FIELD OF THE INVENTION
The present invention describes novel pharmaceutical compositions comprising at least one active agent(s) or its pharmaceutically acceptable salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof; at least one permeation enhancer(s); at least one adsorbent(s); at least one bioadhesive polymer(s) optionally with at least one acid soluble polymer(s) and optionally with other pharmaceutically acceptable excipient(s). Preferably the compositions are in the fast disintegrating gastro-adhesive modified release form which releases the active agent(s) over an extended period of time and may additionally comprise other active agent(s). Further, this invention relates to process of preparation of such novel pharmaceutical compositions and method of using them.
BACKGROUND OF THE INVENTION
Pharmaceutical dosage forms which retain in the stomach for a prolonged period of time after oral administration, and release the active ingredient in a controlled manner are important for delivery of a wide variety of drugs. Various pharmaceutical controlled release drug delivery systems with prolonged gastric retention time have been described in the literature, which involve different technologies. The advantages of using drug delivery systems are many. Of major importance in controlled drug therapy is the improved efficiency in treatment. Controlled drug therapy reduces the required frequency of administration, and single doses at periodic intervals are sufficient, resulting in improved patient compliance.
It is generally known that the rate at which an oral controlled drug delivery system delivers the drug into the blood is not the same as the rate at which it releases the drug into a test aqueous fluid because the gastrointestinal fluid's pH, composition and agitation intensity change with the specific location of the drug delivery system in the gastrointestinal tract i.e. from the stomach to the colon, type and amount of food ingested, and also vary from individual to individual. In addition, the drug may not be absorbed in the same manner and propensity as we move from the stomach to the colon. Some drugs have an "absorption window" i.e. they are absorbed only from the upper parts of the gastrointestinal tract, whereas there are others whose absorption from the colon is not uniform or complete. Thus, the location of the controlled drug delivery system in the gastrointestinal tract as well as the rate at which the controlled drug delivery system moves from the stomach to the colon represent important factors that need to be considered in the design of an oral controlled drug delivery system. It is thus known to those skilled in the art that an oral controlled delivery should be designed not only with a control on the rate at which it releases the
drug over the drug delivery time period (temporal control) but also a control on the location from which it is delivered (spatial control). The spatial control can be achieved by prolonging the period of retention of the system in the stomach. Gastric retention systems are also beneficial when the drug is effective locally in the stomach. Drugs absorbed in the upper part of the gastrointestinal tract may exhibit variability in absorption due to inter and intra-individual variability in gastric emptying and gastrointestinal motility. This variation in absorption may be addressed by administering a dosage form comprising the drug such that a small part of the drug is available as immediate release, and a large part is available as sustained or controlled release.
Bioenhanced compositions are highly desirable for drugs such as valsartan, eprosartan, furosemide, bumetanide, ziprasidone and the like which exhibit poor or incomplete absorption and/or which are preferably absorbed from the upper part of the gastro-intestinal tract and/or which exhibit dissolution rate limited gastro-intestinal absorption. Valsartan is a class of active agents known as angiotensin receptor blockers (ARBs) that is used for treating high blood pressure. Valsartan blocks the ability of angiotensin II to constrict or squeeze arteries and veins, thereby reducing blood pressure and reducing the pressure in the arteries that the heart must pump against. Modified release pharmaceutical compositions and dosage forms are designed to improve the delivery profile of the active agents to be internally administered to humans. A modified release composition is typically used to improve the effects of administered substances by optimizing the kinetics of delivery, thereby increasing bioavailability, convenience, and patient compliance. Hence, bioenhanced composition of Valsartan particularly with modified release characteristics provides advantages over conventional dosage forms including reduced fluctuations in plasma active agent levels, and reduced toxicity. Eprosartan (Teveten®) is an angiotensin II receptor antagonist used for the treatment of high blood pressure. The usual recommended starting dose of TEVETEN® Tablets is 600 mg once daily when used as monotherapy in patients who are not volume-depleted. TEVETEN® Tablets can be administered once or twice daily with total daily doses ranging from 400 mg to 800 mg. Furosemide (4-chloro-2-furfurylamino-5-sulphamoyl benzoic acid) is a drug with a diuretic action which acts at the renal level on the ascending limb of the loop of Henle. In addition to possessing a strong, rapid and short diuretic action, furosemide has a hemodynamic effect on the heart. This drug is used in the treatment of oedema of pulmonary, cardiac or hepatic origin as well as in the treatment of hypertension and in the chronic treatment of cardiac infarction. Bumetanide is a potent diuretic that causes a profound increase in urine output (diuresis) by preventing the kidney from retaining fluid. Specifically, it blocks the reabsorption of sodium and fluid from the
kidney's tubules. Ziprasidone, for treatment of schizophrenia, is generally administered orally (initial dose 20 mg BID) with food whereby the dose being increased upto 80 mg BID in cases where necessary. However, in cases of acute agitation in patients of schizophrenia, it may be given as the mesylate salt by intramuscular injection. It is generally available as oral capsules and intramuscular injectable preparation.
US Publication No. 20040180088 discloses a gastro-retentive controlled active agent delivery system comprising a controlled release core comprising an active agent, a highly swellable polymer and a gas generating agent. PCT Publication No. WO2003/35041 discloses a sustained release oral dosage form for delivering a pharmacologically active agent to the stomach, duodenum, and upper small intestine of a patient with restricted delivery to the lower intestinal tract and colon, the dosage form comprising an active agent incorporated in a matrix of at least one biocompatible, hydrophilic polymer that swells in the presence of water in gastric fluid. PCT Publication No. WO2001/60410 discloses a sustained-release preparation which comprises a physiologically active compound slightly soluble in water, a component obtained by treating with water, a polyvalent metal compound slightly soluble in water, and a biodegradable polymer.
PCT Publication No. WO 01/97805 discloses pharmaceutical compositions comprising valsartan formulated into solid oral dosage forms and claims to have at least 1.2 times more bioavailability than conventional valsartan capsule; but the method of bioenhancement and duration of absorption has not been revealed. PCT Publication No. WO 2004/084870 discloses a ionhanced solid oral dosage form containing pharmaceutically active ingredient solubilized or suspended in a solvent or liquid phase encapsulated in seamless controlled release microcapsules. Additionally it was revealed that microcapsules may be coated to release the pharmaceutically active ingredient at specific sites with predetermined rates, the microcapsules were said to have mucoadhesive properties; but the method of bioenhancement in particular using permeation enhancers has not been revealed. PCT Publication No. WO200534920 describes a solid oral dosage form comprising a fibrate dissolved in a vehicle in order to ensure improved bioavailability of the active ingredient upon oral administration relative to known fibrate formulations, which is hydrophobic, hydrophilic or water-miscible. US Publication No. 20030152620 relates to oral solid pharmaceutical composition comprising valsartan and at least one excipient and which is, on average, at least 1.2 times more bioavailable than a valsartan capsule. US Publication No. 20040219208 reveals a solvent system with improved disintegration degree and dissolution ratio of a hardly soluble active agent by highly concentrating the active
agent through partial ionization, and by establishing optimal conditions for enhancing bioavailability of the active agent such as the co-relation between the acid active agent and the accompanied components, ionization degree of a solvent system, use of an appropriate cation acceptance, water content, selection of optimal mixing ratio of the respective components and use of specific surfactants. However, this invention does not disclose specifically the method of bioenhancement, nor does it disclose the use of permeation enhancers.
Thus from the available prior arts, it is evident that certain active agents have low oral bioavailability and get predominantly absorbed in the upper part of the gastrointestinal tract. Several attempts have been made in the past to improve the bioavailability of such active agents but without much success. Also there are no specific disclosures of compositions available in the prior arts which particularly target the absorption window of the active agents to enhance their bioavailability. Hence there still exists an unmet need for developing bio-enhanced, patient compliant, safe and effective compositions comprising the active agents which particularly target the absorption window of the active agents to enhance their bioavailability. The present invention primarily attempts to satisfy the unmet need by developing compositions for improving the bioavailability of drugs by delivering the active agent at the absorption site preferably over an extended period of time.
SUMMARY OF THE INVENTION
It is an objective of the present invention to provide novel pharmaceutical compositions comprising at least one active agent(s) or its pharmaceutically acceptable salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof; at least one permeation enhancer(s); at least one adsorbent(s) and at least one bioadhesive polymer(s), optionally at least one acid soluble polymer(s) and optionally other pharmaceutically acceptable excipient(s).
It is a objective of the present invention to provide bioenhanced compositions comprising active agent(s) which exhibit poor or incomplete absorption and/or which are preferably absorbed from the upper part of the gastro-intestinal tract and/or which exhibit dissolution rate limited gastrointestinal absorption, wherein the compositions particularly target the absorption window of the active agent(s) delivering the active agent at the absorption site preferably over an extended period of time to enhance their bioavailability.
It is an objective of the present invention to provide novel pharmaceutical compositions comprising at least one active agent(s) or its pharmaceutically acceptable salts, polymorphs,
solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof; at least one permeation enhancer(s); at least one adsorbent(s) and at least one bioadhesive polymer(s), optionally other pharmaceutically acceptable excipient(s), wherein the said composition additionally comprises at least one acid soluble polymer(s).
