EP2595607A2

EP2595607A2 - Medicinal drug for oral administration comprising a mixture of silodosin and a basic copolymer

Info

Publication number: EP2595607A2
Application number: EP11735435.7A
Authority: EP
Inventors: Katrin Rimkus; Sandra Brueck
Original assignee: Ratiopharm GmbH
Current assignee: Ratiopharm GmbH
Priority date: 2010-07-23
Filing date: 2011-07-21
Publication date: 2013-05-29
Also published as: JP2013532651A; WO2012010669A2; WO2012010669A3

Abstract

The invention relates to a medicinal drug for oral administration comprising a mixture of silodosin or a pharmaceutically compatible salt thereof and a basic copolymer. The invention also relates to a method for producing said drug.

Description

A medicament for oral administration comprising a mixture of silodosin and a basic copolymer

The invention relates to a medicament for oral administration comprising a mixture of silodosin or a pharmaceutically acceptable salt thereof and a basic copolymer. Furthermore, the present invention relates to methods for producing such an oral drug.

Silodosin is the international generic name of the compound 1 - (3-hydroxypropyl) -5 - [(2R) - ({2- [2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl} amino) propyl] indoline -7-carboxamide having the following chemical structural formula:

Silodosin is a known drug used to treat the symptoms of benign prostatic hyperplasia (a benign enlargement of the prostate gland). In particular, silodosin is a c-rAdrenoreceptor antagonist which blocks the receptors located in the prostate gland and results in smooth muscle relaxation of the bladder neck, urethra, and prostate associated with facilitated Hama flow. Silodosin is therefore used in particular for the treatment of dysuria. Furthermore, silodosin has been proposed as a male contraceptive.

The production of silodosin is disclosed, for example, in the basic patent EP 0 600 675, which also describes the use of silodosin for the treatment of dysuria. Drug-containing silodosin are currently commercially available, including under the brands Urief ^® and Rapaflo ^®. The currently marketed drugs are hard gelatin capsules. The production of drugs containing the active ingredient silodosin poses a number of difficulties, since silodosin is considered to be photosensitive and should not be exposed to high temperatures. Furthermore, silodosin is incompatible with a number of pharmaceutically acceptable additives which are often used in the manufacture of medicaments, and therefore undesirable degradation products are often produced in the production and storage of silodosin-containing medicaments. Corresponding problems are described, for example, in EP-A 1 574 215 (in which the older designation KMD-3213 is used for silodosin). Furthermore, according to EP-A 1 574 215, problems arise in the solubility of tablets with the active ingredient silodosin and, according to EP-A 1 574 215, it is also difficult to formulate silodosin with a lubricant. When preparing capsules containing the active ingredient silodosin, the mixing time of the capsule contents should have an influence on the release profile of the active ingredient.

To solve these problems, EP-A 1 574 215 discloses some special medicaments, in particular those in which D-mannitol is used as filler and magnesium stearate as lubricant.

JP 2004-175796 discloses tablets disintegrating in the mouth and more particularly relates to the taste masking of unpleasant tasting active ingredients. Silodosin (or KMD-3213) is one of several drugs.

In the manufacture of medicaments containing the active ingredient silodosin, the difficulty also arises that silodosin and in particular the salts of silodosin can be present in amorphous, but also in various polymorphic crystalline forms, as described, for example, in EP-A 1 541 554. Depending on the form, silodosin is more or less hygroscopic. Nor can it be ruled out that, during the manufacture and storage of a drug with the active ingredient silodosin or a pharmaceutically acceptable salt thereof, there will be a (partial) conversion of the polymorphic forms into each other or into the amorphous form, which will affect the pharmacokinetic properties of the drug, in particular the drug release and the bioavailability of the drug and may also affect the hygroscopicity of the drug. This increases the problems that arise in the formulation of these drugs and makes it difficult to provide these drugs with a reproducible and rapid release of active ingredient, which can be easily obtained with a wide variety of excipients and cost. Furthermore, the silodosin in the drug should also have a very high chemical stability and should form as little degradation products of silodosin in the production and storage of the drug.

