EP2379058A1 - Comprimés de rétigabine, de préférence à libération modifiée - Google Patents

Comprimés de rétigabine, de préférence à libération modifiée

Info

Publication number
EP2379058A1
EP2379058A1 EP10709699A EP10709699A EP2379058A1 EP 2379058 A1 EP2379058 A1 EP 2379058A1 EP 10709699 A EP10709699 A EP 10709699A EP 10709699 A EP10709699 A EP 10709699A EP 2379058 A1 EP2379058 A1 EP 2379058A1
Authority
EP
European Patent Office
Prior art keywords
water
retigabine
tablet
soluble
tablets
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Withdrawn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
EP10709699A
Other languages
German (de)
English (en)
Inventor
Kathrin Rimkus
Sandra BRÜCK
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 EP2379058A1 publication Critical patent/EP2379058A1/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • Retigabine tablets preferably with modified release
  • the invention relates to tablets, in particular modified release tablets, comprising (a) retigabine and a combination of (b) water-soluble excipient and (c) non-water-soluble excipient; and a process for their preparation.
  • retigabine The IUPAC name of retigabine [INN] is 2-amino-4- (4-fluorobenzylamino) -1-ethoxycarbonyl-aminobenzene.
  • the chemical structure of retigabine is shown in formula (1) below:
  • Epilepsy is one of the most common neurological diseases and affects about 1% of the population. While a large proportion of epilepsy patients can be treated with anticonvulsants currently available on the market, about 30% of patients are pharmacoresistant. Therefore, it is necessary to develop new anticonvulsants with innovative mechanisms of action.
  • Retigabine an anticonvulsant substance, fulfills these criteria as a potassium channel opener.
  • no pharmaceutical dosage forms are known in the art which permit beneficial oral administration of retigabine in high doses, particularly modified release, for the treatment of epilepsy.
  • WO 02/80898 A2 proposes to formulate retigabine in the form of hard gelatin capsules containing 50, 100 and 200 mg of active ingredient.
  • Hard gelatin capsules are often perceived by patients as unpleasant to the oral. In particular, it is problematic to realize with this method a high active ingredient content (eg 70%) in the capsule.
  • capsules prepared by wet granulation of retigabine are not optimal in terms of their pharmacokinetic properties and allow no modified release.
  • WO 01/66081 A2 proposes retigabine sustained-release formulations prepared by melt granulation, a composition consisting exclusively of retigabine and sucrose fatty acid ester being used.
  • sucrose fatty acid ester is often undesirable because of emulsifier action.
  • the proposed formulations lead to a frequently undesirably slow onset of action.
  • crystalline retigabine may exist in various polymorphic forms.
  • these polymorphs are often unstable but tend to convert to other polymorphic forms.
  • the commonly used retigabine Form A can convert to Form B upon exposure to heat.
  • the polymorphic forms A, B and C have a different solubility profile.
  • the invention therefore relates to a tablet containing
  • the invention furthermore relates to a process for the preparation of the tablets according to the invention, comprising the steps
  • the invention relates to the use of a combination of water-soluble and non-water-soluble hemp substance for producing a modified-release retigabine tablet.
  • the term “retigabine” includes all pharmaceutically acceptable salts, hydrates and solvates thereof.
  • the salts may be acid addition salts.
  • suitable salts are hydrochlorides (e.g., monohydrochloride, dihydrochloride), carbonates,
  • Retigabine is preferably used in the context of this invention in the form of the free base.
  • retigabine is used in the context of this invention in the form of the dihydrochloride.
  • Retigabine can be used in this invention in both amorphous and crystalline form. Retigabine can also be used in the form of a solid solution. Preference is given to using crystalline retigabine.
  • Crystalline retigabine can be present in three different polymorphic forms according to WO 98/31663 (polymorphic forms A, B and C).
  • polymorphic form A is preferably used in the case of crystalline retigabine.
  • the water-soluble substance has a solubility of more than 50 mg / ml, more preferably more than 100 mg / ml, in particular more than 250 mg / ml, for example a water solubility between 250 mg / ml and 1 g / ml.
  • a solubility of more than 50 mg / ml, more preferably more than 100 mg / ml, in particular more than 250 mg / ml, for example a water solubility between 250 mg / ml and 1 g / ml.
