EA045835B1 - PHARMACEUTICAL COMPOSITION CONTAINING PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALT OF LENALIDOMIDE - Google Patents

Description

The present invention relates to a pharmaceutical composition containing a pharmaceutically acceptable acid addition salt of lenalidomide, preferably hydrochloride, exhibiting excellent chemical and physical stability during storage, as well as a method for its preparation. The addition of an acid and the selection of excipients that are not capable of accepting a proton can increase the physicochemical stability of lenalidomide in the pharmaceutical composition, in particular in the finished dosage form, and provide the necessary dissolution and bioavailability of the drug.

Prior Art

Lenalidomide is the international nonproprietary name for 3-(4'-aminoisoindolin-1'-one)-1piperidin-2,6-dione, compound of formula (I):

Although the compound is chiral and contains an asymmetric carbon atom, it was prepared in the form of a racemic mixture because it undergoes racemization under physiological conditions.

The mechanism of action of lenalidomide includes antineoplastic, antiangiogenic, proerythropoietic and immunomodulatory properties. More specifically, lenalidomide inhibits the proliferation of certain hematopoietic tumor cells (including multiple myeloma (MM) plasma tumor cells and cells with chromosome 5 deletions), enhances T cell-mediated immunity and natural killer (NK) cells ) and increases the number of NK-type T cells, inhibits angiogenesis by blocking endothelial cell migration and adhesion and microvessel formation, increases the production of fetal hemoglobin by CD34+ hematopoietic stem cells, and inhibits the production of proinflammatory cytokines (eg, TNF-α (tumor necrosis factor-alpha) and IL-6 (interleukin-6)) by monocytes.

Lenalidomide is used to treat adult patients with previously untreated multiple myeloma, myelodysplastic syndrome, and relapsed or treatment-resistant mantle cell lymphoma.

Lenalidomide is available on the market in free base form and is sold under the trade name Revlimid in the form of oral hard capsules containing 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg and 25 mg of active ingredient. The capsule also contains lactose anhydrous (as a diluent), microcrystalline cellulose (as a diluent), croscarmellose sodium (as a disintegrant) and magnesium stearate (as a lubricant) as inactive ingredients.

The dissociation constant pKa1 indicated in the literature for the primary amino group of lenalidomide is 2.31, _pKa2 for the secondary amino group of lenalidomide is 11.6.

Publication EP 925294 discloses lenalidomide, a method for its preparation, its use and a pharmaceutical composition containing lenalidomide. The patent discloses, among other things, a capsule composition containing the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients, which are microcrystalline cellulose, sodium lauryl sulfate, magnesium stearate.

Publication WO 2005023192 relates to specific crystalline forms of lenalidomide selected from anhydrous forms, dihydrates and hemihydrates. The most stable form of the hemihydrate is disclosed in polymorph Form B, which is present in a commercially available dosage form.

WO 2011050962 discloses acid addition salts of lenalidomide, a process for their preparation and oral dosage forms. Disclosed are acid addition salts prepared using acids having a pKa value in water at 25°C ranging from 10 to +4.

Preferably, strong acids were used that had a pKa value less than (-2). It is indicated that when strong acids are used, dissociation is less pronounced.

The publication also discloses polymorphic forms of acid addition salts. Disclosed are lenalidomide hydrochloride in polymorphic form A, showing characteristic peaks in the X-ray powder diffraction pattern at 2-theta angles of 12.11°, 24.35°, 24.73°, 26.12°, and disclosed lenalidomide sulfate in polymorphic forms A and B. Disclosed is a pharmaceutical dosage form of an acid addition salt of lenalidomide containing an excipient, preferably a lactose-free excipient, and/or a solubilizer and/or a disintegrant. The average particle size of the active ingredient is in the range from 0.1 μm to 100 μm, preferably from 1 μm to 20 μm. Publication 1045835 discloses pharmaceutical compositions containing lactose and/or microcrystalline cellulose or dicalcium phosphate dihydrate as an excipient, croscarmellose sodium as a disintegrant and magnesium stearate as a lubricant. These excipients are similar to those present in the commercially available lenalidomide formulation.

US 2011060010 discloses pharmaceutically acceptable salts of strong acids and lenalidomide, a method for their preparation, polymorphic forms and their use as a medicament. Among others, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, benzenesulfonic acids, p-toluenesulfonic acid, methanesulfonic acid are specifically mentioned. In addition, it is stated that weak acids such as benzoic acid, succinic acid, oxalic acid, fumaric acid, maleic acid, acetic acid do not form salts with lenalidomide. The main advantage of these salts is their increased solubility in water, which is 4 to 5000 times higher than the solubility of lenalidomide. This publication does not disclose a specific pharmaceutical composition.

WO 2011018101 discloses acid addition salts of lenalidomide in which the acid has a pKa value of less than 1, more specifically hydrochloric acid, hydrobromic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acids and p-toluenesulfonic acid. The publication discloses the use of salts in a process for purifying lenalidomide base.

Lenalidomide cocrystals are disclosed in WO2013012485 and WO2014160686.

Publications WO2010054833 and WO2009114601 disclose solid dispersions containing amorphous lenalidomide. Amorphous lenalidomide has been found to generate more contaminants, particularly oxidative contaminants, compared to crystalline lenalidomide, making the use of amorphous lenalidomide on a commercial scale very difficult.

Publication WO2017032870 discloses a pharmaceutical composition containing the active substance lenalidomide in a form selected from base, co-crystal, solvate or salt, wherein lenalidomide has a particle size distribution d(90) ranging from 1 μm to 100 μm. An exemplary pharmaceutical composition contains lactose, microcrystalline cellulose, croscarmellose sodium and magnesium stearate, that is, the same composition was used regardless of which form of lenalidomide was contained in the composition.

As can be seen from the prior art and literature, several pharmaceutical compositions containing lenalidomide salts are described. The disclosed compositions contain inactive ingredients including lactose and proton-accepting compounds such as magnesium stearate, croscarmellose sodium, dicalcium phosphate, sodium lauryl sulfate. These compositions, according to the prior art, do not have sufficient stability and, at the same time, satisfactory solubility.

Therefore, due to problems associated with the stability of lenalidomide in amorphous or pharmaceutically acceptable salt form, there is a need for pharmaceutical compositions containing lenalidomide that are physically and chemically stable, have an improved solubility profile, and are suitable for use on a commercial scale. .

The essence of the invention

According to the present invention, a pharmaceutical composition is disclosed which is a solid composition containing (a) lenalidomide in the form of a pharmaceutically acceptable acid addition salt, (b) an acid that has a pKa value of 4 or less, (c) at least one additional pharmaceutically acceptable excipient, and (d) wherein said composition does not contain excipients capable of accepting a proton, which are selected from:

bases, salts of weak acids where the acid has a pKa value greater than 2, such as salts containing an anion derived from carboxylic acid, silicic acid, phosphoric acid, carbonic acid, and salts of alcohols.

According to a preferred embodiment of the present invention, the pharmaceutical composition contains lenalidomide in the form of a hydrochloric acid addition salt.

According to a preferred embodiment of the present invention, the pharmaceutical composition contains at least one diluent selected from microcrystalline cellulose and mannitol, preferably a combination of microcrystalline cellulose and mannitol.

According to a preferred embodiment of the present invention, the pharmaceutical contains an acid which has a pKa value ranging from 1 to 3.

According to a preferred embodiment of the present invention, the diluent has a loss on drying of less than 5 wt.%, preferably less than 2 wt.%, and most preferably less than 1.5 wt.%.

According to a preferred embodiment of the present invention, all excipients have a loss on drying of less than 5 wt.%, preferably less than 2 wt.%, and most preferably less than 1.5 wt.%.

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According to a preferred embodiment of the present invention, the composition has a pH value of from 1 to 3, preferably from 1 to 2.5, when measured in a 20% (w/v) suspension in water at 25°C.

According to another embodiment of the present invention, there is provided a method for producing a pharmaceutical composition, which includes the following steps:

combining lenalidomide in the form of a pharmaceutically acceptable acid addition salt, an acid that has a pKa value of 4 or less, and one or more excipients;

mixing to obtain a mixture; and compressing the mixture or loading the mixture into a capsule shell.

According to a preferred embodiment of the present invention, the pharmaceutically acceptable acid addition salt of lenalidomide is a hydrochloric acid salt thereof.

According to a preferred embodiment of the present invention, the above described method is carried out in the absence of a solvent.

