EP2146699A2 - Pharmaceutical compositions comprising oxcarbazepine - Google Patents

Pharmaceutical compositions comprising oxcarbazepine

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Publication number
EP2146699A2
EP2146699A2 EP08758478A EP08758478A EP2146699A2 EP 2146699 A2 EP2146699 A2 EP 2146699A2 EP 08758478 A EP08758478 A EP 08758478A EP 08758478 A EP08758478 A EP 08758478A EP 2146699 A2 EP2146699 A2 EP 2146699A2
Authority
EP
European Patent Office
Prior art keywords
oxcarbazepine
pharmaceutical composition
composition according
total weight
particles
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08758478A
Other languages
German (de)
French (fr)
Inventor
Satish G. Dhonde
Ganesh V. Gat
Jawed Hussain
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ratiopharm GmbH
Original Assignee
Ratiopharm GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ratiopharm GmbH filed Critical Ratiopharm GmbH
Publication of EP2146699A2 publication Critical patent/EP2146699A2/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • compositions comprising Oxcarbazepine
  • the present invention relates to a pharmaceutical composition comprising Oxcarbazepine.
  • Oxcarbazepine 10,11-dihydro-10-oxo-5H-dibenzo(b,f)azepine-5-carboxamide, is an anticonvulsant and mood stabilizing drug, used primarily in the treatment of epilepsy and bipolar disorders.
  • Oxcarbazepine has the following chemical structure:
  • Oxcarbazepine is known in dosage forms, such as tablets and liquid dosage forms, e.g. suspensions, which are suitable for ensuring a uniform concentration of active ingredient in the blood, especially in the case of regular adminstration over a prolonged period of treatment.
  • Oxcarbazepine is only poorly soluble in water.
  • WO 02/094774 A2 discloses a dosage form composition for oral adminstration comprising Oxcarbazepine and a wetting agent.
  • the use of the wetting agent in the formulation may show enhanced dissolution rates in the in-vitro conditions, but an effectivity in-vivo has not been shown yet. Further the use of a wetting agent in pharmaceutical compositions is disadvantageous.
  • a pharmaceutical composition which comprises Oxcarbazepine in the form of particles with a mean particle size of about 2 ⁇ m or less and contains not more than about 7 wt.%, preferably not more than 5 wt.%, more preferably not more than about 2 wt.% of a binder, based on the total weight of the composition, dissolves quickly without the need of a wetting agent.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising about 20-90 wt.% of Oxcarbazepin or a pharmaceutically acceptable salt thereof as active ingredient, based on the total weight of the composition, the Oxcarbazepine being in the form of particles, wherein the median particle size of the Oxcarbazepine particles is about 2 ⁇ m or less and the composition does not contain more than about 7 wt.%, preferably not more than 5 wt.%, more preferably not more than about 2 wt.% of a binder, based on the total weight of the composition.
  • WO 02/094774 generally suggests to use a wetting agent, as without a wetting agent a desired dissolution profile of Oxcarbazepine tablets would not be obtained. It is further suggested to reduce the median particle size below 10 ⁇ m for getting a desired dissolution profile. However, the desired dissolution profile could only be obtained for mean particle sizes of 10 ⁇ m and 9 ⁇ m. Reduction of the mean particle size to 1 ,5 ⁇ m provided a tablet containing Oxcarbazepine showing a rather poor dissolution profile.
  • the present invention provides pharmaceutical compositions comprising Oxcarbazepine as active ingredient, wherein the Oxcarbazepine particles have a median particle size of about 2 ⁇ m or less and the composition does not contain more than about 7 wt.%, preferably not more than 5 wt.%, more preferably not more than about 2 wt.% of a binder.
  • Such compositions show to have, contrary to the compositions disclosed in WO 02/094774 lacking a wetting agent, an excellent, quick dissolution of the active ingredient, in particular a dissolution profile such that at least 80 wt.% or more of the active ingredient contained in the tablet is dissolved within 15 minutes without using a wetting agent.
