DESC:The following specification describes the invention and the manner in which it is to be performed:
PHARMACEUTICAL COMPOSITIONS COMPRISING VALSARTAN AND ATORVASTATIN

FIELD OF THE APPLICATION
[001] The present application relates to a composition comprising of valsartan, atorvastatin and one or more pharmaceutically acceptable excipients, meant for treating patients suffering from angina pectoris, atherosclerosis, combined with hypertension and hyperlipidemia, or patients presenting with symptoms or signs of cardiac risk.

BACKGROUND
[002] Hypertension is one of the most prevalent risk factors to develop cardiovascular diseases. If left untreated, hypertension can lead to stroke and heart failure, as well as to multiple organ damage such as kidneys, blood vessels, eyes or brain, and is associated with much morbidity and mortality worldwide. Hypertension is an important risk factor for coronary heart disease, stroke, congestive heart failure, end-stage renal disease, and peripheral vascular disease. Even a healthy individual with normal blood pressure at age 55 has a 90 percent risk of eventually developing hypertension. Various therapeutic anti-hypertensive agents include, but not limited to, ACE inhibitors, calcium-channel antagonists, ß-adrenergic receptor antagonists, angiotensin II receptor antagonists, a-adrenergic receptor antagonists, vasodilators, and diuretic agents.
[003] Angiotensin-converting enzyme (ACE) inhibitors produce vasodilation by inhibiting the formation of angiotensin II. This vasoconstrictor is formed by the proteolytic action of renin (released by the kidneys) acting on circulating angiotensinogen to form angiotensin I. Angiotensin I is then converted to angiotensin II by angiotensin converting enzyme. ACE inhibitors also break down bradykinin (a vasodilator substance). Therefore, ACE inhibitors, by blocking the breakdown of bradykinin, increase bradykinin levels, which can contribute to the vasodilator action of ACE inhibitors. ACE inhibitors are used primarily to treat hypertension, they may also be prescribed for cardiac failure, diabetic nephropathy, renal disease, systemic sclerosis, left ventricular hypertrophy and other related disorders. ACE inhibitors are often used in conjunction with a diuretic in treating hypertension and heart failure.
[004] Angiotensin II receptor antagonists or Angiotensin II antagonists, also known as angiotensin receptor blockers (ARBs), AT1-receptor antagonists or sartans, are a group of pharmaceuticals which modulate the renin-angiotensin-aldosterone system. Their main use is in hypertension (high blood pressure), diabetic nephropathy (kidney damage due to diabetes), congestive heart failure, proteinuria, and prevention of cardiac remodeling after myocardial infarction. ARBs are receptor antagonists that block type 1 angiotensin II (AT1) receptors on bloods vessels and also in other tissues as arterial wall and heart muscle. ARBs act on the surface and inside arterial wall.
[005] Valsartan of formula (I) is chemically described as N-(1-oxopentyl)-N-[[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-L-valine or (2S)-3-methyl-2-[pentanoyl-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]amino]butanoic acid. Because of its ability to inhibit the Angiotensin II receptor, it is widely used for the treatment of hypertension and related diseases and conditions. As an angiotensin II receptor antagonist, valsartan avoids the side-effects of calcium antagonists and shows high stability and obvious curative effects. U.S. patent No: 5,399,578 describes the preparation of valsartan and its pharmaceutically acceptable salt.

[006] U.S. patent no: 6,294,197 describes solid dosage forms comprising a) valsartan and optionally HCTZ, and b) pharmaceutically acceptable additives, produced by a dry granulation method in the absence of water.
[007] PCT publication no: WO 00/38676 describes solid oral dosage forms comprising valsartan.
[008] Atherosclerosis is a condition characterized by irregularly distributed lipid deposits in the intima of arteries, including coronary, carotid and peripheral arteries. Atherosclerotic coronary heart disease (hereinafter termed "CHD") accounts for 53% of all deaths attributable to a cardiovascular event CHD. Hyperlipidemia is a condition of elevated blood lipids/fats including cholesterol, cholesterol esters, phospholipids, triglycerides or lipoproteins in the bloodstream. Elevated low density lipoprotein-cholesterol (LDL-C) and reduced high density lipoprotein-cholesterol (HDL-C) levels are well recognized as risk factors for coronary heart disease (CHD). High levels of blood cholesterol and blood lipids are conditions involved in the onset of atherosclerosis. Inhibitors of 3-hydroxy-3-methylglutaryl- coenzyme A reductase (HMG-CoA reductase) are effective in lowering the level of blood plasma cholesterol, especially low density lipoprotein cholesterol (LDL-C).
[009] HMG-CoA reductase inhibitors also known as statins are a class of drug used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase that is the rate-controlling enzyme (EC 1.1.1.88) of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids. HMG-CoA reductase enzyme plays a central role in the production of cholesterol in the liver. Statins are among the most commonly prescribed drugs in medicine. Clinical studies have shown that statins significantly reduce the risk of heart attack and death in patients with proven coronary artery disease (CAD), and can also reduce cardiac events in patients with high cholesterol levels who are at increased risk for heart disease.
[010] Atorvastatin calcium is a selective, competitive inhibitor of HMG-CoA. As such, atorvastatin calcium is a potent lipid lowering compound,

and is disclosed in U.S. Patent No. 4,681,893, and 5,273,995 which is incorporated herein by reference. It is currently sold as Lipitor® in USA.
[011] U.S. patent no. 6,126,971 covers a pharmaceutical composition comprising a mixture of atorvastatin and calcium carbonate, wherein the presence of calcium carbonate improves the stability of the composition prepared by wet granulation process.
[012] Hypertension frequently coexists with hyperlipidemia and both are considered to be major risk factors for developing cardiac disease ultimately resulting in adverse cardiac events. This clustering of risk factors is potentially due to a common mechanism. Further, patient compliance with the management of hypertension is generally better than patient compliance with hyperlipidemia. It would therefore be advantageous for patients to have a single therapy which treats both of these conditions.
[013] It is desirable to combine multiple active ingredients in a single pharmaceutical composition. Inclusion of multiple ingredients in a single composition generally reduces costs and provides the convenience of consuming a single medication rather than multiple medications for treating individual symptoms. The inherent advantage of a single product combination therapy resides in its improving compliance because fewer pills are required. The therapeutic treatment becomes simplified and there is more potential for improved outcomes.
[014] PCT publication no: WO 99/011260 discloses additive and synergistic combination compositions of atorvastatin and antihypertensive agents, whereby the combinations are useful in treating subjects suffering from angina pectoris, atherosclerosis, combined hypertension and hyperlipidemia.
[015] PCT publication no: WO 03/013609 discloses a sustained release medicine comprising combination of an angiotensin II antagonist with one or more drugs selected from among remedies for hypertension, hypoglycemic drugs, remedies for hyperlipemia, antithrombotic drugs, remedies for menopause and anticancer drugs, with reduced dose and side effects.
[016] Administration of an HMG-CoA reductase inhibitor in formulation with an angiotensin-II-receptor blocker or angiotensin II antagonists is beneficial for the treatment of cardiovascular diseases and renal diseases.
[017] However, a combination comprising two or more active agents certainly involves practical difficulties and challenges due to the physiochemical nature of the active agents. There are various types of combination products dosage forms conceivable but it cannot be predicted which of these dosage forms best combines product stability, pharmacological efficacy, and a reliable manufacturing method. Certain physical/chemical properties of the active agents impart a great challenge in developing formulations involving a combination of two or more actives. The use of certain excipients in a composition may be essential for imparting a desirable property such as stability, desired release or pharmacokinetic profiles, but the same excipients can have a negative impact on these properties when used in inappropriate amounts or ratios. Hence the selection of suitable excipients in appropriate ratios is crucial for attaining any required property in a combination product.
[018] It is therefore necessary to develop a stable formulation by a suitable formulation approach to overcome the incompatibility and stability problems arising from the combination of these two active agents, and also to provide desired release, pharmacokinetics and efficacy comparable or better to the individual commercial products.
[019] There is no approved combination drug product currently available for valsartan and atorvastatin in any market. Thus, a need exists for oral composition comprising combination of valsartan and atorvastatin in a single formulation, which could overcome the stability problems of the combined product and bioequivalent to commercially available standalone products.
[020] Accordingly the present application relates to a composition comprising combination of valsartan and atorvastatin, for treating patients suffering from angina pectoris, atherosclerosis, combined hypertension and hyperlipidemia and those patients presenting with symptoms or signs of cardiac risk.

