WO2007105229A1 - Composition pharmaceutique a liberation controlee et procede associe - Google Patents

Composition pharmaceutique a liberation controlee et procede associe Download PDF

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Publication number
WO2007105229A1
WO2007105229A1 PCT/IN2007/000085 IN2007000085W WO2007105229A1 WO 2007105229 A1 WO2007105229 A1 WO 2007105229A1 IN 2007000085 W IN2007000085 W IN 2007000085W WO 2007105229 A1 WO2007105229 A1 WO 2007105229A1
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WIPO (PCT)
Prior art keywords
agent
composition
acid
copolymers
cellulose
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PCT/IN2007/000085
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English (en)
Inventor
Rajesh Jain
Kour Chand Jindal
Sampath Kumar Devarajan
Sanjay Boldhane
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Panacea Biotec Ltd.
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Application filed by Panacea Biotec Ltd. filed Critical Panacea Biotec Ltd.
Priority claimed from IN686DE2006 external-priority patent/IN2006DE00686A/en
Publication of WO2007105229A1 publication Critical patent/WO2007105229A1/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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

  • the present invention relates to novel controlled release pharmaceutical compositions comprising at least one active agent(s), at least one pH dependent polymer(s), at least one pH independent polymer(s), a channel forming agent(s), and optionally other pharmaceutically acceptable excipients.
  • the present invention also describes process for preparation of such compositions and method of using such compositions.
  • the controlled release compositions are useful in providing therapeutically effective levels of active agent(s) for extended periods of time.
  • Epilepsy afflicts millions of people worldwide, and the disease is more common in children than in adults. For the purposes of drug treatment, it is useful to classify patients according to the type of seizure the patient experiences.
  • the generally accepted classification of epileptic seizures comprises partial seizures consisting of focal and local seizures, and generalized seizures consisting of convulsive or non-convulsive seizures. Partial seizures are classified further as simple partial seizures, complex partial seizures, and partial seizures secondarily generalized. Generalized seizures are classified further as absence seizures, atypical absence seizures, myoclonia seizures, clonic seizures, tonic seizures, tonic-clonic and atonic seizures.
  • Antiepileptic drugs are available for treating epilepsies; however there are many shortcomings associated with these drugs.
  • the drugs often are poorly soluble in aqueous and biological fluids, which property makes it difficult to both provide and dispense the drugs from a dosage form in a known dose over an extended time.
  • the drugs also can be extremely hygroscopic and they may liquefy rapidly, which physical-chemical characteristic dictates against their delivery from a dosage form at a controlled rate over a prolonged period of time. Then too, many drugs exhibit a short half-life that can lead to fluctuations in blood antiepileptic drug levels. These properties can interfere with manufacture and the release of the drugs from dosage form and from pharmaceutical compositions; and these shortcomings are serious drawbacks in the management of epilepsies.
  • Lamotrigine, 3,5-diamino-6-(2,3-dichlorophenyl)-l,2,4-triazine is disclosed in US Patent No. 4,602,017.
  • Products comprising lamotrigine are marketed under the trade name LAMICTAL (TM) by the GlaxoSmithKline. Such products are particularly effective for treatment of CNS disorders, particularly epilepsy, pain, oedema, multiple sclerosis and psychiatric indications including bipolar disorders.
  • Lamotrigine is rapidly and completely absorbed after oral administration with negligible first pass metabolism. The absolute bioavailability is about 98%, which is not affected by food.
  • Existing marketed tablet formulations of Lamotrigine provide immediate release of the active.
  • the peak plasma concentrations occur anywhere from 1.4 to 4.8 hours following drug administration.
  • the disadvantage is that the plasma concentration (pharmacokinetic profile (PK)) achieved with conventional tablets is cyclical, with peaks occurring after administration followed by troughs before the next administration of drug.
  • PK pharmacokinetic profile
  • C max increases proportionately from 0.58 to 4.63 ⁇ g/ml, as does the AUC (29.9 to 211.9 mg/L.hr).
  • Acute and chronic studies in humans have suggested that lamotrigine levels of 1-3 ⁇ g/ml are effective in controlling seizures (Betts et al, 1991). Adverse events associated with lamotrigine are typical of antiepileptic drugs, namely dizziness, ataxia, diplopia, somnolence, headache and asthenia.
