EP2408424A2

EP2408424A2 - Dry processing of retigabine

Info

Publication number: EP2408424A2
Application number: EP10711009A
Authority: EP
Inventors: Jana Paetz; Katrin Rimkus
Original assignee: Ratiopharm GmbH
Current assignee: Ratiopharm GmbH
Priority date: 2009-03-17
Filing date: 2010-03-17
Publication date: 2012-01-25
Also published as: US20120122973A1; WO2010105822A3; DE102009013613A1; CA2760040A1; DE202010017303U1; WO2010105822A2; EA201171140A1

Abstract

The invention relates to dry processing methods for producing oral dosage forms, in particular tablets, containing retigabine and adhesion promoters. The invention further relates to compacted intermediates, containing retigabine and an adhesion promoter. Finally, the invention relates to single and multiple dose containers, preferably sachets and stick packs, containing the intermediate according to the present invention.

Description

Dry processing of retigabine

The invention relates to dry processes for the preparation of oral dosage forms, in particular tablets containing retigabine and adhesion enhancers. Furthermore, the invention relates to compacted intermediates containing retigabine and an adhesion promoter.

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:

(1) Retigabine

Synthetic pathways for retigabine and its use as an antiepileptic drug have been described in EP 0 554 543. WO 01/2953 A2 also discloses the use of retigabine for the treatment of neuropathic pain.

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 them are

Patients pharmacoresistant. Therefore, it is necessary to develop new anticonvulsants with innovative mechanisms of action. Retigabine, an anticonvulsant

Substance fulfills these criteria as potassium channel opener. However, no pharmaceutical dosage forms are known in the art, the advantageous oral administration of retigabine in high doses, especially for the treatment of

Epilepsy, allow.

WO 02/80898 A2 proposes to formulate retigabine in the form of hard gelatine capsules containing 50, 100 and 200 mg of active ingredient. Hard gelatin capsules are made by

Patients often felt uncomfortable with oral use. In particular, it is problematic with this method, a high content of active ingredient (for example 70%) in the

Capsule to be realized It has also been found that capsules by means of

Wet granulation of retigabine are not optimal in terms of their pharmacokinetic properties. WO 01/66081 A2 also proposes retigabine formulations which have been prepared by melt granulation, a composition consisting exclusively of retigabine and sucrose fatty acid ester being used. However, the use of larger amounts of sucrose fatty acid ester is often undesirable because of emulsifier action. In addition, the proposed formulations allow only a delayed release.

Object of the present invention was therefore to overcome the disadvantages mentioned above.

An object of the invention was to provide a pleasant for the patient dosage form, which makes it possible to administer active ingredient amounts of significantly more than 200 mg advantageous.

It is intended to provide the active substance in a form which, if appropriate despite micronization, has good flowability and enables good compression. The resulting tablets are said to have high hardness and low friability.

In particular, it was an object of the invention to provide a process for the preparation of retigabine-containing tablets which show advantageous paintability. When painting the tablets according to the invention there should be no "chipping".

Also, a granular formulation of retigabine should be provided which can be advantageously used to prepare an oral suspension. The granules should flow well, do not segregate during storage and allow an exact dosage of single and multidose containers.

In the development of retigabine formulations, the inventors of the present application were further confronted with the fact that crystalline retigabine may exist in various polymorphic forms. However, as described in WO 98/31663, these polymorphs are often not stable, but tend to convert to other polymorphic forms. For example, the commonly used retigabine Form A can convert to Form B upon exposure to heat. However, the polymorphic forms A, B and C have a different solubility profile.

The different solubility profile results in the patient to an undesirable uneven flooding of the drug. It was therefore an object of the present invention to provide stable retigabine intermediates that form a dosage form can be processed, which allows a uniform as possible flooding in the patient. Both interindividual and intraindividual deviations should be largely avoided.

Furthermore, dosage forms of retigabine are to be provided which ensure good solubility and bioavailability with at the same time good storage stability.

All of the above-mentioned objects are intended to be solved in particular for a high active substance content [drug load].

The tasks could be solved unexpectedly by dry processing of retigabine together with an adhesion enhancer.

The invention therefore provides a process for the preparation of oral administration forms, in particular tablets containing retigabine and adhesion enhancer, wherein the oral administration forms, in particular the tablets, are produced by means of dry compaction or by means of direct compression. Furthermore, the invention relates to tablets which are obtainable according to the embodiments of the method according to the invention described below.

