FIELD OF THE INVENTION
The present invention describes controlled release pharmaceutical compositions comprising microparticles which comprise a core and at least one first coat, wherein the core comprises at least one active agent(s) or its pharmaceutically acceptable salts, derivatives, isomers, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof, optionally at least one water insoluble polymer(s), and optionally one or more pharmaceutically acceptable excipient(s), wherein at least one first coat comprises at least one pH independent polymer(s) alongwith one or more pharmaceutically acceptable excipient(s) Preferably the controlled release pharmaceutical compositions comprise microparticles alongwith at least one in-situ gelling agent(s). at least one cross-linking agent(s) and optionally one or more pharmaceutically acceptable excipient(s), wherein the said compositions are preferably formulated as oral reconstitutable controlled release suspension, which can be reconstituted using a suitable reconstituting medium such as water Further, this invention provides process of preparation of such compositions and method of using them
BACKGROUND OF THE INVENTION
A controlled release preparation is one that achieves slow release of a drug over an extended period of time, thereby extending the duration of drug action over that achieved by conventional delivery Drugs that are administered multiple times per day and drugs with high inter- and/or intra-patient variability can be more therapeutic efficient if administered as controlled release formulation. The advantages of controlled release products are well-known in the pharmaceutical field and include the ability to release the medicament in a controlled manner over a period of time while increasing patient compliance by reducing the number of administrations necessary to achieve the same level. Several controlled release compositions for delivering different pharmaceutically active ingredients and involving different release mechanisms had been described previously In addition, multiple dose liquid formulations are preferable to tablets or capsules because formulations like tablets or capsules cannot be administered to patients with swallowing difficulties and to children or infants, who in any case are incapable of swallowing and for whom in addition, the dose administered has to be adapted according to their weight
US Patent no. 6958161 describes a modified release preparation having one or more coated core elements, each core element comprising an active ingredient selected from the group consisting of the acid salts of doxycychne, tetracycline, oxytetracycline, minocycline, chlortetracychne or demeclocycline and having a modified release coating, wherein a stabilizing coat is provided between each core element and its modified release coating so that, upon in vitro dissolution testing, the amount of active ingredient released at any time on a post-storage dissolution profile is within 40 percentage points of the amount of active ingredient released at any time on a pre-storage dissolution profile. US patent no. 6932981 describes a fast disintegrating controlled release oral composition comprising a core material containing cefuroxime axetil present as controlled release form, and optionally probenecid, said controlled release form comprising a) an outer coating of a polymer
selected from aqueous dispersions of enteric methacrylic acid and methacrylic acid esters anionic copolymers having carboxygroup as the functional group or mixtures thereof and. b)an inner coating of a sustained-release copolymer selected from aqueous dispersions of acrylate and methacrylate pH independent, neutral copolymers having quaternar\ ammonium group as a functional group or mixtures thereof, said composition releases cefuroxime axetil in amounts of more than 80% in 4 hours and the outer coating controls the initial rapid release of cefuroxime axetil from the composition. US patent no 5968554 describes an oral dosage delivery form adapted to deliver a pH dependent water soluble therapeutic agent comprising (a) a core comprising said therapeutic agent in an amount sufficient to deliver from 25-75% of an effective amount of said therapeutic agent over the intended delivery time, (b) an enteric polymer coating over said core, (c) a coating of said therapeutic agent over said enteric polymer coating in an amount sufficient to deliver from 25-75% of an effective amount of said therapeutic agent over the intended deliver) time, and (d) a low pH soluble protective coating over said coating of said therapeutic agent
PCT publication no WO200693838 claims a method for preparing a liquid, controlled-release formulation comprising the steps of blending one or more controlled release microbeads comprising one or more active agents, preparing a dense, thixotropic solution having a density that is at or about the density of the one or more microbeads comprising a thixotropic agent, water and one or more preservatives under conditions that reduce bubble formation, and mixing the microbeads and the thixotropic solutions under conditions that minimize the introduction of bubbles in the liquid US patent no. 4717713 discloses m-situ gelling system for controlled release of drug in suspension form Extended release of water soluble or shghtl) water soluble drugs for longer duration of time period (more than 10 hours) is not possible with in-situ gelling suspension formulations
US patent nos. 4762709 and 6328979, US Publication no 2005181050 and PCT publication nos WO 9827961 and WO 2005117843 disclose controlled release suspension technology based on ion exchange resins. Although ion exchange resins systems (such as Pennkinetic s>stem) provide long extended drug release without significant drug leaching during storage, these systems require chemical binding of drug to the resin which is not suitable for many drugs with ease
Oral pharmaceutical formulations in the form of tablets or capsules for the controlled release of many drugs currently exist. These formulations cannot be administered to patients with swallowing difficulties and to children or infants, who in any case are incapable of swallowing and for whom in addition, the dose administered has to be adapted according to their weight Multiple dose liquid formulations are preferable to tablets or capsules for such applications Drugs that are administered multiple times per day and drugs with high inter- and/or intra-patient variability can be more therapeutic efficient if administered as controlled release formulation Liquid formulations for the controlled release of drugs are difficult to produce. The main difficulties are, avoiding of drug release into the liquid phase during storage of formulation, need of small particle size to avoid gnttiness in mouth and balding of bad taste of drug
Avoiding of drug release into the liquid phase during storage of formulation, while allowing controlled release of drug as soon as it enters the gastrointestinal tract is particularly difficult to achieve for water soluble or even slightly water soluble drugs because drug is stored in liquid for a vety long time (about 10-15 days) compared with the desired release time in the gastrointestinal tract fluids (4-16 hours)
Thus there still exists a need to develop particularly pharmaceutical compositions which upon reconstitution can remain stable for a prolonged period of time at least for the entire duration of therapy and also provide a desired controlled release of the active agent(s) The present invention provides compositions to overcome the limitations of the prior art
SUMMARY OF THE INVENTION
It is an objective of the present invention to provide controlled release pharmaceutical compositions comprising microparticles which comprise a core and at least one first coat, wherein the core comprises at least one active agent(s) or its pharmaceutical!}' acceptable salts, derivatives, isomers, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof; optionally at least one water insoluble polymer(s), and optionally one or more pharmaceutically acceptable excipient(s), wherein the at least one first coat comprises at least one pH independent polymer(s) alongwith one or more pharmaceutical]} acceptable excipient(s)
It is an objective of the present invention to provide controlled release pharmaceutical compositions comprising microparticles which comprise a core and at least one first coat, wherein the core comprises at least one active agent(s) or its pharmaceutical!}' acceptable salts, derivatives, isomers. polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof. optionally at least one 'water insoluble polymer(s), and optionally one or more pharmaceutical 1} acceptable excipient(s); wherein the first coat comprises at least one pH independent polymer(s) alongwith one or more pharmaceutically acceptable excipient(s), and wherein the said composition comprises at least one additional second coating layer comprising at least one pH dependent polymer(s) optionally one or more pharmaceutically acceptable excipient(s)
It is another objective of the present invention to provide controlled release pharmaceutical compositions comprising microparticles alongwith at least one m-situ gelling agent(s), at least one cross-linking agent(s) and optionally one or more pharmaceutically acceptable excipient(s), wherein the said composition are formulated as oral reconstitutable pharmaceutical controlled release suspension, which can be reconstituted using a suitable reconstituting medium