It is also an objective of the present invention to provide novel compositions comprising valsartan or eprosartan, or furosemide or bumetanide or ziprasidone or its pharmaceutically acceptable salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof as the active agent; at least one permeation enhancer(s); at least one adsorbent(s) and at least one bioadhesive polymer(s), optionally at least one acid soluble polymer(s) and optionally with other pharmaceutically acceptable excipient(s).
It is yet another objective of the present invention to provide process for preparation of such
composition which comprises of the following steps:
i) mixing the active agent(s) with permeation enhancer(s), adsorbent(s) and bioadhesive
polymer(s), optionally with acid soluble polymer(s), ii) optionally adding one or more other pharmaceutically acceptable excipients, and iii) formulation of the mixture into a suitable dosage form.
It is yet another objective of the present invention to provide a method of using such composition for prophylaxis, amelioration and/or treatment of a disease or disorder in a subject which comprises administering to a subject in need thereof an effective amount of the composition.
The compositions of the present invention are preferably in the form of fast disintegrating dosage form compositions which either provide an immediate release or a sustained release of the active agent(s), and/or in the form modified release gastro-adhesive dosage form which provides sustained release of the active agent(s). The novel dosage form composition of the present invention may be in the form of uncoated or coated tablets or mini-tablets, layered tablets, capsules, pellets, granules or other dosage forms suitable particularly for oral administration and may be administered either thrice, twice daily or once daily.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel pharmaceutical compositions comprising at least one active agent(s) or its pharmaceutically acceptable salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof; at least one permeation enhancer(s); at least
one adsorbent(s) and at least one bioadhesive polymer(s), optionally with other pharmaceutical^ acceptable excipients.
In an embodiment, the present invention provides bioenhanced compositions comprising active agent(s) which exhibit poor or incomplete absorption and/or which are preferably absorbed from the upper part of the gastro-intestinal tract and/or which exhibit dissolution rate limited gastrointestinal absorption, wherein the compositions particularly target the absorption window of the active agent(s) delivering the active agent at the absorption site preferably over an extended period of time to enhance their bioavailability.
In an embodiment of the present invention is provided novel pharmaceutical compositions comprising at least one active agent(s) or its pharmaceutically acceptable salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof; at least one permeation enhancer(s); at least one adsorbent(s); at least one bioadhesive polymer(s), optionally with other pharmaceutically acceptable excipient(s); additionally comprising at least one acid soluble polymer(s).
In an embodiment of the present invention, the active agent(s) is selected from but not limited to a group comprising poorly water soluble active agents and/or active agent(s) which have low permeability/bioavailability and/or active agent(s) which is preferably absorbed from the upper part of the gastro-intestinal tract and/or active agent(s) which exhibit dissolution rate limited gastro-intestinal absorption.
In a preferred embodiment, the at least one active agent(s) of the present invention is selected from but not limited to a group comprising diuretics such as loop diuretics e.g. ethacrynic acid, furosemide, torsemide, bumetanide and the like; potassium-sparing diuretics e.g. amiloride, eplerenone, spironolactone, triamterene and the like; carbonic anhydrase (CA) inhibitors e.g. acetazolamide, dichlorphenamide, methazolamide, and the like; thiazides e.g. chlorothiazide, chlorthalidone, hydorchlorothiazide, hydroflumethiazide, indapamide, methyclothiazide, metolazone, polythiazide and the like; vasodilators such as alpha-adrenoceptor antagonists (alpha-blockers) e.g. phentolamine, phenoxybenzamine, prazosin, terazosin, doxazosin, trimazosin and the like; angiotensin converting enzyme (ACE) inhibitors e.g. benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, quinapril, ramipril and the like; angiotensin receptor blockers (ARBs) e.g. candesartan, eprosartan, irbesartan, losartan, telmisartan and the like; beta-adrenoceptor agonists (P-agonists) e.g. epinephrine, norepinephrine, dopamine, dobutamine, isoproterenol and the like; calcium-channel blockers (CCBs) e.g. amlodipine,
felodipine, isradipine, nicardipine, nifedipine, nimodipine, nitrendipine, verapamil, diltiazem and the like; centrally acting sympatholytics e.g. clonidine, guanabenz, guanfacine, a-methyldopa and the like; direct acting vasodilators e.g. hydralazine; endothelin receptor antagonists e.g. bosentan; ganglionic blockers e.g. trimethaphan camsylate; nitrodilators e.g. isosorbide dinitrate, isosorbide mononitrate, nitroglycerin, erythrityl tetranitrate, pentaerythritol tetranitrate, sodium nitroprusside and the like; phosphodiesterase (PDE) inhibitors e.g. milrinone, amrinone, sildenafil, tadalafil and the like; potassium-channel openers e.g. minoxidil; cardioinhibitory active agents such as beta-blockers e.g. carteolol, carvedilol, labetalol, nadolol, penbutolol, pindolol, propranolol, sotalol, timolol, acebutolol, atenolol, betaxolol, bisoprolol, esmolol, metoprolol and the like or their pharmaceutically acceptable salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms, or mixtures thereof.
Other active agents that are useful in the present invention include but are not limited to a group comprising ziprasidone; naproxen; ibuprofen; indomethacin; griseofulvin; famotidine; meclizinel; cyclosporine; carbamazipine; methotrexate; itraconazole; dipyridamole; mercaptopurine; halofantrine; amiodarone; lomustine; testosterone; misoprostol; etoposide; rifamycin; azathioprine; glyburide; tolbutamide; aminoglutethimide; taxol; clofibrate; nifedipine; methyldopa; ramipril; hydrochlorothiazide; dicumarol, antibiotics like amoxicillin, ampicillin, cephalexin, and the like or their pharmaceutically acceptable salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms, or mixtures thereof.
In a preferred embodiment of the present invention, the at least one active agent is selected from but not limited to a group comprising valsartan or eprosartan or furosemide or bumetanide or ziprasidone or its pharmaceutically acceptable salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms, or mixtures thereof. In another embodiment, the compositions of the present invention comprises a combination of active agents or their pharmaceutically acceptable salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms, or mixtures thereof.
In an embodiment of the present invention, the permeation enhancer is selected from but not limited to a group comprising medium chain monoglycerides like glyceryl monocaprylate (Imwitor®), glyceryl caprylate/caprate such as (Capmul®MCM) and polyoxyethylene glyceryl caproate such as (Labrasol®), di-fatty acid esters of polyethylene glycols such as Gelucire® 44/14 (primarily a fatty acid ester of polyethylene glycol (PEG-1500), available from Gattefosse, Saint-Priest, France) and Gelucire® 50/13, medium chain fatty acid esters such as medium chain triglycerides, or a mixture of glyceryl tricaprate and tricaprilate (e.g. Miglyol® 812N) and the
like, used either alone or in combination thereof. Permeation enhancers useful in the present invention can be small polar solvents, e.g. ethanol, propylene glycol, dimethylsulfoxide and amphiphilic compounds containing a polar head and a hydrophobic chain, e.g. fatty acids and alcohols, l-dodecylazepan-2-one (Azone), 2-nonyl-l,3-dioxolane (SEPA 009), and dodecyI-2-dimethylaminopropanoate (DDAIP). Other permeation enhancers that are useful in the present invention include but not limited to glycerol monooleate, azone, glycol, pyrrolidone, fatty alcohol, fatty acid and ester thereof, propylene glycol monolaurate (PGML), propylene glycol (PG), oleic acid, lauric acid, oleyl alcohol, lauryl alcohol, vitamin E-TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate) and the like or any other agent which enhances the permeation of the active agent. In another embodiment, two or more permeation enhancers can be used in a suitable mixture to act synergistically. In an embodiment, the amount of permeation enhancer(s) in the composition ranges from about 0.5 % to about 25 %, more preferably from about 1 % to about 15 % by weight of the composition. The permeation enhancer used in the present invention can be solid, semi-solid or liquid type; preferably used in the liquid form.
In another embodiment, the adsorbent used in the present invention is selected from but not limited to a group comprising silicates such as aluminum magnesium metasilicate (e.g. Neusilin®), calcium silicate (e.g. Florite®, Rxcipients® FM1000) and the like; microcrystalline celluloses (e.g. Avicel® PH 101, Avicel® PH 102, Avicel® PH 200, Emcocel®, Fibrocel®, Vivacel®); powdered cellulose; colloidal silicon dioxide (e.g. Aerosil®), and the like, or mixtures thereof. In an embodiment, the amount of adsorbents in the composition ranges from about 0.5 % to about 25 %, more preferably from about 2 % to about 15 % by weight of the composition.