  • the water-soluble auxiliary (b) is a polymer, in particular a hydrophilic polymer.
  • water-soluble excipient includes solid, non-polymeric compounds which preferably have polar side groups and the aforementioned solubility. Examples include sugar alcohols.
  • the water-soluble polymer (b) used in the context of this invention is preferably a polymer having a glass transition temperature (Tg) greater than 15 ° C., more preferably from 40 ° C. to 150 ° C., in particular from 50 ° C. to 100 0 C.
  • Tg glass transition temperature
  • the "glass transition temperature” is the temperature at which amorphous or partially crystalline polymers change from the solid state to the liquid state.
  • Determination of the glass transition temperature is carried out in the context of this invention by means of differential scanning calorimetry (DSC).
  • DSC differential scanning calorimetry
  • Mettler Toledo DSC 1 can be used. It is heated at a rate of 1 - 20 ° C / min, preferably 5-15 ° C / min or at a cooling rate of 5-25, preferably 10-20 ° C / min worked.
  • the polymer usable as the water-soluble polymer (b) preferably has a weight average or number average molecular weight of 1,000 to
  • the resulting solution preferably exhibits one
  • hydrophilic polymers are preferably used as the water-soluble component (b). These are polymers which have hydrophilic groups. Examples of suitable hydrophilic groups are hydroxy, alkoxy, acrylate, methacrylate, sulfonate, carboxylate and quaternary ammonium groups.
  • the water-soluble excipient (b) may comprise, for example, the following polymers: polysaccharides, such as hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC, in particular sodium and calcium salts), hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC); Guar gum, alginic acid and / or alginates, pectin, tragacanth; synthetic polymers such as polyvinylpyrrolidone (povidone), polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and salts thereof, polyacrylamide, derivatives of polymethacrylates (Eudragit ® E, Eudragit ® R, Eudragit ® S), vinylpyrrolidone-vinyl acetate copolymers (for example, Kollidon ® VA64, BASF), polyalkylene glycols such as polypropylene glycol or, preferably, polyethylene
  • component (b) may also comprise solid, non-polymeric compounds, which preferably have polar side groups.
  • these are sugar alcohols or disaccharides.
  • suitable sugar alcohols are mannitol, sorbitol, xylitol, isomalt, glucose, fructose and mixtures thereof.
  • sugar alcohols here also includes monosaccharides.
  • non-water-soluble excipient is generally a pharmaceutical excipient specified in the European Pharmacopoeia which has a water solubility of less than 33 mg / ml, measured at 25 ° C.
  • the non-water-soluble substance preferably has a solubility of 10 mg / ml or less, more preferably of 5 mg / ml or less, in particular of 0.01 to 2 mg / ml (determined in accordance with the column elution method according to EU guideline RL67-548). EEC, Annex V, Chapter A6).
  • the component (c) is preferably a non-water-soluble polymer or a non-water-soluble pharmaceutical excipient having polymer-like properties.
  • Component (c) preferably leads to a modified release of active ingredient. It has been found that the release profile in particular by selecting a component (c) with a suitable molecular weight and degree of crosslinking, with suitable viscosity (based on a solution of component (c) in water), with suitable swelling behavior and / or with suitable glass transition or Melting temperature can be influenced.
  • a component (c) which leads to an immediate release with the proviso that the coating used is a slow-release coating, as described below as component (e3).
  • the non-water-soluble polymer (c) usually has a weight-average molecular weight of 50,000 to 2,500,000 g / mol, preferably 250,000 to 2,000,000 g / mol, more preferably 350,000 to 1,500,000 g / mol.
  • the non-water-soluble polymer (c) may be linear or preferably crosslinked.
  • the resulting solution When the non-water-soluble polymer (c) is dissolved (at least partially) in (distilled) water in an amount of 2% by weight, the resulting solution preferably exhibits a viscosity of more than 2 mPa ⁇ s, more preferably 4 mPa ⁇ s , particularly preferably more than 8 mPa s, in particular more than 10 mPa s and for example up to 500 mPa s, measured at 25 0 C according to Ph. Eur. 6th edition, chapter 2.2.10.
  • the component (c) is preferably a swellable polymer or a swellable substance having polymer-like properties.
