Patent Application
20080138403
Present invention relates to oxcarbazepine pharmaceutical dosage forms that provide oxcarbazepine in bioavailable form.
Oxcarbazepine is chemically known as 10,11-Dihydro-10-oxo-5H-dibenz [b,f]azepine-5-carboxamide. It is indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures in adults and children aged 4-16 with epilepsy. Oxcarbazepine is available commercially under the trade name Trileptal® in the United States of America as 150 mg, 300 mg and 600 mg film-coated tablets and a 300 mg/5 mL (60 mg/mL) suspension. Oxcarbazepine is practically insoluble in water and achieving adequate oral bioavailability from dosage forms containing oxcarbazepine represents the problem before the instant invention.
U.S. Pat. No. 7,037,525 (hereinafter referred to as '525 patent) provides film-coated tablets which comprise a tablet core comprising a therapeutically effective dose of oxcarbazepine, preferably in a finely ground form, having a median particle size of approximately from 2 μm to 12 μm, with a maximum residue on a 40 μm sieve of up to 5% and further excipients that are suitable for the production of granules; and a hydrophilic permeable outer coating. The tablets prepared according to this invention provide the therapeutically effective plasma levels of oxcarbazepine due to use of the specified median particle size of 2 μm to 12 μm.
PCT publication WO2002094774 (hereinafter referred to as publication number '774) discloses a dosage form for oral administration comprising oxcarbazepine and a wetting agent selected from anionic, cationic or non-ionic surface active agents or surfactants.
PCT publication WO2006046105 (hereinafter referred to as publication number '105) provides a pharmaceutical dosage form comprising oxcarbazepine having median particle size from about 14 μm to 30 μm. As discussed in '525 patent, we have also found that such compositions do not always provide adequate bioavailability of oxcarbazepine.
The object of the present invention was to find a novel method of preparation of orally bioavailable dosage forms of oxcarbazepine.
The present invention provides a pharmaceutical dosage forms comprising a mixture of a therapeutically effective amount of oxcarbazepine having median particle size ranging from about 15 μm to about 26 μm and one or more hydrophilic polymers, said mixture being formed by subjecting a suspension comprising said oxcarbazepine and a hydrophilic polymer in a solvent, to mixing in a homogenizer, optionally removing the solvent and converting the said mixture into a dosage form.
In another aspect of the invention, there is provided a process for preparing a pharmaceutical dosage forms comprising a mixture of a therapeutically effective amount of oxcarbazepine having median particle size ranging from about 15 μm to about 26 μm and one or more hydrophilic polymers, the process comprising
a shows the mean plasma concentration vs. time profile obtained upon administration of an embodiment (described in Example 1) of the present invention having 600 mg oxcarbazepine in comparison to that obtained from an equivalent dose of a dosage form having oxcarbazepine of median particle size of approximately 2 μm to 12 μm commercially available under the trade name of Trilepal®.
b shows the mean plasma concentration vs. time profile obtained upon administration of an embodiment (described in Example 2) of the present invention having 600 mg oxcarbazepine in comparison to that obtained from an equivalent dose of a dosage form having oxcarbazepine of median particle size of approximately 2 μm to 12 μm commercially available under the trade name of Trilepal®.
The term therapeutically effective amount of oxcarbazepine used herein means the amount of oxcarbazepine that may be used per unit dosage form ranges from about 100 mg to about 800 mg, preferably about 150 mg to about 700 mg.
According to one embodiment of the present invention, the pharmaceutical dosage form comprises therapeutically effective amount of oxcarbazepine having median particle size (D50) ranging from about 15 μm to about 26 μm.
The present invention provides pharmaceutical dosage form containing oxcarbazepine having median particle size in the range from about 15 μm to about 26 μm in the form of suitable dosage forms that upon oral administration provides bioavailability comparable to that obtained from an equivalent dose of a dosage form having oxcarbazepine of median particle size of approximately 2 μm to 12 μm available commercially under the trade name of Trilepal® (New Drug Application Number 021014 submitted to the United States Food and Drug Administration, USFDA).