  • the pharmaceutical composition according to the present invention contains not more than about 7 wt.%, preferably not more than 5 wt.%, more preferably not more than about 2 wt.% of a binder, based on the total weight of the composition, even more preferably not more than about 1.5 wt.%, in particular not more than about 1 wt.% of a binder.
  • Binders to be used in the compositions of the present invention are such binders known in the art, i.e. compounds which have cohesive properties to act as binders, in particular hydroxypropylmethyl celluloses, hydroxypropyl celluloses (HPC), polyvinyl pyrrolidone (PVP), starches and modified starches.
  • binders e.g. cross-linked polyvinyl pyrrolidone, which can be used as disintegrant and binder, is regarded, according to the present invention, as a binder.
  • compounds which can also be used as excipients or adjuvants different to binders, such as disintegrants, or diluents are, according to the present invention, not regarded as binders, but as disintegrants and diluents, respectively (e.g. cross-linked polyvinyl pyrrolidone is regarded as disintegrant only).
  • the pharmaceutical compositions of the present invention generally comprise Oxcarbazepine as active ingredient, in particular about 20-90 wt.%, based on the total weight of the composition, preferably about 50-80 wt.%, in particular about 60-78 wt.%, e.g. about 73 wt.%.
  • the Oxcarbazepine is in the form of particles and the median particle size of the Oxcarbazepine is about 2 ⁇ m or less, such as about 1.5 ⁇ m or less or about 1 ⁇ m or less.
  • the Oxcarbazepine particles have a narrow particle size distribution being defined by the ratio between the median particle size and the particle size at the 95% quantile. This ratio can be equal to or greater than about 0.4, preferably greater than about 0.45, more preferably greater than about 0.5 and most preferably between about 0.55 and about 0.7, such as for example about 0.60 ⁇ 0.02.
  • particle size distribution means the cummulative volume size distribution of equivalent spherical diameters as determined by laser diffraction in accordance with ISO 13320, preferably at 1.0 bar dispersive pressure in a MASTERSIZER 2000 (Malvern Instruments) equipment in particular as described in Example 4.
  • Median particle size correspondigly, means the median of said particle size distribution (d(0.5) or X 50 (ISO 13320)); d(0.1) corresponds to X 10 (ISO 13320) and d(0.9) corresponds to X 90 (ISO 13320).
  • the pharmaceutical composition of the present invention may further comprise suitable pharmaceutically acceptable excipients and adjuvants, such as diluents, disintegrants, glidants, lubricants, and/or film formers/film coating agents.
  • suitable pharmaceutically acceptable excipients and adjuvants such as diluents, disintegrants, glidants, lubricants, and/or film formers/film coating agents.
  • diluents mannitol, lactose, starch and microcrystalline cellulose can be exemplified.
  • the pharmaceutical composition of the present invention contains about 0-80 wt.% of a diluent, preferably about 10-20 wt.% of a diluent, more preferably about 14-18 wt.% of a diluent, in particular about 17 wt.%, based on the total weight of the composition.
  • Disintegrants preferred for the pharmaceutical composition of the present invention may be selected, as far as they are regarded as disintegrants according to the above definition, from starches or modified starches such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch, celluloses such as microcrystalline celluloses, carboxymethyl celluloses, such as modified sodium carboxymethyl celluloses, algines such as sodium alginate or alginic acid, crosslinked celluloses such as crosscarmellosodium, gums such as guar gum or xanthan gum, crosslinked polymers such as crosspovidone, and effervescent agents such as sodium bicarbonate and citric acid, and mixtures thereof.
  • starches or modified starches such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch
  • celluloses such as microcrystalline celluloses, carboxymethyl celluloses, such as modified sodium carboxymethyl celluloses
  • algines such as sodium alginate or alginic acid
  • the pharmaceutical composition of the present invention preferably contains about 0-20 wt.% of a disintegrant, more preferably about 2-8 wt.% of a disintegrant, even more preferably about 4-6 wt.% of a disintegrant, in particular about 5 wt.% of a disintregrant, based on the total weight of the composition.
  • glidants to be used in the pharmaceutical composition of the present invention talc and colloidal silicone dioxide can be exemplified.