  • the non-water-soluble component (c) is preferably a swellable polymer or a swellable substance having polymer-like properties.
  • Polymer (c) preferably has a swelling index of 1.5 to 4.5, preferably 2.0 to 4.0.
  • the swelling number is the volume in milliliters that includes 1 g of fabric of the optionally adhering mucus after swelling in an aqueous solution after 4 hours. The swelling number is determined according to Ph. Eur. 4th edition, chapter 2.8.4.
  • Component (c) is furthermore preferably a polymer or a swellable substance having a glass transition temperature or a melting temperature of less than 200 ° C., more preferably from 20 ° C. to 180 ° C., in particular from 30 ° C. to 170 ° 0 C.
  • the "glass transition temperature” is the temperature at which amorphous or partially crystalline polymers change from the solid state to the liquid state. In this case, a significant change in physical characteristics, z. As the hardness and elasticity, a. Below the Tg, a polymer is usually glassy and hard, above the Tg it turns into a rubbery to viscous state.
  • DSC differential scanning calorimetry
  • non-water soluble polymers are acrylate-based polymers, for example acrylates, derivatives of the methacrylates (Eudragit ® NE, Eudragit ® RS, Eudragit ® RL); Cellulose derivatives such as ethylcellulose (EC), methylcellulose (MC), cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate; synthetic polymers such as polyvinyl acetate, polyvinyl chloride, nylon, polyamide, polyethylene, cross-linked polyvinylpyrrolidone and polylactide-co-glycolide. Likewise, mixtures of the polymers mentioned are possible.
  • the polymers mentioned here preferably have one or more of the abovementioned functional properties (M w, crosslinking, viscosity in solution, swelling number, melting or glass transition temperature).
  • Microcrystalline cellulose melts at about 250 0 C with decomposition.
  • the use of microcrystalline cellulose usually results in no modified drug release. Therefore, microcrystalline cellulose is not used as component (c) in this invention.
  • waxes and fats can be used as non-water-soluble substances (with polymer-like properties). Suitable waxes or fats are solid at 25 ° C. For example, solid paraffin or beeswax is suitable. However, component (c) does not comprise sucrose fatty acid esters. In preferred embodiments of the present invention, water-soluble excipient (b) and non-water-soluble adjuvant (c) are used in an amount wherein the weight ratio of component (b) to component (c) is 10: 1 to 1:10, more preferably 5: 1 to 1: 5, more preferably 4: 1 to 1: 2, in particular 3: 1 to 1: 1, is.
  • components (b) and (c) are used in particulate form, the volume-average particle size (D50) of components (b) and (c) being less than 500 ⁇ m, preferably 5 to 200 ⁇ m.
  • retigabine is used in micronized form.
  • micronized retigabine in the context of this invention refers to particulate retigabine, which generally has an average particle diameter of from 0.1 to 200 ⁇ m, preferably from 0.5 to 100 ⁇ m, more preferably from 1 to 50, more particularly 1, 5 to 25 microns and especially from 2 to 10 microns having.
  • mean particle diameter in the context of this invention always refers to the D50 value of the volume-average particle diameter, which was determined by means of laser diffractometry.
  • the evaluation according to the Fraunhofer model is carried out, preferably, in which the non-dissolved substance to be measured at 20 0 C
  • the average particle diameter also referred to as the D50 value of the integral volume distribution, is defined in the context of this invention as the particle diameter at which 50% by volume of the particles have a smaller diameter than the diameter corresponding to the D50 value. Likewise, 50% by volume of the particles will then have a larger diameter than the D50.
  • average particle size and “average particle diameter” will be used interchangeably throughout this application.
  • the tablet of the invention may contain the components (a), (b) and (c) in conventional proportions.
  • the tablet according to the invention contains
  • the disintegrant (d) is preferably used in an amount of 1 to 10% by weight, especially 2 to 8% by weight, based on the total weight of the components (a) to (d).
  • disintegrants are generally referred to substances that accelerate the disintegration of a dosage form, in particular a tablet, after being introduced into water.
  • Suitable disintegrants are e.g. organic disintegrants such as carrageenan, croscarmellose and crospovidone.
  • alkaline disintegrants can be used.