  • Rash which has occurred in 10% of patients in placebo-controlled trials has led to discontinuation of therapy in 1% of patients (most common cause of discontinuation) (Besag FMC, CNS Drugs 2000). Skin reactions such as Stevens Johnson Syndrome are potentially fatal and the incidence is higher in children. Neurological side effects are normally seen at higher plasma concentrations which are most likely to occur at peak plasma concentrations. Dose reduction and slow dosage escalation are two techniques to overcome these peak time side effects (Binnie et al, 1987).
  • US Publication No. 2004192690 describes a method of treating a CNS disorder which comprises orally administering to a patient a therapeutically effective amount of lamotrigine or a pharmaceutically acceptable derivative thereof in the form of a sustained release formulation comprising a core comprising lamotrigine or a pharmaceutically acceptable derivative thereof, an outer coating covering said core and the said outer coating including one or more orifices.
  • US Patent No. 5698226 discloses a water-dispersible composition comprises 3% to 90% w/w lamotrigine, 0.25 to 40% of pharmaceutically acceptable swellable clay and an additional pharmaceutically acceptable disintegrating agent, said components being present within the granules of the tablet.
  • PCT Publication No. WO03090693 discloses a pharmaceutical composition comprising a plurality of lamotrigine particles having a specific surface area of from about two to about three and a half square meters per gram.
  • Another PCT Publication No. WO2004108067 discloses a programmed drug delivery system comprising a core composition comprising one or more beneficial agents and pharmaceutically acceptable excipients, wherein at least one excipient swells when exposed to an aqueous environment, a coat surrounding the core composition, wherein the coat is impermeable to the beneficial agent and other core components, but may be permeable or impermeable to water, a passageway in the coat, a composition applied so as to cover the passageway, and optionally, an immediate release composition comprising the same or different beneficial agent.
  • WO2005048979 discloses a modified release pharmaceutical composition consisting of casing comprising at least two micro tablets, which are coated with rate controlling agent(s) optionally in combination with auxiliary pharmaceutical excipient(s), wherein the ratio of pharmaceutical active ingredient to total rate controlling agent(s) ranges between 1:0.1 to 1:100 of each micro tablet.
  • Another PCT Publication No. WO2003104192 discloses a multiparticulate controlled release dosage formulation of lamotrigine or a pharmaceutically acceptable salt thereof, which comprises particles, which comprise lamotrigine, a release rate controlling polymer, and a rapidly disintegrating binder, which will allow the particles to rapidly disperse in an aqueous environment.
  • 20030104052 pertains to sustained release oral dosage form for delivering a pharmacologically active agent to the stomach, duodenum, and upper small intestine of a patient with restricted delivery to the lower intestinal tract and colon, the dosage form comprising a therapeutically effective amount of the pharmacologically active agent incorporated in a matrix of at least one biocompatible, hydrophilic polymer.
  • PCT Publication No. WO2004012741 discloses a method of treating a CNS disorder which comprises orally administering to a patient a therapeutically effective amount of lamotrigine or a pharmaceutically acceptable derivative thereof in the form of a sustained release formulation.
  • US Publication No. 20050175700 discloses an oral dosage form comprising an erodible core, which core comprises a pharmaceutically active weak base or a pharmaceutically acceptable salt or solvate thereof; and an erodible coating around said core, which coating comprises one or more openings characterized in that release of the pharmaceutically active weak base or a pharmaceutically acceptable salt or solvate thereof from the dosage form occurs through the said opening(s) by the erosion of said erodible core and through erosion of said erodible coating under pre-determined pH conditions.
  • US Patent No. 3,728,445 describes a method for preparing a shaped, orally administrable medicinal preparation having extended-release characteristics in the gastrointestinal tract which comprises preparing a mixture of a medicament with a solid sugar excipient, said mixture having a particle size of 100 mesh, granulating said mixture by moistening same with a 5 to 30 percent w/v solution of cellulose acetate phthalate in an amount that provides from 5 to 15 percent by weight of said cellulose acetate phthalate based on the weight of the mixture of medicament and excipient, evaporating solvent and recovering granules having a size between about 1/2 and 3 mm in diameter, and compressing the dried granules under high pressure to form an essentially void-free shaped preparation, said preparation including also a calcium or magnesium salt of a higher fatty acid in an amount of between 1/2 to 10 percent by weight based on the weight of the medicament and excipient to provide same with a 1 to 12 hour release pattern, said preparation having a hardness of at least 5
  • It is an objective of the present invention to provide novel controlled release pharmaceutical composition comprising at least one active agent(s), at least one pH dependent polymer(s), at least one pH independent polymer(s) and at least one channel forming agent(s), optionally with other pharmaceutically acceptable excipients.
