AU2013200050A1 - Solid dosage forms of valsartan and amlodipine and method of making the same - Google Patents

Abstract

C:\NRPortbl\DCC\RBR\4841390_l.DOC-1/4/2013 Monolayer and bilayer solid dosage forms of a combination of valsartan and amlodipine are made.

Description

C:\NRPortbl\DCC\RBR\4841390_l.DOC-1/4/2013 SOLID DOSAGE FORMS OF VALSARTAN AND AMLODIPINE AND METHOD OF MAKING THE SAME BACKGROUND OF THE INVENTION This application is a divisional application of Australian Application No. 2010227062 which is a divisional application of Australian Application No. 2006279670 the specification and drawings of which as originally filed are incorporated herein in their entirety by reference. Field of the Invention [0001] The present invention is directed to solid dosage formulations containing a combination of valsartan and amlodipine, as well as to methods of making such solid dosage forms and a method of treating a subject with such solid dosage forms. Related Background Art [0002] 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 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 drugs or active ingredients dosed simultaneously but as two 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. 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. [0003] 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%. As a result of these complex biopharmaceutical properties, development of a fixed combination dosage form WO 2007/022113 PCT/US2006/031699 of valsartan and amlodipine that is bioequivalent to a free-combination thereof is challenging. [0004] Accordingly, a fixed-combination solid dosage formulation of valsartan and amlodipine that is bioequivalent to the corresponding free-combination would be desirable. SUMMARY OF THE INVENTION [0005] In a first aspect, the present invention is directed to a solid dosage form comprising a combination of valsartan and amlodipine, and pharmaceutically acceptable additives suitable for the preparation of solid dosage forms of valsartan. 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, colorants and combinations thereof. [00061 In certain preferred embodiments of this invention, the solid dosage form is a monolayer tablet. The amount of valsartan employed in such monolayer tablets preferably ranges from about 40 mg to about 640 mg, and more preferably is 80 mg or 160 mg. The amount of amlodipine employed in such monolayer tablets preferably ranges from about 1.25 mg to about 20 mg, and more preferably is 2.5 mg, 5 mg or 10 mg. [00071 In other preferred embodiments of this invention, the solid dosage form is a bilayer tablet having the valsartan in one layer and the amlodipine in another layer. The amount of valsartan employed in such bilayer tablets preferably ranges from about 40 mg to about 640 mg, and more preferably is 320 mg. The amount of amlodipine employed in such bilayer tablets preferably ranges from about 1.25 mg to about 20 mg, and more preferably is 5 mg or 10 mg. [0008] In a second aspect, the present invention is directed to a method of making a solid dosage form of valsartan 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 to form blended/milled material; and (g) compressing the blended/milled material to WO 2007/022113 PCT/US2006/031699 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. [0009] In a third aspect, this invention is directed to solid dosage forms of valsartan made according to the method of the second aspect. [0010] In a fourth aspect, the present invention is directed to a method of making a solid dosage form of valsartan comprising the steps of (a) granulating valsartan and pharmaceutically acceptable additives to form a valsartan granulation; (b) blending amlodipine and pharmaceutically acceptable additives to form an amlodipine blend; and (c) compressing the valsartan granulation and the amlodipine blend together to form a bilayer solid dosage form. In a preferred embodiment of the invention, 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 to form the valsartan granulation. In another preferred embodiment, step (b) comprises a granulation process with the steps of (b1) blending amlodipine 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 an amlodipine granulation. Another preferred embodiment of this invention also includes an optional step, step (d) film coating the bilayer solid dosage form. [0011] In a fifth aspect, this invention is directed to solid dosage forms of valsartan made according to the method of the fourth aspect. [00121 Yet another aspect 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 and amlodipine to a subject in -4 WO 2007/022113 PCT/US2006/031699 need of such treatment. In a preferred embodiment, the solid dosage form is orally administered to the subject. DETAILED DESCRIPTION [0013] The present invention relates to solid dosage forms of valsartan which contain a combination of valsartan and amlodipine. [00141 The first embodiment of the invention is directed to a solid dosage form of valsartan comprising a combination of valsartan and amlodipine, and pharmaceutically acceptable additives suitable for the preparation of solid dosage forms of valsartan. The solid dosage forms of the present invention can take the form of monolayer tablets (having both the valsartan and the amlodipine in one layer) or bilayer tablets (having the valsartan in one layer and the amlodipine in another layer). [0015] Valsartan ((S)-N-valeryl-N-{[2'-(lH-tetrazole-5-yl)-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 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. [0016] Valsartan is employed in an amount typically ranging from about 40 mg to about 640 mg, preferably from about 40 mg to about 320 mg, more preferably from about 80 mg to about 320 mg, and most preferably is about 80 mg or about 160 mg in a monolayer tablet and about 320 mg in a bilayer tablet. The amount of valsartan noted above refers to the amount of free valsartan present in a given solid dosage form. [00171 While both monolayer and bilayer tablets can be formed with any amount of valsartan within the above-noted range, it is important to consider the overall objective of bioequivalence to the free-combination of valsartan and amlodipine. Accordingly, monolayer tablets preferably contain a dose of up to 160 mg of valsartan; higher doses therein do not yield complete bioequivalence when compared with a corresponding free-combination. Hence, valsartan doses higher than 160 mg are better suited for bilayer solid dosage forms of the present invention. In fact, bilayer tablets can accommodate the full range of valsartan WO 2007/022113 - - PCT/US2006/031699 dosage above. It should be noted, however, that changes in the composition, i.e., a change in the type of disintegrant, may modify the dissolution properties of valsartan and achieve bioequivalence even at higher doses in monolayer tablets. [0018] Amlodipine (3-ethyl-5-methyl-2(2-aminoethoxymethyl)-4-(2 chlrorophenyl)- 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. [00191 Amlodipine is employed in an amount ranging from 1.25 mg to about 20 mg, preferably from about 1.875 mg to about 15 mg, more preferably from about 2.5 mg to about 10 mg, and most preferably is about 2.5 mg or about 5 mg in a monolayer tablet and about 5 mg or about 10 mg in a bilayer tablet. The amount of amlodipine noted above refers to the amount of free amlodipine present in a given solid dosage form. [0020] Pharmaceutically acceptable additives suitable for use in the present invention include, without limitation, diluents or fillers, disintegrants, glidants, lubricants, binders, colorants and combinations thereof. Preferred pharmaceutically acceptable additives include diluents and disintegrants. The amount of each additive in a solid dosage formulation may vary within ranges conventional in the art. [0021] Suitable diluents include, without limitation, microcrystalline cellulose (e.g., cellulose MK GR), mannitol, sucrose or other sugars or sugar derivatives, low-substituted hydroxypropyl cellulose, and combinations thereof. When present, a diluent may be employed in an amount ranging from about 15% to about 70%, preferably from about 32% to about 55% 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 15% to about 50%, more preferably in an amount of about 33% by weight of the solid dosage form. For bilayer tablets, a diluent is preferably employed in an amount ranging from about 40% to about 70%, more preferably in an amount of about 55% by weight of the solid dosage form.

