WO2006055659A2 - Fixed dose combination op dutasteride and tamsulosin - Google Patents

Abstract

Pharmaceutical compositions that include a steroid 5-alpha reductase inhibitor in a fixed dose combination with an alpha adrenergic blocker are described.

Description

PHARMACEUTICAL COMPOSITION

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application Serial No. 60/627,998, filed November 15, 2004, the disclosure of which is incorporated herein in its entirety.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions comprising a steroid 5-alpha reductase inhibitor in a fixed dose combination with an alpha adrenergic blocker. More particularly, the present invention relates to a pharmaceutical composition including dutasteride and tamsulosin.

BACKGROUND OF THE INVENTION

Aza steroids are an important class of pharmaceutically active compounds. In particular there are 4-aza steroids and 6-aza steroids known to be inhibitors of the enzyme testosterone 5-alpha-reductase (hereinafter "5-AR inhibitors" or "5-ARIs"). Such compounds are useful in the treatment and/or prevention of benign prostatic hyperplasia ("BPH"), prostate cancer, and other androgen responsive or mediated diseases and conditions. See, for example, U.S. Pat. Nos. 4,377,584 (Rasmusson et al.), 4,220,775 (Rasmusson et al.), 4,732,897 (Cainelli et al.), 4,760,071 (Rasmusson), 4,845,104 (Carlin et al.), 4,859,681 (Rasmusson), 5,302,589 (Frye et al.), 5,438,061 (Bergman et al.), 5,543,406 (Andrews et al.), 5,565,467 (Batchelor et al.), and WO 95/07926 (Batchelor et al.), each of which are herein incorporated by reference with regard to the synthesis of such compounds.

One such 5-ARI, dutasteride, is commercially available from GlaxoSmithKline, and is marketed under the brandname AVODART®. Dutasteride is a dual, aza- steroid 5-α-reductase inhibitor (5-ARI) approved, currently, for the treatment of patients with moderate to severe symptoms of benign prostatic hyperplasia (BPH). Dutasteride binds both the type 1 and type 2 enzymes of 5-α-reductase to inhibit the conversion of testosterone (T) to dihydrotestosterone (DHT), and reduce circulating DHT concentrations by >90%. As a result, prostate volume decreases, symptoms improve, urinary flow increases, and the risk of acute urinary retention or BPH-related surgery declines. As used herein, dutasteride may also be referred to as GM 98745. As noted above, U.S. Pat. No. 5,565,467 is incorporated herein by reference.

Tamsulosin is the generic name for 5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino] propyl]-2-methoxy-benzenesulfonamide and is described in U.S. Pat. No. 4,703,063 and U.S. Pat. No. 4,731 ,478, each of which is herein incorporated by reference. As described in the above-mentioned patents, tamsulosin has alpha-adrenergic blocking activity and is believed useful, inter alia, in the treatment of benign prostatic hyperplasia ("BPH"). Tamsulosin hydrochloride is marketed under various tradenames, including FLOMAX®, HARNAL®, and OMNIC®, for the treatment of symptoms of BPH, such as urinary volume and frequency problems. U.S. Pat. No. 4,772,475 (the "'475 patent") describes a controlled-release pharmaceutical dosage form containing tamsulosin.

In general, the choice of excipients in a pharmaceutical composition is important in order to ensure good solubility of the drug and good bioavailability, stability, robustness, and elegance. See, for example, A. Matso, Excipients Commonly Used in Soft Gelatin Capsules: Their Analysis and Usefulness, Novel Drug Formulation Systems and Delivery Devices International Seminar, pp. 76- 81 ,(1991 ). K. Hutchison, Encapsulation in Softgels for Pharmaceutical Advantage, Spec. Pub. - R. Soc. Chem., Vol. 138, pp 86-97, (1993), M.S. Patel et. al., Advances in Softgel Formulation Technology, Manufacturing Chemist, August 1989, and I. R. Berry, Improving Bioavailability with Soft Gelatin Capsules, Drug & Cosmetic Industry, pp. 32, 102-108, (September, 1983). Particular issues regarding the formulation of hydrophobic drugs are described, for example, in K. Hutchison, Formulation of Softgels For Improved Oral Delivery of Hydrophobic Drugs, Spc. Pub. - R. Soc. Chem., Vol. 161 , pp 133-147 (1995). Thus, while pharmaceutically active compounds can be delivered in a variety of dosage forms, certain active compounds have particularly preferred dosage forms due to the nature of the preferred excipient. As one example, soft gelatin capsules often are preferred when formulating hydrophobic actives.

Dutasteride, as an active ingredient in a pharmaceutical composition, is not readily soluble or easy to dissolve. Dutsateride may, therefore, be referred to as poorly soluble. The solubility challenges presented by dutasteride can affect bioavailability. In fact, the poor solubility can result in reduced or unpredictable bioavailability. Thus, in the case of dutasteride, the currently marketed pharmaceutical formulation is a soft gelatin capsule. The fill includes a mixture of glyceride esters. Esters of glycerol and/or propylene glycol have been used in a variety of formulations. See, for example, U.S. Pat. Nos. 4,316,917 (Antoshkiw et. al.) and 4,343,823 (Todd et. al.). As noted, the composition includes dutasteride dissolved in a fatty acid ester of glycerol or propylene glycol. The fatty acids are preferably carboxylic acids containing from 6 to 12 carbon atoms. Preferably, the ester is a monoester. The compositions are particularly suitable for use as fill formulations for soft gelatin capsules ("softgels"). Based upon human clinical studies, the soft-gelatin capsule formulation had improved bioavailability as compared to other dosage forms. One commercially available glyceride ester product from Abitec (Janesville, Wisconsin), is known as Capmul™ MCM.

As described, various 5-ARI therapies and alpha-blocker therapies are known. An improvement to simplify treatment regimens for BPH and other diseases or conditions affected by 5-alpha reductase inhibition and/or alpha-adrenergic blocking would enhance patient compliance by providing a simplified dosage form containing pharmaceutically acceptable amounts of the two treatments. Thus, an improved formulation would provide a fixed dose combination of a 5-ARI, such as dutasteride, and a alpha-blocker, such as tamsulosin.

SUMMARY OF THE PRESENT INVENTION The present invention includes a fixed dose combination ("FDC") comprising dutasteride and tamsulosin. Preferably the FDC is in the form of a capsule. Preferably the capsule is a hydroxypropylmethylcellulose capsule.

In one embodiment the dutasteride is provided in the form of a softgel and the tamsulosin is provided in the form of beads. In one embodiment the tamsulosin bead further includes a discrete layer comprising tamsulosin and a binder and a pH independent layer. Preferably the pH independent layer is a singular polymethacrylic acid derivative, a mixture of polymethacrylic acid derivatives, ethyl cellulose, a mixture of ethyl cellulose and water soluble polymers, or the aqueous dispersions thereof. Preferably the pH independent layer is ethyl cellulose, Eudragit NE 4OD, a mixture of Eudragit RS and Eudragit RL 3OD in a ratio of about 0-50% w/w RL 3OD, or a mixture of ethyl cellulose and hydroxypropylmethylcellulose in a ratio of about 0-50% w/w hydroxypropyl methylcellulose. Preferably the tamsulosin bead further includes a pH dependent film coat. Preferably the pH dependent polymer film coat is a polymethacrylic acid derivative or a derivative of cellulose. Preferably the pH dependent film coat is Eudragit L 30D-55 or cellulose acetate phthalate.

