WO2008122993A1 - Controlled release formulation of coated microparticles - Google Patents

Controlled release formulation of coated microparticles Download PDF

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Publication number
WO2008122993A1
WO2008122993A1 PCT/IN2008/000232 IN2008000232W WO2008122993A1 WO 2008122993 A1 WO2008122993 A1 WO 2008122993A1 IN 2008000232 W IN2008000232 W IN 2008000232W WO 2008122993 A1 WO2008122993 A1 WO 2008122993A1
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WO
WIPO (PCT)
Prior art keywords
controlled release
agent
composition according
pharmaceutical composition
release pharmaceutical
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Application number
PCT/IN2008/000232
Other languages
French (fr)
Inventor
Rajesh Jain
Kour Chand Jindal
Sanjay Boldhane
Original Assignee
Panacea Biotec Limited
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Publication date
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Publication of WO2008122993A1 publication Critical patent/WO2008122993A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose

Definitions

  • 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).
  • 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.
  • this invention provides process of preparation of such compositions and method of using them.
  • 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.
  • 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 doxycycline, tetracycline, oxytetracycline, minocycline, chlortetracycline 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.
  • 6932981 describes a fast disintegrating controlled release oral composition
  • 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 quaternary 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 delivery 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 in-situ gelling system for controlled release of drug in suspension form. Extended release of water soluble or slightly water soluble drugs for longer duration of time period (more than 10 hours) is not possible with in-situ gelling suspension formulations.
  • 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.
  • microparticles which comprise a core and at least one first coat
  • 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 the at least one first coat comprises at least one pH independent polymer(s) alongwith one or more pharmaceutically acceptable excipient(s).
  • compositions comprising microparticles which comprise a core and at least one first coat
  • 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);
  • 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 in-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).
  • 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 compris
  • compositions comprising microparticles which comprise a core and at least one first coat
  • 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 leas one first coat comprising at least one pH independent polymer(s) alongwith one or more pharmaceutically acceptable excipient(s).
  • 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 (ii) in a suitable reconstituting medium to obtain a controlled release suspension.
  • 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).
  • 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 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 the at least one first coat comprises at least one pH independent polymer(s) alongwith one or more pharmaceutically acceptable excipient(s).
  • 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 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 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).
  • 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
  • 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 pharmaceutically 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 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).
  • the present invention provides controlled release pharmaceutical compositions comprising microparticles alongwith at least one in-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.
  • 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-arthritic; anti-asthmatic; a ⁇ ti-atiierosclerotic; antibacterial; anticholinergic; anticoagulant; anticonvulsant; antidepressant; antidiabetic; antidiarrheal; antidiuretic; anti-emetic; anti-epileptic; antifibrinolytic; antifungal; antihemorrhagic; antihistamine; antihyperlipidemia; antihypertensive; antihypotensive
  • 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.
  • 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.
  • the compositions of the present invention may comprise of active agents which are useful for longer duration of therapy.
  • 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 any loose deposits can be easily resuspended upon shaking prior to use.