  • alkaline disintegrating agents disintegrating agents which when dissolved in water produce a pH of more than 7.0.
  • Suitable alkaline disintegrating agents are salts of alkali and alkaline earth metals. Preferred are sodium, potassium, magnesium and calcium. As anions, carbonate, bicarbonate, phosphate, hydrogen phosphate and dihydrogen phosphate are preferred. Examples are sodium hydrogencarbonate, sodium hydrogenphosphate, calcium hydrogencarbonate and the like.
  • the disintegrating agents used are preferably croscarmellose and crospovidone.
  • the tablet according to the invention may consist of the components (a), (b), (c) and (d). Alternatively, however, further pharmaceutical auxiliaries may be added. In particular, agents for improving the powder flowability and lubricants are added.
  • An example of an additive to improve the powder flowability is dispersed silica, such as known under the trade name Aerosil ®. Preference is given to using silicon dioxide having a specific surface area of from 50 to 400 m 2 / g, determined by gas adsorption in accordance with Ph. Eur., 6th edition of 2.9.26.
  • Additives to improve the powder flowability are usually used in an amount of 0.1 to 3 wt .-%, based on the total weight of the formulation.
  • Lubricants can be used.
  • Lubricants are generally used to reduce sliding friction. In particular, the sliding friction is to be reduced, the tableting on the one hand between the in the die bore up and down moving punches and the die wall and on the other hand between the tablet web and Matrizenwand.
  • suitable lubricants are stearic acid, adipic acid, sodium stearyl fumarate, zinc stearate and / or magnesium stearate.
  • Lubricants are usually used in an amount of from 0.1 to 3% by weight, based on the total weight of the formulation.
  • the unambiguous delimitation is therefore preferably based on the fiction that a substance which is used as a specific excipient is not simultaneously used as a further pharmaceutical excipient.
  • the tablet of the invention containing components (a), (b), (c) and optionally (d) is preferably a modified release tablet.
  • modified release in the context of this invention is understood to mean delayed release, sustained release, sustained release or extended release. It is preferably a kinetics that follows the sustalned release.
  • the tablet according to the invention can be film-coated.
  • Films without influence on the drug release are usually water-soluble (preferably they have a water solubility of more than 250 mg / ml). Enteric-coated films have a pH-dependent solubility. Retarded films are usually non-water soluble (preferably have a water solubility of less than 10 mg / ml).
  • macromolecular substances are used for the inflation (e), for example modified celluloses, polymethacrylates, polyvinylpyrrolidone, polyvinyl acetate phthalate, zein and / or shellac or natural gums, such as carrageenan.
  • film-forming agents which have no influence on the release of active substance (el) are methylcellulose (MC), hydroxypropylmethylcelluslose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), polyvinylpyrrolidone (PVP) and mixtures thereof.
  • MC methylcellulose
  • HPMC hydroxypropylmethylcelluslose
  • HPC hydroxypropylcellulose
  • HEC hydroxyethylcellulose
  • PVP polyvinylpyrrolidone
  • the polymers mentioned should usually have a weight-average molecular weight of 10,000 to 150,000 g / mol.
  • HPMC in particular HPMC having a weight-average molecular weight of from 10,000 to 150,000 g / mol and / or an average degree of substitution of -OCH 3 groups of from 1.2 to 2.0.
  • enteric coatings are cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate and polyvinyl acetate phthalate (PVAP).
  • CAP cellulose acetate phthalate
  • PVAP polyvinyl acetate phthalate
  • Retardbetik e3
  • EC ethylcellulose
  • Surelease ® ethylcellulose
  • Eudragit ® commercially for example as RL or RS and L / S available
  • the coating (e) may be free of active ingredient. However, it is also possible that the coating (e) contains active ingredient (a).
  • the coating (e) contains retigabine in an amount of from 1 to 45% by weight, more preferably from 5 to 35% by weight, especially from 10 to 30% by weight, based on the total weight of the Retigabins contained in the tablet. In this case, it is preferably a coating without influence on the drug release (el).
  • the layer thickness of the coating (e) in the case of a coating without an active ingredient is preferably 2 to 100 ⁇ m, in particular 20 to 60 ⁇ m.
  • the layer thickness of the coating (e) in the case of a coating with active ingredient is preferably 10 ⁇ m to 2 mm, in particular 50 to 500 ⁇ m.
