DE102008057335A1 - Intermediate, useful e.g. as an immunomodulator, for inhibiting the proliferation of certain hematopoietic tumor cells and stimulating erythropoiesis, comprises amorphous lenalidomide and a surface stabilizer - Google Patents

Abstract

Intermediate (I) comprises amorphous lenalidomide (A) and a surface stabilizer (B). Independent claims are included for: (1) the preparation of (I) comprising: either (a) dissolving (A) and (B) in a solvent or its mixture, and (b) freeze-drying the obtained solution; or step (a), and spraying the obtained solution to a support core; or step (a) and spray drying the obtained solution; or mixing (A) and (B), and extruding the mixture; or mixing (A) and (B), milling the mixture, and grinding, where the grinding conditions are preferably selected for transforming crystalline into amorphous lenalidomide; (2) formulation comprising amorphous lenalidomide in the form of (I) and optionally at least one further excipient; and (3) identifying a pharmaceutical excipient, which is suitable as (B) for amorphous lenalidomide, comprising: providing an excipient, which is solid at 25[deg] C, twice heating the solid excipients by differential scanning calorimetry (DSC), and selecting the excipient as suitable if it is visible in the second DSC warm curve and has a glass transition point of 25-100[deg] C. ACTIVITY : Immunomodulator; Cytostatic; Angiogenesis Inhibitor. MECHANISM OF ACTION : Proinflammatory cytokine production inhibitor.

Description

The The invention relates to amorphous lenalidomide together with a surface stabilizer in the form of a stable intermediate. The invention further relates Process for the preparation of stable amorphous lenalidomide and pharmaceutical formulations containing stable amorphous lenalidomide.

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 .-%. Crystalline lenalidomide must be used in micronized form to ensure the required uniformity of content (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 with the fact that crystalline lenalidomide can exist in various polymorphic forms in the development of lenalidomide formulations. As in WO 2005/023192 However, these polymorphs are often not stable, son They tend to transform into 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 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 crystalline lenalidomide, in one stabilized amorphous state can be solved.

object The invention therefore relates to an intermediate containing amorphous lenalidomide and a surface stabilizer. The intermediate provides amorphous lenalidomide in stabilized form.

object The invention also includes various methods of preparation of stabilized amorphous lenalidomide in the form of the invention Intermediate.

After all the invention relates to pharmaceutical formulations containing the amorphous lenalidomide or the inventively stabilized lenalidomide in the form of the 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 "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, usually has an amorphous material, in particular amorphous lenalidomide, an average 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.

The stabilized amorphous lenalidomide used in this invention may consist of amorphous lenalidomide. Alternatively it still can contain small amounts of crystalline lenalidomide components, with the proviso that in the DSC no defined melting point of crystalline lenalidomide. Preferred is a Mixture containing 90 to 99.99 wt .-% amorphous lenalidomide and 0.01 to 10% crystalline lenalidomide, more preferably 95 to 99.9 Wt% amorphous lenalidomide and 0.1 to 5% crystalline lenalidomide.

In the context of this invention, the lenalidomide according to the invention is present in stabilized form, namely in the form of an intermediate containing amorphous lenalidomide and a surface stabilizer. In particular, the intermediate according to the invention consists essentially of amorphous lenalidomide and surface stabilizer. If, as described below, in addition a crystallization inhibitor is used, the intermediate according to the invention can consist essentially of amorphous lenalidomide, surfaces stabilizer and crystallization inhibitor exist. The term "essentially" here indicates that, if appropriate, even small amounts of solvent etc. may be present.

at The surface stabilizer is generally a substance which is suitable, lenalidomide in amorphous form to stabilize. The surface stabilizer is preferably used to a polymer. Furthermore, the surface stabilizer comprises also substances that behave polymer-like. Examples These are fats and waxes. Furthermore, the surface stabilizer comprises solid, non-polymeric compounds, preferably polar side groups exhibit. Examples of these are sugar alcohols or disaccharides. Finally, the term includes surface stabilizer Surfactants, especially surfactants, which are solid at room temperature Form present.