According to a preferred embodiment of the present invention, the above-described method further includes a sieving step, which is carried out before and/or after the mixing step.

According to a preferred embodiment of the present invention, the above-described method further includes the step of adding a lubricant and/or glidant after optional sieving and/or after mixing.

According to a preferred embodiment of the present invention, the above described method includes the following steps:

mixing a pharmaceutically acceptable salt of lenalidomide, preferably the hydrochloride, and a portion of the diluent in a weight ratio of 1:1 to 1:50, preferably 1:2 to 1:30, more preferably 1:3 to 1:25, and /or other excipients and sifting the mixture;

mixing the mixture obtained above with the remainder of the diluent and/or other auxiliary substances in a mixer to obtain a second mixture;

optional - dry sifting of the mixture through a sieve;

adding a lubricant and/or a glidant and then mixing to obtain a third mixture;

pressing the third mixture or loading the mixture into the capsule shell.

Information confirming the possibility of implementing the invention

Definitions.

When used in the context of the present invention, the term proton-accepting excipient means an excipient that exhibits moderate to strong alkaline reactivity, that is, that has a pKb value of less than 12, preferably less than 11, and more preferably less than 10. This group includes bases, salts of weak acids, the acids having a pKa value greater than 2, preferably greater than 3, more preferably greater than 4, for example salts containing an anion derived from carboxylic acid, silicic acid, phosphoric acid, carbonic acid, and salts of alcohols.

Such alkaline compounds are unfavorable because they can accept the proton of the conjugate acid of lenalidomide and therefore can cause the formation of lenalidomide free base.

The composition of the present invention exhibits acidic properties if the suspension of the composition in water has a pH value ranging from 1 to 5, more preferably in the range from 1 to 4, most preferably from 1 to 3. The pH value is determined by measuring the pH value A 20% (w/v) suspension prepared by dispersing the powdered form of the pharmaceutical composition in an appropriate amount of purified water using a pH meter, for example a Radiometer PHM240 pH meter. A detailed description of determining the pH of pharmaceutical compositions is disclosed in the Description of Examples of the Invention section of this publication.

The term excipient when used in the context of the present invention has its normal meaning, that is, it refers to any pharmaceutically acceptable substance that does not itself have therapeutic activity, but is present in the composition for other reasons, for example, to facilitate the dissolution of the active pharmaceutical ingredient (API) ). Pharmaceutically acceptable excipients may be selected, for example, from diluents, lubricants and/or glidants, disintegrants and binders.

The term tablet, as used in the context of the present invention, covers compressed pharmaceutical drug compositions of all shapes and sizes. Particularly preferred are uncoated tablets. The term capsule covers forms of pharmaceutical dosage compositions in which the active pharmaceutical ingredient, optionally mixed with other excipients, is enclosed in a capsule shell.

The term low substituted hydroxypropylcellulose (L-HPC) when used in the context of the present invention refers to a cellulose derivative having a degree of substitution of cellulose hydroxyl groups with hydroxypropoxy groups that does not exceed 20%, typically less than 15% .

The term average particle size as used in the context of the present invention refers to the volumetric average or volumetric mean diameter in the particle size distribution. The average particle size can be determined by laser light scattering using, for example, a Malvern Mastersizer 2000. Particle sizes are determined by measuring the angular distribution of laser light scattered by a homogeneous suspension of particles. Particles to be subjected to particle size measurement are first suspended in an appropriate non-polar dispersant such as n-hexane and then subjected to size determination in a Malvern Mastersizer 2000. Typically, 100 mg to 800 mg of the substance is dispersed in 5-10 ml of dispersant facilities. The particle size of the pharmaceutically acceptable lenalidomide salt is preferably determined using a Hydro S liquid dispersion module. The particle size of the excipients is preferably determined using a Malvern Mastersizer 2000 Scirocco unit with the sample dispersed in a stream of air.

The particle size distribution can also be determined by laser light scattering using, for example, a Malvern Mastersizer 2000 in the same manner as described above for average particle size. The values indicated as d(0.1), d(0.5) and d(0.9) mean that 10%, 50% and 90% of the particles are smaller than these values, respectively.

Two particle size distributions are considered to have the same particle size distribution if the average particle size of at least one of the two particle size distributions lies between the d(0.1) and d(0.9) values of the other particle distribution.

The moisture content is expressed in wt.% and determined by the Karl Fischer method disclosed in the European Pharmacopoeia, version 9.2, monograph 2.5.12 (monograph number 07/2015:20512).

Weight loss during drying is expressed in wt.% and is determined by weighing the sample, drying it until it reaches a constant weight and weighing it again. Drying is preferably carried out in a halogen dryer such as a Mettler Toledo HR73 or R83, or equivalent equipment. The preferred drying conditions are drying at 105°C until constant weight is achieved.

The term low gas and moisture permeable primary packaging, when used in the context of the present invention, means packaging that has a water vapor transmission rate (WVTR value according to ASTM A 1249) of no more than 0.5 g/ m ² /day at 40°C and 75% relative humidity, preferably not more than 0.25 g/m ² /day at 40°C and 75% relative humidity, and oxygen penetration rate (OTR value (from English: oxygen transmission rate) according to ASTM D 3985) no more than 2 ml/m ² /day*bar at 23°C and relative humidity equal to 50%, preferably no more than 1 ml/m ² /day* bar at 23°C and relative humidity equal to 50%.

Unless otherwise expressly stated, all percentages stated in this publication are % by weight based on the total weight of the pharmaceutical composition.

Review.

During the work, the present inventors discovered that compositions containing lenalidomide acid addition salts prepared by methods according to the prior art do not meet the requirements for shelf-stable compositions. It has been found that the acid addition salt of lenalidomide in compositions containing proton-accepting compounds is physically unstable and that significant disproportionation occurs resulting in partial or complete formation of lenalidomide in the free base form. This is shown in more detail in the Reference Examples.

As disclosed in the prior art, the free base form and the acid addition salt forms may have significantly different solubilities, and any changes in the physical form during the manufacturing or storage phase may adversely affect the bioavailability of these dosage forms. The primary objective of the present inventors was to provide a physically and chemically stable form of lenalidomide acid addition salt in a composition.

It has been found that the desired storage stability, in vitro dissolution and processability of the lenalidomide pharmaceutical composition are highly dependent on the nature of the inactive pharmaceutical ingredients used.

Most pharmaceutical compositions disclosed in the prior art contain lactose. Lactose is a reducing sugar that is capable of reacting with compounds containing an amino group in the Maillard reaction. If the drug contains an amino group, then

- 4 045835 it can decompose due to the Maillard reaction. Drugs that contain primary or secondary amines are particularly susceptible to degradation by the Maillard reaction. Lenalidomide is a primary amine. Therefore, the object of the present invention was to develop a composition that would prevent the degradation of lenalidomide through the Maillard reaction.

It has surprisingly been found that by adding an acid and/or using pharmaceutically acceptable excipients that do not contain proton-accepting excipients and/or selecting excipients that render the composition acidic, target stability can be achieved at storage and dissolution profile similar to those obtained from the commercial product Revlimid. This stabilizing effect was surprisingly observed even in the presence of lactose or other reducing sugars. However, it is preferable to avoid the use of reducing sugars as this may further enhance stability.

The present invention provides pharmaceutical compositions that provide beneficial stabilizing effects while maintaining excellent API dissolution characteristics and suitability for industrial scale production. In particular, there are three embodiments of the pharmaceutical composition of the present invention.

According to a first embodiment of the present invention, there is disclosed a pharmaceutical composition comprising (a) as an active ingredient lenalidomide in the form of a pharmaceutically acceptable acid addition salt, b) an acid, and c) at least one additional pharmaceutically acceptable inactive ingredient.

According to a second embodiment of the present invention, there is disclosed a pharmaceutical composition comprising (a) as an active ingredient lenalidomide in the form of a pharmaceutically acceptable acid addition salt, b) optionally an acid, c) at least one additional pharmaceutically acceptable inactive ingredient, and d) which does not contain excipients capable of accepting protons.

According to a third embodiment of the present invention, there is disclosed a pharmaceutical composition comprising (a) as an active ingredient lenalidomide in the form of a pharmaceutically acceptable acid addition salt, b) one or more pharmaceutically acceptable excipients, wherein the excipients are selected such that the pharmaceutical composition exhibits acidic properties .

Pharmaceutical composition.

The following characteristics are common to the pharmaceutical compositions according to all three embodiments of the present invention.

