WO2008084504A2

WO2008084504A2 - Pharmaceutical compositions of angiotensin ii receptor blockers

Info

Publication number: WO2008084504A2
Application number: PCT/IN2008/000017
Authority: WO
Inventors: Pratibha S. Pilgaonkar; Maharukh T. Rustomjee; Anilkumar S. Gandhi; Nagesh R. Palepu
Original assignee: Rubicon Research Private Limited
Priority date: 2007-01-12
Filing date: 2008-01-11
Publication date: 2008-07-17
Also published as: WO2008084504A3

Abstract

The present invention relates to the methods of increasing the bioavailability of Angiotensin II Receptor Blockers (ARBs) by treating it with at least one absorption augmenting agent. In particular, the present invention relates to use of absorption augmenting agents which results in significant increase in the bioavailability as more drug is present in the absorbable form at the absorption site which is in sharp contrast to the currently marketed ARB formulations. In the composition, the ARB may be present in the form of physical blend, solid dispersion, solid solution or complex with absorption augmenting agent. The composition of an ARB with absorption augmenting agent can be incorporated in a tablet, coated tablet, inlay or bilayer tablet or capsule dosage form for immediate release, sustained release, pulsatile release or modified release.

Description

PHARMACEUTICAL COMPOSITIONS OF ANGIOTENSIN II RECEPTOR BLOCKERS

FIELD OF THE INVENTION

The present invention relates to the methods for increasing bioavailability of Angiotensin II Receptor Blockers (ARBs) by increasing their absorption in the gastrointestinal tract.

The invention particularly relates to the use of "absorption augmenting agents" to increase the absorption of ARBs in the gastrointestinal tract.

The present invention also relates to oral solid dosage forms of ARBs prepared by treating pharmaceutically effective amounts of an ARB with at least one "absorption augmenting agent" and incorporating the said treated ARB into a solid dosage form. BACKGROUND OF THE INVENTION

Angiotensin II is a very potent end product chemical that causes the muscles surrounding the blood vessels to contract, thereby significantly narrowing 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 BP 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 (GI) milieu. Another component responsible for low bioavailability of valsartan is ionization of valsartan in the small intestine. The ionized species cannot permeate through the lipidic cell membrane and therefore a significant amount of valsartan is excreted unabsorbed in feces.

The synthesis and use of valsartan are described in US 5399578 and US 2007/0054947. Various polymorphs and salt forms of valsartan are described by US 7105557 and US 6869970. US6294197, US6485745 and US6858228 describe the solid oral dosage forms of valsartan alone or in combination with hydrochlorothiazide (HCTZ) along with a pharmaceutical additive for the preparation of solid dosage forms by a compression method. The solid dosage form according to this invention contains more than 35% by weight of the active agent in the formulation. A process of making such dosage form employing roll compaction is also disclosed. Valsartan immediate release formulations are also described in WO 2007077581, WO 2006066961, WO 2005089720 and WO 2007049291. All these patents describe valsartan formulations having bioavailability in the range of 10-30% and none of them describe any attempts of increasing bioavailability of valsartan.

US 2005/0208130 and US 2003/0152620 detail valsartan tablets which are at least 1.2 times more bioavailable than the conventional valsartan capsule. The tablet formulation according to the invention contains a disintegrant at concentration level of 10-80% based on total weight of the composition. The higher amount of disintegrant ensures that the hydrophobic valsartan is wetted well during the granulation stage. The tablet is readily dispersed as granules in the dissolution medium resulting in a better dissolution and improved bioavailability over the other formulation. This invention does not, however, describe methods to increase solubility or absorption of the valsartan which may increase the bioavailability, in fact tablets and capsules are considered bioequivalent. In US Patent No. 6,485,745 ('745), solid dosage forms of valsartan are described which exhibit accelerated release of the active agent without any reference to its effect on bioavailability.

US patent application 2005/0234016 describes a process for the preparation of amorphous adsorbates of valsartan for use in pharmaceutical formulations. Valsartan is adsorbed on crystalline excipient like lactose or mannitol resulting in valsartan adsorbate. The patent specially focuses on amorphous adsorbates which do not alter the morphology during processing and in which drug can be distributed homogeneously. In another patent application US 2007/0166372 a stabilized coprecipitate of amorphous valsartan is formed with carriers such as polyvinyl pyrrolidone and polyethylene glycol. The coprecipitate is stable over long term storage condition without getting transformed in crystalline form. WO 2005056607 describes cyclodextrin complexation of valsartan in 1 : 1 to 1 :2 stoichiometric ratios. Generally these processes would result in increase in dissolution rate, however no , such data is provided in any of the above patents. This indicates that a mere conversion of valsartan into amorphous form or complexation with cyclodextrin does not increase the . bioavailability of valsartan.

Candesartan cilexitil, like valsartan, is a hydrophobic molecule with poor aqueous solubility resulting in poor oral availability (about 14%). WO 2005/070398 A2 claims pharmaceutical compositions in the form of tablets that include candesartan cilexitil, fatty acid glycerides, a surfactant, a co-solvent and pharmaceutically acceptable additives. The formulation is further coated with a film forming polymer and polyethylene glycol. The co- solvent employed only improves the stability of candesartan and does not alter its solubility or dissolution rate in acidic medium.

US 2005/0220881 provide methods of improving dissolution of Eprosartan by preparing its association complex with one or more solid poloxamers. However, a large amount of poloxamers is required to achieve significant dissolution enhancement. The dosage form development of such a complex that would achieve a higher oral bioavailability becomes very difficult due to weight limitations. Moreover, large amount of poloxamers for chronic use may not be advisable.

