ONCE A DAY FORMULATION OF ANGIOTENSIN RECEPTOR BLOCKERS

Field of the Invention

The present invention provides a once a day formulation of angiotensin receptor blockers (ARBs). The present invention also provides controlled release formulations of ARBs prepared by incorporating pharmaceutically effective amounts of solubilized ARB into a gastroretentive dosage form for once a day administration.

The present invention further provides controlled release compositions of ARBs with improved plasma profile, particularly achieving a significant plasma concentration of ARBs after about 12 hours post administration.

The present invention further provides once a day formulation of ARBs for the treatment and/or prevention of 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.

Background of the Invention

Angiotensin Il is a ^' very potent end product chemical that causes the muscles surrounding the blood vessels to contract, which thereby significantly narrow the blood vessels. This narrowing increases the pressure within arterial vessels, causing high blood pressure

(hypertension). Angiotensin receptor blockers (ARBs) are drugs that block the action of angiotensin II. As a result, arterial vessels dilate and blood pressure is reduced, thereby making it easier for the heart to pump blood. ARBs can therefore also be used to improve heart failure as well as hypertension. In addition, they slow the progression of kidney disease due to high blood pressure or diabetes.

The importance of aggressive blood pressure control is undisputed, but the therapeutic focus is now extending to end-organ protection as a treatment goal of equal importance to blood pressure reduction. Thus, the value of ARBs in slowing the progression of kidney disease due to high blood pressure or diabetes has very positive medical as well as commercial implications.

Drugs in this class include candesartan (Atacand, Astra-Zeneca), eprosartan (Teveten, Solvay & Biovail), irbesartan (Avapro, BMS), losartan (Cozaar, Merck), olmesartan (Benicar, Medoxomil; Sankyo & Forest), telmisartan (Micardis, Boehringer Ingelheim), valsartan (Diovan, Novartis) and pratosartan (Kotobuki). ARBs are used alone or in combination with other classes of antihypertensive agents that include thiazide diuretics, β- blockers, calcium channel blockers, rennin inhibitor, and ACE inhibitors, both for the treatment of hypertension and congestive heart failure.

Valsartan, a selective ARB, is a well-known antihypertensive agent. Valsartan is rapidly absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability of valsartan is about 25% (10-35%). This relatively low bioavailability of valsartan is primarily due to its poor solubility in the acid milieu of the gastrointestinal tract. Valsartan is an acid, and therefore, has good solubility at pH >5 and low solubility in acidic conditions of the gastrointestinal (Gl) milieu. Valsartan becomes ionized in small intestine and hence can not get absorbed in ionized form. Valsartan typically gets absorbed relatively slowly with Tmax in the range of 2-4 hours, however following Cmax the plasma concentration starts reducing reaching to very low level after 10-12 hours.

The synthesis and use of valsartan is described in U.S. Patent 5,399,578. Various polymorphs and salt forms of valsartan are described by U.S. Patent 7,105,557 and U.S.

Patent 6,869,970. Immediate release formulations comprising of different amounts of valsartan in the formulation are described in U.S. Patent 6,294,197, U.S. Patent 6,858,228,

PCT Publication WO 2007/052307 and PCT Publication WO 2008/056375. PCT Publication

WO 2008/056375 describes wet granulation process whereas' other patents describe roll compaction processes for the manufacturing of the dosage form.

U.S. Patent Application 2005/0234016 describes valsartan adsorbates which are prepared by adsorbing valsartan onto excipients like lactose or mannitol. The formulation releases about 90% drug in 30 minutes. Another U.S. Patent Application 2007/0166372 describes a coprecipitate of amorphous valsartan with a pharmaceutically acceptable carrier like polyvinyl pyrrolidone or polyethylene glycol which is formulated in dosage form for oral administration. In U.S. Patent 6,485,745, solid dosage forms of valsartan are described

which exhibit accelerated release of the active agent in pH 6.8 phosphate buffer. PCT Publication WO2006/066961 describes formulations of valsartan' using micronised valsartan. Although this patent increases the solubility of valsartan it failed to increase its bioavailability.

U.S. Patent Application 2002/0132839 and U.S. Patent Application 2003/0152620 discuss pharmaceutical compositions of valsartan tablet dosage form which are at least 1.2 times more bioavailable than the conventional valsartan capsule and are based on the usage of roll compaction method for dosage form manufacture.

Pharmaceutically active agents which exhibit low bioavailability unfortunately create a need for frequent dosing of a large amount of pharmaceuticals in order to provide and maintain therapeutic levels. The need for frequent dosing presents patient compliance problems and the need for large amount of active ingredient may result in increased toxicity. Above prior arts describe various aspects of immediate release formulations, however none of them describe any attempts to increase bioavailability or extend the release of valsartan.

European Patent Application 1897537 describes solid pharmaceutical composition of valsartan containing a pH modifier and pharmaceutically acceptable excipient. It is hypothetized that the presence of pH modifier in the formulation may enhance the intestinal absorption of the drug by promoting protonation of valsartan. PCT Publication WO 2006/113631 relates use of solubility enhancing agents for improving solubility and dissolution rates of ARBs. In vivo study results provided in the patent application details improvement in bioavailability of immediate release valsartan developed using solubilization approach, compared to marketed formulation. Although both these patent applications attempt to increase the bioavailability no special attempts were made for extending the drug release in order to reduce the dosing frequency. It is known that valsartan has a window of absorption and therefore simple incorporation of solubilized valsartan into controlled release formulation may not achieve the desired profile in-vivo.

PCT Publication WO 2007/086078 describes novel pharmaceutical composition comprising active agents exhibiting window of absorption with a permeation enhancer, adsorbent and a bioadhesive polymer. The formulation is in the form of fast disintegrating tablet comprising coated granules of active ingredient. This application does not detail any in-vitro data or in- vivo data exhibiting controlled release or increase in permeability of active ingredient. One of the important determining factors for improving bioavailability of valsartan is the poor solubility of valsartan which is not considered in the patent application.

Thus, though many attempts have been made to formulate immediate release formulations of valsartan with different manufacturing processes and compositions, these attempts have not targeted design of a controlled release formulation. As described earlier, valsartan has low solubility associated with window of absorption, both resulting in poor bioavailability and variability in drug response. Therefore, it becomes important to not only increase the solubility of valsartan but also to address the issue of window of absorption to increase bioavailability, extend drug release and design true once a day compositions.

Controlled release formulations exhibiting different release profiles are disclosed in several patents such as U.S. Patent 6,699,503, U.S. Patent 5,945,125 and U.S. Patent 6,107,276 (the '276 patent). ^' 276 patent describes controlled release of the solubilized active. A controlled release of a solubilized drug will only result in substantial improvement of bioavailability for drugs that are absorbed throughout the gastrointestinal tract. These prior approaches have proven not to be useful for drugs having a narrow window of absorption in the gastrointestinal tract, which demands the release of solubilized drug at or near the site of absorption in order to achieve improved bioavailability.

Hence gastroretentive dosage forms that can hold the active agents with a window of absorption near their main absorption window for extended time periods, thereby achieving controlled release and/or improved bioavailability of the active ingredient can be employed to design true once a day formulations of solubilized ARB such as valsartan.

U. S Patent 6,340,475 ('475 patent), describes a gastroretentive matrix formulation of a water soluble drug. U.S. Patent 5007790, U.S. Patent 6488962, U.S. Patent 6340475 and U.S. Patent 5972389 also describe matrix gastroretentive systems.

U.S. Patent 6,120,803 describes compositions wherein the active agent is incorporated in a polymer matrix that swells upon contact with fluid of stomach. A portion of the polymer matrix is surrounded by a band of insoluble material that prevents the concerned portion of polymer matrix from swelling and provides a segment of the dosage form that is of sufficient rigidity to with stand the environment of the stomach and delay expulsion of the dosage form from the stomach until substantially all of the active agent has been dispersed. This disclosure describes a special kind of gastroretentive system with a polymer band of insoluble material. Application of such a band on the tablets needs special equipment and is difficult to produce on a commercial scale.

U.S. Patent Application 2007/0196396 describes a controlled release oral pharmaceutical composition of pharmacologically active agent with low solubility formulated with solubilizers and swelling polymers along with a swelling enhancer. The formulation swells in the presence of water in gastric fluid such that the size of the dosage form is sufficiently increased to provide retention of the dosage form in the stomach of a patient, which gradually erodes within the gastrointestinal tract over a prolonged time period. This typically describes a matrix formulation wherein drug is dispersed in swelling polymers. This approach however results in prolongation of release and a sizeable amount of drug would remain unreleased. It is very difficult to customize this system for delivery of extremely hydrophobic drug such as valsartan in about 6-8 hours time.