  • the pharmaceutical composition of the present invention preferably contains about 0-2 wt.% of a glidant, more preferably about 0.1-1 wt.% of a glidant, in particular about 0.6 wt.% of a glidant, based on the total weight of the composition.
  • the pharmaceutical composition of the present invention may further contain a lubricant such as talc or magnesium stearate, or other alkali earth metal stearates like calcium, zinc etc., lauryl sulphate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate and a polyethylenglycol, such as PEG 4000.
  • a lubricant such as talc or magnesium stearate, or other alkali earth metal stearates like calcium, zinc etc., lauryl sulphate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate and a polyethylenglycol, such as PEG 4000.
  • the pharmaceutical composition of the present invention contains about 0-2 wt.% of a lubricant, more preferably about 0.5-1.5 wt.% of a lubricant, in particular about 1 wt.% of
  • the pharmaceutical composition of the present invention may further contain a film former, which is preferably applied as the film coating on a solid form of the pharmaceutical composition.
  • a film former is preferably based on hydroxypropylmethyl cellulose (HPMC) and/or on polyvinyl alcohol (PVA).
  • HPMC hydroxypropylmethyl cellulose
  • PVA polyvinyl alcohol
  • the film former is preferably contained in the pharmaceutical composition of the present invention in an amount of about 0-5 wt.%, more preferably about 1-4 wt.%, in particular about 3 wt.%, based on the total weight of the composition, and is preferably applied as a film coating onto the solid forms of the pharmaceutical composition.
  • the pharmaceutical composition of the present invention contains about 0-20 wt.% of a diluent, about 0-10 wt.% of a disintegrant, about 0-2 wt.% of a glidant, about 0-2 wt.% of a lubricant, and about 0-5 wt.% of a film former, each based on the total weight of the composition.
  • the ingredients of the pharmaceutical composition have to sum up to 100 wt.%.
  • composition of the present invention may comprise various other conventional excipients as known to the person skilled in the art, such as colouring agents or sweeteners.
  • the pharmaceutical composition according to the present invention is in the form of a solid pharmaceutical composition, such as a capsule or a tablet, the latter being particularly preferred. Even more preferable the pharmaceutical composition is a film coated tablet. Preferably such a tablet shows a dissolution profile such that about 80 wt.% or more of the active ingredients contained in the tablet is dissolved within 15 minutes.
  • the term "dissolution profile" within this application means the variation in time of the amount of active ingredient, which is dissolved, based on the total amount of this ingredient contained in the solid pharmaceutical composition.
  • the dissolution profile is obtained by dissolving a tablet in an USP apparatus Il in 900 ml water containing 1% SDS (sodiumdodecylsulphate) at 37 0 C under stirring (paddle) with a stirring speed of 60 rpm, and the amount of active ingredient is detected over a range of time, such as 45 minutes at different points of time, e.g. after 5, 10, 15, 20, 30 and 45 minutes.
  • the solid preparation composition of the present invention may be prepared by conventional methods as known to those skilled in the art.
  • the tablets may be prepared by conventional tabletting methods.
  • the tablets are prepared by granulating, preferably wet granulation.
  • the active ingredient together with any excipient may be filled into capsules, such as hard gelatin capsules by conventional methods, for example using a capsule filler suitable for powder filling.
  • the solid pharmaceutical compositions of the present invention compressed as tablets are in a unit dosage form comprising about 150, 300 or 600 mg of Oxcarbazepine.
  • the tablets prepared from the pharmaceutical composition comprising Oxcarbazepine according to the present invention exhibit a dissolution profile being very similar to the dissolution profile of the commercially available Trileptal ® tablets (Novartis Germany).
  • the present invention also relates to a process for the preparation of a pharmaceutical composition according to the present invention comprising mixing the Oxcarbazepine or pharmaceutically acceptable salt thereof being in the form of particles, which preferably have a median particle size of about 2 ⁇ m or less, with the pharmaceutically acceptable excipients and adjuvants, and preparing a solid pharmaceutical composition, preferably a tablet from said mixture, which is optionally film coated.