  • 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.
  • the first coating composition is formulated as a release controlling system that aids in providing controlled release of the active agent(s).
  • the release controlling system for coating the core comprises at least one pH independent polymer(s), and one or more other pharmaceutical excipient(s).
  • 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 polyethylene glycols (PEG® 6000, PEG® 10000), gelatin, polyvinylimidazoles, polyvinylpyridine N-oxides, copolymers of vinylpyrrolidone with long- chained alpha-olefins, copolymers of vinylpyrrolidone with vinylimidazole, poly(vinylpyrrolidone/dimethylaminoethyl methacrylates), polyacrylate polymers (e.g.
  • the pH independent polymer of the present invention is preferably water insoluble.
  • 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. ethylcellulose, or mixtures thereof. More preferably the pH independent polymer is Eudragit® RS 30D.
  • 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.
  • the second coating layer comprises at least one pH dependent polymer(s), and one or more pharmaceutically acceptable excipient(s).
  • the pH dependent polymer is selected from but not limited to a group comprising polyacrylic and polymethacrylic acids and polyacrylate and methacrylate based polymers, and mixtures thereof, such as Eudragit®, for example Eudragit® ElOO, Eudragit® EPO, Eudragit® L, Eudragit® S or the like (Rohm-Pharma, Darmstadt, Germany); reaction products such as hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), cellulose acetate trimillitate (CAT), hydroxypropyl methylcellulose acetate succinate and the like, cellulose derivative such as an alkyl cellulose, a hydroxyalkyl cellulose, a hydroxyalkyl alkylcellulose or a cellulose ester with at least one polybasic acid such as succinic acid, maleic acid, phthalic acid, tetrahydrophthalic acid, hexahydrophthalic acid, trimellitic acid or pyrom
  • the active agent(s) comprises from about 1% to about 90% by weight of dry weight of dry formulation before reconstitution.
  • the first coating composition may constitute about 1% to about 90%, preferably about 10% to about 50% by weight of the total microparticle weight.
  • the additional second coating composition may constitute about 1% to about 90%, preferably about 10% to about 50% by weight of total microparticle weight.
  • 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 HCl 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.
  • 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.
  • the in-situ gelling agent is sodium alginate.
  • 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.
  • the cross-linking agent is a divalent or trivalent 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.
  • the composition of the present invention comprises calcium carbonate as the cross-linking agent.
  • the pharmaceutically 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, 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, 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® PHlOl, Avicel® PH102, Avicel® PHl 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.
  • 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.
  • 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 alg
  • the viscosity enhancing agent is selected from but not limited to group comprising cellulose derivatives, such as hydroxypropyl cellulose, hydroxyethyl 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, polyanhydrides, polyorthoesters, polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terepthalates, polyvinyl alcohols such as polyacrylic acid, polymethacryl
  • the wetting agent useful in the present invention is a surfactant selected from but not limited to a group comprising anionic, cationic, nonionic or zwitterionic surfactant, or combinations thereof.
  • suitable wetting agents include sodium lauryl sulphate, cetrimide, polyethylene glycols; polyoxyethylene- polyoxypropylene block copolymers known as poloxamer; polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl 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
  • the preservative useful in the present invention is selected from but not limited to a group comprising parabens such as methyl paraben or propyl paraben; sodium benzoate, cetrimide 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 polymer system to provide formulation of drug with controlled release profile that does not change during the storage of the liquid formulation.
  • the composition of the present invention can be formulated as fast melt formulations, Iyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, or a combination of immediate release and extended release formulations.
  • the size of the core microparticles may range from about 0.5 ⁇ m to about 2000 ⁇ m preferably about 1 ⁇ m to about 1000 ⁇ m, more preferably from about 50 ⁇ m to about 500 ⁇ m.