US patent application 2002/0012680 describes a pharmaceutical composition of hardly soluble drugs comprising a carrier of mixture of hydrophilic and hydrophobic surfactant which results in clear aqueous solution and thus shows modified dissolution characteristics of poorly water soluble drugs. This patent application is specially based on formation of micelles of drug with the help of mixture of surfactants which results in the desirable increase in solubility of the poorly soluble drugs, especially when the formulation is in the form of gel, cream, capsule or suppository. Patent application WO 2006/113631 relates to ARB compositions which describe use of solubility enhancing agents for improved solubility and dissolution rates of poorly soluble drugs. This solubilized composition is formulated in the form of tablet or capsule for immediate or controlled release. The immediate release capsule formulation exhibited 70 % drug release in 15 minutes followed by 92 % drug release in 120 minutes. Also the solubilization of drug resulted in enhanced bioavailability as evident from in vivo study results when compared with marketed product.

Both these patents attempt to increase bioavailability of drugs having poor solubility, however this provides only part solution and for drugs like valsartan, poor bioavailability may be due to factors such as low solubility, poor absorption characteristics, ionization of drug resulting in low permeability, window of absorption etc. In none of the prior art patents problem of poor absorption of such drugs has been addressed. Increase in solubility alone just provides solution to one of the problem, however in order to achieve the desired increase in bioavailability all above mentioned factors must be considered together and not in isolation. It has been surprisingly found by the present inventors that an ARB, particularly valsartan, when combined with an absorption augmenting agent, significant increase in the bioavailability is achieved as more drug is present in the absorbable form at the absorption site which is in sharp contrast to the currently marketed ARB formulations. This increase in bioavailability may reduce the dose of the ARB required to achieve the desired effect as well as patient to patient variability, and thus, enhances the therapeutic utility of the ARB. Moreover the increased absorption in the gastrointestinal tract provides for possibility of developing a truly once a day formulation of the ARB. The solid dosage form can be manufactured using conventional manufacturing processes and standard processing equipments that are generally used to manufacture the solid dosage form. It was thus surprisingly found that use of an absorption augmenting agent increases the bioavailability of an ARB and improves the therapeutic profile of these molecules. OBJECTS OF THE INVENTION

Accordingly, one object of the present invention is to provide a formulation of Angiotensin II Receptor Blockers (ARBs) having increased bioavailability.

Another object of the present invention is to provide a method for preparing valsartan composition with increased absorption of ARBs in the gastrointestinal tract. SUMMARY OF THE INVENTION

The present invention relates to methods of increasing the bioavailability of ARBs, especially valsartan, and ensuring consistent absorption from the gastrointestinal tract. This invention increases the absorption of ARBs by increasing its absorbable form in the GI tract and thereby reduces inter- and intra-patient variability, which is in contrast to the current marketed oral dosage formulations which have highly variable intra- and inter-patient absorption. This invention also leads to a significant decrease in the time to reach maximum blood concentration (T_max) and extent of absorption (AUC) of an ARB compared to the marketed product.

The invention also relates to a physically and chemically stable formulation of ARBs, in particular, valsartan, utilizing generally recognized as safe (GRAS) excipients. ARBs such as valsartan have functional groups which ionize at higher pH resulting into highly soluble hydrophobic ionic form which has poor permeability. This might be responsible for elimination of unabsorbed drug in feces and poor bioavailability of valsartan. This invention therefore aims to address the consequences of this ionization of valsartan to achieve increased absorption and improved bioavailability. In one aspect, the present invention provides for a composition comprising angiotensin receptor blocker or a salt thereof; and an absorption augmenting agent.

In another aspect, the present invention provides a method of increasing the bioavailability of an ARB. In another aspect, the present invention provides a method of increasing the bioavailability of an ARB by increasing its absorption from the GIT.

In yet another aspect, the present invention provides a method of increasing the bioavailability of an ARB by treating it with at least one absorption augmenting agent.

In another aspect, the present invention provides a method of increasing the bioavailability of valsartan by treating it with at least one absorption augmenting agent.

In yet another aspect, the present invention provides for incorporation of absorption augmenting agent treated ARB into a suitable dosage form.

In another aspect, the present invention provides for development of truly once a day formulation of valsartan. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a graph showing in vivo release profiles of Diovan^® vs. Test formulation of example 6. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

According to the basic principle 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 a better absorption; the drug substance should be lipophilic in nature and have adequate solubility in the GI 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 the ionized form which is not as lipophilic as the neutral free acid and thus 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 GI milieu and poor permeability of the dissolved (ionized) form. The result is low bioavailability of 10-25%. Even those ARBs which do not possess any carboxylic acid functionality exhibit low solubility in acidic/weakly acid medium. PCT application WO 2006/113631 described use of solubilizers to increase solubility of ARBs in acidic environment leading to increase in the bioavailability. Further increase in bioavailability could be achieved by increasing the absorbable form an ARB throughout the GIT and particularly in the lower part of the GIT. It has been surprisingly found that a combination of an ARB or its salt in the presence of certain substances, which are referred to herein as absorption augmenting agent, results in increased absorbable form of the drug leading to an improved bioavailability compared to the marketed presentation.

Accordingly, the present inventors have carried out rigorous experiments for the selection of absorption augmenting agent which, irrespective of their own different characteristics, work in synergy to achieve the desired increase in bioavailability of ARBs. The oral solid formulation of the present invention comprises at least one absorption augmenting agent in combination with an ARB and excipients. Angiotensin II receptor blocker

The active ingredient for the purpose of this invention is selected from candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, pratosartan and other drugs belonging to the category of ARB. In one embodiment of the invention the ARB is valsartan. The active ingredient of the invention may be present in 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. 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, an anti-hypertensive agent, an anti-obesity agent, an antidiabetic agent, a beta-blocker, an inotropic agent, a hypolipidemic agent, or a combination thereof. The antihypertensive agent which might be combined with an ARB include but are not limited to hydrochlorothiazide (HCTZ), a calcium channel blocker, an angiotensin- converting enzyme (ACE) inhibitor, renin inhibitor, or combinations thereof.