DETAILED DESCRIPTION OF THE EMBODIMENTS
[021] The details of one or more embodiments of the present application are set forth in this document. Modifications to embodiments described in this document, and other embodiments, will be evident to those of ordinary skill in the art after a study of the information provided in this document. The information provided in this document, and particularly the specific details of the described exemplary embodiments, is provided primarily for clearness of understanding and no unnecessary limitations are to be understood therefrom. In case of conflict, the specification of this document, including definitions, will control.
[022] Definitions: The terms as used herein have the following meanings:
[023] The term "comprising" (and its grammatical variations) as used herein is meant to be open ended and used in the inclusive sense of "having" or "including" and not in the exclusive sense of "consisting only of." The term "consists essentially of," as used herein means the claimed elements and others, but is meant to exclude things that are inconsistent with the basic and novel characteristics of the inventions.
[024] The terms "a" and "the" as used herein are understood to encompass the plural as well as the singular or otherwise clearly mentioned wherever needed. For example, reference to “an excipient” includes reference to one or more of such excipients, and reference to "the carrier" includes reference to one or more of such carriers.
[025] The terms such as “about,” “up to,” “generally,” and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skilled in the art. This includes, at very least, the degree of expected experimental error, technical error and instrumental error for a given experiment, technique or an instrument used to measure a value. The term “about” is used to provide flexibility to a numerical range endpoint by providing that a given value may be “a little above” or “a little below” the endpoint. As used herein, the term "about" means a slight variation of the value specified, within 10 percent of the value specified. Nevertheless, the term "about" can mean a higher tolerance of variation depending on for instance the experimental technique used. Said variations of a specified value are understood by the skilled person and are within the context of the present invention. As an illustration, a numerical range of "about 1 to about 5" should be interpreted to include not only the explicitly recited values of about 1 to about 5, but also include individual values and sub-ranges within the indicated range. Thus, included in this numerical range are individual values such as 2, 3, and 4 and sub-ranges such as from 1-3, from 2-4, and from 3-5, etc., as well as 1, 2, 3, 4, and 5, individually. This same principle applies to ranges reciting only one numerical value as a minimum or a maximum.
[026] As used herein, the term “at least” refers to presence of recited substance in the composition in recited least amount.
[027] As used herein, the terms "pharmaceutical composition", “composition” and “formulation” are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules. Also the terms “composition” and “formulation” may be used to refer to a mixture of one or more active agents with excipients or other carriers, and include solid pharmaceutical products such as tablets, capsules, sachets, pills, or granules, containing a mixture of two or more compounds, elements or molecules. Furthermore, the term “dosage form” can include one or more composition(s) or formulation(s) provided in a format for administration to a subject like, tablets, capsules, caplets, pills, powders, granules, sachets and the like.
[028] The terms "drug", “active”, “active agent”, and "pharmaceutical" are used interchangeably to refer to a pharmacologically active substance or composition. These terms of art are well-known in the pharmaceutical and medicinal arts.
[029] The term “valsartan” as used herein refers to valsartan, pharmaceutically acceptable salts, base addition salts, all polymorphic forms (amorphous or crystalline), hydrates, anhydrous forms, enantiomers, prodrugs of valsartan and/or mixtures thereof.
[030] The term “atorvastatin” as used herein refers to atorvastatin, pharmaceutically acceptable salts, base addition salts, all polymorphic forms (amorphous or crystalline), hydrates, anhydrous forms, enantiomers, prodrugs of atorvastatin and/or mixtures thereof.
[031] The term "pharmaceutically acceptable salt” includes derivatives of the disclosed compounds which are, within the scope of sound medical judgment, suitable for use in humans and lower animals without undue toxicity, irritation, allergic response and the like, which are well known in the art. The salt can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by the reaction of the pharmaceutically active substance, with a suitable organic base or inorganic base or amino acids. Further refers to pharmaceutically acceptable solvates, including hydrates, of such compounds and such salt.
[032] The term “therapeutically effective amount” or “effective amount” of a drug as used herein, refers to a non-toxic, but sufficient amount of the drug, to achieve therapeutic results in treating a condition for which the drug is known to be effective. In the present application, an effective is an amount of atorvastatin or a pharmaceutically acceptable salt that is approximately from about 10 mg to about 30 mg, or an amount of valsartan or a pharmaceutically acceptable salt that is approximately from about 80 mg to about 160 mg, which is sufficient to treat the patients with hypertension and/or hyperlipidemia or the associated conditions, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. The effective amount of said atorvastatin or a pharmaceutically acceptable salt, or said valsartan or a pharmaceutically acceptable salt, will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, and like factors within the knowledge and expertise of the attending physician.
[033] The term "excipients", "pharmaceutically acceptable excipients" or “carriers” as used herein, refers to any pharmaceutically acceptable materials or components of a pharmaceutical product suitable for the present pharmaceutical preparation and as disclosed herein, that are not having any pharmacological effect, such as a filler, diluent, carrier, etc. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic, do not interact with other components of a composition or drug delivery system in a deleterious manner, and are acceptable for veterinary use as well as human pharmaceutical use. An "excipient" or a “pharmaceutically acceptable excipient" as used in the specification includes both one and more than one such excipients.
[034] The term “stability” or “stable” as used herein includes chemical stability, physical stability and polymorphic stability of the composition of the present invention comprising fixed dose combination of valsartan and atorvastatin, wherein said composition remains within the established specifications to maintain its identity, strength, quality, and purity throughout the storage, retest or expiry period, and does not change or decompose.
[035] The term “commercially available” or “commercial” valsartan composition as used herein refers to the Diovan® oral tablets, available in the strengths of 40mg, 80mg, 160mg and 320mg of valsartan and marketed by Novartis Pharma GmbH, Germany. The term “commercially available” or “commercial” atorvastatin composition as used herein refers to the Lipitor® oral tablets, available in the strengths of 10mg, 20mg, 40mg and 80mg of atorvastatin and marketed by Pfizer Ireland Pharmaceuticals, Ireland.
[036] The term “hypertension” as used herein refers to a condition where the pressure of blood within the blood vessels is higher than normal as it circulates through the body. When the systolic pressure exceeds 140 mmHg or the diastolic pressure exceeds 90 mmHg for a sustained period of time, damage is done to the body. Populations at increased risk due to other conditions, such as diabetes, are recommended to have even lower levels than cited above. The term "hypertension" as used herein is meant to encompass various types of hypertension, including, but not limited to, severe hypertension, pulmonary hypertension, malignant hypertension, or isolated systolic hypertension. The term "severe hypertension" refers to hypertension characterized by a systolic blood pressure of = 180 mmHg and a diastolic blood pressure of = 110 mmHg.
[037] The term “hyperlipidemia” as used herein refers to a condition of abnormally raised levels of lipids such as free cholesterol, cholesterol ester, total cholesterol, low density lipoproteins, very low density lipoproteins, phospholipids or triglycerides in the blood. Although hyperlipidemia does not show specific symptoms by itself, excessive lipids in blood adhere to the blood vessel walls to reduce the blood vessel size and cause atherosclerosis.
[038] In an embodiment, the present application relates to a composition comprising (a) at least one active agent from angiotensin II antagonists and (b) at least one active agent from HMG CoA reductase inhibitors.
[039] In an aspect of the above embodiment, said composition of the present application comprises at least one fast-dissolving carrier and at least one water-insoluble carrier.
[040] In one embodiment, the present application relates to a composition comprising (a) at least one active agent from angiotensin II antagonists, (b) at least one active agent from HMG CoA reductase inhibitors, (c) at least one fast-dissolving carrier and (d) at least one water-insoluble carrier.
[041] In another embodiment, the present application relates to a composition comprising (a) at least one active agent from angiotensin II antagonists, (b) at least one active agent from HMG CoA reductase inhibitors, (c) at least one fast-dissolving carrier and (d) at least one water-insoluble carrier, wherein said composition releases at least about 85% of said angiotensin II antagonist or at least about 85% of said HMG CoA reductase inhibitor, within about 15 minutes, when subjected to an in vitro dissolution study in 900 ml of pH 6.8 phosphate buffer medium at 75 rpm and 37°C using USP type II apparatus.
[042] In another embodiment, the present application relates to a composition comprising (a) at least one active agent from angiotensin II antagonists, (b) at least one active agent from HMG CoA reductase inhibitors, (c) at least one fast-dissolving carrier and (d) at least one water-insoluble carrier, wherein said composition releases at least about 85% of said agents within about 15 minutes, when subjected to an in vitro dissolution study in 900 ml of pH 6.8 phosphate buffer medium at 75 rpm and 37°C using USP type II apparatus.
[043] In another embodiment, the present application relates to a composition comprising (a) at least one active agent from angiotensin II antagonists, (b) at least one active agent from HMG CoA reductase inhibitors, (c) at least one fast-dissolving carrier and (d) at least one water-insoluble carrier, wherein said composition releases at least about 85% of said angiotensin II antagonist within about 15 minutes, when subjected to an in vitro dissolution study in 900 ml of pH 4.5 acetate buffer medium at 50 rpm and 37°C using USP type II apparatus.
[044] In an aspect of the above embodiments, said composition of the present application comprises at least one angiotensin II antagonist selected from, but are not limited to: valsartan, azilsartan, losartan, eprosartan, irbesartan, olmesartan, candesartan and telmisartan, and any pharmaceutically acceptable salts or esters thereof, and any combinations thereof.
[045] In another aspect of the above embodiments, said composition of the present application comprises at least one HMG CoA reductase inhibitor selected from, but are not limited to: atorvastatin, mevastatin, pitavastatin, lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin, and rosuvastatin, and any pharmaceutically acceptable salts or esters thereof, and any combinations thereof.
[046] In one aspect of the above embodiments, the angiotensin II antagonist used in the present application is valsartan or its pharmaceutically acceptable salts or esters thereof.
[047] In another aspect of the above embodiments, the HMG CoA reductase inhibitor used in the present application is atorvastatin or its pharmaceutically acceptable salts or esters thereof.
[048] In one embodiment, the present application relates to a composition comprising (a) therapeutically effective amount of valsartan or a pharmaceutically acceptable salt thereof, (b) therapeutically effective amount of atorvastatin or a pharmaceutically acceptable salt thereof, (c) at least one fast-dissolving carrier and (d) at least one water-insoluble carrier.
[049] In another embodiment, the present application relates to a composition comprising (a) therapeutically effective amount of valsartan or a pharmaceutically acceptable salt thereof, (b) therapeutically effective amount of atorvastatin or a pharmaceutically acceptable salt thereof, (c) at least one fast-dissolving carrier and (d) at least one water-insoluble carrier, wherein said composition releases at least about 85% of valsartan or at least about 85% of atorvastatin, within about 15 minutes, when subjected to an in vitro dissolution study in 900 ml of pH 6.8 phosphate buffer medium at 75 rpm and 37°C using USP type II apparatus.
[050] In another embodiment, the present application relates to a composition comprising (a) therapeutically effective amount of valsartan or a pharmaceutically acceptable salt thereof, (b) therapeutically effective amount of atorvastatin or a pharmaceutically acceptable salt thereof, (c) at least one fast-dissolving carrier and (d) at least one water-insoluble carrier, wherein said composition releases at least about 85% of valsartan and atorvastatin within about 15 minutes, when subjected to an in vitro dissolution study in 900 ml of pH 6.8 phosphate buffer medium at 75 rpm and 37°C using USP type II apparatus.
[051] In another embodiment, the present application relates to a composition comprising (a) therapeutically effective amount of valsartan or a pharmaceutically acceptable salt thereof, (b) therapeutically effective amount of atorvastatin or a pharmaceutically acceptable salt thereof, (c) at least one fast-dissolving carrier and (d) at least one water-insoluble carrier, wherein said composition releases at least about 70% of valsartan within about 15 minutes, when subjected to an in vitro dissolution study in 900 ml of pH 4.5 acetate buffer medium at 50 rpm and 37°C using USP type II apparatus.
[052] In one aspect of the above embodiments, said composition of the present application comprises valsartan or its pharmaceutically acceptable salt, in a dosage range of from about 20mg to about 320mg, about 20mg, about 30mg, about 40mg, about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 120mg, about 140mg, about 160mg, about 180mg, about 200mg, about 220mg, about 240mg, about 260mg, about 280mg, about 300mg or about 320mg.
[053] In one aspect of the above embodiments, said composition of the present application comprises atorvastatin or its pharmaceutically acceptable salt in a dosage range of from about 5mg to about 80mg, about 5mg, about 7.5mg, about 5mg, about 10mg, about 15mg, about 20mg, about 30mg, about 40mg, about 50mg, about 60mg, about 70mg or about 80mg.
[054] In an aspect of the above embodiments, said composition comprises any one of the following dosages:
(a) 160 mg of valsartan and 10 mg of atorvastatin;
(b) 160 mg of valsartan and 20 mg of atorvastatin;
(c) 80 mg of valsartan and 10 mg of atorvastatin; or
(d) 80 mg of valsartan and 20 mg of atorvastatin.
[055] In one embodiment, the present application relates to a composition comprising (a) about 20mg to about 320mg of valsartan or a pharmaceutically acceptable salt thereof, (b) about 5mg to about 80mg of atorvastatin or a pharmaceutically acceptable salt thereof, (c) at least one fast-dissolving carrier and (d) at least one water-insoluble carrier.
[056] In another embodiment, the present application relates to a comprising (a) about 20mg to about 320mg of valsartan or a pharmaceutically acceptable salt thereof, (b) about 5mg to about 80mg of atorvastatin or a pharmaceutically acceptable salt thereof, (c) at least one fast-dissolving carrier and (d) at least one water-insoluble carrier, wherein said composition releases at least about 85% of valsartan or at least about 85% of atorvastatin, within about 15 minutes, when subjected to an in vitro dissolution study in 900 ml of pH 6.8 phosphate buffer medium at 75 rpm and 37°C using USP type II apparatus.
[057] In another embodiment, the present application relates to a composition comprising (a) about 20mg to about 320mg of valsartan or a pharmaceutically acceptable salt thereof, (b) about 5mg to about 80mg of atorvastatin or a pharmaceutically acceptable salt thereof, (c) at least one fast-dissolving carrier and (d) at least one water-insoluble carrier, wherein said composition releases at least about 85% of valsartan and atorvastatin within about 15 minutes, when subjected to an in vitro dissolution study in 900 ml of pH 6.8 phosphate buffer medium at 75 rpm and 37°C using USP type II apparatus.
[058] In another embodiment, the present application relates to a composition comprising (a) about 20mg to about 320mg of valsartan or a pharmaceutically acceptable salt thereof, (b) about 5mg to about 80mg of atorvastatin or a pharmaceutically acceptable salt thereof, (c) at least one fast-dissolving carrier and (d) at least one water-insoluble carrier, wherein said composition releases at least about 70% of valsartan within about 15 minutes, when subjected to an in vitro dissolution study in 900 ml of pH 4.5 acetate buffer medium at 50 rpm and 37°C using USP type II apparatus.
[059] In has been observed that the right amount and right ratio of fast-dissolving carrier to at least one water-insoluble carrier is vital in obtaining the desired dissolution profile for the composition of present application.
[060] In one aspect of the above embodiments, said composition of the present application comprises fast-dissolving carrier in an amount ranging from about 32% to about 44%, based on the total weight of the composition.
[061] In another aspect of the above embodiments, said composition of the present application comprises water-insoluble carrier in an amount ranging from about 15% to about 22%, based on the total weight of the composition.
[062] In another aspect of the above embodiments, said composition of the present application comprises valsartan and atorvastatin contained in a distinct or separate portions or components. Both valsartan and atorvastatin are physically separated, to prevent any incompatibility or stability issues arising due to interaction of these two drugs. In order to achieve this, said composition is prepared in such a way, that both valsartan and atorvastatin are contained as a separate portions or components.
[063] In one embodiment, the present application relates to a composition comprising:
a) a valsartan portion comprising valsartan or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier,
b) a atorvastatin portion comprising atorvastatin or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier, and
c) one or more pharmaceutically acceptable excipients.
[064] In another embodiment, the present application relates to a composition comprising:
a) a valsartan portion comprising about 20mg to about 320mg of valsartan or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier,
b) a atorvastatin portion comprising about 5mg to about 80mg of atorvastatin or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier, and
c) one or more pharmaceutically acceptable excipients.
[065] In another embodiment, the present application relates to a composition comprising:
a) a valsartan portion comprising about 20mg to about 320mg of valsartan or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier,
b) a atorvastatin portion comprising about 5mg to about 80mg of atorvastatin or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier, and
c) one or more pharmaceutically acceptable excipients,
wherein said composition comprises said fast-dissolving carrier in an amount ranging from about 32% to about 44%, based on the total weight of the composition and said water-insoluble carrier in an amount ranging from about 15% to about 22%, based on the total weight of the composition.
[066] In another embodiment, the present application relates to a composition comprising:
a) a valsartan portion comprising about 20mg to about 320mg of valsartan or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier,
b) a atorvastatin portion comprising about 5mg to about 80mg of atorvastatin or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier, and
c) one or more pharmaceutically acceptable excipients,
wherein said valsartan portion comprises at least about 70% of total fast-dissolving carrier present in said composition.