The particle size of oxcarbazepine may be measured using laser light diffraction technique based instrument such as a Malvern Mastersizer Microplus apparatus. Other known methods of measuring particle size may also be used.
In a preferred embodiment of the present invention, the particle size limits for oxcarbazepine were as follows:
In a most preferred embodiment of the present invention, the particle size distribution of oxcarbazepine is such that D10 is not more than 10 microns; D50 is ranging from about 15 μm to about 26 μm and D90 is not more than 50 μm.
According to the present invention, oxcarbazepine is mixed with hydrophilic polymer in a homogenizer. Homogenization may be carried out by a conventional homogenization instruments such as Silverson homogenizer, colloid mill, microfluidizer and the like. Preferably, the homogenization is carried out at high shear to ensure deaggregation and uniform distribution of oxcarbazepine particles in the liquid medium.
Examples of hydrophilic polymers that are subjected to mixing in a homogenizer may be selected from group comprising of vinyl polymers, cellulose derivatives, polyethylene glycols and mixtures thereof.
Examples of the vinyl polymers that may be used in the present invention include, but are not limited to, polyvinyl pyrrolidone, polyvinyl alcohol and the like. Preferably, polyvinyl pyrrolidone (PVP) with an average molecular weight from about 2000 to about 60,000 may be used in amounts in the range from about 2% to about 10% by weight of oxcarbazepine. Higher viscosity grades of polyvinyl pyrrolidone make the process less convenient, but may also be used generally in lower amounts in the range from about 1% to about 5% by weight of oxcarbazepine.
Examples of the cellulose derivatives that may be used as hydrophilic polymers in the present invention include, but are not limited to, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose and mixtures thereof. Preferably, low viscosity grade cellulose derivatives are used. The low viscosity grade cellulose derivatives that may be used may have a viscosity ranging from about 2 to about 50 mPa, preferably from about 2 to about 15 mPas. These are the viscosity values for 2% (w/v) aqueous solutions measured at 20° C. Generally, high viscosity grades of cellulose derivatives having viscosity greater than 5000 cps are not recommended and particularly those having viscosity of about 10,000 cps may in fact reduce release rate of oxcarbazepine.
Examples of low grade viscosity hydroxy propyl methyl cellulose derivatives that may be used include, but are not limited to, E3 Low viscosity (LV) grade having viscosity of 2.4 to about 3.6, E5 LV having viscosity of 4 to about 6, E6 having viscosity ranging from 5 to 7, E15 having viscosity ranging from 12 to 18; E50 having viscosity ranging from 40 to 60; K3 having viscosity ranging from 2.4 to 3.6.
Examples of Low viscosity grades of hydroxypropyl cellulose that may be used include, but are not limited to, grades that give a viscosity in the range from about 200 mPas to 600 mPas (10% aqueous solution at 25° C.). These are available commercially under the trade name Klucel EF.
Hydroxyethyl cellulose may be used as a hydrophlic polymer according to one embodiment of the present invention. The suitable grades of HEC are those that give viscosity ranging from about 7 mPa to about 150 mPa (5% aqueous solution at 25° C.).
Examples of polyethylene glycol that may be used as hydrophilic polymers that are subjected to mixing in a homogenizer include, but are not limited to, polyethylene glycol having average molecular weights ranging from about 1,000 to 8000, preferably, from about 3000 to about 6000. One preferred embodiment of the present invention uses a mixture of polyethylene glycol 4000 and polyvinyl pyrrolidone as the hydrophilic polymer.
According to one embodiment of the present invention, the hydrophilic polymers and oxcarbazepine are subjected to mixing in a homogenizer in a hydrophilic polymers to oxcarbazepine ratios ranging from about 0.01:1 to about 0.3:1, preferably about 0.02:1 to about 0.08:1, most preferably about 0.06:1.
One of the more preferred embodiments of the present invention uses PVP wherein the ratio between PVP and oxcarbazepine ranges from about 0.04:1 to about 0.06:1. In another more preferred embodiment of the present invention, polyethylene glycol is used as a hydrophilic polymer in combination with PVP wherein the ratio of hydrophilic polymer that is subjected to mixing in a homogenizer to oxcarbazepine is about 0.066:1.
