AU2011203238A1 - Solid dosage forms of valsartan, amlodipine and hydrochlorothiazide and method of making the same - Google Patents

Abstract

C \RPonblDCC\RXS\3729375_1.DOC-310WW2OI Monolayer, bilayer and trilayer solid dosage forms of a combination of valsartan, amlodipine and hydrochlorothiazide are made.

Description

Australian Patents Act 1990 - Regulation 3.2A ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Invention Title "Solid dosage forms of valsartan, amlodipine and hydrochlorothiazide and method of making the same" The following statement is a full description of this invention, including the best method of performing it known to us:- -1 SOLID DOSAGE FORMS OF VALSARTAN, AMLODIPINE AND HYDROCHLOROTHIAZIDE AND METHOD OF MAKING THE SAME 5 BACKGROUND OF THE INVENTION This is a divisional of Australian Patent Application No. 2007265138, the entire contents of which are incorporated herein by reference. Field of the Invention [0001] The present invention is directed to solid dosage formulations containing a combination of valsartan, amlodipine and a diuretic such as hydrochlorothiazide, as well as to methods of making such solid dosage forms and a method of treating a subject with such solid dosage foras. Related Background Art 10002] The development of fixed-combination solid dosage formulations of certain active ingredients is challenging. As used herein, "fixed-combination" refers to a combination of two or more drugs or active ingredients presented in a single dosage unit such as a tablet or a capsule; further as used herein, "free-combination" refers to a combination of two or more drugs or active ingredients dosed simultaneously but as two or more dosage units. When formulating fixed-combination solid dosage formulations, the objective is to provide a patient-convenient combination dosage form of active ingredients that is bioequivalent to the corresponding free-combination of the same active ingredients and/or delivers a superior pharmacodynakic effect than the individual components.. Development of fixed-combination dosage formulations that are bioequivalent to the free-combination is challenging due to the multiplicity of challenges arising from pharmacokinetic and pharmaceutical properties of the drugs sought to be combined. 100031 For example, valsartan has an absolute oral bioavailability of only about 25% with a wide range of 10-35%. Valsartan also has pH dependent solubility whereby it ranges from very slightly soluble in an acidic environment to soluble in a neutral environment of the gastrointestinal tract. Further, development of a patient convenient oral dosage form of valsartan is challenging due to its low bulk density. Amlodipine besylate is slightly soluble in water and has an absolute bioavailability of 64-90%. Hydrochlorothiazide is slightly soluble in water and has an oral -2 bioavailability 60-80%. As a result of these complex biopharmaceutical properties, development of a fixed-combination dosage form of valsartan, amlodipine and hydrochlorothiazide that is bioequivalent to a free-combination thereof is challenging. 100041 Accordingly, a fixed-combination solid dosage formulation of valsartan, amlodipine and hydrochlorothiazide that is bioequivalent to the corresponding free combination would be desirable. SUMMARY OF THE INVENTION 100051 In a first embodiment, the present invention is directed to a solid dosage form comprising a combination of valsartan, amlodipine and hydrochlorothiazide, and pharmaceutically acceptable additives suitable for the preparation of solid dosage forms. In preferred embodiments of this invention, amlodipine free base is provided in the form of amlodipine besylate, and the pharmaceutically acceptable additives are selected from diluents, disintegrants, glidants, lubricants, binders, colorants and combinations thereof. 100061 In certain preferred embodiments of this invention, the solid dosage form is a monolayer tablet. In other preferred embodiments of this invention, the solid dosage form is a bilayer tablet, e.g., having the valsartan and the hydrochlorothiazide in one layer and the amlodipine in another layer or having the valsartan in one layer and the amlodipine and the hydrochlorothiazide in another layer or having the valsartan and the amlodipine in one layer and the hydrochlorothiazide in another layer. In other preferred embodiments of this invention, the solid dosage form is a trilayer tablet, e.g., having all three actives in separate layers. The amount of valsartan employed in such solid dosage forms, monolayer or bilayer, preferably ranges from about 40 mg to about 640 mg, preferably 80 mg to 640 mg, and more preferably is 160 mg or 320 mg. The amount of amlodipine employed in such solid dosage forms, monolayer or bilayer, preferably ranges from about 2.5 mg to about 20 mg, and more preferably is 5 mg or 10 mg. The amount of hydrochlorothiazide employed in such solid dosage forms, monolayer or bilayer, preferably ranges from about 6.25 mg to about 50 mg, and more preferably is 12.5 mg or 25 mg. 100071 In a second embodiment, the present invention is directed to a method of making a solid dosage form of valsartan, amlodipine and HCTZ comprising the steps of (a) blending valsartan, amlodipine, hydrochlorothiazide and pharmaceutically acceptable additives to form a blended material; (b) sieving the blended material to - 3 form a sieved material; (c) blending the sieved material to form a blended/sieved material; (d) compacting the blended/sieved material to form a compacted material; (e) milling the compacted material to form a milled material; (f) blending the milled material to form blended/milled material; and (g) compressing the blended/milled material to form a monolayer solid dosage form. A preferred embodiment of this invention also includes an optional step, step (h) film coating the monolayer solid dosage form. 100081 In a third embodiment, this invention is directed to solid dosage forms of valsartan, amlodipine and HCTZ made according to the method of the second embodiment. 100091 In a fourth embodiment, the present invention is directed to a method of making a solid dosage form of valsartan, amlodipine and HCTZ comprising the steps of a) blending valsartan and pharmaceutically acceptable additives to form a blended material; (b) sieving the blended material to form a sieved material; (c) blending the sieved material to form a blended/sieved material; (d) compacting the blended/sieved material to form a compacted material; (e) milling the compacted material to form a milled material; (f) blending the milled material with amlodipine and hydrochlorothiazide to form blended/milled material; and (g) compressing the blended/milled material to form a monolayer solid dosage form. A preferred embodiment of this invention also includes an optional step, step (h) film coating the monolayer solid dosage form. 100101 In a fifth embodiment, this invention is directed to solid dosage forms of valsartan, amlodipine and HCTZ made according to the method of the fourth embodiment. 100111 In a sixth embodiment, the present invention is directed to a method of making a solid dosage form of valsartan, amlodipine and HCTZ comprising the steps of a) blending valsartan, amlodipine, and pharmaceutically acceptable additives to form a blended material; (b) sieving the blended material to form a sieved material; (c) blending the sieved material to form a blended/sieved material; (d) compacting the blended/sieved material to form a compacted material; (e) milling the compacted material to form a milled material; (f) blending the milled material with hydrochlorothiazide to form blended/milled material; and (g) compressing the blended/milled material to form a monolayer solid dosage form. A preferred -4 embodiment of this invention also includes an optional step, step (h) film coating the monolayer solid dosage form. 100121 In a seventh embodiment, this invention is directed to solid dosage forms of valsartan, amlodipine and HCTZ made according to the method of the sixth embodiment. [0013] In an eighth embodiment, the present invention is directed to a method of making a solid dosage form of valsartan, amlodipine and HCTZ comprising the steps of a) blending valsartan, hydrochlorothiazide, and pharmaceutically acceptable additives to form a blended material; (b) sieving the blended material to form a sieved material; (c) blending the sieved material to form a blended/sieved material; (d) compacting the blended/sieved material to form a compacted material; (e) milling the compacted material to form a milled material; (f) blending the milled material with amlodipine to form blended/milled material; and (g) compressing the blended/milled material to form a monolayer solid dosage form. A preferred embodiment of this invention also includes an optional step, step (h) film coating the monolayer solid dosage form. 100141 In a ninth embodiment, this invention is directed to solid dosage forms of valsartan, anlodipine and HCTZmade according to the method of the eighth embodiment. [00151 In a tenth embodiment, the present invention is directed to a method of making a solid dosage form of valsartan, amlodipine and HCTZ comprising the steps of (a) granulating valsartan, pharmaceutically acceptable additives and optionally hydrochlorothiazide to form a valsartan granulation; (b) granulating amlodipine, pharmaceutically acceptable additives and optionally hydrochlorothiazide to form an amlodipine granulation; and (c) compressing the valsartan granulation and the amlodipine granulation together to form a bilayer solid dosage form, wherein hydrochlorothiazide is present in the valsartan granulation and/or the amlodipine blend. In a preferred embodiment of the invention, step (a) comprises the steps of (al) blending valsartan, pharmaceutically acceptable additives and optionally hydrochlorothiazide to form a blended material; (a2) sieving the blended material to form a sieved material; (a3) blending the sieved material to form a blended/sieved material; (a4) compacting the blended/sieved material to form a compacted material; (a5) milling the compacted material to form a milled material; and (a6) blending the -5 milled material to form the valsartan granulation. In another preferred embodiment, step (b) comprises a granulation process with the steps of (bl) blending amlodipine, pharmaceutically acceptable additives and optionally hydrochlorothiazide to form a blended material; (b2) sieving the blended material to form a sieved material; (b3) blending the sieved material to form a blended/sieved material; (b4) compacting the blended/sieved material to form a compacted material; (b5) milling the compacted material to form a milled material; and (b6) blending the milled material to form an amlodipine granulation. Another preferred embodiment of this invention also includes an optional step, step (d) film coating the bilayer solid dosage form. . Hydrochlorothiazide can be incorporated at step al and/or a6, and at step bI and/or b6. [0016] In a eleventh embodiment, this invention is directed to solid dosage forms of valsartan, amlodipine and HCTZ made according to the method of the tenth embodiment. 