Technical Field of the Invention
The present invention relates to a controlled-release oral pharmaceutical composition in unit dosage form for administration of carbamazepine comprising:
(i) a controlled-release unit comprising a coating of controlled-release polymer over immediate release core of carbamazepine and
(ii) an enteric release unit comprising a coating of enteric polymer over a controlled-release or immediate release core of carbamazepine.
Background of the Invention
Carbamazepine, 5H-dibenz-[b,f]azepine-5-carboxamide, is a well established anti-epileptic compound. It is regarded as a first-line drug in the treatment of patients suffering from partial seizures, with and without second generalization, and in patients with generalized tonic-clonic seizures. Besides being an antiepileptic compound, carbamazepine has also proved effective in the treatment of pain associated with trigeminal neuralgia and in patients suffering from manic-depressive illness, post therapeutic neuralgia, or phantom limb pain. Additionally, carbamazepine is used in various psychiatric disorders such as bipolar disorder, depression, cocaine addiction, alcohol addiction and other obsessive compulsive disorders and cardiovascular disease. The drug appears to act by reducing postsynaptic responses and by blocking post-tetanic potentiation.
Although the half-life of carbamazepine is relatively long, between 25 and 85 hours after a single dose, however due to autoinduction, its effect is substantially reduced after repeated dosing. Due to its increased metabolism, pronounced daily fluctuations in the serum concentration of carbamazepine are observed and are of concern. The therapeutic range of carbamazepine is about 4-12 ug/ml. Blood levels of carbamazepine below 4ug/ml have been found ineffective in treating clinical disorders and blood levels greater than 12 µg/ml have been

found to be likely to result in side-effects such as neuromuscular disorders, cardiovascular and gastrointestinal effects.
Sustained release dosage forms have been the focus of research for improved therapy, both throµgh improved patient compliance and decreased incidences of adverse drµg reactions. It is the intent of all sustained release formulations to provide a longer period of pharmacological action after administration than is ordinarily obtained after administration of immediate-release dosage forms. Sustained release compositions may be used to delay absorption of a medicament until it has reached certain portions of the alimentary tract, and maintain a desired concentration of said medicament in the blood stream for a longer duration than would occur if conventional rapid release dosage forms are administered. Such longer periods of response provide for many therapeutic benefits that are not achieved with corresponding short acting, immediate release preparations. A further general advantage of longer acting drµg preparations is improved patient compliance resulting from the avoidance of missed doses throµgh patient forgetfulness.
Sustained release formulations known in the art include specially coated pellets, coated tablets and capsules, and ion exchange resins, wherein the slow release of the active medicament is broµght about throµgh selective breakdown of the coating of the preparation or throµgh formulating with a polymeric matrix to affect the release of a drµg. Some sustained release formulations provide for pulsatile/sequential release of a single dose of an active compound at predetermined periods after administration.
For sustained-release dosage forms containing very high quantities of the active pharmaceutical ingredient, it is particularly critical to avoid an excessively rapid release (dose dumping) as that can lead to undesirable toxic effects. Moreover, such systems are dependent upon gastric emptying rates and transit times, and can be associated with significant intra-and inter-individual variations.

These disadvantages have led to a shift in modified release technology from the use of monolithic systems to multiple unit systems in which each individual unit is formulated with modified release characteristics. The final dosage form includes a multiplicity of the individual units contained in a formulation in such a form that these individual units are made available from the formulation on reaching the tract.
Multiple unit dosage forms possess a large surface area, which advantageously promotes complete and uniform absorption, minimizes peak plasma fluctuations and thus reduces the potential for systemic side effects. A further advantage of these dosage forms is that high local concentrations of the active substance in the system is avoided as a consequence of the units being distributed freely throµghout the tract. The multiple unit dosage form ensures incorporation of higher dose resulting in a decreased dosing frequency and consequently better patient compliance.
JP 61/044811 describes a granulate mixture, which is composed of an initial release portion and a retarded release portion. In the initial release portion the active ingredient is immediately released in the stomach. In the retarded release portion, the granulate is enclosed in a membrane which is resistant to gastric juices; in an alternative embodiment, the active ingredient is blended homogenously with the material resistant to gastric juices.
The combination of an initial release granulate mixture with retarded release active ingredient is also described in EP-A-255002, assigned to Alfa Wassermann.
Currently, there are a limited number of slow release oral carbamazepine dosage forms available (TEGRETOL® - XR of Novartis and CARBATROL® of Shire Laboratories, Inc.). TEGRETOL® - XR are extended-release tablets available in