In a further embodiment of the present invention, the bioadhesive polymer used in the present invention is selected from but not limited to a group comprising polyethylene oxide; chitosan; carbomer; polycarbophil; cellulose ethers; water-soluble cellulose-derivatives such as hydroxypropyl methylcellulose, hydroxyethyl cellulose, or hydroxypropyl cellulose and the like; polyvinyl pyrrolidone; carboxymethyl cellulose; polyvinyl alcohol; sodium alginate; polyethylene glycol, polypropylene glycol, copolymers of polyethylene glycol and polypropylene glycol, and linear and branched derivatives of polyethylene glycol and polyethylene glycol/polypropylene glycol copolymers and the like; natural gums such as xanthan gum, tragacanth, guar gum, acacia gum, locust bean gum, arabic gum and the like; water-dispersible polyacrylates such as polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl copolymers and the like used either alone, or as mixtures thereof. In an embodiment, the
bioadhesive polymer(s) of the present invention also functions as release controlling polymers and are thus useful in releasing the active agent(s) over an extended period of time. In a preferred embodiment, the bioadhesive polymer(s) of the present invention are used in combination and also function as release rate controlling polymers. The amount of bioadhesive polymer(s) in the composition ranges from about 0.5 to about 65 %, more preferably from about 2 % to about 50 % by weight of the composition. In a further preferred embodiment, the bioadhesive polymers of the present invention used is a combination of hydroxypropyl methylcellulose (HPMC) present in the range from about 0.5 to about 30% by weight of the composition and the polyethylene oxide present in the range from about 0.5 to about 30% by weight of the composition. The use of bioadhesive polymers in the compositions of the present invention provides gastro-adhesion of the composition which sticks to the mucosa of the gastro-intestinal tract as such or disintegrates into plurality of particles and then sticks to the gastric mucosa.
In another embodiment of the present invention, the acid soluble polymer is selected from but not limited to a group comprising hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, arabic gum, aminoalkyl methacrylate copolymer, carboxyvinyl polymer and copolymers and the like or mixtures thereof. In a preferred embodiment, the acid soluble polymer is selected from but not limited to aminoalkyl methacrylate copolymer such as Eudragit®EPO, Eudragit®E100, Eudragit®E12.5 and the like or mixtures thereof.
Pharmaceutically acceptable excipient(s) according to the present invention are selected from excipients generally used by persons skilled in the art e.g. diluents or fillers, disintegrants, binders, stabilizers, lubricants, anti-adherents or glidants, antioxidants, vehicles, buffers, preservatives, complexing agents, colorants, flavorants, pH modifiers, channel formers, surfactants, viscosifiers, gelling agents, tonicity modifiers, lipid components, emulsifiers, coating agents, plasticizers, organic solvents, stabilizers, chelating agents, and the like or mixtures thereof. The diluents or fillers useful in the present invention are selected from but not limited to a group comprising lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose, dibasic calcium phosphate, sucrose-based diluents, confectioner's sugar, monobasic calcium sulfate monohydrate, calcium sulfate, calcium lactate, dextrose, dextran, dextrates, inositol, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, cellulose powder, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, glycine, or bentonites, and the like. The channel formers include sorbitol,
mannitol, or the like. The disintegrants used in the present invention are selected from but not limited to a group comprising croscarmellose sodium (e.g. Primellose®, Vivasol®), sodium starch glycollate, cross-linked sodium carboxymethylcellulose (e.g. Ac-di-sol®), starches, pregelatinized starch, celluloses, cross-linked carboxymethylcellulose, crospovidone, clays, alginates, gums and the like. The lubricants used in the present invention are selected from but not limited to a group comprising talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil, sodium stearyl fumarate, glyceryl behenate, waxes and the like, or mixtures thereof. The anti-adherents or glidants are selected from but not limited to a group comprising talc, corn starch, DL-leucine, sodium lauryl sulfate, magnesium stearate, calcium stearate, sodium stearate, colloidal silicon dioxide, and the like, or mixtures thereof. The surfactant useful in the present invention may be anionic such as sodium lauryl sulphate, cationic such as cetrimide or non-ionic such as sorbitan esters or polyoxyethylene sorbitan esters, or mixtures thereof. The stabilizers useful in the present invention are selected from but not limited to a group comprising antioxidants, buffers, acids, alkalis, and like, or mixtures thereof.
In an embodiment of the present invention, the amount of lubricants in the composition ranges from about 0.5 % to about 6 %, more preferably between about 0.5 % to about 3 % by weight of the composition. In an embodiment, the amount of fillers in the composition ranges from about 0.5 % to about 40 %, and more preferably between about 1 % to about 20 % by weight of the composition.
The novel modified release dosage form composition may be in the form of tablets, mini-tablets, capsules, pellets, granules, patches, powders and other dosage forms particularly suitable for oral administration. In a preferred embodiment, the composition of the present invention is in the form of tablets. The tablets can be prepared by either direct compression, dry compression (slugging) or by granulation. In a preferred embodiment of the present invention, the oral composition is prepared by direct compression or compaction granulation. The composition prepared by granulation technique is either aqueous or non-aqueous. The non-aqueous solvent that may be used is selected from a group comprising ethanol, isopropyl alcohol, methylene chloride or acetone. In an embodiment, the compositions of the present invention are in the form of compacted tablets/minitablets, compressed tablets/minitablets, or moulded tablets/minitablets, or the like. The tablets/minitablets may be optionally coated with a functional or nonfunctional coating. By the term 'functional coating', it is herein implied that the coating composition comprises a part of the active agent(s) and/or the coating composition comprises excipient(s) which aid in controlling the rate of release of the active agent(s) and/or the coating composition comprises additionally another active agent(s) which is the same or
different from the active agent(s) present in the composition. The tablets/minitablets may be formulated as layered tablets comprising at least two layers wherein the same active agent(s) is present in all the layers exhibiting different release profiles or one or more additional active agent(s) is present in one or more layers exhibiting different release profiles. The tablet/minitablets may be optionally filled into capsules.
In an embodiment, the compositions of the present invention are in the form of fast disintegrating dosage form compositions which either provide an immediate release and/or a sustained release of the active agent(s), and/or modified release gastro-adhesive dosage form compositions which provides sustained release of the active agent(s) for an extended period of time.
In a preferred embodiment of the present invention, the compositions are in the form of modified release tablets that are formulated into fast disintegrating mucoadhesive multiparticulate systems. The novel modified release system, according to the invention, has been developed by simultaneously executing two primary approaches namely: i) delivering the active agent(s) predominantly at its absorption window i.e. its preferred site of absorption, ii) use of permeation enhancers to improve the permeability of the active agent(s). Additionally a third approach may be simultaneously executed after the aforesaid first and second approaches which comprises releasing active agent(s) in a sustained manner at the absorption window such that most of the active agent(s) gets absorbed by using suitable bioadhesive release rate controlling polymer(s).
The active agent(s) in the present invention have low oral bioavailability which might be due to the drugs being predominantly absorbed from the upper part of the gastrointestinal tract and/or which exhibit dissolution rate limited gastro-intestinal absorption. As conventional tablets have considerably less gastric transit time, the time available for the active agent absorption would be very less. The inventors of the present invention have attempted to enhance the bioavailability of the active agents by delivering the active agent predominantly into the stomach or upper part of the gastro-intestinal tract. The present compositions have an increased gastric residence time in the stomach or upper part of the gastro-intestinal tract, thereby delivering the active agents at its absorption site for substantial duration in a sustained manner. In the present invention, the increase in the gastric residence time of the dosage form is due to its bioadhesive property. The bioadhesive polymers are used in the present invention, preferably in combination, to achieve better bioadhesive property. In a preferred embodiment, the compositions of the present invention provide at least a comparable bioavailability or an improvement in the bioavailability of the active agent by at least 5% compared to the compositions of such active agent known to the art.
In a further embodiment, the compositions of the present invention were subjected to in vitro dissolution study using USP Apparatus Type-2 (Paddles) at 75 RPM using 1000 ml dissolution media of 0.1% Tween 80 in 0.1 N HC1. About 0-40% of the active agent(s) was released within 2 hours and greater than about 40% of the active agent(s) was released after 8 hours of test. In another embodiment of the present invention, the compositions were subjected to in vitro dissolution study using USP Apparatus Type-2 (Paddles) at 50 RPM using 900 ml of pH 5.8 Phosphate buffer as the dissolution media. About 0-65% of the active agent(s) was released within 2 hours and greater than about 65% of the active agent(s) was released after 8 hours of test. It might be however noted that the in vitro dissolution tests described herein serve as illustrations and are not intended to limit the scope of the present invention. Any other dissolution tests could be employed to conduct the in vitro tests on the compositions of the present invention.
In an embodiment of the present invention, the bioadhesive polymers used in combination are polyethylene oxide with hydroxypropyl methylcellulose (HPMC) preferably in about 2:1 ratio, chitosan with polyethylene oxide preferably in about 2:1 ratio and xanthan gum with polyethylene oxide preferably in about 2:1 ratio. These bioadhesive polymers, upon contact with gastric fluids, tend to form a gel like structure and stick to mucosa of gastric wall and tend to retain in the stomach for substantial duration. This improves the delivery of active agents having low bioavailability at the gastric absorption site from where active agents are absorbed predominantly.
In an embodiment wherein the active agent is poorly soluble in water and also in acidic conditions, such as valsartan; increasing the solubility of the active agent in the acidic pH of the gastro-intestinal tract increases the gastric residence time that in turn increases the absorption and lead to increase in the bioavailability of the active agent. In the present invention, it was found that different glycerides of mono- and di- medium chain fatty acids such as glyceryl mono & dicaprate (Capmul® MCM), caprylocaproyl macrogoglycerides (Labrasol®) and macrogolglyceryl stearate (Gelucire® 44/14) can solubilize up to about 0.1 to abut 100 mg of active agent per ml of the glycerides. Hence to enhance the solubility of such active agent in acidic condition, the inventors have used such glycerides either alone or in suitable combination as described herein in the present formulation. These glycerides also enhance the bioavailability of the active agent by means of reducing cell barrier for the permeation of the active agent across the absorption site.