Thus, the above mentioned attempts describe matrix type of gastroretentive systems meant for highly water soluble drugs which can be released by diffusion mechanism and for pharmaceuticals having low solubility, these systems would show prolonged and incomplete release. It therefore becomes very essential that the poorly soluble drug and the swelling polymers are present as different layers in a gastroretentive system.

U.S. Patent 5,780,057 describes a pharmaceutical dosage form for oral administration comprising multilayer tablets where at least one layer can rapidly swell by contact with biological and/ or aqueous fluids, said swelling resulting in a considerable increase in the tablet volume resulting in gastric retention. The formulation exhibits prolonged release of drug over extended time period where the tablets swell at least 50 % or more than the original volume and comprise of 1 to 90 % of swelling and biocompatible polymers in one layer and active drug in adjacent layer. This system is designed for sustained release of drug to upper Gl portion of a patient.

Another PCT application WO 2008/027945 describes an extended release gastro-retentive drug delivery system of valsartan comprising drug layer and a gastro-retentive portion designed for sustained release of drug to the upper Gl portion of a patient. The patent talks about the design of the gastroretentive dosage form and the formulation, however it does not describe drug release profile of the formulation or the bioavailability of valsartan from such formulation. The gastroretentive formulation targets the release of valsartan into the acidic environment (of the stomach) where solubility of valsartan is very low and therefore mere incorporation of valsartan into gastroretentive matrix would not achieve the desired in- vivo absorption profiles.

From these multilayer systems the release of poorly soluble drug may be possible; however for drugs such as valsartan even the release from such systems might be incomplete. This is because of extremely low solubility of valsartan in the acidic environment and therefore solubilization of valsartan is an essential requirement for the successful formulation of a controlled release gastroretentive formulation for once a day administration.

All ARBs and typically valsartan are antihypertensive agents also indicated for cardiovascular disorders such as myocardial infarction, and. endocrine and metabolic disorders. These conditions demand continuous supply of drug to the systemic compartment in order to achieve the desired therapeutic outcome. In other words, controlled release is an important requirement for the agents such as valsartan. Although currently valsartan is administered once a day, with a plasma half life of about 6 to 9 hours the therapeutic effects start waning towards the end of the day. Thus the current treatments are not true once a day

formulations. It is also well known that disorders such as myocardial infraction are early morning pathologies which mean that there is no protection for the patient during this period and patient is prone to such life threatening instances. Typically such instances could be avoided by administering drug twice daily, however this is not the regimen currently employed for ARBs and moreover it alters the patient compliance dramatically. Thus there is a much felt need for a formulation which achieves a true once a day formulation of ARBs that prevents risk to patients being prone to such life threatening situations.

After rigorous experimentation and brain storming it was realized that a successful controlled release formulation of valsartan can be achieved using a combination of solubilization with gastric retention in a system such as, for example, a bilayered tablet formulation. Such a system would ensure the most challenging prerequisites such as gastric retention, desired in-vitro release profile and significant plasma concentration post 12 hours after administration.

Summary of the Invention

The present invention provides once a day formulation of angiotensin receptor blockers (ARBs). The formulation comprises solubilized ARB and is in the form of a gastroretentive dosage form. A method of preparing this controlled release formulation is also disclosed in the present invention.

Objects of the Invention

An object of the present invention is to provide a controlled release formulation of angiotensin receptor blocker (ARB) for once a day administration comprising solubilized ARB. It is a further object of the present invention to provide controlled release formulation for once a day administration is prepared by incorporating the solubilized ARB in the gastroretentive dosage form.

Another object of the present invention is to provide a controlled release formulation for once a day administration in the form of bilayered gastroretentive dosage form having drug layer and gastroretentive layer.

Yet another object is to provide a controlled release formulation wherein the release of solubilized ARB from the drug layer is controlled using release retardants.

A further object of the present invention is to provide a controlled release formulation which has at least two dimensions of greater than 10 mm in 2 hour in 0.1 N hydrochloric acid.

A still further object relates to solubilizing low solubility drugs and further incorporating the solubilized drugs into gastroretentive compositions that are cost efficient to manufacture on a commercial scale

Another object of the present invention is to provide a formulation that achieves significant plasma concentration of ARBs even after about 12 hours post administration thus providing a controlled release formulation for once a day administration.

A further object of the present invention is to provide a novel controlled release formulation of ARB for once a day administration wherein the ARB is valsartan. Furthermore, an object of the present invention is to provide a gastro-retentive composition of solubilized valsartan which releases solubilized valsartan in a controlled manner near absorption site to ensure better absorption of the drug resulting in increased bioavailability coupled with extended release enhancing its therapeutic benefits.

A yet another object is to provide a novel controlled release formulation for an ARB that obtains peak plasma levels in 2.5 to 7.5 hours after administration under various conditions such as fasted, fed with food having high calorific content or fed with food having low calorific content.

In another aspect of the present invention, when the drug is valsartan or a pharmaceutically acceptable salt thereof, the novel controlled release formulation provides a mean maximum plasma concentration (C _max ) of the drug that is about 300 ng/ml to about 6000 ng/ml , based on administration of a 80 mg once-a-day dose of valsartan.

In a further aspect of the present invention, when the drug is valsartan or a pharmaceutically acceptable salt thereof, the novel controlled release formulation provides a mean AUC _0- , _* that is about 8000 ng.hr/ml to about 30000 ng.hr/ml, based on administration of a 80 mg once-a-day dose of valsartan.

In yet another aspect of the present invention, a novel controlled release formulation for an ARB is provided that obtains relative bioavailability of more than 80%.

Another object is to provide a gastroretentive pharmaceutical composition of ARBs that has reduced level of dose frequency and improved patient compliance along with desirable therapeutic outcome.

A further object is to also provide a novel controlled release formulation of ARBs for the treatment and/or prevention of 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

A still further object is also to provide use of the drug delivery system of the present invention for the manufacture of a medicament for the treatment and/or prevention of 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.

A yet another object of the present invention is to provide a novel controlled release formulation of ARBs for the treatment and/or prevention of cardiovascular and endocrine and metabolic disorders in patients who normally do not respond to conventional therapy.

Brief Description of the Drawings

Figure 1 is a graph showing the oral bioavailability (in vivo performance) of valsartan bilayered tablet formulation described under Example 3 as compared to marketed valsartan formulation (Diovan) Figure 2 is a graph showing the oral bioavailability (in vivo performance) of valsartan bilayered tablet formulation described under Example 5 as compared to marketed valsartan formulation (Diovan)

Detailed Description of the Invention According to the basic principles of drug absorption, only the drug in the neutral form present in solution can permeate across the lipid cell membranes. Therefore, it is very essential for better absorption; that the drug substance should be lipophilic in nature and have adequate solubility in the Gl milieu. In general, chemically, most of ARBs have a common feature, i.e., at least one free carboxylic acid group, which makes ARBs insoluble in acid conditions and ionized (soluble form) in alkaline environment. For example, valsartan has a carboxylic acid group, and therefore, it is not readily soluble in acidic medium. Absorption of valsartan in an acidic environment is, therefore, low due to its poor solubility.

However, in an alkaline environment valsartan is in completely ionized form and therefore permeates poorly through the cell membranes. In other words, valsartan has poor absorption in the gastrointestinal tract due to a combination of poor solubility of the free acid form in acidic/weakly acidic Gl milieu and poor permeability of the dissolved (ionized) form. The result is low bioavailability of 10-35%. Even those ARBs which do not possess any carboxylic acid functionality exhibit low solubility in acidic/weakly acid medium. This coupled with rapid elimination ensures that plasma levels fall relatively rapidly. Due to this phenomenon there arises the need to solubilize the ARB and design its controlled release dosage forms to maintain steady plasma levels over the extended time period. All ARBs and in particular valsartan, is known have a window of absorption which further complicates development of a controlled release formulation. Due to window of absorption a standard controlled release system would not be effective as there is no absorption of drug beyond the window of absorption and therefore gastroretentive dosage forms are desired.

Pharmaceutical dosage forms which are retained in the stomach for a prolonged period of time after oral administration and release the active ingredient in a controlled manner are important for a variety of drugs. Design of such specialized dosage forms is a challenge for a formulator because of their actual in vitro release profiles and complexities of physiological effects and their implication for drug release and absorption in vivo. It is therefore important to understand the normal digestive process and the fed state.

In the normal digestive process, the passage of matter through the stomach is delayed by a physiological condition that is variously referred to as the digestive mode, the postprandial mode, or the "fed mode." The difference between the two modes, fasted and fed, lies in the pattern of gastroduodenal motor activity. In the fasting mode, the stomach exhibits a cyclic activity called the interdigestive migrating motor complex ("IMMC"). This activity occurs in four phases: Phase I : It lasts 45 to 60 minutes, is the most quiescent, with the stomach experiencing few or no contractions; Phase Il : It is characterized by sweeping contractions occurring in an irregular intermittent pattern and gradually increasing in magnitude; Phase III : It consists of intense bursts of peristaltic waves in both the stomach and the small bowel, lasting for about 5 to 15 minutes; and Phase IV : It is a transition period of decreasing activity which lasts until the next cycle begins.