It is another objective of the present invention to provide process for preparation of controlled release pharmaceutical compositions comprising microparticles which comprise a core and at least one first coat, wherein the core comprises at least one active agent(s) or its pharmaceutically acceptable salts, derivatives, isomers, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof, optionally at least one water insoluble polymer(s), and optionally one or more
pharmaceutically acceptable excipient(s), and at least one first coat comprising at least one pH independent polymer(s) alongwith one or more pharmaceutically acceptable excipient(s)
It is another objective of the present invention to provide process for preparation of the compositions comprising microparticles which comprise a core and at least one first coat. wherein the core comprises at least one active agent(s) or its pharmaceutically acceptable salts, derivatives, isomers, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof, optionally at least one water insoluble polymer(s), and optionall) one or more pharmaceutically acceptable excipient(s), and at leas one first coat comprising at least one pH independent polymer(s) alongwith one or more pharmaceutical!) acceptable excipient(s)
It is another objective of the present invention to provide process for preparation of such compositions which comprises of the follow mg steps
i) preparation of microparticles comprising a core and at least one first coat, and
ii) optionally dispersing the composition of step (i) in a suitable reconstituting medium to obtain a controlled release suspension
It is another objective of the present invention to provide process for preparation of such
compositions which comprises of the following steps
i) preparation of microparticles comprising a core and at least one first coat,
ii) preparation of a controlled release composition comprising microparticles alongwith at
least one m-situ gelling agent(s), at least one cross-linking agent(s), and optionally one or
more pharmaceutically acceptable excipient(s), and iii) optionally dispersing the composition of step (n) in a suitable reconstituting medium to
obtain a controlled release suspension
It is yet another objective of the present invention to provide a method of using such controlled release composition which comprises administering to a subject in need thereof an effective amount of the composition
The extended release dosage form of the present invention may be preferably in the form of solid, semisolid or liquid dosage form such as dry powder mixture, dispersible tablet or effervescent tablet, capsule, suspension, paste, jelly, syrup or elixir
The controlled release pharmaceutical compositions upon reconstitution remains stable for a prolonged period of time preferably at least for the entire duration of therapy and also provide a controlled release of the active agent(s)
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides controlled release pharmaceutical compositions comprising
microparticles which comprise a core and at least one first coat, wherein the core comprises at least one active agent(s) or its pharmaceutical!) acceptable salts, derivatives, isomers, polymorphs, solvates, hydrates, analogues, enantiomers tautomeric forms or mixtures thereof. optionally at least one water insoluble pohmer(s), and optionally one or more pharmaceutical!) acceptable excipient(s), wherein the at least one first coat comprises at least one pH independent polymer(s) alongwith one or more pharmaceutically acceptable excipient(s)
In an embodiment, the present invention provides controlled release pharmaceutical compositions comprising microparticles which comprise a core and at least one first coat, wherein the core comprises at least one active agent(s) or its pharmaceutical!) acceptable salts, derivatives, isomers, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof, optionally at least one water insoluble polymer(s), and optionally one or more pharmaceutically acceptable excipient(s), wherein the first coat comprises at least one pH independent polymer(s) alongwith one or more pharmaceutically acceptable excipient(s), and wherein the said composition comprises at least one additional second coat comprising at least one pH dependent polymer(s) optionally one or more pharmaceutically' acceptable excipient(s)
In another embodiment, the present invention provides controlled release pharmaceutical compositions comprising microparticles which comprise a core and at least one first coat, wherein the core is comprised essentially of at least one active agent(s) or its pharmaceutical!)' acceptable salts, derivatives, isomers, polymorphs, solvates, hydrates, analogues, enantiomers. tautomeric forms or mixtures thereof; wherein at least one first coat comprises at least one pH independent polymer(s) alongwith one or more pharmaceutical ly acceptable excipient(s), and wherein the said composition comprises at least one additional second coating layer comprising at least one pH dependent polymer(s) optionally one or more pharmaceutical!) acceptable excipient(s)
In another embodiment, the present invention provides controlled release pharmaceutical compositions comprising microparticles alongwith at least one m-situ gelling agent(s), at least one cross-linking agent(s) and optionally one or more other pharmaceutically acceptable excipient(s), wherein the said composition is formulated as oral reconstitutable pharmaceutical controlled release suspension, which can be reconstituted using a suitable reconstituting medium The controlled release pharmaceutical compositions are preferably in the form of a dry powder which is reconstituted preferably using an aqueous medium such as water for oral administration
In an embodiment, the active agent(s) useful in the present invention is selected from but not limited to a group comprising adrenergic agent, adrenocortical steroid, adrenocortical suppressant, aldosterone antagonist; amino acid; anabolic; analeptic, analgesic; anesthetic, anorectic, anti-acne agent, anti-adrenergic; anti-allergic; anti-amebic; anti-anemic, anti-anginal, anti-arthntic, anti-asthmatic, anti-atherosclerotic, antibacterial; anticholinergic, anticoagulant, anticonvulsant; antidepressant, antidiabetic, antidiarrheal.
antidiuretic; anti-emetic, anti-epileptic, antifibnnolytic, antifungal, antihemorrhagic; antihistamine, antihyperlipidemia; antihypertensive, antihypotensive, anti-infective, anti-inflammatory, antimicrobial, antimigraine, antimitotic, antimycotic. antinauseant. antineoplastic, antineutropenic, antiparasitic, antiproliferative, antipsychotic, antirheumatic, antiseborrheic, antisecretory, antispasmodic, antithrombotic, anti-ulcerative; antiviral, appetite suppressant, blood glucose regulator, bone resorption inhibitor, bronchodilator; cardiovascular agent, cholinergic, depressant, diagnostic aid, diuretic, dopaminergic agent, estrogen receptor agonist, fibrinolytic; fluorescent agent, free oxygen radical scavenger, gastric acid supressant; gastrointestinal motility effector, glucocorticoid, hair growth stimulant, hemostatic, histamine H2 receptor antagonists; hormone, hypocholesterolemic, hypoglycemic, hypolipidemic, hypotensive, imaging agent; immunizing agent, immunomodulator, immunoregulator, immunostimulant, immunosuppressant; keratolytic, LHRH agonist, mood regulator, mucolytic, mydriatic, nasal decongestant, neuromuscular blocking agent, neuroprotective, NMDA antagonist, non-honnonal sterol derivative, plasminogen activator, platelet activating factor antagonist, platelet aggregation inhibitor, psychotropic, scabicide; sclerosing agent; sedative; sedative-hypnotic, selective adenosine Al antagonist, serotonin antagonist; serotonin inhibitor, serotonin receptor antagonist; steroid, thyroid hormone, thyroid inhibitor, thyromimetic; tranquilizer; amyotrophic lateral sclerosis agent, cerebral ischemia agent, vasoconstrictor, vasodilator; wound healing agent, xanthine oxidase inhibitor, or mixtures thereof
In preferred embodiment, the active agent of the present invention is selected from but not limited to a group comprising paracetamol, ibuprofen, nimesulide, mycophenolate, carbamazepine. chlorpheniramine, phenylpropanolamine, amoxicillin, erythromycin, ciprofloxacin, tacrolimus, and the like or pharmaceutically acceptable salts, hydrates, polymorphs, esters, and derivatives thereof used either alone or in combination thereof In an embodiment, the active agents useful for the present invention are preferably those which have a shorter to a medium duration of therapy such as analgesics, antibiotics, anti-inflammatory drugs, antipyretics, antihistamines, and the like In another embodiment of the present invention, the compositions of the present invention may comprise of active agents which are useful for longer duration of therapy
The compositions of the present invention are useful in masking the taste of bitter drugs intended for oral administration Further, the controlled release pharmaceutical compositions of the present invention upon reconstitution remains stable for a prolonged period of time at least for the entire duration of therapy and also provide a controlled release of the active agent(s) The reconstituted suspension compositions do not form any substantial sedimentation of the dispersed particles or a hard cake during storage, instead the particles forming an\ loose deposits can be easily resuspended upon shaking prior to use
In an embodiment of the present invention, the water insoluble polymer(s) present in the core composition of the microparticle is selected from but not limited to a group comprising pH independent or pH dependent polymer(s) or mixtures thereof as described hereinafter.