100171 In another embodiment, this invention is directed to a method of making a solid dosage form of valsartan, amlodipine and HCTZ comprising the steps of (a) granulating valsartan, pharmaceutically acceptable additives and optionally amlodipine to form a valsartan granulation; (b) granulating hydrochlorothiazide, pharmaceutically acceptable additives and optionally amlodipine to form a hydrochlorothiazide granulation; and (c) compressing the valsartan granulation and the hydrochlorothiazide granulation together to form a bilayer solid dosage form, wherein amlodipine is present in the valsartan granulation and/or the hydrochlorothiazide blend. In a preferred embodiment of the invention, step (a) comprises the steps of (al) blending valsartan, pharmaceutically acceptable additives and optionally amlodipine to form a blended material; (a2) sieving the blended material to form a sieved material; (a3) blending the sieved material to form a blended/sieved material; (a4) compacting the blended/sieved material to form a compacted material; (a5) milling the compacted material to form a milled material; and (a6) blending the milled material to form the valsartan granulation. In another preferred embodiment, step (b) comprises a granulation process with the steps of(bl) blending hydrochlorothiazide, pharmaceutically acceptable additives and optionally amlodipine to form a blended material; (b2) sieving the blended material to form a sieved material; (b3) blending the sieved material to form a blended/sieved material; (b4) compacting the blended/sieved material to form a compacted material; (b5) -6 milling the compacted material to form a milled material; and (b6) blending the milled material to form a hydrochlorothiazide granulation. Another preferred embodiment of this invention also includes an optional step, step (d) film coating the bilayer solid dosage form. Amlodipine can be incorporated at step al and/or a6, and at step bl and/or b6. 10018] Yet another embodiment of the invention is directed to a method of treating hypertension, congestive heart failure, angina, myocardial infarction, arteriosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, stroke, left ventricular hypertrophy, cognitive dysfunction, headache, or chronic heart failure comprising administering a solid dosage form of valsartan, amlodipine and hydrochlorothiazide to a subject in need of such treatment. In a preferred embodiment, the solid dosage form is orally administered to the subject. DETAILED DESCRIPTION 100191 The present invention relates to solid dosage forms which contain a combination of valsartan, amlodipine and hydrochlorothiazide. 100201 The first embodiment of the invention is directed to a solid dosage form comprising a combination of valsartan, amlodipine and hydrochlorothiazide, and pharmaceutically acceptable additives suitable for the preparation of solid dosage forms. The solid dosage forms of the present invention can take the form of monolayer tablets (having the valsartan, the amlodipine and the hydrochlorothiazide in one layer) or bilayer tablets (e.g., having the valsartan in one layer and the andodipine and the hydrochlorothiazide in another layer or having the valsartan and the hydrochlorothiazide in one layer and the amlodipine in another layer or having the valsartan and the amlodipine in one layer and the hydrochlorothiazide in another layer) or trilayer tablets (e.g., having the valsartan, amlodipine and hydrochlorothiazide all in separate layers.) or a trilayer tablet of two active layers ( amlodipine+HCTZ, amlodipine + valsartan) separated by a non-active layer and a third layer of valsartan or HCTZ or amlodipine. 100211 Valsartan ((S)-N-valeryl-N-{ [2'-(1H-tetrazole-5-yI)-biphenyl-4-yl]-methyl} valine) suitable for use in the present invention can be purchased from commercial sources or can be prepared according to known methods. For example, the preparation of valsartan is described in U.S. Patent No. 5,399,578, the entire -7 disclosure of which is incorporated by reference herein. Valsartan may be used for purposes of this invention in its free form as well as in any suitable salt form. 100221 Valsartan is employed in an amount typically ranging from about 40 mg to about 640 mg, preferably from about 80 mg to about 320 mg, and more preferably is about 160 mg or about 320 mg in a monolayer tablet or a bilayer tablet or a trilayer tablet. The amount of valsartan noted above refers to the amount of free valsartan or salt thereof present in a given solid dosage form. 100231 Amlodipine (3-ethyl-5-methyl-2(2-aminoethoxymethyl)-4-(2-chrorophenyl) 1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate benzenesulphonate) suitable for use in the present invention can be purchased from commercial sources or can be prepared according to known methods. Amlodipine may be used for purposes of this invention in its free form as well as in any suitable salt form; in a preferred embodiment of this invention, amlodipine free base is supplied to the solid dosage forms through the use of amlodipine besylate. 100241 Amlodipine is employed in an amount ranging from 2.5 mg to about 20 mg, preferably from about 5 mg to about 10 mg, and more preferably is about 5 mg or about 10 mg in a monolayer tablet or a bilayer tablet or a trilayer tablet. The amount of amlodipine noted above refers to the amount of free amlodipine present in a given solid dosage form. 100251 Hydrochlorothiazide suitable for use in the present invention can be purchased from commercial sources or can be prepared according to known methods. Hydrochlorothiazide may be used for purposes of this invention in its free form as well as in any suitable salt form. [00261 Hydrochlorothiazide is employed in an amount ranging from 6.25 mg to about 50 mg, preferably from about 12.5 mg to about 25 mg, and more preferably is about 12.5 mg or about 25 mg in a monolayer tablet or a bilayer tablet or a trilayer tablet. The amount of hydrochlorothiazide noted above refers to the amount of free hydrochlorothiazide present in a given solid dosage form. [00271 Pharmaceutically acceptable additives suitable for use in the present invention include, without limitation, diluents or fillers, disintegrants, glidants, lubricants, binders, colorants and combinations thereof. The amount of each additive in a solid dosage formulation may vary within ranges conventional in the art. 100281 Suitable diluents include, without limitation, microcrystalline cellulose (e.g., cellulose MK GR), mannitol, sucrose or other sugars or sugar derivatives, low- -8 substituted hydroxypropyl cellulose, di-calcium phosphate, lactose, and combinations thereof. When present, a diluent may be employed in an amount ranging from about 10% to about 80%, preferably from about 32% to about 51% by weight of the solid dosage form (prior to any optional film coating). For monolayer tablets, a diluent is preferably employed in an amount ranging from about 10% to about 80%, more preferably in an amount ranging from about 32% to about 39% by weight of the solid dosage form. For bilayer tablets, a diluent is preferably employed in an amount ranging from about 10% to about 80%, more preferably in an amount ranging from about 47% to about 51% by weight of the solid dosage form. [00291 Suitable disintegrants include, without limitation, crospovidone, sodium starch glycolate, L-hydroxy propyl cellulose, croscarmellose sodium, and combinations thereof. When present, a disintegrant may be employed in an amount ranging from about 0.5% to about 50%, preferably from about 5% to about 14% by weight of the solid dosage form (prior to any optional film coating). For monolayer tablets, a disintegrant is preferably employed in an amount ranging from about 0.5% to about 50%, more preferably in an amount ranging from about 5% to about 14% by weight of the solid dosage form. For bilayer tablets, a disintegrant is preferably employed in an amount ranging from about 0.5% to about 50%, more preferably in an amount ranging from about 7% to about 10% by weight of the solid dosage form. [00301 Suitable glidants include, without limitation, colloidal silicon dioxide (e.g., Aerosil 200), magnesium trisilicate, powdered cellulose, starch, talc and combinations thereof. When present, a glidant may be employed in an amount ranging from about 0.1% to about 10%, preferably from about 0.6% to about 0.8% by weight of the solid dosage form (prior to any optional film coating). For monolayer tablets, a glidant is preferably employed in an amount ranging from about 0.1 % to about 10%, more preferably in an amount of about 0.7 5% by weight of the solid dosage form. For bilayer tablets, a glidant is employed in an amount ranging from about 0.1% to about 10%, more preferably in an amount of about 0.65% by weight of the solid dosage form. 100311 Suitable lubricants include, without limitation, magnesium stearate, calcium stearate, aluminum or calcium silicate, stearic acid, cutina, PEG 4000-8000, talc and combinations thereof. When present, a lubricant may be employed in an amount ranging from about 0.1% to about 10%, preferably from about 2% to about 3% by weight of the solid dosage form (prior to any optional film coating). For monolayer -9 tablets, a lubricant is preferably employed in an amount ranging from about 0.1% to about 10%, more preferably in an amount of about 2% by weight of the solid dosage form. For bilayer tablets, a lubricant is preferably employed in an amount ranging from about 0.1% to about 10%, more preferably in an amount of about 2% by weight of the solid dosage form. [00321 Suitable binders include, without limitation, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, pregelatinized starch, microcrystalline cellulose (e.g., cellulose MK GR), and combinations thereof. When present, a binder may be employed in an amount ranging from about 0.5% to about 40%, preferably in an amount of about 10% by weight of the solid dosage form (prior to any optional film coating). For monolayer tablets, a binder is preferably employed in an amount ranging from about 0.5% to about 40%, more preferably in an amount of about 10% by weight of the solid dosage form. For bilayer tablets, a binder is preferably employed in an amount ranging from about 0.5% to about 40%, more preferably in an amount of about 10% by weight of the solid dosage form. [0033] Suitable colorants include, without limitation, iron oxides such as yellow, red, and black iron oxide, and titanium dioxide and combinations thereof. When present, a colorant may be employed in an amount ranging from about 0.01% to about 0.1% by weight of the solid dosage form (prior to any optional film coating). In a preferred embodiment, monolayer tablets contain no colorant. Film coating for monolayer tablets are given in the example Tables [00341 The solid dosage forms of the first embodiment of the invention are monolayer or bilayer tablet dosage forms of suitable hardness, e.g., an average hardness ranging from about 60 N to about 350 N for monolayer forms and an average hardness ranging from about 100 N to about 350 N for bilayer forms. Such an average hardness is determined prior to the application of any film coating on the solid dosage forms. In that regard, a preferred embodiment of this invention is directed to solid dosage forms which are film-coated. Suitable film coatings are known and commercially available or can be made according to known methods. Typically the film coating material is a polymeric film coating material comprising materials such as hydroxypropylmethyl cellulose, polyethylene glycol, talc and colorant. Generally, a film coating material is applied in such an amount as to provide a film coating that ranges from about 1% to about 7% by weight of the film coated tablet.