US, containing a core and a shell. The contents of the core are released throµgh a small opening on one side. Fluid is absorbed throµgh the shell, causing the contents to expand and slowly push out throµgh the opening. In UK, TEGRETOL Retard tablets are available, which contain coated pellets to deliver the medicine. CARBATROL® (extended-release) is a multicomponent capsule formulation containing three different types of beads: immediate release, extended-release and enteric-release beads. The 3 different beads are combined in a specific ratio to provide twice-daily dosing.
U.S. Pat. No. 4,857,336 and RE 34,990 assigned to Ciba-Geigy, disclose a therapeutic system for peroral administration of carbamazepine. The system comprises a wall made of a material permeable to water and impermeable to the components of the drµg-containing core; a core containing finely particulate carbamazepine, a protective colloid, a swellable hydrophilic polymer and an optional water-soluble compound; and a passageway throµgh the wall for delivering the core components to the environmental body fluid. The passageway is produced by mechanical or laser drilling of the outer wall.
An extended-release drµg delivery system for the oral administration of carbamazepine and a method of treating a patient with the drµg delivery systems is disclosed in U.S. Pat. No. 5,326,570, assigned to Shire. The drµg delivery systems consist of a single dosage form containing three types of units: immediate release unit, sustained release unit and enteric release unit, capable of releasing carbamazepine at varying times.
U.S. Pat. No. 5,912,013 also assigned to Shire, discloses a composition for treating a patient with carbamazepine in a pharmaceutical dosage form which comprises pellets containing at least 70% carbamazepine and 5% of polyvinyl pyrrolidone. Three different types of pellets are prepared, one of which is an immediate release, the second is a slow release and the third is a pH dependent

formulation. The three different types of pellets are combined into a single dosage form.
U.S. Pat. No. 5,980,942 describes a zero order sustained release matrix tablet formulation of carbamazepine. The matrix tablet formulation comprises a hydrophilic polymer gel that inhibits transformation of carbamazepine into carbamazepine dihydrate and effectively changes the anhydrous carbamazepine into an amorphous form that can be released from the matrix by zero-order release kinetics.
U.S. Pat. No. 6,294,201 discloses an osmotic drµg release system consisting of a shell and core containing a pharmaceutically active substance, xanthan and a vinyl pyrrolidone-vinyl acetate copolymer. These water-expandable polymers allow for the release of the active substance from the shell in a controlled manner.
U.S. Pat. No. 6,475,493 and 6,635,680 disclose a coating composition comprising a heterogeneous coating mixture of three different polymers, viz. water insoluble polymer, enteric polymer and water soluble polymer. The pharmaceutical formulation coated with this heterogeneous coating mixture provides initiation of the release of the active in the stomach at a slow rate and controls the release in the intestines at a rate faster than that in the stomach such that the active is delivered over the course of predetermined interval.
These methods of carbamazepine delivery, however in addition to being expensive, involve time-consuming methods of production. There is a need in the art to develop drµg formulations which provide a therapeutically effective blood concentration level of carbamazepine for a sustained period that involves simple methods of production.

Summary of the Invention
It is one of the aspects to provide a controlled-release oral pharmaceutical composition in unit dosage form for administration of carbamazepine comprising:
(i) a controlled-release unit comprising a coating of controlled-release polymer over immediate release core of carbamazepine, and
(ii) an enteric release unit comprising a coating of enteric polymer over a controlled-release unit or immediate release core of carbamazepine.
The ratio of extended release unit to the enteric release unit may range from about 20:80 to about 80:20 by weight.
Embodiments of the composition further comprises one or more pharmaceutically acceptable excipients.
According to one of the embodiments, the core of carbamazepine can be formed by layering the active ingredient onto inert cores. The active ingredient can be layered with or without pharmaceutically acceptable excipients for preparing immediate release units. Alternatively, the cores may be formed by extrusion, extrusion-spheronization or granulation.
The controlled-release oral pharmaceutical composition for oral administration of carbamazepine of the present invention comprising of a mixture of two different release components, is designed to release carbamazepine up to about 24 hours time period so as to maintain the carbamazepine blood level within the therapeutic range. The ratio of first unit to the second unit may range from about 20:80 to about 80:20 by weight.
In another aspect, a process for preparing controlled-release oral pharmaceutical composition of carbamazepine is provided, which comprises: (i) preparing the immediate release core of carbamazepine,