Eudragit ^® E is a basic copolymer which is prepared from methyl methacrylate, butyl methacrylate and dimethylaminoethyl methacrylate. The use of Eudragit ^® E, which is commercially available for example as Eudragit ^® E 100, Eudragit ^® E PO or Eudragit ^® E 12.5 was, so far been limited mainly to coatings for oral pharmaceutical forms that protect the drug against light and moisture. Furthermore, such coatings are used for drugs having an unpleasant taste or odor, and also for drug forms whose active ingredients are intended to be released in the stomach. US 6,063,399 also discloses that Eudragit ^® E can be used in combination with an anionic copolymer and a plasticizer for the production of self-adhesive matrix systems for transdermal applications.

WO 2006/0201 1 1 discloses pharmaceutical formulations containing acid-labile benzimidazole derivatives in combination with the basic copolymer Eudragit ^® E include. The addition of Eudragit ^® E stabilized the acid-labile benzimidazole derivatives. A possible stabilizing effect of the Eudragit ^® E on light-sensitive and temperature-sensitive active substances can not be found in the publication.

It is an object of the present invention to provide an oral drug which does not exhibit the problems of the prior art which, for example, independently of the polymorphic form of the silodosin used for its production or a pharmaceutically acceptable salt thereof, reproducibly produces a very rapid Provides dissolution and drug release in the stomach and good bioavailability and has an improved shelf life, especially under light and temperature. In addition, the drug should be easy and inexpensive to produce. Preferably, the unpleasant taste of silodosine should be masked. This object is solved by the subject matter of the claims. The solution to this problem is based on the surprising finding that silodosin or its pharmaceutically acceptable salts with basic copolymers form storage-stable mixtures which can be easily processed into oral medicaments. The oral drugs with these mixtures do not have the problems of the prior art. In particular, the silodosin in these oral drugs is chemically very stable and the mixtures are processable with a very large number of conventional pharmaceutical additives without problems to an oral drug. The physical form of silodosin in the oral drug also preferably does not change during storage, and oral drugs with the mixtures of the invention have a reproducible, very rapid release of the active ingredient in the stomach, which does not change significantly during storage of the drug.

In particular, it has surprisingly been found that a basic copolymer significantly reduces the decomposition of silodosin under the action of light and heat, so that the stability of a drug can be improved even under the action of light and heat. The basic copolymers which can be used according to the invention are known to the person skilled in the art. The basic copolymers may have as the basic group, for example, an amino group or a carboxylate group. Preferably, the basic group in the copolymers, which are used according to the invention in admixture with silodosin or a pharmaceutically acceptable salt thereof, an amino group, in particular a tertiary amino group. The amino group of the basic copolymer is usually protonated in solution so that the basic copolymer is a cationic copolymer and is also referred to in some references as a cationic copolymer.

The invention also preferably involves a basic acrylate or methacrylate copolymer, which in turn preferably carries amino groups.

Particularly preferred according to the invention is a copolymer with monomer units derived from methyl methacrylate, butyl methacrylate and dimethylaminoethyl methacrylate. Such basic copolymers are, for example commercially available under the trade name Eudragit ^® E, in particular, it is the products Eudragit ^® E 100, Eudragit ^® E PO and Eudragit ^® E 12.5. Silodosin or a pharmaceutically acceptable salt thereof may be used for the preparation of the oral medicine of the present invention, and the properties of the oral drug of the present invention are preferably independent of whether the drug or drug salt is used in an amorphous form or in a crystalline form or in a particular polymorphic form has been. Finally, the medicaments of the invention are extremely economical and easy to prepare and offer the galenic a great deal of freedom in the choice of possible pharmaceutically acceptable excipients and additives.

The oral drugs according to the invention show excellent storage stability. In particular, the amount of degradation products of silodosin during storage of the oral drug for 3 months at 30 ° C and 65% air humidity is generally below 0.7 wt .-%, preferably below 0.5 wt .-%, based on the Amount of silodosin.

The present invention thus relates to a medicament for oral administration, characterized in that the active ingredient silodosin is present in admixture with a basic copolymer.

The term silodosin and pharmaceutically acceptable salts thereof, as used in the context of this application, of course, all hydrates and solvates of the corresponding compounds are understood. Preferred pharmaceutically acceptable salts of silodosin which can be used in the present invention are acid addition salts. Examples of suitable acid addition salts are hydrochlorides, maleates, oxalates, sulfates, methanesulfonates, isothionates, toluenesulfonates, trifluoroacetates, pyruvates, sulfamides, glutamates, glutarates, sorbates and / or succinates. However, silodosin is preferably used in the form of the free base.