In one of the preferred embodiments of the present invention where the pharmaceutical dosage form is converted into a solid dosage form, the solid dosage form may additionally contain other pharmaceutically acceptable excipients such as wicking agents, disintegrants, binders, lubricants and glidants. Solid dosage forms of the present invention include, but are not limited to, powder, granules, pellets, pills, microspheres, microcapsules, capsules, tablets and the like.
In an embodiment of the present invention, the dosage form is in the form of a tablet. The amount of hydrophilic polymer that is subjected to mixing in a homogenizer may range from about 0.5% to about 20% by weight of the tablet. In one of the preferred embodiments of the present invention where the dosage form is a tablet, the amount of hydrophilic polymers that are subjected to mixing in a homogenizer is used in the range of about 2% to about 10% by weight of the tablet.
When the solid dosage form of the present invention is in the form of powders, granules, pellets, pills, microcapsules, semisolid and the like, it may be conveniently dispensed in a suitable container preferably, packed in a single unit dose into each container. A suitable single unit dose container that may be used for example, may be a sachet, a capsule and the like.
The solid dosage form of the present invention may also be a semisolid containing mixture of oxcarbazepine and the hydrophilic polymer. The semisolid may be prepared by further mixing or milling or homogenizing the said mixture with pharmaceutically acceptable liquid or semisolid vehicles known in the art. Suitable vehicles that may be used include, polyethylene glycol, propylene glycol, fatty acid triglycerides, emulsifiers and the like.
Examples of wicking agents that may be used in the pharmaceutical dosage form of the present invention include, but are not limited to, colloidal silicon dioxide, kaolin, fumed silicon dioxide, microcrystalline cellulose and the like and mixtures thereof. According to one embodiment of the present invention, the wicking agent may be sifted together with oxcarbazepine. The amount of wicking agent that may be used to sift together with oxcarbazepine may range from about 0.1% to about 1.0% by weight of the oxcarbazepine amount, preferably from about 0.3% to about 0.75% by weight of the oxcarbazepine amount.
Examples of disintegrants that may be used in the pharmaceutical dosage forms of the present invention may be selected from the group comprising microcrystalline cellulose, starch, e.g., pregelatinized starch and corn starch, croscarmellose sodium, sodium starch glycolate, crospovidone and the like and mixtures thereof. The amount of disintegrants that may be used ranges from about 0.1% to about 30% by weight of the total weight of the mixture of oxcarbazepine and all other excipients in the dosage form.
Examples of binders that may be used in the pharmaceutical solid dosage form of the present invention may be selected from the group comprising starch, gelatin, dextrin, maltodextrin, natural and synthetic gums like acacia, carboxymethylcellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol and the like and mixtures thereof. The amount of disintegrants may range from about 0.1% to about 20% by weight of the total weight of the mixture of oxcarbazepine and all other excipients in the dosage form.
Examples of the lubricants that may be used in the pharmaceutical solid dosage form of the present invention include, but are not limited to, talc, sodium stearyl fumarate, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils, polyethylene glycol and the like and mixtures thereof. The amount of disintegrants may range from about 0.01% to about 5% by weight of the total weight of the mixture of oxcarbazepine and all other excipients in the dosage form.
Examples of the glidants that may be used in the pharmaceutical solid dosage form of the present invention include, but are not limited to, magnesium stearate, colloidal silicon dioxide, talc and the like. The amount of glidants may range from about 0.01% to about 1% by weight of the total weight of the mixture of oxcarbazepine and all other excipients in the dosage form.
The pharmaceutical dosage form of the present invention may be a liquid dosage form. The liquid dosage form of the present invention may contain pharmaceutical excipients such as suspending agents, flocculants or deflocculating agents, flavouring agents, taste masking agents and the like.
According to the process of the present invention, first the hydrophilic polymer(s) are dissolving in a solvent to get a solution. It is possible to use either an aqueous or an organic solvent for dissolving the hydrophilic polymers. Generally, a solvent in which oxcarbazepine is only slightly soluble is used in the present invention. Preferably, the amount of solvent used ranges from about 50% by weight to about 90% by weight of oxcarbazepine, more preferably from about 60% to about 80% by weight of oxcarbazepine.
