DE102008057285A1 - New intermediate comprising lenalidomide and matrix material, in the form of a solid solution, useful e.g. as immunomodulatory drug, to inhibit proliferation of hematopoietic tumor cells and promote T-cell and natural killer cell immunity - Google Patents

Abstract

Intermediate comprising lenalidomide and a matrix material, in the form of a solid solution, is new. Independent claims are also included for: (1) the preparations of the intermediate; (2) a pharmaceutical composition comprising lenalidomide in the form of the intermediate and optionally at least one further pharmaceutical excipient; and (3) identifying a pharmaceutical excipient, which is suitable as the matrix material for lenalidomide in the form of a solid solution, comprising (i) providing lenalidomide and a pharmaceutical excipient, which is present in solid aggregate form at 25[deg] C, in a ratio of 1:1, (ii) heating twice the solid excipient and identifying the glass transition temperature of the excipient by differential scanning calorimetry, (iii) heating twice lenalidomide and identifying the glass transition temperature of the active substance by differential scanning calorimetry, (iv) heating twice the 1: 1 mixture of lenalidomide and the excipient and identifying the glass transition temperature of the mixture by differential scanning calorimetry, and (iv) selecting the suitable excipient by ensuring that the glass transition temperature of the mixture lies between the glass transition temperature of the excipient and the active substance. ACTIVITY : Immunomodulator; Cytostatic. No biological data given. MECHANISM OF ACTION : None given.

Description

The Invention relates to an intermediate containing lenalidomide and matrix material, wherein the lenalidomide is in the form of a solid solution. The invention further relates to processes for the preparation of a solid solution of lenalidomide and pharmaceutical formulations containing lenalidomide in the form of a solid solution.

lenalidomide is an immunomodulator with multiple effects. He inhibits the proliferation of certain hematopoietic tumor cells, promotes T cells as well as natural killer (NK) cells mediated immunity, stimulates erythropoiesis, inhibits angiogenesis and the production of proinflammatory cytokines such as TNF-α and interleukin-6 and -12. Lenalidomide is at Patients with multiple myeloma admitted. The multiple myeloma is a malignant tumor of B lymphocytes. Despite chemo and Radiotherapy, stem cell transplantation and use of thalidomide and bortezomib the disease in the field is considered to be incurable.

The IUPAC name of lenalidomide [INN] is 3- (4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl) -2,6-piperidinedione. The chemical structure of lenalidomide is shown in formula (1) below:

The The term "lenalidomide" here includes both the (R) as well as the (S) -enantiomer.

Synthetic pathways for lenalidomide have been reported by Müller et al., Bioorganic & Medicinal Chemistry Letters 9 (1999), 1625-1630 , in EP 0 925 294 B1 and in WO 2006/028964 described. The preparation results in a crystalline solid, according to WO 2005/023192 Eight different polymorphic forms (forms A to H) exist.

Lenalidomide is marketed under the trade name Revlimid ^® as a hard gelatin capsule. Revlimid ^® contains lenalidomide in crystalline form and is marketed as hard gelatin capsules containing 5, 10, 15 and 25 mg lenalidomide. The 5 mg capsule has an active ingredient content of about 2.5 wt .-%. To ensure the required content uniformity, crystalline lenalidomide must be micronised (see EMEA Scientific Discussion for Revlimid, 2007).

With However, the micronization of lenalidomide has some disadvantages associated. First, the micronization results in a Active substance with undesirably low flowability. Furthermore, the micronized drug is due to the high toxicity from the point of view of occupational safety more difficult and expensive to handle. Due to the strong enlargement of the Surface during micronization also increases the oxidation sensitivity of the drug to.

task The present invention was therefore the above Overcome disadvantages. It's supposed to be the active ingredient in one Be provided with a good flowability and thus makes it possible, not only to capsules to be processable, but also a good compression to tablets guaranteed. It should also be the active ingredient in a mold be provided, which does not tend to agglomeration. Further should ensure a uniform distribution of the active ingredient to be guaranteed. A micronization of the drug should be avoided.

Further Lenalidomide should be provided in a form that has a high Uniformity of content (content uniformity) allows especially at low drug content (drug load).

The inventors of the present application were further confronted in the development of lenalidomide formulations with the fact that crystalline lenalidomide in various polymorphic forms can exist. As in WO 2005/023192 However, these polymorphs are often unstable but tend to convert to other polymorphic forms. For example, the commonly used lenalidomide hemihydrate (= Form B) can convert to Form A or Form E upon exposure to heat or in a humid environment. As in WO 2005/023192 However, forms A, B and E have a different solubility profile.

The different solubility profile leads to Patients to an undesirable uneven tide of the active ingredient. The object of the present invention was therefore to Lenalidomide in a form to provide the one possible uniform flooding in the patient allows. Both interindividual and intraindividual deviations should be largely avoided.

Farther the drug should be provided in a form that is good Solubility and good bioavailability at the same time good storage stability guaranteed.

The Uniformity of the solubility profile For lenalidomide formulations this is due in particular Of the narrow therapeutic range of lenalidomide of importance.