In an embodiment wherein the active agent has a narrow absorption window; it is intended to release the active agent in a sustained manner at the absorption site over a period of time such that most of the active agent gets absorbed without being pushed away unabsorbed from the
absorption window. Further, wherein the active agent is predominantly absorbed from the stomach or upper part of the gastro-intestinal tract, the bioadhesive system would release the active agent at such desired site. When the system releases the active agent over a period of time in stomach or upper part of the gastro-intestinal tract, there would be more time available for its absorption in that region, so enhanced bioavailability is achieved for the active agent. This is particularly achieved by using high viscosity release controlling polymers in the system. In an embodiment of the present invention, the in vitro release of active agent is particularly targeted to an extended period of preferably 3-18 hours, more preferably for a period of 5-10 hours. Preferably the high viscosity controlled release grades of hydroxypropyl methylcellulose (HPMC) and polyethylene oxide are used particularly in combination to achieve the desired release characteristics of the active agent; however the choice of one or more components in the composition and the quantities in which they shall be used is also governed by the nature and dosage regimen of the active agent. The exact dose of active agent and the particular formulation to be administered depends on individual factors, e.g. the condition to be treated, the desired duration of the treatment and the rate of release of the active agent. For example, in a preferred embodiment, the solid dosage form however, is described to contain 10-320 mg of valsartan, 10-640 mg of eprosartan, 10-80 mg of furosemide, 0.1-2 mg of bumetanide and 10-80 mg of ziprasidone used either as the free base or as its pharmaceutically acceptable salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms, or mixtures thereof.
The solid oral dosage forms according to an embodiment of the present invention may be in the form of preferably a tablet/minitablet or a hard gelatin capsule. The solid oral dosage form according to the present invention is preferably provided with a multi-particulate system, wherein preferably the coated particles comprising the active agent(s) and pharmaceutical ly acceptable excipients, are compressed into tablets along with suitable fillers and disintegrants, or are filled into hard gelatin capsule.
In an embodiment of the present invention is provided a process for preparation of such
composition which comprises of the following steps:
i) mixing the active agent(s) with permeation enhancer(s), adsorbent(s) and bioadhesive
polymer(s) optionally with acid soluble polymer(s), ii) optionally adding one or more other pharmaceutically acceptable excipients, and iii) formulation of the mixture into a suitable dosage form.
In another embodiment of the present invention, the process for preparation of the novel
compositions of the present invention comprises of the following steps:
i) mixing the active agent(s) with permeation enhancer(s), adsorbent(s), and bioadhesive
polymer(s) optionally with acid soluble polymer(s), ii) optionally adding one or more other pharmaceutically acceptable excipient(s), iii) granulation of the mixture with or without a binder using water or a non-aqueous solvent
and drying to obtain dried granules, iv) addition of one or more disintegrants optionally with other pharmaceutically acceptable
excipient(s) extra-granularly and mixing, and v) formulation of the mixture into a suitable dosage form.
In a further embodiment, the present invention also provides a process for preparation of such
novel compositions which comprises of the following steps:
i) mixing the permeation enhancer(s), adsorbent(s) and active agent(s),
ii) mixing the blend in step (i) with bioadhesive polymer(s),
iii) mixing the blend in step (ii) with filler(s) and lubricant(s) and compacting the blend
followed by crushing the compacts obtained and sifting the material through suitable
sieve to obtain granules, iv) coating the granules in step (iii) with acid soluble polymer(s), v) optionally mixing the material of step (iv) with other pharmaceutically acceptable
excipient(s), and vi) formulating the mixture into a suitable dosage form.
In a preferred embodiment of the processes described herein, the processes comprise the adsorption of permeation enhancer(s) on to the adsorbent(s) to obtain a free-flowing powder followed by mixing the powder thus obtained with the active agent(s).
In another preferred embodiment of the present invention, the process of making the novel
compositions comprises of the following steps:
i) adsorbing the permeation enhancer(s) onto the adsorbent(s) with continuous mixing to
form lumps free, free flowing powder, ii) mixing the free flowing powder with active agent(s) to form intimate contact of the active
agent(s) with adsorbed permeation enhancer(s), iii) mixing the blend of step (ii) with one or more bioadhesive polymer(s), iv) roller compacting/slugging the blend of step (iii) along with fillers and lubricant(s),
v) sizing the compacts/slugs into granules or particles of size preferably 50 to 1000 microns,
more preferably 150 to 500 microns, and vi) coating the granules or particles with acid soluble polymer(s) preferably using a
plasticiser to a weight gain of 15 - 50 % w/w, more preferably 20-40% w/w.
The coated granules or particles thus formed are either compressed into tablets along with one or more pharmaceutically acceptable excipients as extra-granular additives such as fillers, disintegrants, lubricants and the like, or filled into a suitable size hard gelatin capsule. When formulated as a tablet, a non-functional coating can be done on the compressed tablets using low viscosity hydroxypropyl methylcellulose or any other film forming polymer known to the art.
In another aspect of the present invention, the extra-granular additives/excipients comprises of filler(s) in the composition ranging from about 5 % to about 90 % by weight of the composition, disintegrant(s) ranging from about 1 % to about 30 % by weight of the composition, and lubricant(s) ranging from about 0.5 % to about 5 % by weight of the composition.
In the preferred embodiment of the present invention, the rate and/or extent of active agent(s) absorbed from the compositions through the stomach and/or upper part of the gastro-intestinal tract is substantially higher as compared to conventional compositions known to the prior art.
In a further embodiment, the compositions of the present invention are studied in healthy human volunteers. The time taken to reach the peak plasma concentration (Cmax) by the compositions of the present invention is in the range of 0.5 - 10 hours (Tmax), preferably in the range of 1-8 hours (Tmax)- In a still further embodiment, the present invention provides a method of using such composition for prophylaxis, amelioration and/or treatment of a disease or disorder in a subject which comprises administering to a subject in need thereof an effective amount of the composition. For example, the composition comprising valsartan as the active agent is useful in the treatment of hypertension, for lowering the blood pressure, either systolic or diastolic or both; the composition comprising eprosartan as the active agent is useful in the treatment of high blood pressure; the composition comprising furosemide as the active agent is useful in the treatment of congestive heart failure and edema; the composition comprising bumetanide as the active agent is useful in the treatment of edema associated with congestive heart failure, hepatic and renal disease including nephrotic syndrome; and the composition comprising ziprasidone as the active agent is useful in the treatment of psychosis, psychotic symptoms (e.g., schizophrenia, an obsessive compulsive disorder, depression, a bipolar disorder, or Tourette's syndrome). In a still
further embodiment, the compositions of the present invention are administered to a subject in need thereof in the fed state or fasted state, preferably in the fasted state.
The term 'about' used in the entire patent specification, unless otherwise explicitly stated,
implies to cover a range of'+ 20%' of the stated parameter. The examples given below serve to
illustrate embodiments of the present invention. However they do not intend to limit the scope of
the present invention.
EXAMPLES
Example 1:
Ingredient Quantity (mg/tablet)
Core composition
1. Valsartan 163.1
2. Glyceryl mono & dicaprate (Capmul® MCM) 30.0
3. Magnesium aluminornetasilicate (Neusilin®) 40.0
4. Polyethylene oxide (Polyox®-WSR 301) 50.0
5. Chitosan 100.0
6. Povidone K-30 32.5
7. Anhydrous lactose (Pharmatose® DCL 21) 6.9
8. Magnesium stearate 2.5 Uncoated granules weight
9. 425.0 Coating composition of granules
10. Aminoalkyl methyacrylate copolymer (Eudragit® EPO) 91.8
11. Polyethylene glycol (PEG 6000) 13.6
12. Sodium lauryl sulfate 11.9
13. Titanium dioxide 10.2
14. Talc 42.5
15. Water q.s. (lost during processing) Net solid (in coating)
16. 170.0 Valsartan granules taken 566.3 Extragranular ingredients
17. Calcium silicate (Rxcipients® FM1000) 212.0
18. Croscarmellose sodium (Ac-Di-Sol®) 53.0
19. Microcrystalline cellulose (Avicel® PH 102) 461.7
20. Magnesium stearate 7.0
Uncoated tablet weight 1300.0
Coating composition of tablets
19. Tabcoat®TC 40.0
20. Dichloromethane q.s. (lost during processing)
21. Isopropyl alcohol q.s. (lost during processing) Coated tablet weight 1240.0 Procedure:
i) Glyceryl mono & dicaprate and Magnesium aluminometasilicate were blended together.
ii) The mixture in step (i) was mixed with Valsartan and passed through sieve #40.
iii) Polyethylene oxide, Chitosan, Anhydrous lactose and Povidone K-30 were passed through
sieve#40 and mixed with blend of step (ii). iv) The mixture in step (iii) was mixed with sieve #40 passed Magnesium stearate and roller
compacted to obtain compacts, v) The compacts in step (iv) were broken into granules, which passed through sieve #30 and
retained on sieve #60. vi) Polyethylene glycol 6000 and Sodium lauryl sulfate were dissolved in water followed by dispersion
of Aminoalkyl methyacrylate copolymer, Talc and Titanium dioxide into the above solution, vii) The granules in step (v) were coated with coating dispersion of step (vi) and then passed
through sieve#24. viii) The granules in step (vii) were mixed with Microcrystalline cellulose, Croscarmellose
sodium and Calcium silicate followed by lubrication with Magnesium stearate. ix) The granules in step (viii) were compressed to obtain tablets.
x) Tabcoat® TC was dispersed in Isopropyl alcohol followed by addition of Dichloromethane. xi) The tablets of step (ix) were finally coated with the coating material of step (x).