The invention further provides an intermediate obtainable by co-dry-curing of retigabine with an adhesion promoter.

Finally, the invention relates to single-dose and multi-dose containers, preferably sachets and stick packs, which contain the intermediate according to the invention.

In the context of this invention, the term "retigabine" comprises 2-amino-4- (4-fluorobenzylamino) -1-ethoxycarbonyl-aminobenzene according to formula (1) above. In addition, the term "retigabine" includes all pharmaceutically acceptable salts, hydrates and solvates thereof.

The salts may be acid addition salts. Examples of suitable salts are hydrochlorides (monohydrochloride, dihydrochloride), carbonates, bicarbonates, acetates, lactates, butyrates, propionates, sulfates, methanesulfonates, citrates, tartrates, nitrates, sulfonates, oxalates and / or succinates. Retigabine is preferably used in the form of the free base or in the form of 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.

Crystalline retigabine can be present in three different polymorphic forms according to WO 98/31663 (polymorphic forms A, B and C). In the context of this invention, the polymorphic form A is preferably used in the case of crystalline retigabine.

The adhesion enhancer is generally a material capable of stabilizing retigabine in compacted or compressed form.

The addition of the adhesion enhancer usually results in one

Enlargement of the interparticle surfaces where (e.g.

Pressing process) can form bonds. Continue to stand out

Adhesion enhancers by increasing the plasticity of the Tablettiermischung so that solid tablets are formed during compression.

In one possible embodiment, the adhesion promoter is a polymer. Furthermore, the term "adhesion enhancer" also includes substances that behave polymer-like. Examples of these are fats and waxes, but not sucrose fatty acid esters. Furthermore, the adhesion promoter comprises solid, non-polymeric compounds which preferably have polar side groups. Examples of these are sugar alcohols or disaccharides.

The adhesion enhancer used in the context of this invention is preferably a polymer which has a glass transition temperature (Tg) greater than 15 ^° C., more preferably from 40 ^° C. to 150 ^° C., in particular from 50 ^° C. to 100 ^° C.

The "glass transition temperature" (Tg) 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. The determination of the glass transition temperature is carried out in the context of this invention by means of differential scanning calorimetry (DSC). For this purpose, z. B. a device from Mettler Toledo DSC 1 can be used. It is carried out at a heating rate of 1-20 ⁰ C / min, preferably 5-15 ° C / min or with a cooling rate of 5-25, preferably 10-20 ° C / min.

Further, the polymer useful as an adhesion promoter preferably has a weight average or number average molecular weight of 1,000 to 500,000 g / mol, more preferably from 2,000 to 90,000 g / mol. When the polymer used to prepare the intermediate is dissolved in water in an amount of 2% by weight, the resulting solution preferably exhibits a viscosity of from 0.1 to 8 mPas, more preferably from 0.3 to 7 mPas, especially from 0 , 5 to 4 mPa's, measured at 25 ⁰ C, and preferably according to Ph. Eur., 6th edition, chapter 2.2.10, determined.

Preference is given to using hydrophilic polymers for the preparation of the intermediate. These are polymers which have hydrophilic groups. Examples of suitable hydrophilic groups are hydroxy, alkoxy, acrylate, methacrylate, sulfonate, carboxylate and quaternary ammonium groups.

The intermediate according to the invention may comprise, for example, the following polymers as adhesion enhancers: polysaccharides, such as hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC, in particular sodium and calcium salts), ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC); microcrystalline cellulose, silicon-modified microcrystalline cellulose (such as Prosolv ^®), guar gum, alginic acid and / or alginates; synthetic polymers such as polyvinylpyrrolidone (povidone), polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and salts thereof, polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate copolymers (e.g., Kollidon ^® VA64, BASF), polyalkylene glycols such as polypropylene glycol or, preferably, polyethylene glycol , co-block polymers of the polyethylene glycol, in particular co-block polymers of polyethylene glycol and polypropylene glycol (Pluronic ^®, BASF), and mixtures of said polymers. Furthermore, starch, starch derivatives, treated starch and pregelatinized starch can be used as adhesion enhancers.