  • 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.
  • 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.
  • 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 ii) optionally dispersing the composition of step (i) in a suitable reconstituting medium to obtain a controlled release suspension.
  • 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.
  • 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) 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 reconstit
  • composition of the present invention 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).
  • 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.
  • the compositions of the present invention are intended for prophylactic or therapeutic use.
  • Reconstitutable Suspension composition 1400 24. Purified water q.s. to 5 ml
  • step (v) The coating dispersion of step (v) was filtered and the filtered material was coated onto the granules of step (iv).
  • Eudragit ® EPO, Sodium lauryl sulphate, Stearic acid and Talc were weighed and dispersed in Purified water.
  • step (vi) The coated granules of step (vi) were again coated with coating dispersion of step
  • step (ix) 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.
  • step (v) The coating dispersion of step (v) was filtered and the filtered material was coated onto the granules of step (iv).
  • step (iv) Hydroxypropyl methylcellulose phthalate, Sodium lauryl sulphate, Stearic acid and Talc were weighed and dispersed in Purified water.
  • step (vi) The coated granules of step (vi) were again coated with coating dispersion of step
  • step (v) The coating dispersion of step (v) was filtered and the filtered material was coated onto the granules of step (iv).
  • Eudragit® ElOO, Sodium lauryl sulphate, Stearic acid and Talc were weighed and dispersed in Purified water.
  • step (vi) The coated granules of step (vi) were again coated with coating dispersion of step
  • step (v ⁇ ). ix) Sucrose, Avicel CL 61 1 , 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 (viii).
  • 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.
  • step (v) Tragacanth, 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).
  • step (i) Cellulose acetate phthalate (CAP), Sodium lauryl sulphate, Stearic acid and Calcium stearate were weighed and dispersed in Purified water.
  • CAP Cellulose acetate phthalate
  • CAP Sodium lauryl sulphate
  • Stearic acid and Calcium stearate were weighed and dispersed in Purified water.
  • the coated granules of step (vi) were again coated with coating dispersion of step (vii).
  • step (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
  • step (vi) The coated granules of step (vi) were again coated with coating dispersion of step (vii).
  • step (ix) Colloidal silica were weighed together and mixed well with the granules obtained in step (viii). 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.
  • step (v) The coating dispersion of step (v) was filtered and the filtered material was coated onto the granules of step (iv).
  • Eudragit ® EPO Sodium lauryl sulphate, Stearic acid and Talc were weighed and dispersed in Purified water.
  • step (viii) The coated granules of step (vi) were again coated with coating dispersion of step (vii).
  • ix) Sucrose, Sodium alginate, Calcium carbonate, Sodium benzoate, Tween ® -80, Colloidal silica, Croscarmellose sodium and Magnesium stearate were weighed together and mixed well with the granules obtained in step (viii).
  • Final blend obtained in step (ix) was compressed into tablet which is dispersible and can be dispersed into purified water q.s. at the time of use.
  • step (v) The coating dispersion of step (v) was filtered and the filtered material was coated onto the granules of step (iv).
  • Eudragit ® EPO Sodium lauryl sulphate, Stearic acid and Talc were weighed and dispersed in Purified water.
  • the coated granules of step (vi) were again coated with coating dispersion of step (vii).
  • 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.
  • step (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
  • step (viii) The coated granules of step (vi) were again coated with coating dispersion of step (vii). ix) The coated granules obtained in step (viii) can be filled into capsules.
  • step (v) The coating dispersion of step (v) was filtered and the filtered material was coated onto the granules of step (iv).
  • Eudragit ® EPO, Sodium lauryl sulphate, Stearic acid and Taic were weighed and dispersed in Purified water.
  • the coated granules of step (vi) were again coated with coating dispersion of step (vii).
  • the coated granules obtained in step (viii) can be compressed into tablet.
  • step (v) 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.

