FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2006
PROVISIONAL SPECIFICATION (See section 10; rule 13)
1. Title of the invention. -"PHARMACEUTICAL COMPOSITIONS OF ANGIOTENSIN II RECEPTOR
BLOCKERS"
2. Applicant(s)
(a) NAME: RUBICON RESEARCH LTD.
(b) NATIONALITY : An Indian Company
(c) ADDRESS: 221-Annexe Bldg, Goregaon -Mulund link road, off. L.B.S.marg, opp.Indira container Yard, Bhandup (West).Mumbai-400078
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

FIELD OF THE INVENTION
The present invention relates to the methods/approaches for increasing the bioavailability
of Angiotensin II Receptor Blockers (ARBs) by increasing absorption of ARBs 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 pharmaceutical^ 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
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diuretics, ({-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 Patent No. 5399578 ('578 patent).
Various polymorphs and salt forms of valsartan are described by WO 04083192,
WO04087681, and WO03066606.
WO 04101535 relates to pharmaceutical compositions and a method of reducing the risk
of morbidity and mortality in patients having symptomatic heart failure comprising
administering to such patient an effective amount of valsartan, or pharmaceutically
acceptable salts thereof, alone or in combination with another therapeutic agent,
optionally in the presence of a pharmaceutically acceptable carrier. This patent describes
the novel use or novel crystalline forms of valsartan, but does not tackle the problem
associated with the poor bioavailability of valsartan.
US Patent No. 6,294,197 ('197 patent) and US Patent Application Publication No.
2003/0035832 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.
In US Patent No. 6,485,745 ('745), solid dosage forms of valsartan are described which
exhibit accelerated release of the active agent in pH 6.8 phosphate buffer. However
release in 0. IN HC1 is not addressed where the solubility of valsartan is minimal.
US Patent Application Publication No. 2002/0132839 and US Patent Application
Publication No. 2003/0152620 discuss pharmaceutical compositions of valsartan tablet
dosage form are at least 1.2 times more bioavailable than the conventional valsartan
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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 normal formulation. The invention does not, however, describe methods to increase solubility of the valsartan itself in the gastric milieu; and therefore, the dissolution of valsartan in 0.1 N HC1 still remains low which results in low bioavailability.
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.
United States Patent Application Publication No. 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 allowed. The low bioavailability associated with poor aqueous solubility warrants administration of larger doses of the ARBs to maintain desired therapeutic activity. PCT application WO 2006/113631 describes use of solubilizing agents for increasing solubility of an ARB such that the release of ARB in the GI tract is independent of physiological pH conditions. The composition as per this invention exhibbits increased bioavailability of valsartan (1.6 fold increase). This increase in bioavailability results in absolute bioavailability of 40% (considering 25% for marketed product Diovan®). No attempts however are made in PCT application WO 2006/113631 to increase the absorbability of the ARB throughout the entire gastrointestinal tract which could further increase its bioavailability.
It is known that particularly for valsartan that 80% of the drug is excreted in feces in unchanged form, which indicate that a large amount of valsartan is excreted without getting absorbed. This data indicate that there is poor absorption of valsartan in the
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gastrointestinal tract (GIT). Thus there remains a need and opportunity for improved
ARB formulation mat increases the absorption of the ARB in GIT and increase its
bioavailability.
SUMMARY OF INVENTION
The present invention relates to methods of predictably increasing the bioavailability of ARBs, especially valsartan, and insuring consistent absorption over a wide pH range of the GI tract. This invention increases the absorption for ARBs 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,™*) 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. This invention also relates to an oral dosage formulation of valsartan having reduced intra- and inter-patient absorption, particularly at low GI pH. The coefficient of variability for Cm,*, the maximum concentration in the blood, is less than about 35%, preferably less than about 30%. The coefficient of variability for the AUC is less than about 45%, preferably 40%, and most preferably 30%.
It has been discovered that an ARB, particularly valsartan, when combined with an absorption augmenting agent, the absorption augmenting agent significantly increases the absorption of an ARB absorption throughout the entire GIT which is in sharp contrast to the currently marketed ARB formulations. The bioavailability will also increase as more drug is present in the absorbable form at the absorption site. The 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 throughout the entire GIT ensures 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.
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In one aspect, the present invention provides a memod of increasing the bioavailability of
an ARB by increasing its absorption throughout the GIT
In another aspect, the present invention provides a method of increasing the
bioavailability of an ARB by administering it with at least one absorption augmenting
agent.
In yet another aspect, the present invention provides a method of increasing the
bioavailability of valsartan by administering it with at least one absorption augmenting
agent.
In another aspect, the present invention provides method of treatment of an ARB with an
absorption augmenting agent in order to increase its bioavailability.
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.
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
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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 either 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. 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.