Example 2:
Ingredient Quantity (mg/tablet)
Core composition
1. Valsartan 163.1
2. Glyceryl monocaprylate (Imwitor®) 30.0
3. Microcrystalline cellulose (Avicel®PH 101) 50.0
4. Hypromellose(Methocel®K100MCR) 50.0
5. Polyethylene oxide (PoIyox®-WSR 301) 25.0
6. Crospovidone 32.5
7. Anhydrous lactose (Pharmatose® DCL 21) 7.9
8. Zinc stearate 2.5 Uncoated granules weight 361.0 Coating composition of granules
9. Xanthan gum 78.5
10. Polyethylene glycol (PEG 6000) 11.5
11. Sodium lauryl sulfate 10.0
12. Titanium dioxide 9.0
13. Talc 36.0
14. Water q.s. (lost during processing) Net solid in coating 145.0 Valsartan granules taken 505.0 Extragranular ingredients
15. Calcium silicate (Rxcipients® FM1000) 200.0
16. Croscarmellose sodium (Ac-Di-Sol®) 50.0
17. Microcrystalline cellulose (Avicel® PH 102) 438.0
18. Zinc stearate 7.0 Uncoated tablet weight 1200.0 Coating composition of tablets
19. Tabcoat®TC 40.0
20. Dichloromethane q.s. (lost during processing)
21. Isopropyl alcohol q.s. (lost during processing) Coated tablet weight 1240.0 Procedure:
i) Glyceryl monocaprylate and Microcrystalline cellulose were blended together.
ii) The mixture in step (i) was mixed with Valsartan and passed through sieve #40.
iii) Hypromellose, Polyethylene oxide, Anhydrous lactose and Crospovidone were passed
through sieve#40 and mixed with blend of step (ii). iv) The mixture in step (iii) was mixed with sieve #40 passed Zinc stearate and roller
compacted to obtain compacts, v) The compacts in step (iv) were broken into granules, which passed through sieve #30 and
retained on sieve #60. vi) Polyethylene glycol 6000 and Sodium lauryl sulfate were dissolved in water followed by
dispersion of Xanthan gum, Talc and Titanium dioxide into the above solution.
vii) The granules in step (v) were coated with coating solution of step (vi) and then passed
through sieve#24. viii) The granules in step (vii) were mixed with Microcrystalline cellulose, Croscarmellose
sodium and Calcium silicate followed by lubrication with Zinc stearate. ix) The granules in step (viii) were compressed to obtain tablets, x) Tabcoat® TC was dispersed in Isopropyl alcohol followed by addition of
Dichloromethane. xi) The tablets of step (ix) were finally coated with the coating material of step (x).
Example 3 :
Ingredient Quantity (mg/tablet)
Core composition
1. Furosemide 40.0
2. Polyoxyethylene glyceryl caproate (Labrasol®) 40.0
3. Calcium silicate (Florite®) 60.0
4. Polycarbophil 40.0
5. Hypromellose(Methocel®K100MCR) 20.0
6. Microcrystalline cellulose (Avicel® PH 102) 9.0
7. Magnesium stearate 1.0 Granules weight 210.0 Extragranular ingredients
8. Microcrystalline cellulose (Avicel ® PH 112) 635.0
9. Calcium carboxymethylcellulose 40.0
10. Calcium silicate (Rxcipients® FM1000) 160.0
11. Magnesium stearate 5.0 Tablet weight 1050.0 Procedure:
i) Polyoxyethylene glyceryl caproate and Calcium silicate were blended together.
ii) The mixture in step (i) was mixed with Furosemide and passed through sieve #40.
iii) Polycarbophil, Hypromellose, and Microcrystalline cellulose were passed through sieve#40
and mixed with blend of step (ii). iv) The mixture in step (iii) was mixed with Magnesium stearate. v) The material of step (iv) was slugged to obtain slugs of desired hardness followed by breaking of
the slugs and passing of the slugs through #30 mesh and retained on sieve # 60 to obtain granules.
vi) The granules of step (v) were mixed with Microcrystalline cellulose, Calcium carboxymethylcellulose, Calcium silicate followed by lubrication with Magnesium stearate. vii) The lubricated granules in step (vi) were compressed to obtain tablets.
Example 4 :
Ingredient Quantity (mg/tablet)
Core composition
1. Bumetanide 2.0
2. Glyceryl Mono & Dicaprate (Capmul® MCM) 10.0
3. Magnesium Aluminometasilicate (Neusilin®) 15.0
4. Microcrystalline Cellulose (Avicel® PH 102) 20.0
5. Mannitol 14.0
6. Hypromellose 2208 (Benecel® MP 874) 12.0
7. Calcium stearate 0.5 Granules weight 73.5 Extragranular ingredients
8. Microcrystalline cellulose (Avicel ®PH 112) 215.0
9. Calcium carboxymethylcellulose 12.0
10. Calcium silicate (Rxcipients® FM1000) 48.0
11. Calcium stearate 1.5 Tablet weight 350.0 Procedure:
i) Glyceryl Mono & Dicaprate and Magnesium Aluminometasilicate were blended together.
ii) The mixture in step (i) was mixed with Bumetanide and passed through sieve #40.
iii) Microcrystalline Cellulose, Hypromellose, and Mannitol were passed through sieve#40 and
mixed with blend of step (ii). iv) The mixture in step (iii) was mixed with Calcium stearate. v) The material of step (iv) was slugged to obtain slugs of desired hardness followed by breaking of
the slugs and passing of the slugs through #30 mesh and retained on sieve # 60 to obtain granules, vi) The granules of step (v) are mixed with Microcrystalline cellulose, Calcium
carboxymethylcellulose, Calcium silicate followed by lubrication with Calcium stearate. vii) The lubricated granules in step (vi) were compressed to obtain tablets.
Example 5 :
Ingredient Quantity (mg/tablet)
Core composition
1. Bumetanide 2.0
2. Polyoxyethylene glyceryl caproate (Labrasol®) 10.0
3. Calcium silicate (Florite®) 15.0
4. Microcrystalline Cellulose (Avicel® PH 102) 27.5
5. Hypromellose(Methocel®K100MCR) 15.0
6. Magnesium stearate 0.5 Granules weight 70.0 Extragranular ingredients
7. Microcrystalline cellulose (Avicel ® PH 112) 218.0
8. Calcium carboxymethylcellulose 12.0
9. Calcium silicate (Rxcipients® FM1000) 48.0
10. Magnesium stearate 0.5 Tablet weight 350.0 Procedure:
i) Polyoxyethylene glyceryl caproate and Calcium silicate were blended together.
ii) The mixture in step (i) was mixed with Bumetanide and passed through sieve #40.
iii) Microcrystalline Cellulose and Hypromellose were passed through sieve#40 and mixed
with blend of step (ii). iv) The mixture in step (iii) was mixed with Magnesium stearate. v) The material of step (iv) was slugged to obtain slugs of desired hardness followed by breaking of
the slugs and passing of the slugs through #30 mesh and retained on sieve # 60 to obtain granules, vi) The granules of step (v) were mixed with Microcrystalline cellulose, Calcium
carboxymethylcellulose, Calcium silicate followed by lubrication with Magnesium stearate. vii) The lubricated granules in step (vi) were compressed to obtain tablets.
Example 6 :
Ingredient Quantity (mg/tablet)
Core composition
1. Bumetanide 2.0
2. Stearoyl Macragol 32 Glyceride (Gelucire® 50/13) 10.0
3. Microcrystalline cellulose (Avicel® PH 102) 27.5
4. Polyethylene oxide (Polyox®-WSR 301) 10.0
5. Hypromellose (Methocel®Kl00 MCR) 15.0
6. Magnesium stearate 0.5 Granules weight 65.0 Extragranular ingredients
7. Microcrystalline cellulose (Avicel ® PH 112) 223.0
8. Calcium carboxymethylcellulose 12.0
9. Calcium silicate (Rxcipients® FM1000) 48.0
10. Magnesium stearate 2.0 Tablet weight 350.0 Procedure:
i) Stearoyl Macragol 32 Glyceride is melted at 55°C followed by dispersion with Bumetanide
and adsorption onto Microcrystalline cellulose to obtain free flowing powder, ii) The blend is passed through sieve #40 and is mixed with Hypromellose and Polyethylene
oxide and passed through sieve #40. iii) The mixture in step (ii) was lubricated with Magnesium stearate. iv) The material of step (iii) was slugged to obtain slugs of desired hardness followed by breaking of
the slugs and passing of the slugs through #30 mesh and retained on sieve # 60 to obtain granules, v) The granules of step (iv) were mixed with Microcrystalline cellulose, Calcium
carboxymethylcellulose, Calcium silicate followed by lubrication with Magnesium stearate. vi) The lubricated granules in step (v) were compressed to obtain tablets.