Abstract

Controlled release compositions comprising microparticles which comprise a core and at least one coat, wherein the core comprises at least one active agent(s), optionally at least one water soluble polymer(s) and optionally one or more pharmaceutically acceptable excipient(s); and at least one coat comprising at least one pH independent polymer(s) along with one or more pharmaceutically acceptable excipient(s) are provided. Preferably the controlled release pharmaceutical compositions comprise microparticles along with 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 pharmaceutical controlled release suspensions, 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.

Description

Controlled Release Formulation of coated microparticles
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 doxycycline, tetracycline, oxytetracycline, minocycline, chlortetracycline 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 quaternary 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 delivery 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 in-situ gelling system for controlled release of drug in suspension form. Extended release of water soluble or slightly 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 20051 17843 disclose controlled release suspension technology based on ion exchange resins. Although ion exchange resins systems (such as Pennkinetic system) 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 grittiness in mouth and balding of bad taste of drug. Avoiding of drug release into the liquid phase during storage of foπnulation, 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 very 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 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 the at least one first coat comprises at least one pH independent polymer(s) alongwith one or more pharmaceutically 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 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 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 in-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 optionally 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 pharmaceutically acceptable excipient(s).
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, and ji) 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 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 (ii) 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 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 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 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 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 pharmaceutically 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 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).
In another embodiment, the present invention provides controlled release pharmaceutical compositions comprising microparticles alongwith at least one in-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-arthritic; anti-asthmatic; aπti-atiierosclerotic; 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, antinauseanr, 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, iiabal 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.
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 any 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 polyethylene glycols (PEG® 6000, PEG® 10000), gelatin, polyvinylimidazoles, polyvinylpyridine N-oxides, copolymers of vinylpyrrolidone with long- chained alpha-olefins, copolymers of vinylpyrrolidone with vinylimidazole, poly(vinylpyrrolidone/dimethylaminoethyl methacrylates), polyacrylate polymers (e.g. Eudragit® NE 30D, Eudragit® RS, Eudragit® RL etc), copolymers of vinylpyrrolidone/dimethylarninopropyl methacry lam ides, 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), including but not limited to veegum, agar, guar gum, locust bean gum, gum arabic, okra gum, bentonite, arabinoglactin, 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. ethylcellulose, or mixtures thereof. More preferably the pH independent polymer 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 pharmaceutically acceptable excipient(s). In an embodiment, the pH dependent polymer is selected from but not limited to a group comprising polyacrylic and polymethacrylic acids and polyacrylate and methacrylate based polymers, and mixtures thereof, such as Eudragit®, for example Eudragit® ElOO, Eudragit® EPO, Eudragit® L, Eudragit® S or the like (Rohm-Pharma, Darmstadt, Germany); reaction products such as hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), cellulose acetate trimillitate (CAT), hydroxypropyl methylcellulose acetate succinate and the like, cellulose derivative such as an alkyl cellulose, a hydroxyalkyl cellulose, a hydroxyalkyl alkylcellulose or a cellulose ester with at least one polybasic acid such as succinic acid, maleic acid, phthalic acid, tetrahydrophthalic acid, hexahydrophthalic acid, trimellitic acid or pyromellitic acid; polyvinyl acetate phthalate (PVAP), polyvinyl acetaldiethylamino acetate, shellac, or mixtures thereof. Preferably the pH dependent polymer used is polymethacrylate polymer such as Eudragit® ElOO 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 dry formulation before reconstitution. The first coating composition may constitute about 1% to about 90%, preferably about 10% to about 50% by weight of the total microparticle weight. The additional second coating composition may 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 HCl 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 trivalent 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 pharmaceutically 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, 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, 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® PHlOl, Avicel® PH102, Avicel® PHl 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 hydroxypropyl cellulose, hydroxyethyl 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, polyanhydrides, polyorthoesters, polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terepthalates, polyvinyl alcohols such as polyacrylic acid, polymethacrylic acid, polyvinyl pyrrolidone and polyvinyl