As noted, in one embodiment the dutasteride portion is a softgel. In one embodiment the softgel comprises a fill that further comprises approximately 0.5 mg dutasteride; 99.49 mg Capmul MCM™; and 0.01 mg butylated hydroxytoluene. In another embodiment the softgel comprises a fill that further comprises approximately 0.5 mg dutasteride; 299.47 mg Capmul™ MCM; and 0.030 mg butylated hydroxytoluene.

In one embodiment the tamsulosin portion of the FDC includes tamsulosin hydrochloride active ingredient; a binder; a diluent; a plasticizer; at least one modified release coat; and at least one pigmented coat. Preferably the binder is povidone; the diluent is microcrystalline cellulose; the plasticizer is triethyl citrate; the at least one modified release coat is ethylcellulose or methacrylic acid copolymer; and the at least one pigmented coat is HPMC with pigment. Further, preferably the tamsulosin portion further includes two modified release coats, one each of ethylcellulose and methacrylic acid copolymer; and two pigmented coats each of HPMC with pigment.

In one embodiment, the tamsulosin portion is composed of, approximately:

In another embodiment of the present invention, a fixed dose combination comprises a dutasteride component, and a tamsulosin component comprising a plurality of beads, wherein each bead in the plurality comprises a discrete layer comprising tamsulosin; and each bead in the plurality further comprises one or more release layers that determine the tamsulosin release rate of the bead. In some embodiments, the one or more release layers is a pH dependent layer. In other embodiments, the one or more release layers is a pH independent layer. In still other embodiments, the one or more release layers are a pH dependent layer and a separate pH independent layer. In yet other embodiments, a first portion of the plurality of beads consists of beads in which the one or more release layers is a pH independent layer, and a second portion of the plurality of beads consists of beads in which the one or more release layers is a pH dependent layer. In some embodiments, the plurality of beads consists of the first portion of the plurality of beads and the second portion of the plurality of beads. In other embodiments, a third portion of the plurality of beads consists of beads in which the one or more release layers are a pH dependent layer and a separate pH independent layer. In still other embodiments, a first portion of the plurality of beads consists of beads in which the one or more release layers are a pH dependent layer and a separate pH independent layer. In some embodiments, a second portion of the plurality of beads consists of beads in which the one or more release layers is a pH dependent layer. In other embodiments, a second portion of the plurality of beads consists of beads in which the one or more release layers is a pH independent layer.

In still another embodiment according to the present invention, a fixed dose combination comprises a dutasteride component, wherein the dutasteride component is a softgel; and a tamsulosin component comprising a plurality of beads, wherein each bead in the plurality of beads comprises a discrete layer comprising tamsulosin hydrochloride and a binder; and each bead in the plurality of beads further comprises one or more release layers that determine the tamsulosin release rate of the bead, wherein a first portion of the plurality of beads consists of beads in which the one or more release layers is a pH independent layer, and a second portion of the plurality of beads consists of beads in which the one or more release layers is a pH dependent layer.

In yet another embodiment according to the present invention, a fixed dose combination comprises a dutasteride component, wherein the dutasteride component comprises 0.5 mg dutasteride; and a tamsulosin component comprising 0.4 mg of tamsulosin hydrochloride and consisting of a plurality of beads, wherein each bead in the plurality comprises a discrete layer comprising tamsulosin hydrochloride and a binder; and each bead in the plurality further comprises one or more release layers that determine the tamsulosin release rate of the bead, wherein a first portion of the plurality of beads consists of beads in which the one or more release layers is a pH independent layer; wherein a second portion of the plurality of beads consists of beads in which the one or more release layers is a pH dependent layer; and wherein the plurality of beads consists of the first portion and the second portion.

In another embodiment of the present invention, a fixed dose combination includes a dutasteride component and a tamsulosin component where the tamsulosin component includes a plurality of beads, wherein each bead includes a discrete layer that includes tamsulosin; in a first portion of the plurality of beads, each bead further includes a pH dependent layer and is devoid of a pH independent layer; and in a second portion of the plurality of beads, each bead further includes a pH independent layer and is devoid of a pH dependent layer. In still another embodiment of the present invention, a fixed dose combination includes a dutasteride component and a tamsulosin component where the tamsulosin component includes a plurality of beads, wherein each bead includes a discrete layer that includes tamsulosin; and in a first portion of the plurality of beads, each bead further includes a pH independent layer and is devoid of a pH dependent layer.

In yet another embodiment of the present invention, a fixed dose combination includes a dutasteride component and a tamsulosin component where the tamsulosin component includes a plurality of beads, wherein each bead includes a discrete layer that includes tamsulosin; and in at least a first portion of the plurality of beads, each bead further includes a pH dependent layer and is devoid of a pH independent layer. The present invention also includes a method for the treatment or prophylaxis of an androgen mediated disease or condition comprising administration of a fixed dose combination of the present invention. Preferably the disease or condition is benign prostatic hyperplasia or prostate cancer. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 illustrates a perspective cross-sectional view of a tamsulosin bead having a pH dependent layer and a pH independent layer according to embodiments of the present invention;

Figure 2 illustrates a perspective cross-sectional view of a tamsulosin bead having a pH dependent layer; and

Figure 3 illustrates a perspective cross-sectional view of a tamsulosin bead having a pH independent layer.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT Terms are used within their accepted meanings. Any specific definitions are meant to clarify, but not limit, the terms defined.

The composition of Capmul™ MCM is a mixture of fatty acid esters of glycerol and is approximately 95% monoester, 1% glycerin, 2% free fatty acid, and less than 0.5% water and is derived from approximately 85% caprylic acid and 15% capric acid (all percentages are weight percents). One active component of the present invention is dutasteride, also referred to as (17-beta-N-(2,5,-bis(trifluoromethyl))-phenylcarbamoyl-4-aza-5-alpha-androst-1 - en-3-one), including salts, solvates, or physiologically functional derivatives thereof. Other similar aza-steroids, such as 17-beta-N-1-(3,4-methylenedioxy-phenyl)- cyclohexylcarbamoyl-^aza-δ-alpha-androst-i -en-3-one and 17-beta-N-(1-(p- chlorophenyl))cyclopentylcarbamoyl-4-aza-5-alpha-androst-1 -en-3-one, may also be useful. These steroids can be prepared by well-known methods, for example as described in the above cited patents, incorporated herein by reference regarding such synthetic method.

The other active component of the present invention is tamsulosin, also referred to as 5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino] propyl]-2-methoxy- benzenesulfonamide, including salts, solvates, and physiologically function derivatives thereof. Tamsulosin can be prepared by well-known methods, for example as described in the above cited patents, incorporated herein by reference regarding such synthetic method. As noted above, tamsulosin hydrochloride is currently marketed throughout the world under several tradenames.

According to an aspect of the present invention, a fixed dose combination includes a dutasteride component and a tamsulosin component. The tamsulosin component includes a plurality of beads, wherein each bead includes a discrete layer that includes tamsulosin; and each bead further includes one or more release layers that determine the tamsulosin release rate of the bead. It is to be understood that there may be other layers in the tamsulosin bead, such as a seal coat, a top coat, or even the tamsulosin layer itself, that have a negligible or substantially negligible impact (e.g., would allow for a release rate of greater than about 90% of the tamsulosin within about 1 hour of ingestion of the bead) on the tamsulosin release rate. Such other layers are not included in the one or more release layers of the bead. Preferably the tamsulosin layer further includes a binder, such as povidone. As will be understood by those skilled in the art, other binders could be used.