The active ingredient may be present in an amount 1-80 %, preferably 5-70% and more preferably 10-60% by weight of the composition. Absorption augmenting agent

The term "absorption augmenting agent" used in the present invention is defined as an agent, which increases the absorption of an ARB in the gastrointestinal tract (GIT) and in particular in the small intestine. The absorption augmenting agent may also help to increase drug absorption in the large intestine. The absorption of the drug can be increased by increasing the absorbable form of the drug using acidulant or by using ion pairing agents which makes the drug more lipophilic or by inhibition of p-glycoprotein mediated efflux.

According to present invention the absorption augmenting agent is selected from a group of acidulants, ion-pairing agents, surfactants and p-glycoprotein inhibitors. The present invention also pertains to a composition containing multiple absorption augmenting agents. In one embodiment of the present invention, the composition according •. to the invention comprises an angiotensin receptor blocker, an acidulant, an ion pairing agent, - a surfactant and a p-glycoprotein inhibitor. Acidulants Acidulants are physiologically compatible water-soluble organic acids which decrease the pH of the dosage form microenvironment or alternatively of the lower gastrointestinal tract. Decrease in pH would prevent ionization of ARB and increase its absorbable form. As used herein, acidulants refer to aliphatic or aromatic, saturated or unsaturated, monobasic acid (monocarboxylic acid), dibasic acid (dicarboxylic acid) or tribasic acid (tricarboxylic acid), with preference given to a compound having 2-10, preferably 2-6 carbon atoms. Examples of the monobasic acid include 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 the dibasic acid include 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 the tribasic acid include hydroxy tribasic acids such as citric acid. The organic acid may be a salt. Examples of the salt of the organic acid include 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.

According to the invention the acidulants like malic acid, tartaric acid, fumaric acid, maleic acid, aspartic acid and citric acid are used as one of the absorption augmenting agents. Acidulants may be employed in an amount sufficient to reduce the pH of the microenvironment or of GI environment up to pH 3.0. Ion-pairing agents

The present invention involves the use of ion pairing agents to modulate the solubility and partitioning behavior of 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. Ion pairing agents can be ionic or non-ionic. Examples of cationic ion pairing agents include α- phosphotidyl choline, cetyl pyridinuim chloride cetyl triammonium bromide, benzalkonium chloride and the like. α-phosphatidylcholines (PC) are the most important ion pairing phospholipids which are predominantly hydrophobic in nature. The phospholipids come from natural sources, like soy beans and egg yolks. Being amphipathic in function, phospholipids have both a lipophilic, hydrophobic domain, as well as a hydrophilic region. This permits phospholipids to associate with lipophilic or hydrophobic active compounds and at the same time to be dispersed in aqueous media, without precipitation. Hence in the presence of water they become thermodynamically stable in the form of bilayer structure. These mono and diacylphospholipids are not only powerful natural solubilizers, but are also suitable for modern pharmaceutical applications. Lipoid S 100 is one of the phospholipids which is a purified soya lecithin containing more than 90% phosphatidyl choline. These exhibit very low toxicity and high tolerability, even for intravenous applications. Phospholipids like Lipoid S 100 are Generally Recognised as Safe (GRAS) by the FDA and are classified as lecithins in most monographs.

In one of the embodiments of the invention, ion pairing agents can be selected from the group consisting of lysolecithin, phosphatidylethanolamine, phosphatidylglycerol, lysophosphatidyl choline, PEG- phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholic acid, taurocholic acid, glycocholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid, ursodeoxycholic acid, taurodeoxycholic acid, glycodeoxycholic acid, cholylsarcosine, caproic acid, caprylic acid, capric acid, lauric acid, oleic acid, lauryl sulfate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and mixtures thereof. Surfactants

These are the agents that can increase the aqueous solubility of lipophilic drugs through micellar solubilisation. This solubility enhancement presents more of the drug substance in the solution phase for potential absorption.

The surfactant may include but not limited to, hydrophilic surfactants, lipophilic surfactants, mixtures there of. The surfactants may be anionic, nonionic, cationic, zwitterionic or amphiphilic. The relative hydrophilicity and hydrophobicity of surfactants is described by HLB (hydrophilic-lipophilic balance) value. Hydrophilic surfactants include surfactants with HLB greater than 10 as well as anionic, cationic, amphiphilic or zwitterionic surfactants for which the HLB scale is not generally applicable. Similarly, lipophilic surfactants are surfactants having an HLB value less than 10.

The hydrophilic non-ionic surfactants may be, but not limited to, polyethylene glycol sorbitan fatty acid esters, polyethylene glycol fatty acid monoesters, PEG-fatty acid diesters, hydrophilic trans-esterification products of alcohols or polyols with at least one member of the group consisting of natural and/or hydrogenated oils. The most 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. Preferred polyols include glycerol, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol and pentaerythritol. Preferred hydrophilic surfactants in this class include PEG-35 castor oil, polyoxyethylene-polypropylene copolymer (Lutrol, BASF), and PEG-40 hydrogenated castor oil.

The amphiphilic surfactants includes, but are not limited to, d-α-tocopheryl polyethylene glycol 1000 succinate and d-α-tocopherol acid salts such as succinate, acetate, etc. The ionic surfactants may 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, oligopeptides, or polypeptides; 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; 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.