The total cycle time for all four phases is approximately 90 minutes. The greatest activity occurs in Phase III, when powerful peristaltic waves sweep the swallowed saliva, gastric secretions, food particles, and particulate debris, out of the stomach and into the small intestine and colon. Phase III thus serves as an intestinal housekeeper, preparing the upper tract for the next meal and preventing bacterial overgrowth.

The fed mode is initiated by nutritive materials entering the stomach upon the ingestion of food. Once the fed mode is established, the stomach generates 3-4 continuous and regular contractions per minute, similar to those of the fasting mode but with about half the

amplitude. The pylorus is partially open, causing a sieving effect in which liquids and small particles flow continuously from the stomach into the intestine while indigestible particles greater in size than the pyloric opening are retropelled and retained in the stomach. This sieving effect thus causes the stomach to retain particles exceeding about 10mm in size for approximately 4 to 6 hours.

Accordingly, the present drug delivery systems are used to administer a drug to the fed stomach and upper G.I. tract while minimizing drug release in the lower G.I. tract and colon. The term "fed mode," as used herein, refers to a state which is typically induced in a patient by the presence of food in the stomach. It has been determined that once the fed mode has been induced, larger particles are retained in the stomach for a longer period of time than smaller particles. Thus, the fed mode is typically induced in a patient by the presence of food in the stomach.

The present invention provides solubilization of ARBs and its incorporation into a g astro retentive system to increase their bioavailability and to provide true once a day formulation. Such a controlled release gastroretentive system ensures availability of maximum amount of drug in solubilized form at or near the site of absorption i.e. absorption window. The slow release of the solubilized drug also ensures that there is no saturation effect, if at all for the absorption process.

Accordingly, the present inventors after meticulously planned experimentation for the selection of optimum solubilizers, gastroretentive layer components which despite erosion, achieve a size that precludes passage through pyloric sphincter to permit gastroretention and release retardants which provides most favorable in-vitro dissolution profiles, have designed controlled release gastroretentive dosage form for once a day administration.

Definitions

The term "controlled release" or "extended release", as used herein, includes, but is not limited to, any non-immediate type of release of ARB that is appropriate to obtain a desired therapeutic or prophylactic response after administration to a subject.

The term "bioavailability", as used herein, includes, but is not limited to, the rate and extent to which the ARB becomes available at the site of action after administration.

The term "relative bioavailability", as used herein, denotes the ratio, expressed as a percentage, of the AUCs of the formulation of the present invention and the orally administered immediate release marketed formulations at the same dosage strength.

The term "C _max " is the highest plasma concentration of the drug attained within the dosing interval.

The term "T _max " is the time period which elapses after administration of the dosage form at which the plasma concentration of the drug attains the highest plasma concentration of drug attained within the dosing interval.

The term "AUC _0-t " as used herein, means area under plasma concentration-time curve from drug administration to last observed concentration at time t.

The term "AUC ₀ . _* ,". as used herein, means area under the plasma concentration-time curve extrapolated to infinite time

The term "single dose" means that the human patient has received a single dose of the drug formulation and the drug plasma concentration has not achieved steady state.

The term "mean", when preceding a pharmacokinetic value (e.g. mean T _013x ) represents the mean value of the pharmacokinetic value taken from a population of patients or healthy volunteers.

Angiotensin Il Receptor Blockers The active ingredient for the purpose of this invention is an angiotensin receptor blocker (ARB) and is selected from candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, pratosartan and other drugs belonging to the category of ARB. The

active ingredient of the invention may be present in crystalline or part crystalline or amorphous form or as a solid solution or dispersion form. The crystalline form may have different polymorphs. All different polymorphs, solvates, hydrates, salts are within the purview of this invention. Also included within the scope of the present invention are the salts, esters, amides, prodrugs, active metabolites, analogs, and the like. In one embodiment of the present invention, the active ingredient is valsartan. In another embodiment the active ingredient is calcium salt of valsartan. Valsartan is employed in an amount typically ranging from about 40 mg to about 640 mg. In one embodiment, the amount of valsartan is from about 40 mg to about 320 mg. In another embodiment, the amount of valsartan is from about 80 mg to about 320 mg. The amount of valsartan noted above refers to the amount of free valsartan present in a dosage form.

In the dosage form of the present invention in addition to ARB; one or more, for example two, furthermore three, active ingredients as specified according to the present invention can be combined. The therapeutic agents, which may be combined with an ARB include, but are not limited to, other anti-hypertensive agents particularly diuretics such as thiazides, rennin inhibitors, ACE inhibitors, anti-obesity agents, anti-diabetic agents, insulin secretion enhancers, insulin sensitizers, beta-blockers, platelet aggregation inhibitors, NEP inhibitors, calcium channel blockers, cox-2 inhibitors, HMG-COA reductase inhibitors, inotropic agents, aldosterone receptor antagonists and hypolipidemic agents and other agents that might be used for treatment of diseases or disorders of cardiovascular system and/or endocrine and metabolic disorders.

The therapeutic agents, which may be combined with an ARB include, but are not limited to amlodipine, hydrochlorothiazide, riampterine, furosemide, tbumetanide chlorothiazide, chlorthalidone, bendroflumethiazide aliskiren, rosiglitazone, pioglitazone, captopril, enalopril or its salts, erythromycin lactobiόnate, ranitidine hydrochloride, sertraline hydrochloride, lercanidipine, atenolol, metoprolol, timolol, propranolol, benazepril, benazeprilat, enalapril, verapamil, atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, aspirin, clopidogrel, , ticlopidine hydrochloride, amoxicillin, cefuroxime axetil, cefaclor, clindamycin, doxifluridine, gabapentin, tramadol, fluoxetine hydrochloride, ciprofloxacin

hydrochloride, acyclovir, levodopa, ganciclovir, bupropion, lisinopril, nateglinide, metformin hydrochloride, vancomycin hydrochloride, epoxymexrenone etc

The active ingredient may be present in an amount from about 1 % to about 80% by weight of the composition. In one embodiment, the active ingredient is present in an amount from about 2% to about 70% by weight of the composition. In another embodiment, the active ingredient is present in an amount from about 5% to about 50%by weight of the composition.

The entire dose of the active ingredient may be present in the solubilized form or alternatively part of the active ingredient is present in solubilized form whereas the other part as non-solubilized form, the ratio of which can vary from 1 :99 to 99:1.

Solubility Enhancing Agent

According to this invention, the increase in instantaneous solubility of an ARB in a composition is achieved by using at least one solubility enhancing agent. The controlled release formulation for the purpose of the present invention for once a day administration comprises such solubilized ARB.

The solubility enhancing agent or solubilizer may include one or more surfactant, pH modifier, complexing agent, hydrotropic agent, and the like. The solubility enhancing agent could be the same or different for different ARB's. This category of excipients also includes excipients that might help in improving the absorption of active ingredient such as acidulants and ion pairing agents.

The solubility enhancing agent as employed in the present invention includes, but is not limited to, hydrophilic surfactants, lipophilic surfactants or mixtures thereof. The relative hydrophilicity and hydrophobicity of surfactants is described by HLB (hydrophilic-lipophilic balance) value. Hydrophilic surfactants include surfactants with HLB greater than 10 while lipophilic surfactants are surfactants having an HLB value less than 10. The surfactants employed in the present invention may also include, but are not limited to, ionic surfactants comprising cationic or anionic surfactants, zwitterionic or amphiphilic surfactants or nonionic surfactants or the like or any combinations thereof.

The ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, or polypeptides; glyceride derivatives of amino acids; lecithins or hydrogenated lecithins; lysolecithins or hydrogenated lysolecithins; phospholipids or derivatives thereof; lysophospholipids or derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acyl lactylates; mono- or di-acetylated tartaric acid esters of mono- or di-glycerides; succinylated mono- or di-glycerides; citric acid esters of mono- or di-glycerides; or mixtures thereof.

The amphiphilic surfactants include, but are not limited to, d-α-tocopheryl polyethylene glycol 1000 succinate and d-α-tocopherol acid salts such as succinate, acetate, etc.

The non-ionic surfactants include, but are not limited to, fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols or sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- or di- glycerides; oil-soluble vitamins/vitamin derivatives; PEG fatty acid esters; polyglycerized fatty acid; polyoxyethylene-polyoxypropylene block copolymers; transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols wherein the commonly used oils are castor oil or hydrogenated castor oil, or an edible vegetable oil such as corn oil, olive oil, peanut oil, palm kernel oil, almond oil and the commonly used polyols include glycerol, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol and pentaerythritol; or mixtures thereof.