The Tasks could be unexpected by overpass of lenalidomide, in particular of crystalline lenalidomide, in the form be solved a solid solution.

object The invention therefore relates to an intermediate containing lenalidomide and matrix material, wherein the lenalidomide is in the form of a solid solution is present. The weight ratio is preferably from lenalidomide to matrix material 10: 1 to 1: 100. The intermediate represents a solid solution of lenalidomide in stabilized Form dar.

object The invention also includes various methods of preparation a solid solution of lenalidomide in the form of the invention Intermediate.

After all the invention relates to pharmaceutical formulations containing Lenalidomid invention in the form of a solid solution or in the form of the invention Intermediate.

in the For purposes of this invention, the term "lenalidomide" includes 3- (4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl) -2,6-piperidinedione according to the above formula (1). In addition, the includes Term "lenalidomide" all pharmaceutically acceptable Salts and solvates thereof.

Of the Term "fixed solution" is in the frame understand that lenalidomide in a matrix, which is in solid state at 25 ° C, molecular is distributed disperse.

It it is preferred that the intermediate of the invention (containing lenalidomide in the form of a solid solution) in Essentially no crystalline or amorphous lenalidomide contains. In particular, the inventive Intermediate less than 15% by weight, more preferably less than 5 wt .-%, of amorphous or crystalline lenalidomide, based on the total weight of the lenalidomide present in the intermediate.

Of the Term "amorphous" is used in the context of this invention used as a name for the state of solids, in which the building blocks (atoms, ions or molecules, i. in the case of amorphous lenalidomide, the lenalidomide molecules) no periodic arrangement over a larger one Range (= remote order) have. In amorphous fabrics are the Building blocks usually not completely random and purely statistically arranged, but distributed so that one certain regularity and similarity with the crystalline state in terms of distance and orientation of the next neighbor are recognizable (= Nahordnung). amorphous Substances therefore preferably have close proximity but no long-range order on. Furthermore, an amorphous substance usually has one Particle size of more than 300 nm.

firm Amorphous substances are isotropic in contrast to the anisotropic crystals. They usually have no defined melting point, but gradually go over slow softening in the liquid state over. Your experimental Differentiation of crystalline substances can be done by means of X-ray diffraction which are not sharp for them, but usually only a few diffuse interferences at small diffraction angles provides.

It is further preferred to be understood by "molecularly disperse" that the Inter mediat no lenalidomide particles having a particle size of greater than 300 nm, more preferably greater than 200 nm, in particular greater than 100 nm. The particle size is determined in this context by means of confocal Raman spectroscopy. The measuring system preferably consists of an NTEGRA-Spektra Nanofinder of the company NT-MDT.

in the This invention is within the scope of this invention solid solution of lenalidomide in stabilized form, namely in the form of an intermediate that is molecularly disperse Lenalidomide and a matrix material. Especially If the intermediate according to the invention consists essentially from molecularly dispersed lenalidomide and matrix material. If - how described below - additionally used a crystallization inhibitor is, so the intermediate of the invention essentially of molecularly dispersed lenalidomide, matrix material and crystallization inhibitor. The term "im Substantial "indicates that, where appropriate still small amounts of solvents, etc. may be included.

at the matrix material is generally a substance, which is suitable lenalidomide in the form of a solid solution to stabilize. Preferably, it is the matrix material to a polymer. Furthermore, the matrix material also includes substances that behave like a polymer. Examples of this are fats and waxes. Furthermore, the matrix material comprises solid, non-polymeric compounds, preferably polar side groups exhibit. Examples of these are sugar alcohols or disaccharides.

After all the term matrix material comprises surfactants, in particular surfactants, which are in solid form at room temperature.

• a) Bereitstellen von Lenalidomid, eines pharmazeutischen Hilfsstoffs, der bei 25°C in festem Aggregatzustand vorliegt, sowie eines 1:1-Gemisches von Lenalidomid und Hilfsstoff;
• b) zweimaliges Aufheizen des festen Hilfsstoffs mittels DSC und Identifizierung der Glasübergangstemperatur des Hilfsstoffs (Tg_Hilf);
• c) zweimaliges Aufheizen des Wirkstoffs Lenalidomid mittels DSC und Identifizierung der Glasübergangstemperatur des Wirkstoff (Tg_Lena);
• d) zweimaliges Aufheizen eines 1:1-Gemisches von Lenalidomid und Hilfsstoff mittels DSC und Identifizierung der Glasübergangstemperatur des Gemisches (Tg_Mix), und
• e) Auswahl des Hilfsstoffs als ”geeignet”, sofern Tg_Mix zwischen Tg_Hilf und Tg_Lena liegt.

Another object of the invention is a method for the identification of a pharmaceutical excipient, which is suitable as a matrix material for a solid lenalidomide solution, and thus can be used for the preparation of the intermediate according to the invention. The method comprises the steps:

• a) providing lenalidomide, a pharmaceutical excipient which is in a solid state at 25 ° C, and a 1: 1 mixture of lenalidomide and excipient;
• b) heating the solid excipient twice by DSC and identification of the glass transition temperature of the excipient (Tg _Hilf );
• c) heating the active substance lenalidomide twice by means of DSC and identification of the glass transition temperature of the active substance (Tg _Lena );
• d) heating a 1: 1 mixture of lenalidomide and excipient twice by means of DSC and identification of the glass transition temperature of the mixture (Tg _Mix ), and
• e) Selection of the excipient as "suitable", provided Tg _{Mix is} between Tg _Hilf and Tg _Lena .

