FIELD OF THE INVENTION
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.
BACKGROUND OF THE INVENTION
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. For instance, 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. In particular for the treatment of epilepsy it is speculated that the troughs may lead to breakthrough seizures and the peak plasma concentration may result in some adverse events.
Over the range 50 to 400 mg as a single dose, Cmax increases proportionately from 0.58 to 4.63 Hg/rnl, 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 |ag/ml are effective in controlling seizures (Belts et al, 1991). Adverse events associated with lamotrigine are typical of antiepileptic drugs, namely dizziness, ataxia, diplopia, somnolence, headache and asthenia. The incidence of such side effects is around 10% (Ramsay RE, 1991); overall, 8.6% of patients were removed from clinical trials because of adverse experiences that included, in addition to rash, nausea/vomiting and intolerable episodes of the CNS-related events (Ramsay RE, 1991; Goa K L et al, 1993). Serious skin reactions (including Steven Johnson Syndrome and Toxic Epidermal Necrolysis) occurring in patients taking lamotrigine was highlighted by the Committee of Safety Medicine (CSM) in 1997 and has subsequently been discussed in the literature (Mitchell P, 1997; Anon., Drug and Therapy Perspectives, 1998). 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. Another PCT Publication No. 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.
US Publication No. 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 credible core and through erosion of said credible 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 kilograms as measured on a hardness tester of U. S. Pharmacopeia specification.
Several attempts to provide dosage forms for delivery of active agent for extended periods of time have been described previously. However, there still exists a need to develop effective controlled release dosage form compositions having reduced side effects which can provide sustained delivery of active agent, that are easier to manufacture, and involves a low formulation cost. The present invention provides such novel controlled release compositions.
SUMMARY OF THE INVENTION
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.
It is also an objective of the present invention to provide 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.
It is also 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), 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.
It is yet another objective of the present invention to provide a method of using such composition which comprises administering to a subject in need thereof an effective amount of the composition.
The novel compositions of the present invention provide therapeutic concentrations of active agent(s) for extended periods of time.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides 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.
In an embodiment, 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.
In another embodiment of the present invention, the pH dependent polymer is present in an amount not less than about 1% by weight of the composition. In another embodiment, the pH independent polymer is present in an amount not less than about 1% by weight of the composition. In yet another embodiment, the pH independent polymer is preferably a water soluble polymer.
In a preferred embodiment, 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.
In an embodiment, 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 (Cmax) 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.
In an embodiment, 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-infective; anti-inflammatory; antimicrobial; antimigraine; antimitotic; antimycotic, antinauseant, antineoplastic, antineutropenic, antiparasitic; antiproliferative; antipsychotic; antirheumatic; antiseborrheic; antisecretory; antispasmodic; antithrombotic; anti-ulcerative; antiviral; appetite suppressant; blood glucose regulator; bone resorption inhibitor; bronchodilator; cardiovascular agent; cholinergic; depressant; diagnostic aid; diuretic; dopaminergic agent; estrogen receptor agonist; fibrinolytic; fluorescent agent; free oxygen radical scavenger; gastric acid supressant; gastrointestinal motility effector; glucocorticoid; hair growth stimulant; hemostatic; histamine H2 receptor antagonists; hormone; hypocholesterolemic; hypoglycemic; hypolipidemic; hypotensive; imaging agent; immunizing agent; immunomodulator; immunoregulator; immunostimulant; immunosuppressant; keratolytic; LHRH agonist; mood regulator; mucolytic; mydriatic; nasal decongestant; neuromuscular blocking agent; neuroprotective; NMDA antagonist; non-hormonal sterol derivative;
plasminogen activator; platelet activating factor antagonist; platelet aggregation inhibitor; psychotropic; radioactive agent; 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; Paget's disease agent; unstable angina agent; vasoconstrictor; vasodilator; wound healing agent; xanthine oxidase inhibitor or mixtures thereof.
Preferably 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.
In an embodiment of the present invention, 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. Also considered useful in the practice of the present invention are for example those selected from the group consisting of polyvinyl acetate phthalate (PVAP), polyvinyl acetaldiethylamino acetate, and 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). Preferably the pH dependent polymer used is hydroxypropyl methylcellulose phthalate (HPMCP) or Eudragit® L30D-55. Preferably hydroxypropyl methylcellulose phthalate (HPMCP) or 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.
In an embodiment of the present invention, 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® K15M), 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, Kollidon® 12PF, Kollidon® 17PF, Kollidon®
K15, Kollidon® K30, Kollidon® K90), vinylpyrrolidones, vinyl acetates, polyvinylimidazoles,
polyvinylpyridine N-oxides, copolymers of vinylpyrrolidone with long-chained alpha-olefins,
copolymers of vinylpyrrolidone with vinylimidazole, poly(vinylpyrrolidone/dimethylaminoethyl
methacrylates), 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, polycarboxylic acids, polyacrylamides, polyvinyl alcohols (PVA, Mowiol® 40-88), optionally hydrolysed polyvinyl acetate, 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, dextrin, cyclodextrins and the like or mixtures thereof.