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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, anti-hypertensive agents particularly HCTZ, anti-obesity agents, anti-diabetic agents, beta-blockers, inotropic agents and hypolipidemic agents. The active ingredient may be present in an amount 5-80 %, preferably 10-70% 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 throughout the GIT. and in particular lower GIT. The term lower GIT includes parts of small intestine such as jejunum and ileum as well as large intestine. The absorption of the drug can be increased by increasing the absorbable form of the drug or inhibition of p-glycoprotein mediated efflux or by entrapping drug in micelles. Absorbable form of the drug can be increased by preventing or reducing its ionization in the GIT by using acidulant or by using ion pairing agents which makes the drug more lipophilic.
According to present invention the absorption augmenting agent is selected from a group of acidulants, ion-pairing agents, surfactants or p-glycoprotein inhibitors. Acidulants:
Acidulants are physiologically compatible water-soluble organic acids which decrease the pH of the lower gastrointestinal tract and increase the absorbable form of an ARB. As used herein, acidulants refer 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
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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.
Preferred are malic acid, tartaric acid, fumaric acid, maleic acid, aspartic acid and citric
acid.
Aciduiants may be employed in an amount sufficient to reduce the pH of the content of
the lower GIT.
Ion-pairing agents
The present invention involves 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 orany 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 a-phosphotidyl choline, cetyl pyridinuim chloride cetyl triammonium bromide, benzalkonium chloride and the like. Surfactants
These are the agents that form micelles and entrap the drug inside micelles. A micelle is an aggregate of surfactant molecules dispersed in a liquid colloid. A typical micelle in aqueous solution forms an aggregate with the hydrophilic head region in contact with surrounding solvent sequestering the hydrophobic tail regions in the micelle center. Surfactant encapsulate the ARB in the micelles such that drug is not exposed to the external milieu of the GIT thus preventing ionization of the ARB. These micelles however, might fuse with the cell membrane and release the drug in unionized absorbable form.
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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-a-tocopheryl polyethylene glycol 1000 succinate and d-a-tocopherol acid salts such as succinate, acetate, etc. The ionic surfactants may be, but 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; 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 lipophilic surfactants may be, 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
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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.
Preferably, the solubility enhancing agent 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, Detains , polyethylene glycol (Carbowax® by DOW), d-a-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS® by Eastman), or mixtures thereof.
More preferably, 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-a-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS® by Eastman- HLB -15), or mixtures thereof. P-glycoprotein inhibitors
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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. Examples of inhibitors of p-glycoprotein include -a-tocopheryl polyethylene glycol 1000 succinate.
In the composition ARB and one or more absorption augmenting agent may be employed in different ratios. The selection of ratio depends 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 50:1 to about 1:50. The preferred ratio of the ARB to absorption augmenting agent ranges from about 25:1 to about 1:25. The most preferred ratio being about 10:1 to about 1:10.
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 treatment using melt granulation or solvent treatment or
physical mixing or complexation method.
Excipients:
The dosage form according to the invention may include other excipients conventionally
known in art such as fillers, binders and lubricants. Fillers such as lactose monohydrate,
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microcrystalline cellulose, dicalcium phosphate or die 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.
A therapeutically effective amount of an ARB, in free or a pharmaceutically acceptable salt form is supplied as a suitable unit dosage form, e.g. a tablet, a capsule.
The dosage form of the present invention can exist in various pharmaceutical dosage forms, including in particular: 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 disintegrate in a liquid (water), coated tablets. The proposed technique of improving wettability and then formulating into a dosage form without using excessive amounts of disintegrating agent can also be applied for other dosage forms for example, powders of given doses packaged in sachets, suspensions, gelatin capsules, soft gelatin capsules, semisolid dosage forms as well as other drug delivery systems.
The 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 can 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.
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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 sustained release formulation. Although not limiting to any hypothesis, it is possible that absorption of ARBs and in particular valsartan may be facilitated or carrier mediated. Ithe cqarrier mediated absorption usually have 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 sustained 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 a sustained release matrix formulation comprising of one or more polymeric or non-polymeric release retardants. 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;
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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.
One or more hydrophilic polymers are preferably 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.
The weight percent of the hydrophilic polymer in the dosage form is about 5 to about 90 weight percent, preferably about 10 to about 70 weight percent, and most preferably about 15 to about 50 weight percent.
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 in the form of an in-lay tablet or compression coated tablet having different release profiles for ARB present different portions of the tablet.
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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 details of the invention, its objects and advantages are explained hereunder in greater
detail in relation to non-limiting exemplary illustrations.
Example 1:
Sustained release tablet of absorption augmenting agent treated Valsartan
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Table 1: Treatment of valsartan with lutrol and Vitamin E TPGS