  • an embodiment is preferred in which 1 to 45 wt .-%, more preferably from 5 to 35 wt .-%, in particular from 10 to 30 wt .-% of the active ingredient amount as an initial dose with immediate release and 55 to 99 wt .-%, more preferably 65 to 95 wt .-%, in particular 70 to 90 wt .-% of the amount of active ingredient as a matrix formulation with sustained release.
  • the pharmaceutical formulation of the invention is preferably compressed into tablets.
  • a wet granulation is proposed for this purpose (see WO 02/080898).
  • wet granulation is also suitable for the preparation of the tablets according to the invention.
  • the intermediates according to the invention are therefore compressed by means of direct compression into tablets or subjected to dry granulation before compression to the tablet.
  • a further aspect of the present invention therefore relates to a dry processing method comprising the steps:
  • step (I) the intermediate and auxiliaries according to the invention are preferably mixed.
  • the mixing can be done in conventional mixers.
  • the retigabine intermediate is first mixed with only a portion of the excipients (e.g., 50% to 95%) prior to compaction (II) and that the remaining portion of adjuvants is added after granulation step (III).
  • the admixing of the excipients should preferably take place before the first compaction step, between several compaction steps or after the last granulation step.
  • step (II) of the process according to the invention the mixture from step (I) is compacted into a rag. It is preferred that this is dry compaction, i. the compaction is preferably carried out in the absence of solvents, in particular in the absence of organic solvents.
  • the compaction conditions are usually chosen such that the intermediate according to the invention is in the form of a compactate (slug), the density of the intermediate being 0.8 to 1.3 g / cm 3 , preferably 0.9 to 1.20 g / cm 3 . especially 1, 01 to 1, 15 g / cm 3 , is.
  • density here preferably refers to the "true density” (ie not to the bulk density or tamped density).
  • the true density can be determined with a gas pycnometer.
  • the gas pycnometer is preferably a helium pycnometer, in particular the device AccuPyc 1340 helium pycnometer manufactured by Micromeritics, Germany is used.
  • the compaction is preferably carried out in a roll granulator.
  • the rolling force is usually 5 to 70 kN / cm, preferably 10 to 60 kN / cm, more preferably 15 to 50 kN / cm.
  • the gap width of the rolling granulator is, for example, 0.8 to 5 mm, preferably 1 to 4 mm, more preferably 1, 5 to 3 mm, in particular 1, 8 to 2.8 mm.
  • step (III) of the process the slug is granulated.
  • the granulation can be carried out by methods known in the art.
  • the granulation conditions are selected so that the resulting particles (granules) have a volume average particle size ((D 50 ) value) of 50 to 800 microns, more preferably 100 to 750 microns, even more preferably 150 to 500 microns , in particular from 200 to 450 microns.
  • D 50 volume average particle size
  • the granulation is carried out in a sieve mill.
  • the mesh size of the sieve insert is usually 0.1 to 5 mm, preferably 0.5 to 3 mm, more preferably 0.75 to 2 mm, in particular 0.8 to 1, 8 mm.
  • step (III) granules can be processed into pharmaceutical dosage forms.
  • the granules are filled, for example, in sachets or capsules.
  • step (IV) of the process the granules obtained in step (III) are compressed into tablets, i. There is a compression to tablets.
  • the compression can be done with tableting machines known in the art.
  • step (IV) of the process pharmaceutical excipients may optionally be added to the granules from step (III).
  • step (IV) usually depend on the type of tablet to be prepared and on the amount of excipients already added in steps (I) or (II). In the case of direct compression, only steps (I) and (IV) of the method described above are performed.
  • step (V) of the method according to the invention the tablets from step (IV) are coated.
  • the customary in the prior art methods for coating in particular for the coating of tablets, find application.
  • the coating materials used reference is made to the above statements.
  • the tableting conditions in both embodiments of the method according to the invention are furthermore preferably chosen such that the resulting tablets have a tablet height to weight ratio of 0.005 to 0.3 mm / mg, more preferably 0.05 to 0.2 mm / mg.