-10 100351 The second embodiment of the present invention is directed to a method of making a solid dosage form of valsartan, amlodipine and HCTZ comprising the steps of (a) blending valsartan, amlodipine, hydrochlorothiazide and pharmaceutically acceptable additives to form a blended material; (b) sieving the blended material to form a sieved material; (c) blending the sieved material to form a blended/sieved material; (d) compacting the blended/sieved material to form a compacted material; (e) milling the compacted material to form a milled material; (f) blending the milled material to form blended/milled material; and (g) compressing the blended/milled material to form a monolayer solid dosage form. The details regarding the valsartan, amlodipine, hydrochlorothiazide and pharmaceutically acceptable additives, i.e., source, amount, etc., are as set forth above with regard to the first embodiment of the invention. This embodiment can be in the form of all possible permutations, e.g., valsartan may be blended alone and amlodipine and hydrochlorothiazide may be added in the final blending step. 100361 In the first step of the method of the second embodiment, valsartan, amlodipine, hydrochlorothiazide and pharmaceutically acceptable additives are blended to form a blended material. Blending can be accomplished using any suitable means such as a diffusion blender or diffusion mixer. In the second step, the blended material is sieved to form a sieved material. Sieving can be accomplished using any suitable means. In the third step of the method of the second embodiment, the sieved material is blended to form a blended/sieved material. Again blending can be accomplished using any suitable means. 100371 In the fourth step, the blended/sieved material is compacted to form a compacted material. Compacting can be accomplished using any suitable means. Typically compacting is accomplished using a roller compactor with a compaction force ranging from about 0.5 kN to about 90 kN, preferably about 20 kN to about 60 kN. Compaction may also be carried out by slugging the blended powders into large tablets that are then size-reduced. 100381 In the fifth step of the method of the second embodiment, the compacted material is milled to form a milled material. Milling can be accomplished using any suitable means. In the sixth step, the milled material is blended to form blended/milled material. Here again blending can be accomplished using any suitable means. In the final step of the method of the second embodiment, the blended/milled material is compressed to form a monolayer solid dosage form. Compression can be - Il accomplished using any suitable means. Typically compression is accomplished using a rotary tablet press. Compression force for such a rotary tablet press typically ranges from about 5 kN to about 40 kN. [0039] Optionally, the method of the second embodiment comprises the step of (h) film coating the monolayer solid dosage form. The details regarding the film coating material, i.e., components, amounts, etc., are as described above with regard to the first embodiment of the invention. Film coating can be accomplished using any suitable means. 100401 In a third embodiment, this invention is directed to solid dosage forms of valsartan made according to the method of the second embodiment. 100411 In a fourth embodiment, the present invention is directed to a method of making a solid dosage form of valsartan amlodipine and HCTZ comprising the steps of a) blending valsartan and pharmaceutically acceptable additives to form a blended material; (b) sieving the blended material to form a sieved material; (c) blending the sieved material to form a blended/sieved material; (d) compacting the blended/sieved material to form a compacted material; (e) milling the compacted material to form a milled material; (f) blending the milled material with amlodipine and hydrochlorothiazide to form blended/milled material; and (g) compressing the blended/milled material to form a monolayer solid dosage form. A preferred embodiment of this invention also includes an optional step, step (h) film coating the monolayer solid dosage form. [0042] In a fifth embodiment, this invention is directed to solid dosage forms of valsartan, amlodipine and HCTZ made according to the method of the fourth embodiment. [0043] In a sixth embodiment, the present invention is directed to a method of making a solid dosage form of valsartan, amlodipine and HCTZ comprising the steps of a) blending valsartan, amlodipine, and pharmaceutically acceptable additives to form a blended material; (b) sieving the blended material to form a sieved material; (c) blending the sieved material to form a blended/sieved material; (d) compacting the blended/sieved material to form a compacted material; (e) milling the compacted material to form a milled material; (f) blending the milled material with hydrochlorothiazide to form blended/milled material; and (g) compressing the blended/milled material to form a monolayer solid dosage form. A preferred -12 embodiment of this invention also includes an optional step, step (h) film coating the monolayer solid dosage form. 100441 In a seventh embodiment, this invention is directed to solid dosage forms of valsartan, amlodipine and HCTZ made according to the method of the sixth embodiment. [0045] In an eighth embodiment, the present invention is directed to a method of making a solid dosage form of valsartan, amlodipine and HCTZ comprising the steps of a) blending valsartan, hydrochlorothiazide, and pharmaceutically acceptable additives to form a blended material; (b) sieving the blended material to form a sieved material; (c) blending the sieved material to form a blended/sieved material; (d) compacting the blended/sieved material to form a compacted material; (e) milling the compacted material to form a milled material; (f) blending the milled material with amlodipine to form blended/milled material; and (g) compressing the blended/milled material to form a monolayer solid dosage form. A preferred embodiment of this invention also includes an optional step, step (h) film coating the monolayer solid dosage form. 100461 In a ninth embodiment, this invention is directed to solid dosage forms of valsartan, amlodipine and HCTZ made according to the method of the eighth embodiment. 100471 The tenth embodiment of the present invention is directed to a method of making a solid dosage form of valsartan, amlodipine and HCTZ comprising the steps of (a) granulating valsartan, pharmaceutically acceptable additives and optionally hydrochlorothiazide to form a valsartan granulation; (b) blending amlodipine, pharmaceutically acceptable additives and optionally hydrochlorothiazide to form an amlodipine blend; and (c) compressing the valsartan granulation and the amlodipine blend together to form a bilayer solid dosage form, wherein hydrochlorothiazide is present in the valsartan granulation and/or the amlodipine blend. The details regarding the valsartan, amlodipine, hydrochlorothiazide and pharmaceutically acceptable additives, i.e., source, amount, etc., are as set forth above with regard to the first embodiment of the invention. 