Polyvinylpyrrolidone, preferably having a weight-average molecular weight of 10,000 to 60,000 g / mol, in particular 12,000 to 40,000 g / mol, copolymer of vinylpyrrolidone and vinyl acetate, in particular having a weight-average molecular weight of 40,000 to 70,000 g / mol and / or are particularly preferably used as adhesion promoters Polyethylene glycol, in particular having a weight-average molecular weight of 2,000 to 10,000 g / mol, and HPMC, in particular having a weight-average molecular weight of 20,000 to 90,000 g / mol and / or preferably a proportion of methyl groups of 10 to 35% and a proportion of hydroxy groups of 1 up to 35%. Furthermore, preference may be given to using microcrystalline cellulose, in particular those having a specific surface area of 0.7-1.4 m ² / g. The determination of the specific surface was carried out by gas adsorption method according to Brunauer, Emmet and Plate. Finally, preference is given to using pregelatinized starch, in particular in formulations having an active ingredient content of more than 70% by weight.

Furthermore, the adhesion promoter also comprises solid, non-polymeric compounds which preferably have polar side groups. Examples of these are sugar alcohols or disaccharides. Examples of suitable sugar alcohols and / or disaccharides are lactose, mannitol, sorbitol, xylitol, isomalt, glucose, fructose, maltose and mixtures thereof. The term sugar alcohols here also includes monosaccharides. In particular, lactose and mannitol are used as adhesion enhancers.

Furthermore, mixtures of said adhesion enhancers are possible.

In preferred embodiments of the present invention, retigabine and adhesion enhancers are used in an amount wherein the weight ratio of retigabine to adhesion enhancer is from 20: 1 to 1:10, more preferably from 10: 1 to 1: 5, even more preferably from 5: 1 to 1: 2 , in particular 4: 1 to 2: 1.

It is advantageous if the adhesion promoter is used in particulate form and a volume-average particle size (D50) of the adhesion enhancer is less than 500 μm, preferably 5 to 200 μm.

In one embodiment of the present invention, retigabine is used in micronized form.

The term "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 μm, preferably from 0.5 to 100 μm, more preferably from 1 to 50 μm, particularly preferably 1 , 5 to 25 microns and especially from 2 to 10 microns.

The term "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. In particular, for determining a Mastersizer 2000 from Malvern Instruments used (wet measurement, a dispersant is used with ultrasound for 60 seconds, 2,000 rpm, 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, then 50% by volume of the particles have a larger diameter than the D50. The terms "average particle size" and "average particle diameter" are used interchangeably throughout this application.

The process according to the invention can generally be carried out in two embodiments, namely as a dry granulation process and as a direct compression process. Both embodiments are carried out in the absence of solvent.

One aspect of the present invention therefore relates to a dry granulation process comprising the steps

(a) mixing retigabine with an adhesion promoter and optionally other pharmaceutical excipients;

(b) compaction into a slug;

(c) granulation of the slug; (D) compression of the resulting granules into tablets, optionally with the addition of other pharmaceutical Hüfsstoffe; and (e) optionally, filming the tablets.

In step (a) retigabine and adhesion enhancers, and optionally further pharmaceutical excipients (described below), are mixed. The mixing can be done in conventional mixers. For example, the mixing can be done in compulsory mixers or tumble mixers, e.g. by means of Turbula T 1OB (Bachofen AG, Switzerland). Alternatively, it is possible that the retigabine is first mixed with only a portion of the hips (e.g., 50 to 95%) prior to compaction (b) and that the remaining TEU of the hips be added after the granulation step (c). In the case of multiple compaction, the admixing of the hides should preferably take place before the first compaction step, between several compaction steps or after the last granulation step.

The mixing conditions in step (a) and / or the compacting conditions in step (b) are usually selected so that at least 30% of the surface area of the resulting retigabine particles is covered with adhesion promoter, more preferably at least 50% of the surface, most preferably at least 70 % of the surface, in particular at least 90% of the surface.

In step (b) of the process according to the invention, the mixture from step (a) is compacted into a rag. 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 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.

The compacting device used preferably has a cooling device. In particular, it is cooled in such a way that the temperature of the compactate 50 ⁰ C, in particular 40 ⁰ C does not exceed.

In step (c) of the process, the slug is granulated. The granulation can be carried out by methods known in the art. For example, the granulation is carried out with the device Comill ^® U5 (Quadro Engineering, USA).

In a preferred embodiment, 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.

