Field of the Invention
The present invention relates to dosage forms of oxcarbazepine for oral administration and to the process for the preparation of such dosage forms.
Backqround of the Invention
Drug insolubility is one of the major challenges in the development of many pharmaceutical products. Over one third drugs listed in the US Pharmacopoeia and about fifty percent of New Chemical Entities are insoluble or poorly soluble in water. The result is that many drugs are marketed as sub-optimal formulations, which after administration lead to poor or erratic bioavailability or a greater risk of adverse side effects. Oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide) a widely used antiepileptic drug has poor solubility in water.
One of the earlier attempts to enhance the dissolution rate and bioavailability of oxcarbazepine relied on particle size reduction of the oxcarbazepine to an order of 2 to 12 µm. A PCT application, WO 98/35681 is an illustration of oxcarbazepine composition for oral administration employing micronized drug particles of 2 to 12 µm ranges. In examples, applicant uses povidone, however, the grade being used PVP PXL, corresponds to crospovidone which act as a disintegrant.
Oxcarbazepine tablets are also known to undergo a color change during storage. The discoloration is caused by the formation of a minor amount of an oxidation product "diketoiminodibenzyl: 10, 11-dihydro-5H-dibenzo [b,f] azepine-10,11-dione. This oxidation product is considered to be pharmacologically harmless. However, the color change is not generally pharmaceutically desirable.
U.S. Patent Nos. 5,472,714 and 5,695,782 describe color stable oxcarbazepine tablets. The color stability has been achieved by providing double coating to the tablets. Oxcarbazepine tablets described therein are provided with hydrophilic, permeable inner layer containing white pigments and further a hydrophilic, permeable outer layer containing white pigments in combination with iron (II) oxide pigments
Our PCT application WO 02/094774, the contents of which are hereby incorporated by reference, discloses an oxcarbazepine formulation comprising oxcarbazepine and wetting agent. In this patent application wetting agent was used with oxcarbazepine having a median particle size of about 20 urn to about 50 µm with a maximum residue of about 10% on a 45
µm to upto 100 µm sieve (which could easily be achieved by milling using conventional equipment).
We have now discovered that presence of a water soluble polymer is essential to obtain a bioequivalent product. Water soluble polymer such a povidone and copovidone provided dosage forms which were bioequivalent to commercially available solid and liquid dosage forms, respectively.
Summary of the Invention
Present invention relates a pharmaceutical dosage form for oral administration comprising oxcarbazepine and a water-soluble polymer selected from the group consisting of povidone, copovidone or mixture thereof.
The dosage form according to the present invention can be a solid or liquid dosage form.
According to another aspect of the present invention, there is provided a solid dosage form for oral administration comprising oxcarbazepine and a water-soluble polymer selected from the group consisting of povidone, copovidone or mixture thereof.
According to another aspect of the present invention, there is provided a suspension dosage form for oral administration comprising oxcarbazepine and a water-soluble polymer selected from the group consisting of povidone, copovidone or mixture thereof.
According to another aspect of the present invention, there is provided a process for the preparation of a solid pharmaceutical dosage form for oral administration comprising oxcarbazepine and a water soluble polymer selected from the group consisting of povidone, copovidone or mixture thereof comprising the steps of
Preparing drug containing granules,
Optionally blending other pharmaceutical excipients with drug containing granules,
compressing into or filling the granules of step a) or blend of step b) into suitable size solid dosage form.
According to another aspect of the present invention, there is provided a process for the preparation of a liquid pharmaceutical dosage form for oral administration comprising oxcarbazepine and a water soluble polymer selected from the group consisting of povidone, copovidone or mixture thereof comprising the steps of
a) dispersing the suspending agent in water,
optionally, dispersing the surfactant in the dispersion of step a),
dispersing water soluble polymer in dispersion of step a) or step b),
dispersing the oxcarbazepine in the dispersion of step c),
optionally dispersing other pharmaceutical excipients in dispersion of step d),
homogenizing till a uniform suspension is obtained.