The pharmaceutical compositions of the present invention are solid pharmaceutical compositions. The compositions may take the form of capsules, powders, tablets, mini-tablets, micro-tablets, coated tablets, coated mini-tablets, coated micro-tablets, pills, lozenges and the like. The pharmaceutical compositions of the present invention are preferably suitable for oral administration. The compositions of the present invention are preferably in the form of capsules or tablets. The capsules may be selected from the group consisting of hard gelatin capsules, gelatin-polyethylene glycol capsules, pullulan capsules, polyvinyl acetate (PVA) capsules, starch capsules, and hydroxypropyl methylcellulose or hypromellose (HPMC) hard capsules. ), hydroxypropyl methylcellulose or hypromellose (HPMC) hard capsules are preferred. HPMC capsules are stable at low humidity levels, have low moisture content (3% to 8%), low water permeability and low static charge. These natural capsules are available in sizes ranging from 00 to 4. Due to the low chemical activity of HPMC capsules, they are suitable for highly active molecules. HPMS is not of animal origin and does not pose a risk of infection by organisms that cause bovine spongiform encephalopathy (BSE) or transmissible spongiform encephalopathy (TSE).

The pharmaceutical compositions of the present invention are preferably formulated in unit dosage form, each dosage form containing from about 0.1 mg to about 50 mg of lenalidomide in a pharmaceutically acceptable salt form, preferably from about 1 mg to about 30 mg of lenalidomide in a pharmaceutically acceptable salt form. salt, more preferably the oral dosage form contains 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg or 20 mg or 25 mg of lenalidomide in the form of a pharmaceutically acceptable salt. The amounts indicated are calculated based on the content of lenalidomide free base.

Active pharmaceutical ingredient.

The following API characteristics apply to all three embodiments of the present invention.

Component (a), a pharmaceutically acceptable acid addition salt of lenalidomide, may be selected from the salts disclosed in WO2011050962, such as hydrochloride, sulfate or

- 5 045835 hydrogen sulfate, from the salts disclosed in publication US 2011/0060010, such as the hydrochloride, hydrobromide, nitrate, besylate, tosylate, mesylate and sulfate, or the salts disclosed in publication WO2011018101, such as salts of lenalidomide with acids having a pKa value below 1, for example - lenalidomide besylate and lenalidomide tosylate. Preferably, the present invention is based on the use of the hydrochloride salt of lenalidomide, more preferably lenalidomide hydrochloride monohydrate, most preferably lenalidomide hydrochloride monohydrate in polymorphic form VIIA disclosed in publication US2011/0060010.

According to one aspect of any embodiment of the present invention, the pharmaceutically acceptable salt of lenalidomide has an average particle size ranging from 1 μm to 150 μm, preferably in the range from 5 μm to 100 μm, and most preferably in the range from 8 μm to 50 μm. µm. In a particularly preferred embodiment of the present invention, the pharmaceutically acceptable salt of lenalidomide has an average particle size ranging from 4 μm to 20 μm.

In another aspect of any of the embodiments of the present invention, the pharmaceutically acceptable salt of lenalidomide has a particle size distribution with d(0.1) ranging from 0.1 μm to 20 μm, d(0.5) ranging from 1 µm to 150 µm, d(0.9) ranging from 10 µm to 300 µm, preferably with d(0.1) ranging from 0.5 µm to 10 µm, d(0.5) , lying in the range from 3 μm to 100 μm, d(0.9), lying in the range from 15 μm to 150 μm, more preferably with d(0.1), lying in the range from 0.5 μm to 5 μm , d(0.5), lying in the range from 4 μm to 70 μm, d(0.9), lying in the range from 20 μm to 100 μm.

In another aspect of any of the embodiments of the present invention, the pharmaceutically acceptable salt of lenalidomide has a particle size distribution with d(0.1) ranging from 0.1 μm to 30 μm, d(0.5) ranging from 1 µm to 150 µm, d(0.9) ranging from 5 µm to 300 µm, preferably with d(0.1) ranging from 0.5 µm to 20 µm, d(0.5) , lying in the range from 3 μm to 70 μm, d(0.9), lying in the range from 10 μm to 150 μm, more preferably with d(0.1), lying in the range from 0.5 μm to 10 μm , d(0.5) in the range from 5 µm to 50 µm, d(0.9) in the range from 10 µm to 100 µm, even more preferably with d(0.1) in the range from 0.5 µm to 5 µm, d(0.5), ranging from 4 µm to 20 µm, d(0.9), ranging from 12 µm to 40 µm.

Acidic component.

The acid component (b) is a mandatory component of the first embodiment of the present invention and an optional component of the second and third embodiments of the present invention. The following characteristics apply to all three embodiments of the present invention.

The acid component (b) is preferably a pharmaceutically acceptable acid. It can be selected from the group of acids and their mixtures, in particular from the group of organic acids, inorganic acids and mixtures thereof. The organic acid may in particular be selected from compounds containing at least one (for example one or two or more) carboxylic acid groups, compounds containing at least one (for example one or two or more) sulfonic acid group, and mixtures thereof. Preferably the organic acid has a total number of carbon atoms of at least 2, preferably at least 4, and up to 20, preferably up to 16, more preferably up to 10 carbon atoms. Preferably, acids are used that have a pKa value of less than 4, more preferably less than 3. It is particularly preferred to use acids that have a pKa value of 0 or more, preferably a pKa value of 1 or more. Acids with multiple acid groups have multiple pKa values. The pKa values reported here are for the first deprotonation, which is the most acidic proton (in other words, it is the smallest pKa value). A stronger acid can also be used, but it is recommended to use the same acid that was used to form the lenalidomide salt. In this way, the risk of (part of) the lenalidomide salt being converted to another salt form can be minimized.

Organic acids may be selected, for example, from compounds of formula (II), compounds of formula (III), compounds of formula (IV), compounds of formula (V) and mixtures thereof:

^R1 -COOH(II)

R ² -SO ₃ H (III)

HOOC- ^R3 -COOH(IV)

HO ₃ SR ⁴ -SO ₃ H (V), where R ¹ can be selected from linear or branched C ₁ -C _2O alkyl (preferably linear or branched C1-C ₁₅ alkyl, in particular linear or branched C ₂ -C ₉ alkyl), optionally substituted with one or more substituents selected from -OH, -SO ₃ H and C1-C4 alkyl; C ₆ -C ₁₂ cycloalkyl, optionally substituted with one or more substituents selected from -OH,

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-SO ₃ H and C ₁ -C ₄ alkyl; linear or branched C2-C ₂₀ alkenyl, optionally substituted with one or more substituents selected from -OH, -SO ₃ H and C ₁ -C ₄ alkyl; C ₆ -C ₁₂ aryl, optionally substituted with one or more substituents selected from -OH, -SO ₃ H and C ₁ -C ₄ alkyl where R ² can be independently selected from linear or branched C ₁ -C _2O alkyl (preferably - linear or branched C ₁ -C ₁₅ alkyl, in particular linear or branched C ₂ -C ₉ alkyl), optionally substituted with one or more substituents selected from -OH, -COOH and C ₁ -C ₄ alkyl; C ₆ -C ₁₂ cycloalkyl, optionally substituted with one or more substituents selected from -OH, -COOH and C ₁ -C ₄ alkyl; linear or branched C ₂ -C ₂₀ alkenyl, optionally substituted with one or more substituents selected from -OH, -COOH and C ₁ -C ₄ alkyl; C ₆ -C ₁₂ aryl, optionally substituted with one or more substituents selected from -OH, -COOH and C ₁ -C ₄ alkyl;

wherein R ³ and R ⁴ may be independently selected from linear or branched C1-C20 alkylene (preferably linear or branched C1-C6 alkylene), optionally substituted with one or more substituents selected from -OH, -COOH, -SO3H and C1- C4 alkyl; C6-C12 cycloalkylene, optionally substituted with one or more substituents selected from -OH, -COOH, -SO3H and C1-C4 alkyl; linear or branched C2-C20 alkenyl, optionally substituted with one or more substituents selected from -OH, -COOH, -SO3H and C1-C4 alkyl; and C6-C12 arylene, optionally substituted with one or more substituents selected from -OH, -COOH, -SO3H and C1-C4 alkyl. Preferably, R ³ and R ⁴ may be independently selected from linear or branched C1-C ₆ alkylene groups (in particular from C ₁ or C ₂ or C ₃ or C ₄ or C ₅ alkylene groups) which are unsubstituted, or which are substituted with at least one (eg, 1, 2, 3, 4) -OH substituent and optionally also substituted with at least one -COOH substituent.