• a) Bereitstellen eines pharmazeutischen Hilfsstoffes, der bei 25°C in festem Aggregatszustand vorliegt. Hierfür können im Allgemeinen die im Europäischen Arzneibuch genannten pharmazeutischen Hilfsstoffe gewählt werden.
• b) Zweimaliges, aufeinanderfolgendes Aufheizen des festen Hilfsstoffs mittels DSC. Hier werden mittels DSC zwei Aufwärmkurven aufgenommen. Die Kurven werden üblicherweise von 20°C bis maximal 20°C unterhalb des Zersetzungsbereichs der zu prüfenden Substanz aufgenommen.

Another object of the invention is a method for identifying a pharmaceutical excipient which is suitable as a surface stabilizer for amorphous lenalidomide, and thus can be used for the preparation of the intermediate according to the invention. The method comprises the steps:

• a) providing a pharmaceutical excipient which is in a solid state at 25 ° C. For this purpose, in general, the pharmaceutical auxiliaries mentioned in the European Pharmacopoeia can be selected.
• b) Twice successive heating of the solid excipient by DSC. Here, two warm-up curves are recorded by DSC. The curves are usually recorded from 20 ° C to a maximum of 20 ° C below the decomposition range of the substance to be tested.

• c) Auswahl des Hilfsstoffs als ”geeignet”, sofern in der zweiten DSC Aufwärmkurve ein Glasübergangspunkt von 20 bis 120°C, bevorzugt von 25°C bis 100°C, zu erkennen ist.

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

• c) Selection of the excipient as "suitable", provided that in the second DSC warm-up curve, a glass transition point of 20 to 120 ° C, preferably from 25 ° C to 100 ° C, can be seen.

object The invention also intermediates, the amorphous lenalidomide and a pharmaceutical excipient selected by the above described methods.

at for the production of the inventive Intermediates used surface stabilizer it is preferably a polymer. That for the production The polymer usable for the intermediate preferably has a glass transition temperature (Tg) greater than 20 ° C, more preferably from 30 ° C to 150 ° C, especially from 40 ° C up to 100 ° C. A polymer with appropriately chosen Tg prevents the recrystallization of the amorphous by immobilization Lenalidomids particularly advantageous.

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 of Mettler Toledo DSC 1 can be used become. It is heated at a rate of 1-20 ° C / min, preferably 5-15 ° C / min or with a cooling rate from 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 1.0 to 8 mPa / s 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 surface stabilizer: 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), Polyalkylengly kole, such as polypropylene glycol or preferably polyethylene glycol, co-block polymers of polyethylene glycol, especially co-block polymers of polyethylene glycol and polypropylene glycol (Pluronic ^® , BASF) 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 surface stabilizer 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 hydroxyl 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 surface stabilizer also includes solid, non-polymeric Compounds which preferably have polar side groups. Examples These are sugar alcohols or disaccharides. Examples are suitable sugar alcohols and / or disaccharides Mannitol, sorbitol, xylitol, isomalt, glucose, fructose, maltose and mixtures thereof. The term sugar alcohols also includes here Monosaccharides. In particular, isomalt and sorbitol are used as surface stabilizers used.

alternative can also waxes such. As cetyl palmitate or carnauba wax be used as a surface stabilizer. Also fats such as glycerol fatty acid esters (e.g. Glycerol palmitate, glycerol behenate, glycerol laurate, glycerol stearate) or PEG-glycerol fatty acid esters.

In a preferred embodiment contains the Intermediate amorphous lenalidomide according to the invention and surface stabilizer, wherein the weight ratio from lenalidomide to surface stabilizer 4: 1 to 1:50, more preferably 2: 1 to 1:20, even more preferably 1: 1 to 1:15, especially 1: 1 to 1:10.