It is an object of the present invention to provide oxcarbazepine having a median particle size about 14 - about 30 urn
It is an object of the present invention to provide a pharmaceutical dosage form for oral administration comprising oxcarbazepine having a median particle size greater than about 14 urn.
Accordingly, the present invention provides a dosage form for oral administration comprising oxcarbazepine having a median particle size about 14 - 30 urn, particularly 14-25 pm
According to another aspect of the present invention, there is provided a tablet dosage form for oral administration comprising oxcarbazepine having a median particle size about 14 - 30 urn, particularly 14-25 urn.
According to another aspect of the present invention, there is provided a suspension dosage form for oral administration comprising oxcarbazepine having a median particle size about 14 - 30 urn, particularly 14-25 urn.
According to another aspect of the present invention, there is provided a process for the preparation of pharmaceutical solid dosage form of oxcarbazepine comprising the steps of-
blending the oxcarbazepine having a median particle of about 14 to about 25 urn with other pharmaceutical excipients,
optionally granulating the blend,
lubricating the blend of step a) or granules of step b), and
compressing into or filling into suitable size solid dosage form.
According to another aspect of the present invention, there is provided a process for the preparation of pharmaceutical liquid dosage form of oxcarbazepine comprising the steps of-
dispersing the suspending agent in water
optionally, dispersing the surfactant in the dispersion of step a)
dispersing the oxcarbazepine having a median particle of about 14 to about 25 urn in the dispersion of step b) or step a),
optionally dispersing other pharmaceutical excipients,
homogenizing till a uniform suspension is obtained.
Detailed description
The object of the present invention is to provide bioequivalent and stable oxcarbazepine dosage form.
Oxcarbazepine, 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxa-mide is an agent of first choice in the treatment of convulsions. The known dosage forms, such as tablets and liquid dosage forms, e.g. suspensions, are suitable for ensuring a uniform concentration of active ingredient in the blood, especially in the case of regularly recurring administration over a prolonged period of treatment.
Povidone polymers, also known as polyvidon, povidonum, PVP, and polyvinylpyrrolidone, are sold under the trade names Kollidon™ (BASF Corp.) and Plasdone™ (ISP Technologies). They are polydisperse macromolecular molecules, with a chemical name of 1-ethenyl-2-pyrrolidinone polymers and 1-vinyl-2-pyrrolidinone polymers. Povidone polymers are produced commercially as a series of products having mean molecular weights ranging from about 10,000 to about 700,000 daltons.
The manufacturing process for povidone polymers produces polymers containing molecules of unequal chain length, and thus different molecular weights. The molecular weights of the molecules vary about a mean or average for each particular commercially available grade. Because it is difficult to determine the polymer's molecular weight directly, the most widely used method of classifying various molecular weight grades is by K-values, based on viscosity measurements. The K-values of various grades of povidone polymers represent a function of the average molecular weight, and are derived from viscosity measurements and calculated according to Fikentscher's formula.
Povidone have diverse roles in a pharmaceutical dosage form. It is used as a dispersing and suspending agent, and has been used as a tablet binder, coating agent, and viscosity-increasing agent in pharmaceutical preparations. It also acts as a surface modifier,
for it to act as surface modifier the povidone polymer must have a molecular weight of less than about 40,000 daltons, as a molecular weight of greater than 40,000 daltons would have difficulty clearing the body. Povidone is known to improve solubility and enhance bioavailability of poorly soluble drugs by the formation of solid dispersion.
Commercially available grades include Plasdone K-17, Plasdone K-25, Plasdone K-30, Plasdone K-29/32, Plasdone K-90, Plasdone K-90D, Plasdone C-15, Plasdone C-30, Kollidon 12 PF, Kollidon 17 PF, Kollidon 25.