  • It is an objective of the present invention to provide novel controlled release pharmaceutical composition comprising at least one active agent(s), at least one pH dependent polymer(s) in an amount not less than about 1% by weight of the composition, at least one pH independent polymer preferably a water soluble polymer in an amount not less than about 1% by weight of the composition and a channel forming agent, optionally with other pharmaceutically acceptable excipients.
  • novel controlled release pharmaceutical composition comprising at least one active agent(s), preferably antiepileptic drugs (AEDs), more preferably lamotrigine or its salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms, derivatives or mixtures thereof as active agent, either alone or in combination with other active agent(s), at least one pH dependent polymer in an amount not less than about 1 % by weight of the composition, at least one pH independent polymer in an amount not less than about 1% by weight of the composition, a channel forming agent in an amount preferably not less than about 2% by weight of the composition, optionally with other pharmaceutically acceptable excipients.
  • active agent(s) preferably antiepileptic drugs (AEDs), more preferably lamotrigine or its salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms, derivatives or mixtures thereof as active agent, either alone or in combination with other active agent(s)
  • novel controlled release pharmaceutical composition comprising at least one active agent(s), at least one pH dependent polymer(s), at least one pH independent polymer(s), at least one hydration inhibitor(s) and at least one channel forming agent(s), optionally with other pharmaceutically acceptable excipients.
  • It is another objective of the present invention to provide process for preparation of such composition which comprises of the following steps: i) mixing the active agent(s) with pH dependent polymer(s), pH independent polymer(s) and channel forming agent(s), ii) optionally adding one or more other excipient(s), and iii) formulating the mixture into a suitable dosage form.
  • It is a further objective of the present invention to provide process for the preparation of such novel composition which comprises of the following steps: i) mixing the active agent(s), pH independent polymer(s), channel forming agent(s), and hydration inhibitor(s), ii) granulating the above with the mixture of pH dependent polymer(s) and a suitable solvent, iii) optionally adding one or more other excipient(s), and iv) formulating the mixture into a suitable dosage form.
  • novel compositions of the present invention provide therapeutic concentrations of active agent(s) for extended periods of time.
  • the present invention provides novel controlled release pharmaceutical composition
  • novel controlled release pharmaceutical composition comprising at least one active agent(s), at least one pH dependent polymer(s), at least one pH independent polymer(s) and at least one channel forming agent(s), optionally with other pharmaceutically acceptable excipients.
  • the active agent(s) used in the present invention is preferably an antiepileptic drug (AED), more preferably lamotrigine or its salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms, derivatives or mixtures thereof.
  • AED antiepileptic drug
  • the pH dependent polymer is present in an amount not less than about 1% by weight of the composition.
  • the pH independent polymer is present in an amount not less than about 1% by weight of the composition.
  • the pH independent polymer is preferably a water soluble polymer.
  • the present invention provides novel controlled release pharmaceutical composition wherein the said system releases the active agent(s) predominantly by diffusion mechanism in pH less than about 4.5 to about 5.5 without any substantial deformation of shape; then by both diffusion and erosion mechanisms in pH above about 5.5 to about 8.5, and thereafter predominantly by erosion mechanism to provide therapeutic concentrations of active agent(s) for extended periods of time.
  • the novel controlled release pharmaceutical compositions of the present invention is intended to reduce the adverse effects or side effects of the active agent(s) by controlling the peak plasma concentration (C max ) such that the concentration of the active agent(s) are substantially below the toxic levels at any point of time. Also the steady state concentrations of the active agent(s) do not exhibit substantial fluctuations. The reduced incidence of these neurological side effects is thus intended to improve patient compliance with the therapy.