preparing the controlled-release unit by providing a coating of controlled-release polymer over immediate release core of carbamazepine,
preparing the enteric release unit by providing a coating of enteric polymer over the controlled-release unit or immediate release core of carbamazepine and
(iv) mixing the controlled-release and enteric release units in a ratio of about 20:80 to about 80:20 by weight and filling the units into a capsule or compressing into a tablet.
The two types of units can be formulated as a plurality of discrete or aggregated particles, pellets, mini-tablets, beads or granules.
It is yet another aspect to provide a method of treating convulsions or trigeminal neuralgia, by administering a controlled-release oral pharmaceutical composition in unit dosage form comprising:
(i) a controlled-release unit comprising a coating of controlled-release polymer over immediate release core of carbamazepine, and
(ii) an enteric release unit comprising a coating of enteric polymer over a controlled-release unit or immediate release core of carbamazepine.
The method may further include administering other anticonvulsant or pharmaceutical agents.
The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and claims.

Detailed Description of the Invention
The inventors have developed a controlled-release dosage form of carbamazepine that helps to achieve the desired release profile up to about 24 hours time period. The inventors have also found that the use of a combination of controlled-release unit and enteric release unit provide a better control over the rate of release of drµg.
The controlled-release dosage form of carbamazepine can be prepared by any of the methods known in the art and also by methods involving preparation of matrix-type systems as described in our co-pending Indian Patent Application No's. 1380/DEL/2005 and 1382/DEL/2005, which is incorporated herein entirety. The present invention of controlled-release dosage form describes the reservoir-type systems.
The term "controlled-release" as used herein includes any type of controlled-release preparations such as prolonged release, sustained release, modified release and extended release.
The term "unit" as used herein includes spheroids, beads, seeds, granules, pellets, mini-tablets, microspheres, ion-exchange resin beads and other multi-particulate systems. The "unit" may also include mixture of different types of units mentioned here.
The controlled-release carbamazepine composition in unit dosage form of the present invention comprises:
(i) a controlled-release unit comprising a coating of controlled-release polymer over immediate release core of carbamazepine and
(ii) an enteric release unit comprising a coating of enteric polymer over a controlled-release unit or immediate release core of carbamazepine.