[067] In another embodiment, the present application relates to a composition comprising:
a) a valsartan portion comprising about 20mg to about 320mg of valsartan or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier,
b) a atorvastatin portion comprising about 5mg to about 80mg of atorvastatin or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier, and
c) one or more pharmaceutically acceptable excipients,
wherein said valsartan portion comprises not more than about 25% of total water-insoluble carrier present in said composition.
[068] In another embodiment, the present application relates to a composition comprising:
a) a valsartan portion comprising about 20mg to about 320mg of valsartan or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier in an amount ranging from about 40% to about 56%, and at least one water-insoluble carrier in an amount ranging from about 4% to about 7%, based on the total weight of the valsartan portion,
b) a atorvastatin portion comprising about 5mg to about 80mg of atorvastatin or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier in an amount ranging from about 16% to about 23% and at least one water-insoluble carrier in an amount ranging from about 34% to about 46%, based on the total weight of the atorvastatin portion, and
c) one or more pharmaceutically acceptable excipients,
wherein said valsartan portion comprises at least about 70% of total fast-dissolving carrier present in said composition.
[069] In another embodiment, the present application relates to a composition comprising:
a) a valsartan portion comprising about 20mg to about 320mg of valsartan or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier in an amount ranging from about 40% to about 56%, and at least one water-insoluble carrier in an amount ranging from about 4% to about 7%, based on the total weight of the valsartan portion,
b) a atorvastatin portion comprising about 5mg to about 80mg of atorvastatin or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier in an amount ranging from about 16% to about 23%and at least one water-insoluble carrier in an amount ranging from about 34% to about 46%, based on the total weight of the atorvastatin portion, and
c) one or more pharmaceutically acceptable excipients,
wherein said valsartan portion comprises not more than about 25% of total water-insoluble carrier present in said composition.
[070] In one aspect of the above embodiments, said fast-dissolving carrier and water-insoluble carrier in valsartan portion are present in a weight ratio from about 7:1 to about 9:1.
[071] In another embodiment, the present application relates to a composition comprising:
a) a valsartan portion comprising about 20mg to about 320mg of valsartan or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier in an amount ranging from about 40% to about 56%, and at least one water-insoluble carrier in an amount ranging from about 4% to about 7%, based on the total weight of the valsartan portion,
b) a atorvastatin portion comprising about 5mg to about 80mg of atorvastatin or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier in an amount ranging from about 16% to about 23%and at least one water-insoluble carrier in an amount ranging from about 34% to about 46%, based on the total weight of the atorvastatin portion, and
c) one or more pharmaceutically acceptable excipients,
wherein said fast-dissolving carrier and water-insoluble carrier in valsartan portion are present in a weight ratio from about 7:1 to about 9:1.
[072] In an aspect of the above embodiments, said composition comprises any one of the following dosages:
(a) 160 mg of valsartan and 10 mg of atorvastatin;
(b) 160 mg of valsartan and 20 mg of atorvastatin;
(c) 80 mg of valsartan and 10 mg of atorvastatin; or
(d) 80 mg of valsartan and 20 mg of atorvastatin.
[073] In an aspect of the above embodiments, said composition of the present application shows at least one of the following release profiles:
i. at least 85% of said valsartan in 15 minutes when subjected to an in vitro dissolution study in 900 ml of pH 6.8 phosphate buffer medium at 75 rpm and 37°C using USP type II apparatus,
ii. at least 85% of said atorvastatin in 15 minutes when subjected to an in vitro dissolution study in 900 ml of pH 6.8 phosphate buffer medium at 75 rpm and 37°C using USP type II apparatus, or
iii. at least 70% of said valsartan in 15 minutes when subjected to an in vitro dissolution study in 900 ml of pH 4.5 acetate buffer medium at 50 rpm and 37°C using USP type II apparatus.
[074] In another embodiment, the present application relates to a composition comprising:
a) a valsartan portion comprising about 20mg to about 320mg of valsartan or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier in an amount ranging from about 40% to about 56%, and at least one water-insoluble carrier in an amount ranging from about 4% to about 7%, based on the total weight of the valsartan portion,
b) a atorvastatin portion comprising about 5mg to about 80mg of atorvastatin or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier in an amount ranging from about 16% to about 23%and at least one water-insoluble carrier in an amount ranging from about 34% to about 46%, based on the total weight of the atorvastatin portion, and
c) one or more pharmaceutically acceptable excipients
wherein said composition shows at least one of the following release profiles:
i. at least 85% of said valsartan in 15 minutes when subjected to an in vitro dissolution study in 900 ml of pH 6.8 phosphate buffer medium at 75 rpm and 37°C using USP type II apparatus,
ii. at least 85% of said atorvastatin in 15 minutes when subjected to an in vitro dissolution study in 900 ml of pH 6.8 phosphate buffer medium at 75 rpm and 37°C using USP type II apparatus, or
iii. at least 70% of said valsartan in 15 minutes when subjected to an in vitro dissolution study in 900 ml of pH 4.5 acetate buffer medium at 50 rpm and 37°C using USP type II apparatus.
.
[075] In one aspect of the above embodiments, said valsartan portion comprises at least about 70% of total fast-dissolving carrier present in said composition.
[076] In another aspect of the above embodiments, said valsartan portion comprises not more than about 25% of total water-insoluble carrier present in said composition.
[077] In yet another aspect of the above embodiments, said fast-dissolving carrier and water-insoluble carrier in valsartan portion are present in a weight ratio from about 7:1 to about 9:1.
[078] In some aspects of the above embodiments, said composition exhibits bioequivalence to commercially available Diovan® and Lipitor® oral formulations.
[079] In one embodiment, the present application relates to a composition comprising (a) therapeutically effective amount of valsartan or a pharmaceutically acceptable salt thereof, (b) therapeutically effective amount of atorvastatin or a pharmaceutically acceptable salt thereof, (c) at least one fast-dissolving carrier and (d) at least one water-insoluble carrier, wherein said composition exhibits bioequivalence to commercially available Diovan® and Lipitor® oral formulations and said bioequivalence is established by 90% Confidence Interval (CI) of the relative mean of Cmax, AUC0-inf and AUC0-t within 80.00% to 125.00% of Diovan® and Lipitor®.
[080] In another embodiment, the present application relates to a composition comprising:
a) a valsartan portion comprising valsartan or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier,
b) a atorvastatin portion comprising atorvastatin or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier, and
c) one or more pharmaceutically acceptable excipients,
wherein said composition exhibits bioequivalence to commercially available Diovan® and Lipitor® oral formulations and said bioequivalence is established by 90% Confidence Interval (CI) of the relative mean of Cmax, AUC0-inf and AUC0-t within 80.00% to 125.00% of Diovan® and Lipitor®.
[081] In another embodiment, the present application relates to a composition comprising:
a) a valsartan portion comprising about 20mg to about 320mg of valsartan or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier,
b) a atorvastatin portion comprising about 5mg to about 80mg of atorvastatin or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier, and
c) one or more pharmaceutically acceptable excipients.
wherein said composition exhibits bioequivalence to commercially available Diovan® and Lipitor® oral formulations and said bioequivalence is established by 90% Confidence Interval (CI) of the relative mean of Cmax, AUC0-inf and AUC0-t within 80.00% to 125.00% of Diovan® and Lipitor®.
[082] In another embodiment, the present application relates to a composition comprising:
a) a valsartan portion comprising about 20mg to about 320mg of valsartan or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier in an amount ranging from about 40% to about 56%, and at least one water-insoluble carrier in an amount ranging from about 4% to about 7%, based on the total weight of the valsartan portion,
b) a atorvastatin portion comprising about 5mg to about 80mg of atorvastatin or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier in an amount ranging from about 16% to about 23%and at least one water-insoluble carrier in an amount ranging from about 34% to about 46%, based on the total weight of the atorvastatin portion, and
c) one or more pharmaceutically acceptable excipients,
wherein said composition exhibits bioequivalence to commercially available Diovan® and Lipitor® oral formulations and said bioequivalence is established by 90% Confidence Interval (CI) of the relative mean of Cmax, AUC0-inf and AUC0-t within 80.00% to 125.00% of Diovan® and Lipitor®.
[083] In an aspect of the above embodiments, said composition comprises any one of the following dosages:
(a) 160 mg of valsartan and 10 mg of atorvastatin;
(b) 160 mg of valsartan and 20 mg of atorvastatin;
(c) 80 mg of valsartan and 10 mg of atorvastatin; or
(d) 80 mg of valsartan and 20 mg of atorvastatin.
[084] In another aspect of the above embodiments, said valsartan portion comprises at least about 70% of total fast-dissolving carrier present in said composition.
[085] In another aspect of the above embodiments, said valsartan portion comprises not more than about 25% of total water-insoluble carrier present in said composition.
[086] In yet another aspect of the above embodiments, said fast-dissolving carrier and water-insoluble carrier in valsartan portion are present in a weight ratio from about 7:1 to about 9:1.
[087] In one aspect of the above embodiments, said composition of present application is useful for treating hypertension and hyperlipidemia.
[088] In some aspects of the above embodiments, said composition is used for treating hypertension and/or hyperlipidaemia or a symptom associated therewith in a patient in need thereof.
[089] In another aspect of the above embodiments, said composition is used for patients with increased risk for atherosclerotic vascular disease due to hypercholesterolemia, with or without hypertension.
[090] In one embodiment, the present application relates to a method for treating hypertension and/or hyperlipidaemia or a symptom associated therewith in a patient in need thereof, the method comprising orally administering a composition comprising (a) therapeutically effective amount of valsartan or a pharmaceutically acceptable salt thereof, (b) therapeutically effective amount of atorvastatin or a pharmaceutically acceptable salt thereof, (c) at least one fast-dissolving carrier and (d) at least one water-insoluble carrier.
[091] In another embodiment, the present application relates to a method for treating patients with increased risk for atherosclerotic vascular disease due to hypercholesterolemia, with or without hypertension, the method comprising orally administering a composition comprising (a) therapeutically effective amount of valsartan or a pharmaceutically acceptable salt thereof, (b) therapeutically effective amount of atorvastatin or a pharmaceutically acceptable salt thereof, (c) at least one fast-dissolving carrier and (d) at least one water-insoluble carrier.
[092] In another embodiment, the present application relates to a method for treating hypertension and/or hyperlipidaemia or a symptom associated therewith in a patient in need thereof, the method comprising orally administering a composition comprising:
a) a valsartan portion comprising valsartan or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier,
b) a atorvastatin portion comprising atorvastatin or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier, and
c) one or more pharmaceutically acceptable excipients.
[093] In another embodiment, the present application relates to a method for treating patients with increased risk for atherosclerotic vascular disease due to hypercholesterolemia, with or without hypertension, the method comprising orally administering composition comprising:
a) a valsartan portion comprising valsartan or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier,
b) a atorvastatin portion comprising atorvastatin or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier, and
c) one or more pharmaceutically acceptable excipients.
[094] In another embodiment, the present application relates to a method for treating hypertension and/or hyperlipidaemia or a symptom associated therewith in a patient in need thereof, the method comprising orally administering composition comprising:
a) a valsartan portion comprising about 20mg to about 320mg of valsartan or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier in an amount ranging from about 40% to about 56%, and at least one water-insoluble carrier in an amount ranging from about 4% to about 7%, based on the total weight of the valsartan portion,
b) a atorvastatin portion comprising about 5mg to about 80mg of atorvastatin or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier in an amount ranging from about 16% to about 23%and at least one water-insoluble carrier in an amount ranging from about 34% to about 46%, based on the total weight of the atorvastatin portion, and
c) one or more pharmaceutically acceptable excipients.
[095] In another embodiment, the present application relates to a method for treating patients with increased risk for atherosclerotic vascular disease due to hypercholesterolemia, with or without hypertension, the method comprising orally administering composition comprising:
a) a valsartan portion comprising about 20mg to about 320mg of valsartan or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier in an amount ranging from about 40% to about 56%, and at least one water-insoluble carrier in an amount ranging from about 4% to about 7%, based on the total weight of the valsartan portion,
b) a atorvastatin portion comprising about 5mg to about 80mg of atorvastatin or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier in an amount ranging from about 16% to about 23%and at least one water-insoluble carrier in an amount ranging from about 34% to about 46%, based on the total weight of the atorvastatin portion, and
c) one or more pharmaceutically acceptable excipients.
[096] In an aspect of the above embodiments, said composition comprises any one of the following dosages:
(a) 160 mg of valsartan and 10 mg of atorvastatin;
(b) 160 mg of valsartan and 20 mg of atorvastatin;
(c) 80 mg of valsartan and 10 mg of atorvastatin; or
(d) 80 mg of valsartan and 20 mg of atorvastatin.
[097] In some aspect of the above embodiments said composition may be administered once daily, twice daily or three times daily or as advised by the physician, to a patient in need thereof.
[098] In another aspect of the above embodiments, said valsartan portion comprises at least about 70% of total fast-dissolving carrier present in said composition.
[099] In another aspect of the above embodiments, said valsartan portion comprises not more than about 25% of total water-insoluble carrier present in said composition.
[100] In yet another aspect of the above embodiments, said fast-dissolving carrier and water-insoluble carrier in valsartan portion is present in a weight ratio from about 7:1 to about 9:1.
[101] In yet another aspect of the above embodiments, wherein said composition exhibits bioequivalence to commercially available Diovan® and Lipitor® oral formulations and said bioequivalence is established by 90% Confidence Interval (CI) of the relative mean of Cmax, AUC0-inf and AUC0-t within 80.00% to 125.00% of Diovan® and Lipitor®.
[102] In some aspects, the composition of present application comprises valsartan having a d50 particle size of about 2 µm to about 20 µm and/ or d90 particle size of about 5 µm to about 25 µm.
[103] In another aspect of the above embodiments, said composition of present application comprises valsartan having a d50 particle size of from about 2 µm to about 20 µm, about 3 µm, about 4 µm, about 5 µm, about 6 µm, about 7 µm, about 8 µm, about 9 µm, about 10 µm, about 11 µm, about 12 µm, about 13 µm, about 14 µm, about 15 µm, about 16 µm, about 17 µm, about 18 µm, about 19 µm, or about 20 µm.
[104] In another aspect of the above embodiments, the composition of present application comprises valsartan having a d90 particle size of from about 5 µm to about 25 µm, about 5 µm, about 6 µm, about 7 µm, about 8 µm, about 9 µm, about 10 µm, about 11 µm, about 12 µm, about 13 µm, about 14 µm, about 15 µm, about 16 µm, about 17 µm, about 18 µm, about 19 µm, about 20 µm, about 21 µm, about 22 µm, about 23 µm, about 24 µm, or about 25 µm.
[105] In one aspect of the present application, said fast-dissolving carrier of the above embodiments is selected from, but not limited to, lactose, dextrose, mannitol, sorbitol, sucrose, and the like and combinations thereof.
[106] In another aspect of the present application, said water-insoluble carrier of the above embodiments is selected from, but not limited to, starch, powdered cellulose, microcrystalline cellulose, calcium phosphate, and the like and combinations thereof.
[107] In another aspect of the above embodiments, said composition of present application further comprises one or more pharmaceutically acceptable excipients such as fillers/diluents, binders, disintegrants, glidants, lubricants, plasticizers, wetting agents, solvents, pigments, opacifiers, sweeteners, coloring agents, antiadherents, coating agents, polymers and the like and combinations thereof.
[108] Suitable examples of diluents that can be used in the present application include, but are not limited to, calcium sulfate, cellulose acetate, dextrates, dextrin, dextrose, fructose, kaolin, lactitol, maltitol, maltodextrin, maltose, polymethacrylates, sodium chloride, sucrose, talc, starches, lactose, mannitol, cellulose derivatives, and the like. Different grades of lactose can be used that include, but are not limited to, lactose monohydrate, lactose DT (direct tabletting), lactose anhydrous, Flowlac™ (available from Meggle Products), Pharmatose™ (available from DMV), and others. Different grades of starch can be used that include, but are not limited to, maize starch, potato starch, rice starch, wheat starch, pregelatinized starches (commercially available as PCS PC10 from Signet Chemical Corporation) and Starch 1500, Starch 1500 LM grade (low moisture content grade) from Colorcon, fully pregelatinized starches (commercially available as National 78-1551 from Essex Grain Products) and others. Different grades of celluloses can be used that include crystalline celluloses or powdered celluloses. Examples of crystalline cellulose products include, but are not limited to, CEOLUS™ KG801, Avicel™ PH101, PH102, PH301, PH302 and PH-F20, microcrystalline cellulose 114, and microcrystalline cellulose 112. Other useful diluents include, but are not limited to, carmellose, sugar alcohols such as mannitol, sorbitol and xylitol, calcium carbonate, magnesium carbonate, sodium carbonate, sodium bicarbonate, light magnesium oxide, heavy magnesium oxide, sodium hydrogen phosphate, disodium hydrogen phosphate, dibasic calcium phosphate, directly compressible grades of dibasic calcium phosphate (Emcompress™) and tribasic calcium phosphate.
[109] Suitable examples of binders that can be used in the present application include, but are not limited to, carboxymethylcelluloses, hydroxyethylcelluloses, dextrin, gelatin, maltodextrin, polyethylene oxides, sodium alginate, hydroxypropylcelluloses, hydroxypropyl methylcelluloses, polyvinylpyrrolidones or povidone (e.g., PVP-K25, PVP-K29, PVP-K30, and PVP-K90D), powdered acacia, gelatin, guar gum, carbomers (e.g., a Carbopol™ product), methylcelluloses, polymethacrylates, and starches, and the like, and mixtures thereof.
[110] Suitable examples of glidants or anti-sticking agents that can be used in the present application include, but are not limited to, talc, silica derivatives, colloidal silicon dioxide and the like or mixtures thereof. These materials improve the flow of other excipients, granules, powder blends etc.