The solubility enhancing agent may be PEG-20-glyceryl stearate (Capmul® by Abitec), PEG-40 hydrogenated castor oil (Cremophor RH 40® by BASF), PEG-35 castor oil, PEG 6 corn oil (Labrafil® by Gattefosse), lauryl macrogol - 32 glyceride (Gelucire 44/14® by Gattefosse), stearoyl macrogol glyceride (Gelucire 50/13® by Gattefosse), polyglyceryl - 10 mono dioleate (Caprol ® PEG 860 by Abitec), propylene glycol oleate (Lutrol OP® by BASF), propylene glycol dioctanoate (Captex® by Abitec), propylene glycol

capryiate/caprate (Labrafac® by Gattefosse), glyceryl monooleate (Peceol® by Gattefosse), glycerol monolinoleate (Maisine ® by Gattefosse), glycerol monostearate (Capmul® by Abitec), PEG- 20 sorbitan monolaurate (Tween 20® by ICI), PEG - 4 lauryl ether (Brij 30® by ICI), sucrose distearate (Sucroester 7® by Gattefosse), sucrose monopalmitate (Sucroester 15® by Gattefosse), polyoxyethylene-polyoxypropylene block copolymer (Lutrol® series BASF), polyethylene glycol 660 hydroxystearate, (Solutol® by BASF), sodium lauryl sulphate, sodium dodecyl sulphate, dioctyl suphosuccinate, L- hydroxypropyl cellulose, hydroxylethylcellulose, hydroxy propylcellulose, propylene glycol alginate, sodium taurocholate, sodium glycocholate, sodium deoxycholate, betains , polyethylene glycol (Carbowax® by DOW), d-α-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS® by Eastman), or mixtures thereof.

In one embodiment the solubility enhancing agent may be PEG-40 hydrogenated castor oil (Cremophor RH 40® by BASF - HLB - 13), lauryl macrogol - 32 glyceride (Gelucire 44/14® by Gattefosse - HLB - 14) stearoyl macrogol glyceride (Gelucire 50/13® by Gattefosse - HLB - 13), PEG- 20 sorbitan monolaurate (Tween 20® by ICI - HLB - 17), PEG - 4 lauryl ether (Brij 30® by ICI- HLB - 9.7), polyoxyethylene-polyoxypropylene block copolymer (Lutrol® series BASF having different HLB ranging from 15-30), Sodium lauryl sulphate (HLB- 40), polyethylene glycol (Carbowax® by DOW), d-α-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS® by Eastman- HLB - 15), or mixtures thereof.

In another embodiment of the present invention, the solubility enhancing agent is polyethylene-polyoxypropylene block copolymer (Lutrol © series BASF having different HLB ranging from 15-30) and d-α-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS® by Eastman- HLB - 15)

The solubilizers may also include pH modifiers such as buffers, amino acids and amino acid sugars and the like.

The complexing agent includes cyclodextrin class of molecules, such as cyclodextrins containing from six to twelve glucose units, especially, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, or their derivatives, such as hydroxypropyl beta cyclodextrins, or

mixtures thereof. The complexing agents may also include cyclic amides, hydroxyl benzoic acid derivatives as well as gentistic acid. In this complexation process, a hydrophilic polymer may be additionally added to further enhance the solubility along with the complexing agent.

The absorption of the drug can be further increased by increasing the absorbable form of the drug or inhibition of p-glycoprotein mediated efflux. Absorbable form of the drug can be increased by preventing or reduciηg its ionization in the GIT by using acidulant or by using ion pairing agents which makes the drug more lipophilic.

Acidulants, physiologically compatible water-soluble organic acids decrease the pH of the lower gastrointestinal tract and increase the absorbable form of an ARB. Acidulants refer to aliphatic or aromatic, saturated or unsaturated, monobasic acid (monocarboxylic acid), dibasic acid (dicarboxylic acid) or tribasic acid (tricarboxylic acid). In one embodiment, the acidulant is an organic acid having 2 to 10 carbon atoms. In another embodiment, the acidulant is an organic acid having 2 to 6 carbon atoms. Examples of a monobasic acid include, but are not limited to, saturated aliphatic monocarboxylic acids such as acetic acid, propionic acid, lactic acid and valeric acid, and monobasic amino acids such as glycine, alanine, valine, leucine and isoleucine. Examples of a dibasic acid include, but are not limited to, saturated aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, glutaric acid and adipic acid, unsaturated aliphatic dicarboxylic acids such as maleic acid and fumaric acid, aromatic dicarboxylic acids such as phthalic acid, dibasic amino acids such as aspartic acid and glutamic acid, and hydroxy dibasic acids such as malic acid and tartaric acid. Examples of a tribasic acid include, but are not limited to, hydroxy tribasic acids such as citric acid. The organic acid may be a salt. Examples of the salt of the organic acid include, but are not limited to, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt, and organic salts such as ammonium salt, with preference given to sodium salt.

In one embodiment of the present invention, the acidulant is malic acid, tartaric acid, fumaric acid, maleic acid, aspartic acid or. citric acid. Acidulants may be employed in an amount sufficient to reduce the pH of the content of the lower GIT.

The present invention may involve the use of ion pairing agents to modulate the solubility and partitioning behavior ARBs which in turn result in increased absorbable form of ARB and improved bioavailability. Ion pairing agents form ion pairs with ARBs by stoichiometric interaction of the cationic group of these agents with acidic functional groups of an ARB. The acidic group may be a carboxylic acid group or any other proton donating group. An ion pair formed being neutral in character will have reduced aqueous solubility and increased permeability compared to ionized form of the drug. Measurement of the apparent partition coefficient, defined as the ratio of the equilibrium concentration in an organic phase to that in an aqueous phase, demonstrates that the solubility of an ARB in an ion pair complex in the organic phase is greater by 2-4 orders of magnitude relative to the ARB itself. Included in the present invention are cationic ion-pairing agents such as, but not limited to, α- phosphotidyl choline, cetyl pyridinuim chloride, cetyl triammonium bromide, benzalkonium chloride and the like.

In the composition of the present invention, the ARB and one or more solubility enhancing agents may be employed in different ratios. The selected ratio depends upon the desired improvement in solubility and the type of solubility enhancing agents employed. It is contemplated within the scope of the invention that the ratio of ARB to solubility enhancing agents may range from about 50:1. to about 1 :50. In one embodiment, the ratio of ARB to solubility enhancing agent is from about 20:1 to about 1 :20. In another embodiment, the ratio of ARB to solubility enhancing agent is from about 10:1 to about 1:10. A combination of solubility enhancing agents may also be included where the total amount of solubility enhancing agent employed is maintained in the above-mentioned ratios.

In the composition, the ARB may be present in the form of physical blend, solid dispersion, solid solution or complex with the solubility enhancing agent. Different processes may be employed to prepare the composition of the ARB with the solubility enhancing agents. It is contemplated within the scope of the invention that the processes may include, but not limited to, solubilization using melt granulation, solvent treatment, wet granulation, physical mixing or spray drying of the dissolved ARB in a solvent with a solubility enhancing agent.

In the case of melt granulation, the solubility enhancing agent is melted. The ARB is then added and mixed with the molten mass, and allowed to solidify to form granules which are then separated from each other.

In another embodiment the solubility enhancing agents are melted. The ARB is then added and mixed with the molten mass. This blend is further mixed with diluents capable of converting this semisolid mass into dry powder. Non limiting examples of such drying agents include celluloses such as microcrystalline cellulose, silicon dioxide, silicates, magnesium aluminium silicate etc. In another illustrative embodiment of this system, the ARB is granulated using a molten solubility enhancing agent. In some cases, the ARB and the solubility enhancing agent both may be melted together and congealed to room temperature.

In using a solvent treatment method, either the solubility enhancing agents or the ARB, or both, are dissolved in a solvent which is then evaporated or spray dried. The resultant mass is a blend of ARB and solubility enhancing agent, such that the solubility of the ARB is increased. The solvent employed in this system may be aqueous or non-aqueous.

In the case of physical mixing, the ARB and the solubility enhancing agent are preferably intimately dry-mixed using a low shear granulator, a V-blender, or a high shear granulator.

In the complexation method, complex of ARB can be prepared using different techniques such as ball milling, solvent evaporation method which includes, but is not limited to, spray drying and lyophilization process, slurry method, and paste method.

It is contemplated within the scope of the invention that a combination of aforementioned processes can be employed. For example, a combination of hot melt process, physical mixing, and solvent treatment method may be employed. In this case, the ARB may be initially granulated with one or more molten solubility enhancing agents, which can be further treated with the same or different solubility enhancing agents in a solvent or with simple physical mixing or vice versa. It is also contemplated within the scope of the invention that

any process known in the art suitable for making pharmaceutical compositions in general may be employed for the purpose of this invention.