Process:
Valsartan was dispersed in molten solubilizers. Diluents and acidulant were dry mixed
and added to the drug-solubilizer premix. The granular mass obtained was sized through a
seive.
Table 2: Composition of Valsartan sustained release tablet

Process:
The granules were blended with extra-granular ingredients and lubricants. The lubricated blend obtained was compressed to get 330.0mg tablets of optimum physical properties.
Example 2:
In-vitro dissolution rate studies of tablets of Examplel
In-vitro dissolution rate studies of the Valsartan tablets of Example 1 were carried out in
0.1N HC1 with following specifications:
Dissolution Test Apparatus: USP Type II
Temperature: 37.5 ± 0.5°C
Dissolution Medium: 0.1N HC1
Rpm: 50
Table 3: In-vitro dissolution rates of tablet of Example 1

17

The sustained release formulation of treated valsartan releases more than 85% of drug in 4 hours. This ensures that solubilized form of valsartan is released gradually over a period of time so that the saturation of the transport moieties does not take place.
Example 3:
Sustained release tablet of treated Valsartan releasing drug in 3 hours
Table 4: Treatment of valsartan with lutrol

Process:
The granulation procedure carried out was as per Example 1
Table 5: Composition of Valsartan sustained release tablet

Process:
The granules were blended with extra-granular ingredients and lubricants. The lubricated
blend was compressed to obtain 280mg tables of desired physical properties.
Example 4:
18

In-vitro dissolution rate studies of tablets of Example3
In-vitro dissolution rate studies of the Valsartan tablets of the invention given in Example
3 were carried out in 0.1N HC1 with following specifications:
Dissolution Test Apparatus: USP Type II
Temperature: 37.5 ± 0.5°C
Dissolution Medium: 0.1NHC1
Rpm: 50
Table 6: In-vitro dissolution rates of tablet of Example 3

Sustained release tablets of valsartan treated with lutrol were successfully prepared for improving bioavailability of valsartan
Example 5:
Sustained release capsule of Candesartan
A) Immediate release mini-tablets
Table 7:Treatment of candesartan

Process:
The granulation procedure followed was as per Example 1
Table 8: Composition of Candesartan Immediate release tablets

19
Extra-granular Ingredients Mg/Tablet
Granules of candesartan treated with Lutrol and Vitamin E TPGS 20.0
Avicel PHI02 (Microcrystalline cellulose) 10.0
Kollidon CL 8.5
Aerosil 200 (Colloidal silicon dioxide) 1.0
Magnesium stearate 0.5
Total 40.0
Process:
The granules were blended with extra-granular ingredients and lubricants. The lubricated blend was compressed on 5mm punches to obtain 40mg mini tablets.
B) Coating composition (16mg drug release at 1.5-3.0 hrs)
Table 9: Composition of Candesartan coated tablet

