Patent Application
20100297195
The present invention relates to controlled release formulations comprising lamotrigine and a process for the preparation thereof.
Lamotrigine is an antiepileptic drug (AED) of the phenyltriazine class. Its chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine, which is structurally designated as:
U.S. Pat. No. 4,602,017 and European Patent No. 0 021 121 disclose lamotrigine or a pharmaceutically acceptable salt thereof, and also methods of treating convulsions and epilepsy. It also describes process of preparation of lamotrigine. Lamotrigine is indicated for use as adjunctive therapy for partial seizures, the generalized seizures of Lennox-Gastaut syndrome, and primary generalized tonic-clonic seizures in adults and pediatric patients (≧2 years of age). It is also indicated for conversion to monotherapy in adults with partial seizures who are receiving treatment with carbamazepine, phenyloin, phenobarbital, primidone, or valproate as the single AED. Further, it is indicated for the maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy.
Oral immediate release and chewable dispersible tablet formulations of lamotrigine are commercially available in the United States of America under the brand names Lamictal® and Lamictal® CD, respectively, from GlaxoSmithKline, USA. Lamotrigine is rapidly and completely absorbed after oral administration with negligible first-pass metabolism (absolute bioavailability is 98%). The bioavailability is not affected by food. Peak plasma concentrations occur anywhere from 1.4 to 4.8 hours following drug administration. It has been observed and well documented in the art that the existing marketed formulations of lamotrigine (immediate release compositions) lead to severe side-effects, primarily to the rapid increase in blood plasma levels after each dosing. It fact, serious rashes requiring hospitalization and discontinuation of treatment have been reported in association with the use of Lamictal®. To ameliorate the drawbacks associated with conventional immediate release formulations, lamotrigine is formulated into a controlled release once-daily dosage form which is available in the USA, as Lamictal® XR extended release tablets from GlaxoSmithKline Inc.
U.S. Publication No. 2004/0043996 discloses a multiparticulate controlled release formulation, which comprises particles of lamotrigine, a release rate controlling polymer, and a rapidly disintegrating binder, which allows the particles to rapidly disperse in an aqueous environment.
U.S. Publication No. 2004/0192690 describes a sustained release tablet formulation comprising: (i) a matrix core containing lamotrigine and a release retarding swellable and/or gellable polymer, and optionally, (ii) a semi-permeable barrier coating thereby allowing diffusion control of drug release by water insoluble polymer or a partially water soluble polymer, wherein the said outer barrier includes of one or more orifices extending from the outside of the coating substantially completely through said coating but not penetrating said core. Such orifices are generally drilled into the tablet by removing certain portions of the coating; typically the orifices can be produced by mechanical drilling, ultrasonic cutting or laser. The orifices can be any shape, for example oval, round, square or even shaped as text, for example a company logo. Such a formulation is referred as DiffCORE® device. Such devices are also described in U.S. Pat. No. 5,004,614.
U.S. Publication No. 2009/0022789 discloses formulations which comprise lamotrigine admixed with a release-equalizing composition comprising a pharmaceutically acceptable organic acid and a release-enhancing polymer, which may be an enteric polymer. Such formulations further contain a release retarding polymer and exhibit a significantly similar rate of release with a similarity factor of at least 50 through the gastrointestinal tract.
In the present case, the inventors have prepared controlled release formulations of lamotrigine using different techniques other than those discussed in the art to formulate a dosage form which manifests fewer side-effects, is patient compliant and can be easily manufactured.
In one general aspect, the present invention provides for a controlled release formulation, which includes: a) a core comprising of lamotrigine and a hydrophilic rate controlling agent; b) a coating comprising of a pH-dependent polymer and a permeation enhancer; and c) a topcoat comprising of lamotrigine in immediate release form, wherein said coating does not include any orifice.
Embodiments of the present invention may include one or more of the following features. For example, the formulation delivers a therapeutically effective amount of lamotrigine for at least up to 20 hours following a once-daily administration. The formulation is in the form of a unit dosage form.
The present formulation exhibits the following in vitro dissolution profile when measured in a USP type II apparatus with alternate sinkers, at 75 rpm, at a temperature of 37° C.±0.5° C. in 900 mL of 0.1 N hydrochloric acid for the first 2 hours followed by media replacement with pH 6.8 phosphate buffer medium: a) not more than about 15% drug released in 2 hours; b) not more than about 40% drug released in 4 hours; and c) not more than about 60% drug released in 8 hours.