It it is preferred that the type and amount of the surface stabilizer be chosen so that the resulting intermediate one Glass transition temperature (Tg) of more than 20 ° C has, preferably> 30 ° 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.

It is advantageous if the surface stabilizer in particulate Form is used, wherein the volume-average particle size (D50) less than 500 μm, preferably 5 to 250 μm, is.

In a preferred embodiment, the inventive Intermediate in addition to amorphous lenalidomide and surface stabilizer nor a crystallization inhibitor based on an inorganic Salt, an organic acid or a polymer with a weight average molecular weight (Mw) of greater 500,000 g / mol. These polymers suitable as crystallization inhibitors are in the context of this invention also as "highly viscous 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 can be obtained by various preparation processes. Depending on the preparation method, the intermediates are obtained in different particle sizes. 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, depending on the respective preparation process.

The term "average particle diameter" in the context of this invention refers to the D50 value of the volume-average particle diameter, which was determined by means of laser diffractometry. In particular, a Mastersizer 2000 from Malvern Instruments was used for the determination (wet measurement with ultrasound 60 seconds, 2000 rpm, the evaluation being carried out according to the Fraunhofer model) and preferably using a dispersant in which the substance to be measured does not react at 20 ° C. solves.

Of the average particle diameter, also called the D50 value of the integral Volume distribution is called, is within the scope of this invention defined as the particle diameter at which 50% by volume of the particles have a smaller diameter than the diameter, which is the D50 value equivalent. Likewise, then 50% by volume of the particles have a larger Diameter as the D50 value.

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

• (a1) Lösen des Lenalidomids, bevorzugt des kristallinen Lenalidomids, und des Oberflächenstabilisators in einem Lösungsmittel oder Lösungsmittelgemisch, und
• (b1) Gefriertrocknen der Lösung aus Schritt (a1).

In a first preferred embodiment, the invention relates to a freeze-drying process, ie a process for the preparation of the intermediate according to the invention, comprising the steps

• (a1) dissolving the lenalidomide, preferably the crystalline lenalidomide, and the surface stabilizer in a solvent or solvent mixture, and
• (b1) freeze-drying the solution from step (a1).

in the Step (a1) is lenalidomide, preferably crystalline lenalidomide, and the surface stabilizer described above, in a solvent or solvent mixture dissolved, preferably completely dissolved.

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 Surface stabilizers are useful in this embodiment in particular modified celluloses such as HPMC and sugar alcohols like isomalt, mannitol 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 (a1). In terms of The type and amount of the crystallization inhibitor is referred to above References.

The Solution from step (a1) is at about 10 to 50 ° C cooled to below freezing (i.e., frozen). Subsequently, the solvent is removed by sublimation away. This is preferably done when the conductivity the solution is less than 2%. The sublimation temperature is preferably determined by the intersection of product temperature and Rx -10 ° C. Sublimation is preferred in one Pressure of less than 0.1 mbar.

To sublimation, the lyophilized intermediate is at room temperature heated.

The Process conditions are in this first embodiment preferably chosen so that the resulting Intermediatteilchen a volume average particle diameter (D50) of 1 to 250 μm, more preferably from 3 to 150 μm, especially from 5 to 100 microns have.

• (a2) Lösen des Lenalidomids, bevorzugt des kristallinen Lenalidomids, und des Oberflächenstabilisators in einem Lösungsmittel oder Lösungsmittelgemisch, und
• (b2) Aufsprühen der Lösung aus Schritt (a2) auf einen Trägerkern.

In a second 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

• (a2) dissolving the lenalidomide, preferably the crystalline lenalidomide, and the surface stabilizer in a solvent or solvent mixture, and
• (b2) spraying the solution from step (a2) onto a carrier core.

in the Step (a2) is lenalidomide, preferably crystalline lenalidomide, and the surface stabilizer described above, in a solvent or solvent mixture dissolved, preferably completely dissolved.