The ratio of the basic copolymer to silodosin is not particularly limited, but the proportion of the basic copolymer is usually at least as high as the content of silodosin. Preferably, the weight ratio of the basic copolymer to silodosin (or the salt thereof) is in the range of 1: 1 to 500: 1, more preferably in the range of 2: 1 to 50: 1.

The mixture of silodosin or a pharmaceutically acceptable salt thereof may be used as such as an oral drug of the present invention, that is, directly be administered to a patient. Preferably, a drug with the mixture of silodosin or a pharmaceutically acceptable salt thereof but still one or more pharmaceutically acceptable excipients. Preferably, the pharmaceutical composition according to the invention is first converted into a unit dosage form which is suitable and customary for oral administration. Suitable unit dosage forms are for example sachets, capsules or tablets. According to the invention, tablets and capsules are preferred, capsules in particular being understood as meaning hard gelatin capsules. According to the invention, the medicament is preferably a capsule or a tablet, most preferably a tablet or a hard gelatin capsule.

For this purpose, the mixture of silodosin or a pharmaceutically acceptable salt thereof and the basic copolymer, for example, directly or without further auxiliaries and additives, for example, transferred to a sachet or capsule or pressed into a tablet or it can first with suitable further auxiliary and Mixed additives and then filled, for example, in a sachet or capsule or pressed into a tablet. Depending on the process for the preparation of the mixture, auxiliaries or additives can already be used in the preparation of the mixture. In addition, it is also possible to mix suitable auxiliaries and additives with the mixture (which may already contain auxiliaries and additives as a result of the preparation) and to convert it into a suitable unit dosage form.

Suitable auxiliaries and additives are known to the person skilled in the art and described, for example, in the European Pharmacopoeia. Possible auxiliaries are, for example, disintegrants, release agents, fillers, binders, additives for improving the powder flowability, lubricants, flow regulators and / or surfactants.

The medicament according to the invention particularly preferably contains at least one disintegrant, preferably in a content in the range from 1 to 10, preferably from 3 to 6,% by weight. An explosive accelerates the disintegration of a dosage form, in particular a tablet, after introduction into water or in contact with the digestive juices. Disintegrators preferred according to the invention are organic disintegrants, such as carageenan, croscarmelose, sodium carboxymethyl starch, soy, polysaccharides and crospovidone. According to the invention, the medicament according to the invention preferably contains, as disintegrant, a so-called "superdisintegrant", to which in particular crosslinked PVP and count cross-linked sodium starch glycolate. Crosslinked PVP is particularly preferably used as disintegrants according to the invention.

Lubricants are generally used to reduce the sliding friction, which may be particularly advantageous in tableting. According to preferred lubricants are stearic acid, adipic acid, sodium (for example, under the brand Pruv ^® distributed) and / or magnesium stearate. The content of lubricant is preferably 0-5, more preferably 0.1-5, especially 0.5-3 wt .-%.

Furthermore, the medicaments according to the invention may also contain binders, for example. Examples of binders are copovidone, gelatin and hydroxypropylcellulose. Other binders are known to those skilled in the art. The content of binder is preferably 0-10, in particular 0.5-10 wt .-%.

Many compounds belong to both the group of disintegrating agents and to the group of binding agents, for example microcrystalline cellulose. Such a compound may of course also be present in the medicaments according to the invention and, depending on the concentration and other constituents, have the function of a binder or of a disintegrating agent.

A pharmaceutical composition according to the invention may further contain additives for improving the flowability, preferably in an amount of 0-5, in particular of 1, 5-4 wt .-%. An example of such an adjuvant is particulate silicon dioxide, which is marketed for example under the trade name Aerosil ^®. Preference is given to silica having a specific surface area of 50-400 m ² / g, determined by gas absorption in accordance with PH Eur., 6th edition, 2.9.26.