The hydrophilic rate controlling agent may be alkylcelluloses; hydroxyalkyl alkylcelluloses; carboxyalkylcelluloses; alkali metal salts of carboxyalkylcelluloses; carboxyalkyl alkylcelluloses; carboxyalkylcellulose esters; other natural, semi-synthetic, or synthetic polysaccharides and gums; polyacrylic acids and the salts thereof; polymethacrylic acids and the salts thereof, methacrylate copolymers; polyvinylalcohol; polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate; combinations of polyvinylalcohol and polyvinylpyrrolidone; polyalkylene oxides; and combinations thereof. For example, the hydrophilic rate controlling agent is hydroxypropyl methylcellulose.
The pH-dependent polymer may be one or more of cellulose acetate phthalate; cellulose acetate trimelliate; hydroxypropyl methylcellulose phthalate; hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate; acrylic acid polymers and copolymers; polymers and copolymers of methacrylic acid and methacrylates, and the like.
The permeation enhancer may be one or more of pore-forming agents, water-soluble compounds and hydrophilic polymers, and the like. For example, the permeation enhancer is polyvinylpyrrolidone, lactose or hydroxypropyl methylcellulose.
The core includes lamotrigine in an amount of at least about 80% (w/w) of the total amount of lamotrigine in the formulation. The amount of hydrophilic rate controlling agent is from about 5% to about 80% (w/w) of the total weight of the formulation. The amount of pH-dependent polymer is from about 1% to about 25% (w/w) of the total weight of the formulation.
The topcoat further of the controlled release formulation may include one or more of hydrophilic polymers, disintegrants and superdisintegrants, diluents, and binders.
The term “controlled release formulation” as referred to herein is defined to mean oral pharmaceutical formulations which when administered releases the active medicament at a relatively constant rate and provides plasma concentrations of the active medicament that remain substantially invariant with time within the therapeutic range of the active medicament over a 24-hour period and encompasses “prolonged release”, “extended release”, modified release”, “delayed release” and “sustained release” formulations. The formulations as described herein deliver a therapeutically effective amount of lamotrigine to a patient for at least up to 20 hours following a once-daily administration. The term “therapeutically effective amount” is an amount of the active agent which stops or reduces the progress of the condition to be treated or which otherwise completely or partly cures or acts palliatively on the condition. Lamotrigine or a pharmaceutically acceptable salt or derivative thereof may be present from an amount of about 1 mg to about 500 mg in the controlled release formulation. Particularly, the controlled release formulation may comprise lamotrigine or a pharmaceutically acceptable salt or derivative thereof in an amount of 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and/or 300 mg. The recommended dose of Lamictal® XR may also be considered as a standard dose.
The controlled release formulation includes a coating, such that the coating does not include any orifice. The term “orifice” as described herein refers to holes, slits, outlets, cracks, apertures, gaps or channels formed mechanically or in situ in the coating which assists in the release of drug from the core.
The “hydrophilic rate controlling agent” as disclosed herein includes without limitation those agents that swell and/or gel in aqueous media. Hydrophilic rate controlling agents suitable for use in the core include alkylcelluloses such as methylcellulose; hydroxyalkylcelluloses, for example, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxybutylcellulose; hydroxyalkyl alkylcelluloses such as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose; carboxyalkylcelluloses such as carboxymethylcellulose; alkali metal salts of carboxyalkylcelluloses such as sodium carboxymethylcellulose; carboxyalkyl alkylcelluloses such as carboxymethyl ethylcellulose; carboxyalkylcellulose esters; other natural, semi-synthetic, or synthetic polysaccharides such as alginic acid, alkali metal and ammonium salts thereof, carrageenans, galactomannans, tragacanth, agar-agar, gum arabic, guar gum, xanthan gum, starches, pectins, such as sodium carboxymethyl amylopectin, chitin derivates such as chitosan, polyfructans, inulin; polyacrylic acids and the salts thereof; polymethacrylic acids and the salts thereof, methacrylate copolymers; polyvinylalcohol; polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate; combinations of polyvinylalcohol and polyvinylpyrrolidone; polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide; and combinations thereof. In one embodiment, the hydrophilic rate controlling agent(s) are the alkyl celluloses, like hydroxypropyl methylcellulose. Suitable types are sold under the trade name of Methocel® by The Dow Chemical Company, such as Methocel® E4M Premium CR, Methocel® K100LV Premium CR, Methocel® K4M, Methocel® K15M, and combinations thereof.