Melt granulation and intimate physical mixture are the most preferred methods for preparing formulations of valsartan according to the present invention. The increase in solubility may be determined by studying the actual solubility studies of the valsartan in presence of the solubility enhancing agent, or by carrying out dissolution studies in an appropriate dissolution medium. In most instances the dissolution method is used, as it allows the comparison of the rate of dissolution of different formulations by determining the amount of valsartan dissolved at different time intervals.

Release Retardants

In order to achieve the controlled release properties, the solubilized ARB is incorporated in the dosage form .with at least one release retardant. Release retardants are excipients polymeric or non-polymeric which by way of various mechanisms retard release of the active ingredient. The release retardants used in the drug layer of the present invention should not release the drug at too rapid a rate so as to result in a rapid passage into and through the gastrointestinal tract (i.e., in less than about four hours), nor should the polymer release too slowly to achieve the desired biological effect.

Release retardants suitable for this invention include excipients well known in the pharmaceutical art for their release retarding properties. Examples of such release retardants include, but are not limited to, polymeric release retardants, non-polymeric release retardants or any combinations thereof.

Polymeric release retardants employed for the purpose of the present invention include, but are not limited to, cellulose derivatives; polyhydric alcohols; saccharides, gums and derivatives thereof; vinyl derivatives, polymers, copolymers or mixtures thereof; maleic acid copolymers; polyalkylene oxides or copolymers thereof; acrylic acid polymers and acrylic acid derivatives; or any combinations thereof.

Cellulose derivatives include, but are not limited to, ethyl cellulose, methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl ethylcellulose, carboxymethylethyl cellulose, carboxy- ethylcellulose, carboxymethyl hydroxyethylcellulose, hydroxyethylmethyl carboxymethyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose (CMC), methylhydroxyethyl cellulose, methylhydroxypropyl cellulose, carboxymethyl sulfoethyl cellulose, sodium carboxymethyl cellulose, or combinations thereof.

Polyhydric alcohols include, but are not limited to, polyethylene glycol (PEG) or polypropylene glycol; or any combinations thereof.

Saccharides, gums and their derivatives include, but are not limited to, dextrin, polydextrin, dextran, pectin and pectin derivatives, alginic acid, sodium alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropyl starch, amylose and amylopectin, CMC agar; guar gum, locust bean gum, xanthan gum, karaya gum, tragacanth., carrageenan, acacia gum, arabic gum or gellan gum or the like; or any combinations thereof.

Vinyl derivatives, polymers, copolymers or mixtures thereof include, but are not limited to, polyvinyl acetate, polyvinyl alcohol, mixture of polyvinyl acetate (8 parts w/w) and polyvinylpyrrolidone (2 parts w/w) (Kollidon SR), copolymers of vinyl pyrrolidone, vinyl acetate copolymers, polyvinylpyrrolidone (PVP); or combinations thereof.

Polyalkylene oxides or copolymers thereof include, but are not limited to, polyethylene oxide, polypropylene oxide, poly (oxyethylene)-poly (oxypropylene) block copolymers (poloxamers) or combinations thereof.

Maleic acid copolymers include, but are not limited to, vinylacetate ^' maleic acid anhydride copolymer, styrene ^' maleic acid anhydride copolymer, styrene ^' maleic acid monoester copolymer, vinylmethylether ^' maleic acid anhydride copolymer, ethylene ^' maleic acid anhydride copolymer, vinylbutyiether ^' maleic acid anhydride copolymer, acrylonitrile ^' methyl

acrylate ^' maleic acid anhydride copolymer, butyl acrylate ^' styrene ^' maleic acid anhydride copolymer or the like or any combinations thereof

Acrylic acid polymers and acrylic acid derivatives include, but are not limited to, carbomers, methacrylic acids, polymethacrylic acids, polyacrylates, polymethacrylates or the like or combinations thereof

Polymethacrylates, include, but are not limited to, a) copolymer formed from monomers selected from methacrylic acid, methacrylic acid esters, acrylic acid and acrylic acid esters c) copolymer formed from monomers selected from ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride, e g those available from Rohm GmbH under the trademark Eudragit ^® like Eudragit RL and RS (trimethylammonioethyl methacrylate copolymer), Eudragit NE30D, Eudragit NE40D and Eudragit NM30D (ethylacrylate methymethacrylate copolymer), or the like or any combinations thereof

Non-polymeric release retardants employed for the purpose of the present invention include, but are not limited to, fats, oils, waxes, fatty acids, fatty acid esters, long chain monohydric alcohols and their esters or combinations thereof

Waxes are esters of fatty acids with long chain monohydric alcohols Natural waxes are often mixtures of such esters, and may also contain hydrocarbons Waxes employed in the present invention include, but are not limited to, natural waxes, such as animal waxes, vegetable waxes, and petroleum waxes (ι e , paraffin waxes, microcrystalline waxes, petrolatum waxes, mineral waxes), and synthetic waxes Specific examples include, but are not limited to spermaceti wax, carnauba wax, Japan wax, bayberry wax, flax wax, beeswax, yellow wax, Chinese wax, shellac wax, lanolin wax, sugarcane wax, candelilla wax, castor wax paraffin wax, microcrystalline wax, petrolatum wax, carbowax, and the like, or mixtures thereof

Waxes are also monoglyceryl esters, diglyceryl esters, or tπglyceryl esters (glycerides) and derivatives and mixtures thereof formed from a fatty acid having from about 10 to about 22 carbon atoms and glycerol, wherein one or more of the hydroxyl groups of glycerol are

substituted by a fatty acid. Glycerides employed in the present invention include, but are not limited to, glyceryl monostearate, glyceryl distearate, glyceryl tristearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monopalmitate, glyceryl palmitostearate, glyceryl dilaurate, glyceryl trilaurate, glyceryl monolaurate, glyceryl didocosanoate, glyceryl tridocosanoate, glyceryl monodocosanoate, glyceryl monocaproate, glyceryl dicaproate, glyceryl tricaproate, glyceryl monomyristate, glyceryl dimyristate, glyceryl trimyhstate, glyceryl monodecenoate, glyceryl didecenoate, glyceryl tridecenoate, glyceryl behenate (compritol), polyglyceryl diisostearate, lauroyl macrogolglycerides (Gelucire), oleoyl macrogolglycerides, stearoyl macrogolglycerides, mixtures . of monoglycerides and diglycerides of oleic acid (Peceol), or combinations thereof.

Fatty acids include, but are not limited to, hydrogenated palm kernel oil, hydrogenated peanut oil, hydrogenated palm oil, hydrogenated rapeseed oil, hydrogenated rice bran oil, hydrogenated soybean oil, hydrogenated sunflower oil, hydrogenated castor oil (Lubritab), hydrogenated cottonseed oil, and mixtures thereof. Other fatty acids include, but are not limited to, decenoic acid, docosanoic acid, stearic acid, palmitic acid, lauric acid, myristic acid, or the like, or mixtures thereof.

Long chain monohydric alcohols include, but are not limited to, cetyl alcohol, or stearyl alcohol or mixtures thereof.

In one embodiment a release retardant with appropriate hydration characteristics employed for the purpose of the present invention is hydroxypropylmethylcellulose.

The amount of release retardant relative to the drug may vary depending on the release rate desired, nature of the retardants and their physicochemical characteristics. The amount of the release retardant in the dosage form generally varies from about 5% to about 95% by weight of the drug, layer. In one embodiment, the amount of release retardant varies from about 5% to about 75% by weight of the drug layer.

Gastroretention

According to the present invention, an additional component of the inventive system comprises increased gastric retention. In one embodiment, the controlled release formulation for once a day administration comprising solubilized ARB is in the form of a gastroretentive dosage form. A number of gastro-retentive sustained release systems are reported in the literature. The following three major approaches describe gastroretentive controlled release devices that may be employed according to the invention:

Floating or buoyant system: These systems have low density enabling them to float on gastric contents after their administration until the system either ^' disintegrates, or the device absorbs fluid to the point where its density increases to an extent that it loses buoyancy and can then pass more easily from the stomach;

Bioadhesive system: This system is designed to imbibe fluid following their administration such that the outer layer becomes a viscous, tacky material that adheres to the gastric mucous/ mucus layer; and

Swelling and expanding system: These systems are designed to be sufficiently s/nall on administration allowing for easy ingestion, but after ingestion rapidly swell or unfold to a size that precludes passage through the pylorus until after drug release has occurred.

In one illustrative embodiment, a modified release, gastroretentive swelling system incorporating solubilized drug is contemplated. The modified release gastro-retentive swelling system according to the invention employs a combination of swelling and floating systems. The swelling polymers employed swell voluminously in the presence of gastric contents to increase the dosage form size such that it precludes its passage through the pylorus and the excipients that impart buoyancy to the dosage form such as gas generating agent ensure that the dosage form floats and remains on the surface of the gastric fluids.