Example 7:
Ingredient Quantity (mg/tablet)
Core composition
1. Ziprasidone hydrochloride 136.79
2. Stearoyl macragol 32 glyceride (Gelucire® 50/13) 67.50
3. Dicalcium phosphate dihydrate 49.97
4. Hypromellose (Methocel® K100 M CR) 60.00
5. Chitosan 90.00
6. Povidone K30 15.00
7. Magnesium stearate 4.50
8. Dichloromethane q.s. (lost during processing) Coating composition of granules
9. Aminoalkyl methyacrylate copolymer (Eudragit® EPO) 68.85
10. Polyethylene glycol 6000 10.20
11. Sodium lauryl sulfate 8.925
12. Titanium dioxide 7.65
13. Talc 31.88
14. Water q.s. (lost during processing) Composition for Ziprasidine MR tablets:
15. Ziprasidone HC1 Coated Granules 171.90
16. Hypromellose 25.00
17. Magnesium stearate 3.10 Procedure:
i) Stearoyl macragol 32 glyceride pastilles were crushed and dissolved in Dichloromethane. ii) Ziprasidone hydrochloride and Dicalcium phosphate dehydrate were mixed together and passed
through sieve#30 followed by granulation with the material of step (i) and then drying the granules, iii) The dried granules were mixed with Hypromellose, Chitosan and Povidone K30 and passed
through sieve#40. iv) The blend of step (iii) was lubricated with Magnesium stearate and roller compacted to
obtain compacts, v) The compacts in step (iv) were broken into granules, which passed through sieve #30 and
retained on sieve #60. vi) Polyethylene glycol 6000 and Sodium lauryl sulfate were dissolved in water followed by dispersion
of Aminoalkyl methyacrylate copolymer, Talc and Titanium dioxide into the above solution, vii) The granules in step (v) were coated with coating solution of step (vi) and then passed
through sieve#24. viii) The granules in step (vii) were mixed with Hypromellose and then lubricated with
Magnesium stearate. ix) The lubricated granules in step (viii) were compressed to obtain tablets.
Example 8:
Ingredient Quantity (mg/tablet)
Core composition
1. Ziprasidone hydrochloride 136.79
2. Stearoyl macragol 32 glyceride (Gelucire® 50/13) 67.50
3. Dicalcium phosphate dihydrate 49.97
4. Hypromellose (Methocel® K100 M CR) 60.00
5. Chitosan 90.00
6. Povidone K30 15.00
7. Magnesium stearate 4.50
8. Dichloromethane q.s. (lost during processing) Coating composition of granules
9. Aminoalkyl methyacrylate copolymer (Eudragit® EPO) 68.85
10. Polyethylene glycol 6000 10.20
11. Sodium lauryl sulfate 8.925
12. Titanium dioxide 7.65
13. Talc 31.88
14. Water q.s. (lost during processing) Composition for Ziprasidine MR tablets:
15. Ziprasidone HC1 Coated Granules 171.90
16. Calcium silicate 49.82
17. Croscarmellose sodium (Ac-Di-Sol®) 12.16
18. Microcrystalline cellulose (Avicel® PH 102) 113.02
19. Magnesium stearate 3.10 Procedure:
i) Stearoyl macragol 32 glyceride pastilles were crushed and dissolved in Dichloromethane.
ii) Ziprasidone hydrochloride and Dicalcium phosphate dehydrate were mixed together and passed
through sieve#30 followed by granulation with the material of step (i) and then drying the granules, iii) The dried granules were mixed with Hypromellose, Chitosan and Povidone K30 and passed
through sieve#40. iv) The blend of step (iii) was lubricated with Magnesium stearate and roller compacted to
obtain compacts, v) The compacts in step (iv) were broken into granules, which passed through sieve #30 and
retained on sieve #60. vi) Polyethylene glycol 6000 and Sodium lauryl sulfate were dissolved in water followed by dispersion
of Aminoalkyl methyacrylate copolymer, Talc and Titanium dioxide into the above solution, vii) The granules in step (v) were coated with coating solution of step (vi) and then passed through
sieve#24. viii) The granules in step (vii) were mixed with Microcrystalline cellulose, Croscarmellose sodium
and Calcium silicate followed by lubrication with Magnesium stearate. ix) The lubricated granules in step (viii) were compressed to obtain tablets.
Example 9:
Ingredient Quantity (mg/capsule)
1. Eplerenone 100.0
2. Caprylocaproyl macrogoglycerides (Labrasol®) 60.0
3. Calcium silicate (Florite®) 200.0
4. Hydroxypropyl methylcellulose (HPMC) 100.0
5. Xanthan gum 60.0
6. Dibasic calcium phosphate 132.0
7. Magnesium stearate 5.0 Coating Composition
8. Aminoalkyl methacrylate copolymer (Eudragit® E 100) 85.5
9. Dibutyl phthalate 8.5
10. Talc 38.0
11. Isopropyl alcohol q.s. (lost during processing)
12. Acetone q.s. (lost during processing) Extragranular ingredient
13. Magnesium stearate 10.0 Procedure:
i) Caprylocaproyl macrogoglycerides, Calcium silicate and Eplerenone were mixed together.
ii) The blend in step (i) was mixed with Hydroxypropyl methylcellulose and Xanthan gum.
iii) The blend in step (ii) was mixed with Dibasic calcium phosphate and Magnesium stearate and
the blend was compacted followed by crushing the compacts which passed through sieve #30 and
retained on sieve #60. iv) The granules in step (iii) were coated with Aminoalkyl methacrylate copolymer, Dibutyl
phthalate and Talc. v) The granules in step (iv) were mixed with Magnesium stearate. vi) The material of step (v) was filled into a hard gelatin capsule.
Example 10:
Ingredient Quantity (mg/tablet)
Core composition
1. Ethacrynate sodium 50.0
2. Glyceryl tricaprate and tricaprilate (Miglyol® 812N) 80.0
3. Calcium silicate (Florite®) 200.0
4. Xanthan gum 100.0
5. Polyethylene oxide (Polyox®-WSR 301) 50.0
6. Mannitol 195.0
7. Calcium stearate 5.0 Coating composition
8. Aminoalkyl methyacrylate copolymer (Eudragit® E 100) 85.5
9. Ethyl phthalate 8.5
10. Colloidal silicon dioxide 38.0
11. Isopropyl alcohol q.s. (lost during processing)
12. Acetone - q.s. (lost during processing) Extragranular ingredients
13. Sodium starch glycollate 100.0
14. Polyvinylpyrrolidone 100.0
15. Microcrystalline cellulose (Avicel® PH 102) 228.0
16. Hydrogenated vegetable oil (Lubritab®) 10.0 Procedure:
i) Glyceryl tricaprate and tricaprilate, Calcium silicate and Microcrystalline cellulose were
blended together, ii) Mixture of step (i) was mixed with Ethacrynate sodium and passed through sieve #40. iii) The blend in step (ii) was mixed with Xanthan gum and Polyethylene oxide, iv) The mixture of step (iii) was mixed with Mannitol and Calcium stearate and roller
compacted to obtain compacts, v) The compacts in step (iv) were broken into granules which passed through sieve #30 and
retained on sieve #60. vi) The granules in step (v) were coated with coating solution comprising Aminoalkyl
methyacrylate copolymer, Ethyl phthalate and Talc, vii) The granules in step (vi) were mixed with Microcrystalline cellulose, Polyvinylpyrrolidone,
Sodium starch glycollate and Hydrogenated vegetable oil. viii) The granules in step (vii) were compressed to obtain tablets.
Example 11:
Ingredient Quantity (mg/tablet)
Core composition
1. Nifedipine 50.0
2. Glyceryl tricaprate and tricaprilate (Miglyol® 612N) 80.0
3. Calcium silicate (Florite®) 200.0
4. Xanthan gum 100.0
5. Polyethylene oxide (Polyox®-WSR 301) 50.0
6. Mannitol 195.0
7. Calcium stearate 5.0 Coating Composition
8. Aminoalkyl methyacrylate copolymer (Eudragit® E 100) 85.5
9. Ethyl phthalate 8.5
10. Colloidal silicon dioxide 38.0
11. Isopropyl alcohol q.s. (lost during processing)
12. Acetone q.s. (lost during processing) Extragranular ingredients
13. Sodium starch glycollate 100.0
14. Polyvinylpyrrolidone 100.0
15. Microcrystalline cellulose (Avicel® PH 102) 228.0
16. Hydrogenated vegetable oil (Lubritab®) 10.0 Procedure:
i) Glyceryl tricaprate and tricaprilate, Calcium silicate and Microcrystalline cellulose were
blended together, ii) The mixture of step (i) was mixed with Nifedipine and passed through sieve #40. iii) The blend in step (ii) was mixed with Xanthan gum and Polyethylene oxide, iv) The mixture of step (iii) was mixed with Mannitol and Calcium stearate and roller
compacted to obtain compacts, v) The compacts in step (iv) were broken into granules which passed through sieve #30 and
retained on sieve #60. vi) The granules in step (v) were coated with coating solution comprising Aminoalkyl
methyacrylate copolymer, Ethyl phthalate and colloidal silicon dioxide, vii) The granules in step (vi) were mixed with Microcrystalline cellulose, Polyvinylpyrrolidone,
Sodium starch glycollate and Hydrogenated vegetable oil. viii) The granules in step (vii) were compressed to obtain tablets.