The amount of hydrophilic rate controlling agent may vary from about 1% (w/w) to about 90% (w/w) of the core. The amount of hydrophilic rate controlling agent in the core may vary from about 5% to about 80% by weight of the total weight of the formulation, in particular from about 5% to about 70%, preferably from about 5% to about 50% by weight of the total weight of the formulation.
The core includes lamotrigine in an amount of at least about 80% by weight of the total amount of lamotrigine in the controlled release formulation as described herein.
The core of the controlled release formulation as described herein may further include one or more of other pharmaceutically acceptable excipient(s). The term “pharmaceutically acceptable excipient(s)” as recited herein includes conventional pharmaceutical additives known in the art, such as diluent(s), binder(s), lubricants(s), granulating solvent(s), glidants(s) or combinations thereof.
Suitable diluents include saccharides like lactose, dextrose, sucrose, fructose, maltose; sugars like mannitol, erythritol, sorbitol, xylitol and lactitol; cellulose derivatives like powdered cellulose, microcrystalline cellulose; dicalcium phosphate, tribasic calcium phosphate, calcium sulphate, calcium carbonate, kaolin and the like.
Suitable binders include starch derivatives like corn starch and pregelatinized starch; cellulose ethers such as carboxymethyl cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose; carboxy vinyl polymers like carbomers; acrylates such as Eudragits; polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer; xanthan gum, guar gum and other such materials routinely used in the art of solid dosage form manufacturing.
Suitable lubricants include magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, powdered stearic acid, magnesium oleate, calcium palmitate, potassium laureate, sodium suberate, vegetable oil, mineral oil and the like. Glidants may be selected from talc, colloidal silicon dioxide, corn starch and the like.
Suitable granulating solvents include water, ethanol, methanol, isopropyl alcohol, methylene chloride, acetone, and solutions of binder in these solvents.
The core may further include pharmaceutically acceptable acid or combinations thereof, wherein such an acid may be selected from adipic acid, ascorbic acid, isoascorbic acid, fumaric acid, citric acid, malic acid, succinic acid, tartaric acid, and the like.
Suitable “pH-dependent polymers” include cellulose acetate phthalate; cellulose acetate trimelliate; hydroxypropyl methylcellulose phthalate; hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate; acrylic acid polymers and copolymers; polymers and copolymers of methacrylic acid and methacrylates (e.g. those available under the trade name Eudragit® from Evonik-Degussa). One or more of such pH-dependent polymers may be incorporated in the said coating. In one embodiment, methacrylate based polymers (e.g. Eudragit® L100-55 and Eudragit® L30D-55) are used.
The amount of pH-dependent polymer in the formulation may be present in an amount of from about 1% (w/w) to about 25% (w/w) of the total weight of the controlled release formulation. The pH-dependent polymer may be present in an amount of from about 1% (w/w) to about 95% (w/w) of the coating composition.
The coating composition as described herein may further include one or more of permeation enhancers, plasticizers, coloring agents, anti-tacking agents, lubricants/glidants, solvents and other conventionally used coating additives.
Suitable permeation enhancers includes pore-forming agent(s), water-soluble compounds and hydrophilic polymers, and may be selected from alkali metal salts, e.g. sodium chloride, sodium bromide and the like; alkaline earth metals, e.g. calcium phosphate, calcium nitrate and the like; transition metal salts, e.g. ferric chloride, ferrous sulfate and the like; polyglycols; ethyl vinyl alcohols; glycerin; pentaerythritol; polyvinyl alcohols; vinylpyrrolidone; N-methylpyrrolidone; saccharides; hydrolyzed starch; pregelatinized starch; carbohydrates, for e.g. glyceraldehydes, erythrose, ribose, arabinose, xylose, glucose, mannose, galactose, maltose, lactose, sucrose and the like; and sugar alcohols, e.g. mannitol and the like. Hydrophilic polymer(s) that may be used as a permeation enhancer may include hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone and the like.
Suitable plasticizers include dibutyl sebacate, polyethylene glycol, triethyl citrate, triacetin, acetylated triacetin, tributyl citrate, glycerol tributyrate, natural, semi-synthetic and synthetic glycerides, monoglyceride, acetylated monoglycerides, fractionated coconut oil, rape oil, olive oil, sesame oil, castor oil, hydrogenated castor oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol, diethyl oxalate, diethyl phthalate, dibutyl phthalate, diethyl malate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, and the like.