The swelling agent used in the present invention includes one or more swellable biocompatible hydrophilic polymers. In one embodiment, the polymers are employed in the dry state or in a form that has substantial capacity for water uptake. Hydrophilic water-

soluble polymers used as swelling agents that are useful in preparation of the said composition of this invention are polymers that are nontoxic and swell in a dimensionally unrestricted manner upon imbibition of gastric fluid. Examples of such swelling polymers employed in the present invention include, but are not limited to, polyalkylene oxides; cellulosic polymers; acrylic acid and methacrylic acid polymers, and esters thereof, maleic anhydride polymers; polymaleic acid; poly(acrylamides); poly(olefinic alcohol)s; poly(N-vinyl lactams); polyols; polyoxyethylated saccharides; polyoxazolines; polyvinylamines; polyvinylacetates; polyimines; starch and starch-based polymers; polyurethane hydrogels; chitosan; polysaccharide gums; alginates; zein; shellac-based polymers; polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium carboxy methylcellulose, calcium carboxymethyl cellulose, methyl cellulose, polyacrylic acid, maltodextrin, pre-gelatinized starch and polyvinyl alcohol, and mixtures thereof.

One or more swelling polymers employed for the purpose of the present invention include, but are not limited to, polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium carboxy methylcellulose, calcium carboxymethyl cellulose, methyl cellulose, polyacrylic acid, maltodextrin, pre-gelatinized starch, polyvinyl alcohol or mixtures thereof.

The weight percent of the hydrophilic swelling polymer in the final compressed dosage form is about 5 to about 95 weight percent. In one embodiment, the weight percent of the hydrophilic swelling polymer in the final compressed dosage form is about 10 to about 70 weight percent. In another embodiment, the weight percent of the hydrophilic swelling polymer in the final compressed dosage form is about 15 to about 50 weight percent.

Some excipients of a special category help the swelling polymers to swell rapidly to a large extent resulting in a dramatic increase in the size of the tablet. At lower concentrations, these excipients are used as superdisintegrants; however at concentration above 5 % w/w these agents function as swelling enhancers and help increase the size of the dosage form.

According to the present invention, swelling enhancers include, but are not limited to, low- substituted hydroxypropyl cellulose, microcrystalline cellulose, cross-linked sodium or

calcium carboxymethyl cellulose, cellulose fiber, cross-linked polyvinyl pyrrolidone, cross- linked polyacrylic acid, cross-linked Amberlite resin, alginates, colloidal magnesium- aluminum silicate, corn starch granules, rice starch granules, potato starch granules, pregelatinised starch and sodium carboxymethyl starch.

In one embodiment of the present invention, the swelling enhancer is cross-linked polyvinyl pyrrolidone. The content of the swelling enhancer is about 5 to about 90 weight percent. In one embodiment, the content of the swelling enhancer is about 10 to about 70 weight percent. In another embodiment, the content of the swelling enhancer is about 15 to about 50 weight percent.

The composition according to the present invention includes at least one hydrophilic swelling polymer with or without a swelling enhancer. When a combination of polymers and excipients is employed for gastric-retention, it allows a rapid and dramatic increase in the size of the tablets. Such a synergistic combination may preferably be employed which allows rapid swelling and maintenance of integrity by polymeric network formed upon swelling of the polymer(s).

The amount and type of swelling agents employed in the invention is very crucial as these agents ensure that there is sufficient swelling for retention of the dosage form despite erosion of the drug layer. These excipients ensure that within 2 hours at least two dimensions of the dosage form namely length and width is more than 10 mm.

According to the present invention, the pharmaceutical composition can further comprise at least one gas generating agent. The gas generating agents also referred to as effervescent agent aid in the formation of highly porous, preferably honeycombed structure and enhances the buoyancy of the formulation. The gas generating agent employed for the purpose of the present invention is selected from, but not limited to, alkali and alkaline-earth metal carbonates and bicarbonates such as sodium bicarbonate, sodium glycine carbonate, potassium bicarbonate, ammonium bicarbonate, sodium bisulfite, sodium metabisulfite, sodium carbonate, potassium carbonate and the like. In one embodiment, the gas generating agent is sodium bicarbonate. The pharmaceutical composition can further

optionally comprise an acid source. The acid source may be, but is not limited to, citric acid, maleic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid, phthalic acid, aspartic acid, glutamic acid, malic acid or tartaric acid.

In a dry granulation process, the gas generating agent may be incorporated into the dosage form by blending it into the expanding composition before or after first compaction. In a wet granulation process, it may be provided as an extragranular constituent after wet granulation. In one embodiment, the gas generating agent is used at concentration from about 0.5 weight % to about 25 weight % of the dosage form. In another embodiment, the gas generating agent and the acid source are together used at a concentration from about 0.5 weight % to about 25 weight % of the dosage form.

The composition of the gastroretentive and drug layer typically may also include other pharmaceutically acceptable excipients such as, but not limited to, binders, lubricants, diluents, disintegrants, glidants, colorants and the like. As is well known to those skilled in the art, pharmaceutical excipients are routinely incorporated into solid dosage forms. This is done to ease the manufacturing process as well as to improve the performance of the dosage form.

Examples of suitable binders include, but are not limited to, starch, pregelatinized starch, polyvinyl prrolidone (PVP), copovidone, cellulose derivatives, such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC) and carboxymethyl cellulose (CMC) and their salts. Examples of suitable diluents include, but are not limited to, starch, dicalcium phosphate, microcrystalline cellulose, lactose monohydrate, dextrate hydrated and the like.

Examples of the lubricant include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, talc, and sodium stearyl fumarate. Compositions of the present invention may optionally also include a glidant such as, but not limited to, colloidal silica, silica gel, precipitated silica, or combinations thereof.

The controlled release formulation for once a day administration of an ARB as per the present invention may be in the form of a monolithic system, an expanding bilayered or

multilayered or in-lay system for oral administration which is adapted to deliver the active agent in a modified manner over extended period.

In a further illustrative embodiment a solid pharmaceutical composition in the form of an expanding bilayered system for oral administration is adapted to deliver an active pharmaceutical agent from a first layer immediately upon reaching the gastrointestinal tract, and to deliver a further pharmaceutical agent which may be same or different, from a second layer, in a modified manner over a specific time period. The second layer is also adapted to provide expanding nature for the dosage system, thereby making the dosage system have greater retention in the stomach.

In a further embodiment the controlled release formulation for once a day administration is a bilayered system comprising a drug layer and a gastroreteritive layer. The drug layer comprises solubilized ARB and at least one release retardant as discussed above. Further, the gastroretentive layer comprises at least one swelling polymer, at least one swelling enhancer and at least one gas generating agent and optionally an acid source. Such a solid pharmaceutical composition for oral administration ensures desired gastroretention and enhanced bioavailability of the ARB with extended release.

In a further illustrative embodiment a solid pharmaceutical composition for oral administration contains an in-lay system which a specialized dosage form comprising a drug containing tablet which is placed in another tablet comprising of excipients that ensure gastric retention. In this system the drug containing tablet is small and is covered from all sides except at least one side with a blend of excipient that ensure the gastric retention.

In yet another illustrative embodiment according to the invention, the dosage form may be optionally coated. Surface coatings may be employed for aesthetic purposes or for dimensionally stabilizing the compressed dosage form or for retarding the drug release. The surface coating may be any conventional coating which is suitable for enteral use. The coating may be carried out using any conventional technique employing conventional ingredient. A surface coating can, for example, be obtained using a quick-dissolving film using conventional polymers such as, but not limited to, hydroxypropyl methyl cellulose,

T/IN2008/000870

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hydroxypropyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, poly methacrylates or the like.

Tablets of the present invention may vary in shape including, but not limited to, oval, triangle, almond, peanut, parallelogram, pentagonal. It is contemplated within the scope of the invention that the dosage form can be encapsulated.

Tablets in accordance with the present invention may be manufactured using conventional techniques of common tableting methods known in the art such as direct compression, wet granulation, dry granulation and extrusion/ melt granulation. Further, the present invention also provides a method of preparing a controlled release formulation of an angiotensin receptor blocker (ARB) for once a day administration in the form of a gastroretentive dosage form comprising:

(a) solubilizing an ARB with at least one solubility enhancing agent to form solubilized ARB;

(b) mixing said solubilized ARB with at least one release retardant and lubricant to form a drug layer;

(c) blending a swelling polymer and a swelling enhancer with the gas generating agent and optionally an acid source and lubricant to form a gastroretentive layer; and

(d) compressing the drug layer and the gastroretentive layer to form a bilayer tablet.

In a further illustrative embodiment, the present invention provides a method of preparing a controlled release formulation of valsartan for once a day administration in the form of a gastroretentive dosage form comprising:

(a) solubilizing valsartan with at least one solubility enhancing agent to form solubilized valsartan;

(b) mixing said solubilized valsartan, at least release retardant and lubricant to form a drug layer; (c) blending a swelling polymer and a swelling enhancer with the gas generating agent and optionally an acid source and lubricant to form a gastroretentive layer; and

(d) compressing the drug layer and the gastroretentive layer to form a bilayer tablet.