Copovidone is a synthetic, 60:40, linear, random copolymer of N-vinyl-2-pyrrolidone and vinyl acetate. The addition of vinyl acetate to the vinylpyrrolidone polymer chain reduces hydrophilicity and glass transition temperature (Tg) of the polymer relative to polyvinyl pyrrohdone (PVP) homopolymer. As a result, copovidone copolymer is an excellent adhesive material and a tougher, more flexible film former than PVP homopolymer. With these unique properties, this copolymer is well suited for use in pharmaceutical formulations as a tablet binder aid for direct compression and dry granulation, as a wet granulation binder, and as an additive to improve the properties of cellulosic-based tablet coatings. Most commonly used grade of copovidone is Plasdone® S-630.
Drug to water soluble polymer ratio may vary from 1:1 to 20:1, in particular 3:1 to 15:1, wherein water soluble polymer may be povidone, copovidone or mixture thereof.
Particle size of oxcarbazepine may be determined by commonly used methods for determining the median particle size, for example particle size measurement using light, for example light-scattering methods or turbidimetric methods, sedimentation methods, for example pipette analysis using an Andreassen pipette, sedimentation scales, photosedimentometers or sedimentation in a centrifugal force field, pulse methods, for example using a Coulter counter, or sorting by means of gravitational or centrifugal force.
In order to produce oxacarbazepine particles, e.g. crystals having the desired particle size, conventional comminution and de-agglomeration techniques may be used, for example grinding in an air-jet mill or impact mill, a ball mill, vibration mill, mortar mill or pin mill.
The other excipients of this invention may be selected from amongst the surfactant, diluents, binders, disintegrants, lubricants, glidants, suspending agent, solvents, antioxidants, preservative, colouring agents, flavouring agents and sweeteners, which are chemically and physically compatible with oxcarbazepine.
The surfactant may be selected from anionic, cationic or non-ionic surface-active agents or surfactants. Suitable anionic surfactants include those containing carboxylate, sulfonate, and sulfate ions such as sodium lauryl sulfate (SLS), sodium laurate, dialkyl sodium sulfosuccinates particularly bis-(2-ethylhexyl) sodium sulfosuccinate, sodium stearate, potassium stearate, sodium oleate and the like. Suitable cationic surfactants include those containing long chain cations, such as benzalkonium chloride, bis-2-hydroxyethyl oleyl amine or the like. Suitable non-ionic surfactants include polyoxyethylene sorbitan fatty acid esters, fatty alcohols such as lauryl, cetyl and stearyl alcohols; glyceryl esters such as the naturally occurring mono-, di-, and tri-glycerides; fatty acid esters of fatty alcohols; polyglycolized glycerides such as Gelucire, polyoxyethylene-polyoxypropylene block co-polymer such as Poloxamer and other alcohols such as propylene glycol, polyethylene glycol, sorbitan, sucrose, and cholesterol.
Diluents of this invention may be selected from any such pharmaceutically acceptable excipients, which give bulk to the oxcarbazepine composition, preferably those diluents may be selected from calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, cellulose-microcrystalline, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, and the like.
Binders of this invention may be selected from any such pharmaceutically acceptable excipient, which have cohesive properties to act as binders. Preferably, those excipients are methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like.
Disintegrants preferred for the present invention may be selected from starches or modified starches such as starch, modified starch, croscarmellose sodium, crospovidone and sodium starch glycolate
Lubricants of the present invention may be selected from colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated vegetable oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, glyceryl monostearate, PEG 4000 and the like.
Glidants of the present invention may be selected from colloidal silicon dioxide and talc.
Suspending agent is selected from the group consisting of polysaccharide, (tragacanth; xanthan gum, bentonite; acacia and lower alkyl ethers of cellulose (including the hydroxy and carboxy derivatives of the cellulose ethers)), a mixture of cellulose and of xanthan gum, a mixture of polyethylene glycol and of sodium carboxymethyl cellulose, a mixture of xanthan gum and of pregelatinized starch, a mixture of microcrystalline cellulose and of sodium carboxymethyl cellulose (Avicel RC 591), dispersed silicon dioxide (Aerosil 200).
The dosage form may further comprise antioxidant, to protect oxcarbazepine from oxidative degradation Antioxidants may be selected from group consisting of ascorbic acid, sodium pyrosulphite, glutathion or sorbic acid.