Depending on the amount of silodosin or the type and amount of the pharmaceutically acceptable silodosin salt and the amount of the basic copolymer and the solvent used in the preparation of the medicament of the invention, the temperature and the pH, it may be advantageous to the mixture of the basic copolymer and active ingredient to add a surfactant. The surfactant is not particularly limited. As an example, polyoxyethylene sorbitan monooleate, sodium lauryl sulfate, polyoxyethylene (20) sorbitan monolaurate, polyalkylene glycol ethers, etc. may be mentioned. Particularly preferred are sodium lauryl sulfate and polyoxyethylene (20) sorbitan monolaurate. The medicaments according to the invention may, for example, also contain one or more release agents. By release agents according to the invention in accordance with the general knowledge materials understood that reduce the agglomeration in the core bed. Examples of suitable release agents are talc, silica gel, polyethylene glycol (preferably with 2000-10000 g / mol weight average molecular weight) and / or glycerol monostearate.

Examples of fillers which are preferred according to the invention are calcium carbonate, magnesium carbonate, magnesium oxide, calcium sulfate, starch, starch derivatives, modified starch, polysaccharides, chitin, cellulose, cellulose derivatives, calcium phosphate, calcium hydrogenphosphate, sucrose, maltodextrin, dextrate, dextrin, dextrose, lactose, lactose derivatives and hydrogenated vegetable oil. Preferred are calcium phosphate, calcium hydrogen phosphate and polysaccharides, in particular dextrin, which is marketed under the brand Emdex ^®.

The following table discloses preferred compositions and concentrations of pharmaceutical compositions of the invention. All data in the table are given in percent by weight, based on the finished product (without consideration of any remaining solvent).

Silodosin or pharmaceutical

1 -8 1 -5 1 -5 1 -5 2-5 acceptable salt thereof

Basic Copolymer 1 -60 1 -60 5-60 5-60 5-60

Fillers 35-95 35-94 35-90 35-90 35-90

Surfactant 0-2 0-2 0-2 0-2 0-2

Blasting agent 1 -10 3-6 1 -10 3-6 3-6

Lubricant 0-5 - 0-5 0,5-4 0,5-4

Binder 0-10 - 0-10 0-10 0-10

Means to improve the

0-5 - 0-5 0,5-3 0,5-3 fluidity

Release agent 0-5 - 0-5 0-3 0-3 The mixing of the usual pharmaceutically acceptable excipients with the mixture for the preparation of a unit dosage form can be carried out in conventional manner in conventional mixers, for example a Turbula T10B can ^® (Bachhofen AG, Switzerland) can be mentioned. The mixing time in commercially available mixers is usually 1 minute to 1 hour, preferably 3 minutes to 20 minutes.

In a preferred embodiment according to the invention, the medicaments according to the invention are optionally compressed into tablets after the addition of further pharmaceutically acceptable excipients and additives. The compression can be done with tableting machines known in the art, such as eccentric presses or concentric presses. In the case of rotary presses, a pressing force of 2-40 kN, preferably 2.5-35 kN, is usually used. As examples of suitable tablet presses the press fats ^® may 102i (Fette GmbH, Germany) are mentioned. In the case of eccentric presses usually a pressing force of 1 -20 kN, preferably from 2.5 to 10 kN is applied. As an example of a suitable eccentric press can be called the commercial product Korsch ^® EKO.

The pressing into tablets takes place according to the invention preferably as dry compression.

If the medicaments according to the invention are in the form of tablets which are swallowed whole, it is preferred to coat these tablets with a film layer. The above proportions of active ingredient and excipients refer to the uncoated tablet. Preferably macromolecular substances are used for the film-coating, for example, modified cellulose, polymethacrylates, polyvinylpyrrolidone, polyvinyl acetate phthalate, Zein, Eudragit ^® and / or shellac. It is also possible according to the invention to provide the tablets with an enteric coating. Enteric coating materials are known in the art.

The layer thickness of the tablet coating is preferably 2-100 μηι.

The tablets according to the invention preferably have a tablet height to weight ratio in the range of 0.005-0.3 mm / mg, particularly preferably 0.05-0.2 mm / mg.

The drug of the present invention preferably contains silodosin or the pharmaceutically acceptable salt thereof in an amount of 0.5 mg to 15 mg, more preferably 2 mg 1 1 mg, in particular from 4 mg to 8 mg. The invention thus z. As oral drugs, especially tablets containing 4 mg or 8 mg silodosin or a pharmaceutically acceptable salt thereof.