  • the process according to the invention is preferably carried out in such a way that the tablets according to the invention contain retigabine in an amount of more than 200 mg to 1000 mg, more preferably from 250 mg to 900 mg, in particular 300 mg to 600 mg.
  • the invention thus relates to tablets containing 300 mg, 400 mg, 450 mg, 600 mg or 900 mg of retigabine.
  • the resulting tablets preferably have a hardness of from 50 to 300 N, particularly preferably from 80 to 250 N, in particular from 100 to 220 N. Hardness is calculated according to Ph.Eur. 6.0, section 2.9.8.
  • the resulting tablets preferably have a friability of less than 3%, particularly preferably less than 2%, in particular less than 1%.
  • the friability is calculated according to Ph.Eur. 6.0, section 2.9.7.
  • the tablets according to the invention usually have a content uniformity of 95 to 105%, preferably 98 to 102%, in particular 99 to 101% of the average content. (That is, all tablets have an active ingredient content of between 95 and 105%, preferably between 98 and 102%, in particular between 99 and 101% of the average active ingredient content.)
  • the "Content Uniformity" is determined according to Ph. Eur.6.0, Section 2.9.6, certainly. The above information on hardness, friability and content Undformtty and release profile relate here preferably to the unformed tablet.
  • the release profile of the tablets according to the invention has a uniform release over time in the case of an active ingredient-free coating (e) according to the USP method (paddle).
  • the release curve shows a uniformly sustained kinetics.
  • the graph preferably has a "slow" slope, i. an increase of less than 0.6-0.8% per minute. In this case, after one hour, (unlike the rapid release) only a maximum of 50% of the active ingredient released.
  • the release profile of the tablets according to the invention has a kinetics in the case of an active ingredient-containing coating (s) according to the USP method (paddle), which indicates an initial dose of the active ingredient within 15 minutes, ie. after 15 minutes, at least 15% of the drug is released. After 15 minutes, the remaining active ingredient will "diffuse" slowly out of the formulation to give a release kinetics that follows the steady-state from that time on. After one hour, a maximum of 65% of the drug is released.
  • the tablet according to the invention thus makes it possible, by interaction of water-soluble excipient and non-water-soluble adjuvant, to provide an advantageous formulation for retigabine, in particular one with modified release.
  • the invention is the use of a combination of water-soluble and non-water-soluble excipient for producing a modified-release retigabine tablet.
  • the active ingredient content of the tablet is preferably more than 50% by weight.
  • retigabine is preferably used as retigabine dihydrochloride, the amount given being based on the amount of free base retigabine. That is, the indication of 300 g of retigabine corresponds to about 372 g of retigabine dihydrochloride.
  • example 1
  • 300 g retigabine was mixed with 200 g of ethyl cellulose and 50 g of polyvinylpyrrolidone and mixed for 15 minutes in free fall mixer Turbula ® WlOB. The resulting mixture was passed through a sieve of size 500 microns and treated with 2 g of magnesium stearate. The resulting mixture was pressed on a rotary press Fette 102i. The tablets were compressed at a retigabine dosage of 300 mg / tablet.
  • the dosage obtained was 600 mg per dose form.
  • Example 5a The Aerosil and the magnesium stearate were added, mixed again and pressed on an eccentric press ( Korsch® EKO). The dosage obtained was 900 mg per dose form.
  • Example 5a The Aerosil and the magnesium stearate were added, mixed again and pressed on an eccentric press ( Korsch® EKO). The dosage obtained was 900 mg per dose form.
  • a of the retigabine was mixed together with half of a mixture of cellulose acetyl phthalate and sorbitol (1: 2) for 10 minutes and sieved.
  • 1 A of the retigabine was mixed together with the other half of the cellulose acetyl phthalate / sorbitol mixture for 10 minutes and aerosol and magnesium stearate were added and mixed for a further 3 minutes.
  • the two prepared mixtures were combined and homogenized for 10 minutes, in order to then be able to perform a compression.
  • the dosage obtained was 400 mg per dose form.
  • Example 2 was modified so that only 3 A of the active ingredient was incorporated into the core.
  • 1 A of the drug was mixed with 30 g of a conventional hydroxypropylmethylcellulose coating (Opadry ® AMB), 10% in water for 3 minutes in an Ultra Turrax ® and sprayed onto the tablets in the form of a varnish.
  • Opadry ® AMB hydroxypropylmethylcellulose coating

