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WO2008122993A1 - Formulation de microparticules enrobées à libération contrôlée - Google Patents

Formulation de microparticules enrobées à libération contrôlée 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
Prior art date
Application number
PCT/IN2008/000232
Other languages
English (en)
Inventor
Rajesh Jain
Kour Chand Jindal
Sanjay Boldhane
Original Assignee
Panacea Biotec Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Panacea Biotec Limited filed Critical Panacea Biotec Limited
Publication of WO2008122993A1 publication Critical patent/WO2008122993A1/fr

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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.

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Abstract

L'invention concerne des compositions à libération contrôlée comprenant : des microparticules qui renferment un noyau et au moins un enrobage, le noyau comprenant au moins un agent actif, facultativement au moins un polymère hydrosoluble et facultativement un ou plusieurs excipients pharmaceutiquement acceptables; et au moins un enrobage renfermant au moins un polymère indépendant du pH ainsi qu'un ou plusieurs excipients pharmaceutiquement acceptables. De préférence, les compositions pharmaceutiques à libération contrôlée de l'invention comprennent des microparticules et au moins un agent de gélification in situ, au moins un agent de réticulation et facultativement un ou plusieurs excipients pharmaceutiquement acceptables, lesdites compositions étant formulées sous la forme de suspensions pharmaceutiques orales à libération contrôlée reconstituables, qui peuvent être reconstituées à l'aide d'un milieu de reconstitution adéquat tel que l'eau. L'invention se rapporte en outre à un procédé de préparation desdites compositions et à un procédé d'utilisation de ces dernières.
PCT/IN2008/000232 2007-04-09 2008-04-08 Formulation de microparticules enrobées à libération contrôlée WO2008122993A1 (fr)

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WO2010089772A3 (fr) * 2009-01-22 2010-10-14 Piramal Healthcare Ltd. Composition pharmaceutique chronothérapeutique
EP1957051A4 (fr) * 2005-11-14 2011-07-06 Teijin Pharma Ltd Comprime se desintegrant rapidement par voie orale
WO2011107855A2 (fr) 2010-03-04 2011-09-09 Torrent Pharmaceuticals Limited Forme dosifiée sous forme de suspension liquide à libération prolongée pour une administration par voie orale
WO2013106824A1 (fr) * 2012-01-13 2013-07-18 Board Of Regents, The University Of Texas System Agents ciblant les récepteurs des éphrines
WO2014059512A1 (fr) * 2012-10-15 2014-04-24 Isa Odidi Formulations de médicament pour administration par voie orale
US8771656B2 (en) 2011-12-14 2014-07-08 Avon Products, Inc Long-lasting easy wash-off cosmetic compositions
US8802139B2 (en) 2003-06-26 2014-08-12 Intellipharmaceutics Corp. Proton pump-inhibitor-containing capsules which comprise subunits differently structured for a delayed release of the active ingredient
US20150110871A1 (en) * 2014-06-02 2015-04-23 David Wong Gastric retentive tablet compositions
US9078827B2 (en) 2006-05-12 2015-07-14 Isa Odidi Pharmaceutical composition having reduced abuse potential
US9132096B1 (en) 2014-09-12 2015-09-15 Alkermes Pharma Ireland Limited Abuse resistant pharmaceutical compositions
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US9795569B2 (en) 2013-03-15 2017-10-24 Allergan Pharmaceuticals International Limited Pharmaceutical soft gelatin capsule dosage form with modified guar gum
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US10238803B2 (en) 2016-05-02 2019-03-26 Sun Pharmaceutical Industries Limited Drug delivery device for pharmaceutical compositions
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US10285908B2 (en) 2014-07-30 2019-05-14 Sun Pharmaceutical Industries Ltd Dual-chamber pack
US10369078B2 (en) 2016-05-02 2019-08-06 Sun Pharmaceutical Industries Limited Dual-chamber pack for pharmaceutical compositions
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CN115998705A (zh) * 2022-08-26 2023-04-25 苏州弘森药业股份有限公司 一种非布司他纳米包合物的制备方法

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US10300021B2 (en) 2005-11-14 2019-05-28 Teijin Pharma Limited Intraorally rapidly disintegrating tablet
US10064828B1 (en) 2005-12-23 2018-09-04 Intellipharmaceutics Corp. Pulsed extended-pulsed and extended-pulsed pulsed drug delivery systems
US9561188B2 (en) 2006-04-03 2017-02-07 Intellipharmaceutics Corporation Controlled release delivery device comprising an organosol coat
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