The suspension for oral administration are usually aqueous based. By "aqueous based" is meant a suspension comprising water, or water and a water-miscible organic solvent or solvents. Suitable solvents are those with water miscible solvents commonly used in the art such as propylene glycol, polyethylene glycol and ethanol. These solvents also acts as solvents for preservatives.
Examples of preservatives include propylparaben, methylparaben, and sorbic acid, sodium benzoate, or sodium bisulphite
Coloring agent of the present invention may be selected from any colorant used in pharmaceuticals that is approved and certified by the FDA. It may include Iron oxide, Lake of Tartrazine, Lake of Quinoline Yellow, Lake of Sunset Yellow and Lake of Erythrosine, Lack of Carmosine Ponceau, Allura Red.
Sweeteners are selected from the group consisting of sucrose, lactose, glucose, aspartame, saccharine, or sorbitol solution.
Examples of suitable flavouring agents include yellow plum lemon, aroma, peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring
The desired dosage form of the present invention could be a tablet, capsule suspension or solution. Tablet dosage form of the present invention can be produced by using conventional tabletting processes such as dry or wet granulation.
In one of the embodiment, the oxcarbazepine solid dosage form may be prepared by
a) Preparing drug containing granules,
i) dispersing a part of drug in water soluble polymer dispersion,
ii) granulating the rest of the drug with dispersion of step i) iii) drying and sieving the granules obtained in step ii)
Optionally blending the drug containing granules with other excipients,
compressing or filling the granules of step a) or blend of step b) into suitable size solid dosage form.
Granulation may be carried out by conventional wet granulation method or by using fluidized bed processor. In case of fluidized bed processor, there are three options available with respect to the spraying pattern of the fluid. These options are top, bottom and tangential spray process.
In top spray granulation, particles are fluidized in the flow of heated air, which is introduced into the product container via a base plate. The coating liquid is sprayed into the fluid bed from above against the air flow (countercurrent) by means of a nozzle. Drying takes place as the particles continue to move upwards in the air flow. Small droplets and a low viscosity of the spray medium ensure that the distribution is uniform. Since a maximum product surface is exposed to the spray mist, this is a fast process and feasible for batches up to 1500 kg. This technique is usually used for coating small particles and granulation of powders.
In bottom spray granulation, the beads are kept in the product chamber and are coated with the solution with help of a Wurster design product chamber with bottom spray nozzle and partition in the middle. The principle of operation in tangential spray is that tangential nozzles are fixed above the rotating plate so as to do different operation using the same insert. The rotating plate is a specially designed perforated plate so that the powder does not fall down and at the same time air can come through the plate creating fluidized effect in the processor.
The tablet dosage form may optionally be coated with functional and/or nonfunctional layers comprising film-forming polymers, if desired. Coating composition comprises of polymer and other coating additives.
Examples of film-forming polymers include ethylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethyl cellulose,
hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate; waxes such as polyethylene glycol; methacrylic acid polymers such as Eudragit ® RL and RS; and the like Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry® may also be used for coating.
Coating additives may be selected from the group comprising of plasticizers, coloring agents, gloss producer, lubricants/glidants.
Polymer solution or dispersion may be prepared in various solvents such as water, ethanol, methanol, isopropyl alcohol, chloroform, acetone, ether or mixtures thereof. The coating composition can be coated onto solid dosage form using techniques such as spray coating in conventional coating pan or fluidized bed processor, or dip coating.
The invention is further illustrated by the following examples but they should not be construed as limiting the scope of this invention in any way.
(TABLE REMOVED)

Drug Containing Granules
Povidone and Co-povidone were dissolved in purified water.
Some amount of Oxcarbazepine was sifted and dispersed in solution of step 1
3. Sodium lauryl sulfate was dissolved in purified water and transferred to dispersion of
step 1 under stirring.
4. Pregelatinized Starch and remaining quantity of Oxcarbazepine were sifted together.
5. Blend of step 4 was granulated with the dispersion of step 3 using top spray granulation
process in fluidized bed processor.
