Technical Field of the Invention
The present invention relates to a multiple-unit modified release carbamazepine composition for oral administration comprising; (i) at least one extended release unit, and (ii) at least one enteric release unit.
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 trigeminal neuralgia and in patients suffering from manic-depressive illness, post therapeutic neuralgia, or phantom limb pain. 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 were 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 to be ineffective in treating clinical disorders and blood levels greater than 12 ug/ml have been found to be likely to result in side-effects such as neuromuscular disorders, cardiovascular and gastrointestinal effects. Conventional carbamazepine formulations are taken typically 3-4 doses per day to maintain effective blood concentration. This is very bothersome for ambulatory patients, leading to poor patient compliance.
Sustained release dosage forms have been the focus of research for improved therapy, both through improved patient compliance and decreased incidences of .adverse drug 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 drug preparations is improved patient compliance resulting from the avoidance of missed doses through 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 brought about through selective breakdown of the coating of the preparation or through formulating with a polymeric matrix to affect the release of a drug. 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 throughout 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 through a small opening on one side. Fluid is absorbed through the shell, causing the contents to expand and slowly push out through 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 drug-containing core; a core containing finely particulate carbamazepine, a protective colloid, a swellable hydrophilic polymer and an optional water-soluble compound; and a passageway through 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 drug delivery system for the oral administration of carbamazepine and a method of treating a patient with the drug delivery systems is disclosed in U.S. Pat. No. 5,326,570, assigned to Shire. The drug 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 drug 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 drug 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 multiple-unit modified release carbamazepine composition for oral administration comprising:
(i) at least one extended release unit comprising carbamazepine, rate-controlling polymer(s) and other pharmaceutically acceptable excipients, and
(ii) at least one enteric release unit comprising a coating of enteric polymer over an extended release or immediate release core of carbamazepine, wherein
the extended release core comprises carbamazepine, rate-controlling polymers and pharmaceutically acceptable excipients, and
the immediate release core comprises carbamazepine and pharmaceutically acceptable excipients.
The ratio of extended release unit to the enteric release unit may range from about 20:80 to about 80:20 by weight.
According to one of the embodiments, the extended release unit comprises carbamazepine dispersed in a matrix of one or more rate-controlling polymers and other pharmaceutically acceptable excipients. Alternatively, carbamazepine and one or more rate-controlling polymers are layered onto inert cores to provide extended release unit.
According to one embodiment, the enteric release unit is prepared by providing a coating of enteric polymers over a core comprising carbamazepine.
The core may be an extended-release unit comprising carbamazepine dispersed in a matrix of one or more rate-controlling polymers. Alternatively, the core may be an immediate-release unit comprising carbamazepine.
The cores 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 or layered with rate-controlling polymer matrix for
preparing extended-release units. Alternatively, the cores may be formed by extrusion, extrusion-spheronization or granulation.
The modified release carbamazepine composition for oral administration of the present invention comprising of a mixture of two different release components, is designed to release carbamazepine for up to about 12 hours time period and to maintain the carbamazepine blood level within the therapeutic range. The ratio of extended release unit to the enteric release unit may range from about 20:80 to about 80:20 by weight.
In another aspect, a process for preparing modified-release pharmaceutical composition of carbamazepine is provided, which comprises:
(i) preparing the extended release unit comprising carbamazepine with one or
more rate-controlling polymers and other pharmaceutical^ acceptable
excipients, (ii) preparing the enteric release unit by providing an enteric polymer coating
over a core comprising carbamazepine. (iii) mixing the extended 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, beads or granules.
It is yet another aspect to provide a method of treating convulsions or trigeminal neuralgia, by administering a multiple unit modified release carbamazepine composition comprising:
(i) at least one extended release unit, and
(ii) at least one enteric release unit.
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 modified dosage form of carbamazepine that helps to achieve the desired release profile up to about 12 hours time period. The inventors have also found that the use of a combination of extended release unit and enteric release unit provide a better control over the rate of release of drug.
The term "modified release" as used herein includes any type of modified release such as prolonged release, sustained release, controlled release and extended release.
The term "unit" as used herein includes spheroids, beads, microspheres, seeds, granules, pellets, ion-exchange resin beads and other multi-particulate systems.
The modified release carbamazepine composition in unit dosage form of the present invention comprises:
(i) at least one extended release unit comprising carbamazepine, rate-controlling polymer(s) and other pharmaceutically acceptable excipients, and
(ii) at least one enteric release unit comprising a coating of entericty polymer over an extended release or immediate release core of carbamazepine, wherein
the extended release core comprises carbamazepine, rate-controlling polymers and pharmaceutically acceptable excipients, and
the immediate release core comprises carbamazepine and pharmaceutically acceptable excipients.
The ratio of extended release unit to the enteric release unit in the modified-release composition may range from about 20:80 to about 80:20 by weight.
The extended release units containing carbamazepine can be formulated by blending carbamazepine with rate-controlling polymers and other pharmaceutically acceptable
excipients, by the processes known in the art, such as, simple granulation followed by sieving; extrusion and marumerization or spheronization; rotogranulation; peptization; micropelletization, etc. Alternatively, the blend comprising carbamazepine and rate-controlling polymers is layered onto inert cores as powder or as suspension or solution in a suitable solvent or as powder.