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Emergency Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur des comprimés, en particulier des comprimés à libération modifiée, contenant (a) de la rétigabine, ainsi qu'une combinaison de (b) un adjuvant hydrosoluble et (c) un adjuvant non hydrosoluble, ainsi que sur un procédé pour leur préparation.
EP10709699A 2009-03-17 2010-03-17 Comprimés de rétigabine, de préférence à libération modifiée Withdrawn EP2379058A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102009013612A DE102009013612A1 (de) 2009-03-17 2009-03-17 Retigabin-Tabletten, bevorzugt mit modifizierter Freisetzung
PCT/EP2010/001692 WO2010105824A1 (fr) 2009-03-17 2010-03-17 Comprimés de rétigabine, de préférence à libération modifiée

Publications (1)

Publication Number Publication Date
EP2379058A1 true EP2379058A1 (fr) 2011-10-26

Family

ID=42167610

Family Applications (1)

Application Number Title Priority Date Filing Date
EP10709699A Withdrawn EP2379058A1 (fr) 2009-03-17 2010-03-17 Comprimés de rétigabine, de préférence à libération modifiée

Country Status (6)

Country Link
US (1) US20120058183A1 (fr)
EP (1) EP2379058A1 (fr)
CA (1) CA2760068A1 (fr)
DE (2) DE102009013612A1 (fr)
EA (1) EA201171142A1 (fr)
WO (1) WO2010105824A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102009013613A1 (de) * 2009-03-17 2010-09-23 Ratiopharm Gmbh Trockenverarbeitung von Retigabin
PL3199145T3 (pl) 2016-01-28 2019-06-28 G.L. PHARMA GmbH Stabilizowana formulacja preparatu kwasu foliowego/żelaza
EP3199167A1 (fr) 2016-01-28 2017-08-02 G.L. Pharma GmbH Medicament destine a traiter des carences en fer et en acide folique
CN114760990A (zh) * 2019-12-02 2022-07-15 泽农医药公司 钾通道开放剂埃佐加滨的儿科即释制剂

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001001970A2 (fr) * 1999-07-01 2001-01-11 Glaxo Group Limited Nouvelles utilisations des agents d'ouverture du canal potassique
WO2009015667A1 (fr) * 2007-08-01 2009-02-05 H. Lundbeck A/S Utilisation d'agents d'ouverture kncq des canaux potassiques pour réduire des symptomes ou traiter des troubles et des états dans lesquels le système dopaminergique est détruit

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4200259A1 (de) 1992-01-08 1993-07-15 Asta Medica Ag Neue 1,2,4-triaminobenzol-derivate und verfahren zu deren herstellung
DE19701694A1 (de) 1997-01-20 1998-07-23 Asta Medica Ag Neue Modifikationen des 2-Amino-4-(4-fluorbenzylamino)-l-ethoxycarbonyl-aminobenzen sowie Verfahren zu ihrer Herstellung
US6117900A (en) 1999-09-27 2000-09-12 Asta Medica Aktiengesellschaft Use of retigabine for the treatment of neuropathic pain
SK13252002A3 (sk) 2000-03-08 2003-07-01 Awd. Pharma Gmbh & Co. Kg Farmaceutické prípravky
US20020015730A1 (en) * 2000-03-09 2002-02-07 Torsten Hoffmann Pharmaceutical formulations and method for making
AR033095A1 (es) 2001-04-04 2003-12-03 Wyeth Corp Metodos para el tratamiento de motilidad gastrica hiperactiva
WO2010009433A1 (fr) * 2008-07-18 2010-01-21 Valeant Pharmaceuticals International Formulation à libération modifiée et procédés d'utilisation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001001970A2 (fr) * 1999-07-01 2001-01-11 Glaxo Group Limited Nouvelles utilisations des agents d'ouverture du canal potassique
WO2009015667A1 (fr) * 2007-08-01 2009-02-05 H. Lundbeck A/S Utilisation d'agents d'ouverture kncq des canaux potassiques pour réduire des symptomes ou traiter des troubles et des états dans lesquels le système dopaminergique est détruit