It is also particularly advantageous according to the invention that the medicaments according to the invention and in particular the tablets according to the invention have outstanding content uniformity which is in the range of 95-105% of the average content, preferably in the range of 98-102% of the average content, particularly preferably in the range from 99-101% of the average salary. The content uniformity is determined according to PH Eur. 6.0 Section 2.9.6.

The tablets according to the invention have a particularly advantageous rapid in vitro release profile. The release profile of the tablets according to the invention, determined according to the USP Paddle Method Apparatus II, is such that after 60 minutes usually at least 40%, preferably at least 60%, in particular at least 80% of the active ingredient is stirred at a stirring speed of 50 rpm in 0.1 N HCl ( pH 1 .2) at 37 ° C is released. The release profile of the tablets according to the invention does not change significantly during storage, which is also a particular advantage of the tablets according to the invention.

The content data in this application in each case relate to the total weight of the medicament according to the invention, unless otherwise stated or obvious due to the circumstances.

The mixtures of silodosin or a pharmaceutically acceptable salt thereof and the basic copolymer can be prepared by various techniques. Preferred processes are dry mixing, wet granulation, melt granulation, spray drying, lyophilization and melt extrusion, particularly preferred are wet granulation, melt granulation and spray drying.

In a preferred method of the invention, silodosin or a pharmaceutically acceptable salt thereof is mixed with a basic copolymer in the presence of a solvent and optionally further pharmaceutically acceptable excipients. Subsequently, a granulation step is performed. The granules is optionally (preferably) dried and the dried granules are optionally sieved.

In this invention preferred method silodosin or a pharmaceutically acceptable salt thereof is introduced together with a basic copolymer and optionally with other pharmaceutically acceptable excipients and additives in a suitable solvent. Here, first, the silodosin or the pharmaceutically acceptable salt thereof may be added to the solvent, and then the basic copolymer may be added, or first, the basic copolymer may be initially charged in a solvent and then the silodosin or the pharmaceutically acceptable salt thereof may be added. Alternatively, the basic copolymer and silodosine or a pharmaceutically acceptable salt thereof may be added simultaneously to the solvent. The resulting mixture is then homogenized, granulated (optionally using a filler and optionally further active ingredients) and, if appropriate, dried, resulting in the formation of a granulate. The granules are dried, optionally sieved to a desired particle size. The optionally sieved granules thus obtained represent a preferred embodiment of the medicament according to the invention with the mixture of silodosin or a pharmaceutically acceptable salt thereof and the basic copolymer.

In this preferred method, the choice of the solvent is not particularly limited. All solvents which dissolve or suspend the silodosin or the silodosin salt and the basic copolymer to a sufficient extent are suitable for this purpose. Optionally, a surfactant can be added to improve the solubility of the compounds in the solvent.

Preference is given to pharmaceutically acceptable solvents and particular preference is given to CC ₄ -alcohols and also acetone, if appropriate mixed with other solvents and with water. Ethanol, isopropanol or an isopropanol-acetone-water mixture is very particularly preferably used, it being possible for constituents of isopropanol and acetone in the isopropanol-acetone-water mixture to be in the range of 10-90%, more preferably in the range of 70 -30%, most preferably about 50%. In this first preferred embodiment, enough solvent is used to form a solution or suspension of the silodosin or salt thereof and the basic copolymer.

In this preferred embodiment of the method according to the invention, the formation of the mixture according to the invention takes place in that silodosin or a pharmaceutically acceptable salt thereof, the basic copolymer and optionally further pharmaceutically acceptable additives and optionally a surfactant are introduced into a suitable solvent as explained above and dissolved or suspended ; the solution or suspension is then optionally applied to a filler and granulated. Optionally, it is possible that the suspension already has a suitable consistency to carry out a granulation without the use of another filler. In this case it is preferred to carry out the granulation of the suspension as such. If the process produces a solution or a liquid suspension which is not yet suitable for direct granulation, the solution or suspension can be applied to a filler as described above and then granulated. The granules are optionally dried and optionally sieved to a suitable particle size.

The granulation is carried out in conventional devices for granulation, eg Diosna P1 / 6, DIOSNA Dierks & Söhne GmbH. Preferably, the granulation is carried out such that the granules have a volume-average particle size (D50 value) in the range of 75-800 μιΐΊ, more preferably in the range of 100-500 pm. The weight average particle size, for example, by sieve analysis, for example using a Retsch ^® AS 2000 apparatus are determined, wherein an amplitude of 1, 5 seconds, an interval of 10 minutes and a sample weight of 20 g can be given as exemplary measurement condition.