  • the novel compositions of the present invention release the active agent preferably for a period of about 4-24 hours.
  • the release is based on two mechanisms, firstly by diffusion in pH less than about 5.5 i.e. in acidic environment and then by both diffusion and erosion in pH more than about 5.5 i.e. near neutral aqueous buffer systems.
  • the polymer system preferably used for controlling release rate in the present invention comprises of at least one pH dependent polymer(s) and at least one pH independent but water soluble polymer(s), alongwith a channel forming agent(s) optionally with at least one hydration inhibitor(s).
  • the said system is unique because it provides the desired release profile of the active agent by using two release mechanisms, wherein the channel former(s) creates the micro-channels in the matrix system in both acidic and near neutral aqueous buffer systems, and thus enhances the efficiency of the release mechanisms. Also the desired release profile of the active agent(s) can be obtained with the polymer system of the present invention without any need for a functional coating or any other mechanism like formulation of osmotic systems etc. Moreover, the granulation technique preferably used to formulate the compositions of the present invention is simple and involves low processing cost.
  • the active agent of the present invention is selected from but not limited to a group comprising active agent(s) such as 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-in
  • the active agent of the present invention is an anti-epileptic drug (AED) selected from but not limited to a group comprising phenytoin, mephenytoin, phenobarbital, primidone, carbamazepine, ethosuximide, methsuximide, phensuximide, trimethadione, clonazepam, clorazepate, phenacemide, paramethadione, primaclone, clobazam, felbamate, flunarizine, lamotrigine, progabide, vigabatin, eterobarb, gabapentin, oxcarbazepine, ralitoline, tiagabine, sulthiame and tioridone or pharmaceutically acceptable salts, hydrates, polymorphs, esters, and derivatives thereof used either alone or in combination thereof.
  • AED anti-epileptic drug
  • the pH dependent polymer is selected from but not limited to a group comprising at least one 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 such as hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), cellulose acetate trimillitate (CAT) and hydroxypropyl methylcellulose acetate succinate or mixtures thereof.
  • HPMCP hydroxypropyl methylcellulose phthalate
  • CAP cellulose acetate phthalate
  • CAT cellulose acetate trimillitate
  • PVAP polyvinyl acetate phthalate
  • PVAP polyvinyl acetaldiethylamino acetate
  • shellac Particularly useful are poly acrylic and methacrylic acids and polyacrylate and methacrylate based polymers and copolymers, and mixtures thereof, such as Eudragit®, for example Eudragit® L, Eudragit® S or the like (Rohm-Pharma, Darmstadt, Germany).
  • the pH dependent polymer used is hydroxypropyl methylcellulose phthalate (HPMCP) or Eudragit® L30D-55.
  • HPMCP hydroxypropyl methylcellulose phthalate
  • Eudragit® L30D-55 is present in an amount not less than about 2.5% w/w of the composition, most preferably about 4-40% w/w of the composition.
  • the pH independent polymer is selected from but not limited to a group comprising alkyl celluloses such as methyl cellulose, hydroxyalkyl alkylcelluloses such as hydroxypropyl methylcellulose (Methocel® Kl 5M), hydroxyalkyl celluloses such as hydroxypropyl cellulose (Klucel® HF, Klucel® EXF) and hydroxyethyl cellulose (Natrosol® 250HX, Natrosol® 250G), polyethylene glycols (PEG® 6000, PEG® 10000), copolymers of ethylene oxide with propylene oxide (Poloxamer® 407, Poloxamer® 188 or the like), gelatin, polyvinylpyrrolidones (PVP, —
  • 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, dextrin, cyclodextrins and the like or mixtures thereof.
  • veegum agar, guar gum, locust bean gum, gum arabic, okra gum, bentonite, arabinoglactin, pectin, tragacanth, scleroglucan, dextran, amylose, amylopectin, dextrin, cyclodextrins and the like or mixtures thereof.
  • the pH independent polymer is a water soluble polymer selected from a group comprising hydroxyalkyl celluloses such as hydroxypropyl cellulose and hydroxyethyl cellulose or mixtures thereof.
  • hydroxyethyl cellulose is present in an amount not less than 1% w/w of the composition, most preferably about 2.5-30% w/w of the composition. 5
  • the ratio of the pH dependent polymer and the pH independent polymer is 1:10 to 10:1, preferably 1:5 to 5:1 by weight of the composition.