Furthermore, the granulation conditions can be selected so that not more than 55% of the particles have a size of less than 200 microns or the average particle diameter (D50) is between 100 and 450 microns.

Furthermore, the granulation conditions are preferably selected so that the resulting granules have a bulk density of 0.2 to 0.85 g / ml, more preferably 0.3 to 0.8 g / ml, especially 0.4 to 0.7 g / ml , exhibit. The Hausner factor is usually in the range of 1, 02 to 1, 3, more preferably from 1, 04 to 1, 20 and in particular from 1, 04 to 1, 15. In this case, "Hausner factor" is the ratio of tamped density understood to bulk density.

In a preferred embodiment, the granulation is carried out in a sieve mill. In this case, 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.

In a preferred embodiment, the method is adapted such that a multiple compaction takes place, wherein the granulate resulting from step (c) is recycled one or more times for compaction (b). The granules from step (c) are preferably recycled 1 to 5 times, in particular 2 to 3 times.

The granules resulting from step (c) can be processed into pharmaceutical dosage forms. For this purpose, the granules are filled, for example, in sachets or capsules. The invention therefore also capsules and Sachets containing a granulated pharmaceutical composition obtainable by the dry granulation process of the present invention.

Preferably, the granules resulting from step (c) are compressed into tablets (= step (d) of the process according to the invention).

In step (d), compression into tablets takes place. The compression can be done with tableting machines known in the art. The compression is preferably carried out in the absence of solvents.

Examples of suitable tableting machines are eccentric presses or concentric presses. For example, a fats 102i (Fette GmbH, Germany) can be used. In the case of rotary presses, a pressing force of from 2 to 40 kN, preferably from 2.5 to 35 kN, is usually used.

In step (d) of the process, pharmaceutical excipients may optionally be added to the granules of step (c). The amounts of excipients added in step (d) usually depend on the type of tablet to be prepared and on the amount of excipients already added in steps (a) or (b).

In optional step (e) of the process according to the invention, the tablets from step (d) are film-coated. In this case, the usual in the prior art method for filming tablets can be used.

Preferably, macromolecular materials are used for the coating, for example modified celluloses, polymethacrylates, polyvinyl pyrrolidone, polyvinyl acetate phthalate, zein and / or shellac or natural gums, e.g. Carrageenan.

Preference is given to using 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.

The layer thickness of the coating is preferably 2 to 100 .mu.m, in particular 5 to 50 microns.

In addition to the dry compaction and granulation process described above, another aspect of the present invention is a compacted intermediate containing retigabine. A further subject of the invention is therefore an intermediate obtainable by co-dry-drying of retigabine with an adhesion promoter. With regard to the properties of the retigabine to be used and of the adhesion promoter to be used, reference is made to the above explanations. The intermediate according to the invention can be prepared by the steps (a) and (b) of the method according to the invention explained above.

The compaction conditions for the preparation of the intermediate according to the invention are usually selected 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 , in particular 1, 01 to 1, 15 g / cm ³ .

The term "density" herein preferably refers to the "true density" (i.e., not 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.

It is preferred that the type and amount of the adhesion promoter be chosen so that the resulting intermediate has a glass transition temperature (Tg) of more than 20 ⁰ C, preferably> 30 ⁰ C.

It is preferred that the type and amount of the adhesion promoter be chosen so that the resulting intermediate is storage stable. "Storage-stable" means that in the intermediate according to the invention after 3 years of storage at 25 ^° C. and 50% relative atmospheric humidity, the proportion of crystalline retigabine-based on the total amount of retigabine-is at most 60% by weight, preferably at most 30% by weight. %, more preferably at most 15 wt .-%, in particular at most 5 wt .-%, is.

All the above statements on the intermediate according to the invention also apply to the process product resulting in step (b).

The intermediates according to the invention can be comminuted, for example granulated (as described above under step (c) of the process according to the invention). The intermediates according to the invention are usually in particulate form and have an average particle diameter (D ₅₀ ) of from 1 to 750 μm, preferably from 1 to 350 μm, depending on the preparation process.

The intermediate of the invention is usually used for the preparation of a pharmaceutical formulation. For this purpose, in one embodiment, the

Intermediate - if appropriate together with other excipients (see explanations below) - in single and multidose containers, preferably sachets and embroidery Packs, filled. The invention therefore also single and multidose containers, preferably sachets and stick packs containing the granules of the invention.