[111] Suitable examples of lubricants that can be used in the present application include, but are not limited to, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, talc, glyceryl behenate, glyceryl monostearates, palmitic acid, carnauba wax, calcium soaps, zinc stearate, polyoxyethylene monostearates, calcium silicate, silicon dioxide, macrogols, and mixtures thereof.
[112] Suitable examples of disintegrants that can be used in the present application include, but are not limited to, carmellose calcium, carboxymethylstarch sodium, croscarmellose sodium, crospovidones, and low-substituted hydroxypropylcelluloses. Examples of commercially available crospovidone products include, but are not limited to crosslinked povidone, KOLLIDON™ CL, POLYPLASDONE™ XL, XI-10, and INF-10. Examples of low-substituted hydroxypropylcelluloses include, but are not limited to, low-substituted hydroxypropylcellulose LH11, LH21, LH31, LH22, LH32, LH20, LH30, LH32, and LH33. Other useful disintegrants include sodium starch glycolate (type A or type B), colloidal silicon dioxide and starches. In some embodiments, disintegrants can be combined with other excipients in a process of granulating, i.e., intragranularly, and/or in the preparation of a compression mixture, i.e., extragranularly.
[113] Suitable examples of alkalizing agents that can be used in the present application include, but are not limited to, one or more of alkaline earth metal salts, alkali metal salts, and organic alkalizing agents. Alkaline earth metal salts include, for example, calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, aluminum magnesium hydroxide, and the like. Alkali metal salts include, for example, disodium hydrogen orthophosphate, sodium silicate, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium aluminate, sodium or potassium citrate, carbonate, bicarbonate, phosphate, sulfate, benzoate, ascorbate, and the like. Examples of organic alkalizing agents include amines; specific examples of amines including N- methylglucamine, guanine, and arginine.
[114] Suitable examples of colorants that can be used in the present application include any FDA approved colors including, but are not limited to, Food Yellow No. 5, Food Red No. 2, Food Blue No. 2, food lake colorants, iron oxides, lake of sunset yellow, lake of quinoline yellow, lake of erythrosine, titanium dioxide, FD&C colorants, and the like or mixtures thereof.
[115] Suitable examples of coating agents that can be used in the present application include, but are not limited to, pre-formulated film-coating materials such as OPADRY® products (manufactured by COLORCON), including OPADRY® White OY58900, OPADRY® White AMB OYB28920, etc.), other hydrophilic or hydrophobic substances, and mixtures thereof. Useful components for coating include, but are not limited to, film formers, plasticizers, antiadherents, opacifiers, solvents, and optionally colorants, lubricants, pigments, antifoam agents, and polishing agents.
[116] Suitable examples of polymers that can be used in the present application include, but are not limited to, water soluble, water swellable, water insoluble, pH dependent, pH independent, or mixtures thereof. Pharmaceutically acceptable polymers in the context of the application include, but are not limited to, polyethylene glycols (e.g., molecular weight less than about 400), hydroxymethyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, methylcelluloses, carboxymethylcelluloses (CMC), sodium CMC, carboxyethyl celluloses, carboxy polymethylenes, hydroxypropyl methyl phthalates, polyvinylpyrrolidones, cellulose acetates, sodium alginate, gums such as acacia gum, guar gum, tragacanth gum, and xanthan gum, methacrylic acid copolymers such as poly(butylmethacrylate), (2-dimethylaminoethyl)methacrylates, methylmethacrylates, Eudragit™ products designated as E100 or E12.5 or EPO, polyvinyl acetal diethylaminoacetate, chitosan, and the like, including any mixtures thereof.
[117] Suitable examples of wetting agents that can be used in the present application include surfactants such as sodium lauryl sulfate, cetrimide, polysorbates such as polysorbate 80, poloxamers such as poloxamer 188 and poloxamer 407, sodium carboxymethylcelluloses, hydrogenated oils, polyoxyethylene glycols, polyoxypropylene glycols, sorbitan fatty acid esters (e.g., SPAN® surfactants), polyoxyethylene sorbitan fatty acid esters (e.g., TWEEN® surfactants), polyglycolized glycerides, available commercially such as GELUCIRE® 40/14, GELUCIRE® 42/12, and GELUCIRE® 50/13, Vitamin E TGPS, and any mixtures thereof.
[118] Suitable examples of solvents that can be used in the present application include, but are not limited to, water, methanol, ethanol, acidified ethanol, acetone, diacetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulphoxide, N,N-dimethylformamide, tetrahydrofuran, and any mixtures thereof.
[119] In another aspect of the above embodiments, said composition may comprise an inert film coating. Suitable examples of coating agents that can be used for this purpose include, but are not limited to, pre-formulated film-coating materials such as OPADRY® products (manufactured by COLORCON), including OPADRY® White OY58900, OPADRY® White AMB OYB28920, etc.), other hydrophilic or hydrophobic substances, and mixtures thereof.
[120] In an aspect of the above embodiments, said composition of the present is formulated into oral dosage form of tablets, capsules, caplets, pills, wafers, films, powders, granules or sachets.
[121] In one aspect of the above embodiments, said composition of the present application comprises valsartan and atorvastatin physically separated from each other and contained in a distinct or separate portions or layers or components. Both valsartan and atorvastatin are physically separated, to prevent any incompatibility or stability issues arising due to interaction of these two drugs. In order to achieve this, said composition is prepared in such a way, that both valsartan and atorvastatin contained as a separate portions or components.
[122] In another aspect, said physical separation is achieved by formulating the two components into separate layers, coats or shells to obtain a multi- or bilayer formulation, a dry-coated (core in a shell) formulation, a molded delivery system, or a spray coated formulation. In some aspects, the physical separation is achieved through particulate systems (multiparticulates) that comprise particles of different populations of each components and further formulated to final formulation, e.g. capsules, sachets, stickpacks filled with multiparticulates, tablets or mini-tablets obtained from compressing multiparticulates, otherwise as such granules or beads, which can subsequently be filled into capsules. Another form of a physical separation is a capsule filled with multiparticulates of one of the components, and one or more tablets or minitablets obtained from compressing multiparticulates, such as granules or beads, of the other component. In another aspect, the physical separation may be any combination of the above two approaches such as multiparticulates, such as pellets, or minitablets provided with a layer, coat or shell where the layer, coat or shell contains one of the components and the multiparticulates or minitablets contain the other of the components.
[123] In another aspect of the embodiments, the composition of present application is prepared as a bilayered tablets.
[124] In one embodiment, the present application relates to a bilayered tablet comprising:
a) a valsartan portion comprising valsartan or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier,
b) a atorvastatin portion comprising atorvastatin or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier, and
c) one or more pharmaceutically acceptable excipients.
[125] In another embodiment, the present application relates to a bilayered tablet comprising:
a) a valsartan portion comprising about 20mg to about 320mg of valsartan or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier,
b) a atorvastatin portion comprising about 5mg to about 80mg of atorvastatin or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier, and
c) one or more pharmaceutically acceptable excipients.
[126] In another embodiment, the present application relates to a bilayered tablet comprising:
a) a valsartan portion comprising about 20mg to about 320mg of valsartan or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier in an amount ranging from about 40% to about 56%, and at least one water-insoluble carrier in an amount ranging from about 4% to about 7%, based on the total weight of the valsartan portion,
b) a atorvastatin portion comprising about 5mg to about 80mg of atorvastatin or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier in an amount ranging from about 16% to about 23%and at least one water-insoluble carrier in an amount ranging from about 34% to about 46%, based on the total weight of the atorvastatin portion, and
c) one or more pharmaceutically acceptable excipients.
[127] In an aspect of the above embodiments, said bilayered tablet comprises any one of the following dosages:
(e) 160 mg of valsartan and 10 mg of atorvastatin;
(f) 160 mg of valsartan and 20 mg of atorvastatin;
(g) 80 mg of valsartan and 10 mg of atorvastatin; or
(h) 80 mg of valsartan and 20 mg of atorvastatin.
[128] In an embodiment, the present application relates to a bilayered tablet wherein the weight ratio of the valsartan portion and the atorvastatin portion is in the range of about 1:0.2 to 1:2.
[129] In another aspect of the above embodiments, said valsartan portion comprises at least about 70% of total fast-dissolving carrier present in said bilayered tablet.
[130] In another aspect of the above embodiments, said valsartan portion comprises not more than about 25% of total water-insoluble carrier present in said bilayered tablet.
[131] In yet another aspect of the above embodiments, said fast-dissolving carrier and water-insoluble carrier in valsartan portion are present in a weight ratio from about 7:1 to about 9:1.
[132] In one aspect of the above embodiments, said composition of the present application is prepared by the processes well known in the art.
[133] In another aspect, the processes includes any methods known to a person skilled in the art such as, but not limited to, direct compression, dry granulation, wet granulation, roller compaction, slugging-deslugging, fluidized bed granulation by spraying a suspension or dispersion of drug in a conventional coating pan or fluidized bed equipment (such as a Wurster or Glatt) to prepare drug containing granules, followed by drying of the granules when desired granule size is achieved. Such prepared drug containing granules can be mixed with extragranular materials to prepare desired final pharmaceutical composition.
[134] In one aspect of the above embodiments, said process comprises dry granulation method, comprises at least one step selected from dry mixing, direct compression, or dry granulation such as compaction, slugging or combinations thereof. The dry process can be carried out by compacting/decompacting or slugging/deslugging a powder mixture or direct compression, in which an active agent and excipients are mixed together and granulated. These prepared granules can optionally be mixed with extragranular materials to prepare desired final pharmaceutical composition.
[135] In another aspect of the above embodiments, said process comprises wet granulation methods, wherein said process comprises preparing a mixture comprising an active agent and one or more pharmaceutically acceptable excipients, and mixing with a granulating liquid, wherein said solvent is an aqueous solvent or a non-aqueous solvent or a combination of aqueous and non-aqueous solvents. The granulation liquid may be either used alone or, more usually, as a solvent containing a dissolved binder or as a suspension containing a dispersed binder. These prepared granules can optionally be mixed with extragranular materials to prepare desired final pharmaceutical composition.
[136] In wet granulation process, there are no particular limitations on solvents used for granulation. Suitable examples of solvents include, but are not limited to, aqueous or any of organic solvents, like water, lower alcohols such as methanol and ethanol, ketones such as acetone and methyl ethyl ketone, methylene chloride, and the like or any mixtures thereof.
[137] In another aspect of the above embodiments, said process comprises melt granulation methods, in which a substance that melts on heating is mixed with an active agent, melted together and granulated and dried. These prepared granules can optionally be mixed with extragranular materials to prepare desired final pharmaceutical composition.
[138] Suitable equipment used for preparing granules include, but are not limited to, planetary mixer, a screw mixer and the like; high-speed mixing granulation methods using a Henschel mixer, a Super mixer and the like; extruding granulation methods using a cylindrical granulator, a rotary granulator, a screw extruding granulator, a pellet mill type granulator and the like; wet high-shear granulation methods; fluidized-bed granulation methods; compression granulation methods; crushing granulation methods; and spraying granulation methods can be used.
[139] After granulation, the granules can be dried using an oven dryer, a fluidized bed dryer, and the like, crushing, and sieving can be carried out to obtain granules or fine granules for use. Moreover, a granulation solvent may be used when preparing the composition according to the present application.
[140] Suitable equipment that can be used for processing the composition of present application, include but are not limited to, rapid mixer granulators, planetary mixers, mass mixers, ribbon mixers, fluid bed processors, mechanical sifters, blenders, roller compacters, extrusion-spheronizers, compression machines, capsule filling machines, rotating bowls or coating pans, tray dryers, fluid bed dryers, rotary cone vacuum dryers, and the like, multi-mills, fluid energy mills, ball mills, colloid mills, roller mills, hammer mills, and the like, equipped with a suitable screen.
[141] In an embodiment, the present application relates to a process to prepare a composition comprising (a) therapeutically effective amount of valsartan or a pharmaceutically acceptable salt thereof, (b) therapeutically effective amount of atorvastatin or a pharmaceutically acceptable salt thereof, (c) at least one fast-dissolving carrier and (d) at least one water-insoluble carrier.
[142] In another embodiment, the present application relates to a process to prepare a composition comprising:
a) a valsartan portion comprising valsartan or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier,
b) a atorvastatin portion comprising atorvastatin or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier, and
c) one or more pharmaceutically acceptable excipients.
[143] In another embodiment, the present application relates to a process to prepare a composition comprising:
a) a valsartan portion comprising about 20mg to about 320mg of valsartan or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier,
b) a atorvastatin portion comprising about 5mg to about 80mg of atorvastatin or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier, and
c) one or more pharmaceutically acceptable excipients.
[144] In another embodiment, the present application relates to a process to prepare a composition comprising:
a) a valsartan portion comprising about 20mg to about 320mg of valsartan or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier in an amount ranging from about 40% to about 56%, and at least one water-insoluble carrier in an amount ranging from about 4% to about 7%, based on the total weight of the valsartan portion,
b) a atorvastatin portion comprising about 5mg to about 80mg of atorvastatin or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier in an amount ranging from about 16% to about 23%and at least one water-insoluble carrier in an amount ranging from about 34% to about 46%, based on the total weight of the atorvastatin portion, and
c) one or more pharmaceutically acceptable excipients.
[145] In one aspect of the above embodiments, said valsartan portion is prepared by dry granulation process and said atorvastatin portion is prepared by wet granulation process.
[146] In another aspect of the above embodiments, said valsartan portion comprises at least about 70% of total fast-dissolving carrier present in said composition.
[147] In another aspect of the above embodiments, said valsartan portion comprises not more than about 25% of total water-insoluble carrier present in said composition.
[148] In yet another aspect of the above embodiments, said fast-dissolving carrier and water-insoluble carrier in valsartan portion are present in a weight ratio from about 7:1 to about 9:1.
[149] In an aspect of the above embodiments, said composition comprises any one of the following dosages:
(a) 160 mg of valsartan and 10 mg of atorvastatin;
(b) 160 mg of valsartan and 20 mg of atorvastatin;
(c) 80 mg of valsartan and 10 mg of atorvastatin; or
(d) 80 mg of valsartan and 20 mg of atorvastatin.
[150] In an aspect of the above embodiments, said composition of the present application is stable for at least about 3 months upon storage at 40°C and 75% relative humidity (RH) or for at least about 12 months upon storage at 25°C and 60% relative humidity (RH). It is observed, the total valsartan-related impurities of not more than about 1.0%, and total atorvastatin-related impurities of not more than about 3.0%.
[151] In an embodiment, the present application relates to a process of preparing a composition comprising:
a) a valsartan portion comprising about 20mg to about 320mg of valsartan or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier,
b) a atorvastatin portion comprising about 5mg to about 80mg of atorvastatin or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier, and
c) one or more pharmaceutically acceptable excipients,
wherein said composition is stable for at least about 3 months upon storage at 40°C and 75% RH or for at least about 12 months upon storage at 25°C and 60% RH.
[152] In another embodiment, the present application relates to a process of preparing a composition comprising:
a) a valsartan portion comprising about 20mg to about 320mg of valsartan or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier in an amount ranging from about 40% to about 56%, and at least one water-insoluble carrier in an amount ranging from about 4% to about 7%, based on the total weight of the valsartan portion,
b) a atorvastatin portion comprising about 5mg to about 80mg of atorvastatin or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier in an amount ranging from about 16% to about 23%and at least one water-insoluble carrier in an amount ranging from about 34% to about 46%, based on the total weight of the atorvastatin portion, and
c) one or more pharmaceutically acceptable excipients,
wherein said composition is stable for at least about 3 months upon storage at 40°C and 75% RH or for at least about 12 months upon storage at 25°C and 60% RH.
[153] In an aspect of the above embodiments, said composition of present application is formulated in the form of tablets, capsules, lozenges, caplets, pills, wafers, films, powders, granules or sachets.
[154] In another aspect, said composition can be packaged in suitable pharmaceutically acceptable packaging materials that include, but not limited to, of polyethylene and/or polypropylene and/or glass, and blisters or strips composed of aluminum or high-density polypropylene, or polyvinyl chloride, or polyvinyl chloride coated with polyvinylidene dichloride, generally termed PVC/PVDC.
[155] In some aspects, the packaging container may include oxygen absorbers and/or desiccants along with packaging materials.
[156] In other aspects, the composition of the present application may be provided in primary packaging, wherein the packages are HDPE containers including a desiccant.
[157] In other aspects, the composition of the present application may be packed in HDPE containers together with Stabilox® as an oxygen absorber.
[158] In other aspects, the composition of the present application may be provided in primary packaging, wherein the packages are aluminum foil blisters.
[159] In other aspects, the composition of the present application may be in the form of a tablet and that may be formed in any shapes and sizes such as round, elongated, capsule-shaped, and may be embossed or debossed.
[160] The present application is further illustrated by the examples which are provided merely to be exemplary of the pharmaceutical composition described above and do not limit the scope of the application. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.
[161] The present invention is illustrated below by reference to the following examples. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the present invention, and not to be construed as limiting the application. The following examples may include compilations of data that are representative of data gathered at various times during the course of development and experimentation related to the present invention.