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
EUROPEAN MEDICINES AGENCY: "Trobalt : EPAR - Public assessment report", 20 January 2011 (2011-01-20), XP055048834, Retrieved from the Internet <URL:http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/001245/human_med_001431.jsp&mid=WC0b01ac058001d124> [retrieved on 20130108] *
GLAXO SMITH KLINE: "Result Summary for VRX-RET-E22-105", 8 January 2013 (2013-01-08), XP055048815, Retrieved from the Internet <URL:http://www.gsk-clinicalstudyregister.com/result_detail.jsp;jsessionid=3591439B169BC797536F71EBD8802BEC?protocolId=VRX-RET-E22-105&studyId=D12FDA55-D43B-4998-AD06-B52ABCC5B711&compound=retigabine> [retrieved on 20130108] *
GLAXO SMITH KLINE: "Trobalt Filmtabletten", 1 March 2011 (2011-03-01), XP055048835, Retrieved from the Internet <URL:http://www.fachinfo.de/data/fi/jsearch/FachInfo/data/fi/pdf/01/29/012945.pdf> [retrieved on 20130108] *
See also references of WO2010105824A1 *

Also Published As

Publication number Publication date
EA201171142A1 (ru) 2012-04-30
CA2760068A1 (fr) 2010-09-23
DE202010017302U1 (de) 2011-12-06
WO2010105824A1 (fr) 2010-09-23
US20120058183A1 (en) 2012-03-08
DE102009013612A1 (de) 2010-09-23

Similar Documents

Publication Publication Date Title
EP2334284B1 (fr) Cinacalcet compacté
EP2364141B2 (fr) Moxifloxacine compactée
WO2000041681A2 (fr) FORMULATIONS DE MEDICAMENTS CONTENANT UN OPIOIDE ET UN α-AGONISTE
EP2415460A1 (fr) Formulations pour l&#39;administration orale de prégabaline
EP2408431A1 (fr) Rétigabine solide sous forme non cristalline
DE102009015702A1 (de) Tabletten enthaltend Dapoxetin und Trockenverarbeitungsverfahren zu deren Herstellung
WO2010043408A2 (fr) Fésotérodine microencapsulée
DE102008046650A1 (de) Quetiapin enthaltende Retardtablette
EP2309995A1 (fr) Formulation pharmaceutique pour la réduction de la pression artérielle pulmonaire
WO2008034655A1 (fr) Préparation analgésique perorale solide
DE102008057284A1 (de) Tabletten enthaltend Lenalidomid und Adhäsionsverstärker
EP2490674A2 (fr) Cinacalcet granulé par fusion
DE202010017303U1 (de) Trockenverarbeitung von Retigabin
EP1847258B1 (fr) Compositions pharmaceutiques comprenant thieno[3,2-c]pyridine comme agent active et des glycérols partielles comme lubrifiante
EP1648420A2 (fr) Medicament a base de 6-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol caracterise par une liberation differee du principe actif
WO2010105824A1 (fr) Comprimés de rétigabine, de préférence à libération modifiée
WO2007031326A2 (fr) Formulation a effet retard de 3-(2-dimethylaminomethyle-cyclohexyle)-phenol
EP2566461A2 (fr) Tapentadol solide sous forme non cristalline
EP2445484A1 (fr) Aprépitant sous forme de solution solide
EP2732812A1 (fr) Comprimé de pramipexol à libération prolongée
DE102008057285A1 (de) 3-(4-Amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-piperidindion in Form einer festen Lösung
EP2380560A1 (fr) Comprimé matriciel contenant du pramipexol
EP2382967A1 (fr) Aliskiren sous forme d&#39;une dispersion solide
DE102008057335A1 (de) Amorphes Lenalidomid
DE102012113098A1 (de) Monolithische Arzneiform zur modifizierten Freisetzung einer Wirkstoffkombination

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20110610

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20120620

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20131115