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 Surface stabilizers are useful in this second Embodiment in particular modified celluloses such HPMC, sugar alcohols such as isomalt and sorbitol and polyethylene glycol, in particular polyethylene glycol having 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 (a2). In terms of The type and amount of the crystallization inhibitor is referred to above References.

In step (b2), the solution from step (a2) is sprayed onto a carrier core. Suitable carrier cores are particles consisting of pharmaceutically acceptable adjuvants, in particular 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 (b2) 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 in this second embodiment are preferably selected such that the resulting intermediate particles have a volume-average particle diameter (D ₅₀ ) of 50 to 800 μm, more preferably of 150 to 650 μm.

• (a3) Lösen des Lenalidomids, bevorzugt des kristallinen Lenalidomids, und des Oberflächenstabilisators in einem Lösungsmittel oder Lösungsmittelgemisch, und
• (b3) Sprühtrocknung der Lösung aus Schritt (a3).

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

• (a3) dissolving the lenalidomide, preferably the crystalline lenalidomide, and the surface stabilizer in a solvent or solvent mixture, and
• (b3) spray-drying the solution from step (a3).

The third embodiment is described by the six Preparation method particularly preferred.

in the Step (a3) is lenalidomide, preferably crystalline lenalidomide, and the surface stabilizer described above, in a solvent or solvent mixture dissolved, preferably completely dissolved.

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 Surface stabilizers are useful in this embodiment in particular modified celluloses such as HPMC, polyvinylpyrrolidone and copolymers thereof and sugar alcohols such as isomalt and sorbitol or mixtures thereof.

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 Subsequent step (b3) is spray-dried the solution from step (a3). 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 in this third embodiment are preferably selected such that the resulting intermediate particles have a volume-average particle diameter (D ₅₀ ) of from 1 to 250 μm, more preferably from 2 to 150 μm, in particular from 3 to 100 μm.

• (a4) Vermischen von Lenalidomids, bevorzugt von kristallinem Lenalidomid, und polymerem Oberflächenstabilisator, und
• (b4) Extrudieren des Gemisches.

In a fourth 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

• (a4) mixing lenalidomide, preferably crystalline lenalidomide, and polymeric surface stabilizer, and
• (b4) extruding the mixture.

in the Step (a4) is lenalidomide, preferably crystalline lenalidomide, with the surface stabilizer preferably in a mixer mixed. In this embodiment of the invention Process becomes a surface stabilizer in polymeric Form used.

When polymeric surface stabilizers are suitable in this fourth embodiment, in particular polyvinylpyrrolidone and vinyl pyrrolidone-vinyl acetate copolymers and polyvinyl alcohols, Methacrylates and HPMC.

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 (a4). In terms of The type and amount of the crystallization inhibitor is referred to above References.

in the Step (b4), the mixture is extruded. This can usual Melt extruder can be used. For example, a Leistritz Micro 18 used.

The Extrusion temperature depends on the type of polymeric surface stabilizer from. It is usually between 40 and 250 ° C, preferably between 80 and 160 ° C.

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

The process conditions in this fourth embodiment are preferably selected such that the resulting intermediate particles have a volume average particle diameter (D ₅₀ ) of 150 to 1000 μm, more preferably a D ₅₀ of 250 to 800 μm.

• (c4) 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

• (c4) Injection molding of the extrudate into molds for pharmaceutical dosage forms.

Examples are forms for tablets.

• (a5) Vermischen von Lenalidomid, bevorzugt von kristallinem Lenalidomid, und Oberflächenstabilisator, und
• (b5) Vermahlen der Mischung aus Schritt (a5), wobei die Mahlbedingungen bevorzugt so gewählt werden, dass ein Übergang von kristallinem zu amorphem Lenalidomid erfolgt.

In a fifth preferred embodiment, the invention relates to a milling process, ie a process for the preparation of the intermediate according to the invention, comprising the steps

• (a5) mixing lenalidomide, preferably crystalline lenalidomide, and surface stabilizer, and
• (b5) milling the mixture from step (a5), wherein the milling conditions are preferably chosen such that a transition from crystalline to amorphous lenalidomide takes place.