Examples:
[162] Example 1:
[163] The pharmaceutical compositions of present application are prepared as mentioned in Examples 1A, 1B, 1C, and 1D and in Table 1 below.
Table 1
Valsartan and Atorvastatin Tablets
Example 1A 1B 1C 1D 1E
S. No. Strengths (Valsartan/Atorvastatin) 160/20 160/10 80/20 80/10 160/40
Valsartan portion Ingredients % w/w % w/w % w/w % w/w % w/w
Intragranular
1 Valsartan 32 32 32 32 32
2 Lactose monohydrate 48.7 48.7 48.7 48.7 13.9
3 Microcrystalline cellulose 5.6 5.6 5.6 5.6 39.5
4 Crospovidone 6.4 6.4 6.4 6.4 6.5
5 Silica colloidal anhydrous (Aerosil 200) 0.4
6 Magnesium Stearate 0.5 0.5 0.5 0.5 0.4
7 Talc 0.5 0.5 0.5 0.5 0.4
Extra granular
8 Crospovidone 5.2 5.2 5.2 5.2 5.2
9 Silica colloidal anhydrous 0.8 0.8 0.8 0.8 1
10 Magnesium Stearate 0.2 0.2 0.2 0.2 0.6
11 Ferric oxide 0.1 0.1 0.1 0.1 0.1
Atorvastatin portion Ingredients % w/w % w/w % w/w % w/w % w/w
Intragranular
1 Atorvastatin Calcium Trihydrate (eq to Atorvastatin) 7.23 7.23 7.23 7.23 7.23
2 Calcium Carbonate Precipitated 22 22 22 22 22
3 Microcrystalline cellulose 40 40 40 40 40
4 Lactose monohydrate 19.47 19.47 19.47 19.47 19.47
5 Croscarmellose sodium 5 5 5 5 5
6 Polysorbate 80 0.8 0.8 0.8 0.8 0.8
7 Hydroxy propyl cellulose 2 2 2 2 2
Extragranular
8 Croscarmellose sodium 3 3 3 3 3
9 Magnesium stearate 0.5 0.5 0.5 0.5 0.5
Film coating - Opadry white OY 58900 (Hypromellose, Polyethylene glycol & Titanium dioxide)