In another embodiment of the present invention, the first coating composition is formulated as a release controlling system that aids in providing controlled release of the active agent(s) In an embodiment, the release controlling system for coating the core comprises at least one pH independent polymer(s), and one or more other pharmaceutical excipient(s) In an embodiment, the pH independent polymer is selected from but not limited to a group comprising alkyl celluloses such as methyl cellulose, hydroxyalkyl celluloses such as hydroxypropyl cellulose (HPC, Klucel® HF) and hydroxyethyl cellulose (HEC, Natrosol® 250 HX), high molecular weight pol> ethylene glycols (PEG® 6000, PEG® 10000), gelatin, polyvinyhmidazoles, polyvinylpyndine N-oxides, copolymers of vinylpyrrolidone with long-chained alpha-olefins, copolymers of vinylpyrrolidone with vinv Imidazole, poly(vinylpyrrohdone/dimethylaminoethyl methacrylates), polyacrylate polymers (e g Eudragit® NE 30D, Eudragit® RS, Eudragit® RL etc), copolymers of vmylpyrrolidone/dimethylaminoprop>l methacrylamides, copolymers of vinylpyrrolidone/ dimethylaminopropyl acrylamides. quaternised copolymers of vinylpyrrohdones and dimethylaminoethyl methacrylates. terpoKmers of vinylcaprolactam/ vinylpyrrolidone/ dimethylaminoethyl methacrylates, copolymers of vinylpyrrolidone and methacrylamidopropyl-tnmethylammonium chloride, terpolymers of caprolactam/vinylpyrrohdone/dimethylaminoethyl methacrylates. copolymers of styrene and acrylic acid, polyacrylamides, copolymers of ethyl aery late with methacrylate and methacrylic acid, copolymers of maleic acid with unsaturated hydrocarbons and mixed polymerisation products of the said polymers, polysaccharide gums, both natural and modified (semi-synthetic), including but not limited to veegum, agar, guar gum, locust bean gum, gum arabic, okra gum, bentonite, arabinoglactm. pectin, tragacanth, scleroglucan. dextran, amylose, amylopectin, and the like or mixtures thereof
In an embodiment, the pH independent polymer of the present invention is preferably water insoluble. In a preferred embodiment of the present invention, the water insoluble pH independent polymer is selected from a group comprising polyacrylate polymers e g Eudragit® NE 30D. Eudragit® RS, Eudragit® RS 30D, Eudragit® RL etc , or a cellulosic polymer e g ethvlcellulose. or mixtures thereof. More preferably the pH independent pol) mer is Eudragit® RS 30D
In another embodiment of the present invention, the microparticles comprise at least one additional second coating layer comprising at least one pH dependent preferably water insoluble polymer(s) optionally one or more pharmaceutically acceptable excipient(s) The second coating layer over the first layer is intended to provide stability to the formulation by avoiding leaching of active agent(s) in the liquid phase after reconstitution during storage. In an embodiment, the second coating layer comprises at least one pH dependent polymer(s), and one or more pharmaceuticall> acceptable excipient(s). In an embodiment, the pH dependent polymer is selected from but not limited to a group comprising polyacrylic and polymethacr>hc acids and polyacrylate and methacrylate based polymers, and mixtures thereof, such as Eudragit®, for example Eudragit® El00, Eudragit® EPO. Eudragit® L, Eudragit® S or the like (Rohm-Pharma, Darmstadt, Gennany), reaction products such
as hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), cellulose acetate trimillitate (CAT), hydroxypropyl meth\lcellulose acetate succinate and the like, cellulose derivative such as an alkyl cellulose, a h>droxyalkyl cellulose, a hydro\>alkyl alk\lcellulose or a cellulose ester with at least one polybasic acid such as succinic acid, maleic acid, phthahc acid, tetrahydrophthalic acid, hexahydrophthahc acid, trimelhtic acid or p\romelhtic acid. pol\vin\l acetate phthalate (PVAP), polyvinyl acetaldiethylamino acetate, shellac, or mixtures thereof Preferably the pH dependent polymer used is polymethacrylate polymer such as Eudragit® El00 or Eudragit® EPO More preferably the pH dependent polymer used is Eudragit® EPO
In an embodiment of the present invention, the active agent(s) comprises from about 1% to about 90% by weight of dry weight of dr> formulation before reconstitution The first coating composition may constitute about 1% to about 90%, preferably about 10% to about 50%o b> weight of the total microparticle weight The additional second coating composition ma> constitute about 1% to about 90%, preferably about 10% to about 50% by weight of total microparticle weight
In an embodiment of the present invention, the reconstituted suspension composition comprising paracetamol as an active agent provides a release of at least about 30% of the active agent in about 6 hours, about 35%-75% in about 10 hours and not less than about 75% of the active agent after 20 hours when tested in vitro in 500 ml 0 1 N HC1 as dissolution media using the USP Apparatus Type-II (paddle) at 50 RPM Further, no significant difference in the release profile of active agent was found even when the composition was stored upto 7 days after reconstitution The composition of the present invention is capable of releasing the active agent(s) along the gastrointestinal tract and independent of pH conditions of gastrointestinal tract to achieve and maintain therapeutic concentrations of the active agent(s) for prolonged periods of time
In an embodiment of the present invention, the in-situ gelling agent present in the controlled release pharmaceutical composition is selected from but not limited to a group comprising alginates such as sodium alginate, or gums such as locust bean gum, xanthan gum, tragacanth, xylan, arabinogalactan, agar, gellan gum, scleroglucan, guar gum, apricot gum (Prunus armeniaca, L), carrageenan, pectin, acacia gum, dragon gum, hog gum, talha, dextran, and gum arabic and the like, or mixtures thereof. In a preferred embodiment, the in-situ gelling agent is sodium alginate In an embodiment of the present invention, the cross-linking agent present in the controlled release pharmaceutical composition is selected from but not limited to a group comprising calcium carbonate, calcium sulfate, calcium chloride, aluminium chloride, magnesium chloride, calcium lactate, magnesium sulfate, and the like or mixtures thereof. Preferably the cross-linking agent is a divalent or tnvalent metal cation salt, and acts as a gelation facilitating agent which facilitates the in-situ formation of a gel upon reconstitution of the composition using an aqueous reconstituting medium. More preferably, the composition of the present invention comprises calcium carbonate as the cross-linking agent
In another embodiment of the present invention, the pharmaceutical acceptable excipient(s) of the present invention are selected from but not limited to a group comprising diluents, lubricants binders, fillers, viscosity modifiers, surfactants, anti-caking agents, thixotropic agents, antioxidants, colorants, flavoring agents, sweeteners, preservatives, glidants, chelating agents. plasticizers, vehicles, wetting agents, complexing agents, buffering agents, preservatives, suspending agents, release modifiers, viscosity enhancing agents, and the like known to the art used either alone or in combination thereof It will be appreciated that certain excipients used in the present composition can serve more than one purpose