Ingredients mg/tab
Core tablet as prepared in part A 40.0
Hydromellose (Methocel E 5 LV) 2.40
Ethyl cellulose (Surelease) (used as a aqueous dispersion) 1.35
Glycerin 0.25
Total 44.0
Process:
HPMC E5LV was dispersed in aqueous dispersion of Ethyl cellulose under stirring to
which glycerin was added.
Part of the mini-tablets prepared in part A were coated with combination of hypromellose and ethylcellulose for 10% weight gain to retard drug release for 1.5-3.0 hrs.
Two tablets each of A and B were filled into a size 00 capsule to get the desired release profile.
20

Example 6:
In-vitro dissolution rate studies of mini-tablet containing capsule of Example 5
In-vitro dissolution rate studies of the Candesartan tablets of the invention given in
Example 5 were carried out in 0.1N HC1 with following specifications:
Dissolution Test Apparatus: USP Type I
Temperature: 37.5 ± 0.5°C
Dissolution Medium: 0.1NHC1
Rpm: 100
Table 10: In-vitro dissolution rates of the mini-tablets containing capsule of Example 5

Time Percentage of Vaisartan released
0.0 0.0
1.0 33.2
2.0 53.0
3.0 83.4
Example 7:
Vaisartan Bilayer tablet
A) Immediate-release layer
Table 11: Treatment of vaisartan with Lutrol

Intra-granular Ingredients Mg/Tablet
Vaisartan 100.0
Lutrol 127MP(Poloxamer) 50.0
Citric acid 45.0
Zeopharm 600 (Calcium silicate) 75.0
Avicel PHI 02 (Microcrystalline cellulose) 25.0
Kollidon CL 25.0
Total 355.0
Process:
The granulation procedure was same as given in Example 1.
Table 12: Composition of Vaisartan Immediate release layer

Extra-granular Ingredients Mg/Tablet
21

Granules of valsartan treated with Lutrol 355.0
Citric acid 45.0
Avicel PHI02 (Microcrystalline cellulose) 150.0
Kollidon CL 65.0
Aerosil 200 (Colloidal silicon dioxide) 13.0
Magnesium stearate 7.0
Total 600.0
Process:
The granules were blended with extra-granular ingredients and lubricants to prepare the
lubricated blend.
B) Sustained release layer
Table 13: Treatment of Valsartan with Lutrol

Intra-granular ingredients Mg/tablet
Valsartan 60.0
Lutro 127 MP (Poloxamer) 30.0
Zeopharm 600 (Calcium silicate) 40.0
Avicel PHI02 (Microcrstalline cellulose) 30.0
Total 160.0
Process:
The granulation procedure followed was same as Example 1.
Table 14: Composition of Valsartan sustained release layer

Extra-granular ingredients Mg/tablet
Valsartan granules treated with Lutrol 160.0
Methocel K100LV (Hydroxypropylmethyl cellulose) 35.0
Avicel PHI02 (Microcrystalline cellulose) 100.0
Citric acid 95.0
Aerosil 200 (colloidal silicon dioxide) 7.0
Magnesium stearate 3.0
Total 400.0
22

Process:
The granules were blended with extra-granular agents and lubricants to obtain lubricated
blend.
C) Valsartan Bilayered tablets
600mg of Blend of A and 400mg of Blend of B was compressed to obtain 1 OOOmg
bilayer tablet.
Example 8:
In-vitro dissolution studies of tablet of Example 7:
In-vitro dissolution rate studies of the Valsartan Bilayer tablet of the invention given in Example 7 were carried out in O.IN HCl for 2 hours followed by 6.8 phosphate buffer for another 4 hours with following specifications: Dissolution Test Apparatus: USP Type II Temperature: 37.5 ± 0.5°C Rpm: 50
Table 15: In-vitro dissolution rates of the Valsartan bilayer tablet of Example 7