[164] Procedure:
1. Preparation of Valsartan portion:
(a) Valsartan and other intragranular materials were sifted together, blended and lubricated
(b) The lubricated blend obtained in the step (a) was compacted using roller compactor to prepare granules, and the granules were milled to desired size using suitable compactor screens
(c) The extragranular materials were sifted together and blended with the granules obtained in step (b), followed by the lubrication of the blend.
2. Preparation of Atorvastatin portion:
(a) Atorvastatin and other intragranular materials were sifted together and mixed in a rapid mixture granulator for about 10 minutes
(b) A binder solution was prepared by dissolving polysorbate 80 in purified water at 50°C, and adding hydroxy propyl cellulose to the solution and homogenizing to dissolve it.
(c) The obtained mixture of step (a) was granulated using a binder solution of step (b)
(d) The granules obtained in step (c) were dried and sifted or milled
(e) The extragranular materials were sifted and blended with the granules obtained in step (d),
3. Compression:
(a) The prepared Valsartan portion and Atorvasatatin portion were compressed together as bilayered tablets
(b) The tablets prepared in step (a) are further coated and packed in suitable packaging materials.

[165] Example 2:
[166] The pharmaceutical compositions as prepared in Examples 1A-1D were subjected to dissolution studies in pH 6.8 phosphate buffer medium. The study was conducted using 900 ml media, at 75 rpm and 37°C using USP type II apparatus. The dissolution results are shown in Table 2A.
Table-2A Dissolution data of Valsartan and Atorvastatin Tablets in pH 6.8 phosphate buffer.