Suitable diluents include for example pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, starch, dibasic calcium phosphate, saccharides, and/or mixtures of the foregoing. Examples of diluents include microcrystalline celluloses such as Avicel® PH101, Avicel® PH102, Avicel® PHI 12, Avicel® PH200, Avicel® PH301 and Avicel® PH302, lactose such as lactose monohydrate, lactose anhydrous and Pharmatose® DCL21, including anhydrous, monohydrate and spray dried forms, dibasic calcium phosphate such as Emcompress®, mannitol such as Pearlitol® SD200; starch, sorbitol, sucrose; glucose, or the like, or mixtures thereof
Suitable binder useful in the present invention is selected from but not limited to a group comprising polyvinylpyrrolidone (e g PVP K-90 or PVP K-30). copovidone (e g Plasdone® S630), cellulosic polymers (e g hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or the like), gums such as xanthan, alginates such as sodium alginate, polyvinylacetate, or suitable mixtures thereof. More preferably, copovidone (e g Plasdone® S630) is useful as a binder
In an embodiment of the present invention, the viscosity enhancing agent is selected from but not limited to group comprising cellulose derivatives, such as hydroxypropyI cellulose. hydrox>ethyl cellulose, hydroxypropyl methyl cellulose, methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and its derivatives, microcrystalline cellulose, carbomers. carageenan, vinyl polymers, polyoxyethylene-polyoxypropylene polymers or co-polymers (Pluronics®), polysaccharides such as glycosaminoglycans, agar, pectin, alginic acid, dextran, starch and chitosan, proteins, poly(ethyleneoxide), acrylamide polymers, polyhydroxy acids, polyanhydndes, polyorthoesters, polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terepthalates, polyvinyl alcohols such as polyacryhc acid, polymethacryhc acid, polyvinyl pyrrolidone and polyvinyl alcohol, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polysiloxanes. polyvinyl acetates, polystyrene, polyurethanes, synthetic celluloses, polyacryhc acids, polybutync acid, polyvalenc acid. poly(lactide-co-caprolactone), and copolymers, derivatives, and the like, or mixtures thereof
In another embodiment of the present invention, the wetting agent useful in the present invention is a surfactant selected from but not limited to a group comprising anionic, cationic, nonionic or
zwitteriomc surfactant, or combinations thereof Examples of suitable wetting agents include sodium lauryl sulphate, cetnmide, polyethylene glycols. polyox\ethylene-polyoxypropylenc block copolymers known as poloxamer, polyglycenn fatty acid esters such as decaglvceryl monolaurate and decaglvcervl monomyristate; sorbitan fatty acid ester such as sorbitan monostearate (SPAN® 80), polyoxyethylene sorbitan fatty acid ester such as polyoxyethylene sorbitan monooleate (TWEEN® 80. TWEEN® 40), polyethylene glycol fatty acid ester such as polyoxyethylene monostearate, polyoxyethylene alkyl ether such as polyoxyethylene lauryl ether, polyoxyethylene castor oil and hardened castor oil, such as polyoxyethylene hardened castor oil. and the like or mixtures thereof
In another embodiment of the present invention, the preservative useful in the present invention is selected from but not limited to a group comprising parabens such as methyl parabcn or prop} I paraben; sodium benzoate. cetnmide and the like or mixtures thereof Suitable lubricants are selected from but not limited to a group comprising talc; stearic acid, magnesium stearate. calcium stearate, colloidal silicon dioxide such as Aerosil® 200, sodium stearyl fumarate. hydrogenated vegetable oil and the like or mixtures thereof Suitable sweeteners include sucrose, saccharin, compressible sugar, aspartame, saccharin, or mixtures thereof Suitable anticaking agent useful in the present invention is amorphous silica
In an embodiment of the present invention, the pharmaceutical dosage form composition of the present invention is formulated as an oral dosage form either as a solid, semi-solid, or a liquid preparation such as tablets, capsules, patches, powders, granules, dry syrup, suspension, topical gels, solutions, emulsions, and the like In an embodiment, the composition of the present invention is preferably a liquid or semisolid oral dosage form such as suspension, paste, jelly, syrup or elixir The granulation technique is either aqueous or non-aqueous, more preferably wet granulation In preferred embodiment, powder or granular formulations may be manufactured using techniques which are generally conventional in the field of manufacture of pharmaceutical formulations and in the manufacture of dry formulations for reconstitution into such formulations For example a suitable technique of manufacture comprises mixing dry powdered or granulated ingredients with suitable excipient(s) and compressing to form solid dosage forms like tablets or dispersing in a suitable medium to form liquid dosage composition In preferred embodiment, the present invention relates to liquid pharmaceutical formulations like suspensions for oral administration of active agent(s) wherein the composition releases the active agent(s) in a controlled manner such that the release profile of the active agent does not change during the storage of the liquid formulation
In another embodiment of the present invention, the suspension may be provided in the form of a dry powder or granular substance comprising the active agent(s) and one or more excipient(s), which may be freshly prepared into the liquid suspension form by simply adding water and mixing so as to obtain a homogeneous and stable formulation The dry suspension may be prepared by mixing the active agent(s) in the form of powder or granules alongwith one or more

suspension adjuvant(s) The granulations may be prepared according to various conventional granulation techniques well known to person skilled in the art. more preferably by wet granulation or may result from simple physical mixing of the various components More preferably granules are coated with pol}mer system to provide formulation of drug with controlled release profile that does not change during the storage of the liquid formulation
In another embodiment, the composition of the present invention can be formulated as fast melt formulations, lyophihzed formulations, delayed release formulations, extended release formulations, pulsatile release formulations, or a combination of immediate release and extended release formulations In another embodiment of the present invention, the size of the core microparticles may range from about 0 5 µm to about 2000 µm preferably about 1 µm to about 1000 µm, more preferably from about 50 urn to about 500 µm In an embodiment, the present invention provides liquid taste masked controlled release pharmaceutical formulations for oral administration of active agents which produces bad or bitter taste in mouth of a subject upon administration
In an embodiment, the appropriate amount of any pharmaceutically' active agent(s) in the dosage form will depend on the particular agent and/or the intended daily dose and/or the intended use Unless explicitly indicated herein, it is to be understood that appropriate daily doses for the various agents will be known to those of ordinary skill in the art of pharmaceutical formulation and pharmacology and/or can be found in the pertinent texts and literature
In an aspect of the present invention is provided a process for preparation of such compositions which comprises of the following steps
i) preparation of microparticles comprising a core and at least one first coat, and
li) optionally dispersing the composition of step (I) in a suitable reconstituting medium to obtain a controlled release suspension
In another embodiment of the present invention is provided a process for the preparation of such
composition which comprises of the following steps
i) preparation of microparticles comprising a core and at least one first coat.