Preferably each bead in the plurality of beads further includes a bead core, such as a commercially available microcrystalline cellulose bead (e.g., Celphere beads) or a sugar bead, which may be referred to as non-pareils. The bead core is preferably a sphere, but may be various other shapes as will be understood by those skilled in the art.

The tamsulosin can be any of the various forms (e.g, free base, pharmaceutically acceptable salts or solvates) of tamsulosin or can be a mixture of these forms. The tamsulosin is preferably tamsulosin hydrochloride. The total amount of tamsulosin hydrochloride present in the fixed dose combination is preferably from a lower limit of 0.1 , 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9 to an upper limit of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0 mg or more. More preferably, the total amount of tamsulosin hydrochloride present in the fixed dose combination is 0.4 mg. Those skilled in the art will understand that forms of tamsulosin other than tamsulosin hydrochloride can be used in the present invention, and in such cases the foregoing dosage ranges can be adjusted such that the same quantity of the active tamsulosin is administered in the fixed dose combination. The tamsulosin layer may be various weight percentages with respect to the final bead weight as will be understood by those skilled in the art. The tamsulosin layer is preferably from a lower limit of 0.01 , 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11 , 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.20 to an upper limit of 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21 , 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31 , 0.32, 0.33, 0.34, 0.34, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41 , 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50 or more % w/w of the final bead weight.

In some embodiments, the one or more release layers is a pH dependent layer. Preferably the pH dependent layer is a polymethacrylic acid derivative or a derivative of cellulose. In some embodiments, the pH dependent layer is Eudragit L 30D-55 or cellulose acetate phthalate. The pH dependent layer may be various weight percentages with respect to the final bead weight as will be understood by those skilled in the art. The pH dependent layer is preferably from a lower limit of 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9 or 10 to an upper limit of 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24 or 25% w/w of the final bead weight.

In other embodiments, the one or more release layers is a pH independent layer. Preferably the pH independent layer is a singular polymethacrylic acid derivative, a mixture of polymethacrylic acid derivatives, ethyl cellulose, a mixture of ethyl cellulose and water soluble polymers, or the aqueous dispersions thereof. In some embodiments, the pH independent layer is ethyl cellulose, Eudragit NE 40D, a mixture of Eudragit RS and Eudragit RL 3OD in a ratio of about 0-50% w/w RL 3OD, or a mixture of ethyl cellulose and a pore-forming material. The ethyl cellulose may be various ethyl celluloses, such as Surelease®, which is commercially available from Colorcon of West Point, Pennsylvania, or Aquacoat, which is commercially available from FMC BioPolymer of Philadelphia, Pennsylvania. When an ethyl cellulose such as Aquacoat is use, one skilled in the art will understand that a plasticizer such as medium chain triglycerides or dibutyl sebacate may need to be included in the layer. A preferred pore-forming material is hydroxypropylmethyl cellulose, such as Opadry Clear Y-1-19025-A which is commercially available from Colorcon of West Point, Pennsylvania. However, as will be understood by those of skill in the art, other pore-forming materials such as povodone or lactose, for example, can be used. When a mixture of ethyl cellulose and a pore-forming material is used, the amount of pore-forming material in the mixture is preferably from a lower limit of 0.1 , 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, or 49 to an upper limit of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, or 50 w/w of the mixture of ethyl cellulose and pore-forming material. The pH independent layer may be various weight percentages with respect to the final bead weight as will be understood by those skilled in the art. The pH independent layer is preferably from a lower limit of 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9 or 10 to an upper limit of 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24 or 25% w/w of the final bead weight. In still other embodiments, the one or more release layers are a pH dependent layer as described above and a separate pH independent layer as described above. In some embodiments, the pH dependent layer is adjacent the pH independent layer. In other embodiments, the pH dependent layer is separated from the pH independent layer by one or more intervening layers, such as a seal coat.

In some embodiments, the tamsulosin component consists of the plurality of beads, which is to say that the entire dosage of tamsulosin in the fixed dose combination is presented in the plurality of beads. In other embodiments, the plurality of beads only make up a portion of the tamsulosin component, with the remainder of the tamsulosin component comprising other presentations of tamsulosin, such as the individual units described in U.S. Patent No. 4,772,475, or tamsulosin-containing beads other than those described above (e.g., devoid of a release component). In some embodiments, a first portion of the plurality of beads consists of beads in which the one or more release layers is a pH independent layer as described above, and a second portion of the plurality of beads consists of beads in which the one or more release layers is a pH dependent layer as described above. In some embodiments, the first portion of the plurality of beads is from a lower limit of 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, or 70 to an upper limit of 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74 or 75 percent w/w of the plurality of beads, and the second portion of the plurality of beads is from a lower limit of 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 to an upper limit of 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54,

55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74 or 75 percent w/w of the plurality of beads, with the first and second portions together comprising from a lower limit of 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98 or 99 to an upper limit of 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100 percent w/w of the plurality of beads. In some embodiments, the plurality of beads consists of the first portion of the plurality of beads and the second portion of the plurality of beads. Preferably, in these embodiments where the plurality of beads consists of the first portion and the second portion, the first portion of the plurality of beads is from a lower limit of 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55,

56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, or 84 to an upper limit of 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, or 85 percent w/w of the beads, with the remaining beads in the plurality being the second portion of the plurality of beads. In other embodiments, the plurality of beads includes a third portion that consists of beads in which the one or more release layers are a pH dependent layer as described above and a separate pH independent layer as described above. In still other embodiments, a first portion of the plurality of beads consists of beads in which the one or more release layers are a pH dependent layer as described above and a separate pH independent layer as described above. In some embodiments, a second portion of the plurality of beads consists of beads in which the one or more release layers is a pH dependent layer. In some of these embodiments, the plurality of beads consists of the first portion of the plurality of beads and the second portion of the plurality of beads. In other embodiments, a second portion of the plurality of beads consists of beads in which the one or more release layers is a pH independent layer. In some of these other embodiments, the plurality of beads consists of the first portion of the plurality of beads and the second portion of the plurality of beads.

In any of the foregoing embodiments of this aspect of the present invention, some or all of the beads in the plurality or a portion of the plurality can further include one or more seal coats. Seal coat materials can be, for example, hydroxypropyl methyl cellulose, such as Opadry which is commercially available from Colorcon of West Point, Pennsylvania; however, one of ordinary skill in the art will understand that various other seal coat materials may be used. When a bead includes more than one seal coats, the seal coats may be of the same material or different materials. Seal coats may be positioned between the bead core and the first layer, typically the tamsulosin layer, between any of the various layers in the bead, and/or as the exterior layer of the bead, in which case the seal coat is a top coat.