Preferably, the organic acid is selected from the group consisting of oxalic, pyruvic, malonic, lactic, glyceric, fumaric, maleic, oxaloacetic, tartaric, dihydroxytartaric, oxoglutaric, citric, salicylic, gentisic, phthalic acids or mixtures thereof. More preferably, the organic acid is selected from oxalic acid, maleic acid, pyruvic acid, malonic acid, tartaric acid, or a mixture thereof. It is most preferable to use tartaric acid.

Suitable inorganic acids are phosphoric acid, boric acid and silicic acid. The preferred inorganic acid is phosphoric acid.

Excipients.

The following information on excipients is equally applicable to the first and third embodiments of the present invention. If we are talking about the second embodiment of the present invention, then the information below is applicable only with the understanding that auxiliary substances capable of accepting a proton cannot be used.

The diluent may be selected from the group consisting of polysaccharides, mono- or disaccharides or sugar alcohols, preferably it is selected from starch, cellulose, sugar alcohols or a mixture thereof. The polysaccharide is preferably a polysaccharide containing from 200 to 10,000 monosaccharide residues, preferably from 500 to 10,000 monosaccharide residues, preferably glucose residues. The cellulose may be selected from powdered cellulose, microcrystalline cellulose, silicated microcrystalline cellulose. The starch may be selected from starches derived from any suitable plant source, for example corn, rice, tapioca, potato, preferably the starches are modified starches such as pregelatinized starch, which is a type of modified starch that has been processed to make the starch more fluid and direct compressibility. Partially or fully pregelatinized starches can be used. Monosaccharides, oligosaccharides and sugar alcohols can be selected from glucose, fructose, sucrose, lactose monohydrate, anhydrous lactose, raffinose, isomaltose, trehalose, dextrates, mannitol, erythritol, sorbitol, maltitol, xylitol and lactitol, compressible sugars and mixtures thereof. Preferably, the diluent is not selected from lactose, calcium salts of phosphoric acid, carbonic acid or sulfuric acid, such as calcium hydrogen phosphate anhydrous or hydrate or calcium carbonate. If such less preferred excipients are nevertheless used, it is important to provide sufficient acid to obtain a satisfactory level of stability.

In one aspect of the present invention, preferably low moisture content diluents are used having a drying loss of less than 8 wt.%, preferably less than 5 wt.%, more preferably less than 2.5 wt.% and most preferably less than 1. 5 wt.% as measured using a halogen dryer such as Mettler Toledo HR73 or R 83 or equivalent equipment. In a preferred aspect, one or more other excipients in the composition also satisfy the specified dryness conditions. According to a particularly preferred aspect, all excipients satisfy this dryness condition.

According to a particularly preferred embodiment of the present invention, the diluent is selected from powdered celluloses (Eur. Pharm.), microcrystalline celluloses and/or sugar alcohols. More preferably, the pharmaceutical composition of the present invention contains at least one diluent selected from microcrystalline cellulose or mannitol.

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The microcrystalline cellulose is preferably selected from microcrystalline cellulose with an average particle size ranging from 10 µm to 200 µm, preferably from 20 µm to 150 µm, and/or a moisture content of less than or equal to 5%. In particular, the microcrystalline cellulose may be selected from microcrystalline cellulose with an average particle size of 20 μm and a moisture content of less than or equal to 5%, such as Avicel PH-105, from microcrystalline cellulose with an average particle size of 50 μm, and less than or equal to 5% moisture content, such as Avicel PH-101 or Vivapur 101, microcrystalline cellulose with an average particle size of 50 μm and less than or equal to 2% moisture content, such as Avicel PH-113 , from microcrystalline cellulose with an average particle size ranging from 90 µm to 120 µm, and with a moisture content less than or equal to 5%, such as Avicel PH-102 or Vivapur 102, from microcrystalline cellulose with an average particle size ranging from range from 90 µm to 120 µm, and with a moisture content less than or equal to 1.5%, such as Avicel PH-112.

The mannitol may preferably be selected from mannitol having an average particle size ranging from 50 µm to 300 µm, preferably from 100 µm to 250 µm.

Surprisingly, it has been discovered that the use of a mixture of microcrystalline cellulose and mannitol not only produces compositions with physical and chemical stability, but this combination of diluents allows these compositions to be prepared with excellent dose uniformity, weight variations and flow properties.

Preferably, the compositions of the present invention further contain starch, and more preferably modified starch (ie, pregelatinized starch). Starch can be used as a binder, diluent or disintegrant, while pregelatinized starch is preferably used as a binder and disintegrant. The modified starch may be selected from modified starch having an average particle size ranging from 10 µm to 100 µm, preferably from 30 µm to 70 µm. More specifically, the modified starch may be selected from modified starch with an average particle size of about 50 microns, such as Starch 1500 and Starch 1500 LM. The amount of starch, preferably modified starch, in the composition typically ranges from about 1% by weight to about 30% by weight. Preferably, the amount of starch ranges from about 5% to about 20%, more preferably from about 10% to about 20%, by weight of the composition.

The amount of diluent in the composition typically ranges from about 50% by weight to about 99% by weight. Preferably, the amount of diluent ranges from about 60% to about 95%, more preferably from about 70% to about 90%, by weight of the composition.

The weight ratio of mannitol to microcrystalline cellulose in the composition is typically in the range of 5:1 to 1:5, preferably the weight ratio is in the range of 3:1 to 1:1, more preferably in the range of 2:1 to 1: 1.

To produce the compositions of the present invention, it is preferred that the particle size of all excipients be within the same particle size range to minimize segregation of the components of the mixture. The average particle sizes of the excipients used are preferably in the range from 20 µm to 200 µm, more preferably in the range from 50 µm to 150 µm. The main advantages of using excipients with particle sizes of the same order are high content homogeneity due to a low tendency to segregation and good fluidity, ensuring high mass stability at different tableting/capsule production speeds.

In the composition of the present invention, the diluent may simultaneously serve as a binder and/or disintegrant.

The pharmaceutical compositions of the present invention may contain additional ingredients selected from a wide variety of excipients known in the field of pharmaceutical compositions, such as disintegrants, binders, lubricants and glidants.

Suitable disintegrants may be selected from crospovidone, starch, corn starch, pregelatinized starch, sodium starch glycolate, hydroxypropyl starch, microcrystalline cellulose, sodium and/or calcium salts of carboxymethylcellulose, cross-linked carboxymethylcellulose (e.g. croscarmellose sodium and/or croscarmellose calcium), polacrilin potassium, low-substituted hydroxypropylcellulose (L-HPC), sodium and/or calcium alginate, sodium docusate, methylcellulose, agar, guar gum, chitosan, alginic acid or mixtures thereof. According to an aspect of the present invention, it is preferable to use a disintegrant that is not sodium starch glycolate, sodium and/or calcium salts of carboxymethylcellulose, cross-linked carboxymethylcellulose (for example, croscarmellose sodium and/or croscarmellose calcium), polacriline potassium, low-substituted hydroxypropylcellulose (L-HPC), sodium and /or calcium alginate, sodium docusate. Preferably, the disintegrants are selected from corn starch, pregelatinized starch, crospovidone. Preferably, the leavening agent is not selected from

- 8 045835 group of compounds that can act as proton acceptors, such as sodium and/or calcium salts of carboxymethylcellulose, cross-linked carboxymethylcellulose (for example, croscarmellose sodium and/or croscarmellose calcium), polacriline potassium, sodium and/or calcium alginate, docusate sodium .

Suitable binders may be selected from povidone (polyvinylpyrrolidone), copovidone (a copolymer of vinylpyrrolidone and vinyl acetate), powdered cellulose, crystalline cellulose, microcrystalline cellulose, silicated microcrystalline cellulose, cellulose derivatives such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose and hydroxypropyl methylcellulose, or others cellulose ethers, corn, potato or rice starch, pregelatinized starch, α-starch or dextrin, gum arabic, pullulan, polymethacrylates or mixtures of binders. Preferably, the dry binders may be selected from copovidone, povidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, starch derivatives such as pregelatinized starch, low-substituted hydroxypropylcellulose or mixtures thereof. More preferably, the pharmaceutical composition of the present invention contains at least one binder selected from microcrystalline cellulose, hydroxypropylcellulose or starch or mixtures thereof. Microcrystalline cellulose and starches simultaneously act as a binder, disintegrant and diluent and therefore the use of additional binder and/or disintegrant can be avoided if microcrystalline cellulose and/or starch are used in the composition of the present invention.