  • the present invention relates to the use of Oxcarbazepine or a pharmaceutically acceptable salt thereof in the form of particles having a median particle size of about 2 ⁇ m or less for the preparation of a pharmaceutical composition according to the present invention.
  • a dissolution profile of the tablets of example 1 is shown in Figure 1.
  • a dissolution profile of the tablets of example 2 is shown in Figure 2.
  • the following examples are merely intended to illustrate the invention and should not be construed as limiting.
  • Oxcarbazepine film coated tablets containing 150, 300 and 600 mg of Oxcarbazepine
  • the coating composition is the same except for the use of different colors e.g.
  • Oxcarbazepine Microcrystalline cellulose (Avicel PH 101) and Hydroxypropyl methyl cellulose (Methocel E5 LV) in a mixer (High shear mixer granulator) and dry mix to ensure adequate mixing;
  • Oxcarbazepine film coated tablets containing 150, 300 and 600 mg of Oxcarbazepine
  • the coating composition is the same except for the use of different colors e.g.
  • Oxcarbazepine Microcrystalline cellulose (Avicel PH 101) and Hydroxypropyl methyl cellulose (Methocel E5 LV) in a mixer (High shear mixer granulator) and dry mix to ensure adequate mixing;
  • Coating compositions for Oxcarbazepine film coated tablets containing 150, 300 and
  • Particle size determination (PSD) method Particle size determination (PSD) method:

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  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

The present invention relates to pharmaceutical compositions containing Oxcarbazepine having a median particle size of about 2 μm or less.

Description

Pharmaceutical compositions comprising Oxcarbazepine
The present invention relates to a pharmaceutical composition comprising Oxcarbazepine.
Oxcarbazepine, 10,11-dihydro-10-oxo-5H-dibenzo(b,f)azepine-5-carboxamide, is an anticonvulsant and mood stabilizing drug, used primarily in the treatment of epilepsy and bipolar disorders. Oxcarbazepine has the following chemical structure:
Oxcarbazepine is known in dosage forms, such as tablets and liquid dosage forms, e.g. suspensions, which are suitable for ensuring a uniform concentration of active ingredient in the blood, especially in the case of regular adminstration over a prolonged period of treatment. However, Oxcarbazepine is only poorly soluble in water.
One of the earlier attempts to enhance the dissolution rate and bioavailability of Oxcarbazepine relied on particle size reduction of the Oxcarbazepine in an order of 2-12 μm. International Application WO 98/35681 discloses a composition of Oxcarbazepine for oral adminstration employing micronized drug particles in the size of 2-12 μm. However, the dissolution profile of such compositions is still not satisfactory.
Therefore, later attempts to enhance the dissolution rate were conducted involving the use of a wetting agent in the formulations. WO 02/094774 A2 discloses a dosage form composition for oral adminstration comprising Oxcarbazepine and a wetting agent. The use of the wetting agent in the formulation may show enhanced dissolution rates in the in-vitro conditions, but an effectivity in-vivo has not been shown yet. Further the use of a wetting agent in pharmaceutical compositions is disadvantageous.
Therefore, there is still a need for pharmaceutical compositions comprising Oxcarbazepine which are fast dissolving without the need to use a wetting agent.
It has now surprisingly be found that a pharmaceutical composition which comprises Oxcarbazepine in the form of particles with a mean particle size of about 2 μm or less and contains not more than about 7 wt.%, preferably not more than 5 wt.%, more preferably not more than about 2 wt.% of a binder, based on the total weight of the composition, dissolves quickly without the need of a wetting agent. Therefore, the present invention relates to a pharmaceutical composition comprising about 20-90 wt.% of Oxcarbazepin or a pharmaceutically acceptable salt thereof as active ingredient, based on the total weight of the composition, the Oxcarbazepine being in the form of particles, wherein the median particle size of the Oxcarbazepine particles is about 2 μm or less and the composition does not contain more than about 7 wt.%, preferably not more than 5 wt.%, more preferably not more than about 2 wt.% of a binder, based on the total weight of the composition.