  • the channel forming agent(s) is selected from but not limited to a group comprising hydrophilic substances, for example, polyglycols, ethyl vinyl alcohols, glycerin, pentaerythritol, polyvinyl alcohols, polyvinyl pyrrolidone, vinyl pyrrolidone, N-methyl pyrrolidone, polysaccharides such as dextrines and/or hydrolyzed starch, saccharides, sugar alcohols and the like or mixtures thereof.
  • Polyglycols such as polyethylene glycol and/or polypropylene glycol are preferred. Saccharides, e.g.
  • lactose, glucose, mannose, galactose, and/or fructose can be used, either alone or in combination thereof.
  • Sugar alcohols such as mannitol, sorbitol, hexitol, dulcitol, xylitol, ribitol, and/or erythrol can be used, either alone or in combination thereof.
  • Starches such as partially gelatinized starch (Starch® 1500) can be used.
  • the channel forming agent used is selected from a group comprising saccharides and/or partially gelatinized starch and the like.
  • the saccharide and/or partially gelatinized starch is present in an amount not less than about 10% w/w of the composition, most preferably about 25-40% w/w of the composition.
  • novel controlled release pharmaceutical composition additionally comprises at least one hydration inhibitor(s).
  • the hydration inhibitor is selected from but not limited to a group comprising stearic acid, glyceryl monostearate, glyceryl behenate
  • Compritol® 888 ATO glyceryl monooleate, glyceryl palmitostearate, microcrystalline wax, stearyl alcohol, cetyl alcohol, cetostearyl alcohol, hydrogenated castor oil, tristearin, waxes, polyvinyl acetates, polyethylenes, polypropylenes, polyamides, ethylene glycol polyterephthalate, polyvinyl chlorides, polyformaldehyde chlorides, polycarbonates, ethylene copolymers, polyethers, polyurethanes, polyacrylonitriles, shellac, rosin, or mixtures thereof.
  • novel controlled release pharmaceutical composition comprising at least one active agent(s), at least one pH dependent polymer(s), combination of two pH independent polymer(s), at least one hydration inhibitor(s) and at least one channel forming agent(s), optionally with other pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients of the present invention are selected from but not limited to a group comprising diluents, disintegrants, binders, mucoadhesive agents, fillers, bulking agents, anti-adherants, anti-oxidants, buffering agents, complexing agents, carriers, colorants, flavoring agents, coating agents, plasticizers, organic solvents, stabilizers, preservatives, lubricants, solubilizers, glidants, chelating 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; Pearlitol® SD200; starch such as starch® 1500; sorbitol; sucrose; glucose, or the like or mixtures thereof.
  • Suitable mucoadhesive agents include for example thiolated polymers (thiomers), glycoproteins, synthetic polymers such as poly (acrylic acid) (PAA), hydroxypropyl methylcellulose and poly (methylacrylate) derivatives, naturally occurring polymers such as hyaluronic acid and chitosans, certain carbohydrates, plant lectins, bacterial adhesins, methylcellulose, sodium carboxymethyl cellulose, carbopol and the like.
  • Suitable solubilizers include for example polyvinyl pyrrolidone, polyethylene glycol, propylene glycol, cyclodextrin and its derivatives, poloxamer, ethylene oxide-propylene oxide copolymer surfactants, polyalkylene glycol and their derivatives, polyoxyethylene alkyl ethers, polyvinylpyrrolidone, and polar solvents or mixtures thereof.
  • Suitable binders include for example starch, povidone, hydroxypropyl methylcellulose, partially pregelatinised starch, hydroxypropyl cellulose or mixtures thereof.
  • Suitable lubricants are selected from but not limited to a group comprising colloidal silicon dioxide (such as Aerosil® 200), talc, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, hydrogenated vegetable oil and the like or mixtures thereof.
  • colloidal silicon dioxide such as Aerosil® 200
  • talc stearic acid
  • magnesium stearate magnesium stearate
  • calcium stearate calcium stearate
  • sodium stearyl fumarate hydrogenated vegetable oil and the like or mixtures thereof.