Lubricants (lubricants) and glidants are preferably used in the compositions of the present invention in the usual standard manner.

Suitable lubricants may be selected from lubricants, fatty acids, fatty acid esters including glyceride esters (for example, selected from glyceryl monostearate, glyceryl tribehenate and glyceryl dibehenate, for example Compritol 888), from the group of metal salts of fatty acids containing from 12 to 20 atoms carbon such as magnesium, calcium, aluminum or zinc stearates, magnesium palmitate and magnesium oleate, hydrogenated vegetable oil, hydrogenated castor oil, talc, wax (for example, STEROTEX NF, Lubriwax (a type of hydrogenated vegetable oil), beeswax or spermaceti), boric acid, sodium stearyl fumarate, macroheads, sugar esters (eg sorbitan monostearate and sucrose monopalmitate), inorganic materials (eg talc), polymers (eg PEG) or mixtures thereof. Preferably, the lubricant is selected that is not metal salts of fatty acids containing from 12 to 20 carbon atoms, such as magnesium, calcium, aluminum or zinc stearates, magnesium palmitate and magnesium oleate, and is not sodium stearyl fumarate. Lubricants are preferably selected from stearic acid, glyceryl behenate, hydrogenated vegetable oil or mixtures thereof; it is most preferable to use glyceryl behenate or stearic acid.

Preferably, the composition does not contain lubricants that can act as proton acceptors, such as metal salts of fatty acids containing from 12 to 20 carbon atoms, such as magnesium, calcium, aluminum or zinc stearates, magnesium palmitate and magnesium oleate, or sodium stearyl fumarate.

The pharmaceutical composition of the present invention may further contain one or more glidants. In some aspects of the present invention, one or more glidants are selected from colloidal silica, talc, and magnesium trisilicate. In a preferred aspect, talc and magnesium silicate are not used. Most preferably, anhydrous colloidal silica is used.

In preferred aspects of the present invention, the active ingredient is uniformly distributed in a matrix formed by the other ingredients of the composition. According to a more preferred embodiment of the present invention, the pharmaceutical composition of the present invention contains:

Lenalidomide (added in salt form): 0.2% to 20%, more preferably 1% to 10%, even more preferably 2% to 8%, most preferably 3% to 8%;

diluent: 50% to 99%, more preferably 60% to 95%, most preferably 70% to 90%;

acid: 0% to 10%, more preferably 2% to 8%, most preferably 3% to 7%;

binder: 0% to 30%, more preferably 0% to 20%, most preferably 0% to 15%;

baking powder: 0% to 30%, more preferably 0% to 20%, most preferably 0% to 15%;

lubricant: 0.25% to 10%, more preferably 1% to 5%, most preferably 1.5% to 3%;

- 9 045835 slip agent: from 0.25% to 10%, more preferably from 1% to 5%, most preferably from 1.5% to 3%;

wherein the pharmaceutical composition preferably does not contain excipients capable of acting as proton acceptors.

Lenalidomide should be added in the form of its pharmaceutically acceptable salt. However, the above relative amounts should be calculated in terms of the free base content of lenalidomide. In those aspects in which the pharmaceutical compositions of the present invention contain an excipient having multiple functions, that is, one excipient is used as a diluent and/or binder, etc., the permissible relative amount of the excipient is determined by the highest percentage specified in the above composition. For example, if the composition of the present invention contains microcrystalline cellulose, which can act as a diluent, binder and disintegrant, then its proportion is determined by the highest specified value, that is, from 50% to 99% as a diluent. Each function of an excipient with multiple functions should not be determined separately.

In a preferred aspect, the composition of the present invention contains from 1% to 10% lenalidomide (in the form of a pharmaceutically acceptable salt, preferably in the form of lenalidomide hydrochloride), from 60% to 95% by weight of a diluent selected from microcrystalline cellulose and/or mannitol , from 3 wt.% to 8 wt.% acid, from 0 wt.% to 15 wt.% binder selected from pregelatinized starch or hydroxypropylcellulose, and from 0 wt.% to 5 wt.% disintegrant, preferably selected from low-substituted hydroxypropylcellulose (L-HPC), and from 0.25 wt.% to 5 wt.% lubricant, preferably selected from glyceryl behenate or stearic acid, and from 0.25 wt.% to 5 wt.% glidant, preferably selected from from colloidal anhydrous silicon dioxide.

In an even more preferred aspect, the composition of the present invention contains from 1% to 10% lenalidomide (in the form of a pharmaceutically acceptable salt, preferably in the form of lenalidomide hydrochloride), from 60% to 95% by weight of a diluent selected from microcrystalline cellulose and mannitol and combinations thereof, from 3 wt% to 8 wt% tartaric acid, from 5 wt% to 15 wt% a binder, preferably selected from pregelatinized starch, and from 1 wt% to 5 wt% lubricant, preferably selected from glyceryl behenate.

In a preferred aspect, the pharmaceutical composition of the present invention is in the form of tablets or capsules, such as hard gelatin or HPMC capsules, preferably HPMC capsules.

The invention also relates to a packaged pharmaceutical composition containing the pharmaceutical composition described above, which is in a primary package with low gas and moisture permeability. Primary packaging with low gas and moisture permeability may contain materials such as aluminum or polychloro-3-fluoroethylene homopolymer/PVC laminate. Typically, the packaging thickness may range from 10 µm to 40 µm for Al/Al blisters and from 10 µm to 110 µm for Al-polychloro-3-fluoroethylene homopolymer/PVC laminate blisters. Optionally, the packaged pharmaceutical composition may further contain a desiccant. The desiccant may be placed within the packaging unit along with the dosage form, such as a tablet, and/or in the closure system, and/or it may be incorporated into the walls of the primary packaging unit. For example, the pharmaceutical composition may be packaged in containers made of glass or polymeric materials, with or without a desiccant.

Method according to the present invention.

The pharmaceutical compositions of the present invention can be produced using wet or dry methods. The present invention provides, as a further embodiment, methods for preparing the compositions of the present invention. The methods described below are suitable for the preparation of all pharmaceutical compositions of the present invention (to the extent that the components of the particular pharmaceutical compositions are compatible with the components specified in connection with the methods described below).

According to one aspect of the present invention, pharmaceutical compositions are prepared by wet methods, such as wet granulation.

According to a preferred aspect of this embodiment of the present invention, the pharmaceutical compositions are prepared by dry methods, such as direct compression, dry mixing or dry granulation, and more preferably by dry mixing.

The present inventors have discovered that compositions prepared by dry processes exhibit an improved dissolution profile and improved physical and chemical stability compared to compositions prepared by wet granulation.

The inventors of the present invention have unexpectedly discovered that stable pharmaceutical compositions containing lenalidomide in the form of a pharmaceutically acceptable salt as the active ingredient, which exhibit high storage stability and excellent dose uniformity, can be prepared by a simple dry mixing method if lenalidomide is in pharmaceutically acceptable form. acceptable salt is first mixed homogeneously with a specified excipient and then subjected to sieving, followed by optional addition of other excipients, optional mixing, optional sieving and compression or encapsulation of the mixture. Mixing the compounds can be carried out in the form of one or more stages. For example, the active ingredient may first be mixed with a portion of the diluent and this mixture may then be combined with a mixture of other ingredients. The entire process is preferably carried out in the absence of a solvent.

The most important advantages associated with the quality of the composition are processing without any need for moisture and heat, which are mandatory in most wet granulation processes. Such a method may improve the stability of the compositions of the present invention.

Among the preferred dry methods, dry mixing is the most preferred because it avoids the high compression pressures used in impact or roller compaction, so that an additional stabilizing effect can be achieved through dry mixing.

The methods described below are intended to prepare the pharmaceutical compositions of the present invention. This means that the ingredients (API, excipients) listed below must comply with the essential features described for the pharmaceutical compositions of the present invention, and that they preferably correspond to the features described as preferred features of the pharmaceutical compositions of the present invention.

In a preferred aspect of this embodiment of the present invention, there is provided a method for preparing the pharmaceutical compositions of the present invention, which includes:

combining a pharmaceutically acceptable salt of lenalidomide and at least one excipient or mixture of excipients;

optional sifting;

mixing to obtain a mixture;

compressing the mixture into the desired solid dosage form or encapsulating the mixture.