WO 2007/022113 PCT/US2006/031699 [00221 Suitable disintegrants include, without limitation, crospovidone, sodium starch glycolate, L-hydroxy propyl cellulose, and combinations thereof When present, a disintegrant may be employed in an amount ranging from about 2% to about 40%, preferably from about 7% to about 13% 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 2% to about 40%, more preferably in an amount of about 13% by weight of the solid dosage form. For bilayer tablets, a disintegrant is preferably employed in an amount ranging from about 2% to about 40%, more preferably in an amount of about 7% by weight of the solid dosage form. [0023] 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 1% 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 1% 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 0.7% by weight of the solid dosage form. [0024] Suitable lubricants include, without limitation, magnesium 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 5%, preferably from about 2% to about 3% by weight of the solid dosage form (prior to any optional film coating). For monolayer tablets, a lubricant is preferably employed in an amount ranging from about 0.1% to about 5%, more preferably in an amount of about 3% 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 5%, more preferably in an amount of about 2% by weight of the solid dosage form. [0025] Suitable binders include, without limitation, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, pregelatinized starch and combinations thereof. When present, a binder may be employed in an amount ranging from about 2% to about 40%, preferably from about 7% to about WO 2007/022113 PCT/US2006/031699 13% 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 2% to about 40%, more preferably in an amount of about 13% by weight of the solid dosage form. For bilayer tablets, a binder is preferably employed in an amount ranging from about 2% to about 40%, more preferably in an amount of about 7% by weight of the solid dosage form. [0026] Suitable colorants include, without limitation, iron oxides such as yellow, white, red, and black iron oxide, 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. [0027] 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 30 N to about 180 N for monolayer forms and an average hardness ranging from about 250 N to about 300 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. Typically, a film coating material is applied in such an amount as to provide a film coating that ranges from about 1% to about 6% by weight of the film-coated tablet. [00281 The second embodiment of the present invention is directed to a method of making a solid dosage form of valsartan 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 to form blended/milled material; and (g) compressing the blended/milled material to form a monolayer solid dosage form. The details regarding the valsartan, WO 2007/022113 8 PCT/US2006/031699 amlodipine, and pharmaceutically acceptable additives, i.e., source, amount, etc., are as set forth above with regard to the first embodiment of the invention. [0029] In the first step of the method of the second embodiment, valsartan, amlodipine 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. [00301 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 20 kN to about 60 kN, preferably about 30 kN to about 40KN. Compaction may also be carried out by slugging the blended powders into large tablets that are then size-reduced. [00311 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 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 2 kN to about 30 kN. 100321 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. [00331 A third embodiment of the present invention is directed to a monolayer solid dosage form of valsartan made according to the method of the second embodiment.