Here Two warm-up curves are recorded by DSC. The Curves are usually from 20 ° C to maximum 20 ° C below the decomposition range of the test to be tested Absorbed substance. The term "1: 1 mixture" refers to a mixture of 50% by weight of lenalidomide and 50% by weight of adjuvant, that was made by mixing.

For this a device from Mettler Toledo DSC 1 can be used. It is preferred at a heating rate of 1-20 ° C / min 5-15 ° C / min or with a cooling rate of 5-25, preferably 10-20 ° C / min worked

object The invention also relates to an intermediate of molecularly disperse lenalidomide and a pharmaceutical excipient as a matrix material, wherein the excipient identified according to the above method and wherein preferably the weight ratio of lenalidomide to matrix material is 10: 1 to 1: 100.

at for the production of the inventive Intermediate used matrix material is preferred to a polymer. That for the production of the intermediate usable polymer preferably has a glass transition temperature (Tg) greater than 20 ° C, more preferably of 25 ° C, especially 35 ° C. A polymer with appropriately chosen Tg prevented by immobilization the regression of the molecular lenalidomide dispersion Colloids or particles.

As "glass transition temperature" (Tg) is the temperature at which amorphous or semi-crystalline Transition of polymers from the solid state to the liquid state. A significant change in physical parameters, z. As the hardness and elasticity, a. Below the Tg is a polymer usually glassy and hard, above the Tg it goes into a rubbery to viscous Condition over. The determination of the glass transition temperature takes place within the scope of this invention dynamic differential calorimetry (DSC).

For this a device from Mettler Toledo DSC 1 can be used. It is preferred at a heating rate of 1-20 ° C / min 5-15 ° C / min or with a cooling rate of 5-25, preferably 10-20 ° C / min worked.

Further has the polymer useful for preparing the intermediate preferred a number average molecular weight of 1,000 to 500,000 g / mol to, more preferably from 2,000 to 90,000 g / mol. Will that become Preparation of the intermediate polymer used in water in one Amount of 2 wt .-% dissolved, so shows the resulting solution preferably a viscosity of 0.1 to 18 mPa / s, more preferably from 0.5 to 15 mPa / s, in particular from 1 to 8 mPa / s, measured at 25 ° C.

Prefers For example, hydrophilic polymers are used to prepare 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 hydrophilic polymers as matrix material: polysaccharides, such as hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC, in particular sodium and calcium salts), ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC); microcrystalline cellulose, polyvinyl pyrrolidone, 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, copolymers Block polymers of polyethylene glycol, in particular co-block polymers of polyethylene glycol and polypropylene glycol (Pluronic ^® , BASF), polyethylene oxide and mixtures of the polymers mentioned.

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 the matrix material 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 specific surface area is determined using the gas adsorption method of Brunauer, Emmet and Teller.

Further the matrix material also comprises solid, non-polymeric compounds, which preferably have polar side groups. Examples of this are sugar alcohols or disaccharides. Examples of suitable Sugar alcohols and / or disaccharides are mannitol, sorbitol, xylitol, Isomalt, glucose, fructose, maltose and mixtures thereof. The term Sugar alcohols here also includes monosaccharides. In particular, will Isomalt and sorbitol used as matrix material.

alternative can also waxes such. Cetyl palmitate or carnauba wax be used as matrix material. Likewise, fats such as glycerol fatty acid esters (eg glycerol palmitate, glycerol behenate, glycerol laurate, Glycerol stearate) or PEG-glycerol fatty acid ester become.

In a preferred embodiment contains the Intermediate lenalidomide and matrix material according to the invention, wherein the weight ratio of lenalidomide to matrix material 2: 1 to 1: 100, more preferably 1: 1 to 1:50, even more preferably 1: 2 to 1:30, in particular 1: 5 to 1:20.

In a preferred embodiment is in the Intermediate according to the invention to a "single-phase" intermediate. By this is meant that matrix material and molecularly disperse Lenalidomid are distributed substantially homogeneously.

It it is preferred that the type and amount of the matrix material chosen so be that the resulting intermediate a glass transition temperature (Tg) of more than 20 ° C, preferably> 25 ° C.

It It is preferred that the type and amount of the polymer be chosen be that the resulting intermediate is storage stable. Under "storage stable" becomes understood that in the intermediate according to the invention after 3 years storage at 25 ° C and 50% relative humidity the proportion of crystalline lenalidomide - based on the total amount to lenalidomide - at most 60 wt .-%, preferably at most 30 Wt .-%, more preferably at most 15 wt .-%, in particular at most 5 Wt .-%, is.

In a preferred embodiment, the inventive Intermediate in addition to lenalidomide and matrix material nor a crystallization inhibitor based on an inorganic Salt, an organic acid or a high molecular weight Polymers with an average molecular weight of greater 500,000 g / mol.

These suitable as a crystallization inhibitor polymers are in the context This invention also referred to as "high viscosity polymer". Their weight average molecular weight is usually below 5,000,000 g / mol. A preferred high viscosity polymer is Povidone.

Prefers if the crystallization inhibitor is ammonium chloride, Citric acid or povidone K 90 (according to Ph. Eur. 6.0).

Of the Crystallization inhibitor can generally be used in an amount of From 1 to 30% by weight, preferably from 2 to 25% by weight, more preferably from 5 to 20 wt .-%, based on the total weight of the intermediate used become.