100481 In the first step of the method of the tenth embodiment, valsartan is granulated with pharmaceutically acceptable additives and optionally hydrochlorothiazide to form a valsartan granulation. Valsartan granulation can be accomplished by any suitable means. In a preferred embodiment of this invention, - 13 valsartan granulation is accomplished by (al) blending valsartan, pharmaceutically acceptable additives and optionally hydrochlorothiazide to form a blended material; (a2) sieving the blended material to form a sieved material; (a3) blending the sieved material to form a blended/sieved material; (a4) compacting the blended/sieved material to form a compacted material; (a5) milling the compacted material to form a milled material; and (a6) blending the milled material to form the valsartan granulation. Hydrochlorothiazide can be incorporated at step al and/or a 6 . [00491 The blending of step (al) can be accomplished using any suitable means. Typically the valsartan, pharmaceutically acceptable additives and optionally the hydrochlorothiazide are dispatched to a suitable vessel such as a diffusion blender or diffusion mixer. The sieving of step (a2) can be accomplished using any suitable means. The blending of step (a3) can be accomplished using any suitable means. The compacting of step (a4) can be accomplished using any suitable means. Typically compacting is accomplished using a roller compactor with a compaction force ranging from about 0.5 kN to about 90 kN, preferably about 20-60 kN. Compaction may also be carried out by slugging the blended powders into large tablets that are then size-reduced. The milling of step (a5) can be accomplished using any suitable means. Typically the compacted material is milled through a screening mill. The blending of step (a6) can be accomplished using any suitable means. Preferably the milled material is blended, often with a pharmaceutically acceptable additive such as a lubricant, in a diffusion blender. [00501 In the second step of the method of the tenth embodiment, amlodipine is blended with pharmaceutically acceptable additives and optionally hydrochlorothiazide to form an amlodipine blend. Amlodipine granulation can be accomplished by any suitable means. In a preferred embodiment, blending step (b) comprises the process of granulating amlodipine. Amlodipine granulation can be accomplished by any suitable means including but not limited wet granulation, dry granulation, melt granulation or dry blend. In a more preferred embodiment of this invention, amlodipine granulation is accomplished by (bl) blending amlodipine, pharmaceutically acceptable additives and optionally hydrochlorothiazide to form a blended material; (b2) sieving the blended material to form a sieved material; (b3) blending the sieved material to form a blended/sieved material; (b4) compacting the blended/sieved material to form a compacted material; (b5) milling the compacted material to form a milled material; and (b6) blending the milled material to form an -14 amlodipine granulation. Hydrochlorothiazide can be incorporated at step bl and/or b6. Hydrochlorothiazide can be incorporated by any suitable means including but not limited wet granulation, dry granulation, melt granulation or dry blend. 100511 The blending of step (bl) can be accomplished using any suitable means. The sieving of step (b2) can be accomplished using any suitable means. The blending of step (b3) can be accomplished using any suitable means. The compacting of step (b4) can be accomplished using any suitable means. Typically compacting is accomplished using a roller compactor with a compaction force ranging from about 0.5 kN to about 90kN, preferably about 20 kN to about 60 kN. The milling of step (b5) can be accomplished using any suitable means. Typically the compacted material is milled through a screening mill. The blending of step (b6) can be accomplished using any suitable means. 100521 In the final step of the method of the tenth embodiment, the valsartan granulation and the amlodipine blend are compressed together to form a bilayer solid dosage form. Compression can be accomplished using any suitable means. Typically compression is accomplished using a bilayer rotary tablet press. Typical compression force ranges from about 5 kN to about 40 kN. 100531 In this embodiment, hydrochlorothiazide is present in one of the valsartan granulation and the amlodipine blend. In other words, the inclusion of hydrochlorothiazide in the bilayer solid dosage form is not optional; only its placement in the same, i.e., in the valsartan layer or in the amlodipine layer, is variable. However, in other embodiments hydrochlorothiazide may be present alone in a separate layer. 100541 Optionally, the method of the tenth embodiment comprises the step of (d) film coating the bilayer solid dosage form. The details regarding the film coating material, i.e., components, amounts, etc., are as described above with regard to the first embodiment of the invention. Film coating can be accomplished using any suitable means. [00551 An eleventh embodiment of the present invention is directed to a bilayer solid dosage form of valsartan, amlodipine and HCTZ made according to the method of the tenth embodiment. [00561 In another embodiment, this invention is directed to a method of making a solid dosage form of valsartan, amlodipine and HCTZ comprising the steps of(a) granulating valsartan, pharmaceutically acceptable additives and optionally - 15 amilodipine to form a valsartan granulation; (b) granulating hydrochlorothiazide, pharmaceutically acceptable additives and optionally amlodipine to form a hydrochlorothiazide granulation; and (c) compressing the valsartan granulation and the hydrochlorothiazide granulation together to form a bilayer solid dosage form, wherein amlodipine is present in the valsartan granulation and/or the hydrochlorothiazide blend. In a preferred embodiment of the invention, step (a) comprises the steps of (al) blending valsartan, pharmaceutically acceptable additives and optionally amlodipine to form a blended material; (a2) sieving the blended material to form a sieved material; (a3) blending the sieved material to form a blended/sieved material; (a4) compacting the blended/sieved material to form a compacted material; (a5) milling the compacted material to form a milled material; and (a6) blending the milled material to form the valsartan granulation. In another preferred embodiment, step (b) comprises a granulation process with the steps of (b 1) blending hydrochlorothiazide, pharmaceutically acceptable additives and optionally amlodipine to form a blended material; (b2) sieving the blended material to form a sieved material; (b3) blending the sieved material to form a blended/sieved material; (b4) compacting the blended/sieved material to form a compacted material; (b5) milling the compacted material to form a milled material; and (b6) blending the milled material to form a hydrochlorothiazide granulation. Another preferred embodiment of this invention also includes an optional step, step (d) film coating the bilayer solid dosage form. Amlodipine can be incorporated at step al and/or a6, and at step bI and/or b6. 100571 Yet another embodiment of the invention is directed to a method of treating hypertension, congestive heart failure, angina, myocardial infarction, arteriosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, stroke, left ventricular hypertrophy, cognitive dysfunction, headache, or chronic heart failure. The method comprises administering a solid dosage form of valsartan, amlodipine and hydrochlorothiazide to a subject in need of such treatment. In a preferred embodiment, the solid dosage form is orally administered to the subject. [0058] Specific embodiments of the invention will now be demonstrated by reference to the following examples. It should be understood that these examples are disclosed solely by way of illustrating the invention and should not be taken in any way to limit the scope of the present invention.