In some or any of the foregoing embodiments of this aspect of the present invention, the dutasteride can be provided in the form of a softgel, for example. The softgel preferably includes dutasteride, a vehicle such as Capmul™ MCM described above , and an anti-oxidant such as butylated hydroxytoluene. As will be understood by those skilled in the art, other vehicles and anti-oxidants may be used. Also, as will be understood by those skilled in the art, dutasteride may be provided in a form other than a softgel. As noted, in one embodiment the dutasteride component is a softgel. In one embodiment the softgel comprises a fill that further comprises approximately 0.5 mg dutasteride; 99.49 mg Capmul MCM ™; and 0.01 mg butylated hydroxytoluene. In another embodiment the softgel comprises a fill that further comprises approximately 0.5 mg dutasteride; 299.47 mg Capmul™ MCM; and 0.030 mg butylated hydroxytoluene.

In some or any of the foregoing embodiments of this aspect of the present invention, the fixed dose combination can be in the form of a capsule, for example. Preferably the capsule is a hydroxypropylmethylcellulose capsule.

According to another aspect of the present invention, a fixed dose combination includes a dutasteride component and a tamsulosin component where the tamsulosin component includes a plurality of beads, wherein each bead includes a discrete layer that includes tamsulosin; in a first portion of the plurality of beads, each bead further includes a pH dependent layer and is devoid of a pH independent layer; and in a second portion of the plurality of beads, each bead further includes a pH independent layer and is devoid of a pH dependent layer. Preferably the tamsulosin layer further includes a binder, such as povidone. As will be understood by those skilled in the art, other binders could be used. Preferably, each of the beads in the plurality of beads further includes a bead core as described above. The fixed dose combination can be in the form of a capsule, for example, as described above. The dutasteride component can be any of the various dutasteride components described above. The pH dependent layer and the pH independent layer can be any of the various pH dependent and pH independent layers described above. In some embodiments, the plurality of beads consists of the first and second portions. In other embodiments, the plurality of beads further includes a third portion within which each bead further includes a pH dependent layer and a pH independent layer. In some embodiments the tamsulosin component consists of the plurality of beads. In other embodiments, the tamsulosion component further includes an additional presentation of tamsulosin as described above. The tamsulosin in the tamsulosin component is as described above.

According to still another aspect of the present invention, a fixed dose combination includes a dutasteride component and a tamsulosin component where the tamsulosin component includes a plurality of beads, wherein each bead includes a discrete layer that includes tamsulosin; and in a first portion of the plurality of beads, each bead further includes a pH independent layer and is devoid of a pH dependent layer. Preferably the tamsulosin layer further includes a binder, such as povidone. As will be understood by those skilled in the art, other binders could be used. Preferably, each of the beads in the plurality of beads further includes a bead core as described above. The fixed dose combination can be in the form of a capsule, for example, as described above. The dutasteride component can be any of the various dutasteride components described above. The pH independent layer and the pH dependent layer can be any of the various pH independent and dependent layers described above. In some embodiments, the plurality of beads includes a second portion within which each bead further includes a pH dependent layer and a pH independent layer. In some embodiments the tamsulosin component consists of the plurality of beads. In other embodiments, the tamsulosion component further includes an additional presentation of tamsulosin as described above. The tamsulosin in the tamsulosin component can be any of the various tamsulosin described above.

According to yet another aspect of the present invention, a fixed dose combination includes a dutasteride component and a tamsulosin component where the tamsulosin component includes a plurality of beads, wherein each bead includes a discrete layer that includes tamsulosin; and in at least a first portion of the plurality of beads, each bead further includes a pH dependent layer and is devoid of a pH independent layer. Preferably the tamsulosin layer further includes a binder, such as povidone. As will be understood by those skilled in the art, other binders could be used. Preferably, each of the beads in the plurality of beads further includes a bead core as described above. The fixed dose combination can be in the form of a capsule, for example, as described above. The dutasteride component can be any of the various dutasteride components described above. The pH dependent layer and the pH independent layer can be any of the various pH dependent and independent layers described above. In some embodiments, the plurality of beads includes a second portion within which each bead further includes a pH dependent layer and a pH independent layer. In some embodiments the tamsulosin component consists of the plurality of beads. In other embodiments, the tamsulosion component further includes an additional presentation of tamsulosin as described above. The tamsulosin in the tamsulosin component can be any of the various tamsulosin described above.

As will be understood by those skilled in the art, any of the various embodiments of the tamsulosin component described herein could be utilized in a pharmaceutical formulation of tamsulosin that does not include dutasteride. In some embodiments, the tamsulosin component is provided in a capsule, for example, as described above.

Other potential therapeutic components to the present invention include vitamins, minerals, growth promoting agents, growth hormone secretagogues, growth hormone releasing factor and its analogs, growth hormone and its analogs, somatomedins, an alpha-adrenergic agonist, serotonin 5-HT_D agonists, bisphosphonates, testosterone, SARMs and/or with other modulators of nuclear hormone receptors, and/or therapies for unstable bladder, including Vesicare™. An anti-oxidant optionally may be used in the composition. Suitable anti¬ oxidants include butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and ascorbic acid. A particularly preferred anti-oxidant is butylated hydroxytoluene. Antioxidants may be used alone or in combination.

EXAMPLES

In the following Tables and experiments, certain abbreviations are used: MiIIi Q™ plus water is a reverse osmosis water, CMC is carboxy methyl cellulose, THF is tetrahydrofuran, DMSO is dimethylsulfoxide, PG is propylene glycol, Labrafil™ is a mixture of unsaturated polyglycolyzed gylcerides obtained by partial alcoholysis of corn oil or apricot kernel oil, consisting of glycerides and polyethylene glycol esters. Unless stated otherwise, all % are by weight, for example, "v/v" means % by volume.

EXPERIMENTALS

All batches were processed using standard pharmaceutical processes. Those skilled in the art will appreciate that other forms of processing are applicable. The description below should be interpreted as preferential embodiments of the present invention. Dutasteride Component

Several processes are available for synthesis of the dutasteride portion of the present invention. The same or similar processes as those described below can be used for the manufacture of 0.01 , 0.05, 0.5, 2.5, 5.0, and 10.0 mg soft-gelatin capsules.

One option for the dutasteride component includes the preparation of fill formulations suitable for use in gelatin capsules. The gelatin capsule would then be further encapsulated into a fixed dosage form with the tamsulosin component. One preferred fill solution is described in Table A:

Table A

As will be appreciated by those skilled in the art, the active and vehicle quantities may be adjusted based on the purity of the batch of active ingredient. The MDC is melted at a minimum of 40⁰C, a major portion is added to the manufacturing tank (Becomix®, or equivalent jacketed vessel) and the material maintained at 40 - 60⁰C under a nitrogen blanket or vacuum. Partial drums of MDC may be pre-mixed prior to manufacturing tank addition. Nitrogen blanket or vacuum is maintained throughout the remainder of the process.

Butylated Hydroxytoluene (BHT) is added to the tank. Dutasteride may be dispersed in a portion of the MDC, and the slurry transferred to the manufacturing tank or added directly to the manufacturing tank. The remainder of the MDC is added to the manufacturing tank and the mixture is stirred until the drug substance and BHT are dissolved. Preferably, a visual inspection is performed. The solution is cooled, deaerated under vacuum, transferred to holding tanks, blanketed with nitrogen, and maintained at 25 - 33⁰C until encapsulation.

The gelatin may be prepared by blending gelatin NF, glycerin USP, sorbitol special, and purified water USP. The resulting mixture may be heated in a pressurized reactor to melt the gelatin. The gelatin may be maintained in the molten state until used for encapsulation. One preferred gelatin shell is described in Table B:

Table B

Preferably, the gelatin formulation is obtained from Cardinal Health, Inc. Beinheim, France. Purified water is removed during the capsule drying process. The gelatin shell moisture equilibrates to approximately less than 10% w/w. MCT and lecithin are used as lubricants for processing.