Suitable anti-tacking agents include adipic acid, magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, Sterotex®, glyceryl monostearate, talc, silica, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and the like.
The coating composition may further include one or more solvents. Suitable solvents for the coating composition may include isopropyl alcohol (IPA), water, methylene chloride and mixtures thereof. Various combinations of solvents may be used such as isopropyl alcohol and water, isopropyl alcohol and methylene chloride and the like.
The controlled release formulation may further be coated with a topcoat of lamotrigine in an immediate release form, wherein the active ingredient is released immediately upon ingestion and thus ensures a rapid onset of action.
The amount of lamotrigine present in the topcoat is at least about 5% by weight of the total amount of lamotrigine present in the controlled release formulation as referred to herein.
The topcoat may further include one or more of hydrophilic polymer(s), disintegrant(s), superdisintegrant(s), diluent(s), binder(s) and other conventionally used pharmaceutically acceptable excipients as described herein.
Suitable disintegrants and superdisintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, guar gum, magnesium aluminium silicate, sodium starch glycolate, corn starch, potato starch, pregelatinized starch, low-substituted hydroxypropylcellulose, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, and methacrylic acid divinylbenzene copolymer salts.
The controlled release formulation may further include a non-functional coating. The non-functional coating may include any pharmaceutically acceptable colourants or opacifiers including water soluble dyes, aluminium lakes of water soluble dyes and inorganic pigments such as titanium dioxide and iron oxide. It may also contain one or more plasticizing agents conventionally used in polymeric film coatings, for examples, polyethylene glycol, propylene glycol, dibutyl sebacate, mineral oil, sesame oil, diethyl phthalate and triacetin. Proprietary non-functional coating materials, such as Opaspray® and Opadry®, obtainable from Colorcon Ltd., UK, may be used.
The controlled release formulation may also include additional active ingredients, for example, other antiepileptic drugs selected from phenyloin, phosphenyloin, trimethadione, carbamazepine, oxcarbazepine, valproates (valproic acid, sodium valproate, and divalproex sodium), tiagabine, levetiracetam, brivacetam, seletracetam, pregabalin, gabapentin, topiramate, beclamide, felbamate, zonisamide, valpromide, mesuximide, pheneturide and the like.
The “core” of the controlled release formulation as used herein, may be in the form of tablets, minitablets, capsules, granules, pellets, beads or pills. The cores may be formulated following any conventional techniques known in the art, namely dry granulation, aqueous or non-aqueous wet granulation, melt granulation, direct compression, roller compactation, pelletization, melting, intimate and non-intimate blending, kneading, and the like.
The core as described herein may be coated with the respective coating composition(s) using various techniques, such as perforated pan, fluidized bed technique, compression coating, drug layering or spraying.
The controlled release formulations may be compressed into tablets. Alternately, one or more of the controlled release formulation as discussed herein may be dispensed as a unit dosage form. The formulations may be filled in hard-gelatin capsules such that a therapeutically effective amount of the active ingredient is available per dosage form. Alternately, one or more of the controlled release formulations as referred to herein may be packed into an appropriate packaging for single or unit dose administration.
In one embodiment, a controlled release formulation includes
In another embodiment, a controlled release formulation includes
In yet another embodiment, a controlled release formulation includes
In another embodiment, a controlled release formulation includes
In one aspect of the above embodiments, the hydrophilic rate-controlling agent(s) is hydroxypropyl methylcellulose, polyethylene oxide, xanthan gum, or combinations thereof.
In another aspect of the above embodiments, the pH-dependent polymer(s) is methacrylate copolymer, hydroxypropyl methylcellulose phthalate, or combinations thereof.
In another aspect of the above embodiments, the permeation enhancer(s) is hydroxypropyl methylcellulose, polyvinylpyrrolidone, or combinations thereof.
From the above it is apparent that various modifications and combinations of the formulations detailed in the text may be made without departing from the spirit and scope of the invention. The invention as described herein may be illustrated by the following examples but is not to be construed to be limiting by them.
Lamotrigine is blended with the hydrophilic rate controlling agent(s) (hydroxypropyl methylcellulose) and all other excipients that are present in the core (other than magnesium stearate and talc) in a suitable blender and are sifted through sieves of suitable size. The blend is further blended with magnesium stearate and talc. The final blend is compressed into tablets.