ii) preparation of a controlled release composition comprising microparticles alongwith at
least one in-situ gelling agent(s), at least one cross-linking agent(s), and optionally one or
more pharmaceutically acceptable excipient(s), and iii) optionally dispersing the composition of step (I) in a suitable reconstituting medium to
obtain a controlled release suspension
In another embodiment of the present invention is provided a process for the preparation of such composition which comprises of the following steps
i) preparing a core composition by mixing the active agent(s) with diluent(s) and granulating with pH independent water insoluble polymer(s) optionally with a binder,
ii) providing a first coating on the core composition with a coating composition comprising
pH independent water insoluble polymer(s) optional 1> alongwith one or more
pharmaceutically acceptable excipient(s), iii) optionally providing a second coating on the composition of step (n) with a coating
composition comprising pH dependent water insoluble polymer(s) optionally alongwith
one or more pharmaceutically acceptable excipient(s), iv) mixing the double coated granules of step (in) with m-situ gelling agent(s), cross-linking
agent(s) optionally alongwith one or more pharmaceutically acceptable excipient(s), and v) optionally dispersing the composition of step (iv) in a suitable reconstituting medium to
obtain a controlled release suspension
In yet another embodiment of the present invention is provided method of using such composition. which comprises administering to a subject in need thereof an effective amount of the composition The composition of the present invention is useful in the management of one or more diseases/disorders which includes prophylaxis, amelioration and/or treatment of such disease(s) or disorder(s)
In a further embodiment is provided the use and method of using the compositions of the present invention for the preparation of medicament for the treatment of one or more diseases or disorders selected from but not limited to a group comprising viral infections, bacterial infections, hypertension, treatment of heart failure, management of CNS disorders, epilepsy and various cardiovascular disorders which depends on the specific active agent used in the composition In an embodiment, the compositions of the present invention are intended for prophylactic or therapeutic use
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:
S. No. Ingredient Quantity (mg/ 5 ml)
A) Core composition
1. Paracetamol 120 00
2. Microcrystalline cellulose 31 25
3. Eudragit® RS30D 18.71
4. Copovidone 1 54
5. Purified water q s (lost in processing)
B) Coating dispersion-1
6. Eudragit® RS30D 200 00
7. Triethyl Citrate 3 5
8. Talc 20 00
9. Purified water q s (lost in processing)
C) Coating dispersion-2
10 Eudragit®EPO 70 00
11. Sodium lauryl sulfate 5 00
12 Stearic acid 10 00
13. Talc 15 00
14 Purified water qs (lost in processing)
D) Reconstitutable Suspension composition
15. Double Coated Granules 500.00
16. Sodium alginate(KeItone HVCR) 50 00
17. Sodium citrate J 00 18 Calcium carbonate 5 00

19. Sucrose 834 00
20. Sodium benzoate 5 20
21. Tween-80 0 80
22. Amorphous silica 5 00
E) Reconstituted Suspension
23. Reconstitutable Suspension composition 1400
24. Purified water q s to 5 ml Procedure:
i) Paracetamol and microcrystalline cellulose were weighed together and mixed well
ii) Eudragit® RS30D and Copovidone were weighed together and mixed well with water to
make granulating fluid iii) The mixture prepared in step (I) was granulated with granulating fluid of step (n) to obtain granules iv) The granules were dried and passed through sieve #60 and retained on sieve #80, and the
granules retained on sieve #80 were collected v) Eudragit RS30D, Tnethyl citrate and talc were weighed and dispersed in Purified water vi) The coating dispersion of step (v) was filtered and the filtered material was coated onto the
granules of step (iv) vii) Eudragit EPO, Sodium lauryl sulphate, Stearic acid and Talc were weighed and dispersed
in Purified water. viii) The coated granules of step (vi) were again coated with coating dispersion of step (vu) ix) Sucrose, Sodium alginate, Sodium citrate, Calcium carbonate, Sodium benzoate, Tween*-80 and
Amorphous silica were weighed together and mixed well with the granules obtained in step (vm) x) The powder mixture obtained in step (ix) can be reconstituted prior to use by adding
Purified water q.s. to 5 ml and mixing to obtain a suspension
Example-2:
S. No. Ingredient Quantity (nig/ 5 ml)
A) Core composition
1. Nimesulide 50 00
2. Lactose 20 00 3 Polyethylene glycol 10 00

4. Copovidone 1 20
5. Purified water qs (lost in processing)
B) Coating dispersion-1
6 Eudragit® NE 30D 100 00
7 Triethyl Citrate 2 00 8. Talc 10 00
9 Purified water q s (lost in processing)
C) Coating dispersion-2
10. Hydroxypropyl methylcellulose phthalate 55 00
11. Sodium lauryl sulfate 2 00 12 Stearic acid 5 00

13. Talc 7 50
14. Purified water qs (lost in processing)
D) Reconstitutable Suspension composition
15. Double Coated Granules 262 70
16. Xanthan gum 22 00
17. Calcium sulfate 3 00
18. Sucrose 500 00
19. Sodium benzoate 5 00
20. Tween-80 1 00
21. Colloidal silica 6 30
E) Reconstituted Suspension
22. Reconstitutable Suspension composition 800 00
23. Purified water q s. to 5 ml Procedure:
i) Nimesulide and lactose were weighed together and mixed well
ii) Polyethylene glycol and Copovidone were weighed together and mixed well with water to
make granulating fluid
iii) The mixture prepared in step (i) was granulated with granulating fluid of step (n) to obtain granules
iv) The granules were dried and passed through sieve #60 and retained on sieve #80, and the
granules retained on sieve #80 were collected
v) Eudragit® NE 30D, Triethyl citrate and talc were weighed and dispersed in Purified water
vi) The coating dispersion of step (v) was filtered and the filtered material was coated onto the
granules of step (iv) vii) Hydroxypropyl methjlcellulose phthalate. Sodium laur> 1 sulphate. Stearic acid and Talc
were weighed and dispersed in Purified water viii) The coated granules of step (vi) were again coated with coating dispersion of step (vn) ix) Sucrose, Xanthan gum. Calcium sulfate. Sodium ben/oate, Twecn"-80 and Colloidal silica
were weighed together and mixed w ith granules obtained in step (vm) x) The powder mixture obtained in step (ix) can be reconstituted prior to use by adding
Purified water q.s to 5 ml and mixing to obtain a suspension
Example-3:
S. No. Ingredient Quantity (mg)
A) Core composition
1. Mycophenolate Mofetil 250 0
2. Starch 35 00
3. Ethyl cellulose 20 00
4. Polyvinylpyrrolidone 1 20
5. Purified water q s (lost in processing)
B) Coating dispersion-1
6. Hydroxypropyl cellulose 70 00
7 Tnethyl Citrate 1 50
8. Talc 8 00
9. Purified water q s (lost in processing)
C) Coating dispersion-2
10. Eudragit®E100 55 00
11. Sodium lauryl sulfate 2 00
12. Stearic acid 5 00
13. Talc 7 30
14 Purified water q s (lost in processing)
D) Reconstitutable Suspension composition
15 Double Coated Granules 455 00
16. AvicelCL611 33 00
17. Locust bean gum 22 00
18. Aluminium chloride 3 00
19. Sucrose 500 00
20. Sodium benzoate 5.00
21. Sorbitan monostearate (SPAN®-80) 100
22. Colloidal silica 6 30
E) Reconstituted Suspension
23. Reconstitutable Suspension composition 1025 30
24 Purified water q s to 5 ml
Procedure:
i) Mycophenolate Mofetil and starch were weighed together and mixed well
ii) Ethyl cellulose and Polyvinylpyrrolidone were weighed together and mixed well with water
to make granulating fluid iii) The mixture prepared in step (1) was granulated with granulating fluid of step (n) to obtain granules iv) The granules were dried and passed through sieve #60 and retained on sieve #80, and the
granules retained on sieve #80 were collected v) Hydroxypropyl cellulose, Tnethyl citrate and talc were weighed and dispersed in Purified water vi) The coating dispersion of step (v) was filtered and the filtered material was coated onto the