In a more preferred aspect of this embodiment of the present invention, a method for preparing the pharmaceutical compositions of the present invention includes:

mixing a pharmaceutically acceptable salt of lenalidomide and a portion of a diluent and/or other excipients;

sifting the mixture;

mixing the mixture with the remainder of the diluent and/or other excipients in a mixer to obtain a homogenized mixture;

optional dry sifting of the mixture through a sieve;

adding a lubricant and/or glidant and mixing to form a molding mixture;

compressing the compression mixture into the desired solid dosage form or encapsulating the compression mixture.

This dry screening step may be advantageous for separating cohesive particles and increasing composition uniformity.

In an even more preferred aspect of this embodiment of the present invention, there is provided a method for preparing the pharmaceutical compositions of the present invention, which includes:

mixing a pharmaceutically acceptable lenalidomide salt and a portion of a diluent in a weight ratio ranging from 1:1 to 1:50, preferably 1:2 to 1:30, more preferably 1:3 to 1:25, and/or with other excipients;

sifting the mixture;

mixing the mixture obtained above with the remainder of the diluent and/or other auxiliary substances in a mixer to obtain a homogenized mixture;

optional dry sifting of the mixture through a sieve;

adding a lubricant and/or glidant and mixing to form a mixture;

compressing the mixture into the desired solid dosage form or encapsulating the mixture.

This dry screening step may be advantageous for separating cohesive particles and increasing composition uniformity.

Alternatively, the composition of the present invention can be prepared by dry granulation methods.

The dry granulation method includes a method comprising:

optionally sieving the pharmaceutically acceptable lenalidomide salt and at least one excipient or mixture of excipients;

- 11 045835 granulation of a pharmaceutically acceptable salt of lenalidomide and at least one excipient or mixture of excipients using methods known in the art, such as impact and/or roller compaction;

optionally mechanically grinding and sieving the resulting granules or compacted particles to obtain a granulate having the desired particle size distribution;

adding one or more excipients or a mixture of excipients to the granulate, followed by mixing to obtain a mixture;

compressing the mixture to obtain the desired solid dosage form or encapsulating the mixture;

or a method comprising:

optionally sieving the pharmaceutically acceptable lenalidomide salt and at least one excipient or mixture of excipients;

granulating a portion of the optionally sieved pharmaceutically acceptable lenalidomide salt and at least one excipient or mixture of excipients using methods known in the art, such as impact and/or roller compaction;

optionally mechanically grinding and sieving the resulting granules or compacted particles to obtain a granulate having the desired particle size distribution;

adding the remainder of the pharmaceutically acceptable lenalidomide salt and at least one excipient or mixture of excipients to the granulate to form a mixture;

compressing the mixture into the desired solid dosage form or encapsulating the mixture.

Mixing the pharmaceutically acceptable salt of lenalidomide and at least one excipient or mixture of excipients can be carried out in standard devices used for mixing powders, for example, in mixers without moving parts (passive mixers), fluidized bed mixers, diffusion mixers, biconical diffusion mixers , biconical mixers, tubular mixers, cubic mixers, planetary mixers, Y-shape, V-shape or high shear mixers.

In another embodiment of the present invention, the same equipment can be used to produce a pressing mixture with a preliminary step of producing granulate through granulation, described by the term dry granulation.

Dry granulation can be accomplished by methods known in the art, such as impact and/or roller compaction, the latter being preferred. The pharmaceutically acceptable lenalidomide salt, optionally sieved to remove agglomerates, is typically mixed with at least one excipient or mixture of excipients and dry granulated into granules/compacted material using a roller press or tablet press. The resulting granules/compacted material are crushed and optionally screened to obtain a uniform granule size distribution of the dry granulate.

Alternatively, the composition of the present invention can be prepared by wet granulation methods.

The wet granulation method includes a method that includes:

dissolving or suspending an acid and optionally at least one excipient in a solvent selected from the group consisting of water, alcohols such as ethanol, propanol, 2-propanol, butanol, ketones such as acetone, methyl ethyl ketone, tert-butyl methyl ketone, or a mixture thereof wherein preferably the solvent is selected from water to obtain a granulating liquid;

granulating a mixture of an optionally sieved pharmaceutically acceptable salt of lenalidomide and at least one excipient or mixture of excipients with a granulating liquid using methods known in the art, such as a fluid bed granulator or a high shear granulator;

optionally drying, mechanically grinding and/or sieving the resulting granulate to obtain a granulate with the desired particle size distribution;

adding the remainder of at least one excipient or mixture of excipients to the granulate to form a mixture;

compressing the mixture to obtain the desired solid dosage form or encapsulating the mixture;

or a method that includes:

dissolving or suspending the acid in a solvent selected from the group consisting of water, alcohols such as ethanol, propanol, 2-propanol, butanol, ketones such as acetone, methyl ethyl ketone, tert-butyl methyl ketone or a mixture thereof, preferably the solvent being selected from water, to obtain a granulating liquid;

mixing excipients, excluding lubricant, to obtain a mixture of excipients;

- 12 045835 granulating a mixture of excipients with a granulating liquid using methods known in the art, such as a fluid bed granulator or a high shear granulator;

optionally drying, mechanically grinding and/or sieving the resulting granulate to obtain a granulate with the desired particle size distribution;

adding a pharmaceutically acceptable salt of lenalidomide and the remainder of at least one excipient or mixture of excipients, including a lubricant, to the granulate to form a mixture;

compressing the mixture into the desired solid dosage form or encapsulating the mixture.

The following examples illustrate the present invention and in no way limit the scope of the present invention as defined by the appended claims.

Description of embodiments of the invention

Methods. Stability test.

Binary mixtures and pharmaceutical compositions were stored in vials at a temperature of 40°C and relative humidity of 75% for 1 month or at a temperature of 50°C and relative humidity of 75% for 14 days. The disproportionation effect was monitored using a powder X-ray diffraction pattern. X-ray powder diffraction data were obtained to determine whether the sample remained in its original acid addition salt form, indicating its stability under these conditions, or whether it was partially or completely transformed into another crystalline material, such as the free base form, which indicates that it is not stable under these conditions.

Powder X-ray diffraction patterns were obtained using a PANalytical PW3040/60 X'Pert PRO diffractometer using CuKa radiation at a wavelength of 1.541874 A.

pH value of pharmaceutical composition:

The pH of the pharmaceutical composition (20% w/v suspension) was determined as follows: the tablets were finely crushed in a mortar or the capsule shell was opened and the powder was optionally ground finely in a mortar, after which a 20% w/v suspension of the powder was prepared in freshly boiled and cooled water. After stirring the suspension for 15 minutes, the pH value of the sample suspension was measured at a temperature ranging from 20° C. to 25° C. using a suitable calibrated pH meter Radiometer PHM240 using a combination glass electrode XC161.

Examples.

Binary mixtures of excipients disclosed in table. 1 was prepared and tested for stability under stress conditions.

Table 1

API Reference example 1 Reference example 2 Reference example 3 Reference example 4 Lenalidomide HC1H ₂ O + + + + + Microcrystal, cellulose Mannitol + + + Isomalt + Stearate Md + + + Croscarmellose sodium + Starch 1500 + Stability test 1 month at 40°C/75% RH HCI salt HCI salt Mixture of HCI salt and free base Mixture of HCI salt and free base Mixture of HCI salt and free base

Examples of the compositions of the present invention and reference examples of the preparation of a pharmaceutical composition are disclosed in table. 2, table. 3 and table. 4.

- 13 045835

table 2

Reference example 5 Example 1 Example 2 Example 3 Example 4 Example 5 Lenalidomide HC1H ₂ O 30 mg 30 mg 30 mg 30 mg 30 mg 30 mg Microcrystal, cellulose MCC 102 150 mg 150 mg 150 mg 150 mg 150 mg 150 mg Mannitol 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg Wine acid 15 mg 15 mg Lemon acid 20 mg 20 mg Stearate Md 4 mg Croscarmellose sodium 12 mg Starch 1500 40 mg 40 mg 40 mg Stability test 1 month at 40°C/75% RH Mixture of HCI salt and free base HCI salt HCI salt HCI salt HCI salt HCI salt Stability test 3 months at 30°C/65% RH Mixture of HCI salt and free base HCI salt HCI salt HCI salt HCI salt HCI salt

Table 3

Example 6 Example 7 Example 8 Example 9 Example 10 Example eleven Example 12 Lenalidomide HCI H ₂ O 30 mg 30 mg 30 mg 30 mg 30 mg 30 mg 30 mg MCC 102 150 mg 150 mg 150 mg 150 mg 150 mg 150 mg 150 mg Mannitol 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg Wine acid 15 mg 15 mg 15 mg Lemon acid 20 mg 20 mg 20 mg L-HPC 40 mg 40 mg Stearic acid 8 mg 8 mg 8 mg Glyceryl behenate 8 mg 8 mg Stability test - 1 month at 40°C/75% RH HCI salt HCI salt HCI salt HCI salt HCI salt HCI salt HCI salt Stability test - 3 months at 30°C/65% RH HCI salt HCI salt HCI salt HCI salt HCI salt HCI salt HCI salt

Method for preparing pharmaceutical compositions from examples and reference examples.