In a further embodiment, however, the intermediate according to the invention is preferably compressed into tablets as described above in step (d) of the method according to the invention.

In the case of direct compression, only steps (a) and (d) and optionally (e) of the method described above are performed. The invention therefore provides a process comprising the steps

(a) mixing retigabine with an adhesion promoter and optionally other pharmaceutical excipients; and (d) directly compressing the resulting mixture into tablets, as well

(e) optionally, filming the tablets.

In principle, explanations to steps (a), (d) and (e) above also apply to direct compression.

In a preferred embodiment, in the case of direct compression in step (a), a common grinding of retigabine and adhesion enhancer takes place. Optionally, additional pharmaceutical excipients may be added.

The milling conditions are usually selected to cover at least 30% of the surface area of the resulting retigabine particles with adhesion enhancer, more preferably at least 50% of the surface, more preferably at least 70% of the surface, especially at least 90% of the surface.

Milling is generally carried out in conventional grinding equipment, for example in a ball mill, air jet mill, pin mill, classifier mill, cross beater mill, disc mill, mortar mill, rotor mill. The meal is usually 0.5 minutes to 1 hour, preferably 2 minutes to 50 minutes, more preferably 5 minutes to 30 minutes.

It is preferred in the case of direct compression that in step (d) a mixture is used, wherein the particle size of the active ingredient and excipients is coordinated. Preference is given to using retigabine, adhesion enhancers and optionally further pharmaceutical auxiliaries in particulate form having an average particle size (D50) of from 35 to 250 μm, more preferably from 50 to 200 μm, in particular from 70 to 150 μm. Both in the case of dry granulation and in the case of direct compression, in addition to retigabine and adhesion enhancers, further pharmaceutical auxiliaries can be used. These are the adjuvants known to the person skilled in the art, in particular those described in the European Pharmacopoeia. The same applies to the use of the intermediate according to the invention for filling into single and multi-dose containers.

Examples of auxiliaries used are disintegrants, release agents, emulsifiers, pseudo-emulsifiers, fillers, additives to improve the powder flowability, lubricants, wetting agents, gelling agents and / or lubricants. Optionally, other auxiliaries can be used.

As 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. Also used are alkaline disintegrants. By alkaline disintegrating agents are meant disintegrating agents which when dissolved in water produce a pH of more than 7.0.

Preferably, inorganic alkaline disintegrants may be used, especially 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 formulation according to the invention optionally contains fillers. Fillers are generally to be understood as meaning substances which serve to form the tablet body in the case of tablets with small quantities of active ingredient (for example less than 70% by weight). That is, fillers produce by "stretching" of the active ingredients sufficient Tablettiermasse. So fillers are usually used to obtain a suitable tablet size.

Examples of preferred fillers are talc, calcium phosphate, sucrose, calcium carbonate, magnesium carbonate, magnesium oxide, maltodextrin, calcium sulfate, dextrates, dextrin, dextrose, hydrogenated vegetable oil, kaolin, sodium chloride, and / or potassium chloride.

Fillers are usually used in the present case in a small amount, since a high active ingredient content is desired. For example, the Fillers in an amount of 0 to 20 wt .-%, more preferably from 0 to 10 wt .-%, based on the total weight of the formulation can be used.

An example of an additive to improve the powder flowability is dispersed silica, such as known under the trade name Aerosil ^®.

Additives for improving the powder flowability are usually used in an amount of 0.1 to 3% by weight, based on the total weight of the formulation.

Furthermore, lubricants can be used. Lubricants are generally used to reduce sliding friction. In particular, the sliding friction is to be reduced, which in tableting on the one hand between the in the die bore moving up and down punches and the die wall and on the other hand between the tablet web and die wall exists. Suitable lubricants are e.g. Stearic acid, adipic acid, sodium stearyl fumarate and / or magnesium stearate.

Lubricants are usually used in an amount of from 0.1 to 5% by weight, preferably from 0.5 to 3% by weight, based on the total weight of the formulation.

It is in the nature of pharmaceutical excipients that they partially perform multiple functions in a pharmaceutical formulation. For the purposes of this invention, 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 ratio of active ingredient to auxiliaries is preferably selected such that the formulations resulting from the process according to the invention (ie, for example, the tablets according to the invention) contain from 35 to 90% by weight, more preferably from 55 to 85% by weight, in particular from 60 to 80% by weight. % Retigabine and

10 to 65 wt .-%, more preferably 15 to 45 wt .-%, in particular 20 to 40 wt .-% pharmaceutically acceptable excipients.