WO 02/094774 generally suggests to use a wetting agent, as without a wetting agent a desired dissolution profile of Oxcarbazepine tablets would not be obtained. It is further suggested to reduce the median particle size below 10 μm for getting a desired dissolution profile. However, the desired dissolution profile could only be obtained for mean particle sizes of 10 μm and 9 μm. Reduction of the mean particle size to 1 ,5 μm provided a tablet containing Oxcarbazepine showing a rather poor dissolution profile.
Contrary to that disclosure the present invention provides pharmaceutical compositions comprising Oxcarbazepine as active ingredient, wherein the Oxcarbazepine particles have a median particle size of about 2 μm or less and the composition does not contain more than about 7 wt.%, preferably not more than 5 wt.%, more preferably not more than about 2 wt.% of a binder. Such compositions show to have, contrary to the compositions disclosed in WO 02/094774 lacking a wetting agent, an excellent, quick dissolution of the active ingredient, in particular a dissolution profile such that at least 80 wt.% or more of the active ingredient contained in the tablet is dissolved within 15 minutes without using a wetting agent. The pharmaceutical composition according to the present invention contains not more than about 7 wt.%, preferably not more than 5 wt.%, more preferably not more than about 2 wt.% of a binder, based on the total weight of the composition, even more preferably not more than about 1.5 wt.%, in particular not more than about 1 wt.% of a binder. Binders to be used in the compositions of the present invention are such binders known in the art, i.e. compounds which have cohesive properties to act as binders, in particular hydroxypropylmethyl celluloses, hydroxypropyl celluloses (HPC), polyvinyl pyrrolidone (PVP), starches and modified starches. Compounds which can also be used as excipients or adjuvants different to binders, such as disintegrants, or diluents, are, according to the present invention, regarded as binders (e.g. cross-linked polyvinyl pyrrolidone, which can be used as disintegrant and binder, is regarded, according to the present invention, as a binder).
In one embodiment of the present invention compounds which can also be used as excipients or adjuvants different to binders, such as disintegrants, or diluents, are, according to the present invention, not regarded as binders, but as disintegrants and diluents, respectively (e.g. cross-linked polyvinyl pyrrolidone is regarded as disintegrant only).
The pharmaceutical compositions of the present invention generally comprise Oxcarbazepine as active ingredient, in particular about 20-90 wt.%, based on the total weight of the composition, preferably about 50-80 wt.%, in particular about 60-78 wt.%, e.g. about 73 wt.%. The Oxcarbazepine is in the form of particles and the median particle size of the Oxcarbazepine is about 2 μm or less, such as about 1.5 μm or less or about 1 μm or less. Preferably the Oxcarbazepine particles have a narrow particle size distribution being defined by the ratio between the median particle size and the particle size at the 95% quantile. This ratio can be equal to or greater than about 0.4, preferably greater than about 0.45, more preferably greater than about 0.5 and most preferably between about 0.55 and about 0.7, such as for example about 0.60 ± 0.02.
As used herein, "particle size distribution" means the cummulative volume size distribution of equivalent spherical diameters as determined by laser diffraction in accordance with ISO 13320, preferably at 1.0 bar dispersive pressure in a MASTERSIZER 2000 (Malvern Instruments) equipment in particular as described in Example 4. "Median particle size", correspondigly, means the median of said particle size distribution (d(0.5) or X50 (ISO 13320)); d(0.1) corresponds to X10 (ISO 13320) and d(0.9) corresponds to X90 (ISO 13320).
The pharmaceutical composition of the present invention may further comprise suitable pharmaceutically acceptable excipients and adjuvants, such as diluents, disintegrants, glidants, lubricants, and/or film formers/film coating agents. As diluents mannitol, lactose, starch and microcrystalline cellulose can be exemplified. The pharmaceutical composition of the present invention contains about 0-80 wt.% of a diluent, preferably about 10-20 wt.% of a diluent, more preferably about 14-18 wt.% of a diluent, in particular about 17 wt.%, based on the total weight of the composition.