The dosage form having a single layer or multi-layer composition, coated or uncoated, swells after ingestion gradually upon contact with gastric fluid. The time taken for swelling may vary from about 15 minutes to about 4 hours. In one embodiment, the time taken for swelling is within about 15 minutes to about 3 hours. In another embodiment, the time taken for swelling is within about 15 minutes to about 2 hours. Two dimensions of the dosage form namely length and width expand to more than about 8 mm. In one embodiment, the length and width of the dosage form expand to more than about 10 mm. In another embodiment, the length and width of the dosage form expand to more than about 12 mm. Particularly from a bilayered tablet formulation, solubilised ARB is released by an erosion mechanism. This means that, to achieve a desired release profile, drug layer has to continuously erode or, in other words, the size of the drug layer decreases continuously. Thus there are two antagonistic phenomena occurring simultaneously in such formulations, namely, one - swelling of the dosage form for gastric retention arid two - erosion of the drug layer. It was surprisingly found that despite of erosion of the drug layer, gastric retention can be achieved. The pyloric sphincter, controlling the movement of the contents of the stomach into the intestine is 8-10 mm in diameter. Thus gastric retention is possible by ensuring that at least two dimensions of the dosage form are greater than 8 mm after swelling within 2 hours in media simulating typical gastric environment (0.1 N hydrochloric acid). The erosion of the drug layer is evident from the fact that, despite using rapidly swelling polymers and swelling enhancers in large amounts in gastroretentive layer, the formulation swells less than 50% by volume in 30 minutes. Swelling in-vitro is determined under two different set of conditions:

Test 1 : USP dissolution apparatus Il with 900 ml of simulated gastric fluid at 100 rpm and 37°C, with dimensions measured physically using vernier calipers at the end of 30 minutes. Volume of the tablet is determined from the dimensions and % increase in volume of the tablet with respect to initial volume is calculated. Test 2: USP dissolution apparatus Il with 900 ml of 0.1 N hydrochloric acid at 75 rpm and 37°C with dimensions measured physically using vernier calipers at the end of 30 minutes, 1 , 2, 4 and 6 hours. Width of the tablet is particularly recorded.

Floating time of the tablet is also recorded during Test 2 which is less than 60 minutes. In one embodiment, the floating time of the tablet is less than 30 minutes. In another embodiment, the floating time of the tablet is less than 15 minutes. A combination of floating and swelling ensures that following oral administration to a patient, the dosage form is retained in the upper gastrointestinal tract for a time period of about 30 min to about 12 hours. In one embodiment, the dosage form is retained in the upper gastrointestinal tract for a time period of about 1 hour to about 10 hours. In another embodiment, the dosage form is retained in the upper gastrointestinal tract for a time period of about 1 hour to about 8 hours.

The present invention describes a unique combination of technologies wherein a solubilized drug is incorporated into a swelling matrix of release retardant and has a gastroretentive layer to achieve controlled release once a day formulation. Modified release is thus achieved by; integrity of the matrix and the need for the gastric fluid to diffuse into the matrix or is achieved by controlled rate of diffusion of drug from the matrix and/or by controlled erosion of the matrix. Tablets formulated according to the invention allow for controlled release of valsartan (Table A) and the in vitro release rate corresponds to the following % rate of valsartan released as shown in the following tablets which are determined in USP dissolution apparatus Il (rotation speed of 50 rpm) using a suitable buffer preferably 0.1 N hydrochloric acid.

TABLE A

In one embodiment, the formulation particularly suited for once-a-day dosing has an in-vitro release rate corresponding to the following % rate of valsartan released as shown in Table B:

TABLE B

Another formulation in accordance with the invention, also particularly suited for once-a-day dosing, has an in vitro release rate corresponding to the following % rate of valsartan released as shown in Table C:

TABLE C

Yet another formulation in accordance with the present invention, also particularly suited for once-a-day dosing, has an in vitro release rate corresponding to the following % rate of valsartan released as shown in Table D:

TABLE D

In one embodiment of the present invention, the dissolution rate in vitro upon release of the controlled release preparation for administration once daily is between 5 and 50% (by weight) valsartan released after 1 hour, between 10 and 75% (by weight) valsartan released after 2 hours, between 20 and 95% (by weight) valsartan released after 4 hours, between 40 and 100% (by weight) valsartan released after 8 hours, more than 50% (by weight) valsartan released after 12 hours, more than 70% (by weight) released after 18 hours and more than 80% (by weight) valsartan released after 24 hours.

The novel controlled release formulation as per the embodiments of the instant invention exhibits certain desired features when administered to human subjects. The maximum plasma concentration (C _max ) of the drug achieved is about 300 ng/ml to about 6000 ng/ml, based on administration of a 80 mg once-a-day dose of valsartan. It is contemplated for purposes of the present invention that a given plasma level (e.g., C _max ) of valsartan per specified dose will be directly proportional to other doses of valsartan. Such proportional doses and plasma levels are contemplated to be within the scope of the invention. Time required to achieve peak plasma concentration is between 2.5 to 7.5 hours after administration and mean AUC ₀ .« is about 8000 ng.hr/ml to about 30000 ng.hr/ml, based on administration of a 80 mg once-a-day dose of valsartan. Thus compared to the marketed immediate release formulation one embodiment provides higher C _max and AUC values. Also Tmax is higher indicating controlled release and gastric retention. Also a significant plasma concentration of valsartan is achieved after about 12 hours post administration. The plasma concentrations after 12 hrs post administration achieved with controlled release formulation of present invention are greater than 300 ng/ml. These pharmacokinetic parameters can be achieved after administration under various conditions such as fasted, fed with food having

high calorific content or fed with food having low calorific content. Also these pharmacokinetic parameters result in a relative bioavailability of more than 80%. In one embodiment, the relative bioavailability is more than 90%. In another embodiment, the relative bioavailability is more than 100% with marketed immediate release formulation. In yet another embodiment, the relative bioavailability is more than 120%.

In an aspect of the present invention there is provided a method of treating hypertension, congestive heart failure, angina, myocardial infarction, diabetic cardiac myopathy, renal insufficiency, arteriosclerosis, diabetic nephropathy, peripheral vascular disease, stroke, left ventricular hypertrophy, cognitive dysfunction, headache, or chronic heart failure comprising administering the controlled release formulation of solubilized ARB of the present invention to a subject in need of such treatment.

In another aspect Of the present invention there is provided use of the controlled release formulations of solubilized ARB such as valsartan for once a day administration for the treatment and/or prevention of hypertension, congestive heart failure, angina, myocardial infarction, diabetic cardiac myopathy, renal insufficiency, arteriosclerosis, diabetic nephropathy, peripheral vascular disease, stroke, left ventricular hypertrophy, cognitive dysfunction, headache, or chronic heart failure. In another aspect of the present invention there is provided use of the controlled release formulations of solubilized ARB such as valsartan for once a day administration for the treatment and/or prevention of cardiovascular, endocrine or metabolic disorders in patients who normally do not respond to conventional therapy.

While the present invention has been described in terms of its specific illustrative embodiments, 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 invention. The details of the invention, its objects and advantages are explained hereunder in greater detail in relation to non-limiting exemplary illustrations.

Example 1 Solubilization of valsartan using combination of surfactants

Valsartan was mixed with different combinations of solubility enhancing agents under continuous mixing. The solubility of the resulting granules was determined in 0.1 N HCI.

Table 1 : Determination of solubility of valsartan with different combinations of solubility enhancing agents

* SLS - Sodium lauryl sulphate

In combination of surfactants as used in above table, maximum increase in solubility was achieved by a combination of Cremophor RH40 and SLS in the ratio 1 :1 :0.1.

Example 2 Preparation of solubilized valsartan and evaluation of drug release

Poloxamer 407 was mixed well with valsartan in a beaker in the ratio of 1 :1 (valsartan: poloxamer 407). To this mixture 3 parts microcrystalline cellulose was added and blended well. The dissolution of these granules was studied as follows:

In-vitro dissolution studies

In-vitro dissolution studies were carried out with following specifications

Dissolution Medium: 0.1 N HCL

Dissolution Test Apparatus: USP Type Il

Temperature: 37 ± 0.5 ⁰ C

Rpm: 50

Sampling intervals: 15, 30, 60 and 120 minutes

Table 2: In vitro dissolution studies of valsartan alone and solubilized valsartan

A significant increase in the dissolution rate was achieved for valsartan with a solubility enhancing agent. At the end of 120 min only 15% of pure valsartan was dissolved. However in the case of solubilized valsartan, more than 95% of the drug was dissolved in 120 min.