Preferably 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. Preferably the 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.
In a preferred embodiment of the present invention, 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.
In the present invention, 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. Preferably the channel forming agent used is selected from a group comprising saccharides and/or partially gelatinized starch and the like. Preferably 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.
In a preferred embodiment, novel controlled release pharmaceutical composition additionally comprises at least one hydration inhibitor(s).
In an embodiment of the present invention, 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.
In preferred embodiment, 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® PH101, Avicel® PH102, Avicel® PHI 12, Avicel® PH200, Avicel® PH301 and Avicel® PH302; lactose such as lactose monohydrate, lactose anhydrous and Pharmatose® DCL21, including anhydrous, monohydrate and spray dried forms; dibasic calcium phosphate such as Emcompress®; mannitol; 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.
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 Gelucires, and the like or mixtures thereof.

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.
In an embodiment of the present invention is provided 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.
In a further embodiment, 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. In an embodiment, 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.
In a further embodiment, the present composition can be formulated by spray drying or lyophilizing the active agent with complexing agent to make complex. In an embodiment, 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.
In a further embodiment, 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.
In a further embodiment, 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.
In an embodiment, 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, dichloroethane, chloroform and the like; ketones such as acetone, methyl ketone and the like; amides such as dimethylformamide, dimethyl acetamide and the like; or suitable mixtures thereof.
In a further embodiment, 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). In a preferred embodiment of the present invention, 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. Preferably the solvent used is a combination of about 10% aqueous solvent and about 90% non-aqueous solvent
or any suitable combinations thereof. In an embodiment, 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. Preferably 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 non-aqueous technique(s). The tablets/minitablets may be optionally filled into capsules.
In yet another embodiment of the present invention is provided a method of using such novel controlled release compositions. The compositions comprising antiepileptic drug(s) as the active agent(s) are useful for management of epilepsy and reducing the occurrence of adverse events.
The examples given below serve to illustrate embodiments of the present invention. However they do not intend to limit the scope of present invention.
EXAMPLES
Example 1
S. No. Ingredient mg/tablet
1. Lamotrigine 200.00
2. Lactose (Pharmatose® DCL21) 12.38
3. Partially pregelatinised starch (Starch® 1500) 75.00
4. Glyceryl behenate (Compritol® 888ATO) 150.00
5. Hydroxyethyl cellulose (Natrosol® 250G) 25.00
6. Hydroxy Propyl Cellulose (Klucel® EXF) 25.00
7. Copolymer of methacrylic acid & Ethyl acrylate (Eudragit® L30D 55) 20.00
8. Magnesium stearate 5.13
9. Purified water q.s.
Procedure:
i) Lamotrigine, Lactose, Hydroxy ethyl cellulose, Hydroxy propyl cellulose, pregelatinised starch and Glyceryl behenate were mixed together and passed through #40 sieve and mixed.
ii) Copolymer of methacrylic acid & Ethyl acrylate was added in sufficient quantity of purified water.
iii) The blend of step (i) was granulated using granulating fluid of step (ii) and the wet mass was passed through #12 followed by #22 sieves.
iv) The wet mass of Step (iii) was dried.
v) The granules of Step (iv) were lubricated with Magnesium stearate and were compressed into tablets.
Example 2
S. No. Ingredient mg/tablet
1. Lamotrigine 200.00
2. Lactose (Pharmatose® DCL21) 200.00
3. Hydroxyethyl cellulose 25.00
4. Hydroxypropyl methylcellulose phthalate 70.00
5. Magnesium stearate 5.00
6. Acetone q.s
Procedure:
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.
Example 3
S. No. Ingredient mg/tablet
1. Lamotrigine 200.00
2. Lactose (Pharmatose® DCL21) 190.00
3. Hydroxypropyl cellulose 25.00
4. Cellulose acetate phthalate 80.00
5. Zinc stearate 5.00
6. Acetone q.s
Extra granular Ingredient
7. Lactose 25.00
8. Hydroxypropyl methylcellulose (Methocel® E5) 25.00
Procedure:
i) 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.
vi) The granules of Step (v) were mixed with Lactose and Hydroxypropyl methylcellulose and were compressed into tablets.
Example 4
S. No. Ingredient mg/capsule
1. Gabapentin 100.0
2. Dibasic calcium phosphate (Emcompress®) 152.5
3. Hydroxypropyl cellulose 120.0
4. Polyvinylpyrrolidone 20.0
5. Hydroxypropyl methylcellulose phthalate 90.0
6. Beta cyclodextrin 10.0
7. Sodium stearyl fumarate 7.5
8. Acetone q.s.
Procedure:
i) Gabapentin, Dibasic calcium phosphate, Polyvinylpyrrolidone and Hydroxypropyl cellulose
were mixed together and passed through # 40 sieve, ii) Hydroxypropyl methylcellulose phthalate and Beta cyclodextrin were together dissolved 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 Sodium stearyl fumarate and filled into
capsules.