WO 2007/022113 PCT/US2006/031699 [0034] The fourth embodiment of the present invention is directed to a method of making a solid dosage form of valsartan comprising the steps of (a) granulating valsartan and pharmaceutically acceptable additives to form a valsartan granulation; (b) blending amlodipine and pharmaceutically acceptable additives to form an amlodipine blend; and (c) compressing the valsartan granulation and the amlodipine blend together to form a bilayer solid dosage form. The details regarding the valsartan, amlodipine, and pharmaceutically acceptable additives, i.e., source, amount, etc., are as set forth above with regard to the first embodiment of the invention. [0035] In the first step of the method of the fourth embodiment, valsartan is granulated with pharmaceutically acceptable additives to form a valsartan granulation. Valsartan granulation can be accomplished by any suitable means. In a preferred embodiment of this invention, valsartan granulation is accomplished by (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 to form the valsartan granulation. [0036] The blending of step (al) can be accomplished using any suitable means. Typically the valsartan and pharmaceutically acceptable additives 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 20 kN to about 60 kN, preferably about 35 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.

WO 2007/022113 -10- PCT/US2006/031699 [00371 In the second step of the method of the fourth embodiment, amlodipine is blended with pharmaceutically acceptable additives to form an amlodipine blend. Amlodipine blending 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 wet granulation or dry granulation. In a more preferred embodiment of this invention, amlodipine granulation is accomplished by (bl) blending amlodipine 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 an amlodipine granulation. [0038] 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 20 kN to about 50 kN, preferably about 30 kN to about 40 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. 100391 In the final step of the method of the fourth 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 35 kN. [00401 Optionally, the method of the fourth 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.