Example 3 Formulation of valsartan bilayered tablet

A. Drug layer

Table 3 Composition of Drug layer

Microcrystalline cellulose, USP 95

Fumaric acid, USP 48

Dextrate hydrated , USP 45

Hydroxy propyl methyl cellulose, USP (Low viscosity) 15

Hydroxy propyl methyl cellulose, USP (Medium viscosity) 30

Colloidal silicon dioxide, USP 5

Magnesium stearate, USP 5

Iron oxide red, Ph. Eur. 1

Total 464

Procedure

Valsartan was mixed well with solubilizers in jacketed rapid mixer granulator followed by addition of the diluents. The granulated blend was sized to get the granules which were further mixed with hydroxy propyl methyl cellulose along with other additives and lubricated with magnesium stearate. The lubricated blend was then used for compression of bilayer tablets after preparation of gastroretentive (GR) layer granules.

B. Gastroretentive Layer

Table 4 Composition of Gastroretentive (GR) layer

Procedure

All ingredients were dry mixed in rapid mixer granulator, granulated using povidone solution and subsequently dried in a fluidized bed dryer to get desired loss on drying. Sized dried granules were blended with sodium bicarbonate and citric acid and then lubricated using magnesium stearate.

These lubricated GR granules were compressed with lubricated drug layer blend to get a bilayered tablet.

The bilayered tablet was compressed having following parameters:

Punch size 22 X 10

Swelling in SGF after 30 min (% volume increase) 37.8

Width in 1 hr. in 0.1 N HCI (mm) 12.23

Floating in 0.1 N HCI (min) 3

Although the % volume increase of the dosage form in 30 min is only 37%, the dosage form achieves width of 12.3 mm in 1 hour.

In vitro dissolution study

In-vitro dissolution studies of the valsartan tablets were carried out in 900 ml 0.1 N HCI with following specifications:

Dissolution Test Apparatus: USP Type Il

Temperature: 37 ± 0.5 ⁰ C

Dissolution Medium: 900 ml 0.1 N HCI

Rpm: 50

Table 5 Dissolution data of valsartan bilayered tablet

Comparative oral availability study

A complete crossover study was designed to evaluate in vivo performance of valsartan tablets of example 3 under fed condition with respect to Diovan® in healthy male volunteers (n=6) under fasted condition. Pharmacokinetic parameters such as T _ma χ, C _max , AUC _0- oo and AUCo- _t were calculated from the data.

Table 6: Summary statistics of pharmacokinetic parameters

The present invention exhibited a higher C _max and AUC _0-t compared to the marketed product (Figure 1). Test product also exhibited effective higher plasma levels even after 12 hours of dosing.

Example 4 Formulation of bilayered tablet

A. Drug layer

Table 7 Composition of drug layer

B. Gastroretentive Layer

Table 8 Composition of Gastroretentive layer

Lubricated blend of drug layer and GR layer was prepared as per procedure described for example 3. The bilayered tablets were compressed having following parameters.

Punch size 21 X 9

Width in 1 hr. in 0.1 N HCI (mm) 12.06

Floating in 0.1 N HCI (min) 3.5

Dissolution Data:

Drug release from the bilayer tablets was studied as described in example 3, the results are tabulated below. .

Table 9 Dissolution data of valsartan bilayer tablet

Example 5 Formulation of valsartan bilayered tablet

A. Drug layer

Table 10 Composition of Drug layer

retentive Layer

Table 11 Composition of Gastroretentive layer

Lubricated blend of drug layer and GR layer was prepared as per procedure described for example 3. The bilayered tablet was compressed having following parameters.

Physical Parameters

Punch size 19 X 10

Swelling 30 min in simulated gastric fluid (%) 34.4

Width in 1 hr. in 0.1 N HCI (mm) 12.55

Floating in 0.1 N HCI (min) 2

Dissolution Data

Drug release from the bilayered tablets was studied as described in example 3, the results are tabulated below.

Table 12 Dissolution data of valsartan bilayer tablet

Formulation exhibited desired in vitro release profile as well as the swelling properties.

Comparative oral availability study

A complete cross over study was designed to evaluate in vivo performance of valsartan bilayered tablet of example 5 under fed condition versus Diovan® under fasting condition in healthy male volunteers. Pharmacokinetic parameters such as Tmax, Cmax, AUC _0-4 and

AUCo-K, were calculated from the data.

Table 13 Summary statistics of pharmacokinetic parameters

From table 13 it is evident that test formulation exhibited higher AUC values as compared to reference product, Diovan. Results also indicated that the formulation was retained in stomach for prolonged period of time; giving controlled release of the drug, resulting in higher drug levels as compared to Diovan.

Example 6 Formulation of coated valsartan bilayered tablet

A. Drug layer Table 14 Composition of Drug layer

Iron oxide red, Ph. Eur.

Total 464

B. Gastroretentive Layer

Table 15 Composition of Gastroretentive layer

Lubricated blend of drug layer and GR layer was prepared as per procedure described for example 3. The bilayered tablet was compressed having following parameters.

These tablets were further coated with hydroxy propyl methyl cellulose to a weight gain of

2% w/w.

Core Coated

Punch size 19 X 10 -

Swelling in SGF in 30 min (% increase in volume) 38 35

Width in 1 hr. in 0.1 N HCI (mm) 12.6 12.5

Floating in 0.1 N HCI (min) 2.5 3.5

Dissolution Data

Drug release from the bilayered tablets was studied as described in example 3, the results are tabulated below.

Table 16 Dissolution data of valsartan bilayer tablet

Coating of the tablet with hydroxy propyl methyl cellulose maintained the swelling behavior of the GR layer both in terms of % volume increased and width of the tablet.

Example 7 Formulation of valsartan bilayered tablet A. Drug layer

Table 17 Composition of Drug layer

B. Gastroretentive Layer

Table 18 Composition of Gastroretentive layer

Lubricated blend of drug layer and GR layer was prepared as per procedure described for example 3. The bilayered tablet was compressed having following parameters.

Punch size 19 X 10

Width in 1 hr. in 0.1 N HCI (mm) 12.45 Floating in 0.1 N HCI (min) 17-18

Dissolution Data

Drug release from the bilayered tablets was studied as described in example 3, the results are tabulated below.

Table 19 Dissolution data of valsartan bilayer tablet

Example 8 Formulation of valsartan bilayered tablets A. Drug Layer

Table 20 Composition of Drug Layer

B. Gastroretentive layer

Table 21 Composition of Gastroretentive layer

The bilayered tablet was compressed having following parameters.

Weight of tablet (mg) 1430

Punch size 22 X 10

Thickness of tablet (mm) 8.15-8.30

Hardness 120-150 N

Friability at 100 rpm 0.55

Dissolution Data

Drug release from the bilayered tablets was studied as described in example 3, the results are tabulated below.

In vitro dissolution study In-vitro dissolution studies of the valsartan tablets were carried out as per following specifications:

Dissolution Test Apparatus: USP Type Il

Temperature: 37 ± 0.5 ⁰ C

Dissolution Medium: 18 00 ml 0.1N HCi Rpm: 50

Table 22 Dissolution data of valsartan bilayered tablet

Example 9 Valsartan Inlay tablet

A. Drug Core

Table 23 Composition of Drug core

Procedure:

Valsartan was mixed well with solubilizers in jacketed rapid mixer granulator followed by addition of the diluents. The granulated blend was sized to get the granules which were further mixed to hydroxy propyl methyl cellulose along with other additives and lubricated with magnesium stearate. The lubricated blend was then used for compression of biiayer tablets after preparation of gastroretentive (GR) layer granules.

Physical parameters:

Thickness 4.98-5.01

Hardness 90-100 N

Disintegration Time 35 min

Tablets with good hardness and optimum disintegration time were obtained using this composition.

B. Gastroretentive layer

Table 24 Composition of Gastroretentive layer

Procedure:

All ingredients were dry mixed in rapid mixer graήulator, granulated using povidone solution and subsequently dried in a fluidized bed dryer to get desired loss on drying. Sized dried granules were blended with sodium bicarbonate and citric acid and then lubricated using magnesium stearate.

These lubricated GR granules were compressed with lubricated drug layer blend of table 23 to get an inley tablet.

Physical parameters of Inlay tablets:

Floating time 3-4 min Initial dimensions 22 X 10 X 6.85 Swelling after 1hr 27 X 16 X 11 Swelling after 2hr 27 X 10 X 12 Hardness 95-101

Inlay tablets with good floating and swelling properties were obtained.

In vitro dissolution study

In-vitro dissolution rate studies of the Valsartan tablets of Example 9 were carried out in

0.1 N HCI with following specifications:

Dissolution Test Apparatus: USP Type Il

Temperature: 37 ± 0.5 ⁰ C

Dissolution Medium: 0.1N HCI

Rpm: 75

Table 25 Dissolution data of valsartan inlay tablet