alcohol, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polysiloxanes, polyvinyl acetates, polystyrene, polyurethanes, synthetic celluloses, polyacrylic acids, polybutyric acid, polyvaleric 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 zwitterionic surfactant, or combinations thereof. Examples of suitable wetting agents include sodium lauryl sulphate, cetrimide, polyethylene glycols; polyoxyethylene- polyoxypropylene block copolymers known as poloxamer; polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl 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 paraben or propyl paraben; sodium benzoate, cetrimide 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 polymer 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, Iyophilized 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 μm 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 ii) 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) 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.
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 q.s. (lost in processing)
D) Reconstitu table Suspension composition
15. Double Coated Granules 500.00 16. Sodium aIginate(Ke!tone HVCR) 50.00
17. Sodium citrate 1.00
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 (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) Eudragit® RS30D, 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) 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
(vii). 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 (viii). 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 (mg/ 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 q.s. (lost in processing)
B) Coating dispersion-1
6. Eudragit® NE 3OD 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 q.s. (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 (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) 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 methylcellulose phthalate, 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
(vϋ). ix) Sucrose, Xanthan gum, Calcium sulfate, Sodium benzoate, Tween®-80 and Colloidal silica were weighed together and mixed with granules obtained in step (viii). 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-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/ Triethyl Citrate 1.50
8. Talc 8.00
9. Purified water q.s. (lost in processing)
C) Coating dispersion-2
10. Eudragit® ElOO 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. Avicel CL 6I l 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) 1.00
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 (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) 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) Eudragit® ElOO, 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
(vϋ). ix) Sucrose, Avicel CL 61 1 , 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 (viii). 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-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 1.00
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 (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) Tragacanth, 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) 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 (vii). ix) Sorbitol, Carrageenan, Magnesium sulfate, Sodium benzoate, Polyoxyethylene 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® RS3 OD 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)
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 (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, 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 (vii). ix) Sucrose, Dextran, Magnesium sulfate, Sodium benzoate, Tween®-80 and
Colloidal silica were weighed together and mixed well with the granules obtained in step (viii). 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. Triethyl 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 (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) Eudragit® RS30D, 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) 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 (vii). ix) Sucrose, Sodium alginate, Calcium carbonate, Sodium benzoate, Tween®-80, Colloidal silica, Croscarmellose sodium and Magnesium stearate were weighed together and mixed well with the granules obtained in step (viii). x) Final blend obtained in step (ix) was compressed into tablet which is dispersible 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. Microcrystalline cellulose 75.00 33.. HHyyddrrooxxyyeetthhyyll cceelllluulloossee 45.00
4. Polyvinylpyrrolidone 3.75
5. Purified water q.s. (lost in processing)
Coating dispersion-1
6. Hydroxypropyl cellulose 120.00
77.. SStteeaarriicc aacciidd 20.00
8. Talc 60.00
9. Purified water q.s. (lost in processing)
Coating dispersion-2
10. Eudragit® ElOO 106.92
11 11.. SSooddiiuumm llaauurryyll ssuullffaattee 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 microcrystalline cellulose were weighed together and mixed well. ii) Hydroxyethyl cellulose and Polyvinylpyrrolidone 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) 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 (vii). 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.
ExampIe-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
1 1. 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, 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 (vii). ix) The coated granules obtained in step (viii) can be filled into capsules.
Example-9:
5. 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 1 1. 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 well, ii) Hydroxyethyl cellulose and Polyvinylpyrrolidone 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) 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 Taic were weighed and dispersed in Purified water. viii) The coated granules of step (vi) were again coated with coating dispersion of step (vii). ix) The coated granules obtained in step (viii) can be compressed into tablet.
Example-10:
S. No. Ingredient Quantity (mg)
A) Core composition 11.. AAmmooxxiicciilllliinn 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 (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) 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.