In one more embodiment of the invention the lipophilic surfactants are selected, but 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; hydrophobic 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; oil-soluble vitamins/vitamin derivatives; polyethylene glycol (PEG) sorbitan fatty acid esters; PEG glycerol fatty acid esters; polyglycerized fatty acid; polyoxyethylene-polyoxypropylene block copolymers; sorbitan fatty acid esters; or mixtures thereof. According to one more embodiment of the invention the surfactant may be PEG-20- glyceryl stearate (Capmul® by Abitec), PEG-40 hydrogenated castor oil (Cremophor RH 40® by BASF), 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 caprylate/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.

According to still one more embodiment of the present invention, the absorption augmenting agent may be selected from 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. P-glycoprotein inhibitors

P-glycoprotein is one of several cellular efflux pumps known as part of the ATP binding cassette. P-glycoprotein has a protective role against many xenobiotic substrates. P- glycoprotein is an ATP-dependent efflux pump that exports drugs and endogenous metabolites out of the cell, thus affecting distribution within the body. P-glycoprotein is specifically localised on the apical membrane of secretory cells, where it plays an important defensive role in secreting xenobiotics and metabolites into the intestinal lumen, urine and bile. In support of these functions, human p- glycoprotein is present at high levels in the intestinal mucosa, lumenal membranes of the renal proximal tubules, the biliary canalicular membrane of hepatocytes etc. ARBs are known to be substrate for p- glycoprotein and therefore may be responsible efflux of ARBs and ultimately for low bioavailability of these compounds. Inhibition of intestinal p- glycoprotein therefore can increase the bioavailability of ARBs. In one of the embodiment of the invention, inhibitors of p-glycoprotein include -α- tocopheryl polyethylene glycol 1000 succinate.

In the composition ARB and one or more absorption augmenting agents may be employed in different ratios. The selection of ratio depends on the type of absorption augmenting agent employed. It is contemplated within the scope of the invention that the ratio of ARB to absorption augmenting agent can range from about 99: 1 to about 1 :99. The preferred ratio of the ARB to absorption augmenting agent ranges from about 20:1 to about 1 :20. The most preferred ratio being about 10:1 to about 1 : 10.

The invention also comprises the compositions involving use of multiple absorption augmenting agents to enhance absorption of pharmacologically active agent from the composition. A combination of absorption augmenting agent may also be included wherein the total amount of absorption augmenting agent employed is maintained in the above- mentioned ratios.

In the composition, the ARB may be present in the form of physical blend, semi solid mixture, solid solution or complex with the absorption augmenting agent. Different non- limiting processes may be employed for the treatment of an ARB with absorption augmenting agent. It is contemplated within the scope of the invention that the processes may include, but not limited to, processes such as melt granulation or solvent treatment or physical mixing or complexation method. In the case of melt granulation, the absorption augmenting agent is melted and ARB is added to the molten mass. The mass is allowed to solidify to form granules which are then separated from each other. In another illustrative embodiment of this system, the ARB is granulated using a molten absorption augmenting agent. In some cases, the ARB and the absorption augmenting agent both may be melted together and congealed to room temperature.

In using a solvent treatment method, either the absorption augmenting 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 absorption augmenting agent. The solvent employed in this system may be aqueous or non-aqueous. In the case of physical mixing, the ARB and the absorption augmenting agents are preferably intimately dry-mixed using a Hobart mixture, 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 spray drying and lyophilization process, slurry method, paste method, etc.

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 absorption augmenting agents, which can be further treated with the same or different absorption augmenting 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. According to one more embodiment of the invention, melt granulation and intimate physical mixture are the methods for preparing valsartan according to the present invention.

The increase in absorbable form can be determined using partition coefficient determination methods or in vitro dissolution studies and finally in - vivo study in human volunteers may be undertaken to validate in vitro data.

The dosage form according to the invention may include other excipients conventionally known in art such as fillers, disintegrants, binders and lubricants. Fillers such as lactose monohydrate, microcrystalline cellulose, dicalcium phosphate or the like may be used. Binders like polyvinyl pyrrolidone (PVP), copovidone or the like may be used. Lubricants such as Aerosil-200, magnesium stearate and hydrogenated vegetable oils and triglycerides of stearic acid, palmitic acid or the like may be utilized.

The disintegrating agent may be selected from a group but not limited to the following: starch, sodium starch glycolate, pregelatinised starch, crosslinked poly vinyl pyrrolidone, cross linked carboxy methyl cellulose, ion exchange resin, the most preferred being sodium starch glycolate. The disintegrant may be present in an amount ranging from about 0.0% to about 20%, more preferably about 0.5% to about 15.0% and most preferably from about 1 to about 10% by weight based on the total weight of the composition.

The composition may be incorporated in various pharmaceutical dosage forms, including, but not limited to, tablets which disintegrate in stomach, tablets which can disintegrate in the mouth, tablets which can disintegrate by effervescence in a liquid (water), tablets which can be dispersed in a liquid (such as water), coated tablets, powders of given doses packaged in sachets, suspensions, gelatin capsules, soft gelatin capsules, semisolid dosage forms, and other drug delivery systems.

In yet another embodiment of this invention the composition may further be incorporated in various other non limiting pharmaceutical drug delivery systems such as targeted release, pulsatile release, modified release tablets or systems like gastroretentive, osmotically controlled delivery systems, enteric coated tablets or any other delivery system thereof. The preferred dosage form of the present invention is a solid dosage form, preferably a tablet, which 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 could be encapsulated. Tablets in accordance with the 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.

In one 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 functional purposes. 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 ingredients. A surface coating can for example be obtained using a quick-dissolving film using conventional polymers such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, poly methacrylates or the like.

In another embodiment of the present invention, the composition may optionally be coated with a functional coat. The coat can be employed using hydrophilic polymers, hydrophobic polymers, waxes etc. either alone or in combination, along with plasticizers, colorants, opacifiers etc. The functional coat may provide a desired retardation of release profile. The functional coat may also inhibit the release of active ingredient in the stomach, if so desired.