Time Percentage of Valsartan released
0.0 0.0
1.0 26.3
2.0 47.8
4.0 62.6
6.0 84.0
Example 9:
Pulsed release Valsartan tablet
A) Immediate release granules Table 16: Treatment of valsartan with Vitamin E TPGS

Intra-granular ingredients Mg/Tablet
Valsartan 50.0
Vitamin E TPGS 25.0
Neusilin 30.0
23

Total

105.0

Process: The granulation procedure followed was as per Example 1.
Table 17: Composition of immediate release Valsartan granules

Extra-granular ingredients Mg/Tablet
Valsartan granules treated with Vitamin E TPGS 105.0
Avicel PHI02 (Microcrystalline cellulose) 78.0
Kollidon CL 30.0
Aerosil 200 (Colloidal silicon dioxide) 11.0
Magnesium stearate 4.0
Total 228.0
Process:
The granules were blended with extra-granular ingredients and lubricants to obtain lubricated blend.
Enteric coated Valsartan spheres
Table 18:Composition of Valsartan spheres

Ingredients Mg/unit
Valsartan 30.0
Fumaric acid 35.0
Avicel PH102 (Microcrystalline cellulose) 50.0
Polyvinyl pyrolidone K30 5.0
Purified water Quantity sufficient
Total 120.0
Process:
Valsartan, fumaric acid and MCC were wet granulated with aqueous solution of the PVP
K.30. The granulated mass was extruded and spheronized to obtain spheres of diameter
lmm.

Enteric coating of Valsartan spheres: Table 19:Eudragit coated Valsartan spheres

24

Ingredients Mg/unit
Valsartan spheres 120.0
Eudragit LI00 7.0
Triethyl citrate 2.0
Talc 3.0
Total 132.0
Process:
22% coating solution was prepared as follows:
Eudragit was gradually dispersed in purified water under stirring. This was followed by
Triethyl citrate and Talc. Stirring was continued for 45 minutes to obtain homogenous
coating solution.
Valsartan spheres were coated with this Eudragit L 100 solution in a fluidized bed
processor for 10% weight gain
228mg of blend A and 132mg of spheres of C were compressed to obtain 360mg tablet.
Example 10:
Partition study of Valsartan-acidulant mix
Method: Shake flask method
System of partitioning: n-octanol and 6.5pH aqueous buffer
Table 20: % of valsartan partitioned

Substance partitioned Percentage of substance partitioned in 6.5pH aqueous buffer (ionized form) Percentage of substance partitioned in n-octanol(unionized form)
Valsartan 98.55 1.45
Valsartan + Fumaric acid (5:6) 42.3 57.7
Valsartan + citric acid (5:9) 46.8 53.2
25

This example demonstrate that the acidulant is able to reduce the pH of the buffer. The reduction pH results in decreased ionization of valsartan and therefore more amount of valsartan partition into n-octanol layer indicating the possibility of increased absorption
Example 11:
Sustained release Valsartan tablet employing ion-pairing agent
Table 21: Intra-granular composition of Valsartan sustained release tablet

Intra-granular ingredients Mg/Tablet
Valsartan 80.0
Cetyl pyridinium bromide 80.0
Avicel PHI 02 (Microcrystalline cellulose) 100.0
Polyvinyl pyrolidone K30 10.0
Purified water Quantity sufficient
Total 270.0
Process:
Ion-pair association complex of valsartan with cetyl pyridinum bromide is made in water at a suitable pH. This complex is isolated and employed for granulation. The complex is mixed with diluents and granulated using polyvinyl pyrolidone as binder.
Table 22: Composition of Valsartan sustained release tablet

Extra-granular ingredients Mg/tablet
Granules of valsartan containing valsartan as ion pair complex 270.0
Avicel PHI02 (Microcrystalline cellulose) 50.0
Methocel K100LV (Hydroxypropylmethyl cellulose) 40.0
Magnesium stearate 5.0
Aerosil 200 (colloidal silicon dioxide) 10.0
Total 375.0
Process:
The granules were blended with extra-granular ingredients and lubricated. The lubricated
blend was compressed to obtain 375mg tablets.
26