WO 2007/022113 11 PCT/US2006/031699 [00411 A fifth embodiment of the present invention is directed to a bilayer solid dosage form of valsartan made according to the method of the fourth embodiment. [0042] 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 as defined by the first, third or fifth embodiments of this invention to a subject in need of such treatment. In a preferred embodiment, the solid dosage form is orally administered to the subject. [0043] 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. EXAMPLE 1 80/2.5 MG TABLET [00441 A monolayer solid dosage form of valsartan was made using the ingredients set forth in Table 1 below. Table 1. Ingredient (mg) % A valsartan 80.00 48.78 B amlodipine besylate 3.47* 2.11** C microcrystalline 54.53 33.25 cellulose D crospovidone 20.00 12.20 E colloidal silicon 1.50 0.91 dioxide F magnesium stearate 3.00 1.83 (I) G magnesium stearate 1.50 0.91 ____ (II) ___________ ___________ total 164.00 * - corresponds to 2.5 mg amlodipine free base ** - corresponds to 1.52% amlodipine free base [00451 Ingredients A-F are placed into a diffusion blender and blended. Then, the blended material is sieved. Next, the sieved material is blended again in a WO 2007/022113 - 12 - PCT/US2006/031699 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.) 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 80/5 MG TABLET [00461 A monolayer solid dosage form of valsartan was made using the ingredients set forth in Table 2 below. Table 2. Ingredient (mg) % A valsartan 80.00 47.90 B amlodipine besylate 6.94* 4.15** C microcrystalline cellulose 54.06 32.37 D crospovidone 20.00 11.98 E colloidal silicon dioxide 1.50 0.90 F magnesium stearate (I) 3.00 1.80 G magnesium stearate (II) 1.50 0.90 total 167.00 * - corresponds to 5 mg amlodipine free base ** - corresponds to 2.99% amlodipine free base [00471 Ingredients A-F 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 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.) 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.