In another illustrative embodiment according to the invention, the absorption augmenting agent treated ARB may be incorporated into a formulation for modified release. Although not limiting to any hypothesis, it is possible that absorption of ARBs and in particular valsartan may be facilitated or carrier mediated. The carrier mediated absorption usually has some transport moieties which can get saturated with higher concentrations of molecules being transported. It is therefore advantageous to release the drug in small amounts in modified or pulsatile manner so as to use these carriers most effectively and ultimately achieving increased bioavailability. The excipients employed for such modified release formulation ensures better control over release profile and also complete release of the drug in the desired time interval.

In a further illustrative embodiment according to the invention, the absorption augmenting agent treated ARB may be incorporated into modified release matrix formulation comprising of one or more polymeric or non-polymeric excipients.

Examples of polymers which can be used 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; zein; shellac -based polymers; polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium carboxy methylcellulose, calcium carboxymethyl cellulose, methyl cellulose, polyacrylic acid, Polyvinyl alcohol : Polyvinylpyrrolidone copolymers (e.g. Kollidon SR) maltodextrin, pre-gelatinized starch and polyvinyl alcohol, copolymers and mixtures thereof.

In one more embodiment of the invention, one or more hydrophilic polymers are selected from the group consisting of 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 and mixtures thereof.

According to one embodiment of this invention, the weight percent of the hydrophilic polymer in the dosage form is about 5 to about 90.

In one more embodiment of the invention, the weight percent of the hydrophilic polymer in the dosage form is about 10 to about 70,

In yet another embodiment of the invention the weight percent of the hydrophilic polymer in the dosage form is about 15 to about 50.

In a further illustrative embodiment a solid pharmaceutical composition may be in the form of a multilayer system for oral administration. The system may be adapted to deliver two different actives such as the absorption augmenting agent-treated ARB in one layer and hydrochlorothiazide in another layer.

In a further illustrative embodiment a solid pharmaceutical composition in the form of a multilayer 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 controlled manner over a specific time period. The second layer may have pellets of ARB with enteric coat for release in the intestine.

In a further illustrative embodiment a solid pharmaceutical composition is in the form of an in-lay tablet or compression coated tablet having different release profiles for ARB present in different portions of the tablet.

In a further illustrative embodiment a solid pharmaceutical composition in the form of an expanding multilayer 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 controlled 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 another illustrative embodiment according to the invention, the absorption augmenting agent treated ARB may be incorporated into an osmotically controlled drug delivery system. The excipient ensures better control over release profile and also complete release of the drug in the desired time interval. 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 capsules may be filled with formulation which is in the form of powder, pellets, minitablets, tablets, coated tablets, coated minitablets, semisolid composition or liquid composition or the like. The pellets may be of different sizes and can be filled in capsules or compressed into tablets. Pellets can also be coated for achieving a desired release profile or for targeting drug to a particular region of GIT.

The present invention provides oral solid dosage forms of ARBs that are about 1.2 to 4 times more bioavailable than the conventional immediate release dosage forms. The increase in bioavailability is evident from the decrease in T_max (time to reach maximum blood concentration), and the increase in C_max (the maximum blood concentration), AUCo-t, and

AUC_O-00 (the extent of absorption, or area under the blood concentration vs. time curve). Due to the increase in relative bioavailability, the novel composition will also be able to reduce the variability typically associated with an ARB, especially where the ARB is valsartan.

This composition may also achieve peak plasma concentration in less than 4 hours, preferably in less than 3 hours, and more preferably in less than 2 hours. The achieved T_max value is also faster than the conventional immediate release formulation. This composition may also achieve peak plasma concentration of at least 80 ng/ml/mg of valsartan dose and area under the blood concentration vs. time curve of atleast 500 ng/ml/mg of valsartan dose.

According to one embodiment, the composition of valsartan as described in the present invention may be used to treat the diseases described below and to deliver the absorbable form of the drug over the wide pH range of the GI tract to increase the bioavailability. Therefore, the dose and frequency of administration can be reduced, compared with administration of conventional valsartan. Moreover, the inter- and intra- patient variability associated with the current formulation of valsartan can also be reduced. Therefore, it is expected that there will be an increased therapeutic effect from this composition of the present invention of valsartan.

Examples of the diseases to be treated by this agent include 1. circulatory disease, such as hypertension, cardiac disease (heart failure, myocardial infarction, valvular disease), peripheral circulatory insufficiency; 2. kidney disease, e.g., glomerulonephritis, renal insufficiency; 3. cerebral dysfunction, e.g., stroke, Alzheimer's disease, depression, amnesia, dementia; 4. diabetic complications, e.g., retinopathy, nephropathy; 5. arteriosclerosis manifested by hypertension, stroke, heart attack, angina, or ischemia of gastrointestinal (GI) tract or extremities; 6. unique conditions, e.g.; hyperaldosteronism, multiple system organ failure, scleroderma; and 7. anxiety neurosis, catatonia, and dyspepsia. Many of these conditions are caused or exacerbated by vasoconstriction expressed secondary to angiotensin II.

The details of the invention, its objects and advantages are explained hereunder in greater detail in relation to non-limiting exemplary illustrations. Examples:

Example 1 - Treatment of valsartan with a surfactant (Gelucire) and incorporation into tablet Table 1: Immediate release formulation of valsartan

Gelucire was melted in a beaker at about 50°C and to the molten mass valsartan was added in the ratio of 1 :0.5 (valsartan: Gelucire) and mixed for 15 minutes. To this mixture 2 parts microcrystalline cellulose was added and mass stirred further till it achieved room temperature. The blend was then mixed with all other excipients, lubricated and compressed into tablets. Example 2 - Treatment of valsartan with a p-glycoprotien inhibitor and incorporation into tablet

Table 2: Immediate release formulations of Valsartan

Valsartan and vitamin E TPGS was weighed in a jacketed mixer and heated. The resultant mass was further mixed without heat till it attained room temperature. The resultant granules were further mixed with all other excipients, lubricated and compressed into tablets.