One preferred encapsulation method includes preparing soft gelatin beadlets which are prepared by a rotary die process. The heated gelatin is fed to the encapsulation machine where it enters two spreader boxes, which cast the gelatin on a cooling drum, thus forming two gelatin ribbons. Each gelatin ribbon is lubricated with medium chain triglycerides (MCT), such as fractionated coconut oil, on the internal side and with MCT containing 0.3% w/w lecithin on the external side. The MCT prevents the gelatin from sticking to the equipment. The lecithin prevents the beadlets from sticking together after manufacture, prior to drying. The ribbons are then conveyed to the encapsulation rollers. Die cavities designed to form the size 2 round beadlets are located on the circumference of the two adjacent rollers that rotate and press the gelatin ribbons between them. The fill solution is maintained under nitrogen at 25 - 33°C, filtered, and injected, by a pump, between the gelatin ribbons forcing them to expand and fill the die cavities. As the beadlets are filled, they are simultaneously shaped, sealed and cut from the gelatin ribbon by the encapsulation rollers.

Beadlet fill and shell weight and seal thickness tests are performed. Filled beadlets are transferred to rotating drying baskets. The beadlets are tumbled in each basket to remove sufficient moisture for improved handling. The beadlets are then transferred onto trays, the trays are stacked, and the stacks are placed in drying tunnels and allowed to dry until the moisture level of the fill solution is not more than 2% (w/w). A hardness test is performed to ensure the hardness of the beadlets is between 9 and 12 newtons and the beadlets are removed from the drying tunnel.

As noted, one preferred embodiment includes a fill that contains 0.5 mg dutasteride dissolved into 99.49 mg of Capmul™ MCM, with 0.01 mg butylated hydroxytoluene (BHT). The fill, of 100 mg total weight, is encapsulated into a soft gelatin capsule, size #2, round. The filled soft gelatin capsules are dried and, optionally, imprinted.

Another preferred embodiment is a 300 mg fill softgel in a #5 oblong soft gelatin capsule. The embodiment includes 0.5 mg dutasteride dissolved into 299.47 mg Capmul™ MCM, with 0.030 mg BHT for a 300 mg total fill weight. As will be appreciated, the soft gelatin capsules are dried and optionally imprinted. Although particular methods for encapsulation and drying are described, one skilled in the art will appreciate that any of a number of known methods may be used alternatively.

Tamsulosin Component

A. Tamsulosin Beads Having a pH Dependent Layer and a pH Independent Layer

As illustrated in Figure 1 , an embodiment of the present invention includes a tamsulosin bead 10. The bead 10, which may be referred to as a bead, a sphere, a microparticle, or other similar terms, preferably includes a pH dependent layer 12. The pH dependent layer 12 is a discrete film coat. The material may provide enteric protection. As will be appreciated by those skilled in the art, enteric protection may be partial or complete. The pH dependent layer is from a lower limit of 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9 or 10 to an upper limit of 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24 or 25% w/w of the final bead weight. Preferably the pH dependent layer 12 is a derivative of polymethylacrylic acid or a derivative of cellulose. More preferably the pH dependent layer 12 is Eudragit L 30D-55 polymethylacrylic acid or cellulose acetate phthalate. Dry mixtures of these acrylic enteric polymers that require aqueous mixing are also suitable for the pH dependent coat. Examples include Acryl-EZE®, which is commercially available from Colorcon of West Point, Pennsylvania, and Sureteric, which is commercially available from Colorcon of West Point, Pennsylvania.

The bead 10 includes a pH independent layer 14. The pH independent layer 14 is a discrete film coat of a singular polymethacrylic acid derivative, a mixture of polymethacrylic acid derivatives, ethyl cellulose, mixtures of ethyl cellulose and water soluble polymers, or the aqueous dispersions of any of the aforementioned polymers. The pH independent layer is from a lower limit of 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9 or 10 to an upper limit of 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24 or 25% w/w of the final bead weight. Preferably the pH independent film layer 14 is ethyl cellulose (such as Surelease®), Eudragit NE 4OD polymethylacrylic acid derivative, a combination of Eudragit RS and Eudragit RL 30 D polymethylacrylic acids derivatives in a ratio of about 0-50% w/w of the RL 30D₁ or a combination of ethylcellulose and hydroxypropylmethyl cellulose in a ratio of about 0-50% w/w of the hydroxypropylmethylcellulose. The bead 10 preferably includes a seal coat 16. Seal coat 16 preferably is an about 1-10% w/w coat of film, preferably commercially available such as hydroxypropylmethylcellutose that may contain pigments or lakes to provide color. Although seal coat 16 is depicted as beneath pH independent layer 14, the seal coat 16 optionally may be added between the pH dependent layer 12 and pH independent layer 14, or may be added on top of the pH dependent layer 12 to provide color and/or protection to the final bead 10.

The bead 10 includes drug layer 18. Drug layer 18 includes tamsulosin hydrochloride and a suitable binder. The binder is polyvinylpyrrolidone, hydroxypropylmethylcellulose ("HPMC"), or the like. Preferably, the binder is polyvinylpyrrolidone, more preferably PVP K29-32.

The bead 10 includes sphere 20. Sphere 20 preferably is a commercially available microcrystalline cellulose bead, such as Celphere beads or a sugar sphere, which may be referred to as non-pareils. Although the bead in Figure 1 is illustrated with a particular shape, the actual shape of the bead 10 is determined by the shape of the sphere 20. Preferably sphere 20 is spherical or oblong. Thus, the illustration in Figure 1 should not be considered as limiting the present invention to any particular geometric shape.

Embodiments of the present invention that utilize the bead structure described above with reference to Figure 1 are described in Examples 1-18 below:

Example 1

A solution of PVP K29-32 and a suitable amount of water was prepared in a mixing vessel. A suspension of tamsulosin HCI in a suitable amount of water was prepared by adding the drug to the water while homogenizing. The PVP K29-32 solution was added to the tamsulosin HCI suspension and mixed thoroughly. The resulting suspension was sprayed on the Celphere CP-507 beads in a fluidized bed fitted with a bottom-spray Wurster column using the conditions listed below in Table 1.

A pH independent layer was prepared through spray coating a suspension onto the drug layer. Preferably, a Eudragit NE 4OD coating suspension was prepared by adding a homogenized suspension of talc to a suitable amount of polymer dispersion. A suitable amount of water was added to make a coating suspension that contains about 20 %w/w solids. While mixing, the coating suspension was sprayed to the drug coated beads using the settings listed in Table 1.

As described below, an optional seal coat may be added, for example as a top coat to provide color.

A pH dependent layer was prepared through spray coating a suspension to the pH independent-coated bead. A Eudragit L 30D-55 coating suspension was prepared by adding a required amount of triethyl citrate to a polymer dispersion and a suitable amount of water to make a coating suspension that contains about 20 %w/w solids. While mixing, the coating suspension was sprayed to the pH independent polymer/drug coated beads using the settings listed in Table 1. After applying the polymer coat(s), including the pH dependent and pH independent coats, the beads were cured in an oven at 35⁰C to 60⁰C for 15-24 hours.