In this information, the amount of adhesion enhancer which was used in the process according to the invention or for the preparation of the intermediate according to the invention, calculated as an adjuvant. That is, the amount of active ingredient refers to the amount of retigabine contained in the formulation.

It has been found that the formulations according to the invention (ie the tablets according to the invention or the granules according to the invention, which consist of Step (c) of the method according to the invention results and can be filled in, for example, stick packs or sachets) both as an immediate release dosage form (immediate release or "IR") and as a dosage form with modified release (modi fi ed release or "MR" for short). ) to serve.

In a preferred embodiment for an IR formulation, especially in the form of a peroral tablet, a relatively high amount of disintegrant is used. In this preferred embodiment, therefore, the pharmaceutical formulation of the invention contains 1 to 30 wt .-%, more preferably 3 to 15 wt .-%, in particular 5 to 12 wt .-% disintegrant, based on the total weight of the formulation.

In a preferred embodiment for an MR formulation, especially in the form of a peroral tablet, a relatively small amount of disintegrant is used. In this preferred embodiment, therefore, contains the inventive pharmaceutical formulation

0, 1 to 10 wt .-%, more preferably 0.5 to 8 wt .-%, in particular 1 to 5 wt .-% disintegrant, based on the total weight of the formulation.

In the case of the MR formulation, croscarmellose or crospovidone is preferred as disintegrants. In the case of the IR formulation alkaline disintegrants are preferred.

Furthermore, the conventional retardation techniques can be used for the MR formulation.

The abovementioned pharmaceutical excipients can be used in the two preferred embodiments (dry granulation and direct compression). 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 method according to the invention is preferably carried out such that the tablet according to the invention contains 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.

Furthermore, 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. In addition, 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.

Finally, the tablets according to the invention usually have a uniformity of content 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 between 95 and 105%, preferably between 98 and 102%, in particular between 99 and 101% of the average active ingredient content.) The "Content Unfi ormity" is according to Ph. Eur.6.0, Section 2.9. 6, determined.

The release profile of the tablets according to the invention usually has a released content of at least 30%, preferably at least 60%, in particular at least 90%, in the case of an IR formulation according to the USP method after 10 minutes.

The release profile of the tablets according to the invention usually has a released content of 10, preferably 20, in particular 30% after 60 minutes in the case of an MR formulation according to the USP method.

The above information on hardness, friability, content uniformity and release profile preferably relate here to the unformed tablet for an IR formulation. For a modified release tablet, the release profile refers to the total formulation.

The tablets produced by the process according to the invention may be tablets which are swallowed whole (unfiltered or preferably film-coated). It may also be Disperstabletten. "Disperstablette" is here understood to mean a tablet for the production of an aqueous suspension for oral use.

In the case of tablets which are swallowed whole, it is preferred, as explained above under step (e), that they be coated with a film layer. However, the above-mentioned ratios of active ingredient to excipient relate to the unpainted tablet.

For sachets, the following auxiliaries are usually used:

The granules (intermediate) described above, in a preferred embodiment after the dry processing, additionally with one or more several flavors, such as peppermint flavor, added. The proportion of flavoring agent is usually 0.1 to 10% by weight, preferably 2 to 4% by weight, based on the total weight of the formulation. For the purposes of this application, the term "flavorings" is to be understood as defined in Council Directive 88/388 / EEC of 22 June 1988. Instead of the peppermint flavor, other flavors such as spearmint, lemon or the like can be used.

In addition, in a preferred embodiment, the intermediate is added to a sweetener, the sweetening agent preferably being used in an amount of from 0.1 to 4, more preferably from 1 to 3,% by weight, based on the total weight of the formulation. For example, sachharin sodium, e.g. in a concentration of 1 -3 wt. Aspartame in a concentration of 2 to 4 wt .-% are used. Otherwise, other common sweeteners can be used.

The sachet formulation can also contain an effervescent body consisting of a mixture of citric acid and sodium bicarbonate, for example in the ratio 1: 2, and preferably 5 to 15% by weight, e.g. about 10 wt .-%, of the total amount.

