agent component of the color coating com position comprises titanium dioxide; e) optionally, a second therapeutic agent; and the optional antioxidant component of the color coating f) an optional chelating component; comprises ascorbic acid or a salt thereof, and wherein the coating composition of step ii is applied by a the optional chelating component of the color coating continuous Sugar coating technique. comprises EDTA. 68. A process of claim 67 wherein: 60. A process of claim 56 wherein: the filler component comprises one or more of Sucrose, a) the filler component of the coating composition of step mannitol, lactose, powdered cellulose, microcrystalline ii comprises from about 5% to about 30% by weight of cellulose, malodextrin, Sorbitol, starch, Xylitol, car the pharmaceutical formulation; boxymethyl cellulose, carboxyethyl cellulose, hydroxyethyl celluloses, microcrystalline celluloses, b) the binder component of the coating composition of starches, anhydrous dicalcium phosphate, Sodium step i comprises from about 1% to about 10% by starch glycolates, and metal aluminosilicates; weight of the pharmaceutical formulation; the binder component comprises one or more of hydrox c) the wetting agent component of the coating composi ypropylmethylcellulose, carboxymethyl cellulose, car tion of step i comprises from about 0.01% to about 2% boxyethyl cellulose, hydroxyethyl celluloses, microc by weight of the pharmaceutical formulation; rystalline celluloses, starches and polyvinyl d) the optional antioxidant component of the coating pyrrolidine; composition of step i comprises from 0% to about 2% the wetting agent component comprises one or more of by weight of the pharmaceutical formulation; sucrose palmitate, Poloxamer 188, metal alkyl sulfates, sodium lauryl sulfate, polyoxyethylene sorbitan fatty e) the baZedoxifene acetate comprises from about 0.1% to acid esters, polyethylene glycols, polyoxyethylene cas about 20% by weight of the pharmaceutical formula tor oil derivatives, docusate sodium, quaternary ammo tion; and nium amine compounds, Sugar esters of fatty acids and f) the optional chelating component of the coating com glycerides of fatty acids; and position comprises from 0% to about 0.1% by weight of the pharmaceutical formulation. the optional antioxidant component, when present, com prises one or more of ascorbic acid, Sodium ascorbate, 61. A process of claim 60 wherein the conjugated estro citric acid and ascorbyl palmitate, nicotinamide ascor gens is present in an amount of from about 0.10 to about 1.0 bate, propyl gallate, alpha tocopherol, beta tocopherol, ng. gamma tocopherol, and BHA/BHT; and 62. A process of claim 60 wherein the baZedoxifene is present in an amount of from about 1 to about 50 mg, based the optional chelating component, when present, com on the weight of the baZedoxifene free base. prises EDTA. US 2007/0003623 A1 Jan. 4, 2007 19

69. A process of claim 67 wherein: 70. A process of claim 67 further comprising the step of: the filler component of the coating comprises Sucrose; iii) coating the coated core with a color coating compo the binder component of the coating comprises hydrox sition to form a color coated composition. ypropylmethylcellulose; 71. A process of claim 70 further comprising the step of: the wetting agent component of the coating comprises iv) coating the color coated composition with a clear Sucrose palmitate; coating composition to form a clear coat thereon. 72. A process of claim 67 wherein the first therapeutic the optional antioxidant component of the coating, when agent comprises conjugated estrogens, and the second thera present, comprises ascorbic acid, or a salt thereof, and peutic agent comprises baZedoxifene or a salt thereof. the optional chelating component of the coating, when present, comprises EDTA.