The Intermediates according to the invention are different Manufacturing process available. Depending on the manufacturing process become the intermediates in different particle sizes receive. Usually, the invention Intermediate in particulate form and have one average particle diameter (D50) from 1 to 750 μm, on, depending on the respective manufacturing process

Of the Term "average particle diameter" refers in the context of this invention to the D50 value of the volume average Particle diameter determined by laser diffractometry has been. In particular, a Mastersizer 2000 of Malvern Instruments uses (wet measurement with ultrasound 60 sec, 2000 rpm, whereby the evaluation takes place according to the Fraunhofer model and preferably a dispersant is used in which the substance to be measured does not dissolve). The mean particle diameter, also called the D50 value of the integral volume distribution is used in the context of this invention as the particle diameter at which 50% by volume of the particles have a smaller diameter have as the diameter, which corresponds to the D50 value. Likewise have then 50% by volume of the particles a larger one Diameter as the D50 value.

object The invention further provides a process for the preparation of the invention Intermediate. Below are three preferred embodiments for such a method explained.

• (a1) Lösen des Lenalidomids und des Matrixmaterials in einem Lösungsmittel oder Lösungsmittelgemisch, und
• (b1) Aufsprühen der Lösung aus Schritt (a1) auf einen Trägerkern.

In a first preferred embodiment, the invention relates to a "pellet layering process", ie a process for the preparation of the intermediate according to the invention, comprising the steps

• (a1) dissolving the lenalidomide and the matrix material in a solvent or solvent mixture, and
• (b1) spraying the solution from step (a1) onto a carrier core.

in the Step (a1) becomes lenalidomide and the matrix material described above in a solvent or solvent mixture dissolved, preferably completely dissolved. It can be used crystalline or amorphous lenalidomide. Preference is given to using crystalline lenalidomide.

When Solvents are suitable for. As water, alcohol (eg. Methanol, ethanol, isopropanol), dimethyl sulfoxide (DMSO), acetone, Butanol, ethyl acetate, heptane, pentanol or mixtures thereof. Prefers a mixture of water and ethanol is used.

When Matrix materials are useful in this first embodiment in particular modified celluloses such as HPMC (preferably with a weight average molecular weight from 20,000 to 90,000 g / mol), Sugar alcohols such as isomalt and sorbitol and polyethylene glycol, in particular Polyethylene glycol with a molecular weight of 2,000 to 10,000 g / mol.

Provided the intermediate to be prepared additionally a crystallization inhibitor based on an inorganic salt or an organic acid or a highly viscous polymer, it may also be added in step (a1). In terms of The type and amount of the crystallization inhibitor is referred to above References.

In step (b1), the solution from step (a1) is sprayed onto a carrier core. Suitable carrier cores are particles consisting of pharmaceutically acceptable excipients, especially so-called "Neutral pellets". Pellets are preferably used, which are available under the trade name Cellets ^® and containing a mixture of lactose and microcrystalline cellulose or Sugarspheres representing a mixture of starch and sugar.

Prefers Step (b1) is carried out in a fluidized-bed dryer, for example in a Glatt GPCG 3 (Glatt GmbH, Germany). It is preferred with supply air temperatures of 60 to 80 ° C, with product temperatures of 30 to 40 ° C and with a spray pressure of 1 to 1.5 bar worked.

The Process conditions are in this first embodiment preferably chosen so that the resulting Intermediatteilchen a volume average particle diameter (D50) of 50 to 800 μm, more preferably from 150 to 650 microns have.

• (a2) Lösen von Lenalidomid und des Matrixmaterials in einem Lösungsmittel oder Lösungsmittelgemisch, und
• (b2) Sprühtrocknung der Lösung aus Schritt (a2).

In a second preferred embodiment, the invention relates to a spray-drying process for the preparation of the intermediate according to the invention, comprising the steps

• (a2) dissolving lenalidomide and the matrix material in a solvent or solvent mixture, and
• (b2) spray-drying the solution from step (a2).

in the Step (a2) becomes lenalidomide and the matrix material described above in a solvent or solvent mixture dissolved, preferably completely dissolved. It can be used crystalline or amorphous lenalidomide. Preference is given to using crystalline lenalidomide.

When Solvents are suitable for. As water, alcohol (eg. Methanol, ethanol, isopropanol), dimethyl sulfoxide (DMSO), acetone, Butanol, ethyl acetate, heptane, pentanol or mixtures thereof. Prefers an ethanol / water mixture is used.

When Matrix materials are useful in this embodiment in particular modified celluloses such as HPMC (preferably with a weight average molecular weight from 20,000 to 90,000 g / mol), Polyvinyl pyrrolidone and copolymers thereof (preferably with a weight average Molecular weight from 20,000 to 70,000 g / mol) and sugar alcohols like isomalt and sorbitol.

Provided the intermediate to be prepared additionally a crystallization inhibitor based on an inorganic salt or an organic acid or a highly viscous polymer, it may also be added in step (a2). In terms of The type and amount of the crystallization inhibitor is referred to above References.

in the subsequent step (b2) is spray drying the solution from step (a2). The spray drying is usually carried out in a spray tower. For example, a Büchi B-191 is suitable (Büchi Laboratory Technology GmbH, Germany). Preference is given to an inlet temperature selected from 100 ° C to 150 ° C. The amount of air is z. B. 500 to 700 liters / hour and the aspirator runs preferably at 80 to 100%.