Example 12:
Valsartan compression-coated tablet
A) Immediate release layer of Valsartan compression-coated tablet Table 23: Treatment of Valsartan with lutrol and Vitamin E TPGS compression coated tablet

Intra-granular ingredients Mg/tablet
Valsartan 50.0
Poloxamer 407 ( Lutrol 127MP) 25.0
Vitamin E TPGS 25.0
Neusilin 50.0
Total 150.0
Process:
The procedure followed was the same as in Example 1
Table 24: Composition of Valsartan compression coated tablet

Extra-granular ingredients Mg/tablet
Valsartan granuled treated with Lutrol and Vitamin E TPGS 150.0
Avicel PHI02 (Microcrystalline cellulose) 80.0
Kollidon CL 30.0
Magnesium stearate 4.0
Aerosil 6.0
Total 270.0
Process:
The granules were blended with extra-granular ingredients and lubricants to obtain the
lubricated blend.
Table 25: Core composition of enteric coated tablet

Ingredients Mg/Tablet
Valsartan 30.0
Phosphotidyl choline 10.0
Poloxamer 407 ( Lutrol 127MP) 15.0
Vitamin E TPGS 15.0
27

Avicel PHI 02 (Microcrystalline cellulose) 80.0
Polyvinyl pyrolidone 5.0
Purified water Quantity sufficient
Magnesium stearate 2.0
Aerosil 3.0
Total 180.0
Process:
Valsartan was treated with phosphotidyl choline, lutrol and Vitamin E TPGS. Granules
thus obtained were further blended with Avicel and granulated with aqueous solution of
PVP. The granules were lubricated with the lubricants and compressed to obtain 180mg
tablets.
Enteric coated Valsartan tablet
Table 26: Composition of enteric coated tablet

Ingredients Mg/Tablet
Core tablet 180.0
Eudragit LI00 10.5
Triethyl citrate 3.5
Talc 4.0
Total 198.0
Process:
22% coating solution of Eudragit LI00 was prepared by gradually dispersing Eudragit in
water under stirring. This was followed by addition of TEC and Talc.
The tablets were coated in Automated Gans coater for a weight increase of 10%.
These enteric coated tablets were compression coated with lubricated blend of A to get a
compression-coated tablet of 465mg.
Example 13:
Valsartan sustained release tablet
Table 27: Treatment Valsartan with Lutrol, Vitamin E TPGS and phosphatidyl choline

Intragranular Ingredients Mg/Tablet
Valsartan 50.0
Vitamin E TPGS 15.0
Lutrol 127 MP 20.0
28

Phosphotidyl choline 40.0
Neusilin 85.0
Total 210.0
Process:
The granulation procedure followed was as per Example 1
Table 28: Composition of Valsartan sustained release tablet

Extra-granular Ingredients Mg/Tablet
Valsartan Granules treated with Lutrol, Vitamin E TPGS and phosphatidyl choline 210.0
Kollidon SR 200.0
Avicel PHI02 (Microcrystalline cellulose) 50.0
Magnesium stearate 4.5
Aerosil 200 (Colloidal silicon dioxide) 10.5
Total 475.0
Process:
The granules were blended with extra-granular ingredients and lubricants. The lubricated
blend was compressed to obtain 475mg tablets.
Example 14:
In-vitro dissolution rate studies of tablets of Example 13
In-vitro dissolution rate studies of the Valsartan tablets of the invention given in Example
13 were carried out in 0.1 N HCl (2 hours) followed by pH 6.8 phosphate buffer for
another 6 hours with following specifications:
Dissolution Test Apparatus: USP Type II
Temperature: 37.5 ± 0.5°C
Rpm: 50
Table 29: In-vitro dissolution rates of tablet of Example 13

Time Percentage of Valsartan released
0.0 0.0
1.0 14.4
2.0 27.5
29

Dated this 12th day of January 2007

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