Lenalidomide hydrochloride and all excipients according to the composition were weighed into a glass vial. A gelatin capsule was added to the vials. The bottles were then capped and the contents were gently mixed to obtain a homogeneous mixture. The vials were subjected to stressful conditions.

Reference examples according to WO2011050962.

Pharmaceutical compositions were prepared as described in publication WO2011050962 (example 1 and example 3, binary mixtures were prepared with dicalcium phosphate dihydrate, which according to publication WO2011050962, p. 23, I. 6-23, was recognized as an excipient that provided increased storage stability).

- 14 045835

Table 4

Reference example 6 Reference example 6 Reference example 7 Lenalidomide HC1H ₂ O 22.8 mg 17.1 mg 17.1 mg MCC 102 160 mg 120 mg Lactose anhydrous 240 mg Dicalcium hydrogen phosphate 381 mg 381 mg Wine acid Ac-Di-Sol 24 mg 18 mg Stearate Md 8 mg 6 mg Stability test - 1 month at 40°C/75% RH Free base Free base Free base

Method for preparing pharmaceutical compositions according to reference examples.

The mixtures were prepared in the form of physical mixtures with mass ratios according to the composition disclosed in WO2011050962.

Lenalidomide hydrochloride in the form of monohydrate (Form VII) and all excipients according to the composition were weighed into a glass vial. A gelatin capsule was added to the vials. The bottles were then capped and the contents were gently mixed to obtain a homogeneous mixture. The vials were subjected to stressful conditions.

Stability test.

As can be seen from the stability test results, excipients capable of accepting protons, such as magnesium stearate, croscarmellose sodium or dicalcium hydrogen phosphate, caused the conversion of the salt to the free base form of lenalidomide. On the other hand, the presence of additional acid and/or the absence of alkaline excipients stabilized the physical form of the lenalidomide acid addition salt and no or only small amounts of disproportionation were observed.

Examples according to the present invention. Composition of the capsule.

Table 5

Example 13 Example 14 Example 15 Example 16 Example 17 Example 18 Example 19 mg/capsule Lenalidomide HC1H ₂ O 30.25 30.25 30.25 30.25 30.25 30.25 30.25 Microcrystalline cellulose Avicel PH 102 146.75 106.75 106.75 114.25 91.75 102.75 102.75 Mannitol (Parteck M200) 200.00 200.00 200.00 200.00 200.00 200.00 200.00 Wine acid 15.00 15.00 15.00 7.50 30.00 15.00 15.00 L-HPC LH21 40.00 40.00 40.00 40.00 40.00 Starch 1500 - 40.00 - - - - - Glyceryl behenate Compritol 888 8.00 8.00 8.00 8.00 8.00 8.00 8.00 LDC Kluckel EF - - - - - - 4.00 Total 400.00 400.00 400.00 400.00 400.00 400.00 400.00 Stability test - 1 month at 40°C/75% RH HCI salt HCI salt HCI salt HCI salt HCI salt HCI salt HCI salt

Method for examples 12 to 16.

Lenalidomide hydrochloride and half a portion of mannitol were mixed using a vortex mixer and sieved through a 0.50 mm sieve to obtain a powder mixture. The mixture was then mixed with the remaining leavening agent (starch or L-HPC), tartaric acid and the remainder of the mannitol and passed through a 0.50 mm sieve to obtain a homogenized mixture. Avicel was used to rinse the screen and the mixture was added. The mixture was stirred, Compritol 888 was added to it and mixed again. The composition was encapsulated in capsules containing 30.25 mg of lenalidomide hydrochloride (equivalent to 25 mg of lenalidomide free base).

Method for examples 17 and 18:

The granulating solution was prepared by dissolving Klucel and tartaric acid in water.

- 15 045835

A mixture of lenalidomide hydrochloride, Parteck, Avicel and half a portion of L-HPC LH21 was prepared in a mortar. The mixture was granulated with the granulating solution to form granules, additional water was added and granulated again. The granules were dried in an oven. After sifting the granulate through a 1.0 mm sieve, the granules were mixed with the remainder of the L-HPC LH21. Compritol 888 was added to the sifted mixture and mixed. The composition was encapsulated in capsules containing 30.25 mg of lenalidomide hydrochloride (equivalent to 25 mg of lenalidomide free base).

Characteristics of the lenalidomil hydrochloride monohydrate particles used in the presented compositions of Examples 1 to 20:

Table 6

Average diameter (µm) d(0.1) (µm) d(0.5) (µm) d(0.9) (µm) 10.6 4.0 8.8 21

Stability test.

The capsules were stored in vials at a temperature of 40°C and a relative humidity of 75% for 1 month. The physical stability of the samples was monitored using powder X-ray diffraction patterns. As can be seen from the results, the physical form remained the same, no disproportionation effect was observed.

Additional examples of the present invention. Composition of the capsule.

Table 7

Example 20 Example 21 Example 22 Example 23 Example 24 Example 25 Example 26 Example 27 mg/capsule mg/capsule mg/capsule mg/capsule mg/capsule mg/capsule mg/capsule mg/capsule Lenalidomide HC1H ₂ O 30.25 30.25 30.25 30.25 30.25 30.25 30.25 6.05 Mannitol M200 200.00 200.00 200.00 200.00 200.00 - - 100.00 Mannitol M100 - - - - - 200.00 106.40 - MSS RN 102 106.40 91.05 109.88 112.54 106.40 - - 62.27 MCC PH101 - - - - - 106.40 200.00 - Starch 1500 40.00 40.00 40.00 40.00 40.00 40.00 40.00 40.00 Compritol 888 8.00 8.00 8.00 8.00 - 8.00 8.00 4.00 Stearic acid - - - - 8.00 - - - Wine acid - 30.70 - - 15.35 15.35 15.35 7.68 Ground tartaric acid 15.35 Maleic acid - - 11.87 - - - - - Oxalic acid - - - 9.21 - - - - Total 400.00 400.00 400.00 400.00 400.00 400.00 400.00 400.00 Stability test -1 month at 40°C/75% RH HCI salt HCI salt HCI salt HCI salt HCI salt HCI salt HCI salt HCI salt

Method for preparing pharmaceutical compositions according to additional examples 20 to 27.

A finely ground powder (triturate) was prepared from the API, acid (tartaric, maleic or oxalic) and microcrystalline cellulose (powder 1). The resulting finely ground powder was mixed and sifted through a sieve with a mesh size of 0.5 mm. After this, baking powder (starch 1500) and 1/2 the amount of mannitol were added. The mixture thus obtained was mixed and sifted through a sieve with a mesh size of 0.5 mm (powder 2). The remainder of the mannitol was used to rinse the screen and then added to Powder 2. The mixture was stirred long enough to obtain sufficient homogeneity of the API. Finally, the sifted lubricant (Compritol 888 or stearic acid, which has been sieved using a 0.5 mm sieve) was added and the resulting mixture was mixed. The capsules were filled manually using compaction as an intermediate step.

Examples of compositions with acid-coated excipients.

- 16 045835

Table 8

Example 28 Example 29 Example 30 mg/capsule mg/capsule mg/capsule Lenalidomide HC1H ₂ O thirty thirty thirty Mannitol M200 200 200 200 MSS RN102 107 107 107 Starch 1500 40 40 40 Wine acid 15 - - Maleic acid - 15 - Oxalic acid - - 15 Compritol 888 8 8 8 Total 400 400 400 Test for HCI salt HCI salt HCI salt stability -1 month at 40°C/75% RH

Cooking method for examples 28 to 30.