Examples of the solvents that may be used include, but are not limited to, purified water, isopropyl alcohol, dichloromethane and the like and mixture thereof. The type of solvent that may be used depends on the nature of hydrophilic polymer that is being used. In one preferred embodiment of the present invention, polyvinyl pyrrolidone is used as the hydrophilic polymer and a mixture of isopropyl alcohol and dichloromethane is used as the solvent.
In one embodiment of the present invention, the amount of hydrophilic polymer that is subjected to mixing in a homogenizer ranges from about 5% to about 30% by weight of the solvent, more preferably from about 10% to about 25% by weight of the solvent.
According to the process of the present invention, the pharmaceutical dosage form may be prepared by first dissolving the hydrophilic polymer in a solvent. In one of the preferred embodiments, oxcarbazepine is blended with diluent such as Aerosil preferably by sifting the two together through a sieve and the mixture obtained is added with stirring into the solution of hydrophilic polymer in the solvent. The slurry obtained is subjected to mixing in a homogenizer. A slurry that is obtained may be easily flowable to one that is of the paste like consistency that is amenable to mixing in a homogenizer.
In a preferred embodiment of the present invention, a colloid mill is used for mixing. In a more preferred embodiments of the present invention, the clearance between the stator and the rotor of the colloid mill (by CIP Machineries Pvt. Ltd; model: COLLOID HHZ) is adjusted between 5 to 10 units on the attached scale. The speed of the homogenizer may be adjusted to about 5000 rpm. Generally, more than one pass through the homogenizer, for example two passes may be required to get smooth slurry of oxcarbazepine particles in a solution comprising the hydrophilic polymer.
In one embodiment of the present invention, purified water is used as a solvent. The slurry so obtained may itself constitute a suspension dosage form or additional pharmaceutical excipients may be added to obtain a suspension dosage form suitable for oral administration. Alternately, when the solvent includes a non-aqueous solvent, then the solvent may be removed completely or to an acceptable trace levels in further processing, and the dry powder mixture obtained is converted to a suspension using known art and suitable pharmaceutically acceptable excipients.
In one embodiment of the present invention, multiparticulates dosage forms, for example, multiparticulates may be obtained from the slurry. The slurry may be dried to remove the solvent and the dried mass is sieved. The granules may be filled into capsules, sachets or any other suitable unit dose container. In an alternate embodiment, the slurry may be dried until a wet mass is obtained. The wet mass may be granulated by conventional granulation or extrusion-spheronization and the granules may be filled into capsules, sachets or any other suitable unit dose container. Any of the dried multiparticulate mixtures obtained as set forth may be formulated into a suspension dosage form by dispersing them in a suitable pharmaceutically acceptable liquid vehicle. In a preferred embodiment of the present invention, the slurry is converted into tablets. The slurry is mixed with pharmaceutical excipients and granulated to form wet granules. Preferably, the granulation is carried out using heat and vacuum to remove the solvent completely or to pharmaceutically acceptable trace levels.
Preferably no residual solvent is present after drying was completed. For example, in embodiments of the present invention, where dichloromethane is used as a solvent, the residual dichloromethane content is not more than 360 μg per unit dosage form, more preferably it is absent. Similarly, residual isopropyl alcohol content is not more than 3120 μg per unit dosage form, preferably less than 1000 μg per unit dosage form, more preferably less than 800 μg unit dosage form. In preferred embodiments, the total residual solvent (other than water) content is not more than 1000 μg per unit dosage form.
The examples that follow are provided as illustrations and do not limit the scope of the present invention.
A slurry containing oxcarbazepine and hydrophilic polymer in a mixture of isopropyl alcohol and dichloromethane was prepared according to the composition in Table 1 as follows.
The oxcarbazepine and Aerosil were sifted together through sieve #40 ASTM. The PVP K-30 and polyethylene glycol 4000 were dissolved in 1:1 mixture of isopropyl alcohol and dichloromethane. The oxcarbazepine and Aerosil mixture was added to the solution of hydrophilic polymer under a propeller stirrer. After addition was complete stirring was continued for further 10 minutes. The slurry obtained was passed through colloid mill (by CIP Machineries Pvt. Ltd; model: COLLOID HHZ) and recirculated for 15 minutes at a clearance setting of 7 of the attached scale. The colloid mill was rinsed with minimum amount of solvent mixture.