6. The granules were dried and passed through sieve.
Blend
7 Microcrystalline cellulose, crospovidone were sifted together and blended with granules of step 6
Magnesium Stearate was passed sieve and blended with blend of step 7.
Blend of step 8 was compressed into suitable size tablets.
Tablets were film coated with the coating composition given in the table above.
The oxcarbazepine tablets were tested in 1% sodium lauryl sulphate in water according to the procedure described in the United States Pharmacopoeia XXIII, Apparatus USPII (Paddle) @ 60 rpm. A comparative dissolution profile with Trileptal® - 600 mg (commercially available tablets of Novartis) is given in Table 1.
TABLE 1: Dissolution profile of oxcarbazepine tablets (prepared by example 1) in comparison with "Trileptal®", in 1% aqueous sodium lauryl sulphate solution at 37°C /60 rpm using apparatus USP II (Paddle) / 900ml.
(TABLE REMOVED)

Further, bioavailability study of the Oxcarbazepine tablets (600 mg) of Example 1 was carried out on healthy male volunteers (n =15) taking Trileptal® Tablets tablet (600 mg) produced by Novartis as the reference, the results of which are represented in Table 2.
Open randomized, 2 treatment, 2 period, 2 sequence, single dose crossover, was used for comparative bioavailability study of oxcarbazepine 600 mg tablet against Trileptal® tablets 600 mg of Novartis under fast and fed conditions:
Table 2: Pharmacokinetic parameters obtained through the bioavailability studies of Oxcarbazepine tablets and Trileptal® tablets.
(TABLE REMOVED)

AUCo-oc for Oxcarbazepine tablets was within 80-125% as per FDA guidelines on bioequivalence (Table 2). Above results show that Oxcarbazepine tablets 600 mg prepared as per Example 1 have bioavailability comparable to the reference product, Trileptal® tablet 600 mg of Novartis.
The tablet of the present invention thus provide an effective delivery system for the administration of oxcarbazepine to patients in need of such treatment.
(TABLE REMOVED)

1. Methyl paraben, propyl paraben and sorbic acid were dissolved in propylene glycol.
2. Polyoxyl 8 stearate was dispersed in warm water.
3. Povidone and copovidone was dispersed in dispersion of step 2.
Microcrystalline cellulose and carboxymethyl cellulose was dispersed in water.
Colloidal silicon dioxide was dispersed in the dispersion of step 4.
6. Dispersion of step 3 was added to dispersion of step 5.
7. Oxcarbazepine was dispersed in the dispersion of step 6 under continuous
homogenization.
8 Hydroxyethylcellulose was dispersed in oxcarbazepine dispersion.
9. Noncrystallizing sorbitol solution was added to oxcarbazepine dispersion of step 8.
10. A solution of sodium saccharin and ascorbic acid was prepared in water and added
to dispersion of step 9.
Preservative solution of step 1 was added to dispersion of step 10.
The dispersion of step 11 was homogenized till a uniform suspension is obtained and volume is made with purified water.
The oxcarbazepine suspension were tested in 1 % sodium lauryl sulphate in water according to the procedure described in the United States Pharmacopoeia XXIII, Apparatus USPII (Paddle) @ 50 rpm A comparative dissolution profile with Trileptal® suspension 300 mg/5ml (commercially available suspension of Novartis) is given in Table 3.
TABLE 3: Dissolution profile of oxcarbazepine suspension (prepared by examples 2) in comparison with "Trileptal®", in 0.6% aqueous sodium lauryl sulphate solution at 37°C/50 rpm using apparatus USP II (Paddle) / 900ml.
(TABLE REMOVED)

Further, bioavailability study of the Oxcarbazepine suspension (300 mg/5 ml) of Example 2 was carried out on healthy male volunteers (n=16) taking Trileptal® suspension (300 mg/5ml) produced by Novartis as the reference, the results of which are represented in Table 4.