-16 EXAMPLE 1 160/12.5/5 MG TABLET 100591 A monolayer solid dosage form of valsartan, amlodipine and HCTZ was made using the ingredients set forth in Table I below. Table 1. Ingredient (mg) % A valsartan 160.00 40.00 B hydrochlorothiazide 12.50 3.13 C amlodipine besylate 6.94* 1.74 D microcrystalline 154.56 38.64 1 cellulose E crospovidone 54.00 13.50 F colloidal silicon 3.00 0.75 dioxide G magnesium stearate 6.00 1.50 (I) H magnesium stearate 3.00 0.75 (II) __total 400.00 * - corresponds to 5 mg amlodipine free base [00601 Ingredients A-G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient H in a diffusion blender. (This second blending step achieves the desired level of lubricant for the granulation and, in certain cases, combines sub-divided batches of ingredients A-G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated. [00611 Ingredients A, C, D, E, F, and G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient B and H in a diffusion blender. (This second blending step achieves the desired level of B and H for the granulation and, in certain cases, combines sub-divided batches of ingredients A, C, D, E, F, and G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated.

- 17 100621 Ingredients A, B, D, E, F, and G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient C and H in a diffusion blender. (This second blending step achieves the desired level of B and H for the granulation and, in certain cases, combines sub-divided batches of ingredients A, B, D, E, F, and G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated. 100631 Ingredients A, D, E, F, and G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient B, C and H in a diffusion blender. (This second blending step achieves the desired level of B, C, and H for the granulation and, in certain cases, combines sub divided batches of ingredients A, D, E, F, and G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated. EXAMPLE 2 160/12.5/10 MG TABLET 100641 A monolayer solid dosage form of valsartan, amlodipine and HCTZ was made using the ingredients set forth in Table 2 below. Table 2. Ingredient (mg) % A valsartan 160.00 40.00 B hydrochlorothiazide 12.50 3.13 C amlodipine besylate 13.87* 3.47 D microcrystalline 147.63 36.91 cellulose E crospovidone 54.00 13.50 F colloidal silicon 3.00 0.75 dioxide G magnesium stearate 6.00 1.50 (1) H magnesium stearate 3.00 0.75 (II) total 400.00 - 18 * - corresponds to 10 mg amlodipine free base 100651 Ingredients A-G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient H in a diffusion blender. (This second blending step achieves the desired level of lubricant for the granulation and, in certain cases, combines sub-divided batches of ingredients A-G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated. [00661 Ingredients A, C, D, E, F, and G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient B and H in a diffusion blender. (This second blending step achieves the desired level of B and H for the granulation and, in certain cases, combines sub-divided batches of ingredients A, C, D, E, F, and G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated. [00671 Ingredients A, B, D, E, F, and G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient C and H in a diffusion blender. (This second blending step achieves the desired level of B and H for the granulation and, in certain cases, combines sub-divided batches of ingredients A, B, D, E, F, and G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated. [00681 Ingredients A, D, E, F, and G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient B, C and H in a diffusion blender. (This second blending step achieves the desired level of B, C, and H for the granulation and, in certain cases, combines sub- - 19 divided batches of ingredients A, D, E, F, and G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated. EXAMPLE 3 160/25/10 MG TABLET 100691 A monolayer solid dosage form of valsartan, amlodipine and HCTZ was made using the ingredients set forth in Table 3 below. Table 3. Ingredient (mg) % A valsartan 160.00 40.00 B hydrochlorothiazide 25.00 6.25 C amlodipine besylate 13.87* 3.47 D microcrystalline 135.13 33.78 cellulose E crospovidone 54.00 13.50 F colloidal silicon 3.00 0.75 dioxide G magnesium stearate 6.00 1.50 (I) ___________ ___________ H magnesium stearate 3.00 0.75 (II) ___________ ___________ total 400.00 * - corresponds to 10 mg amlodipine free base 100701 Ingredients A-G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient H in a diffusion blender. (This second blending step achieves the desired level of lubricant for the granulation and, in certain cases, combines sub-divided batches of ingredients A-G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated. [00711 Ingredients A, C, D, E, F, and G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient B and H in a diffusion blender. (This second blending step achieves the desired level of B and H for the granulation and, in certain cases, - 20 combines sub-divided batches of ingredients A, C, D, E, F, and G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated. [00721 Ingredients A, B, D, E, F, and G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient C and H in a diffusion blender. (This second blending step achieves the desired level of B and H for the granulation and, in certain cases, combines sub-divided batches of ingredients A, B, D, E, F, and G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated. 100731 Ingredients A, D, E, F, and G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient B, C and H in a diffusion blender. (This second blending step achieves the desired level of B, C, and H for the granulation and, in certain cases, combines sub divided batches of ingredients A, D, E, F, and G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated. EXAMPLE 4 160/25/5 MG TABLET 100741 A monolayer solid dosage form of valsartan,amlodipine and HCTZ was made using the ingredients set forth in Table 4 below. Table 4. Ingredient (mg) % A valsartan 160.00 40.00 B hydrochlorothiazide 25.00 6.25 C amlodipine besylate 6.94* 1.74 D microcrystalline 142.06 35.51 cellulose E crospovidone 54.00 13.50 F colloidal silicon 3.00 0.75 dioxide G magnesium stearate 6.00 1.50 ____ (I)____________