The particle size distribution of oxcarbazepine was checked after subjecting the slurry of oxcarbazepine and the hydrophilic polymer in a solvent, to mixing in a colloid mill. The particle size was determined by Malvern laser diffraction technique. The particles were dispersed in an aqueous dispersion medium of Tween 20 (0.1 ml/litre). The results are given in Table 2.
The slurry containing the homogenized mixture of the present invention was converted into tablet dosage form having a composition given in Table 3 as follows.
The slurry was discharged into a jacketed rotary mixer granulator. Steam was circulated through the jacket and vacuum applied. Avicel and crospovidone mixture was added and a wet mass obtained was kneaded. It was passed through sieve # 8 ASTM and dried in a fluid bed at 55° C. until the loss of drying was not more than 1.2% by w/w. This amount is attributable mainly to the trace water that is usually present in isopropyl alcohol.
The dried mass was passed through sieve # 20 ASTM and mixed with lubricants. Granules were compressed into tablets. The tablets were further coated with aqueous polyvinyl alcohol suspension till 2.5% weight gain is achieved. The residual dichloromethane content was less than 30 μg per tablet and the residual isopropyl alcohol content was less than 800 μg per tablet.
A slurry containing oxcarbazepine (median particle size D50=24.91 μm, D10=6.59 μm and D90=63.31 μm) and hydrophilic polymer in a mixture of isopropyl alcohol and dichloromethane was prepared according to the composition in Table 4 as follows.
Oxcarbazepine and Aerosil were sifted together. PVP K-30 was dissolved in a 1:1 mixture of isopropyl alcohol and dichloromethane. Oxcarbazepine and Aerosil were added to the PVP-K-30 solution in the solvent under a propeller stirrer. After addition was complete stirring was continued for further 10 minutes. The slurry of oxcarbazepine was passed through colloid mill (by CIP Machineries Pvt. Ltd; model: COLLOID HHZ) and recirculated for 15 minutes at the clearance setting of 5 of the attached scale. The mill was rinsed with minimum amount of solvent mixture. Rinsing was added to the slurry. The slurry was sprayed in trays and placed in tray dryer set at 35° C.
The slurry containing the homogenized mixture of the present invention was converted into tablet dosage form having a composition given in Table 5 as follows.
The dried slurry was removed from oven and mixture of Avicel and croscarmellose was added to it and the mass was kneaded, sieved through 8 # and dried at 55° C. The dried mass was passed through 20 # sieve and lubricated. The granules were compressed into tablets and were coated film coated.
The bioavailability of the oral pharmaceutical dosage form (tablet) of oxcarbazepine of the present invention and that of oxcarbazepine tablets containing equivalent dose of oxcarbazepine having a median particle size of approximately 2 μm to about 12 μm, commercially available under the trade name of Trileptal® tablets (600 mg) were studied. A single-dose, open label, randomized, comparative and two-way crossover study, with a seven-day washout period, was undertaken for the same.
Healthy male volunteers (n=number of volunteers, n=64 for Example 1 and n=40 for Example 2) were enrolled for two-way crossover study. The subjects were fasted overnight before dosing and for 4 hours thereafter. Drinking water was prohibited 2 hours before dosing and 2 hours thereafter, but was allowed at all other times. Standard meals were provided at 4, 6 and 8 hours after dosing and at appropriate times thereafter. Meal plans were identical for both the periods.
Subjects received a single tablet of oxcarbazepine prepared according to Example 1 and Example 2 respectively (600 mg) with 240 ml of drinking water at ambient temperature as the test medication, and a single oral dose of Trileptal® (600 mg oxcarbazepine) also with 240 ml of drinking water at ambient temperature as the reference medication.
The results of the bioavailability study are given in
a and
| Number | Date | Country | Kind |
|---|---|---|---|
| 2012/MUM/2006 | Dec 2006 | IN | national |