Example 12:
Ingredient Quantity (mg/tablet)
Core composition
1. Diltiazem 300.0
2. Glyceryl monocaprylate (Imwitor®) 60.0
3. Microcrystalline cellulose 100.0
4. Sodium alginate 100.0
5. Hydroxypropyl methylcellulose 50.0
6. Anhydrous Lactose (Pharmatose® DCL 21) 42.3
7. Zinc stearate 5.0 Coating composition
8. Aminoalkyl methyacrylate copolymer (Eudragit® EPO) 85.5
9. Triacetin 8.5
10. Talc 37.7
11. Isopropyl alcohol q.s. (lost during processing)
12. Acetone q.s. (lost during processing) Extragranular ingredients
13. Calcium carboxymethylcellulose 100.0
14. Microcrystalline cellulose (Avicel® PH 102) 301.0
15. Magnesium stearate 10.0 Procedure:
i) Glyceryl monocaprylate and Microcrystalline cellulose were blended together.
ii) The mixture in step (i) was mixed with Diltiazem and was passed through sieve #40.
iii) The blend in step (ii) was mixed with Sodium alginate and Hydroxypropyl methylcellulose.
iv) The mixture in step (iii) was mixed with Anhydrous Lactose and Zinc stearate and roller
compacted to obtain compacts, v) The compacts in step (iv) were broken into granules which passed through sieve #30 and
retained on sieve #60. vi) The granules in step (v) were coated with coating solution comprising Aminoalkyl
methyacrylate copolymer, Triacetin and Talc, vii) The granules in step (vi) were mixed with Microcrystalline cellulose, Calcium
carboxymethylcellulose and Magnesium stearate. viii) The granules in step (vii) were compressed to obtain tablets.
Example 13:
Ingredient Quantity (mg/tablet)
Core composition
1. Cefprozil 500.0
2. Glyceryl monocaprylate (Imwitor®) 60.0
3. Microcrystalline cellulose (Avicel® PH 102) 100.0
4. Sodium alginate 100.0
5. Hydroxypropylmethyl cellulose 50.0
6. Anhydrous Lactose (Pharmatose® DCL 21) 42.3
7. Zinc stearate 5.0 Coating composition
8. Aminoalkyl methacrylate copolymer (Eudragit® EPO) 85.5
9. Triacetin 8.5
10. Talc 37.7
11. Isopropyl alcohol q.s. (lost during processing)
12. Acetone q.s. (lost during processing) Extragranular ingredients
13. Calcium carboxymethylcellulose 100.0
14. Microcrystalline cellulose (Avicel® PH 102) 100.0
15. Zinc stearate 10.0 Procedure:
i) Glyceryl monocaprylate and Microcrystalline cellulose were blended together.
ii) The mixture in step (i) was mixed with Cefprozil and was passed through sieve #40.
iii) The blend in step (ii) was mixed with Sodium alginate and Hydroxypropyl methylcellulose.
iv) The mixture in step (iii) was mixed with Anhydrous Lactose and Zinc stearate and roller
compacted to obtain compacts, v) The compacts in step (iv) were broken into granules which passed through sieve #30 and retained
on sieve #60. vi) The granules in step (v) were coated with coating solution comprising Aminoalkyl methacrylate
copolymer, Triacetin and Talc, vii) The granules in step (vi) were mixed with Microcrystalline cellulose, Calcium
carboxymethylcellulose and Zinc stearate. viii) The granules in step (vii) were compressed to obtain tablets.
Example 14:
Ingredient Quantity (mg/tablet)
Core composition
1. Amoxicillin trihydrate 500.0
2. Glyceryl monocaprylate (Imwitor®) 60.0
3. Microcrystalline cellulose(Avicel® PH 102) 100.0
4. Sodium alginate 100.0
5. Hydroxypropylmethyl cellulose 50.0
6. Anhydrous Lactose (Pharmatose® DCL 21) 42.3
7. Magnesium stearate 5.0 Coating composition
8. Aminoalkyl methyacrylate copolymer (Eudragit® El 00) 85.5
9. Triacetin 8.5
10. Talc 37.7
11. Isopropyl alcohol q.s. (lost during processing)
12. Acetone q.s. (lost during processing) Extragranular ingredients
13. Calcium carboxymethylcellulose 100.0
14. Microcrystalline cellulose (Avicel® PH 102) 100.0
15. Magnesium stearate 10.0 Procedure:
i) Glyceryl monocaprylate and Microcrystalline cellulose were blended together.
ii) The mixture in step (i) was mixed with Amoxicillin trihydrate and was passed through sieve
#40. iii) The blend in step (ii) was mixed with Sodium alginate and Hydroxypropyl methylcellulose. iv) The mixture in step (iii) was mixed with Anhydrous Lactose and Magnesium stearate and roller
compacted to obtain compacts, v) The compacts in step (iv) were broken into granules which passed through sieve #30 and
retained on sieve #60. vi) The granules in step (v) were coated with coating solution comprising Aminoalkyl
methyacrylate copolymer, Triacetin and Talc, vii) The granules in step (vi) were mixed with Microcrystalline cellulose, Calcium
carboxymethylcellulose and Magnesium stearate. viii) The granules in step (vii) were compressed to obtain tablets.
Example 15:
A) Fast disintegrating layer
Ingredient Quantity (mg/tablet)
1. Benazepril hydrochloride 20.0
2. Fatty acid ester of polyethylene glycol (Gelucire® 44/14) . 100.0
3. Magnesium aluminometasilicate (Neusilin®) 100.0
4. Povidone K30 65.0
5. Lactose monohydrate 220.0
6. Microcrystalline Cellulose (Avicel®PH 102) 281.0
7. Croscarmellose Sodium (Ac-Di-Sol®) 100.0
8. Sodium starch glycollate 50.0
9. Calcium silicate (Rxcipients® FM1000) 25.0
10. Magnesium stearate 5.0 Procedure:
i) Fatty acid ester of polyethylene glycol was mixed with Magnesium aluminometasilicate
with stirring to make it free flowing powder and the powder was passed through sieve # 40. ii) The blend of step (i) was mixed with Benazepril hydrochloride and passed through sieve
#40. iii) Povidone K30, Lactose monohydrate and Microcrystalline cellulose were passed through
sieve # 40 and mixed with the blend of step (ii). iv) Croscarmellose sodium and Sodium starch glycollate were passed through sieve # 40 and
mixed with the blend of step (iii). v) Magnesium stearate and calcium silicate were passed through sieve # 40 and mixed with
the blend of step (iv). B) Controlled release layer
Ingredient Quantity (mg/tablet)
Core composition
1. Hydrochlorothiazide 12.5
2. Fatty acid ester of polyethylene glycol (Gelucire® 44/14) 60.0
3. Magnesium aluminometasilicate (Neusilin®) 100.0
4. Hypromellose(Methocel®K100MCR) 100.0
5. Polyethylene oxide (Polyox®-WSR 303) 100.0
6. Povidone K30 65.0
7. Anhydrous Lactose (Pharmatose® DCL 21) 22.0
8. Zinc stearate 5.0 Coating composition
9. Aminoalkyl methyacrylate copolymer (Eudragit® El2.5) 105.0
10. Polyethylene glycol 6000 16.0
11. Polyoxyethylene sorbitan monostearate (Tween® 80) 10.5
12. Purified water q.s. (lost during processing)
13. Talc 60.5 Extragranular ingredients
14. Calcium silicate (Rxcipients® FM1000) 25.0
15. Croscarmellose sodium (Ac-Di-Sol®) 100.0
16. Microcrystalline cellulose (Avicel® PH 102) 281.0
17. Zinc stearate 10.0 Procedure:
i) Fatty acid ester of polyethylene glycol was mixed with Magnesium aluminometasilicate
with stirring to make it free flowing powder and the powder was passed through sieve # 40. ii) The blend of step (i) was mixed with Hydrochlorothiazide and passed through sieve # 40. iii) Hypromellose, Polyethylene oxide, Povidone K30 and Anhydrous Lactose were passed
through sieve # 40; and were mixed with the blend of step (ii). iv) Zinc stearate was passed through sieve # 40 and mixed with the blend of step (iii). v) The blend of step (iv) was roller compacted to obtain granules which passed through sieve
# 30 and retained on sieve # 60. vi) Polyethylene glycol 6000 was dissolved in purified water followed by the dispersion of
Aminoalkyl methyacrylate copolymer and Polyoxyethylene sorbitan monostearate into it
using a high shear homogenizer. vii) Talc was dispersed in to the dispersion of step (vi) using a high shear homogenizer. viii) The granules of step (v) were coated with the coating material of step (vii) and dried, ix) The extra-granular ingredients namely Calcium silicate, Croscarmellose sodium,
Microcrystalline cellulose and Zinc stearate were sifted through sieve # 40 and mixed, x) The coated granules were mixed with the material of step (ix). The material of step A(v) was compressed with the material of step B(x) to obtain bilayered tablets.