Time (minutes) ? Example -1A Example-1B Example-1C Example-1D
Valsartan % release Atorvastatin % release Valsartan % release Atorvastatin % release Valsartan % release Atorvastatin % release Valsartan % release Atorvastatin % release
5 99 89 96 90 99 86 93 93
10 102 99 101 99 101 100 98 103
15 103 101 101 100 102 103 99 104
30 104 102 102 100 103 104 99 104

[167] To compare the effect of varying ratios of fast-dissolving carrier and water-insoluble carrier on the release of valsartan, the compositions of Example 1A and 1E were subjected to dissolution studies in pH 4.5 acetate buffer medium. The study was conducted using 900 ml media, at 50 rpm and 37°C using USP type II apparatus. The dissolution results are shown in Table 2B.

Table-2B Dissolution data of Valsartan in pH 4.5 acetate buffer

Time (minutes) ? % drug release
Example-1A Example-1E
0 0 0
5 53 31
10 69 41
15 77 48
30 86 61
45 90 67
60 92 75

Example 3:
[168] An open label, randomized, two-treatment, three-period, three-sequence, single dose crossover bioequivalence study was performed comparing the composition of Example-1A tablets containing (Valsartan 160mg and Atorvastatin 20mg), versus commercially available Diovan® (Novartis Pharma GmbH, Germany) tablets containing 160 mg of valsartan and commercially available Lipitor® (Pfizer Ireland Pharmaceuticals, Ireland) tablets containing 20mg of atorvastatin, in healthy, adult, male subjects under fasting condition. Tables 3a and 3b present the data of atorvastatin and valsartan respectively from the study results.

Table – 3a: Pharmacokinetic data - Atorvastatin:
PK
parameters (units) Geometric least squares means and ratio 90% confidence interval ISCV%
Example-1A
(N = 43) Lipitor®
(N = 86) (T/R) %
Cmax
(ng/mL) 17.155 17.382 98.69 88.11% - 110.55% 37.69
AUC0-t (ng.h/mL) 76.443 78.493 97.39 93.24% - 101.72% 14.05
AUC0-inf (ng.h/mL)@ 80.288 82.121 97.77 93.60% - 102.13% 13.44

Table – 3b: Pharmacokinetic data - Valsartan:
PK
parameters (units) Geometric least squares means and ratio 90% confidence interval ISCV%
Example-1A
(N = 43) Diovan®
(N = 86) (T/R) %
Cmax (ng/mL) 6685.680 5693.680 117.42 107.11% - 128.73% 30.14
AUC0-t (ng.h/mL) 43942.485 38965.972 112.77 104.23% - 122.01% 25.66
AUC0-inf (ng.h/mL)@ 44808.786 39524.091 113.37 104.79% - 122.66% 25.36

[169] Example 4:
[170] The pharmaceutical compositions as prepared in Example 1 were subjected to accelerated stability testing for a period of 6 months under storage conditions at 40°C /75% RH. At the end of 3 months, the compositions were tested for various parameters and the results of Example 1A and 1D are shown in Tables 4a and 4d respectively.

Table – 4a: Stability data (3 months, at 40°C /75% RH) – Example: 1A
Impurities ? Lactam Imp Cyclo FP Cyclo IP Imp H Dihydroxy Imp Diketo Imp Ato HUII TI-Ato Imp-C Val Val HUII TI-Val
Months ?
0 0.043 0.054 0.102 0.057 0.025 0.032 0.021 0.462 0.043 0.038 0.135
1 0.059 0.132 0.179 0.222 0.038 0.072 0.026 0.792 0.053 0.041 0.154
2 0.092 0.190 0.241 0.314 0.068 0.109 0.040 1.144 0.034 0.053 0.112
3 0.126 0.244 0.172 0.531 0.115 0.133 0.049 1.472 0.053 0.050 0.100
Imp: Impurity; TI: Total Impurities; Ato: Atorvastatin; Val: Valsartan
Table – 4b: Stability data (3 months, at 40°C /75% RH) – Example: 1D
Impurities ? Lactam Imp Cyclo FP Cyclo IP Imp H Dihydroxy Imp Diketo Imp Ato HUII TI Ato Imp-C Val Val HUII TI Val
Months ?
0 0.056 0.071 0.127 0.059 0.025 0.032 0.080 0.545 0.047 0.029 0.101
1 0.079 0.151 0.251 0.248 0.063 0.100 0.033 0.938 0.066 0.040 0.174
2 0.161 0.201 0.217 0.309 0.125 0.123 0.057 1.345 0.066 0.039 0.159
3 0.208 0.294 0.290 0.415 0.143 0.166 0.058 1.792 0.074 0.048 0.122
Imp: Impurity; TI: Total Impurities; Ato: Atorvastatin; Val: Valsartan

[171] Example 5:
[001] The pharmaceutical compositions as prepared in Example 1 were subjected to long-term stability testing for a period of 24 months under storage conditions at 25°C and 60% RH. At the end of 24 months, the compositions were tested for various parameters and the results of Examples 1A, 1B, 1C and 1D are shown in Tables 5a, 5b, 5c, and 5d respectively.