Table 1

Typical Glatt 1.1 Settings

Druα Laver Drug Layer pH pH pH PH PH Type: independent independent independent independent dependent PVP K29-32

Polymer: Eudragit NE Surelease® Surelease Eudragit Eudragit L 4OD RS/RL 30D-55

®/ Opadry Conditions Clear

Inlet 45-66⁰C 28°C 50-66°C 50-66°C 40-50⁰C 40-50°C Temperature

Product 28-40⁰C 25-28°C 34-45°C 34-45°C 26-35°C 27-4O⁰C Temperature

Outlet 29-39⁰C 24⁰C 44°C 44°C 26⁰C 27⁰C Temperature

Airflow 75-120 m³/hr 100 m³/hr 75-120 m³/hr 75-120 m³/hr 75-120 m³/hr 75-120 m³/hr

Atomization 1.5 Bar 2 Bar 2-2.5 Bar 2-2.5 Bar 2 Bar 2 Bar Air

Spray Rate 3.3-10g/min 1.5-2.2g/min 1.4-6.0g/min 1.4-6.0g/min 2.1-6.0g/min 3.3-6.5g/min Wurster Plate B or C D C C C C

Column 15-25 mm 15-25 mm 15-25 mm 15-25 mm 15-25 mm 15-25 mm Height

Shaking 15sec/5sec 15sec/5sec 15sec/5sec 15sec/5sec 15sec/5sec 15sec/5sec Interval/Time

Examples 2 and 3

Component Dry Weight Basis

Example 2 Example 3 g % w/w g % w/w

Druα-coated Bead

Tamsulosin HCI 0.284 0.131 0.284 0.126

Celphere CP-507 199.5 92.32 199.5 88.24

PVP K29-32 0.284 0.131 0.284 0.126

Functional Coats

Eudragit RS30D 13.04 6.03 13.04 5.76

Eudragit RL30D 0.688 0.318 0.688 0.304

Eudragit L30D-55 0 0 9.10 4.02

Glyceryl 0.688 0.318 0.688 0.304

MonoStearate

Polysorbate 80 0.26 0.120 0.26 0.115

Triethyl Citrate 1.37 0.634 2.28 1.01

Total 216.1 100 226.2 100

The above formulations were prepared similar to the process described in Example 1 above, except the first polymer coat, namely the pH independent coat was a mixture of Eudragit RS/RL in a ratio of about 95/5. The mixed polymer coating solution was prepared by adding suitable amounts of both polymer dispersions to a suitable mixing vessel and adding about 10 % w/w, on the dry polymer basis, triethyl citrate, 5 % w/w glyceryl monostearate, and about 1.9 % w/w polysorbate 80. The resulting coating suspension was sprayed on the drug-coated beads using the settings listed in Table 1.

Examples 4 and 5

Component Dry Weight Basis

Example 4 Example 5 g % w/w g % w/w

Druα-coated Bead

Tamsulosin HCI 0.282 0.133 0.282 0.123

Celphere CP-507 199.5 94.02 199.5 86.85

PVP K29-32 0.282 0.133 0.282 0.123

Opadry (seal coat) 2.0 0.943 2.0 0.871

Functional Coats

Surelease® 10.1 4.76 10.1 4.40

Eudragit L30D-55 0 0 15.91 6.93

Triethyl Citrate 0 0 1.58 0.688

Total 212.2 100 229.7 100.0

The above formulations were prepared similar to the process described in Example 1 above, except a seal coat of Opadry Clear, Y-1-19025-A, was sprayed onto the drug coated beads at a 1 % w/w level prior to applying the functional polymer coat(s). The seal coat was a 8 % w/w solution of the Opadry Clear in water and was applied with the same machine settings as the Surelease® listed in Table 1.

The first polymer coat, namely the pH independent coat, is commercially available ethyl cellulose polymer dispersion, Surelease®. The polymer coating suspension was prepared by adding suitable amounts of Surelease® to a suitable mixing vessel and adding sufficient water to make a suspension containing about 15 % w/w solids. The resulting coating suspension was sprayed on the drug-coated beads using the settings listed in Table 1. After applying the polymer coatings, the beads were cured for 2 hours at 60⁰C in an oven.

Examples 6 and 7

Component Dry Weight Basis

Example 6 Example 7 g % w/w 9 % w/w

Druα-coated Bead

Tamsulosin HCI 0.284 0.128 0.284 0.119

Cellsphere CP-507 199.6 89.87 199.6 83.65

PVP K29-32 0.284 0.128 0.284 0.119

Opadry (seal coat) 2.0 0.900 2.0 0.838

Functional Coats

Opadry (with 1.0 0.450 1.0 0.419

Surelease®)

Surelease® 18.93 8.52 18.93 7.93

Eudragit L30D-55 0 0 14.94 6.26

Triethyl Citrate 0 0 1.49 0.624

Total 222.1 100 238.6 100

The above formulations were prepared similar to the process described in Example 1 above, except the first polymer coat after the seal coat (the pH independent layer) is a mixture of Surelease® and Opadry Clear, Y-1-19025-A. The polymer coating suspension was prepared by adding suitable amounts of Surelease® and Opadry Clear to a suitable mixing vessel and adding sufficient water to make a suspension containing about 15 % w/w solids. The resulting coating suspension was sprayed on the drug-coated beads using the settings listed in Table 1.

Similar to the methods described above, additional embodiments are described in Examples 8-18. Note that some embodiments utilize Opadry White YS 1-18202 as a top coat to provide color. The topcoat of Opadry White YS-1 -18202 can be applied using the processing conditions listed for Surelease® coat in Table 1. The coating suspension is prepared by adding the Opadry to water, while stirring, at a 12% w/w solids level. Examples 8-14

N)

Examples 15-17

as

Example 18

B. Tamsulosin Beads Having a pH Independent Layer and Devoid of a pH Dependent Layer

As illustrated in Figure 2, an embodiment of the present invention includes a tamsulosin bead 210. The bead 210, which may be referred to as a bead, a sphere, a microparticle, or other similar terms, includes a pH dependent layer 214, which is similar to the pH dependent layer 14 described above with reference to Figure 1.

Unlike the bead 10 described in Figure 1 , the bead 210 does not include a pH dependent layer.

The bead 210 preferably includes a seal coat 216, which is similar to the seal coat 16 described above with reference to Figure 1. Although seal coat 216 is depicted as beneath independent layer 214, the seal coat 216 optionally may be added on top of the pH independent layer 214 to provide color and/or protection to the final bead 210.

The bead 210 includes drug layer 218, which is similar to drug layer 18 described above with reference to Figure 1. The bead 210 includes sphere 220, which is similar to sphere 20 described above with reference to Figure 1.

Although the bead in Figure 2 is illustrated with a particular shape, the actual shape of the bead 210 is determined by the shape of the sphere 220. Preferably sphere 220 is spherical or oblong. Thus, the illustration in Figure 2 should not be considered as limiting the present invention to any particular geometric shape.

An embodiment of the present invention that utilizes the bead structure described above with reference to Figure 2 is described in detail in Example 19 below:

Example 19

The above formulation was prepared using processes similar to those described, in Examples 4 and 5 above, except that a top coat of 2% w/w Opadry White YS-1- 18202 was added for color. Also, the curing was carried out in the fluid bed by fluidizing the finished beads at a product temperature of 6O⁰C for 1 hour.