Example 16:
Ingredient Quantity (mg/capsule)
1. Cefdinir 300.0
2. Fatty acid ester of polyethylene glycol (Gelucire® 44/14) 100.0
3. Magnesium aluminometasilicate (Neusilin®) 100.0
4. Dextrose 220.0
5. Microcrystalline cellulose (Avicel® PH 102) 281.0
6. Croscarmellose sodium (Ac-Di-Sol®) 100.0
7. Talc 5.0
Procedure:
i) Fatty acid ester of polyethylene glycol was mixed with Magnesium aluminometasilicate
with stirring to make it free flowing powder and powder was passed through sieve # 40. ii) The blend of step (i) was mixed with Cefdinir and passed through sieve # 40. iii) Dextrose and Microcrystalline cellulose were passed through sieve # 40 and mixed with
the blend of step (ii). iv) Croscarmellose sodium was passed through sieve # 40 and mixed with blend of step (iii). v) Talc was passed through sieve # 40 and mixed with the blend of step (iv). vi) The material of step (v) was filled into hard gelatin capsules.
Example 17:
Ingredient Quantity (mg/capsule)
1. Bumetanide 2.0
2. Fatty acid ester of polyethylene glycol (Gelucire® 44/14) 20.0
3. Powdered cellulose 20.0
4. Mannitol 14.0
5. Microcrystalline cellulose (Avicel® PH 102) 20.0
6. Sodium starch glycollate 3.0
7. Hydrogenated vegetable oil (Lubritab®) 1.0 Procedure:
i) Fatty acid ester of polyethylene glycol was mixed with powdered cellulose with stirring to make
it free flowing powder and the powder was passed through sieve # 40. ii) The blend of step (i) was mixed with Bumetanide and passed through sieve # 40. iii) Mannitol and Microcrystalline cellulose were passed through sieve # 40 and mixed with the
blend of step (ii). iv) Sodium starch glycollate was passed through sieve # 40 and mixed with the blend of step (iii). v) Hydrogenated vegetable oil was passed through sieve #40 and mixed with the blend of step (iv). vi) The material of step (v) was compressed into tablets.

We claim:
1. A novel pharmaceutical composition comprising at least one active agent(s) or its pharmaceutically acceptable salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof; at least one permeation enhancer(s); at least one adsorbent(s) and at least one bioadhesive polymer(s); optionally with at least one acid soluble polymer(s) and other pharmaceutically acceptable excipient(s); wherein the active agent(s) is selected from a group comprising poorly water soluble active agents and/or active agents which have low permeability/bioavailability and/or active agent(s) which are preferably absorbed from the upper part of the gastro-intestinal tract and/or active agent(s) which exhibit dissolution rate limited gastro-intestinal absorption.
2. A composition according to claim 1, which is a bioenhanced composition comprising active agent(s) which exhibit poor or incomplete absorption and/or which are preferably absorbed from the upper part of the gastro-intestinal tract and/or which exhibit dissolution rate limited gastro-intestinal absorption, wherein the compositions particularly target the absorption window of the active agent(s) delivering the active agent at the absorption site preferably over an extended period of time to enhance their bioavailability.
3. A composition according to claims 1 or 2, wherein the active agent is selected from a group comprising diuretics; vasodilators; angiotensin converting enzyme (ACE) inhibitors; angiotensin receptor blockers (ARBs); beta-adrenoceptor agonists (P-agonists); calcium-channel blockers (CCBs); centrally acting sympatholytics; direct acting vasodilators; endothelin receptor antagonists; ganglionic blockers; nitrodilators; phosphodiesterase (PDE) inhibitors; potassium-channel openers; cardioinhibitory active agents or their pharmaceutically acceptable salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms, or mixtures thereof.
4. A composition according to claims 1 or 2, wherein the active agent is valsartan or eprosartan or furosemide or bumetanide or ziprasidone or its pharmaceutically acceptable salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms, or mixtures thereof.
5. A composition according to claims 1 to 4, wherein the permeation enhancer is selected from a group comprising medium chain monoglycerides, di-fatty acid esters of polyethylene glycols, medium chain fatty acid esters, small polar solvents, amphiphilic compounds containing a polar head and a hydrophobic chain, glycerol monooleate, azone, glycol, pyrrolidone, fatty alcohol, fatty acid and ester thereof, propylene glycol
monolaurate (PGML), propylene glycol (PG), oleic acid, lauric acid, oleyl alcohol, lauryl alcohol, vitamin E-TPGS used either alone or in combination thereof.
6. A composition according to claims 1 to 4, wherein the adsorbent is selected from a group comprising silicates such as aluminum magnesium metasilicate or calcium silicate; microcrystalline celluloses; powdered cellulose; colloidal silicon dioxide, or mixtures thereof.
7. A composition according to claims 1 to 4, wherein the bioadhesive polymer is selected from a group comprising polyethylene oxide; chitosan; carbomer; polycarbophil; cellulose ethers; water-soluble cellulose derivatives such as hydroxypropyl methylcellulose, hydroxyethyl cellulose or hydroxypropyl cellulose; polyvinyl pyrrolidone; carboxymethyl cellulose; polyvinyl alcohol; sodium alginate; polyethylene glycol, polypropylene glycol, copolymers of polyethylene glycol and polypropylene glycol, and linear and branched derivatives of polyethylene glycol and polyethylene glycol/polypropylene glycol copolymers; natural gums such as xanthan gum, tragacanth, guar gum, acacia gum, locust bean gum or arabic gum; water-dispersible polyacrylates such as polyacrylic acid, methylmethacrylate copolymer or carboxyvinyl copolymers used either alone, or as mixtures thereof.
8. A composition according to claim 1, wherein the acid soluble polymer is selected from a group comprising hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, arabic gum, aminoalkyl methacrylate copolymer, carboxyvinyl polymer and copolymers, or mixtures thereof.
9. A composition according to claim 1, wherein the pharmaceutically acceptable excipient(s) are selected from a group comprising diluents, disintegrants, binders, fillers, bulking agents, anti-adherents, anti-oxidants, buffering agents, colorants, flavoring agents, coating agents, plasticizers, organic solvents, stabilizers, preservatives, lubricants, glidants, chelating agents, surfactants, used either alone or in combination thereof.
10. A composition according to any one of the preceding claims, wherein the composition is in the form of fast disintegrating dosage form compositions which either provide an immediate release or a sustained release of the active agent, and/or modified release gastro-adhesive dosage form compositions which provides sustained release of the active agent(s) for an extended period of time.
11. A process for the preparation novel controlled release pharmaceutical composition according to claim 1, which comprises of the following steps:
i) mixing the active agent(s) with permeation enhancer(s), adsorbent(s) and bioadhesive
polymer(s) optionally with acid soluble polymer(s), ii) optionally adding other pharmaceutically acceptable excipient(s), and iii) formulation of the mixture into a suitable dosage form.
12. A process for the preparation novel controlled release pharmaceutical composition
according to claim 1, which comprises of the following steps:
i) mixing the active agent(s) with permeation enhancer(s), adsorbent(s), and bioadhesive polymer(s) optionally with acid soluble polymer(s),
ii) optionally adding one or more other pharmaceutically acceptable excipient(s),
iii) granulation of the mixture with or without a binder using water or a non-aqueous solvent and drying to obtain dried granules,
iv) addition of one or more disintegrants optionally with other pharmaceutically acceptable excipient(s) extra-granularly and mixing,
v) formulation of the mixture into a suitable dosage form.
13. A process for the preparation novel controlled release pharmaceutical composition
according to claim 1, which comprises of the following steps:
i) mixing the permeation enhancer(s), adsorbent(s) and active agent(s),
ii) mixing the blend in step (i) with bioadhesive polymer(s),
iii) mixing the blend in step (ii) with filler(s) and lubricant(s) and compacting the blend
followed by crushing the compacts obtained and sifting the material through suitable
sieve to obtain granules, iv) coating the granules in step (iii) with acid soluble polymer(s), v) optionally mixing the material of step (iv) with other pharmaceutically acceptable
excipient(s), vi) formulating the mixture into a suitable dosage form.
14. A process for the preparation novel controlled release pharmaceutical composition
according to claim 1, which comprises of the following steps:
i) adsorbing the permeation enhancers) onto the adsorbent(s) with continuous mixing to
form lumps free, free flowing powder, ii) mixing the free flowing powder with active agent(s) to form intimate contact of the active
agent(s) with adsorbed permeation enhancer(s), iii) mixing the blend of step (ii) with one or more bioadhesive polymer(s), iv) roller compacting/slugging the blend of step (iii) along with fillers and lubricant(s),
v) sizing the compacts/slugs into granules or particles of size preferably 50 to 1000 microns,
more preferably 150 to 500 microns, vi) coating the granules or particles with acid soluble polymer preferably using a plasticizer preferably to a weight gain of 15 - 50 % w/w, more preferably 20 - 40 % w/w. 15. The pharmaceutical composition and process thereof substantially as herein described and illustrated by the examples.