Disintegrants preferred for the pharmaceutical composition of the present invention may be selected, as far as they are regarded as disintegrants according to the above definition, from starches or modified starches such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch, celluloses such as microcrystalline celluloses, carboxymethyl celluloses, such as modified sodium carboxymethyl celluloses, algines such as sodium alginate or alginic acid, crosslinked celluloses such as crosscarmellosodium, gums such as guar gum or xanthan gum, crosslinked polymers such as crosspovidone, and effervescent agents such as sodium bicarbonate and citric acid, and mixtures thereof. The pharmaceutical composition of the present invention preferably contains about 0-20 wt.% of a disintegrant, more preferably about 2-8 wt.% of a disintegrant, even more preferably about 4-6 wt.% of a disintegrant, in particular about 5 wt.% of a disintregrant, based on the total weight of the composition.
As glidants to be used in the pharmaceutical composition of the present invention talc and colloidal silicone dioxide can be exemplified. The pharmaceutical composition of the present invention preferably contains about 0-2 wt.% of a glidant, more preferably about 0.1-1 wt.% of a glidant, in particular about 0.6 wt.% of a glidant, based on the total weight of the composition.
The pharmaceutical composition of the present invention may further contain a lubricant such as talc or magnesium stearate, or other alkali earth metal stearates like calcium, zinc etc., lauryl sulphate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate and a polyethylenglycol, such as PEG 4000. Preferably the pharmaceutical composition of the present invention contains about 0-2 wt.% of a lubricant, more preferably about 0.5-1.5 wt.% of a lubricant, in particular about 1 wt.% of a lubricant, based on the total weight of the composition.
The pharmaceutical composition of the present invention may further contain a film former, which is preferably applied as the film coating on a solid form of the pharmaceutical composition. Such film former is preferably based on hydroxypropylmethyl cellulose (HPMC) and/or on polyvinyl alcohol (PVA). The film former is preferably contained in the pharmaceutical composition of the present invention in an amount of about 0-5 wt.%, more preferably about 1-4 wt.%, in particular about 3 wt.%, based on the total weight of the composition, and is preferably applied as a film coating onto the solid forms of the pharmaceutical composition.
Preferably the pharmaceutical composition of the present invention contains about 0-20 wt.% of a diluent, about 0-10 wt.% of a disintegrant, about 0-2 wt.% of a glidant, about 0-2 wt.% of a lubricant, and about 0-5 wt.% of a film former, each based on the total weight of the composition. The ingredients of the pharmaceutical composition have to sum up to 100 wt.%.
Besides the above compounds the pharmaceutical composition of the present invention may comprise various other conventional excipients as known to the person skilled in the art, such as colouring agents or sweeteners.
Preferably the pharmaceutical composition according to the present invention is in the form of a solid pharmaceutical composition, such as a capsule or a tablet, the latter being particularly preferred. Even more preferable the pharmaceutical composition is a film coated tablet. Preferably such a tablet shows a dissolution profile such that about 80 wt.% or more of the active ingredients contained in the tablet is dissolved within 15 minutes.
The term "dissolution profile" within this application means the variation in time of the amount of active ingredient, which is dissolved, based on the total amount of this ingredient contained in the solid pharmaceutical composition. The dissolution profile is obtained by dissolving a tablet in an USP apparatus Il in 900 ml water containing 1% SDS (sodiumdodecylsulphate) at 37 0C under stirring (paddle) with a stirring speed of 60 rpm, and the amount of active ingredient is detected over a range of time, such as 45 minutes at different points of time, e.g. after 5, 10, 15, 20, 30 and 45 minutes. The solid preparation composition of the present invention may be prepared by conventional methods as known to those skilled in the art. The tablets may be prepared by conventional tabletting methods. Preferably the tablets are prepared by granulating, preferably wet granulation.
Alternatively the active ingredient together with any excipient may be filled into capsules, such as hard gelatin capsules by conventional methods, for example using a capsule filler suitable for powder filling.
Preferably the solid pharmaceutical compositions of the present invention compressed as tablets are in a unit dosage form comprising about 150, 300 or 600 mg of Oxcarbazepine.
Surprisingly, the tablets prepared from the pharmaceutical composition comprising Oxcarbazepine according to the present invention exhibit a dissolution profile being very similar to the dissolution profile of the commercially available Trileptal® tablets (Novartis Germany).