____________

-21 Ingredient (mg) % H magnesium stearate 3.00 0.75 (II) total 400.00 * - corresponds to 5 mg amlodipine free base 10075] Ingredients A-G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient H in a diffusion blender. (This second blending step achieves the desired level of lubricant for the granulation and, in certain cases, combines sub-divided batches of ingredients A-G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated. 100761 Ingredients A, C, D, E, F, and G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient B and H in a diffusion blender. (This second blending step achieves the desired level of B and H for the granulation and, in certain cases, combines sub-divided batches of ingredients A, C, D, E, F, and G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated. 100771 Ingredients A, B, D, E, F, and G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient C and H in a diffusion blender. (This second blending step achieves the desired level of B and H for the granulation and, in certain cases, combines sub-divided batches of ingredients A, B, D, E, F, and G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated. 100781 Ingredients A, D, E, F, and G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a - 22 diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient B, C and H in a diffusion blender. (This second blending step achieves the desired level of B, C, and H for the granulation and, in certain cases, combines sub divided batches of ingredients A, D, E, F, and G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated. EXAMPLE 5 320/25/10 MG TABLET [00791 A monolayer solid dosage form of valsartan, amlodipine and HCTZ was made using the ingredients set forth in Table 5 below. Table 5. Ingredient (mg) % A valsartan 320.00 40.00 B hydrochlorothiazide 25.00 3.13 C amlodipine besylate 13.87* 1.73 D microcrystalline 309.12 38.64 cellulose E crospovidone 108.00 13.50 F colloidal silicon 6.00 0.75 dioxide G magnesium stearate 12.00 1.50 1 (I) H magnesium stearate 6.00 0.75 ____ (II) ___________ ___________ total 800.00 * - corresponds to 10 mg amlodipine free base 100801 Ingredients A-G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient H in a diffusion blender. (This second blending step achieves the desired level of lubricant for the granulation and, in certain cases, combines sub-divided batches of ingredients A-G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated.

- 23 100811 Ingredients A, C, D, E, F, and G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient B and H in a diffusion blender. (This second blending step achieves the desired level of B and H for the granulation and, in certain cases, combines sub-divided batches of ingredients A, C, D, E, F, and G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated. 100821 Ingredients A, B, D, E, F, and G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient C and H in a diffusion blender. (This second blending step achieves the desired level of B and H for the granulation and, in certain cases, combines sub-divided batches of ingredients A, B, D, E, F, and G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated. 100831 Ingredients A, D, E, F, and G are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient B, C and H in a diffusion blender. (This second blending step achieves the desired level of B, C, and H for the granulation and, in certain cases, combines sub divided batches of ingredients A, D, E, F, and G.) Next, the blended/milled material is compressed into monolayer solid dosage forms using a rotary tablet press, and the monolayer solid dosage forms are optionally film coated. EXAMPLE 6 160/12.5/5; 160/12.5/10; 160/25/5; 160/25/10 and 320/25/10 MG TABLET 100841 A bilayer solid dosage form of valsartan, amlodipine and HCTZ was made using the ingredients set forth in Table 6 below.

- 24 Table 6. Ingredient (mg) valsartan/hydrochlorothiazide layer A valsartan 320.00 35.56 B hydrochlorothiazide 25.00 2.78 C microcrystalline 151.00 16.78 cellulose D crospovidone 80.00 8.89 E colloidal silicon dioxide 6.00 0.67 F magnesium stearate (I) 12.00 1.33 G magnesium stearate (II) 6.00 0.67 subtotal 600.00 amlodipine layer H amlodipine besylate 13.87* 1.54 I microcrystalline 279.03 31.00 cellulose J sodium starch glycolate 6.00 0.67 K colorant 0.20 0.02 L magnesium stearate (III) 0.30 0.03 M magnesium stearate (IV) 0.60 0.07 subtotal 300.00 total 900.00 - corresponds to 10 mg amlodipine free base - 25 Table 7 160/25/10mg 160/2 /5mg 160/12.5/5mg 160/12.5/10mg Ingredient mg/unit % mg/unit % mg/unit % mg/unit % Valsartan and HCTZ layer A Valsartan DS 160.00 26.67 160.00 35.56 160.00 35.56 160.00 26.67 B HCTZ 25.00 4.17 25.00 5.56 12.50 2.78 12.50 2.08 C Avicel 102 63.00 10.50 63.00 14.00 85.50 19.00 85.50 14.25 o Crospovidone 40.00 6.67 40.00 8.89 30.00 6.67 30.00 5.00 E Cab-O-Sil 3.00 0.50 3.00 0.67 3.00 0.67 3.00 0.50 F Mag. St.() 6.00 1.00 6.00 1.33 6.00 1.33 6.00 1.00 G Mag. St.( 11) 3.00 0.50 3.00 0.67 3.00 0.67 3.00 0.50 Sub-total 300.00 300.00 300.00 300.00 Amlodipine layer Amlodipine b H Besylate 13.87' 2.31 6.94 1.54 6.94 1.54 13.87' 2.31 Avicel I PH102 279.03 46.51 139.51 31.00 139.51 31.00 279.03 46.51 Sodium Starch J Glycolate 6.00 1.00 3.00 0.67 3.00 0.67 6.00 1.00 Iron oxide K yellow 0.20 0.03 0.10 0.02 0.10 0.02 0.20 0.03 L Mag. St. (III) 0.30 0.05 0.15 0.03 0.15 0.03 0.30 0.05 M Mag. St. (IV) 0.60 0.10 0.30 0.07 0.30 0.07 0.60 0.10 Sub-total 300.00 150.00 150.00 300.00 Total 600.00 100.00 450.00 100.00 450.00 100.00 600.00 100.00 a corresponds to 10 mg amlodipine free base; ' corresponds to 5 mg arlodipine free base [00851 First, the valsartan is granulated by combining ingredients A-F in a diffusion blender. Then, the blended material is sieved through a screen. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient G in a diffusion blender. (This second blending step achieves the desired level of lubricant for the granulation and, in certain cases, combines sub-divided batches of ingredients A-F.) 100861 Second, the amlodipine besylate is granulated by combining ingredients H-L in a diffusion blender. Then, the blended material is sieved through a screen. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient M in a diffusion blender. (This second blending step achieves the desired level of lubricant for the granulation and, in certain cases, combines sub-divided batches of ingredients H-L.) -26 100871 Finally, the valsartan granulation and the amlodipine granulation are compressed into bilayer solid dosage forms using a bilayer rotary tablet press, and the bilayer solid dosage forms are optionally film coated. EXAMPLE 7 160/12.5/5; 160/12.5/10; 160/25/5; 160/25/10 and 160/12.5/5 MG TABLET 100881 A bilayer solid dosage form of valsartan, amlodipine and HCTZ was made using the ingredients set forth in Table 8 and 9 below. Table 8. Ingredient (mg)% valsartan layer A valsartan 160.00 34.78 B microcrystalline 108.00 23.48 cellulose C crospovidone 30.00 6.52 D colloidal silicon dioxide 3.00 0.65 E magnesium stearate (1) 6.00 1.30 F magnesium stearate (II) 3.00 0.65 subtotal 310.00 amlodipine/hydrochlorothiazide layer G amlodipine besylate 6.94* 1.51 H hydrochlorothiazide 12.50 2.72 I microcrystalline 127.02 27.61 cellulose J sodium starch glycolate 3.00 0.65 K colorant 0.10 0.02 L magnesium stearate (III) 0.15 0.03 M magnesium stearate (lV) 0.30 0.07 subtotal 150.00 total 460.00 * - corresponds to 5 mg amlodipine free base Table 9: 160/25/10mg 160/25/5mg 160/12.5/10mg 320/25/10mg Ingredient mg/unit % me/unit % mg/unit % mg/unit % Valsartan layer -27 A Valsartan DS 160.00 26.23 160.00 26.23 160.00 26.23 320.00 34.78 B Avicel 102 108.00 17.70 108.00 17.70 108.00 17.70 216.00 23.48 C Crospovidone 30.00 4.92 30.00 4.92 30.00 4.92 60.00 6.52 D Cab-O-Sil 3.00 0.49 3.00 0.49 3.00 0.49 6.00 0.65 E Mag. St.( 1) 6.00 0.98 6.00 0.98 6.00 0.98 12.00 1.30 F Mag. St.( 11) 3.00 0.49 3.00 0.49 3.00 0.49 6.00 0.65 Sub-total 310.00 310.00 310.00 620.00 Amlodipine and HCTZ _ layer Amlodipine G Besylate 13.87 2.27 6.94 1.14 13.87 2.27 13.87 1.51 H HCTZ 25.00 4.10 25.00 4.10 12.50 2.05 25.00 2.72 Avicel I PH102 254.03 41.64 260.96 42.78 266.53 43.69 254.03 27.61 Sodium Starch J Glycolate 6.00 0.98 6.00 0.98 6.00 0.98 6.00 0.65 Iron oxide K yellow 0.20 0.03 0.20 0.03 0.20 0.03 0.20 0.02 L Mag. St. (Il) 0.30 0.05 0.30 0.05 0.30 0.05 0.30 0.03 M Mag. St.(IV) 0.60 0.10 0.60 0.10 0.60 0.10 0.60 0.07 Sub-total 300.00 _ _ 300.00 300.00 300.00 Total 610.00 100.00 610.00 100.00 610.00 100.00 920.00 100.00 (00891 First, the valsartan is granulated by combining ingredients A-E in a diffusion blender. Then, the blended material is sieved through a screen. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient F in a diffusion blender. (This second blending step achieves the desired level of lubricant for the granulation and, in certain cases, combines sub-divided batches of ingredients A-E.) 100901 Second, the amlodipine besylate is granulated by combining ingredients G-L in a diffusion blender. Then, the blended material is sieved through a screen. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient M in a diffusion blender. (This second blending step achieves the desired level of lubricant for the granulation and, in certain cases, combines sub-divided batches of ingredients G-L.) 100911 Finally, the valsartan granulation and the amlodipine granulation are compressed into bilayer solid dosage forms using a bilayer rotary tablet press, and the bilayer solid dosage forms are optionally film coated.