The enteric release unit can be prepared by providing a coating of enteric polymers over a core comprising carbamazepine. The core may an extended-release unit or immediate release unit comprising carbamazepine.
The immediate release units containing carbamazepine can be formulated as a plurality of discrete or aggregated particles, pellets, beads or granules. 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; extrusion and marumerization or spheronization; rotogranulation; peptization; micropelletization, etc. Alternatively, the immediate release units are 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, pergelatinized starch, dicalcium phosphate, celphere and non-pareils. The cores may be of any geometric shape, though spheres are particularly used for the case of uniform coating.
The rate controlling polymers are 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).
The enteric release unit is prepared by providing a coating of enteric polymers over a core comprising carbamazepine. 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.
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 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 centrifugal fluidizing (CF) granulator, a fluidized bed process, or any other suitably automated coating equipment.
Immediate release units 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, phosphatide 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 sugar, sucrose, sugar compressible, sugar 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, polyvinyJ alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, and propylene glycol.
Suitable lubricants and glidants 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.
Coating 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 multiple unit modified release carbamazepine composition for oral administration comprising (i) at least one extended release unit, and (ii) at least one enteric unit, may be administered in combination with other medicines, for example, other anti epileptic drugs, like lithium carbonate, phenobarbitone, sodium valporate, phenytoin, gabapentin, lamotrigine, etc.
Example 1:
Part A: Preparation of Extended Release Units
(Table Removed)
1. Carbamazepine, hydroxypropyl methylcellulose and microcrystalline cellulose were granulated with aqueous solution of copolymer of polyvinylpyrrolidone and vinyl acetate (Copovidone) in water.
2. The wet mass was extruded, spheronized, dried and sieved to get spherical units.
Part B: Preparation of Enteric Release Units
(Table Removed)
1. Carbamazepine, microcrystalline cellulose, lactose, citric acid and sodium lauryl sulphate were granulated with aqueous solution of copolymer of polyvinylpyrrolidone and vinyl acetate (Copovidone) in water.
2. The wet mass was extruded, spheronized, dried and sieved to get spherical units.
3. The spherical units of step 2 were coated with the coating composition provided in the table upto a weight build up of about 15%.
Part C: Preparation of Modified release carbamazepine compositions
The extended release units and enteric release units were blended in a desired ratio and filled into capsules.
Example 2:
Preparation of Modified Release carbamazepine compositions
(Table Removed)
1. Carbamazepine, hydroxypropyl methylcellulose and microcrystalline cellulose were granulated with water.
2. The wet mass was extruded, spheronized, dried and sieved to get spherical extended release units.
3. A part of prepared extended release units of step (2) were coated with the coating composition provided in the table upto a weight build up of about 15% to prepare enteric release units.
4. The extended release units of step (2) and the enteric release units of step (3) were blended in a desired ratio and filled into capsules.

WE CLAIM:
1. A multiple-unit modified release carbamazepine composition for oral administration
comprising:
(i) at least one extended release unit comprising carbamazepine, rate-controlling polymer(s) and other pharmaceutically acceptable excipients, and
(ii) at least one enteric release unit comprising a coating of enteric polymer over an extended release or immediate release core of carbamazepine, wherein
the extended release core comprises carbamazepine, rate-controlling polymers and pharmaceutically acceptable excipients, and
the immediate release core comprises carbamazepine and pharmaceutically acceptable excipients.
2. The composition according to claim 1 wherein the ratio of extended 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 rate-controlling polymers are selected from one or more of cellulose derivatives, starch, polyvinyl pyrrolidone, gums, alginates and acrylic acid derivatives.
4. The composition according to claim 1 wherein the enteric release unit comprises enteric polymers 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.
5. The composition according to claim 1 wherein the pharmaceutically acceptable excipients comprise one or more of diluents, binders, lubricants, glidants and colorants.
6. The composition according to claim 1 wherein the immediate release core additionally comprise surfactants and pH-modifiers.
7. The composition according to any of the preceding claims prepared by a process comprising steps of:
(i) preparing the extended release unit comprising carbamazepine with one or more rate-controlling polymers and other pharmaceutically acceptable excipients
(ii) preparing the enteric release unit by providing an enteric polymer coating over a core comprising carbamazepine
(iii) mixing the extended 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.
8. The composition according to claim 7 wherein the extended release unit is prepared by blending carbamazepine with rate-controlling polymers and other pharmaceutically acceptable excipients or by spraying the blend comprising carbamazepine and rate-controlling polymers onto inert cores.
9. The composition according to claim 7 wherein the immediate release core is prepared by blending carbamazepine with pharmaceutically acceptable excipients or by layering carbamazepine over inert cores.
10.A multiple unit modified release carbamazepine composition for oral administration comprising:
(i) at least one extended release unit, and
(ii) at least one enteric release unit
substantially as described and illustrated herein.