Prefers crystalline lenalidomide and surface stabilizer in step (a5). The mixture is ground in step (b5). The mixing can be done before or during the grinding take place, d. H. Steps (a5) and (b5) can be simultaneous respectively.

Provided the intermediate to be prepared additionally a crystallization inhibitor based on an inorganic salt or an organic acid it may also contain in step (a5) or (b5) to be added. Regarding type and quantity of Crystallization inhibitor is referred to above directed.

The Grinding conditions are preferably chosen such that a transition from crystalline to amorphous lenalidomide.

The Grinding is generally carried out in conventional grinding equipment, preferably in a ball mill, for example in one Retsch PM 100.

The Meal is usually 10 minutes to 10 hours, preferably 30 minutes to 8 hours, more preferably 2 Hours to 6 hours.

When Surface stabilizers are useful in this fifth Embodiment in particular polyvinylpyrrolidone, modified Celluloses such as HPMC, sugar alcohols such as isomalt and sorbitol and Polyethylene glycol, in particular polyethylene glycol having a molecular weight from 2,000 to 10,000 g / mol.

The process conditions in this fifth embodiment are preferably selected such that the resulting intermediate particles have a volume average particle diameter (D ₅₀ ) of from 1 to 350 μm, more preferably from 10 to 250 μm, in particular from 50 to 150 μm.

The Intermediate of the invention (i.e. stabilized amorphous lenalidomide) is commonly used to 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 .-% amorphous 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 surface stabilizer, optionally for the production of the inventive Intermediate was used, calculated as an excipient. This means, the amount of active ingredient refers to the amount of amorphous lenalidomide, which is included 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 (modified release or "MR" for short) to be able to serve.

• (i) 1 bis 50 Gew.-%, mehr bevorzugt 2 bis 25 Gew.-%, insbesondere 5 bis 15 Gew.-% amorphes 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 .-% amorphous 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. Prefers used are alkaline disintegrants. Under alkaline disintegrants are explosives to be understood when dissolved in water produce a pH of more 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, calcium hydrogencarbonate 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.-% amorphes 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. used relatively small amount of disintegrant. In this preferred embodiment, therefore, the phar invention contains pharmaceutical formulation

• (I) 1 to 50 wt .-%, more preferably 2 to 25 wt .-%, in particular 5 to 15 wt .-% amorphous 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.

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.

Further Lubricants can be used. Serve lubricant generally to reduce sliding friction. In particular, should the sliding friction are reduced, the tabletting on the one hand between the up and down in the die bore moving punches and the Matrizenwand and on the other hand between tablet bar and Matrizenwand consists. Suitable lubricants provide z. Stearic acid, Adipic acid, sodium stearyl fumarate and / or magnesium stearate represents.

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 subjected to the tablet of 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 (a4) and (b4) or pellet layering (process steps (a2) and (b2)) he follows.

A Dry granulation is particularly preferred when producing of the intermediate by means of spray drying (method steps (a3) and (b3)), freeze-drying (process steps (a1) and (b1)) or grinding (process steps (a5) and (b5)) 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) become 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 intermediate initially only with part of the Auxiliary substances (eg 50 to 95%) are mixed before compaction (II) is, and that the remaining part of the excipients after the granulation step (III) is added. In 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 process granulates the slug. The granulation can be carried out by methods known in the art respectively.

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.

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 (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%, up. 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. 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 indicates in the case of an IR formulation according to the USP method after 10 minutes usually a released content of at least 30%, preferably at least 50%, in particular at least 70% up.

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 1a: Preparation of the Intermediate by grinding

following Approach to 1000 dosage forms was prepared.

5 g of lenalidomide were mixed with 5 g of HPMC and 0.3 g of Aerosil in a ball mill milled for 10 h.

A Further processing could according to Examples 6 and 7 done.