WO 2007/022113 - 13 - PCT/US2006/031699 EXAMPLE 3 160/5 MG TABLET [00481 A monolayer solid dosage form of valsartan was made using the ingredients set forth in Table 3 below. Table 3. Ingredient (mg) % A valsartan 160.00 48.78 B amlodipine besylate 6.94* 2.11** C microcrystalline 109.06 33.25 cellulose D crospovidone 40.00 12.20 E colloidal silicon 3.00 0.91 dioxide F magnesium stearate (I) 6.00 1.83 G magnesium stearate (II) 3.00 0.91 total 328.00 * - corresponds to 5 mg amlodipine free base ** - corresponds to 1.52% amlodipine free base [00491 Ingredients A-F 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 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.) 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 4 160/10 MG TABLET [0050] A monolayer solid dosage form of valsartan was made using the ingredients set forth in Table 4 below. Table 4. ingredient (mg) % A valsartan 160.00 47.90 B amlodipine besylate 13.87* 4.15** C microcrystalline 108.13 32.37 cellulose I D crospovidone 40.00 11.98 WO 2007/022113 -14- PCT/US2006/031699 E colloidal silicon 3.00 0.90 dioxide F magnesium stearate (1) 6.00 1.80 G magnesium stearate (II) 3.00 0.90 total 334.00 * - corresponds to 10 mg amlodipine free base ** - corresponds to 2.99% amlodipine free base [0051] Ingredients A-F are placed into a diffusion blender and blended. 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.) 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 5 320/5 MG TABLET [0052] A monolayer solid dosage form of valsartan was made using the ingredients set forth in Table 5 below. Table 5. ingredient (mg) % A valsartan 320.00 49.46 B amlodipine besylate 6.94* 1.07 C microcrystalline 216.07 cellulose 33.40 D crospovidone 80.00 12.36 E colloidal silicon 6.00 dioxide 0.93 F magnesium stearate (I) 12.00 1.85 G magnesium stearate (II) 6.00 0.93 total 647.00 * - corresponds to 5 mg amlodipine free base [00531 Ingredients A-F are placed into a diffusion blender and blended. Then, the blended material is sieved through 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 WO 2007/022113 - 15 - PCT/US2006/031699 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.) 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 6 320/5 MG TABLET [00541 A bilayer solid dosage form of valsartan was made using the ingredients set forth in Table 6 below. Table 6. Ingredient (mg) % valsartan layer A valsartan 320.00 34.78 B microcrystalline 216.00 23.48 cellulose C crospovidone 60.00 6.52 D colloidal silicon dioxide 6.00 0.65 E magnesium stearate (I) 12.00 1.30 F magnesium stearate (II) 6.00 0.65 subtotal 620.00 amlodipine layer G amlodipine besylate 6.94* 0.75 H microcrystalline 285.96 31.08 cellulose I sodium starch glycolate 6.00 0.65 J colorant 0.20 0.02 K magnesium stearate (III) 0.30 0.03 L magnesium stearate (IV) 0.60 0.07 subtotal 300.00 total 920.00 * - corresponds to 5 mg amlodipine free base [0055] First, the valsartan is granulated by combining ingredients A-E in a diffusion blender. Then, the blended material is sieved through a screen. Next, WO 2007/022113 -16- PCT/US2006/031699 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.) [0056] Second, the amlodipine besylate is granulated by combining ingredients G-K 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 L 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-K.) [0057] 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 7 320/10 MG TABLET [00581 A bilayer solid dosage form of valsartan was made using the ingredients set forth in Table 7 below. Table 7. Ingredient (mg) % valsartan layer A valsartan 320.00 34.78 B microcrystalline 216.00 23.48 cellulose C crospovidone 60.00 6.52 D colloidal silicon dioxide 6.00 0.65 E magnesium stearate (I) 12.00 1.30 F magnesium stearate (II) 6.00 0.65 Subtotal 620.00 amlodipine layer WO 2007/022113 -17- PCT/US2006/031699 G amlodipine besylate 13.87* 1.51 H microcrystalline 279.03 30.33 cellulose I sodium starch glycolate 6.00 0.65 J Colorant 0.20 0.02 K magnesium stearate (III) 0.30 0.03 L magnesium stearate (IV) 0.60 0.07 Subtotal 300.00 Total 920.00 * - corresponds to 10 mg amlodipine free base [0059] 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.) [00601 Second, the amlodipine besylate is granulated by combining ingredients G-K 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 with ingredient L 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-K.) [00611 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. BIOEQUIVALENCE TESTING [00621 The bioavailability of the fixed-combination dosage forms of the present invention was compared with that of the corresponding free-combinations. The term "bioavailability", as used herein, is defined as a measure of the rate and WO 2007/022113 -18- PCT/US2006/031699 amount of drug which reaches the systemic circulation unchanged following the administration of the dosage form. The test (fixed-combination) and the reference (free-combination) dosage forms were administered orally to the subjects, and plasma samples were collected over a 48-hour time period. The plasma samples were analyzed for concentration of valsartan and amlodipine. Statistical comparison was performed on the maximum plasma concentration (Cmax) achieved with the test and reference and on the area under the plasma concentration vs. time curve (AUC). For the test and reference product to be bioequivalent, 90% confidence intervals for AUC and Cmax ratios should fall within 0.8-1.25. [0063] Obtaining bioequivalence between test and reference products is challenging, particularly for combinations of