Open randomized, 2 treatment, 2 period, 2 sequence, single dose crossover, was used for comparative bioavailability study of oxcarbazepine 300mg/5ml suspension against Trileptal® suspension 300mg/5 ml of Novartis under fast and fed conditions'
Table 4: Pharmacokinetic parameters obtained through the bioavailability studies of Oxcarbazepine suspension and Trileptal® suspension.
(TABLE REMOVED)

AUCo-oc for Oxcarbazepine suspension was within 80-125% as per FDA guidelines on bioequivalence (Table 4). Above results show that Oxcarbazepine suspension 300mg/5ml prepared as per Example 2 has bioavailability comparable to the reference product, Trileptal® suspension 300mg/5ml of Novartis.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

WE

CLAIM:

1. A pharmaceutical dosage form for oral administration comprising oxcarbazepine and a water soluble polymer selected from the group consisting of povidone, copovidone or mixture thereof.
2. The dosage form according to claim 1 wherein oxcarbazepine has median particle size of about 14 - about 25 urn.
3. The dosage form according to claim 1 wherein oxcarbazepine to water soluble polymer ratio may vary from 1:1 to 20:1.
4. The dosage form according to claim 3 wherein drug to water soluble polymer ratio may vary from 3:1 to 15:1.
5. The dosage form according to claim 1 wherein the dosage form is a solid,
6. The dosage form according to claim 5 wherein the solid dosage form is a capsule.
7. The dosage form according to claim 5 wherein the solid dosage form is a tablet.
8. The dosage form according to claim 7 wherein the tablet is coated.
9. The dosage form according to claim 5 wherein the dosage form further comprises pharmaceutical excipients.
10. The dosage form according to claim 9 wherein the pharmaceutical excipients include surfactant, diluents, binders, disintegrants, lubricants, glidants and coloring agents.
11. The dosage form according to claim 1 wherein the dosage form is a liquid.
12. The dosage form according to claim 11 wherein the liquid dosage form is a solution.
13. The dosage form according to claim 11 wherein the dosage form is a suspension.
14. The dosage form according to claim 11 wherein the dosage form in addition to oxcarbazepine comprises pharmaceutical excipients.
15. The dosage form according to claim 14 wherein the pharmaceutical excipients include solvents, antioxidants, suspending agent, preservatives, surfactant, sweeteners and flavoring agent.
16. The dosage form according to claim 13 wherein it is prepared by the process comprising:
a) dispersing the suspending agent in water
b) optionally, dispersing the surfactant in the dispersion of step a)
c) dispersing water soluble polymer in dispersion of step a) or step b)
d) dispersing the oxcarbazepine in the dispersion of step c),
e) optionally dispersing other pharmaceutical excipients,
f) homogenizing till a uniform suspension is obtained.
17. A process for the preparation of a solid pharmaceutical dosage form for oral
administration comprising oxcarbazepine and a water soluble polymer selected from
the group consisting of povidone, copovidone or mixture thereof comprising the steps
of
a) Preparing drug containing granules,
b) Optionally blending the other pharmaceutical excipients with drug containing granules,
c) compressing or filling the granules of step a) or blend of step b) into suitable size solid dosage form.
18. The process according to claim 17 drug containing granules are prepared by process
comprising the steps of:
a) dispersing a part of drug in water soluble polymer dispersion,
b) granulating the rest of the drug with dispersion of step a)
c) drying and sieving the granules obtained in step b)

19. The process according to 18 wherein dispersion of step a) further comprises surfactant.
20. The process according to claim 18 wherein granulation is carried out in fluidized bed processor.
21. The process according to claim 18 wherein granulation is carried out by conventional wet granulation method.
22. A pharmaceutical dosage form for oral administration comprising oxcarbazepine, a water soluble polymer comprising a mixture of povidone and copovidone and a surfactant.
23. Use of the dosage form as defined in any of the preceding claims in the treatment of partial seizures in adults with epilepsy and as adjunctive therapy in the treatment of partial seizures in children ages 4-16 with epilepsy.
24. A pharmaceutical dosage form for oral administration comprising oxcarbazepine as described and illustrated herein.