A D50 value for the volume average particle size means that 50% of the particles are smaller in volume than the D50 value and 50% in volume greater than the D50 value.

The granules obtained can then be dried in a customary manner, the drying preferably taking place in such a way that the residual solvent content in the granules is at most 0.5%, more preferably at most 0.3%. This is also the preferred content Residual solvent in the medicament of the invention. The drying can be carried out in a conventional drying oven, preferably under reduced pressure, at a temperature in the range from 20 to 70 ° C., in particular at 30 to 60 ° C., particularly preferably at 35 to 50 ° C. and over a period of at least one hour, preferably at least one and a half hours, for example about two hours. Since the silodosin in the medicaments according to the invention has a markedly high stability, the choice of the drying conditions is not particularly limited. In particular, a decomposition of the active ingredient is to be feared only when drying for a long time at very high temperatures.

After drying, the medicament of the invention is obtained.

In a further preferred method according to the invention, the silodosin or the pharmaceutically acceptable salt thereof is combined with the basic copolymer and optionally further pharmaceutically acceptable additives in a suitable solvent or in a solvent mixture at a temperature of from 20 to 70 ° C, preferably from 30 to 60 ° C solved. Subsequently, the solution is subjected to spray drying. The process of spray-drying is known to the person skilled in the art. In accordance with the invention, any suitable spray drying process can be used using known and commercially available spray drying equipment.

The spray drying is carried out at a suitable temperature. Since it has been found according to the invention that the basic copolymer stabilizes the inherently temperature-sensitive silodosin, spray-drying may be carried out at a suitable higher temperature of above 70 ° C, especially 80 ° C and above, for example at 85 ° C or another suitable for spray drying Temperature be performed. This forms a preferred according to the invention drug.

In this second preferred embodiment, silodosin or a pharmaceutically acceptable salt thereof and the basic copolymer preferred according to the invention are dissolved in a suitable solvent or optionally a suitable solvent mixture. As solvent or solvent mixture, the same solvents or solvent mixtures can be used, which were explained above in connection with the first preferred embodiment (granulation). However, that is it is necessary for the process of spray-drying, that a complete solution of the components to be subjected to the spray-drying is present, so that according to the invention only those solvents or solvent mixtures are used in this method, the silodosin or the pharmaceutically acceptable salt thereof and completely dissolve the basic copolymer used (and the optionally further pharmaceutically acceptable auxiliaries and additives). Also in this embodiment, if necessary, a surfactant may be used to improve the solubility.

Subsequently, the resulting solution is subjected to spray drying according to the invention at a preferred temperature of 30 to 110 ° C., preferably at 50 to 100 ° C., particularly preferably at 70 to 90 ° C.

Spray-drying may be carried out by means of conventional spray-drying equipment, e.g. with Büchi B-290, Büchi Labortechnik GmbH. Preferably, the spray drying is performed such that the spray dried material has a volume average particle size (D50 value) of <15pm, more preferably <10m. In the case of the above very small particle sizes, the volume-average particle size is preferably determined by means of a particle meter from Malvern type designation: Mastersizers 2000S. The final spray-dried mixture is preferably treated with a suitable pharmaceutically acceptable filling agent, which has optionally been granulated with other pharmaceutically acceptable excipients and additives, and over a period of at least one minute, preferably one to 20 minutes, e.g. mixed over a period of about 5 minutes.

As the filler, in principle, any known pharmaceutically acceptable filler can be used, as indicated above.

In another method which is likewise preferred according to the invention, the silodosin or the pharmaceutically acceptable salt thereof is subjected to melt extrusion with the basic copolymer and optionally with further pharmaceutically acceptable additives. The extrudate obtained is comminuted after cooling, sieved to a desired particle size and mixed with other pharmaceutically acceptable additives. The product thus obtained is preferably further processed to a unit dosage form, in particular to a tablet or hard gelatin capsule. The melt extrusion process takes place at a preferred temperature according to the invention of 40 to 110 ° C., preferably 30 to 90 ° C., more preferably 50 to 70 ° C. Melt extrusion can be carried out using melt extruders known in the art, for example HAAKE ^* PolyLab QC, ThermoFischer Scientific Inc.