A dissolution test was performed on beads prepared in this example 19 using USP apparatus II. The paddle speed was 100 RPM. Typically, the dissolution test was performed in two stages with the pH increasing in Stage 2. Thus, the media for Stage 1 was 0.05N HCI, whereas the media for Stage 2 included the media from Stage 1 plus sufficient 0.2M sodium phosphate buffer to raise the pH to approximately 6.3. The Stage 2 buffer was added after a two hour sample was pulled in Stage 1 media. The analysis was performed by HPLC and many suitable methods are possible as those skilled in the art would understand. Dissolution data from six, 0.4 mg tamsulosin HCI doses are presented in Table 2. Note the gradual release of tamsulosin HCI over a 12 hour period.

Table 2

C. Tamsulosin Beads Having a pH Dependent Layer and Devoid of a pH Independent Layer

As illustrated in Figure 3, an embodiment of the present invention includes a tamsulosin bead 310. The bead 310, which may be referred to as a bead, a sphere, a microparticle, or other similar terms. The bead 310 includes a pH dependent layer 312, which is similar to the pH dependent layer 12 described above with reference to Figure 1.

The bead 310 is devoid of a pH independent layer, which is described above as pH independent layer 14 with reference to Figure 1. The bead 310 preferably includes a seal coat 316, which is similar to seal coat 16 described above with reference to Figure 1. Although seal coat 316 is depicted as beneath pH dependent layer 312, the seal coat 316 optionally may be added on top of the pH dependent layer 312 to provide color and/or protection to the final bead 310. The bead 310 includes drug layer 318, which is similar to the drug layer 18 described above with reference to Figure 1.

The bead 310 includes sphere 320, which is similar to the sphere 20 described above with reference to Figure 1.

Although the bead in Figure 3 is illustrated with a particular shape, the actual shape of the bead 310 is determined by the shape of the sphere 320. Preferably sphere 320 is spherical or oblong. Thus, the illustration in Figure 3 should not be considered as limiting the present invention to any particular geometric shape. An embodiment of the present invention that utilizes the bead structure described above with reference to Figure 3 is described in detail in Example 20 below: Example 20

Component Dry Weight Basis g % w/w

Druα-coated Bead 1 9 0 150

Tamsulosin HCI

Celphere CP-507 1000 79.06

PVP K29-32 2.0 0.158

Opadry (seal coat) 50.2 3.96

Functional Coat

Acryl-EZE® 210.8 16.67

Total 1264.9 100

The above formulation was prepared using processes similar to those described in Example 1 above, except that a commercially available acrylic enteric polymer, Acryl- EZE® , was used as the only functional coat. To prepare a 20% w/w solution of Acryl-EZE® for spraying, a suitable amount of powdered product was added to water while mixing. The product was allowed to mix for 0.5-1.0 hour prior to spraying. The coat was applied using the parameters listed is Table 1. After the coat was applied, the product was dried for an additional 15 minutes at 28-35°C in the fluid bed.

The dissolution test described in Example 19 was used to evaluate beads produced in Example 20. As example 20 is prepared with an enteric coat, little or no product is released at low pH. However when the pH is increased by adding Stage 2 media, the tamsulosin HCI is released as shown in Table 3.

Table 3

Fixed Dose Combination

For purposes of the present invention, any capsule filling technology is believed to be adequate for preparing a fixed dose combination of the above- described components. Preferably, the required amount of tamsulosin beads will be added based on using volume or weight as a basis using an automated process as will be appreciated by those skilled in the art. Preferably, a dutasteride soft gelatin capsule will be added using a similar automated process. The fill order should not be considered critical to the present invention. Rather, the tamsulosin beads and dutasteride softgel may be used to fill the capsule in either order.

The following examples illustrate the use of single beads and bead mixtures in small batches using beads produced in Examples 19 and 20. In Example 23, the weight ratio of beads required to produce a capsule containing 0.4 mg of tamsulosin hydrochloride from Example 19 and Example 20, is about 67/33. The actual ratio can be any ratio that is mechanically feasible to automatically fill. Preferably, the ratio is between 25 and 75 % of any one bead used in a mixture. Additionally, the use of beads from Examples 19 and 20 are merely for illustration as any of the beads produced in the 20 bead examples can be used to create capsules with beads that have different compositions.

Although specific embodiments of the present invention are herein illustrated and described in detail, the invention is not limited thereto. The above detailed descriptions are provided as exemplary of the present invention and should not be construed as constituting any limitation of the invention. Modifications will be obvious to those skilled in the art, and all modifications that do not depart from the spirit of the invention are intended to be included with the scope of the appended claims.

Claims

What is claimed is:

1. A fixed dose combination comprising: dutasteride; and tamsulosin.

2. The combination of claim 1 in the form of a capsule.

3. The combination of claim 2 wherein the capsule is a hydroxypropylmethylcellulose capsule.

4. The combination of claim 1 wherein the dutasteride is provided in the form of a softgel and the tamsulosin is provided in the form of beads, and further wherein the dutasteride and tamsulosin are filled into a capsule.

5. The combination of claim 4 wherein the tamsulosin bead further comprises: a discrete layer comprising tamsulosin and a binder; and a pH independent layer.

6. The combination of claim 5 wherein the pH independent layer is a singular polymethacrylic acid derivative, a mixture of polymethacrylic acid derivatives, ethyl cellulose, a mixture of ethyl cellulose and water soluble polymers, or the aqueous dispersions thereof.

7. The combination of claim 6 wherein the pH independent layer is ethyl cellulose, Eudragit NE 4OD, a mixture of Eudragit RS and Eudragit RL 3OD in a ratio of about 0-50% w/w RL 3OD, or a mixture of ethyl cellulose and hydroxypropylmethylcellulose in a ratio of about 0-50% w/w hydroxypropyl methylcellulose.

8. The combination of claim 5 further comprising: a pH dependent film coat.

9. The combination of claim 8 wherein the pH dependent polymer film coat is a polymethacrylic acid derivative or a derivative of cellulose.

10. The combination of claim 9 wherein the pH dependent film coat is Eudragit L 30D-55 or cellulose acetate phthalate.

11. The combination of claim 1 wherein the dutasteride portion is a softgel.

12. The combination of claim 11 wherein the softgel comprises a fill that further comprises approximately:

0.5 mg dutasteride;

99.49 mg Capmul MCM™; and

0.01 mg butylated hydroxytoluene.

13. The combination of claim 11 wherein the softgel comprises a fill that further comprises approximately:

0.5 mg dutasteride;

299.47 mg Capmul™ MCM; and

0.030 mg butylated hydroxytoluene.

14. The combination of claim 1 wherein the tamsulosin portion further comprises: tamsulosin hydrochloride active ingredient; a binder; a diluent; a plasticizer; at least one modified release coat; and at least one pigmented coat.

15. The combination of claim 14 wherein: the binder is povidone; the diluent is microcrystalline cellulose; the plasticizer is triethyl citrate; the at least one modified release coat is ethylcellulose or methacrylic acid copolymer; and the at least one pigmented coat is HPMC with pigment.

16. The combination of claim 15 wherein the tamsulosin portion further comprises: two modified release coats, one each of ethylcellulose and methacrylic acid copolymer; and two pigmented coats each of HPMC with pigment.

17. A method for the treatment or prophylaxis of an androgen mediated disease or condition comprising administration of the combination of claim 1.