The present invention also relates to a process for the preparation of a pharmaceutical composition according to the present invention comprising mixing the Oxcarbazepine or pharmaceutically acceptable salt thereof being in the form of particles, which preferably have a median particle size of about 2 μm or less, with the pharmaceutically acceptable excipients and adjuvants, and preparing a solid pharmaceutical composition, preferably a tablet from said mixture, which is optionally film coated.
Further the present invention relates to the use of Oxcarbazepine or a pharmaceutically acceptable salt thereof in the form of particles having a median particle size of about 2 μm or less for the preparation of a pharmaceutical composition according to the present invention.
A dissolution profile of the tablets of example 1 is shown in Figure 1.
A dissolution profile of the tablets of example 2 is shown in Figure 2. The following examples are merely intended to illustrate the invention and should not be construed as limiting.
Example 1:
Oxcarbazepine film coated tablets, containing 150, 300 and 600 mg of Oxcarbazepine
For all strength (150, 300 and 600 mg) the coating composition is the same except for the use of different colors e.g.
For 600 mg strength Red Iron oxide, Black Iron oxide, Yellow Iron oxide and Titanium Dioxide.
For 300 mg strength colors are Yellow Iron oxide and Titanium dioxide.
For 150 mg strength colors are Black Iron oxide, Red Iron oxide, Titanium dioxide and Yellow Iron oxide. Manufacturing Process:
-mixing of Oxcarbazepine, Microcrystalline cellulose (Avicel PH 101) and Hydroxypropyl methyl cellulose (Methocel E5 LV) in a mixer (High shear mixer granulator) and dry mix to ensure adequate mixing;
-addition of water as granulating liquid to the mixture, and kneading in a mixer (High shear mixer granulator) until an adequate consistency is achieved;
-drying the wet granules in a fluidized bed;
-addition of the deagglomerated (Quadro Comill) Polyvinylpyrrolidone XL (Polyplasdone XL), Magnesium sterate and Colloidal silicon dioxide (Aerosil 200) and mixing (Bin blender);
-compressing the final mixture to form the tablets (Rotary press);
-coating of the tablets with an aqueous film former solution (as defined above) in a rotary coating pan (Ganson coating pan).
Comparative Dissolution profiles for Example 1
Reference: Trileptal 300, (Novartis France), Batch number T 0047.
Medium: 1 % SDS in Water, 900 ml
Apparatus: USP Type Il (Paddle), 60 rpm
The data is illustrated in Figure 1. Example 2:
Oxcarbazepine film coated tablets, containing 150, 300 and 600 mg of Oxcarbazepine
For all strength (150, 300 and 600 mg) the coating composition is the same except for the use of different colors e.g.
For 600 mg strength Red Iron oxide, Black Iron oxide, Titanium dioxide and Yellow Iron oxide.
For 300 mg strength colors are Titanium dioxide, Yellow Iron oxide.
For 150 mg strength colors are Black Iron oxide, Titanium dioxide, Red Iron oxide, Yellow Iron oxide. Manufacturing Process:
-mixing of Oxcarbazepine, Microcrystalline cellulose (Avicel PH 101) and Hydroxypropyl methyl cellulose (Methocel E5 LV) in a mixer (High shear mixer granulator) and dry mix to ensure adequate mixing;
-addition of water as granulating liquid to the mixture, and kneading in a mixer (High shear mixer granulator) until an adequate consistency is achieved;
-drying the wet granules in a fluidized bed;
-addition of the deagglomerated (Quadra Comill) Modified Sodium Carboxymethyl cellulose (Nymcel ZSX), Magnesium sterate and Colloidal silicon dioxide (Aerosil 200) and mixing (Bin blender);
-compressing the final mixture to form the tablets (Rotary press);
-coating of the tablets with an aqueous film former solution (as defined above) in a rotary coating pan (Ganson coating pan).