In-vitro dissolution rate studies

In-vitro dissolution rate studies were carried out with following specifications Dissolution Test Apparatus: USP Type II

Temperature: 37.5 ± 0.5⁰C

Dissolution Medium: Dissolution studies were carried out in 0.1N HCL (900ml)

RPM: 75

Sampling intervals: 15, 30, 60 and 120 minutes Sampling volume: 10ml Table 3: Dissolution profile of Formulation #2 (Table 8) in OAN HCL

The developed formulation exhibited much higher and much faster drug release profile compared to the marketed Diovan tablet as well as other exploratory valsartan formulations, formulations #1 and #3 Although vitamin E TPGS might work by inhibiting p- glycoprotein, it is also important to note that it also increases solubility and hence dissolution of valsartan.

Example 3 - Treatment of valsartan with a surfactant Table 4: Immediate release formulation of Valsartan

Valsartan was mixed physically with Lutrol F 127. This blend was then further mixed with all other excipients, lubricated and compressed into tablets. Example 4 - Treatment of valsartan with a combination of surfactant and p- glycoprotein inhibitor

Table 5: Immediate release capsule formulation of Valsartan

Vitamin E TPGS and Lutrol 127MP (Poloxamer 407, USP) were melted together at about 60°C.Valsartan was added to the molten mixture under continuous mixing. Microcrystalline cellulose (Avicel PH 102) was added to the mass and cooled to room temperature to produce solid granules. Microcrystalline cellulose (Avicel PH 102) and a portion of Crospovidone (KollidonCL) were mixed with the above solid agglomerates. These agglomerates granulated with copovidone dissolved in a mixture of Isopropyl Alcohol : Purified Water (7:3). Wet mass was passed through #12 mesh sieve and dried. Dried granules were mixed with remaining portion of Crospovidone (Kollidon.CL), lubricated with Magnesium stearate and filled into capsules. Example 5 - Treatment of valsartan with a combination of absorption augmenting agents Table 6- Immediate release formulation of Valsartan

.#

Procedure:

Valsartan was dispersed in molten lutrol and Vitamin E TPGS. Other diluents of intragranular phase including acidulant were dry mixed and added to the blend. The granular mass obtained was sized through a sieve and. The granules were blended with extra-granular ingredients and lubricants. The lubricated blend obtained was compressed to get tablets of optimum physical properties. Example 6 - Treatment of valsartan with a combination of absorption augmenting agents

Table 7: Immediate release formulation of Valsartan

Process:

Valsartan was dispersed in molten lutrol, vitamin E TPGS and Lipoid SlOO. Lipoid SlOO is phosphatidyl choline which is employed here as an ion pairing agent. Other diluents of intragranular phase including acidulant were dry mixed and added to the blend. The granular mass obtained was sized through a sieve and. The granules were blended with extra- granular ingredients and lubricants. The lubricated blend obtained was compressed to get tablets of optimum physical properties. Example 7: Comparative oral availability study

The cross study was designed to evaluate in vivo performance of valsartan tablets of Example 6 (Test) with respect to Diovan® (Reference) in healthy male volunteers under fasting condition. Pharmacokinetic parameters, T_max (time to reach maximum drug concentration in blood), C_max (maximum plasma concentration), AUC_0-1 (area under plasma concentration vs. time curve from 0 hours to the time of last sample collected), and Tmax were calculated from the data. Table 8: Summary statistics of pharmacokinetic parameters

The present invention exhibited a higher C_max and AUC₀._t compared to the marketed product (Figure 1). Thus test product exhibited significantly higher plasma blood levels, making the preparation more bioavailable as compared to the marketed product. This is only possible if both solubility and absorption of valsartan is increased which is the case with the present invention.

Example 8: Sustained release tablet of treated Valsartan Table 9: Treatment of valsartan with combination of absorption augmenting agents

Process:

The granulation procedure carried out was as per Example 5. The granular mass obtained was sized through a sieve. Table 10: Extra granular composition of valsartan sustained release tablets

Table 11: In vitro dissolution rate - using the parameters as shown in example 7

Example 8: Valsartan Coated tablets

The core tablets of valsartan were formulated using the intragranular and extragranular compositions as shown in table 12.

Table 12: Treatment of valsartan with combination of absorption augmenting agents

Procedure:

Valsartan was dispersed in molten lutrol and Vitamin E TPGS. Other diluents of intragranular phase including acidulant were dry mixed and added to the blend. The granular mass obtained was sized through a sieve and. The granules were blended with extra-granular ingredients and lubricants. The lubricated blend obtained was compressed to get tablets of optimum physical properties. These core tablets were then coated using HPMCP HS 50 based system (Shin Etsu) at weight gain of 4 and 6% w/w. Dissolution data Evaluation: Dissolution medium: 0.1N HCl 1 hour followed by 4.5 acetate buffer for 1 hour The pH change involves complete media change Dissolution volume: 900 ml

Table 13: Dissolution data ofvalsartan coated tablets

Example 9: Gastroretentive tablets ofvalsartan A. Drug Core

Table 14- Composition of drug core

Procedure:

Valsartan was dispersed in molten lutrol and vitamin E TPGS. Remaining diluents were dry mixed and added to the drug premix. The granular mass obtained was sized through a sieve. The granules were blended with extra-granular ingredients and lubricants. The lubricated blend obtained was compressed to get tablets of optimum physical properties.