granules of step (iv) vii) Eudragit® El00, Sodium laury 1 sulphate, Stearic acid and Talc were weighed and
dispersed in Purified water viii) The coated granules of step (vi) were again coated with coating dispersion of step (vii) ix) Sucrose, Avicel CL 611, Locust bean gum. Aluminium chloride, Sodium benzoate,
Sorbitan monostearate (SPAN®-80) and Colloidal silica were weighed together and mixed
well with the granules obtained in step (vm) x) The powder mixture obtained in step (ix) can be reconstituted prior to use by adding
Purified water q s to 5 ml and mixing to obtain a suspension
ExampIe-4:
S. No. Ingredient Quantity (mg/sachet)
A) Core composition
1. Carbamezapine 100 00
2. Avicel® PH301 20 00 3 Eudragit® RS30D 10 00

4. Hydroxypropyl cellulose 1 20
5. Purified water q s (lost in processing)
B) Coating dispersion-1
6. Tragacanth 100 00
7. Triethyl Citrate 2 00
8. Talc 10 00
9. Purified water q s (lost in processing)
C) Coating dispersion-2
10. Cellulose acetate phthalate (CAP) 55 00
11. Sodium lauryl sulfate 2 00
12. Stearic acid 5 00
13. Calcium stearate 7 50
14. Purified water q.s (lost in processing)
D) Reconstitutable Suspension composition
15. Double Coated Granules 312 70
16. Carrageenan 22 00
17. Magnesium sulfate 3 00
18. Sorbitol 500 00
19. Sodium benzoate 5 00
20. Polyoxyethylene monostearate I 00
21. Colloidal silica 6 30 Procedure:
i) Carbamezapine and Avicel® PH301 were weighed together and mixed well
ii) Eudragit® RS30D and Hydroxypropyl cellulose were weighed together and mixed well
with water to make granulating fluid iii) The mixture prepared in step (l) was granulated with granulating fluid of step (u) to obtain granules iv) The granules were dried and passed through sieve //60 and retained on sieve //80. and the
granules retained on sieve #80 were collected v) Tragacanth, Tnethyl citrate and talc were weighed and dispersed in Purified waler vi) The coating dispersion of step (v) was filtered and the filtered material was coated onto the
granules of step (iv) vii) Cellulose acetate phthalate (CAP), Sodium lauryl sulphate, Stearic acid and Calcium
stearate were weighed and dispersed in Purified water viii) The coated granules of step (vi) were again coated with coating dispersion of step (vn) ix) Sorbitol, Carrageenan, Magnesium sulfate. Sodium benzoate, Pol>o\vethylene
monostearate and Colloidal silica were weighed together and mixed well with the granules
obtained in step (viii) and filled into a sachet
Example-5:
S. No. Ingredient Quantity (mg/ 5 ml)
A) Core composition
1. Amoxicillin 100 00
2. Dibasic calcium phosphate (Emcompress®) 20 00
3. Eudragit® RS30D 10 00
4. Polyvinylpyrrolidone (PVP K-90) 1 20
5. Purified water q s. (lost in processing)
B) Coating dispersion-1
6. Gelatin 100 00
7. Triethyl Citrate 2 00
8. Stearic acid 10 00
9. Purified water q s. (lost in processing)
C) Coating dispersion-2
10 Hydroxypropyl methylcellulose acetate succinate 55 00
11. Cetrimide 2 00
12. Stearic acid 5 00 13 Talc 7 50
14. Purified water qs (lost in processing)
D) Reconstitutable Suspension composition
15 Double Coated Granules 312 70
16. Dextran 22 00
17. Magnesium sulfate 3 00
18. Sucrose 500 00
19. Sodium benzoate 5 00
20. Tween-80 1 00
21. Colloidal silica 6 30
E) Reconstituted Suspension
22. Reconstitutable Suspension composition 800 00
23. Purified water q s to 5 ml Procedure:
i) Amoxicillin and Dibasic calcium phosphate (Emcompress®) were weighed together and
mixed well ii) Eudragit® RS30D and Polyvinylpyrrolidone (PVP K-90) were weighed together and mixed
well with water to make granulating fluid iii) The mixture prepared in step (l) was granulated with granulating fluid of step (n) to obtain granules iv) The granules were dried and passed through sieve #60 and retained on sieve #80, and the
granules retained on sieve #80 were collected v) Gelatin, Triethyl citrate and Stearic acid were weighed and dispersed in Purified water vi) The coating dispersion of step (v) was filtered and the filtered material was coated onto the
granules of step (iv). vii) Hydroxypropyl methylcellulose acetate succinate, Cetrimide. Stearic acid and Talc were
weighed and dispersed in Purified water viii) The coated granules of step (vi) were again coated with coating dispersion of step (vn) ix) Sucrose, Dextran, Magnesium sulfate, Sodium benzoate, Tween*-80 and Colloidal silica
were weighed together and mixed well with the granules obtained in step (vui) x) The powder mixture obtained in step (ix) can be reconstituted prior to use by adding
Purified water q.s. and mixing to obtain a suspension for once daily administration
Example-6:
S. No. Ingredient Quantity (mg/tablet)
A) Core composition
1. Tacrolimus 5.00
2. Lactose anhydrous 20 00
3 Eudragit® RS30D 15 00
4. Copovidone 1 30
5 Purified water q s (lost in processing)
B) Coating dispersion-1
6. Eudragit® RS30D 150 00
7. Tnethyl Citrate 10 00
8. Talc 60 00
9. Purified water q s (lost in processing)
C) Coating dispersion-2
10. Eudragit® EPO 55 00
11. Sodium lauryl sulfate 2 00
12. Stearic acid 5 00
13. Talc 7 50
14. Purified water q.s. (lost in processing)
D) Final blend composition
15. Double Coated Granules 327 80
16. Sodium alginate(Keltone HVCR) 20 00
17. Calcium carbonate 5 00
18. Croscarmellose sodium 40 00
19. Sucrose 10 00
20. Sodium benzoate 4 90
21. Tween-80 1.00
22. Colloidal silica 6 30
23. Magnesium stearate 2 00 Procedure:
i) Tacrolimus and Lactose anhydrous were weighed together and mixed well
ii) Eudragit® RS30D and Copovidone were weighed together and mixed well with water to
make granulating fluid
iii) The mixture prepared in step (i) was granulated with granulating fluid of step (n) to obtain granules
iv) The granules were dried and passed through sieve #60 and retained on sieve #80, and the
granules retained on sieve #80 were collected
v) Eudragit RS30D, Tnethyl citrate and talc were weighed and dispersed in Purified water
vi) The coating dispersion of step (v) was filtered and the filtered material was coated onto the
granules of step (iv)
vii) Eudragit® EPO, Sodium lauryl sulphate, Stearic acid and Talc were weighed and dispersed
in Purified water,
viii) The coated granules of step (vi) were again coated with coating dispersion of step (vn)
ix) Sucrose, Sodium alginate. Calcium carbonate. Sodium benzoate. Tweenh-80, Colloidal silica, Croscarmellose sodium and Magnesium stearate were weighed together and mixed well with the granules obtained in step (vui)
x) Final blend obtained in step (ix) was compressed into tablet which is dispcr^siblc and can be dispersed into purified water q s at the time of use
Example-7:
S. No. Ingredient Quantity (mg/tablet)
Core composition
1. Methyl phenidate 100 00
2. Microcrystalhne cellulose 75 00 3 Hydroxyethyl cellulose 45 00

4. Polyvinylpyrrolidone 3 75
5. Purified water q s (lost in processing) Coating dispersion-1
6. Hydroxypropyl cellulose 120 00
7. Stearic acid 20 00
8. Talc 60.00
9. Purified water q s (lost in processing) Coating dispersion-2
10. Eudragit®E100 106 92
11. Sodium lauryl sulfate 10 68
12. Stearic acid 15 72
13. Talc 67 84
14. Purified water q s (lost in processing) Effervescent tablet composition
15. Double Coated Granules 10 00
16. Xanthun gum 1 50
17. Calcium chloride 0 40
18. Sodium bicarbonate 0.10
19. Starch 2.00
20. Sucrose 57.90
21. Methyl paraben 0 20
22. Tween® 80 0 08
23. Amorphous silica 0 20 Procedure:
i) Methyl phenidate and microcrystalhne cellulose were weighed together and mixed well ii) Hydroxyethyl cellulose and Polyvinylpyrrolidone were weighed together and mixed well with water to make granulating fluid
hi) The mixture prepared in step (1) was granulated with granulating fluid of step (n) to obtain
granules iv) The granules were dried and passed through sieve #60 and retained on sieve #80. and the
granules retained on sieve #80 were collected v) Hydroxypropyl cellulose. Stearic acid and Talc were weighed and dispersed in Purified water vi) The coating dispersion of step (v) was filtered and the filtered material was coated onto the
granules of step (iv) vii) Eudragit EPO, Sodium lauryl sulphate, Stearic acid and Talc were weighed and dispersed