Comparative Dissolution profiles for example 2
Reference: Trileptal 300, Novartis (Germany), Batch number T 5001
Medium: 1 % SDS in Water, 900 ml
Apparatus: USP Type Il (Paddle), 60 rpm
The data is illustrated in Figure 2. Example 3:
Coating compositions for Oxcarbazepine film coated tablets, containing 150, 300 and
600 mg of Oxcarbazepine
The following film coating compositions can be used in the tablets obtained in examples 1 and 2.
Film coating compositions:
1) for 600 mg tablet
Example 4:
Particle sizes of the Oxcarbazepine particles used in examples 1 and 2:
Particle size determination (PSD) method:

Claims

Ciaims
1. Pharmaceutical composition comprising about 20-90 wt% of Oxcarbazepine or a pharmaceutically acceptable salt thereof as active ingredient, based on the total weight of the composition, the Oxcarbazepine or the pharmaceutically acceptable salt thereof being in the form of particles, characterized in that the median particle size of the Oxcarbazepine particles or the pharmceutically acceptable salt thereof is about 2 μm or less, and the composition contains not more than about 7 wt.% of a binder, based on the total weight of the composition.
2. Pharmaceutical composition according to claim 1 , characterized in that it contains not more than 5 wt.%, preferably not more than 2 wt.%, of a binder, based on the total weight of the composition.
3. Pharmaceutical composition according to any of the preceding claims containing about 50-80 wt.% of Oxcarbazepine, based on the total weight of the composition.
4. Pharmaceutical composition according to any of the preceding claims wherein the binder is hydroxypropylmethyl cellulose.
5. Pharmaceutical composition according to any of the preceding claims, characterized in that it further comprises about 0-80 wt.% of a diluent, about 0-20 wt.% of a disintegrant, about 0-2 wt.% of a glidant, about 0-2 wt.% of a lubricant, and about 0-5 wt.% of a film former, each based on the total weight of the composition.
6. Pharmaceutical composition according to any of the preceding claims which is in the form of a tablet.
7. Pharmaceutical composition according to claim 6, which is a film coated tablet.
8. Pharmaceutical composition according to claim 6 or 7, characterized in that it shows a dissolution profile such that 80 wt.% or more of the active ingredient contained in the tablet is dissolved within 15 minutes.
9. Process for the preparation of a pharmaceutical composition according to claims 6 to 8, comprising mixing the Oxcarbazepine or a pharmaceutically acceptable salt thereof being in the form of particles with the pharmaceutically acceptable excipients and adjuvants, preparing tablets from said mixture and optionally film coating said tablets.
10. Use of Oxcarbazepine of a pharmaceutically acceptable salt thereof in the form of particles having a median particle size of about 2 μm or less for the preparation of a pharmaceutical composition according to any one of the claims 1-8.
EP08758478A 2007-05-23 2008-05-13 Pharmaceutical compositions comprising oxcarbazepine Withdrawn EP2146699A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1078CH2007 2007-05-23
PCT/EP2008/003814 WO2008141751A2 (en) 2007-05-23 2008-05-13 Pharmaceutical compositions comprising oxcarbazepine

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Publication number Priority date Publication date Assignee Title
EP2968354B1 (en) * 2013-03-15 2019-11-13 Aprecia Pharmaceuticals LLC Rapidly dispersible dosage form of oxcarbazepine
WO2015063670A1 (en) * 2013-10-30 2015-05-07 Wockhardt Limited Solid oral modified-release composition comprising oxcarbazepine or a pharmaceutically acceptable salt thereof

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Publication number Priority date Publication date Assignee Title
CO4920215A1 (en) * 1997-02-14 2000-05-29 Novartis Ag OXACARBAZEPINE TABLETS COATED WITH A FILM AND METHOD FOR THE PRODUCTION OF THESE FORMULATIONS
WO2002094774A2 (en) * 2001-05-18 2002-11-28 Ranbaxy Laboratories Limited Oxcarbazepine dosage forms
JP2008538783A (en) * 2006-01-31 2008-11-06 テバ ファーマシューティカル インダストリーズ リミティド Pharmaceutical preparation containing oxcarbazepine having broad and multimodal particle size distribution and preparation method thereof

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Title
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