Example 1b: Preparation of the Intermediate by grinding

The following formulation for 1000 dosage forms was ground as described in Example 1a:
5 g of lenalidomide
5 g Povidone ^® 25
2 g of Aerosil

Example 1c: Preparation of the Intermediate by grinding

The following formulation for 1000 dosage forms was ground as described in Example 1a:
5 g of lenalidomide
5 g isomalt
1 g of L-HPC

Example 2: Preparation of the Intermediate by lyophilization

following Approach to 1000 dosage forms was prepared.

5 Lenalidomide was dissolved in water / ethanol together with 10 g of mannitol solved. This solution was up to -55 ° C supercooled and freezed. When the conductivity reached less than 2%, the frozen mass became at a temperature determined by intersection of product temperature and Rx -10 ° and dried at a pressure of less than 0.1 mbar or the solvent removed by sublimation.

To drying, the lyophilized material to room temperature (20-25 ° C) brought.

A Further processing could according to Examples 6 and 7 done.

Example 3a: Preparation of the Intermediate by melt extrusion

following Approach to 1000 dosage forms was prepared.

5 g lenalidomide were extruded together with 10 g PEG 8000 and 1 g of Pluronic ^® F68 at a temperature cascade of 80-180 ° C in a melt extruder Leistritz Micro. 1 The extrudate strands were cooled.

Example 3b: Preparation of the Intermediate by melt extrusion

following Approach to 1000 dosage forms was prepared.

5 g lenalidomide were extruded together with 10 g of povidone and at a temperature ^® VA64 cascade of 80-180 ° C in a melt extruder Leistritz Micro. 1 The extrudate strands were cooled.

A Further processing was possible after screening according to examples 6 and 7 take place.

Example 4a: Preparation of the Intermediate by pellet layering

following Approach to 1000 dosage forms was prepared.

5 g lenalidomide was dissolved together with 20 g Povidone VA 64 ^® in water / ethanol and applied to 200 g Cellets ^®.

While of the process the supply air temperature was approx. 60-80 ° C, Product temperature 32-40 ° C and the spray pressure about 1-1.5 bar.

A Further processing could according to Examples 6 and 7 done.

Example 4b: Preparation of the Intermediate by pellet layering

The pellet layering was carried out as described in Example 4a, using the following approach:
5 g of lenalidomide
12 g of sorbitol
1.5 g of talc

Example 5a: Preparation of the Intermediate by spray drying

following Approach to 1000 dosage forms was prepared.

5 g of lenalidomide were dissolved in water / ethanol with 10 g of HPMC and 2 g of citric acid and spray-dried on a Büchi TYP B 191 spray tower. The following parameters were observed:
Temperature 130 ° C, spray rate 5-20%, aspirator performance 35-90%, flow control 30-75%.

The maintaining spray dried material was at 30 ° C for 24 h After drying in a rack drying oven.

A Further processing could according to Examples 6 and 7 done.

Example 5b: Preparation of the Intermediate by spray drying

The spray drying was carried out as described in Example 5a, using the following approach:
5 g of lenalidomide
5 g Avicel ^® PH 102
3 g Povidone ^® 25

Example 5c: Preparation of the Intermediate by spray drying

The spray drying was carried out as described in Example 5a, using the following approach:
5 g of lenalidomide
10 g Povidone ^® VA 64

Example 5d: Preparation of the Intermediate by spray drying

The spray drying was carried out as described in Example 5a, using the following approach:
5 g of lenalidomide
10g HPMC

Example 6: Preparation of tablets

For the preparation of tablets, the following formulation was used. 1. Intermediate according to Example 5d 15 mg 2. Prosolv® ^® 90 110 mg 3. Talcum 1 mg 4. Sodium bicarbonate 25 mg 5. Magnesium stearate 1.5 mg 6. Aerosil 0.8 mg

The Ingredients 1 and 3 were placed on a tumbler mixer for 5 min (Turbula TB 10) premixed. This mixture was made with 70% of the ingredients 2, 4, 5 and 6 compacted by means of Walzenkompaktor and sieved with a mesh size of 1.25 mm. The Kompaktat was with the remaining Substances mixed and pressed into tablets.