For the preparation of extrudates silodosin or a pharmaceutically acceptable salt thereof is mixed with the basic copolymer, optionally with the addition of further pharmaceutically acceptable auxiliaries and additives. This mixture is introduced into an extruder and processed there to a homogeneous melt. A preferred extruder has a screw profile. The screw profile should include kneading blocks, since the shear forces generated by the kneading blocks contribute to the melting of the mixture and thus also to the dissolution of the active ingredient in the excipient. The temperature profile is chosen so that the highest temperatures are set in the cylinder in which the kneading blocks are seated. In one embodiment using a multi-cylinder extruder, it is preferable to determine how much the mixture is melted by varying the two middle cylinders in the process. On the temperature of the last two cylinders in front of the nozzle plate, the viscosity of the melt can be regulated. There is a minimum temperature for each system, otherwise the nozzle becomes clogged. The extrusion is preferably carried out at an outlet pressure of about 20 bar to about 100 bar, in particular from about 20 bar to about 50 bar.

In the melt extrusion according to the invention, e.g. the following auxiliaries and additives are used: poly (methyl acrylate-co-methyl methacrylate-co-methacrylic acid), poly (methacrylic acid-co-methyl methacrylate) 1: 2, hydroxypropyl cellulose, ethyl cellulose, cellulose acetate butyrate, cellulose acetate phthalate, poly (ethylene oxide), poly (ethylene glycol) , Poly (vinylpyrrolidone), poly (vinylacetate), hydroxypropylmethylcellulose phthalate, polyvinylpyrrolidone-co-vinylacetate, hydroxypropylmethylcellulose,

Hydroxypropylmethyl cellulose acetate succinate, poly (lactide-co-glycolide), polyvinyl alcohol, chitosan lactate, pectin, carbomer, polycarbophil, poly (ethylene-co-vinyl acetate), polyethylenes, poly (vinyl acetate-co-methacrylic acid), polycaprolactone, carnauba wax, ethylene vinyl acetate copolymer , Glycerol palmitostearate, starch, maltodextrin, isomalt, citric acid, sodium bicarbonate, polyvinyl alcohol-polyethylene glycol copolymer. The resulting extrudate is typically in strands of different lengths, which are broken after exiting the extruder after cooling. The fragments can be comminuted with a mill, eg a centrifugal mill, to obtain fractions of a certain particle size. Depending on the grinding process, one can produce particles of different sizes. Typically, the particle size is 10- 1000 μιη. This corresponds at the same time to the particle size of most of the auxiliaries used for the preparation of solid dosage forms, thus enabling a better mixing of the ground extrudate with the excipients. In general, small extrudate particles release the active ingredient more quickly than coarse particles.

A particularly preferred method according to the invention for preparing an oral medicament comprises the following steps: a) introducing the silodosin or a pharmaceutically acceptable salt thereof with a basic copolymer and optionally with further pharmaceutically acceptable additives into a suitable solvent or a solvent mixture;

b) preparation of a solution or suspension and its subsequent granulation (if necessary using a filler) and drying;

c) sieving the dried granules;

d) addition of further commercially available pharmaceutical auxiliaries for producing a flowable granule;

e) optionally adding further pharmaceutical excipients and filling in a hard gelatin capsule or pressing the granules and any excipients present in a tablet.

Also preferred according to the invention is a process for preparing an oral medicament comprising the steps of a) introducing the silodosine or a pharmaceutically acceptable salt thereof and a basic copolymer, optionally with further pharmaceutically acceptable auxiliaries, into a suitable solvent or a solvent mixture at an optionally elevated temperature of 20 to 70 ° C; b) spray-drying the resulting solution;

c) addition of further pharmaceutically acceptable auxiliaries;

d) filling in a hard gelatin capsule or compressing the spray-dried material and the optional excipients to a tablet.

Also preferred according to the invention is a process for preparing an oral medicament comprising the following steps: a) melt extruding the silodosin or a pharmaceutically acceptable salt thereof with the basic copolymer and optionally with further pharmaceutically acceptable excipients;

b) comminution and sieving of the resulting extrudate;

c) mixing with other pharmaceutical excipients and filling in a hard gelatin capsule or pressing into a tablet.