Claims

Claims
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).
2. The controlled release pharmaceutical composition comprising microparticles according to claim 1 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).
3. 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 preferably formulated as oral reconstitutable controlled release suspension, which can be reconstituted using a suitable reconstituting medium such as water.
4. 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; antiinflammatory; 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.
5. The controlled release pharmaceutical composition according to claim 4, wherein the active agent is selected from a group comprising paracetamol, ibuprofen, nimesulide, mycophenolate, carbamazepine, chlorpheniramine, phenylpropanolamine, amoxicillin, erythromycin, ciprofloxacin, metformin, tacrolimus, and the like or pharmaceutically acceptable salts, hydrates, polymorphs, esters, and derivatives thereof used either alone or in combination thereof.
6. The controlled release pharmaceutical composition according to claim 1 , wherein the water insoluble polymer is selected from a group comprising pH independent or pH dependent polymer(s) or mixtures thereof
7. The controlled release pharmaceutical composition according to claim 1 or 6, wherein the pH independent polymer is selected from a group comprising alkyl celluloses such as methyl cellulose, hydroxyalkyl celluloses such as hydroxypropyl cellulose and hydroxyethyl cellulose, high molecular weight polyethylene glycols, gelatin, polyvinylimidazoles, polyvinylpyridine N-oxides, copolymers of vinylpyrrolidone with long-chained alpha-olefins, copolymers of vinylpyrrolidone with vinylimidazole, poly(vinylpyrrolidone/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 (semisynthetic), including but not limited to veegum, agar, guar gum, locust bean gum, gum arabic, okra gum, bentonite, arabinoglactin, pectin, tragacanth, scleroglucan, dextran, amylose, amylopectin, and the like or mixtures thereof.
8. The controlled release pharmaceutical composition according to claim 7, wherein the pH independent polymer is water insoluble.
9. The controlled release pharmaceutical composition according to claim 8, wherein the water insoluble pH independent polymer is selected from a group comprising polyacrylate polymers such as Eudragit® NE 3OD, Eudragit® RS, Eudragit® RS 3OD, Eudragit® RL or a cellulosic polymer such as ethylcellulose (Ethocel std 10 cps) or mixtures thereof.
10. The controlled release pharmaceutical composition according to claim 2 or claim 6, wherein the pH dependent polymer is selected from a group comprising polyacrylic and polymethacrylic acids and polyacrylate and methacrylate based polymers, and mixtures thereof, such as Eudragit® ElOO, Eudragit® EPO, Eudragit® L, Eudragit® S; reaction products such as hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), cellulose acetate trimillitate (CAT), hydroxypropyl methylcellulose acetate succinate and the like, cellulose derivative such as an alkyl cellulose, a hydroxyalkyl cellulose, a hydroxyalkyl alkylcellulose or a cellulose ester with at least one polybasic acid such as succinic acid, maleic acid, phthalic acid, tetrahydrophthalic acid, hexahydrophthalic acid, trimellitic acid or pyromellitic acid; polyvinyl acetate phthalate (PVAP), polyvinyl acetaldiethylamino acetate, shellac, or mixtures thereof.
11. The controlled release pharmaceutical composition according to claim 10, wherein the pH dependent polymer is polymethacrylate polymer such as Eudragit® ElOO or Eudragit® EPO.
12. 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.
13. The controlled release pharmaceutical composition according to claim 3, 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 HCl as dissolution media using the USP Apparatus Type-II (paddle) at 50 RPM.
14. The controlled release pharmaceutical composition according to claim 3, wherein the in-situ gelling agent is selected from 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, carrageenan, pectin, acacia gum, dragon gum, hog gum, talha, dextran, and gum arabic and the like, or mixtures thereof.
15. The controlled release pharmaceutical composition according to claim 14, wherein the in-situ gelling agent is sodium alginate.
16. The controlled release pharmaceutical composition according to claim 3, 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, and the like or mixtures thereof.
17. The controlled release pharmaceutical composition according to claim 16, wherein the cross-linking agent is a divalent or trivalent metal cation salt.
18. 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, and the like known to the art used either alone or in combination thereof.
19. The controlled release pharmaceutical composition according to claim 1, wherein the composition may be formulated as an oral dosage form either as a solid, semisolid, or a liquid preparation such as tablets, capsules, patches, powders, granules, dry syrup, suspension, gels, jelly, syrup, elixir, solutions, emulsions, and the like.
20. The controlled release pharmaceutical composition according to claim 19, wherein the composition is a liquid or semisolid oral dosage form such as suspension, paste, jelly, syrup or elixir.
21. 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.
22. 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.
23. The process for the preparation of controlled release pharmaceutical composition according to claim 22, 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.
24. The process for the preparation of controlled release pharmaceutical composition according to claim 22, 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.
25. A method of using the pharmaceutical composition according to claim 1 , which comprises administering to a patient in need thereof an effective amount of the composition.
26. A method of using the pharmaceutical composition according to claim 25, for the treatment of one or more diseases or disorders selected from a group comprising viral infections, bacterial infections, hypertension, treatment of heart failure, management of CNS disorders, epilepsy and various cardiovascular disorders.
27. Use of a composition according to claim 1, for the treatment of one or more diseases or disorders selected from 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.
28. The pharmaceutical compositions substantially as herein described and illustrated by the examples.
29. The processes for the preparation of pharmaceutical compositions substantially as herein described and illustrated by the examples.
PCT/IN2008/000232 2007-04-09 2008-04-08 Controlled release formulation of coated microparticles WO2008122993A1 (en)

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