  • Suitable carrier is selected from but not limited to a group comprising crospovidone, cross-linked polymeric cyclodextrin, dextran, cellulose, alginates, silica gel, titanium dioxide, aluminum oxides; cellulose derivatives such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose; starches such as cross-linked sodium carboxymethyl starch, maize, rice, corn and potato starch, polyethylene glycols; sugars, saccharide such as lactose and dextrose; sugar alcohols, such as sorbitol or mannitol; non-pareil seed such as Microcrystalline Cellulose Spherical Seed Core (celphere®); croscarmellose sodium (Ac-Di-sol®), sodium starch glycolate, polyvinyl alcohol, ascorbic acid, carbopols, polyethylene oxide, mixtures of mono-, di-, and triglycerides with polyethylene glycol (PEG) esters of fatty acids such as Ge
  • Suitable complexing agents include for example cyclodextrin, preferably a beta- cyclodextrin, more preferably a hydroxypropyl beta cyclodextrin and the like, or mixtures thereof
  • Suitable disintegrants include for example crosslinked polyvinyl pyrrolidone, cornstarch, potato starch, maize starch and modified starches, croscarmellose sodium, sodium starch glycollate, or mixtures thereof.
  • a process for the preparation of such novel composition which comprises of the following steps: i) mixing the active agent(s) with pH dependent polymer(s), pH independent polymer(s) and channel forming agent(s), ii) optionally adding one or more other excipient(s), and iii) formulating the mixture into a suitable dosage form.
  • It is a further objective of the present invention to provide process for the preparation of such novel composition which comprises of the following steps: i) mixing the active agent(s), pH independent polymer(s), channel forming agent(s), and hydration inhibitor(s), ii) granulating the above with the mixture of pH dependent polymer(s) and a suitable solvent, iii) optionally adding one or more other excipient(s), and iv) formulating the mixture into a suitable dosage form.
  • the present composition can be formulated by spray drying or lyophilizing the active agent(s) with a suitable solubilizer or low viscosity pH independent polymers to get free flowing powder.
  • active agent is preferably formulated as an aqueous or non-aqueous solution with said solubilizer or pH independent polymers and then spray dried or lyophilized using techniques known to the art to obtain dry powder which is then further processed with other excipient(s) into suitable dosage form.
  • the present composition can be formulated by spray drying or lyophilizing the active agent with complexing agent to make complex.
  • active agent is preferably formulated as an aqueous or non-aqueous solution with said complexing agent and then spray dried or lyophilized using techniques known to the art to obtain dry powder which is then further processed with other excipient(s) into suitable dosage form.
  • the present composition can be formulated by spraying the active agent with binder on to the inert carrier by using fluid bed coater, mixing the granules with the pH dependent polymer(s) and the pH independent polymer(s), optionally adding one or more other excipient(s), and formulating the mixture into a suitable dosage form.
  • the present composition can be formulated by coating the blend or compacted granules comprising an active agent alongwith pH independent but water soluble polymer and channel forming agent by a solution of pH dependent polymer in appropriate solvent, optionally adding one or more other excipient(s), and formulating the mixture into a suitable dosage form.
  • the pharmaceutical composition of the present invention further comprises of a solvent.
  • the solvent used is selected from but not limited to a group comprising water; alcohols such as methanol, ethanol, propanol, isopropyl alcohol, butanol, monomethoxyethanol, ethylene glycol monomethylether and the like; ethers such as diethyl ether, dibutyl ether, diisobutyl ether, dioxane, tetrahydrofuran, ethylene glycol and the like; aliphatic hydrocarbons such as n-hexane, cyclohexane and n- heptane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile and the like; organic acids such as acetic acid, propanoic acid and the like; esters such as ethyl acetate; aliphatic halogenated hydrocarbons such as dichloromethane, dichlor
  • the composition of the present invention is preferably in the form of solid dosage forms such as tablets, capsules, pellets or the like, more preferably as tablets.
  • the tablets can be prepared by either wet granulation, direct compression, or by dry compression (slugging).
  • the oral composition is prepared by wet granulation.
  • the granulation technique is either aqueous or non-aqueous or a suitable combination thereof.
  • the aqueous solvent useful in the present invention is preferably water and the non-aqueous solvent useful in the present invention is selected from a group comprising acetone, ethanol, isopropyl alcohol or methylene chloride, or mixtures thereof.