-28 EXAMPLE 8 160/12.5/5; 160/12.5/10; 160/25/5; 160/25/10 and 320/25/10 Mg Tablet 100921 A bilayer solid dosage form of valsartan, amlodipine and HCTZ was made using the ingredients set forth in Table 10 and 11 below. Table 10 Ingredient 160/25/10mg 160/25/5mg mg/unit % mg/unit % Valsartan and amlodipine layer A Valsartan DS 160.00 25.24 160.00 25.48 Amlodipine B besylate 13.87 2.19 6.94 1.10 C Avicel PH102 108.13 17.06 109.07 17.37 D Crospovidone XL 40.00 6.31 40.00 6.37 E Cab-o-sil 3.00 0.47 3.00 0.48 F Mg. Stearate (1) 6.00 0.95 6.00 0.96 G Mg. Stearate (1) 3.00 0.47 3.00 0.48 Sub-total 334.00 328.00 HCTZ layer H HCTZ 25.00 3.94 25.00 3.98 I Avicel PH 102 267.90 42.26 267.90 42.66 Sodium Starch J Glycolate 6.00 0.95 6.00 0.96 K Iron oxide yellow 0.20 0.03 0.20 0.03 L Mag. St. (III) 0.30 0.05 0.30 0.05 M Mag. St. (IV) 0.60 0.09 0.60 0.10 Sub-total 300.00 300.00 Total 634.00 100.00 628.00 100.00 -29 Table 11 Ingredient 160/12.5/5mg 160/12.5/10Omg 320/25/10mg mg/unit m%/unit % me/unit % Valsartan and amlodipine layer A Valsartan DS 160.00 33.06 160.00 25.48 320.00 33.47 Amlodipine B besylate 13.87 2.87 6.94 1.10 13.87 1.45 C Avicel PH102 108.13 22.34 109.07 17.37 I218.13 22.82 D Crospovidone XL 40.00 8.26 40.00 6.37 80.00 8.37 E Cab-o-siI 3.00 0.62 3.00 0.48 6.00 0.63 F Mg. Stearate (1) 6.00 1.24 6.00 0.96 12.00 1.26 G Mg. Stearate (1) 3.00 0.62 3.00 0.48 6.00 0.63 Sub-total 334.00 328.00 656.00 SHCTZ layer I__ ___ H HCTZ 12.50 2.58 12.50 1.99 25.00 2.62 1 Avicel PH 102 133.95 27.68 280.40 44.65 267.90 28.02 Sodium Starch J Glycolate 3.00 0.62 6.00 0.96 6.00 0.63 K Iron oxide yellow 0.10 0.02 0.20 0.03 0.20 0.02 L Mag. St. (111) 0.15 0.03 0.30 0.05 0.30 0.03 M Mag. St. (IV) 0.30 0.06 0.60 0.10 0.60 0.06 Sub-total 150.00 300.00 300.00 Total 484.00 100.00 628.00 100.00 956.00 100.00 100931 First, the valsartan is granulated by combining ingredients A-F in a diffusion blender. Then, the blended material is sieved through a screen. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient G in a diffusion blender. (This second blending step achieves the desired level of lubricant for the granulation and, in certain cases, combines sub-divided batches of ingredients A-F.) [00941 Second, the HCTZ is granulated by combining ingredients H-L in a diffusion blender. Then, the blended material is sieved through a screen. Next, the sieved material is blended again in a diffusion blender. The blended/sieved material is then compacted using a roller compactor. The compacted material is milled through a screen and then blended with ingredient M in a diffusion blender. (This second blending step achieves the desired level of lubricant for the granulation and, in certain cases, combines sub-divided batches of ingredients H-L.) [00951 Finally, the valsartan granulation and the amlodipine granulation are compressed into bilayer solid dosage forms using a bilayer rotary tablet press, and the bilayer solid dosage forms are optionally film coated.

-30 100961 While the invention has been described above with reference to specific embodiments thereof, it is apparent that many changes, modifications, and variations can be made without departing from the inventive concept disclosed herein. Accordingly, it is intended to embrace all such changes, modifications, and variations that fall within the spirit and broad scope of the appended claims. All patent applications, patents, and other publications cited herein are incorporated by reference in their entirety.