18. The method of claim 17 wherein the disease or condition is benign prostatic hyperplasia or prostate cancer.

19. A fixed dose combination comprising: a dutasteride component; and a tamsulosin component comprising a plurality of beads, wherein each bead in the plurality of beads comprises a discrete layer comprising tamsulosin and a binder; and each bead in the plurality of beads further comprises one or more release layers that determine the tamsulosin release rate of the bead.

20. The combination of claim 19, wherein the tamsulosin component consists of the plurality of beads.

21. The combination of claim 20, wherein the one or more release layers is a pH dependent layer.

22. The combination of claim 21 , wherein the pH dependent layer is a polymethacrylic acid derivative or a derivative of cellulose.

23. The combination of claim 22, wherein the pH dependent layer is Eudragit L 30D-55 or cellulose acetate phthalate.

24. The combination of claim 20, wherein the one or more release layers is a pH independent layer.

25. The combination of claim 24, wherein the pH independent layer is a singular polymethacrylic acid derivative, a mixture of polymethacrylic acid derivatives, ethyl cellulose, a mixture of ethyl cellulose and water soluble polymers, or the aqueous dispersions thereof.

26. The combination of claim 25, wherein the pH independent layer is ethyl cellulose, Eudragit NE 4OD, a mixture of Eudragit RS and Eudragit RL 3OD in a ratio of about 0-50% w/w RL 3OD, or a mixture of ethyl cellulose and hydroxypropylmethylcellulose in a ratio of about 0.1-50% w/w hydroxypropyl methylcellulose.

27. The combination of claim 20, wherein the one or more release layers are a pH dependent layer and a separate pH independent layer.

28. The combination of claim 27, wherein the pH dependent layer is adjacent the pH independent layer.

29. The combination of claim 27, wherein the pH dependent layer is separated from the pH independent layer by one or more intervening layers.

30. The combination of claim 20, wherein a first portion of the plurality of beads consists of beads in which the one or more release layers is a pH independent layer, and wherein a second portion of the plurality of beads consists of beads in which the one or more release layers is a pH dependent layer.

31. The combination of claim 30, wherein the plurality of beads consists of the first portion of the plurality of beads and the second portion of the plurality of beads.

32. The combination of claim 31 , wherein the first portion of the plurality of beads is from 15 to 75 percent w/w of the beads.

33. The combination of claim 31 , wherein the first portion of the plurality of beads is from 25 to 65 percent w/w of the beads.

34. The combination of claim 31 , wherein the first portion of the plurality of beads is from 30 to 40 percent w/w of the beads.

35. The combination of claim 30, wherein a third portion of the plurality of beads consists of beads in which the one or more release layers are a pH dependent layer and a separate pH independent layer.

36. The combination of claim 20, wherein a first portion of the plurality of beads consists of beads in which the one or more release layers are a pH dependent layer and a separate pH independent layer.

37. The combination of claim 36, wherein a second portion of the plurality of beads consists of beads in which the one or more release layers is a pH dependent layer.

38. The combination of claim 37, wherein the plurality of beads consists of the first portion of the plurality of beads and the second portion of the plurality of beads.

39. The combination of claim 36, wherein a second portion of the plurality of beads consists of beads in which the one or more release layers is a pH independent layer.

40. The combination of claim 39, wherein the plurality of beads consists of the first portion of the plurality of beads and the second portion of the plurality of beads.

41. The combination of claim 19 in the form of a capsule.

42. The combination of claim 41 , wherein the capsule is a hydroxypropylmethylcellulose capsule.

43. The combination of claim 19, wherein the dutasteride component is a softgel.

44. The combination of claim 43 wherein the softgel comprises a fill that further comprises approximately:

0.5 mg dutasteride;

99.49 mg Capmul MCM ™; and

0.01 mg butylated hydroxytoluene.

45. The combination of claim 43 wherein the softgel comprises a fill that further comprises approximately:

0.5 mg dutasteride;

299.47 mg Capmul™ MCM; and

0.030 mg butylated hydroxytoluene.

46. The combination of claim 19, wherein the tamsulosin is present as tamsulosin hydrochloride.

47. A method for the treatment or prophylaxis of an androgen mediated disease or condition comprising administration of the combination of claim 19.

48. The method of claim 47 wherein the disease or condition is benign prostatic hyperplasia or prostate cancer.

49. A fixed dose combination comprising: a dutasteride component, wherein the dutasteride component is a softgel; and a tamsulosin component consisting of a plurality of beads, wherein each bead in the plurality of beads comprises a discrete layer comprising tamsulosin hydrochloride and a binder; and each bead in the plurality of beads further comprises one or more release layers that determine the tamsulosin release rate of the bead, wherein a first portion of the plurality of beads consists of beads in which the one or more release layers is a pH independent layer; wherein a second portion of the plurality of beads consists of beads in which the one or more release layers is a pH dependent layer; and wherein the plurality of beads consists of the first portion and the second portion.

50. The combination of claim 49, wherein the pH dependent layer is a polymethacrylic acid derivative or a derivative of cellulose.

51. The combination of claim 50, wherein the pH dependent layer is Eudragit L 30D-55 or cellulose acetate phthalate.

52. The combination of claim 49, wherein the pH independent layer is a singular polymethacrylic acid derivative, a mixture of polymethacrylic acid derivatives, ethyl cellulose, a mixture of ethyl cellulose and water soluble polymers, or the aqueous dispersions thereof.

53. The combination of claim 52, wherein the pH independent layer is ethyl cellulose, Eudragit NE 4OD, a mixture of Eudragit RS and Eudragit RL 3OD in a ratio of about 0-50% w/w RL 3OD, or a mixture of ethyl cellulose and hydroxypropylmethylcellulose in a ratio of about 0.1-50% w/w hydroxypropyl methylcellulose.

54. The combination of claim 49 in the form of a capsule.

55. The combination of claim 54, wherein the capsule is a hydroxypropylmethylcellulose capsule.

56. The combination of claim 49 wherein the softgel comprises a fill that comprises approximately:

0.5 mg dutasteride;

99.49 mg Capmul MCM™; and

0.01 mg butylated hydroxytoluene.

57. The combination of claim 49 wherein the softgel comprises a fill that comprises approximately:

0.5 mg dutasteride;

299.47 mg Capmul™ MCM; and

0.030 mg butylated hydroxytoluene.

58. The combination of claim 49, wherein the tamsulosin component comprises 0.4 mg of tamsulosin hydrochloride.

59. A method for the treatment or prophylaxis of an androgen mediated disease or condition comprising administration of of the combination of claim 49.

60. The method of claim 59 wherein the disease or condition is benign prostatic hyperplasia or prostate cancer.

61. A fixed dose combination comprising: a dutasteride component, wherein the dutasteride component comprises 0.5 mg dutasteride; and a tamsulosin component comprising 0.4 mg of tamsulosin hydrochloride and consisting of a plurality of beads, wherein each bead in the plurality of beads comprises a discrete layer comprising tamsulosin hydrochloride and a binder; and each bead in the plurality of beads further comprises one or more release layers that determine the tamsulosin release rate of the bead, wherein a first portion of the plurality of beads consists of beads in which the one or more release layers is a pH independent layer; wherein a second portion of the plurality of beads consists of beads in which the one or more release layers is a pH dependent layer; and wherein the plurality of beads consists of the first portion and the second portion.