Example 7: Preparation of capsules

For the preparation of capsules, the following formulation was used. 1. Intermediate according to Example 5d 15 mg 2. Lactose monohydrate 80 mg 3. microcrystalline cellulose 60 mg 4. Talcum 1 mg 5. Sodium bicarbonate 15 mg 6. Magnesium stearate 1.5 mg 7. Aerosil 0.8 mg

The Ingredients 1 and 4 were placed on a tumbler mixer for 5 min (Turbula TB 10) premixed. This mixture was 70% of the remaining Components compacted by roller compactor and sieved with a Mesh size of 1.25 mm. The Kompaktat was with the remaining Substances mixed and filled into capsules.

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, 0110]
• - 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]
• - EMEA "Scientific Discussion" for Revlimid, 2007 [0006]

Claims (19)

Intermediate, containing amorphous lenalidomide and a surface stabilizer. Intermediate according to claim 1, characterized characterized in that the surface stabilizer is um a polymer, preferably a polymer having a glass transition temperature (Tg) greater than 25 ° C is. Intermediate according to claim 1, characterized characterized in that the surface stabilizer is um a sugar alcohol. Intermediate according to one of claims 1 to 3, characterized in that the weight ratio of Lenalidomide to surface stabilizer 1: 1 to 1:10. 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 polymer having a weight average molecular weight of more than 500,000 g / mol or mixtures thereof. The intermediate of claim 6, 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 surface stabilizer in. a solvent or solvent mixture, and (b1) freeze-drying the solution from step (a1). Process for the preparation of an intermediate according to of claims 1 to 7 comprising the steps (A2) Dissolve lenalidomide and the surface stabilizer in a solvent or solvent mixture, and (b2) spraying the solution from step (a2) on a carrier core. Process for the preparation of an intermediate according to of claims 1 to 7 comprising the steps (A3) Dissolve lenalidomide and the surface stabilizer in a solvent or solvent mixture, and (b3) spray-drying the solution from step (A3). Process for the preparation of an intermediate according to of claims 1 to 7 comprising the steps (A4) Mixing lenalidomide and surface stabilizer, and (b4) extruding the mixture. Process for the preparation of an intermediate according to of claims 1 to 7 comprising the steps (A5) Mixing lenalidomide and surface stabilizer, and (b5) milling the mixture of step (a5), wherein the Grinding conditions are preferably chosen so that a transition from crystalline to amorphous lenalidomide. Intermediate, obtainable by a process according to one of claims 8 to 12. Pharmaceutical formulation containing amorphous Lenalidomide in the form of an intermediate according to a of claims 1 to 7 and 13 and optionally at least another pharmaceutical excipient. A pharmaceutical formulation according to claim 14, containing (i) 1 to 50% by weight of amorphous lenalidomide and (Ii) 5 to 25 wt .-% disintegrant, based on the total weight of the dosage form. Pharmaceutical formulation according to claim 15, characterized in that it is an alkaline disintegrant, especially sodium bicarbonate, is. Pharmaceutical formulation according to one of claims 14 to 16, in the form of capsules or tablets, wherein the tablets are preferably prepared by means of dry granulation become. Method for identifying a pharmaceutical Excipient used as surface stabilizer for amorphous Lenalidomide is suitable, comprising the steps: a) Provide of a pharmaceutical excipient which at 25 ° C in solid State of aggregation is present, b) heating the solid twice Excipient using DSC, and c) selecting the excipient as "suitable", provided in the second DSC warm-up curve a glass transition point of 25 to 100 ° C can be seen. Intermediate of amorphous lenalidomide and a pharmaceutical Excipient, wherein the excipient with a method according to claim 18 was identified.