The compressed tablets are loaded in a coating pan and coated using an aqueous dispersion of the pH-dependent polymer (Eudragit® L30D55), permeation enhancer (hydroxypropyl methylcellulose or lactose), plasticizer (triethyl citrate) and anti-tacking agent (talc) until the desired weight gain is achieved.
Eighty percent of the total amount of lamotrigine is blended with the hydrophilic rate controlling agent(s) (hydroxypropyl methylcellulose) and all other excipients that are present in the core (other than magnesium stearate and talc) in a suitable blender and are sifted through sieves of suitable size. The blend is further blended with magnesium stearate and talc. The final blend is compressed into tablets.
The compressed tablets are loaded in a coating pan and are coated using an aqueous dispersion of the pH-dependent polymer (Eudragit L30D55), permeation enhancer (polyvinylpyrrolidone), plasticizer (triethyl citrate) and anti-tacking agent (talc) until the desired weight gain is achieved.
The coated tablets are loaded in a coating pan and are coated using a non-aqueous solution comprising the remaining twenty percent of the total amount of lamotrigine, and the other excipients present in the topcoat.
Lamotrigine is blended with hydrophilic rate controlling agent (hydroxypropyl methylcellulose), microcrystalline cellulose, lactose, and granulated using a solution of polyvinylpyrrolidone in isopropyl alcohol in a rapid mixer granulator. The granules so obtained are dried and subjected to sizing. The sized granules are blended with magnesium stearate and talc. The final blend is compressed into tablets.
The compressed tablets are loaded in a coating pan and are coated using an aqueous dispersion of the pH-dependent polymer (Eudragit® L30D55), permeation enhancer (hydroxypropyl methylcellulose), plasticizer (triethyl citrate) and anti-tacking agent (talc) until the desired weight gain is achieved.
Lamotrigine is blended with the hydrophilic rate controlling agent(s) (hydroxypropyl methylcellulose) and all other excipients that are present in the core (other than magnesium stearate and talc) in a suitable blender and are sifted through sieves of suitable size. The blend is further blended with magnesium stearate and talc. The final blend is compressed into tablets.
The compressed tablets are loaded in a coating pan and coated using an aqueous dispersion of the pH-dependent polymer (Eudragit® L30D55), plasticizer (triethyl citrate) and anti-tacking agent (talc) until the desired weight gain is achieved.
Seventy-five percent of the total amount of lamotrigine is blended with the hydrophilic rate controlling agent(s) (hydroxypropyl methylcellulose) and all other excipients that are present in the core (other than magnesium stearate and talc) in a suitable blender and are sifted through sieves of suitable size. The blend is further blended with magnesium stearate and talc. The final blend is compressed into tablets.
The compressed tablets are loaded in a coating pan and are coated using an aqueous dispersion of the pH-dependent polymer (Eudragit L30D55), plasticizer (triethyl citrate) and anti-tacking agent (talc) until the desired weight gain is achieved.
The coated tablets are loaded in a coating pan and are coated using a non-aqueous solution comprising the remaining twenty five percent of the total amount of lamotrigine, and the other excipients present in the topcoat.
Lamotrigine is blended with hydrophilic rate controlling agent (hydroxypropyl methylcellulose), microcrystalline cellulose, lactose, and granulated using a solution of polyvinylpyrrolidone in isopropyl alcohol in a rapid mixer granulator. The granules obtained are dried and subjected to sizing. The sized granules are blended with magnesium stearate and talc. The final blend is compressed into tablets.
The compressed tablets are loaded in a coating pan and are coated using an aqueous dispersion of the pH-dependent polymer (Eudragit L30D55), plasticizer (triethyl citrate) and anti-tacking agent (talc) until the desired weight gain is achieved.
Tablets of Examples 9-13 were subjected to in vitro dissolution studies in a USP type II apparatus with alternate sinkers, at 75 rpm, at a temperature of 37° C.±0.5° C. in 900 mL of 0.1 N hydrochloric acid for the first 2 hours and followed by media replacement with pH 6.8 Phosphate buffer medium. Aliquot of samples were withdrawn at predetermined time intervals and replaced with an equal amount of fresh media. Samples were processed and analysed. Dissolution profiles of these tablets are provided in Table 1.
| Number | Date | Country | Kind |
|---|---|---|---|
| 1038/DEL/2009 | May 2009 | IN | national |