Table – 5a: Stability data (24 months, at 25°C and 60% RH) – Example: 1A
Specification Related Substances/Impurities
Testing Period (In Months) Valsartan Atorvastatin
Maximum unspecified individual Imp Imp A (Enantiomeric Purity by HPLC) Total Impurities (Val)
(Excluding Imp A)
Imp H Lactam Imp ATV Cyclo IP ATV Cyclo FP Sum of Dihydroxy Epoxy and Diketo Epoxy Impurities Maximum unspecified individual Imp Total Impurities (Ato)
NMT 0.20% NMT 1.0% NMT 1.0% NMT 1.5% NMT 1.0% NMT 1.0% NMT 1.0 % NMT 1.5% NMT 2.0% NMT 4.0%
Initial 0.029 0.03 0.03 Less than LOQ 0.059 ND 0.56 0.071 0.013 0.23
3 0.046 0.09 0.03 0.07 0.13 0.16 0.15 0.14 0.019 0.75
6 0.034 0.12 0.02 0.16 0.08 0.24 0.21 0.19 0.019 1.04
9 0.04 0.1 0.04 0.1 0.1 0.3 0.3 0.2 0.02 1.1
12 0.04 0.1 0.03 0.1 0.1 0.3 0.3 0.3 0.04 1.3
18 0.04 0.1 0.03 0.1 0.1 0.3 0.4 0.4 0.03 1.5
24 0.03 0.03 0.03 0.2 0.1 0.4 0.5 0.4 0.03 1.9
Imp: Impurity; ATV: Atorvastatin; Ato: Atorvastatin; Val: Valsartan; LOQ (Imp H)=0.047
Table – 5b: Stability data (24 months, at 25°C and 60% RH) – Example: 1B
Specification Related Substances/Impurities
Testing Period (In Months) Valsartan Atorvastatin
Maximum unspecified individual Imp Imp A (Enantiomeric Purity by HPLC) Total Impurities (Val)
(Excluding Imp A)
Imp H Lactam Imp ATV Cyclo IP ATV Cyclo FP Sum of Dihydroxy Epoxy and Diketo Epoxy Impurities Maximum unspecified individual Imp Total Impurities (Ato)
NMT 0.20% NMT 1.0% NMT 1.0% NMT 1.5% NMT 1.0% NMT 1.0% NMT 1.0 % NMT 1.5% NMT 2.0% NMT 4.0%
Initial 0.043 0.1 0.03 Less than LOQ
0.053 Less than LOQ 0.56 0.56 0.013 0.25
3 0.046 0.09 0.03 0.06 0.05 0.17 0.11 0.13 0.029 0.65
6 0.051 0.11 0.03 0.12 0.05 0.11 0.2 0.2 0.028 0.94
9 0.045 0.1 0.03 0.11 0.05 0.18 0.24 0.2 0.02 0.9
12 0.04 0.1 0.03 0.1 0.1 0.2 0.3 0.3 0.02 1.2
18 0.05 0.1 0.03 0.1 0.1 0.2 0.3 0.3 0.03 1.3
24 0.04 0.1 0.03 0.2 0.1 0.3 0.4 0.4 0.05 1.8
Imp: Impurity; ATV: Atorvastatin; Ato: Atorvastatin; Val: Valsartan; LOQ (Imp H)=0.047; LOQ (ATV Cyclo IP)=0.047

Table – 5c: Stability data (24 months, at 25°C and 60% RH) – Example: 1C
Specification Related Substances/Impurities
Testing Period (In Months) Valsartan Atorvastatin
Maximum unspecified individual Imp Imp A (Enantiomeric Purity by HPLC) Total Impurities (Val)
(Excluding Imp A)
Imp H Lactam Imp ATV Cyclo IP ATV Cyclo FP Sum of Dihydroxy Epoxy and Diketo Epoxy Impurities Maximum unspecified individual Imp Total Impurities (Ato)
NMT 0.20% NMT 1.0% NMT 1.0% NMT 1.5% NMT 1.0% NMT 1.0% NMT 1.0 % NMT 1.5% NMT 2.0% NMT 4.0%
Initial 0.04 0.07 0.03 Less than LOQ
0.045 0.149 0.058 0.061 0.014 0.39
3 0.028 0.06 0.04 0.05 0.08 0.22 0.12 0.11 0.025 0.59
6 0.033 0.14 0.03 0.08 0.07 0.21 0.17 0.13 0.018 0.79
9 0.041 0.13 0.03 0.09 0.08 0.29 0.24 0.18 0.024 1.01
12 0.04 0.2 0.03 0.1 0.1 0.3 0.3 0.3 0.02 1.3
18 0.04 0.1 0.03 0.1 0.1 0.3 0.3 0.3 0.03 1.5
24 0.11 0.2 0.04 0.1 0.1 0.5 0.4 0.3 0.03 1.5
Imp: Impurity; ATV: Atorvastatin; Ato: Atorvastatin; Val: Valsartan; LOQ (Imp H) =0.047
Table – 5d: Stability data (24 months, at 25°C and 60% RH) – Example: 1D
Specification Related Substances/Impurities
Testing Period (In Months) Valsartan Atorvastatin
Maximum unspecified individual Imp Imp A (Enantiomeric Purity by HPLC) Total Impurities (Val)
(Excluding Imp A)
Imp H Lactam Imp ATV Cyclo IP ATV Cyclo FP Sum of Dihydroxy Epoxy and Diketo Epoxy Impurities Maximum unspecified individual Imp Total Impurities (Ato)
NMT 0.20% NMT 1.0% NMT 1.0% NMT 1.5% NMT 1.0% NMT 1.0% NMT 1.0 % NMT 1.5% NMT 2.0% NMT 4.0%
Initial 0.07 0.03 0.1 0.088 0.044 0.112 0.073 0.082 0.013 0.41
3 0.028 0.02 0.07 0.08 0.04 0.2 0.11 0.11 0.018 0.58
6 0.038 0.03 0.14 0.12 0.06 0.27 0.22 0.17 0.02 1.05
9 0.041 0.03 0.11 0.13 0.11 0.3 0.26 0.22 0.027 1.22
12 0.04 0.03 0.1 0.1 0.1 0.3 0.3 0.2 0.03 1.2
18 0.04 0.03 0.1 0.1 0.1 0.4 0.4 0.3 0.03 1.5
24 0.06 0.04 0.1 0.2 0.1 0.5 0.5 0.4 0.04 2
Imp: Impurity; ATV: Atorvastatin; Ato: Atorvastatin; Val: Valsartan;
,CLAIMS:CLAIMS
1. A composition comprising:
(a) therapeutically effective amount of valsartan or a pharmaceutically acceptable salt thereof,
(b) therapeutically effective amount of atorvastatin or a pharmaceutically acceptable salt thereof,
(c) at least one fast-dissolving carrier and
(d) at least one water-insoluble carrier, wherein said composition releases at least about 85% of valsartan and/or at least about 85% of atorvastatin, within about 15 minutes, when subjected to an in vitro dissolution study in 900 ml of pH 6.8 phosphate buffer medium at 75 rpm and 37°C using USP type II apparatus.

2. The composition of claim 1, wherein said composition comprises fast-dissolving carrier in an amount ranging from about 32% to about 44% and water-insoluble carrier in an amount ranging from about 15% to about 22%, based on the total weight of the composition.

3. The composition of claim 1, wherein said composition comprises valsartan and atorvastatin physically separated from each other and contained in a distinct or separate portions or layers.

4. The composition of claim 3, wherein said valsartan portion comprises at least one fast-dissolving carrier in an amount ranging from about 40% to about 56%, and at least one water-insoluble carrier in an amount ranging from about 4% to about 7%, based on the total weight of the valsartan portion.

5. The composition of claim 3, wherein said valsartan portion comprises at least about 70% of total fast-dissolving carrier present in total composition.

6. The composition of claim 1, wherein said composition comprises any one of the following dosages:
(a) 160 mg of valsartan and 10 mg of atorvastatin;
(b) 160 mg of valsartan and 20 mg of atorvastatin,
(c) 80 mg of valsartan and 10 mg of atorvastatin, or
(d) 80 mg of valsartan and 20 mg of atorvastatin.

7. The composition of claim 6, wherein said composition exhibits bioequivalence to commercially available Diovan® and Lipitor® oral formulations and said bioequivalence is established by 90% Confidence Interval (CI) of the relative mean of Cmax, AUC0-inf and AUC0-t within 80.00% to 125.00% of Diovan® and Lipitor®.

8. A bilayered tablet composition comprising:
(a) a valsartan portion comprising about 20mg to about 320mg of valsartan or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier,
(b) a atorvastatin portion comprising about 5mg to about 80mg of atorvastatin or a pharmaceutically acceptable salt thereof, at least one fast-dissolving carrier and at least one water-insoluble carrier, and
(c) one or more pharmaceutically acceptable excipients.

9. The composition of claim 8, wherein,
(a) the valsartan portion comprises at least one fast-dissolving carrier in an amount ranging from about 40% to about 56%, and at least one water-insoluble carrier in an amount ranging from about 4% to about 7%, based on the total weight of the valsartan portion, and
(b) the atorvastatin portion comprises at least one fast-dissolving carrier in an amount ranging from about 16% to about 23%, and at least one water-insoluble carrier in an amount ranging from about 34% to about 46%, based on the total weight of the atorvastatin portion.

10. The composition of claim 8, wherein the weight ratio of the valsartan portion and the atorvastatin portion is in the range of about 1:0.2 to 1:2.