drugs, and the result cannot be predicted apriori. The challenge of bioequivalence is more pronounced if one or more drugs has solubility limitations and variable absorption (e.g., valsartan). Comparison of dissolution (release of the drugs from the dosage forms into a solvent medium such as an aqueous buffer) is often used to guide dosage development to obtain bioequivalence. However, drug dissolution (in vitro dissolution) may not fully correlate with in vivo (in animal or human body) drug absorption. This invention is directed to solid dosage formulations containing valsartan and amlodipine in a fixed-combination form that is bioequivalent to the free-combination. [00641 A fixed-combination solid dosage form (monolayer tablet) of valsartan and amlodipine besylate (160/10 mg) made in accordance with Example 4 was compared with a free-combination of 160 mg valsartan and 10mg amlodipine besylate tablets in an open-label, randomized, single dose, three period, crossover study in twenty-seven healthy human volunteers. It was found that the in vitro dissolution of valsartan from the fixed-combination monolayer tablets, when tested using a USP II apparatus in a test medium such as pH 4.5 phosphate solution or pH 6.8 phosphate solution, was similar to the dissolution of valsartan in the free-combination. The difference between the percent of valsartan dissolved from the fixed- and free-combination dosage formulations was no more than 10% at 10, 20, or 30 minutes, by which time the dissolution was nearly complete. However, the dissolution of amlodipine from the fixed-combination tablet was different from that of amlodipine in the free-combination in both pH WO 2007/022113 -19- PCT/US2006/031699 4.5 and 6.8 media. In pH 6.8 phosphate solution, amlodipine in the fixed combination dosage form dissolved faster by about 30% fraction dissolved at 30 minutes, for example. In pH 4.5 phosphate solution, the dissolution of amlodipine from the fixed-combination was slower than the dissolution of amlodipine as a free-combination by about 35% fraction dissolved at 30 minutes, for example. Surprisingly, however, when the bioavailability of the fixed combination tablets of valsartan and amlodipine besylate were compared with the free-combination, the 90% confidence interval for AUC and Cmax ratios were within the interval of 0.80-1.25 for amlodipine. This result indicated that amlodipine in the fixed-combination dosage form was bioequivalent to that in the free-combination. For valsartan, the 90% confidence interval for AUC fell within 0.80-1.25. The 90% confidence interval for Cmax was 0.77-1.21, only slightly outside of 0.80 on the lower limit. The ratio of the means of Cmax from the fixed- and free-combinations was very close (0.97). This result indicated that valsartan from the fixed-combination was nearly bioequivalent to that in the free combination, and, by increasing the number of subjects, the statistical 90% interval range of 0.8-1.25 may be achieved for Cmax also. [00651 In addition, a fixed-combination solid dosage form (monolayer tablet) of valsartan and amlodipine besylate (320/5 mg) made in accordance with Example 5 was compared with a free-combination of 320 mg valsartan and 5 mg amlodipine besylate tablets in an open-label, randomized, single dose, three period, crossover study in healthy human volunteers. It was found that the in vitro dissolution of valsartan from the fixed-combination monolayer tablets, when tested using a USP II apparatus in a test medium such as pH 4.5 phosphate solution or pH 6.8 phosphate solution, was similar to the dissolution of valsartan in the free-combination. The difference between the percent of valsartan dissolved from the fixed- and free-combination dosage formulations was no more than 10% at 10, 20, or 30 minutes, by which time the dissolution was nearly complete. However, the dissolution of amlodipine from the fixed-combination tablet was different from that of amlodipine in the free-combination in both pH 4.5 and 6.8 media. In pH 6.8 phosphate solution, amlodipine in the fixed combination dosage form dissolved faster by about 15% fraction dissolved at 30 minutes, for example. In pH 4.5 phosphate solution, the dissolution of amlodipine from the fixed -combination was slower than the dissolution of C:\NRPortbl\DCC\RBR\4841390_l.DOC-1/4/2013 - 20 amlodipine as a free-combination by about 45% fraction dissolved at 30 minutes, for example. Very surprisingly, when the bioavailability of the fixed-combination tablets of valsartan and amlodipine besylate were compared with the free-combination, the 90% confidence interval for AUC and Cmax geometric mean ratios were within the interval of 0.80-1.25 for amlodipine. This result indicated that amlodipine in the fixed-combination dosage form was bioequivalent to that in the free-combination. For valsartan, the 90% confidence interval for AUC was 0.77 - 0.99. The 90% confidence interval for Cmax was 0.63-0.98. This result indicated that valsartan from the fixed-combination was not bioequivalent to that in the free-combination. However, this result led to another aspect of the inspection, namely the development of a bilayer fixed-combination dosage formulation of valsartan as shown in Examples 6 and 7. [0066] 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. [0067] Throughout this specification and the claims which follow, unless the context 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. [0068] 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 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.