C:\NRPoIblDCC\RXS\3729375... DOC-30/06/20l1 -30 [00961 While the invention has been described above with reference to specific embodiments thereof, it is apparent that many changes, modifications, and variations can be made without departing from the inventive concept disclosed herein. Accordingly, it is intended to embrace all such changes, modifications, and variations that fall within the 5 spirit and broad scope of the appended claims. All patent applications, patents, and other publications cited herein are incorporated by reference in their entirety. [0097] The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an 10 acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates. [00981 Throughout this specification and the claims which follow, unless the context 15 requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. 20 25 30

Claims (28)

1. A solid dosage form comprising: valsartan; amlodipine; hydrochlorothiazide; and pharmaceutically acceptable additives suitable for the preparation of solid dosage forms of valsartan.

2. The solid dosage form of claim 1, wherein the amlodipine is provided in the form of amlodipine besylate.

3. The solid dosage form of claim 1, wherein the solid dosage form takes the form of a monolayer tablet.

4. The solid dosage form of claim 1, wherein the solid dosage form takes the form of a bilayer tablet.

5. The solid dosage form of claim 4, wherein the bilayer tablet has the valsartan and the hydrochlorothiazide in a first layer and the amlodipine in a second layer.

6. The solid dosage form of claim 4, wherein the bilayer tablet has the valsartan in a first layer and the amlodipine and the hydrochlorothiazide in a second layer.

7. The solid dosage form of claim 1, wherein the valsartan is employed in an amount ranging from about 80 mg to about 640 mg.

8. The solid dosage form of claim 7, wherein the valsartan is employed in an amount selected from 160 mg and 320 mg.

9. The solid dosage form of claim 1, wherein the amlodipine is employed in an amount ranging from about 2.5 mg to about 20 mg.

10. The solid dosage form of claim 9, wherein the amlodipine is employed in an amount selected from 5 mg and 10 mg. -32

11. The solid dosage form of claim 1, wherein the hydrochlorothiazide is employed in an amount ranging from about 6.25 mg to about 50 mg.

12. The solid dosage form of claim 11, wherein the hydrochlorothiazide is employed in an amount selected from 12.5 mg and 25 mg.

13. The solid dosage form of claim 1, wherein the pharmaceutically acceptable additives are selected from the group consisting of diluents, disintegrants, glidants, lubricants, binders, colorants and combinations thereof.

14. A method of making a solid dosage form comprising the steps of: (a) blending valsartan, amlodipine, hydrochlorothiazide and pharmaceutically acceptable additives to form a blended material; (b) sieving the blended material to form a sieved material; (c) blending the sieved material to form a blended/sieved material; (d) compacting the blended/sieved material to form a compacted material; (e) milling the compacted material to form a milled material; (f) blending the milled material to form blended/milled material; and (g) compressing the blended/milled material to form a monolayer solid dosage form.

15. The method of claim 14 further comprising the step of: (h) film coating the monolayer solid dosage form.

16. A method of making a solid dosage form comprising the steps of: (a) granulating valsartan, pharmaceutically acceptable additives and optionally hydrochlorothiazide to form a valsartan granulation; (b) blending amlodipine, pharmaceutically acceptable additives and optionally hydrochlorothiazide to form an amlodipine blend; and (c) compressing the valsartan granulation and the amlodipine blend together to form a bilayer solid dosage form, wherein hydrochlorothiazide is present in the valsartan granulation and/or the amlodipine blend.

17. The method of claim 16, wherein step (a) comprises the steps of: - 33 (al) blending valsartan, pharmaceutically acceptable additives and hydrochlorothiazide to form a blended material; (a2) sieving the blended material to form a sieved material; (a3) blending the sieved material to form a blended/sieved material; (a4) compacting the blended/sieved material to form a compacted material; (a5) milling the compacted material to form a milled material; and (a6) blending the milled material to form the valsartan granulation.

18. The method of claim 16, wherein step (a) comprises the steps of: (al) blending valsartan and pharmaceutically acceptable additives to form a blended material; (a2) sieving the blended material to form a sieved material; (a3) blending the sieved material to form a blended/sieved material; (a4) compacting the blended/sieved material to form a compacted material; (a5) milling the compacted material to form a milled material; and (a6) blending the milled material and hydrochlorothiazide to form the valsartan granulation.

19. The method of claim 16, wherein step (b) comprises a granulation process comprising the steps of: (bl) blending amlodipine, pharmaceutically acceptable additives and hydrochlorothiazide to form a blended material; (b2) sieving the blended material to form a sieved material; (b3) blending the sieved material to form a blended/sieved material; (b4) compacting the blended/sieved material to form a compacted material; (b5) milling the compacted material to form a milled material; and (b6) blending the milled material to form an amlodipine granulation.

20. The method of claim 16, wherein step (b) comprises a granulation process comprising the steps of: (bl) blending amlodipine and pharmaceutically acceptable additives to form a blended material; (b2) sieving the blended material to form a sieved material; -34 (b3) blending the sieved material to form a blended/sieved material; (b4) compacting the blended/sieved material to form a compacted material; (b5) milling the compacted material to form a milled material; and (b6) blending the milled material and hydrochlorothiazide to form an amlodipine granulation.

21. The method of claim 16 further comprising the step of: (d) film coating the bilayer solid dosage form.

22. A method of making a solid dosage form comprising the steps of: (a) granulating valsartan, pharmaceutically acceptable additives and amlodipine to form a valsartan granulation; (b) blending hydrochlorothiazide, pharmaceutically acceptable additives to form a hydrochlorothiazide blend; and (c) compressing the valsartan granulation and the hydrochlorothiazide blend together to form a bilayer solid dosage form.

23. The method of claim 22, wherein step (a) comprises the steps of: (al) blending valsartan, pharmaceutically acceptable additives and amlodipine to form a blended material; (a2) sieving the blended material to form a sieved material; (a3) blending the sieved material to form a blended/sieved material; (a4) compacting the blended/sieved material to form a compacted material; (a5) milling the compacted material to form a milled material; and (a6) blending the milled material to form the valsartan granulation.

24. The method of claim 22, wherein step (a) comprises the steps of: (al) blending valsartan and pharmaceutically acceptable additives to form a blended material; (a2) sieving the blended material to form a sieved material; (a3) blending the sieved material to form a blended/sieved material; (a4) compacting the blended/sieved material to form a compacted material; (a5) milling the compacted material to form a milled material; and - 35 (a6) blending the milled material and amlodipine to form the valsartan granulation.

25. The method of claim 22, wherein step (b) comprises a granulation process comprising the steps of: (bl) blending hydrochlorothiazide and pharmaceutically acceptable additives to form a blended material; (b2) sieving the blended material to form a sieved material; (b3) blending the sieved material to form a blended/sieved material; (b4) compacting the blended/sieved material to form a compacted material; (b5) milling the compacted material to form a milled material; and (b6) blending the milled material to form a hydrochlorothiazide granulation.

26. The method of claim 22 further comprising the step of: (d) film coating the bilayer solid dosage form.

27. A method of treating hypertension, congestive heart failure, angina, myocardial infarction, arteriosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, stroke, left ventricular hypertrophy, cognitive dysfunction, headache, or chronic heart failure, wherein the method comprises administering a solid dosage form as defined in claim 1 to a subject in need of such treatment.

28. The method of treating according to claim 27, wherein the solid dosage form is orally administered to the subject.