The following examples illustrate the invention. example 1

A mixture of 12 g silodosin, 62 g Eudragit ^® E PO and 6 g of polyvinylpyrrolidone and 6 g of polyethylene glycol was granulated with 80 ml of a mixture of Eudragit ^® E 12.5 and 3 g sodium lauryl sulfate and over a period of 2 hours at 40 ° C dried. The granules were passed through a 710 pm sieve and then further dried for a further 2 hours. To the dried granules was added 420 g of calcium hydrogen phosphate. The resulting material was mixed for 15 minutes, then 3 g of magnesium stearate was added and the material was mixed for a further 3 minutes.

One half of the resulting granules were filled in capsules of size 3 with 4 mg dosage, the other half was compressed into tablets with a dosage of 4 mg. Example 2

8 g of silodosin and 15 g of Eudragit ^® E 100 were dissolved at a temperature of 50 ° C with stirring in 100 mL ethanol (1 5 hours magnetic stirrer) and spray-dried with a spray drier Buchi brand B-290 at a temperature of 85 ° C ,

170 g Emdex ^® (dextrin) was treated with 4 mg Tween ^® 20 (2% based on the total amount of drug), granulated and then (2 mg magnesium stearate) mixed with 1% magnesium stearate. To the previously prepared spray dried material, the mixture Emdex ^® was added. The entire mixture was then mixed for a period of 5 minutes. One half was filled into hard gelatin capsules with 8 mg dosage, the other half was compressed into tablets with a dosage of 8 mg.

Example 3

4 g of silodosin and 100 g of Eudragit ^® E 100 were subjected to at maximum temperature you of 60 ° C a melt extrusion process. After cooling, the resulting extrudate was comminuted to a particle size of less than 500 μm using a mill and sieved. To the powder was added 10 g of sodium bicarbonate, 50 g of calcium hydrogenphosphate and 1 g of magnesium stearate.

One half was filled into hard gelatin capsules with 8 mg dosage, the other half was compressed into tablets with a dosage of 8 mg.

Claims

claims

1 . A pharmaceutical composition for oral administration comprising a mixture of silodosin or a pharmaceutically acceptable salt thereof and a basic copolymer.

2. A pharmaceutical composition according to claim 1, wherein the basic copolymer is an acrylate or methacrylate copolymer.

3. A pharmaceutical composition according to claim 1 or 2, wherein the basic copolymer is a copolymer with amino groups.

4. A pharmaceutical composition according to any one of claims 1-3, wherein the copolymer is a copolymer with monomer units derived from methyl methacrylate, butyl methacrylate and dimethylaminoethyl methacrylate.

5. Medicament according to one of claims 1 -4, which is a capsule or a tablet.

6. Medicament according to one of claims 1 -5 comprising at least one further pharmaceutically acceptable additive.

7. A pharmaceutical composition according to claim 6, wherein the additive is a surfactant, a binder, a filler, a disintegrant, a lubricant or a mixture of two or more of these ingredients.

8. Medicament according to one of claims 1-7, characterized in that it liberates in aqueous solution at a pH of 1, 1 within an hour at least 80% of active ingredient.

A pharmaceutical composition according to any one of claims 1-8, wherein the weight ratio of silodosin or the pharmaceutically acceptable salt thereof to the basic copolymer ranges from 1: 1 to 1: 500.

A process for producing a pharmaceutical composition according to any one of claims 1 to 9, wherein the silodosin or the pharmaceutically acceptable salt thereof and the basic copolymer

a) optionally mixed with further pharmaceutically acceptable additives in the presence of a solvent, then granulated, the granules optionally dried and optionally dried granules are sieved, or

b) dissolved in a solvent optionally with further pharmaceutically acceptable additives and the solution is then subjected to spray drying or

c) is subjected to a melt extrusion, optionally with the addition of further pharmaceutically acceptable additives

and the product from step a), b) or c) is converted into a unit dosage form, optionally with the addition of further pharmaceutically acceptable additives.

1 1. The method of claim 10, wherein the unit dosage form is a capsule or a tablet.

Use of a basic copolymer for stabilizing silodosin or a pharmaceutically acceptable salt thereof in a medicament for oral administration.