The Process conditions are in this second embodiment preferably chosen so that the resulting Intermediatteilchen a volume average particle diameter (D50) of 1 to 250 μm, more preferably from 2 to 150 μm, in particular from 3 to 100 μm exhibit.

• (a3) Vermischen von Lenalidomid und Matrixmaterial, und
• (b3) Extrudieren des Gemisches.

In a third preferred embodiment, the invention relates to a melt extrusion process, ie a process for the preparation of the intermediate according to the invention, comprising the steps

• (a3) mixing lenalidomide and matrix material, and
• (b3) extruding the mixture.

The Third embodiment is of the four described manufacturing methods particularly preferred.

in the Step (a3) lenalidomide with the matrix material is preferably in mixed with a mixer. In this embodiment of the the method according to the invention is preferred Matrix material used in polymeric form. It can be crystalline or amorphous lenalidomide. Preference is given to crystalline Lenalidomide used.

Suitable polymeric matrix materials in this fourth embodiment are in particular polyvinylpyrrolidone and vinylpyrrolidone-vinyl acetate copolymers and also polyvinyl alcohols, methacrylates and HPMC. The weight average molecular weight of the polymers used is usually 20,000 to 90,000 g / mol. Alternatively, a sugar alcohol, especially isomalt, may be used.

Provided the intermediate to be prepared additionally a crystallization inhibitor based on an inorganic salt or an organic acid or a highly viscous polymer, it may also be added in step (a3). In terms of The type and amount of the crystallization inhibitor is referred to above References.

in the Step (b3), the mixture is extruded. The mixture from step (a3) is usually in the extruder to a processed homogeneous melt.

When Extruders can use conventional melt extruders become. The screw profile of the extruder preferably contains Kneading blocks. The shear forces generated thereby contribute to the melting of the mixture and thus to dissolution of the active ingredient in the matrix material. For example, a Leistritz Micro 18 used.

The Extrusion temperature depends on the type of matrix material from. It is usually between 50 and 250 ° C, preferably between 100 and 200 ° C. The extrusion takes place preferably at an outlet pressure of 10 bar to 100 bar, more preferably at 20 to 80 bar.

The cooled melt is usually through a Raspelsieb (eg Comill U5) crushed and thus a uniform Grain size subject.

The Process conditions are in this third embodiment preferably chosen so that the resulting Intermediatteilchen a volume average particle diameter (D50) of 150 to 1000 microns, more preferably have a D50 of 250 to 800 microns.

• (c3) Spritzgießen des Extrudats in Formen für pharmazeutische Darreichungsformen.

Instead of granulation of the extrudate can also be done a "direct injection". In this case, the method according to the invention comprises the step

• (c3) Injection molding of the extrudate into molds for pharmaceutical dosage forms.

Examples are forms for tablets.

The Intermediate of the invention (i.e. molecular disperse lenalidomide) is commonly used for Preparation of a pharmaceutical formulation used.

object The invention is therefore a pharmaceutical formulation containing Intermediate according to the invention and pharmaceutical Excipients.

in this connection these are the auxiliaries known to the person skilled in the art, for example those described in the European Pharmacopoeia.

Examples for auxiliaries used are disintegrants, release agents, Emulsifiers, pseudo-emulsifiers, fillers, additives to improve powder flowability, lubricants, Wetting agents, gelling agents and / or lubricants. If necessary, you can still other auxiliaries are used.

The ratio of active ingredient to auxiliaries is preferably chosen so that the resulting formulations
1 to 50 wt .-%, more preferably 2 to 25 wt .-%, in particular 5 to 15 wt .-% lenalidomide and
50 to 99 wt .-%, more preferably 75 to 98 wt .-%, in particular 85 to 95 wt .-% pharmaceutically acceptable excipients.

at This information is the amount of matrix material, if necessary for the preparation of the intermediate according to the invention was used, calculated as an excipient. That is, the Amount of active ingredient refers to the amount of lenalidomide that contained in the formulation.

It has been shown that the intermediates of the invention suitable as both a basis for a dosage form with immediate release (immediate release or "IR" for short) as well as with modified release (modfied release or short "MR") to be able to serve.

• (i) 1 bis 50 Gew.-%, mehr bevorzugt 2 bis 25 Gew.-%, insbesondere 5 bis 15 Gew.-% Lenalidomid und
• (ii) 5 bis 30 Gew.-%, mehr bevorzugt 10 bis 25 Gew.-%, insbesondere 12 bis 22 Gew.-% Sprengmittel, bezogen auf das Gesamtgewicht der Formulierung.

In a preferred embodiment for an IR formulation, a relatively high amount of disintegrant is used. In this preferred embodiment, therefore, contains the inventive pharmaceutical formulation

• (I) 1 to 50 wt .-%, more preferably 2 to 25 wt .-%, in particular 5 to 15 wt .-% lenalidomide and
• (ii) 5 to 30% by weight, more preferably 10 to 25% by weight, in particular 12 to 22% by weight of disintegrant, based on the total weight of the formulation.

When Blasting agents are generally referred to as substances that cause disintegration a dosage form, in particular a tablet, after introduction accelerate in water. Suitable disintegrants are z. B. organic Disintegrants such as carrageenan, croscarmellose and crospovidone. As well used are alkaline disintegrants. Under alkaline disintegrants are to be understood as disintegrating agents when dissolved in water produce pH greater than 7.0.