  • the solvent used is a combination of about 10% aqueous solvent and about 90% non-aqueous solvent or any suitable combinations thereof.
  • the compositions of the present invention are in the form of compressed tablets, moulded tablets, mini-tablets, capsules, pellets, granules and products prepared by extrusion or film cast technique, and the like.
  • the tablets/minitablets may be optionally coated with a nonfunctional coating to form a nonfunctional layer.
  • the nonfunctional coating may be a film coating done by using film forming agents optionally alongwith one or more excipients by using techniques known to the art. Such coating may be done by using aqueous and/or nonaqueous technique(s).
  • the tablets/minitablets may be optionally filled into capsules.
  • compositions comprising antiepileptic drug(s) as the active agent(s) are useful for management of epilepsy and reducing the occurrence of adverse events.
  • Lactose (Pharmatose® DCL21) 200.00
  • Step (i) Lamotrigine, Lactose and Hydroxyethyl cellulose were mixed together and passed through # 40 sieve. ii) Hydroxypropyl methylcellulose phthalate was dissolved in sufficient quantity of acetone. iii) The mixture in Step (i) was granulated with the granulating fluid of Step (ii). iv) The wet mass of Step (iii) was dried and passed through # 30 sieve to get granules. v) The granules of Step (iv) were lubricated with Magnesium stearate and were compressed into tablets.
  • Lactose (Pharmatose® DCL21) 190.00
  • Step (v) Lamotrigine, Lactose and Hydroxypropyl cellulose were mixed together and passed through # 40 sieve.
  • ii) Cellulose acetate phthalate was dispersed in sufficient quantity of Acetone, iii)
  • the mixture in Step (i) was granulated with the granulating fluid of Step (ii).
  • iv) The wet mass of Step (iii) was dried and passed through # 30 sieve to get granules, v) The granules of Step (iv) were lubricated with Zinc stearate.
  • the granules of Step (v) were mixed with Lactose and Hydroxypropyl methylcellulose and were compressed into tablets.
  • Step (i) Oxcarbazepine, Mannitol and Hydroxymethyl cellulose were mixed together and passed through # 40 sieve.
  • ii) Cellulose acetate phthalate and Copolymer of ethylene and propylene oxide were together dispersed in sufficient quantity of Acetone.
  • iii) The blend of Step (i) was granulated by using Step (ii) granulating fluid,
  • iv) The wet mass of Step (iii) was dried and passed through # 30 sieve to get granules, v) The granules of Step (iv) were lubricated with Hydrogenated vegetable oil and compressed into tablets.
  • Step (i) Verapamil, Mannitol, Hydroxypropyl cellulose and Hydroxyethyl cellulose were mixed together and sifted through # 40 sieve.
  • Anionic methacrylate polymer was dissolve in sufficient quantity of Isopropyl alcohol and Dichloromethane.
  • Step (ii) The blend of Step (i) was granulated by using Step (ii) granulating fluid, iv) The wet mass of Step (iii) was dried and passed through # 30 sieve to get granules, v) The granules of Step (iv) were lubricated with Calcium stearate and compressed into tablets.
  • Acetone q.s Procedure Phenytoin sodium, Lactose and Polyvinyl alcohol were mixed together and sifted through # 40 sieve. ii) Cellulose acetate phthalate was dispersed in sufficient quantity of Acetone, iii) The blend of Step (i) was granulated by using Step (ii) granulating fluid. iv) The wet mass of Step (iii) was dried and passed through # 30 sieve to get granules, v) The granules of Step (iv) were lubricated with Calcium stearate and compressed into tablets.

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  • Health & Medical Sciences (AREA)
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  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne de nouvelles compositions pharmaceutiques à libération contrôlée comprenant au moins un agent actif, au moins un polymère dépendant du pH, au moins un polymère indépendant du pH, de préférence hydrosoluble, un agent formant des canaux et éventuellement d'autres excipients pharmaceutiquement acceptables. L'invention concerne également un procédé de préparation de telles compositions et un procédé d'utilisation de telles compositions. Les compositions à libération contrôlées sont utiles pour l'administration de niveaux thérapeutiquement efficaces d'un ou de plusieurs agents actifs pendant des durées prolongées.