As explained above, the subject of the invention is not only the method according to the invention, but also the tablets produced by this method. It has also been found that the tablets produced by this process preferably have a bimodal pore size distribution. The invention thus relates to tablets containing retigabine or a pharmaceutically acceptable salt thereof and adhesion enhancers and optionally pharmaceutically acceptable auxiliaries, wherein the tablets have a bimodal pore size distribution.

This tablet according to the invention is produced when the granules from method step (c) are compressed. This compact consists of solid and pores. The pore structure can be further characterized by determining the pore size distribution.

The pore size distribution was determined by mercury porosimetry. Mercury porosimetry measurements were carried out with the "Poresizer" porosimeter from Micromeritics, Norcross, USA. The pore sizes were calculated assuming a surface tension of mercury of 485 raN / m. From the cumulative pore volume, the pore size distribution was calculated as the sum distribution or proportion of the pore fractions in percent. The average pore diameter (4V / A) was calculated from the total specific Mercury intrusion volume (VgCS _1n ,) and the total pore area (Ages, _* ,,.) Determined according to the following equation.

4V / A = ^{4 'VgeSte} ^ ^{ml / 8} ^

Ages ^ [m ² / g]

By "bimodal pore size distribution" is meant that the pore size distribution has two maxima. The two maxima are not necessarily separated by a minimum, but a head-and-shoulders formation is also considered bimodal in the sense of the invention.

The formulations according to the invention are preferably used for the treatment of epilepsy and neuropathic pain. The invention thus relates to the use of dry-compacted retigabine for the treatment of epilepsy and neuropathic pain.

The invention will be illustrated by the following examples.

EXAMPLES In all examples, retigabine is preferably used as retigabine dihydrochloride, the amount given being based on the amount of free base retigabine. That is, the statement 300 mg retigabine corresponds to about 372 mg retigabine dihydrochloride.

Example Ia: Direct Compression of Retigabine (IR)

Retigabine 400 mg

Lactose monohydrate 200 mg

Microcrystalline cellulose 45 mg

Magnesium stearate 5 mg silica 1 mg

Croscarmellose 5 mg

Retigabine was premixed together with lactose in the tumbler mixer (Turbula) for 10 min. Subsequently, all other constituents were supplemented except for magnesium stearate and mixed for a further 30 minutes. After addition of magnesium stearate was remixed again for 2 min. The final mixture was on a rotary press with punches, which have the following properties: 10 mm round blconvex, pressed. The tablets had a hardness of about 1 10 N. Subsequently, the tablets could optionally be coated with a coating.

For filming hypromellose (Pharmacoat 603) and polyethylene glycol 6000 was added with water, and after dissolving with separately prepared suspension of titanium dioxide and iron oxide combined in water. The tablet cores were coated with the resulting suspension in the perforated drum coater.

Example Ib:

Example Ia was repeated using 10 mg of magnesium stearate.

Example 2a: Dry Granulation of Retigabine and Compression to Tablets (IR)

Retigabine 300 mg

Povidone VA64 300 mg

Prosolv ^® (Si-modifϊzierte microcryst. Cellulose) 80 mg

Sodium bicarbonate 40 mg Magnesium stearate 4 mg

Silica 4 mg

Retigabine has been pre-mixed together with povidone VA64, sodium bicarbonate and 50 wt .-% of Prosolv ^®, magnesium stearate and silicon dioxide and then compacted (rolling force 30 kN / cm, slit width 2 mm), The resulting intermediate was purified by a sieve mill (1, 0 mm) granulated and compressed with the remaining Prosolv ^® , magnesium stearate and silica to tablets.

The resulting tablets could be film-coated (as described under Example Ia).

Example 2b:

Example 2a was repeated using 8 mg of magnesium stearate.

Example 3a: Direct Compression of Retigabine (SR)

Retigabine 600 mg

Pharmacoat ^® 603 (retarding hydroxypropylmethyl cellulose) 300 mg Prosolv ^® 50 mg

Talc 4 mg

Magnesium stearate 4 mg Retigabine was mixed with hydroxypropylmethylcellulose and Prosolv ^® (Turbula Tlob, 30 minutes). Mäggelnstearät and talc were added to the mixture and all mixed together for another 3 minutes.

The finished mixture is pressed into tablets. For this purpose, an eccentric press Korsch EKO is used with a pressing force of 10 kN.