More preferably inorganic alkaline disintegrating agents are used, in particular salts of alkali and alkaline earth metals. Prefers Here are sodium, potassium, magnesium and calcium to call. When Anions are carbonate, bicarbonate, phosphate, hydrogen phosphate and dihydrogen phosphate are preferred. Examples are sodium bicarbonate, Sodium hydrogenphosphate, potassium bicarbonate and the like.

Especially sodium bicarbonate is preferred as the disintegrant, in particular used in the above quantities.

• (i) 1 bis 50 Gew.-%, mehr bevorzugt 2 bis 25 Gew.-%, insbesondere 5 bis 15 Gew.-% Lenalidomid und
• (ii) 0 bis 10 Gew.-%, mehr bevorzugt 0,1 bis weniger als 5 Gew.-%, insbesondere 1 bis 4 Gew.-% Sprengmittel, bezogen auf das Gesamtgewicht der Formulierung.

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

• (I) 1 to 50 wt .-%, more preferably 2 to 25 wt .-%, in particular 5 to 15 wt .-% lenalidomide and
• (ii) 0 to 10% by weight, more preferably 0.1 to less than 5% by weight, in particular 1 to 4% by weight, of disintegrant, based on the total weight of the formulation.

in the Case of MR formulation is croscarmellose or crospovidone as Explosives preferred.

Further can for the MR formulation the usual Retardation techniques are used.

In a preferred embodiment contains the formulation according to the invention 2 to 8 wt .-%, more preferably 3 to 7% by weight, in particular 4 to 6% by weight, of release agent, based on the total weight of the formulation. This embodiment is used in particular for the production of tablets.

Under Release agents are usually understood as substances which reduce the agglomeration in the core bed. Examples are talc, Silica gel, polyethylene glycol (preferably at 2,000 to 10,000 g / mol weight average molecular weight) and / or glycerol monostearate.

Farther contains the pharmaceutical formulation (both for IR as well as MR) preferably one or more of the above mentioned auxiliaries. These are explained in more detail below.

The contains inventive formulation preferably fillers. Under fillers are in the General to understand substances that contribute to the formation of the tablet body for tablets with small amounts of active ingredient (eg less than 70% by weight) serve. That is, fillers produce by "stretching" the Active ingredients a sufficient Tablettiermasse. fillers So usually serve to a suitable tablet size to obtain.

Examples of preferred fillers are lactose, lactose derivatives, starch, starch derivatives, treated starch, 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. Also Prosolv® ^® (Rettenmaier & Söhne, Germany) can be used.

fillers are usually used in an amount of from 1 to 80% by weight, more preferably from 30 to 60% by weight, based on the total weight the formulation used.

An example of an additive for improving powder flowability is particulate silica, e.g. B. known under the trade name Aerosil ^® .

additions to improve the powder flowability are usually in an amount of 0.1 to 3 wt .-%, based on the total weight the formulation used.

Furthermore, lubricants can be used. Lubricants are generally used to reduce sliding friction. In particular, the sliding friction is to be reduced, which consists during tabletting on the one hand between the up in the die bore and from moving punches and the die wall and on the other hand between the tablet web and die wall. Suitable lubricants provide z. As stearic acid, adipic acid, sodium stearyl fumarate (Pruv ^®) and / or magnesium stearate is.

lubricant are usually in an amount of 0.1 to 3 wt .-%, based on the total weight of the formulation used.

The pharmaceutical formulation of the invention is preferably compressed into tablets. In the prior art, a wet granulation by means of gelatin solution is proposed (see EP 0 925 294 B1 Example 20).

It However, it has been shown that the properties of the resulting Tablets can be improved when wet granulation is avoided.

The Intermediate according to the invention are therefore by means of Direct compression pressed into tablets or before pressing to the tablet is subjected to a dry granulation. Intermediate with a bulk density of less than 0.5 g / ml are preferred processed by dry granulation.

A Direct compression is particularly preferred when producing of the intermediate by melt extrusion (process steps (a3) and (b3) or pellet layering (process steps (a1) and (b1)) he follows.

A Dry granulation is particularly preferred when producing of the intermediate by means of spray drying (method steps (a2) and (b2)) takes place.

• (I) Bereitstellen des erfindungsgemäßen Intermediats sowie eines oder mehrerer (insbesondere der vorstehend beschriebenen) pharmazeutischen Hilfsstoffe;
• (II) Kompaktierung zu einer Schülpe; und
• (III) Granulierung bzw. Zerkleinerung der Schülpe.

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

• (I) providing the intermediate according to the invention and one or more (in particular the above-described) pharmaceutical excipients;
• (II) compaction to a scab; and
• (III) Granulation or comminution of the scab.

in the Step (I) is lenalidomide in the form of the solid solution (i.e., in the form of the intermediate of the invention) and adjuvants preferably mixed. The mixing can be done in usual Mixers done. Alternatively, it is possible that the lenalidomide according to the invention first only with a part of the excipients (eg 50 to 95%) before compaction (II) is mixed, and that the remaining part of the excipients after the granulation step (III) is added. In the case of multiple compaction should the admixing of the auxiliaries preferably before the first compacting step, between several compaction steps or after the last granulation step respectively.

in the Step (II) of the method according to the invention the mixture from step (I) is compacted into a rag. It is preferred that this is a dry compaction acts, d. H. the compaction is preferably carried out in the absence of solvents, especially in the absence of organic Solvents.