B. Gastroretentive matrix

Table 15: Composition of Gastroretentive matrix

Procedure:

The ingredients of intragranular composition as shown in table 15 were granulated using solution of kollidon 30 and passed through the sieve and dried, which were then mixed with the extragrnular ingredients. This mass was then lubricated and used for compression of inlay tablet using drug core of table 14. In vito dissolution study

In-vitro dissolution rate studies of the Valsartan tablets of Example 9 were carried out in 0.1N HCl with following specifications: Dissolution Test Apparatus: USP Type II Temperature: 37.5 ± 0.5⁰C Dissolution Medium: 0. IN HCl Rpm: 75

Table 16 : Dissolution data of valsartan inlay tablet

Example 10: Valsartan bilayer tablet A. Drug containing layer

Table 17: Composition of drug containing layer

Procedure:

Valsartan was dispersed in molten lutrol and vitamin E TPGS. Remaining diluents were dry mixed and added to the drug premix. The granular mass obtained was sized through a sieve.

B. Gastroretentive layer

Table 18: Composition of Gastroretentive layer

The ingredients of intragranular composition as shown in table 18 were granulated using solution of kollidon 30 and passed through the sieve and dried, which were then mixed with the extragrnular ingredients. This mass was then lubricated. Granules containing valsartan and GR layer were compressed as bilayer tablet. Example 11: Treatment of Candesartan with absorption augmenting agents Table 19: Treatment of candesartan

Candesartan is dispersed in molten vitamin E TPGS, Gelucire and Lipoid SlOO. Remaining diluents are dry mixed and added to the drug premix. The granular mass obtained is sized through a sieve and mixed with extragranular ingredient and compressed into tablets. Example 12: Treatment of Candesartan with absorption augmenting agents Table 20: Treatment of candesartan

Candesartan is dispersed in molten lutrol and Lipoid SlOO. Remaining diluents are dry mixed and added to the drug premix. The granular mass obtained is sized through a sieve and mixed with extragranular ingredient and compressed into tablets. Example 13: Treatment of Telmisartan with absorption augmenting agents 37 JL -^ Ji s A i t έi u u uy

Table 21: Treatment of telmisartan

Telmisartan is dispersed in molten lutrol Lipoid S 100 and lauryl macrogol - 32 glyceride (Gelucire 44/14. Remaining diluents are dry mixed and added to the drug premix. The granular mass obtained is sized through a sieve and mixed with extragranular ingredient and compressed into tablets.

Claims

1. A composition comprising: an angiotensin receptor blocker or a salt thereof; and at least one absorption augmenting agent.

2. The composition as claimed in claim 1 wherein said absorption augmenting agent is an acidulant, an ion pairing agent, a surfactant or a p-glycoprotein inhibitor.

3. The composition as claimed in claim 2 wherein said acidulant is an aliphatic or aromatic, saturated or unsaturated, monobasic (monocarboxylic acid), dibasic or tribasic acid, an organic acid salt, a dibasic amino acid or a dihydroxy dibasic or tribasic acid.

4. The composition as claimed in claim 3 wherein said acidulant is maleic acid, tartaric acid, fumaric acid, aspartic acid, malic acid or citric acid.

5. The composition as claimed in claim 2 wherein said ion pairing agent is phosphatidyl choline, cetyl pyridinium chloride, cetyl triammonium bromide or benzalkonium chloride.

6. The composition as claimed in claim 2 wherein said surfactant is an anionic, nonionic, cationic or zwitterionic hydrophilic surfactant, a lipophilic surfactant or a mixture thereof.

7. The composition as claimed in claim 6 wherein said surfactant is PEG- 40 hydrogenated castor oil, lauryl macrogol-32 glyceride, stearoyl macrogol glyceride, PEG-20 sorbitan monolaurate, PEG-4 lauryl ether, polyoxyethylene-polypropylene copolymer, sodium lauryl sulphate, polyethylene glycol, d-α- tocopheryl polyethylene glycol 1000 succinate or a mixture thereof.

8. The composition as claimed in claim 2 wherein said p-glycoprotein inhibitor is α- tocopheryl polyethylene glycol or a derivative thereof.

9. The composition as claimed in claim 1 comprising said angiotensin receptor blocker in an amount of about 1% to about 80% of said composition.

10. The composition as claimed in claim 9 comprising said angiotensin receptor blocker in an amount of about 5% to about 70% of said composition.

1 1. The composition as claimed in claim 10 comprising said angiotensin receptor blocker in an amount of about 10% to about 60% of said composition.

12. The composition as claimed in claim 1 wherein said angiotensin receptor blocker is candesartan, irbesartan, losartan, olmesartan, telmisartan, valsartan or pratosartan, or a salt thereof.

13. The composition as claimed in claim 1 wherein said angiotensin receptor blocker is valsartan or a salt thereof.

14. The composition as claimed in claim 13 wherein T_max is about 1 hour to about 2 hours.

15. The composition as claimed in claim 13 wherein T_max is about 1 hour to about 2 hours and C_max is at least 80 ng/ml per mg of the valsartan dose.

16. The composition as claimed in claim 13 wherein T_max is about 1 hour to about 2 hours and AUC is at least 500 ng hr/ml per mg of the valsartan dose.

17. The composition as claimed in claim 13 wherein coefficient of variation (CV) for the AUC is no more than 50%.

18. The composition as claimed in claim 13 wherein the coefficient of variation (CV) for the Cmax is no more than 40%.

19. The composition as claimed in claim 1 comprising an angiotensin receptor blocker and multiple absorption augmenting agents, said absorption augmenting agents comprising a surfactant, an acidulant, an ion pairing agent and a p-glycoprotein inhibitor.