in Purified water viii) The coated granules of step (vi) were again coated with coating dispersion of step (vn) ix) Xanthun gum. Calcium chloride, Sodium bicarbonate, Starch, Sucrose, Methyl paraben,
Tween® 80 and Amorphous silica were weighed together and mixed well with the granules
obtained in step (viii) and compressed into tablet
Example-8:
S. No. Ingredient Quantity (mg/capsule)
A) Core composition
1. Paracetamol 100 00
2. Lactose 20 00
3. Eudragit® RS30D 10 00
4. Polyvinylpyrrolidone (PVP K-90) 1.20
5. Purified water q s (lost in processing)
B) Coating dispersion-1
6. Gelatin 100 00
7 Triethyl Citrate 2 00
8. Stearic acid 10.00
9. Purified water q s (lost in processing)
C) Coating dispersion-2
10. Hydroxypropyl methylcellulose acetate succinate 55.00
11. Cetrimide 2 00
12. Stearic acid 5 00
13. Talc 7.50
14. Purified water q s (lost in processing)
Procedure:
i) Paracetamol and Lactose were weighed together and mixed well
ii) Eudragit® RS30D and Polyvinylpyrrolidone (PVP K-90) were weighed together and mixed
well with water to make granulating fluid iii) The mixture prepared in step (i) was granulated with granulating fluid of step (ii) to obtain
granules, iv) The granules were dried and passed through sieve #60 and retained on sieve #80. and the
granules retained on sieve #80 were collected v) Gelatin, Triethyl citrate and Stearic acid were weighed and dispersed in Purified water vi) The coating dispersion of step (v) was filtered and the filtered material was coated onto the
granules of step (iv) vii) Hydroxypropyl methylcellulose acetate succinate. Cetnmide. Stearic acid and Talc were
weighed and dispersed in Purified water viii) The coated granules of step (vi) were again coated with coating dispersion of step (vn) ix) The coated granules obtained in step (vm) can be filled into capsules
Example-9:
S. No. Ingredient mg/tablet
Core composition
1. Methyl phenidate 100 00
2. Microcrystalline cellulose 75 00
3. Hydroxyethyl cellulose 45 00
4. Polyvinylpyrrolidone 3 75
5. Purified water q s (lost in processing) Coating dispersion-1
6. Hydroxypropyl cellulose 120 00
7. Stearic acid 20 00 8 Talc 60 00

9. Purified water q s (lost in processing) Coating dispersion-2
10. Eudragit®E100 106 92
11. Sodium lauryl sulfate 10 68
12. Stearic acid 15 72
13. Talc 67 84
14. Purified water q s (lost in processing) Procedure:
i) Methyl phenidate and microcrystalline cellulose were weighed together and mixed wefl
ii) Hydroxyethyl cellulose and Polyvinylpyrrolidone were weighed together and mixed well
with water to make granulating fluid iii) The mixture prepared in step (l) was granulated with granulating fluid of step (n) to obtain
granules, iv) The granules were dried and passed through sieve #60 and retained on sieve #80, and the
granules retained on sieve #80 were collected, v) Hydroxypropyl cellulose, Stearic acid and Talc were weighed and dispersed in Purified water
vi) The coating dispersion of step (v) was filtered and the filtered material was coated onto the
granules of step (IV) vii) Eudragif1EPO, Sodium lauryl sulphate, Stearic acid and Talc were weighed and dispersed
in Purified water viii) The coated granules of step (vi) were again coated with coating dispersion of step (vn) ix) The coated granules obtained in step (vin) can be compressed into tablet
Example-10:
S. No. Ingredient Quantity (mg)
A) Core composition
1 Amoxicillin 250 0
2 Starch 35 00
3 Ethyl cellulose 20 00

4. Polyvinylpyrrolidone 1 20
5. Purified water q s (lost in processing)
B) Coating dispersion
6. Hydroxypropyl cellulose 70 00
7. Triethyl Citrate 1 50
8. Talc 8 00
9. Purified water q s (lost in processing) Procedure:
i) Amoxicillin and Starch were weighed together and mixed well
ii) Ethyl cellulose and Polyvinylpyrrolidone were weighed together and mixed well with water
to make granulating fluid iii) The mixture prepared in step (l) was granulated with granulating fluid of step (u) to obtain
granules, iv) The granules were dried and passed through sieve #60 and retained on sieve //80, and the
granules retained on sieve #80 were collected v) Hydroxypropyl cellulose, Triethyl citrate and Talc were weighed and dispersed in Purified water. vi) The coating dispersion of step (v) was filtered and the filtered material was coated onto the
granules of step (iv). vii) The coated granules obtained in step (vi) was compressed into tablet which is dispersible
and can be dispersed into purified water q.s at the time of use

We Claim:
1. The controlled release pharmaceutical compositions comprising microparticles which comprise a core and at least one first coat, wherein the core comprises at least one active agent(s) or its pharmaceutically acceptable salts, derivatives, isomers, polymorphs, solvates. hydrates, analogues, enantiomers. tautomeric forms or mixtures thereof; optionally at least one water insoluble polymer(s), and optionally one or more pharmaceutically acceptable excipient(s); wherein at least one first coat comprises at least one pH independent polymer(s) alongwith one or more pharmaceutically acceptable excipient(s) and wherein the said composition comprises at least one additional second coating layer comprising at least one pH dependent polymer(s) optionally one or more pharmaceutically acceptable excipient(s).
2. The controlled release pharmaceutical composition according to claim 1 which comprises of microparticles alongwith at least one in-situ gelling agent(s). at least one cross-linking agent(s) and optionally one or more pharmaceutically acceptable excipient(s) wherein the said compositions are formulated as oral reconstitutable controlled release suspension, which can be reconstituted using a suitable reconstituting medium such as water.
3. The controlled release pharmaceutical composition according to claim 1, wherein the active
agent is selected from a group comprising adrenergic agent; adrenocortical steroid;
adrenocortical suppressant; aldosterone antagonist; amino acid; anabolic; analeptic;
analgesic; anesthetic; anorectic; anti-acne agent; anti-adrenergic; anti-allergic; anti-amebic;
anti-anemic; anti-anginal; anti-arthritic; anti-asthmatic; anti-atherosclerotic; antibacterial;
anticholinergic; anticoagulant; anticonvulsant; antidepressant; antidiabetic; antidiarrheal;
antidiuretic; anti-emetic; anti-epileptic; antifibrinolytic; antifungal; antihemorrhagic;
antihistamine; antihyperlipidemia; antihypertensive; antihypotensive; anti-infective; anti
inflammatory; antimicrobial; antimigraine; antimitotic; antimycotic, antinauseant,
antineoplastic, antineutropenic, antiparasitic; antiproliferative; antipsychotic; antirheumatic;
antiseborrheic; antisecretory; antispasmodic; antithrombotic; anti-ulcerative; antiviral;
appetite suppressant; blood glucose regulator; bone resorption inhibitor; bronchodilator;
cardiovascular agent; cholinergic; depressant; diagnostic aid; diuretic; dopaminergic agent;
estrogen receptor agonist; fibrinolytic; fluorescent agent; free oxygen radical scavenger;
gastric acid supressant; gastrointestinal motility effector; glucocorticoid; hair growth
stimulant; hemostatic; histamine H2 receptor antagonists; hormone; hypocholesterolemic;
hypoglycemic; hypolipidemic; hypotensive; imaging agent; immunizing agent;
immunomodulator; immunoregulator; immunostimulant; immunosuppressant; keratolytic;
LHRH agonist; mood regulator; mucolytic; mydriatic; nasal decongestant; neuromuscular
blocking agent; neuroprotective; NMDA antagonist; non-hormonal sterol derivative;
plasminogen activator; platelet activating factor antagonist; platelet aggregation inhibitor;
psychotropic; scabicide; sclerosing agent; sedative; sedative-hypnotic; selective adenosine Al
antagonist; serotonin antagonist; serotonin inhibitor; serotonin receptor antagonist; steroid;
thyroid hormone; thyroid inhibitor; thyromimetic; tranquilizer; amyotrophic lateral sclerosis
agent; cerebral ischemia agent; vasoconstrictor; vasodilator: wound healing agent; xanthine oxidase inhibitor, or mixtures thereof.