The compaction conditions are usually selected so 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 .

Of the The term "density" preferably refers to this on the "true density" (ie not on the bulk density or tamped density). The true density can be measured with a gas pycnometer be determined. Preferably, the gas pycnometer is to a helium pycnometer, in particular, the device AccuPyc 1340 Helium pycnometer manufactured by Micromeritics, Germany.

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

In Step (iii) of the procedure granulates the slug. The granulation can be carried out by methods known in the art respectively.

In In a preferred embodiment, the granulation conditions chosen so that the resulting particles (granules) a volume average particle size ((D50) value) from 50 to 800 μm, more preferably from 100 to 750 μm, more preferably 150 to 500 μm, in particular from 200 to 450 μm.

In In a preferred embodiment, the granulation takes place in a sieve mill. In this case, the Mesh size of the sieve insert 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 In a preferred embodiment, the method is so adapted that a Mehrfachkompaktierung takes place, the off Step (III) granules resulting once or more for compaction (II) is returned. The granulate is preferred from step (III) recycled 1 to 5 times, in particular 2 to 3 times.

The granules resulting from step (III) can be converted into pharmaceutical Dosage forms are processed. For this purpose, the granules for example, filled in sachets or capsules. Prefers the granules resulting from step (III) are compressed into tablets (= Step IV).

In Step (IV) of the process are those obtained in step (III) Granules pressed into tablets, d. H. there is a compression to tablets. The compression may be with those known in the art Tabletting done.

In Step (IV) of the process may optionally include the granules from step (III) pharmaceutical excipients are added.

The Amounts of excipients added in step (IV) are usually dependent on the type of tablet to be prepared and on the amount Excipients already added in steps (I) or (II) has been.

in the In the case of direct compression, only steps (I) and (IV) of the method described above.

The Tabletting conditions are preferably chosen so that the resulting tablets a ratio of tablet height to weight of 0.005 to 0.3 mm / mg, more preferably 0.05 to 0.2 mm / mg.

Further the resulting tablets preferably have a hardness from 50 to 200N, more preferably from 80 to 150N. The Hardness becomes according to Ph. Eur. 6.0, section 2.9.8 determined.

moreover The resulting tablets preferably show friability of less than 5%, more preferably of less than 3%, in particular less than 2%. The friability is calculated according to Ph. Eur. 6.0, section 2.9.7.

After all have the tablets of the invention usually a "Content Uniformity" of 90 to 110%, preferred from 95 to 105%, in particular from 98 to 102% of the average Salary up. The "content uniformity" is according to Ph. Eur. 6.0, section 2.9.6. certainly.

The release profile of the tablets according to the invention has in the case of an IR formulation according to USP method after 10 minutes usually a released content of at least 30%, preferably at least 50%, in particular at least 70%.

The Release profile of the tablets according to the invention indicates in the case of an MR formulation according to the USP method after 60 minutes usually a released content of at least 10%, preferably at least 20%, especially at least 30%, up.

The above information on hardness, friability, content Uniformity and release profile are preferred here on the unfiltered tablet for an IR formulation. For a modified release tablet refers to the release profile on the overall formulation.

at the product produced by the process according to the invention Tablets can be swallowed whole (unfiltered or preferably filmed) act. Likewise it can be to chewable tablets or to act on Disperstabletten. Under "Disperstablette" is in this case a tablet for the preparation of an aqueous suspension understood as oral.

in the In the case of tablets swallowed whole, it is preferable that they are covered with a film layer. in this connection may be the conventional methods in the art find application for the application of tablets. The above However, ratios of active ingredient to excipient relate on the unpainted tablet.

For the filming preferably uses macromolecular substances, for example, modified celluloses, polymethacrylates, polyvinylpyrrolidone, Polyvinyl acetate phthalate, zein and / or shellac or natural Rubber, such as. B. Carageenan.

The Layer thickness of the coating is preferably 1 up to 100 μm.

The Invention is illustrated by the following examples become.

EXAMPLES

Example 1: Preparation of the Intermediate by melt extrusion and subsequent compression to tablets

The active ingredient was melted with ^Povidon® VA 64 in the ratio 1:10 in the melt extruder at temperatures below 200 ° C and extruded in a temperature cascade. A nozzle plate with a hole diameter of 1 mm was used. The twin-screw extruder Leistritz ^® micro 18 was equipped with various screw elements. A kneading unit was installed to ensure the required mixing and solution of the active ingredient in the polymer.

The resulting extrudate was cooled and sieved at 1.00 mm on a Comill ^® U5.