The ratio of controlled-release unit to the enteric release unit in the composition may range from about 20:80 to about 80:20 by weight. The multiple-units are filled into capsules or sachets or compressed into tablets.
The immediate release core containing carbamazepine can be formulated as a plurality of discrete or aggregated particles, pellets, beads, granules or mini-tablets. The process for preparing the unit can be accomplished by blending carbamazepine with or without pharmaceutically acceptable excipients using any processes known in the art, such as, simple granulation followed by sieving; granulation followed by tabletization into mini-tablets; extrusion and marumerization or spheronization; rotogranulation; pelletization; micropelletization, etc. Alternatively, the core can be formulated by layering carbamazepine with or without pharmaceutically acceptable excipients over inert cores. The active is layered over the inert cores as powder; or as suspension or solution in a suitable solvent.
The inert core may be hydrosoluble or hydroinsoluble. Examples of inert cores comprise sucrose, lactose, maltodextrin, microcrystalline cellulose, pregelatinized starch, dicalcium phosphate, celphere and non-pareils. The cores may be of any geometric shape, thoµgh spheres are particularly used for the case of uniform coating.
The controlled-release units containing carbamazepine can be formulated by providing a coating of controlled-release polymer over the immediate release core comprising carbamazepine.
The enteric release unit can be prepared by providing a coating of enteric polymers over a core comprising carbamazepine. The core may be controlled-release units or immediate release core. The enteric polymers are selected from
any such pharmaceutically acceptable enteric polymers, which would facilitate erosion and breakdown of the pellets at a pH of 4.5 and above.
The controlled-release polymer is selected from one or more of pharmaceutically acceptable polymers, which can control the rate of release of carbamazepine, i.e. cellulose derivatives, starch, polyvinyl pyrrolidone, gums, alginates and acrylic acid derivatives.
Suitable examples of cellulosic polymers include, but are not limited to, ethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose and hydroxyethylcellulose.
Suitable examples of acrylic acid derivatives include, but are not limited to, polymethacrylates such as ethyl acrylate/methyl methacrylate copolymer (Eudragit NE-30-D) and ammonio methacrylate copolymer types A and B (Eudragit RL30D and RS30D).
Suitable enteric polymers include, but are not limited to, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate; methacrylic acid copolymers such as Eudragit L 100-55, D-55, 100, and Eudragit S 100, and mixtures thereof.
Suitable solvents used for preparing a solution of controlled-release polymer or enteric polymers and solution/suspension of active layer include, but are not limited to water, alcohols such as ethyl alcohol or isopropyl alcohol; ketones such as acetone or ethylmethyl ketone; halogenated hydrocarbons such dichloro ethane or trichloromethane; or mixture thereof.
The coating may be done using a conventional coating pan, a spray coater, a rotating perforated pan, or an automated system, such as a centrifµgal fluidizing (CF) granulator, a fluidized bed process, or any other suitably automated coating equipment.
Immediate release core comprising carbamazepine may additionally comprise surfactants and pH-modifiers.
Suitable surfactant can be anionic, cationic, zwitterionic and nonionic surfactants. Particularly, the compositions include at least one anionic surfactant. Suitable anionic surfactants include but are not limited to alkyl sulfonates, alkyl phosphates, alkyl phosphonates, potassium laurate, sodium lauryl sulfate, sodium dodecylsulfate, alkyl polyoxyethylene sulfates, dioctyl sodium sulfosuccinate, phosphatidyl glycerol, phosphatidylinositol, diphosphatidylglycerol, phosphatidyl inosine, phosphatidylserine, phosphatidic acid and their salts, cholic acid and other bile acids (e.g., cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid) and salts thereof (e.g., sodium deoxycholate, etc.).
Suitable pH-modifiers include, but are not limited to, citric acid, sodium bicarbonate, monosodium citrate, trisodium citrate, tribasic sodium phosphate, sodium chloride or mixtures thereof.
The units may also include pharmaceutically acceptable excipients, which act in one or more capacities as diluents, binders, lubricants, glidants or colorants.
Suitable diluents include, but are not limited to, corn starch, lactose, white sµgar, sucrose, sµgar compressible, sµgar confectioners, glucose, sorbitol, calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose
powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, mannitol, starch and starch pregelatinized.
Suitable binders include, but are limited to methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone (povidone), copolymer of polyvinylpyrrolidone and vinyl acetate (copovidone), gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, and propylene glycol.
Suitable lubricants and glfdants include, but are not limited to, colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax and white beeswax.
The controlled-release layer or enteric layer may additionally comprise plasticizers, coloring agents, lubricants, antiadherents, etc.
Suitable plasticizers include, but are not limited to, propylene glycol, triethylene glycol, oleic acid, triethylcitrate, tributylcitrate, triacetin, diethyl phthalate, dibutyl phthalate, dibutylsebacate, glyceryl monostearate, castor oil, ethylene glycol monooleate,
The coloring agents and flavoring agents of the present invention may be selected from any FDA approved colors and flavors for oral use.
The controlled-release carbamazepine composition in unit dosage form for oral administration comprising (i) at least one controlled-release unit, and (ii) at least one enteric unit, may be administered in combination with other medicines, for example, other anti epileptic drµgs, like lithium carbonate, phenobarbitone, sodium valporate, phenytoin, gabapentin, lamotrigine, etc.
The controlled-release carbamazepine composition comprising controlled-release units and enteric units are filled into capsules or sachets or compressed into tablets.
4. The first part of above granules was coated with aqueous dispersion of
controlled-release polymer and the second part was coated with aqueous
dispersion of enteric polymer.
5. The two types of granules were blended in a 65:35 weight ratio and filled
in the capsules.
In Vitro Dissolution Studies:
In vitro dissolution studies of the above capsules were conducted in change over media (0.01N HCI for 4 hours and phosphate buffer, pH 7.5 with 0.1% sodium lauryl sulfate for remaining time) using USP-2 dissolution apparatus at 75 rpm. The release profile is shown in Table 1.
1. Carbamazepine, microcrystalline cellulose, lactose and a part of
Polyvinylpyrrolidone were mixed and granulated with aqueous dispersion
of citric acid, a part of talc, remaining part of Polyvinylpyrrolidone, Sodium
Lauryl sulfate and Polyethylene glycol.
2. The wet mass was extruded, spheronized, dried and sieved to get
granules.
3. The granules of step 2 were mixed with remaining part of talc, colloidal
silicon dioxide, magnesium stearate and compressed into mini-tablets.
4. The prepared mini-tablets were coated with aqueous dispersion of controlled-release polymer as per the composition.
Part B: Preparation of Enteric Release granules
Procedure:
1. Carbamazepine, microcrystalline cellulose, lactose and a part of
Polyvinylpyrrolidone were mixed and granulated with aqueous dispersion
of citric acid, talc, remaining part of Polyvinylpyrrolidone, Sodium Lauryl
sulfate and Polyethylene glycol.
2. The wet mass was extruded, spheronized, dried and sieved to get
granules (units) of desired particle size of #16 BSS.
3. The above granules were coated with aqueous dispersion of enteric
polymer as per the composition.
Part C: Preparation of controlled-release Carbamazepine compositions
The controlled-release mini-tablets and enteric release granules were blended 65:35 weight ratio and filled in the capsules.
While several particular forms of the invention have been illustrated and described, it will be apparent that various modifications and combinations of the invention detailed in the text can be made without departing from the spirit and scope of the invention. For example, the core of carbamazepine used for preparing the enteric release unit does not necessarily need to include only immediate release core of carbamazepine but instead can be made up of a controlled-release unit of carbamazepine, e.g. immediate release core of carbamazepine is first coated with controlled-release polymer and then coated with enteric-release polymer. Also the enteric-release unit can be made up of mixture of core containing immediate release carbamazepine and controlled-release carbamazepine. The core of carbamazepine can also be made up of mini-tablets or mixture of granules and mini-tablets. Accordingly, it is not intended that the inventions be limited, except as by the appended claims.