20. The composition as claimed in claim 19 wherein said angiotensin receptor blocker is valsartan or a salt thereof, said surfactant is a polyoxyethylene-polypropylene copolymer, said acidulant is fumaric acid, said ion pairing agent is phosphatidyl choline and said p- glycoprotein inhibitor is α-tocopheryl polyethylene glycol or a derivative thereof.

21. The composition as claimed in claim 1 wherein the ratio of said angiotensin receptor blocker to said absorption augmenting agent is about 99:1 to about 1 :99.

22. The composition as claimed in claim 21 wherein the ratio of said angiotensin receptor blocker to said absorption augmenting agent is about 20:1 to about 1 :20.

23. The composition as claimed in claim 22 wherein the ratio of said angiotensin receptor blocker to said absorption augmenting agent is about 10: 1 to about 1 :10.

24. The composition as claimed in claim 1 further comprising at least one filler, at least one binder, at least one lubricant, or a mixture thereof.

25. The composition as claimed in claim 1 wherein said composition is incorporated into a drug delivery system, said drug delivery system is a modified release, controlled release, osmotically controlled release, pulsatile release, gastroretentive system or targeted release system.

26. The composition as claimed in claim 25 wherein said drug delivery system is a modified release system.

27. The composition as claimed in claim 26 wherein said modified release system comprises polyalkylene oxide, cellulosic polymer, acrylic acid, methacrylic acid polymer, ester of acrylic acid and methacrylic acid polymer, maleic anhydride polymer, polymaleic acid, polyacrylamide; poly(olefinic alcohol), poly(N-vinyl lactam), polyol, polyoxyethylated saccharide, polyoxazoline, polyvinylamine, polyvinylacetate, polyimine, starch, starch-based polymer, polyurethane hydrogel, chitosan, polysaccharide gum, zein, shellac-based polymer, 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 copolymer, or a mixture thereof.

28. The composition as claimed in claim 1 wherein said composition is a tablet or a capsule.

29. The composition as claimed in claim 1 further comprising an anti-hypertensive agent, an anti-obesity agent, an anti-diabetic agent, a beta-blocker, an inotropic agent, a hypolipidemic agent, or a combination thereof.

30. The composition as claimed in claim 29 wherein said anti-hypertensive agent is a hydrochlorothiazide (HCTZ), a calcium channel blocker, an angiotensin-converting enzyme (ACE) inhibitor, renin inhibitor, or combinations thereof.

31. A method for making a valsartan composition for increasing the absorption of valsartan, said method comprising the steps of:

(a) providing valsartan or a salt thereof;

(b) providing at least one absorption augmenting agent; and (c) treating said valsartan with said absorption augmenting agent.

32. The method as claimed in claim 31 wherein step (c) comprises melt granulation, wet granulation, intimate physical mixing, spray drying, solvent evaporation or another complexation method.

33. The method as claimed in claim 31 wherein said absorption augmenting agent comprises an acidulant, an ion pairing agent, a surfactant, a p-glycoprotein inhibitor or a combination thereof.

34. The method as claimed in claim 31 wherein the ratio of said valsartan to said absorption augmenting agent is about 20:1 to about 1 :20.

35. The method as claimed in claim 34 wherein the ratio of said valsartan to said absorption augmenting agent is about 10:1 to about 1 :10.

36. The method as claimed in claim 31 further comprising the step of adding at least one filler, at least one disintegrant, at least one binder, at least one lubricant or a combination thereof.

37. The method as claimed in claim 31 wherein said composition is incorporated into a drug delivery system, said drug delivery system is a sustained release, modified release, controlled release, osmotically-controlled release, pulsatile release, gastroretentive system or targeted release system.

38. The method as claimed in claim 37 wherein said drug delivery system is a modified release system.

39. The method as claimed in claim 38 wherein said modifed release system comprises polyalkylene oxide, cellulosic polymer, acrylic acid, methacrylic acid polymer, ester of acrylic acid and methacrylic acid polymer, maleic anhydride polymer, polymaleic acid, polyacrylamide; poly(olefinic alcohol), poly(N-vinyl lactam), polyol, polyoxyethylated saccharide, polyoxazoline, polyvinylamine, polyvinylacetate, polyimine, starch, starch-based polymer, polyurethane hydrogel, chitosan, polysaccharide gum, zein, shellac-based polymer, 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 copolymer, or a mixture thereof.

40. The method as claimed in claim 31 further comprising the step of tableting the mixture.

41. The method as claimed in claim 31 further comprising the step of adding an antihypertensive agent, an anti-obesity agent, an anti-diabetic agent, a beta-blocker, an inotropic agent, a hypolipidemic agent, or a combination thereof.

42. The method as claimed in claim 41 wherein said anti-hypertensive agent is hydrochlorothiazide (HCTZ), a calcium channel blocker, an angiotensin converting enzyme (ACE) inhibitor, a renin inhibitor, or a combination thereof.

43. A method for treating a disease comprising administering to a mammal in need thereof a therapeutically effective amount of the composition of claim 1, said disease comprising circulatory disease, kidney disease, cerebral dysfunction, diabetic complication, arteriosclerosis, hyperaldosteronism, multiple system organ failure, scleroderma, anxiety neuroses, catatonia or dyspepsia.

44. The method as claimed in claim 43 wherein said circulatory disease is hypertension, cardiac disease or peripheral circulatory insufficiency.

45. The method as claimed in claim 43 wherein said kidney disease is glomerulonephritis or renal insufficiency.

46. The method as claimed in claim 43 wherein said cerebral dysfunction is stroke, Alzheimer's disease, depression, amnesia or dementia.

47. The method as claimed in claim 43 wherein said diabetic complication is retinopathy or nephropathy.

48. The method as claimed in claim 43 wherein said arteriosclerosis is manifested by hypertension, stroke, heart attack, angina or ischemia of the gastrointestinal tract or extremities.