Example 3b:

Example 3a was repeated using 8 mg of magnesium stearate.

Example 4a: Direct compression of retigabine (IR)

Retigabine 900 mg

Pregelatinized starch 200 mg

Magnesium stearate 5 mg

The active ingredient was mixed with the starch for 20 minutes in the tumbler (Turbula WOBO) and then the magnesium stearate was added.

The finished mixture was mixed again for 3 minutes and then pressed on an eccentric press (Korsch, EKO).

Example 4b:

Example 4a was repeated, 10 mg of magnesium stearate was used.

Example 5: Sachet containing dry granulated intermediate

Retigabine 900 mg

Microcrystalline Cellullose 200 mg Polyvinylpyrrolidone 100 mg

Sachharin sodium 150 mg

Peppermint flavor 40 mg

Citric acid 50 mg

Sodium bicarbonate 100 mg

Retigabine was mixed with sodium bicarbonate, microcrystalline cellulose, polyvinylpyrrolidone, citric acid and peppermint flavor and then compacted (40 kN, 2 mm). The compact was sieved through a sieve of grain size 0.8 mm with concomitant comminution (Comill ^® U5). The resulting granules were filled into sachets. Example 6 Effervescent tablet

Retigabine 900 mg

Microcrystalline Cellullose 200 mg Polyvinylpyrrolidone 200 mg

Peppermint flavor 40 mg

Citric acid 50 mg

Sodium bicarbonate 100 mg Magnesium stearate 5 mg Aerosil ^® 3 mg

The ingredients except the lubricant were dry mixed (Turbula W 10B) and sieved (710 μτn). The magnesium stearate was added and the final mixture was compressed to an effervescent tablet.

Claims

claims

1. A process for the preparation of oral dosage forms, in particular tablets, containing retigabine and adhesion enhancer, wherein the dosage forms are prepared by means of dry compacting or direct compression.

2. The method according to claim 1, comprising the steps

(b) compaction into a slug;

(c) granulation of the slug;

(D) compression of the resulting granules into tablets, optionally with the addition of further pharmaceutical excipients; and (e) optionally, filming the tablets.

3. The method according to claim 2, wherein the compaction (b) is performed in a roll compactor and the rolling force is 5 to 70 kN / cm, preferably 10 to 50 kN / cm.

4. The method of claim 2 or 3, wherein the granulation conditions in step (c) are selected so that not more than 55% of the particles have a size of less than 200 microns or the average particle diameter (D50) is between 100 and 450 microns.

5. The method according to claim 1, comprising the steps

(a) mixing retigabine with an adhesion promoter and optionally other pharmaceutical excipients; and (d) directly compressing the resulting mixture into tablets, and (e) optionally, coating the tablets.

6. The method of claim 5, wherein in step (a) a common grinding of retigabine and adhesion enhancer takes place.

7. The method according to claim 5 or 6, wherein in step (d) a mixture of retigabine, adhesion enhancers and optionally further pharmaceutical excipients having an average particle size (D50) of 50 to 250 microns is used.

8. The method according to any one of claims 1 to 7, wherein retigabine in an amount of 55 to 90 wt .-%, based on the total weight of all substances used, is used.

9. tablets obtainable by a process according to any one of claims 1 to 8.

10. Tablets according to claim 9 having a friability of less than 3%, with a uniformity of the content of 95 to 105% and with a hardness of 50 to 250 N, the tablets containing 250 to 900 mg of retigabine.

1 1. Intermediate obtainable by dry co-compacting retigabine with an adhesion enhancer.

12. Intermediate according to claim 10, wherein the density of the intermediate 0.8 to 1, 3 g / cm ³ , preferably 0.9 to 1, 20 g / cm ³ .

13. Intermediate according to claim 10 or 11, wherein the adhesion promoter used is a polymer having a weight-average molecular weight of less than 90,000 g / mol and a glass transition temperature (Tg) of greater than 20 ^° C. after heating twice or using a sugar alcohol.

14. Intermediate according to one of claims 10 to 13, wherein the weight ratio of retigabine to adhesion enhancer is 5: 1 to 1: 2.

15. sachet or stick pack, containing an intermediate according to any one of claims 1 1 to 14.

Use of dry-compacted retigabine for the treatment of epilepsy and neuropathic pain.