Subsequently, it was premixed with talc and blended with Avicel ^®, lactose, sodium bicarbonate, Aerosil ^® and magnesium stearate (Turbula T10B ^®) and into a tablet pressed (Fette ^® 102 i). This tablet was used in a pan-coater, e.g. B. Lödige ^® LHC 25 coated with HPMC. The coating solution further contained dye, PEG, talc and titanium dioxide. lenalidomide 15 mg Povidone ^® VA 64 150 mg talc 6 mg Avicel ^® 30 mg lactose 20 mg Aerosil ^® 1.3 mg magnesium stearate 2.6 mg sodium bicarbonate 20.64 mg HPMC 3 mg PEG 0.5 mg talc 1 mg Titanium dioxide 0.4 mg dye 0.1 mg

Example 2: Preparation of the Intermediate by pellet layering and filling in capsules

The active ingredient was dissolved with sorbitol in ethanol / water and applied to a placebopellet in the fluidized bed apparatus (GPC3 Smooth). During the process, the supply air temperature was approx. 65 ° C, the spray compressed air approx. 1 bar, and the nozzle size 1.2 mm. During the process, intervals were set up. The cooled pellets were filled into capsules. lenalidomide 25 mg sorbitol 160 mg Sugarspheres ^® 200 mg

Example 3: Preparation of the Intermediate by spray drying and subsequent compaction and compression to tablets

Of the Active ingredient was dissolved in water with HPMC and citric acid. This solution was applied to a Büchi Mini Spray Dryer spray dried.

The spray dried material was premixed with Lutrol and compacted with sodium bicarbonate and Pruv ^® and Prosolv ^® and pressed together with the rest amount of excipients into a tablet. This tablet was used in a pan-coater, e.g. B. Lödige ^® LHC 25 coated with HPMC. The coating solution further contained dye, PEG, talc and titanium dioxide. lenalidomide 25 mg HPMC 160 mg citric acid 20.04 mg Lutrol 2 mg Prosolv ^® 80 mg sodium bicarbonate 20 mg Pruv ^® 2.6 mg HPMC 3 mg PEG 0.5 mg talc 1 mg Titanium dioxide 0.4 mg dye 0.1 mg

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• - EP 0925294 B1 [0005, 0102]
• - WO 2006/028964 [0005]
• WO 2005/023192 [0005, 0010, 0010]

Cited non-patent literature

• Müller et al., Bioorganic & Medicinal Chemistry Letters 9 (1999), 1625-1630 [0005]

Claims (18)

Intermediate containing lenalidomide and matrix material, wherein the lenalidomide is in the form of a solid solution. Intermediate according to claim 1, wherein the weight ratio of lenalidomide to matrix material 10: 1 to 1: 100. Intermediate according to claim 1 or 2, characterized in that it is in the matrix material to a polymer, preferably a polymer having a glass transition temperature (Tg) of greater than 20 ° C is. Intermediate according to claim 1 or 2, characterized in that it is in the matrix material to a sugar alcohol. Intermediate according to one of claims 1 to 4, characterized in that the glass transition temperature (Tg) of the intermediate is more than 20 ° C. Intermediate according to one of claims 1 to 5, characterized in that it additionally comprises a crystallization inhibitor based on an inorganic salt, an organic acid, a high-viscosity polymer or mixtures thereof. The intermediate of claim 5, wherein the Crystallization inhibitor to citric acid, ammonium chloride, Povidone K 90 or mixtures thereof. Process for the preparation of an intermediate according to of claims 1 to 7 comprising the steps (A1) Dissolve lenalidomide and the matrix material in one Solvent or solvent mixture, and (B1) Spraying the solution from step (a1) onto one Carrier core. Process for the preparation of an intermediate according to of claims 1 to 7 comprising the steps (A2) Dissolve lenalidomide and the matrix material in one Solvent or solvent mixture, and (B2) Spray-drying the solution from step (a2). Process for the preparation of an intermediate according to of claims 1 to 7 comprising the steps (A3) Mixing lenalidomide and matrix material, and (b3) Extrude of the mixture. Intermediate, obtainable by a process according to one of claims 8 to 10. Pharmaceutical formulation containing lenalidomide in the form of an intermediate according to one of the claims 1 to 7 and 11 and optionally at least one further pharmaceutical Excipient. Pharmaceutical formulation according to claim 12, containing (i) 1 to 50% by weight lenalidomide and (Ii) 5 to 25 wt .-% disintegrant, based on the total weight of Dosage form. Pharmaceutical formulation according to claim 13, characterized in that it is an alkaline disintegrant, especially sodium bicarbonate, is. Pharmaceutical formulation according to one of claims 12 to 14, containing 3 to 7 wt .-% release agent, based on the total weight of the formulation. Pharmaceutical formulation according to one of claims 12 to 15, in the form of capsules or tablets, wherein the tablets are preferably prepared by means of dry granulation become. A method of identifying a pharmaceutical excipient useful as a solid solution lenalidomide matrix material comprising the steps of: a) providing lenalidomide, a pharmaceutical excipient which is solid state at 25 ° C and a 1: 1 mixture of lenalidomide and excipient; b) heating the solid excipient twice by DSC and identification of the glass transition temperature of the excipient (Tg _Hilf ); c) heating the active substance lenalidomide twice by means of DSC and identification of the glass transition temperature of the active substance (Tg _Lena ); d) heating the 1: 1 mixture of lenalidomide and excipient twice by means of DSC and identification of the glass transition temperature of the mixture (Tg _Mix ), and e) selecting the excipient as "suitable" if Tg _{Mix is} between Tg _Hilf and Tg _Lena . Intermediate of molecularly disperse lenalidomide and a pharmaceutical excipient as a matrix material, wherein the excipient with a method according to claim 17 was identified and where the weight ratio of lenalidomide to matrix material is 10: 1 to 1: 100.