4. The controlled release pharmaceutical composition according to claim 3, wherein the active agent is selected from a group comprising paracetamol, ibuprofen, nimesulide, mycophenolate, carbamazepine, chlorpheniramine, phenylpropanolamine, amoxicillin, erythromycin, ciprofloxacin, metformin, tacrolimus, or pharmaceutical^' acceptable salts, hydrates, polymorphs, esters, and derivatives thereof used either alone or in combination thereof.
5. The controlled release pharmaceutical composition according to claim 1, wherein the water insoluble polymer is selected from a group comprising pH independent or pi I dependent polymer(s) or mixtures thereof
6. The controlled release pharmaceutical composition according to claim 1 or 5, wherein the pH independent polymer is selected from a group comprising alkyl celluloses, hydroxyalkyl celluloses, high molecular weight polyethylene glycols, gelatin, polyvinylimidazoles. polyvinylpyridine N-oxides, copolymers of vinylpyrrolidone with long-chained alpha-olefins, copolymers of vinylpyrrolidone with vinyiimidazole, polyvinylpyrrolidone /dimethylaminoethyl methacrylates), polyacrylate polymers, copolymers of vinylpyrrolidone/dimethylaminopropyl methacrylamides, copolymers of vinylpyrrolidone/ dimethylaminopropyl acrylamides, quaternised copolymers of vinylpyrrolidones and dimethylaminoethyl methacrylates, terpolymers of vinylcaprolactam/ vinylpyrrolidone/ dimethylaminoethyl methacrylates, copolymers of vinylpyrrolidone and methacrylamidopropyl-trimethylammonium chloride, terpolymers of caprolactam/vinylpyrrolidone/dimethylaminoethyl methacrylates, copolymers of styrene and acrylic acid, polyacrylamides, copolymers of ethyl acrylate with methacrylate and methacrylic acid, copolymers of maleic acid with unsaturated hydrocarbons and mixed polymerisation products of the said polymers, polysaccharide gums, both natural and modified (semi-synthetic), or mixtures thereof.
7. The controlled release pharmaceutical composition according to claim 6, wherein the pH independent polymer is water insoluble selected from a group comprising polyacrylate polymers or a cellulosic polymer, or mixtures thereof.
8. The controlled release pharmaceutical composition according to claim 1 or claim 5, wherein the pH dependent polymer is selected from a group comprising polyacrylic and polymethacrylic acids and polyacrylate and methacrylate based polymers, and mixtures thereof; reaction products, cellulose derivative, a hydroxyalkyl cellulose, a hydroxyalkyl alkylcellulose or a cellulose ester with at least one polybasic acid: polyvinyl acetate phthalate, polyvinyl acetaldiethylamino acetate, shellac, or mixtures thereof.
9. The controlled release pharmaceutical composition according to claim 1, wherein the active
agent(s) comprises from about 1% to about 90% by weight of dry weight of dry formulation before reconstitution.
10. The controlled release pharmaceutical composition according to claim 2. wherein the reconstituted suspension composition comprising paracetamol as an active agent provides a release of at least about 30% of the active agent in about 6 hours, about 35%-75% in about 10 hours and not less than about 75% of the active agent after 20 hours when tested in vitro in 500 ml 0.1 N HC1 as dissolution media using the USP Apparatus Type-ll (paddle) at 50 RPM.
11. The controlled release pharmaceutical composition according to claim 2, wherein the in-situ gelling agent is selected from a group comprising alginates, or gums, or mixtures thereof.
12. The controlled release pharmaceutical composition according to claim 2, wherein the cross-linking agent is selected from a group comprising calcium carbonate, calcium sulfate, calcium chloride, aluminium chloride, magnesium chloride, calcium lactate, magnesium sulfate, or mixtures thereof.
13. The controlled release pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable excipient(s) are selected from a group comprising diluents, lubricants, binders, fillers, viscosity modifiers, surfactants, anti-caking agents, thixotropic agents, anti-oxidants, colorants, flavoring agents, sweeteners, preservatives, glidants. chelating agents, plasticizers, vehicles, wetting agents, complexing agents, buffering agents. preservatives, suspending agents, release modifiers, viscosity enhancing agents, used either alone or in combination thereof.
14. The controlled release pharmaceutical composition according to claim 1, wherein the composition may be formulated as an oral dosage form either as a solid, semi-solid, or a liquid preparation such as tablets, capsules, patches, powders, granules, dry syrup, suspension, gels, jelly, syrup, elixir, solutions, emulsions, and the like.
15. The controlled release pharmaceutical composition according to claim 1 wherein composition may be formulated as fast melt formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, or a combination of immediate release and extended release formulations.
16. The process for the preparation of controlled release pharmaceutical composition according to claim 1, which comprises of the following steps:
i) preparation of microparticles comprising a core and at least one first coat, and ii) optionally dispersing the composition of step (i) in a suitable reconstituting medium to obtain a controlled release suspension.
17. The process for the preparation of controlled release pharmaceutical composition according
to claim 16, which comprises of the following steps:
i) preparation of microparticles comprising a core and at least one first coat,
ii) preparation of a controlled release composition comprising microparticles alongwith at
least one in-situ gelling agent(s), at least one cross-linking agent(s), and optionally one or
more pharmaceutically acceptable excipient(s), and iii) optionally dispersing the composition of step (i) in a suitable reconstituting medium to
obtain a controlled release suspension.
18. The process for the preparation of controlled release pharmaceutical composition according
to claim 16, which comprises of the following steps:
i) preparing a core composition by mixing the active agent(s) with diluent(s) and
granulating with pH independent water insoluble polymer(s) optionally with a binder, ii) providing a first coating on the core composition with a coating composition comprising
pH independent water insoluble polymer(s) optionally alongwith one or more
pharmaceutically acceptable excipient(s), iii) optionally providing a second coating on the composition of step (ii) with a coating
composition comprising pH dependent water insoluble polymer(s) optionally alongwith
one or more pharmaceutically acceptable excipient(s), iv) mixing the double coated granules of step (iii) with in-situ gelling agent(s), cross-linking
agent(s) optionally alongwith one or more pharmaceutically acceptable excipient(s), and v) optionally dispersing the composition of step (iv) in a suitable reconstituting medium to
obtain a controlled release suspension.
19. The pharmaceutical compositions and processes for the preparation of pharmaceutical
compositions substantially as herein described and illustrated by the examples.