Claims (27)

1. A solid dosage form of valsartan and amlodipine besylate comprising: valsartan; amlodipine besylate; and pharmaceutically acceptable additives suitable for the preparation of solid dosage forms of valsartan, wherein the valsartan and amlodipine besylate are provided in the dosage of valsartan/amlodipine besylate is 80/2.5 mg tablet, 80/5 mg tablet, 160/5 mg tablet, 160/10 mg tablet, 320/5 mg tablet, 320/10 mg tablet.

2. The solid dosage form of claim 1, wherein the dosage of valsartan/amlodipine besylate is 80/2.5 mg tablet.

3. The solid dosage form of claim 2 in the form of a monolayer tablet.

4. The solid dosage form of claim 1, wherein the dosage of valsartan/amlodipine besylate is 80/5 mg tablet.

5. The solid doage form of claim 4 in the form of a monolayer tablet.

6. The solid dosage form of claim 1, wherein the dosage of valsartan/amlodipine besylate is 160/5 mg tablet.

7. The solid dosage form of claim 6 in the form of a monolayer tablet.

8. The solid dosage form of claim 1, wherein the dosage of valsartan/amlodipine besylate is 160/10 mg tablet.

9. The solid doage form of claim 8 in the form of a monolayer tablet.

10. The solid dosage form of claim 1, wherein the dosage of valsartan/amlodipine besylate is 320/5 mg tablet. C:\NRPortbl\DCC\RBR\4841390_l.DOC-1/4/2013 - 22

11. The solid dosage form of claim 10 in the form of a monolayer tablet.

12. The solid dosage form of claim 10 in the form of a bilayer tablet.

13. The solid dosage form of claim 1, wherein the dosage of valsartan/amlodipine besylate is 320/10 mg tablet.

14. The solid dosage form of claim 13 in the form of a bilayer tablet.

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

16. A method of making a solid dosage form of valsartan and amlodipine besylate in claim 1 comprising the steps of: (a) blending valsartan, amlodipine besylate 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.

17. The method of claim 16 further comprising the step of: (h) film coating the monolayer solid dosage form with a polymeric film coating.

18. A method of making a solid dosage form of valsartan and amlodipine besylate in claim 1 comprising the steps of: (a) granulating valsartan and pharmaceutically acceptable additives to form a valsartan granulation; C:\NRPortbl\DCC\RBR\4841390_l.DOC-1/4/2013 - 23 (b) blending amlodipine and pharmaceutically acceptable additives to form an amlodipine blend; and (c) compressing the valsartan granulation and the amlodipine blend together to form a bilayer solid dosage form.

19. The method of claim 18, 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 to form the valsartan 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; (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.

21. A solid dosage form comprising: a) active ingredients which are (i) valsartan and (ii) amlodipine besylate; b) pharmaceutically acceptable additives comprising one or more (iii) diluents and (iv) disintegrants, c) the valsartan and amlodipine besylate are provided in the dosage selected from the group consisting of 80/2.5 mg tablet, 80/5 mg tablet, 160/5 mg tablet, 160/10 mg tablet, 320/5 mg tablet or 320/10 mg tablet, based on valsartan/amlodipine free base; d) the 80/2.5 mg tablet, 80/5 mg tablet, 160/5 mg tablet, and 160/10 mg tablet C:\NRPortbl\DCC\RBR\4841390_l.DOC-1/4/2013 - 24 are in the form of a monolayer tablet; the 320/10 mg tablet is in the form of a bilayer tablet; and the 320/5 mg tablet is in the form of a monolayer tablet or a bilayer tablet; e) the active ingredients and excipients of item b) are present in the following percentages in the tablet based on the solid dosage form in the monolayer tablet not including a film coating: i) about 15 to about 33% by weight diluent; and f) optionally, a film coating on said monolayer tablet or bilayer tablet; g) wherein the solid dosage form is bioequivalent to the corresponding free combinations of the foregoing active ingredients when the solid dosage form and free-combinations are orally administered.

22. The solid dosage form of claim 21, wherein the dosage of valsartan/amlodipine besylate is 80/2.5 mg in the form of a monolayer tablet.

23. The solid dosage form of claim 21, wherein the dosage of valsartan/amlodipine besylate is 80/5 mg in the form of a monolayer tablet.

24. The solid dosage form of claim 21, wherein the dosage of valsartan/amlodipine besylate is 160/5 mg in the form of a monolayer tablet.

25. The solid dosage form of claim 21 wherein the dosage of valsartan/amlodipine besylate is 160/10 mg in the form of a monolayer tablet.

26. The solid dosage form of claim 21, wherein the dosage of valsartan/amlodipine besylate is 320/5 mg in the form of a bilayer tablet.

27. The solid dosage form of claim 21, wherein the dosage of valsartan/amlodipine besylate is 320/10 mg tablet in the form of a bilayer tablet.