PCT/IN2007/000085 2006-03-14 2007-03-07 Composition pharmaceutique a liberation controlee et procede associe WO2007105229A1 (fr)

Applications Claiming Priority (2)

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IN686/DEL/2006 2006-03-14
IN686DE2006 IN2006DE00686A (fr) 2003-09-09 2007-03-07

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009139504A3 (fr) * 2008-05-15 2010-09-30 Otsuka Pharmaceutical Co., Ltd. Formulation pharmaceutique solide
EP2236160A3 (fr) * 2009-03-31 2011-12-14 Sanovel Ilac Sanayi ve Ticaret A.S. Compositions de Dimeboline à libération modifiée
WO2017026950A1 (fr) 2015-08-07 2017-02-16 Santa Farma Ilac San. A. S. Formulations de propivérine à libération contrôlée
CN111107843A (zh) * 2017-06-30 2020-05-05 财团法人工业技术研究院 用于治疗自体免疫神经疾病及/或神经退化性疾病的方法以及用于液体剂型与控制释放剂型的药物制剂
WO2020101586A1 (fr) 2018-11-16 2020-05-22 Santa Farma İlaç Sanayi̇ A.Ş. Formulations de propivérine à libération contrôlée
WO2022115056A1 (fr) 2020-11-27 2022-06-02 Santa Farma Ilac Sanayii A.S. Compositions de formulation à libération prolongée comprenant de la propivérine
CN115381791A (zh) * 2022-09-21 2022-11-25 迪沙药业集团有限公司 一种盐酸氟桂利嗪药物组合物

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Publication number Priority date Publication date Assignee Title
US20040062778A1 (en) * 2002-09-26 2004-04-01 Adi Shefer Surface dissolution and/or bulk erosion controlled release compositions and devices
US20040073996A1 (en) * 2002-10-21 2004-04-22 Hill Eva H. Soft gel interior tub

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040062778A1 (en) * 2002-09-26 2004-04-01 Adi Shefer Surface dissolution and/or bulk erosion controlled release compositions and devices
US20040073996A1 (en) * 2002-10-21 2004-04-22 Hill Eva H. Soft gel interior tub

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009139504A3 (fr) * 2008-05-15 2010-09-30 Otsuka Pharmaceutical Co., Ltd. Formulation pharmaceutique solide
JP2011520774A (ja) * 2008-05-15 2011-07-21 大塚製薬株式会社 固形医薬製剤
KR101585280B1 (ko) * 2008-05-15 2016-01-13 오츠카 세이야쿠 가부시키가이샤 고형 의약 제제
EA022712B1 (ru) * 2008-05-15 2016-02-29 Оцука Фармасьютикал Ко., Лтд. Твердая фармацевтическая композиция
EP2236160A3 (fr) * 2009-03-31 2011-12-14 Sanovel Ilac Sanayi ve Ticaret A.S. Compositions de Dimeboline à libération modifiée
WO2017026950A1 (fr) 2015-08-07 2017-02-16 Santa Farma Ilac San. A. S. Formulations de propivérine à libération contrôlée
CN111107843A (zh) * 2017-06-30 2020-05-05 财团法人工业技术研究院 用于治疗自体免疫神经疾病及/或神经退化性疾病的方法以及用于液体剂型与控制释放剂型的药物制剂
CN111107843B (zh) * 2017-06-30 2024-01-09 财团法人工业技术研究院 化合物用于制备治疗自体免疫神经疾病及/或神经退化性疾病的药物的用途以及其液体剂型与控释剂型的药物制剂
WO2020101586A1 (fr) 2018-11-16 2020-05-22 Santa Farma İlaç Sanayi̇ A.Ş. Formulations de propivérine à libération contrôlée
WO2022115056A1 (fr) 2020-11-27 2022-06-02 Santa Farma Ilac Sanayii A.S. Compositions de formulation à libération prolongée comprenant de la propivérine
CN115381791A (zh) * 2022-09-21 2022-11-25 迪沙药业集团有限公司 一种盐酸氟桂利嗪药物组合物
CN115381791B (zh) * 2022-09-21 2023-06-16 迪沙药业集团有限公司 一种盐酸氟桂利嗪药物组合物

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