Example 5
S. No. Ingredient mg/tablet
1. Oxcarbazepine 150.0
2. Mannitol 205.0
3. Hydroxymethyl cellulose 30.0
4. Cellulose acetate phthalate 50.0
5. Copolymer of ethylene and propylene oxide 10.0
(Poloxamer 407)
6. Hydrogenated vegetable oil 5.0
7. Acetone q-s
Procedure:
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.
Example 6
S. No. Ingredient mg/tablet
1. Verapamil 240.0
2. Mannitol 250.0
3. Hydroxypropyl cellulose 10.0
4. Hydroxyethyl cellulose 20.0
5. Anionic methacrylate polymer 60.0
6. Calcium stearate 5.0
7. Isopropyl alcohol q.s
8. Dichloromethane q.s
Procedure:
i) Verapamil, Mannitol, Hydroxypropyl cellulose and Hydroxyethyl cellulose were mixed
together and sifted through # 40 sieve, ii) Anionic methacrylate polymer was dissolve in sufficient quantity of Isopropyl alcohol and
Dichloromethane.
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.
Example 7
S. No. Ingredient mg/tablet
1. Phenytoin sodium 100.0
2. Lactose (Pharmatose® DCL21) 200.0
3. Polyvinyl alcohol 60.0
4. Cellulose acetate phthalate 25.0
5. Calcium stearate 5.0
6. Acetone q.s
Procedure:
i) 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.

We Claim:
1. A 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 channel forming agent(s), optionally at least one hydration inhibitor(s) and
optionally other pharmaceutically acceptable excipients.
2. The composition as claimed in claim 1, wherein the ratio of the pH dependent polymer(s)
and the pH independent polymer(s) is 1:10 to 10:1.
3. The composition as claimed in claim 1, wherein the active agent is selected from 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 its pharmaceutically acceptable salts, hydrates,
polymorphs, esters, and derivatives thereof.
4. The composition as claimed in claim 3, wherein the active agent is lamotrigine or
pharmaceutically acceptable salts, hydrates, polymorphs, esters, and derivatives thereof.
5. The composition as claimed in claim 1, wherein the pH dependent polymer is selected
from a group comprising 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, cellulose acetate phthalate, cellulose acetate trimillitate and
hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, polyvinyl
acetaldiethylamino acetate, shellac, poly acrylic & methacrylic acids and polyacrylate &
methacrylate based polymers and copolymers used either alone or in combination thereof.
6. The composition as claimed in claim 1, wherein the pH independent polymer is selected
from the group comprising alkyl celluloses such as methyl cellulose, hydroxyalkyl
alkylcelluloses such as hydroxypropyl methylcellulose, hydroxyalkyl celluloses such as
hydroxypropyl cellulose and hydroxyethyl cellulose, polyethylene glycols, copolymers of
ethylene oxide with propylene oxide, gelatin, polyvinylpyrrolidones, vinylpyrrolidones,
vinyl acetates, polyvinylimidazoles, polyvinylpyridine N-oxides, copolymers of
vinylpyrrolidone with long-chained alpha-olefins, copolymers of vinylpyrrolidone with
vinylimidazole, poly(vinylpyrrolidone/dimethylaminoethyl methacrylates), 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, polycarboxylic acids, polyacrylamides, polyvinyl alcohols, optionally hydrolysed polyvinyl acetate, 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, bentonite, arabinoglactin, pectin, tragacanth, scleroglucan, dextran, amylose, amylopectin, dextrin, cyclodextrins, or mixtures thereof.
7. The composition as claimed in claim 1, wherein the channel forming agent is selected
from a group comprising polyglycols, ethyl vinyl alcohols, glycerin, pentaerythritol,
polyvinyl alcohols, polyvinyl pyrrolidone, vinyl pyrrolidone, N-methyl pyrrolidone,
polysaccharides, hydrolyzed starch, pregelatinized starch, saccharides, sugar alcohols and
the like or mixtures thereof.
8. The composition as claimed in claim 1, wherein the hydration inhibitor is selected from a
group comprising stearic acid, glyceryl monostearate, glyceryl behenate, 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, and the like or mixtures thereof.
9. The composition as claimed in claim 1, wherein the pharmaceutically acceptable
excipients are selected from 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, used either alone or in combination thereof.
10. A process of preparation of the composition as claimed in claim 1, 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.
11. A process for the preparation of the composition as claimed in claim 1 , 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 material of step (i) 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.
12. The pharmaceutical compositions and processes for the preparation of pharmaceutical
compositions substantially as herein described and illustrated by the examples.