The prescribed amount of acid (tartaric, maleic or oxalic) was dissolved in 20 g of water. The fluidized bed method was used to slowly spray the solution onto the excipients (mannitol, MCC and starch) and prevent particle agglomeration. Screened lubricant (Compritol 888, screened using a 0.5 mm sieve) was then added and the resulting mixture was mixed. Finally, the API was added and the resulting mixture was stirred long enough to obtain sufficient homogeneity of the API. The capsules were filled manually using compaction as an intermediate step.

Example of a composition for wet granulation.

Preparation method for example 31: composition for wet granulation.

A fluidized bed method was used to perform wet granulation. Klucel EF was dissolved in a sufficient amount of solvent (purified water, ethanol, isopropanol, acetone or a mixture of any of these solvents with water) to obtain a 4% solution. After this, the entire amount of tartaric acid was added to the solution. The diluents, API and 1/2 disintegrant were mixed in a fluidized bed granulator until the API was sufficiently homogeneous. A granulating liquid was sprayed onto the mixture to ensure sufficient agglomeration of the powder mixture. After completion of spraying the binder solution, the spray system was rinsed with purified water. The resulting granulate was dried and sifted through a sieve with a mesh size of 1 mm. 1/2 part of the sifted baking powder was added to the granulate and the resulting mixture was mixed. Finally, sifted Compritol was added to the granulate and the resulting mixture was mixed again. The capsules were filled manually using compaction as an intermediate step.

Characteristics of lenalidomide hydrochloride monohydrate particles used in the presented compositions of Examples 20 to 31.

Table 10

Average diameter (µm) d(0.1) (µm) d(0.5) (µm) d(0.9) (µm) 11.9 2.3 9.6 24

- 17 045835

Additional examples of the present invention.

Examples 32 and 33.

Table 11

Example 32 Example 33 mg/capsule mg/capsule Lenalidomide HC1H ₂ O 30.35 30.35 Mannitol 172 172 MSS 85.37 85.37 Starch 1500 34.4 34.4 Wine acid 15 15 Compritol 888 6.88 6.88 Total 344.0 344.0 Capsule type Gelatin HPMS Stability test -1 month at 40°C/75% RH HCI salt HCI salt

The method of obtaining pharmaceutical compositions according to additional examples 32 and 33.

Finely ground powder was prepared from API, tartaric acid and MCC (Powder 1). The resulting powder was mixed and sifted through a sieve with a mesh size of 0.5 mm. After this, baking powder (starch 100) and 1/2 part of mannitol were added. The mixture thus obtained was mixed and sifted through a sieve with a mesh size of 0.5 mm (powder 2). The remainder of the mannitol was used to rinse the screen and then added to Powder 2. The mixture was stirred long enough to obtain sufficient homogeneity of the API. Finally, sifted lubricant (Compritol, sifted using a 0.5 mm sieve) was added and the resulting mixture was mixed. The capsules were filled manually using compaction as an intermediate step.

Characteristics of lenalidomide hydrochloride monohydrate particles used in the presented compositions of Examples 32 and 33.

Table 12

Average diameter (µm) d(0.1) (µm) d(0.5) (µm) d(0.9) (µm) 11.1 1.8 5.4 17

The pharmaceutical compositions of Examples 32 and 33 unexpectedly had the same bioavailability of lenalidomide. As confirmed in a comparative randomized single-dose crossover bioavailability study in healthy volunteers, the 90% confidence intervals for absorption parameters comparing Example 33 to Example 32 were entirely within the bioequivalence range of 80% to 125%.

Additional examples of the present invention. Examples 34 to 40.

Table 13

Example 34 Example 35 Example 36 Example 37 Example 38 Example 39 Example 40 mg/capsule mg/capsule mg/capsule mg/capsule mg/capsule mg/capsule mg/capsule Lenalidomide HC1H ₂ O 3.04 6.07 9.11 12.14 18.21 24.28 30.35 Mannitol 51.50 103.00 130.50 174.00 104.40 139.20 174.00 MSS 31.66 63.33 78.82 105.10 52.13 69.51 86.89 Starch 1500 10.30 20.60 26.10 34.80 20.88 27.84 34.80 Wine acid 4.44 8.88 11.25 15.00 9.00 12.00 15.00 Compritol 888 2.06 4.12 5.22 6.96 4.18 5.57 6.96 Total 103 206 261 348 208.8 278.4 348 Capsule type HPMS HPMS HPMS HPMS HPMS HPMS HPMS

Method for preparing pharmaceutical compositions according to additional examples 34 to 40.

Finely ground powder was prepared from API, tartaric acid and MCC (Powder 1). The resulting powder was mixed and sifted through a sieve with a mesh size of 0.5 mm. The disintegrant (starch 100) and 2/3 of the mannitol were then sifted (using a 0.6 mm sieve), added to Powder 1 and the resulting mixture was stirred long enough to obtain sufficient homogeneity of the API (Powder 2). Compritol was then mixed with 1/3 mannitol, the resulting mixture was sieved (through a 0.6 mm sieve) and added to Powder 2. The final mixture was stirred until Compritol was sufficiently homogeneous in the final encapsulation mixture. The capsules were filled manually using compaction as an intermediate step.

Characteristics of lenalidomide hydrochloride monohydrate particles used in the presented compositions of Examples 34 and 40.

- 18 045835

Table 14

Average diameter (µm) d(0.1) (µm) d(0.5) (µm) d(0.9) (µm) 9.7 2.0 7.4 18

Claims (13)

1. A pharmaceutical composition which is a solid composition containing (a) lenalidomide in the form of a pharmaceutically acceptable acid addition salt, (b) an acid that has a pKa value of 4 or less, (c) at least one additional pharmaceutically acceptable excipient , and (d) wherein said composition does not contain excipients capable of accepting a proton, which are selected from: bases, salts of weak acids where the acid has a pKa value greater than 2, such as salts containing an anion derived from carboxylic acid, silicic acid, phosphoric acid, carbonic acid, and salts of alcohols. 2. The pharmaceutical composition according to claim 1, characterized in that it contains lenalidomide in the form of an acid addition salt of hydrochloric acid. 3. Pharmaceutical composition according to any one of claims 1 to 2, characterized in that it contains at least one diluent selected from microcrystalline cellulose and mannitol, preferably a combination of microcrystalline cellulose and mannitol. 4. Pharmaceutical composition according to any one of claims 1 to 3, characterized in that it contains an acid which has a pKa value ranging from 1 to 3. 5. Pharmaceutical composition according to any one of claims 3 to 4, characterized in that the diluent has a loss on drying of less than 5 wt.%, preferably less than 2 wt.%, and most preferably less than 1.5 wt.%. 6. The pharmaceutical composition according to claim 5, characterized in that all excipients have a drying loss of less than 5 wt.%, preferably less than 2 wt.%, and most preferably less than 1.5 wt.%. 7. Pharmaceutical composition according to any one of claims 1 to 6, characterized in that the composition has a pH value from 1 to 3, preferably from 1 to 2.5, when measured in a 20% (w/v) suspension in water at 25°C. 8. A method for producing a pharmaceutical composition according to any one of claims 1 to 7, which includes the following steps: combining lenalidomide in the form of a pharmaceutically acceptable acid addition salt, an acid that has a pKa value of 4 or less, and one or more excipients; mixing to obtain a mixture; and compressing the mixture or loading the mixture into a capsule shell. 9. The method of claim 8, wherein the pharmaceutically acceptable acid addition salt of lenalidomide is a hydrochloric acid salt thereof. 10. The method according to claim 8 or 9, characterized in that it is carried out in the absence of a solvent. 11. Method according to any one of claims 8 to 10, characterized in that it further includes a sieving step, which is carried out before and/or after the mixing step. 12. Method according to any one of claims 8 to 11, characterized in that it further includes the step of adding a lubricant and/or glidant after optional sieving and/or after mixing. 13. The method according to any one of claims 8-12, characterized in that it includes the following stages: mixing a pharmaceutically acceptable salt of lenalidomide, preferably hydrochloride, and part of the diluent in a mass ratio of 1:1 to 1:50, preferably from 1 :2 to 1:30, more preferably from 1:3 to 1:25, and/or other excipients and sifting the mixture; mixing the mixture obtained above with the remainder of the diluent and/or other auxiliary substances in a mixer to obtain a second mixture; optional - dry sifting of the mixture through a sieve; adding a lubricant and/or a glidant and then mixing to obtain a third mixture; pressing the third mixture or loading the mixture into the capsule shell.