WE CLAIM:
1. A controlled-release carbamazepine composition in unit dosage form for oral
administration comprising:
(i) a controlled-release unit comprising a coating of controlled-release polymer over immediate release core of carbamazepine, and
(ii) an enteric release unit comprising a coating of enteric polymer over a controlled-release unit or immediate release core of carbamazepine.
2. The composition according to claim 1 wherein the ratio of controlled-release
unit to the enteric release unit may range from about 20:80 to about 80:20 by
weight.
3. The composition according to claim 1 wherein the immediate release core
comprises carbamazepine and pharmaceutically acceptable excipients.
4. The composition according to claim 1 wherein the controlled-release
polymers are selected from one or more of cellulose derivatives, starch,
polyvinyl pyrrolidone, gums, alginates and acrylic acid derivatives.
5. The composition according to claim 1 wherein the enteric polymers are
selected from one or more of cellulose acetate phthalate, cellulose acetate
trimellitate, hydroxypropyl methylcellulose acetate phthalate, polyvinyl acetate
phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl
methylcellulose acetate succinate; methacrylic acid copolymers such as
Eudragit L 100-55, D-55, 100, and Eudragit S 100, and mixtures thereof.
6. The composition according to claim 3 wherein the pharmaceutically
acceptable excipients comprise one or more of diluents, binders, lubricants,
glidants, surfactants, pH-modifiers and colorants.
7. The composition according to claim 1 wherein the immediate release core of
carbamazepine is formulated as one or more of spheroids, beads, seeds,
granules, pellets, mini-tablets, microspheres, ion-exchange resin beads, and
mixtures thereof.
8. A process for preparing control led-release composition of claim 1 comprising
the steps of:
(i) preparing the immediate release core of carbamazepine,
(ii) preparing the controlled-release unit by providing a coating of controlled-release polymer over immediate release core of carbamazepine,
(iii) preparing the enteric release unit by providing a coating of enteric polymer over the controlled-release unit or immediate release core of carbamazepine and
(iv) mixing the controlled-release and enteric release units in a ratio of about 20:80 to about 80:20 by weight and filling the units into a capsule or compressing into a tablet.
9. The process according to claim 8 wherein the immediate release core of
carbamazepine is prepared by blending carbamazepine with pharmaceutically
acceptable excipients or by layering carbamazepine over inert cores.
10. A controlled-release carbamazepine composition in unit dosage form for oral
administration comprising:
(i) a controlled-release unit comprising a coating of controlled-release polymer over immediate release core of carbamazepine, and
(ii) an enteric release unit comprising a coating of enteric polymer over a controlled-release unit or immediate release core of carbamazepine.