EA039874B1 - Composition of pomalidomide for treatment of diseases associated with tumor necrosis factor (tnf) - Google Patents

Abstract

The invention relates to the field of chemical and pharmaceutical industry, and concerns a pharmaceutical composition containing pomalidomide or its pharmaceutically acceptable salt as an active substance, as well as sodium starch glycolate and pharmaceutically acceptable auxiliary compounds. The pharmaceutical composition is characterized by high bioavailability and stability in comparison with the registered drug "Imnovid". The proposed composition can be used to treat diseases and disorders associated with increased production of tumor necrosis factor.

Description

The technical field to which the invention belongs

The invention relates to the field of pharmaceutical industry and concerns a pharmaceutical composition containing pomalidomide or its pharmaceutically acceptable salt as an active substance, as well as sodium starch glycolate and pharmaceutically acceptable auxiliary compounds. The pharmaceutical composition is characterized by high bioavailability and stability. This composition can be used to treat diseases and disorders caused by impaired production of TNF (tumor necrosis factor).

State of the art

Tumor necrosis factor (TNF) is an extracellular protein, a multifunctional pro-inflammatory cytokine synthesized mainly by monocytes and macrophages. Excessive production of TNF causes hemodynamic disorders (reduces myocardial contractility, minute blood volume, diffusely increases capillary permeability), has a cytotoxic effect on body cells. Dysregulation of TNF in humans is associated with various diseases, such as:

arthritis (Keffer J., et al., (December 1991). Transgenic mice expressing human tumor necrosis factor: a predictive genetic model of arthritis. The EMBO Journal. 10(13):4025-31);

Alzheimer's disease (Swardfager W., et al., (2010). A meta-analysis of cytokines in Alzheimer's disease. Biol. Psychiatry. 68 (10): 930-941);

clinical depression (Dowlati Y., et al., (2010). A meta-analysis of cytokines in major depression. Biol. Psychiatry. 67(5): 446-457);

psoriasis (Victor F.C., Gottlieb A.B. (2002). TNF-alpha and apoptosis: implications for the pathogenesis and treatment of psoriasis. J. Drugs Dermatol. 1(3):264-75);

inflammatory bowel disease (Crohn's disease, ulcerative colitis) (Brynskov J., et al., (2002). Numor necrosis factor alpha converting enzyme (TACE) activity in the colonic mucosa of patients with inflamatory bowel desease. Gut. 51(1) :37-43).

TNF also plays a direct role in the activation of retroviral replication, including the HIV-1 retrovirus (Poll et al., AIDS Res. Hum. Retrovirus, 191-197 (1992)).

Numerous studies have shown that the concentration of TNF in serum is increased in patients with cancer of various forms [Ferrajoli A., et al. The clinical significance of tumor necrosis factor-alpha plasma level in patients having chronic lymphocytic leukemia. Blood. 2002; 100(4):1215-9, X. Wang, Y. Lin. Tumor necrosis factor and cancer, buddies or foes, Acta Pharmacol. sin. Nov. 2008; 29(11):1275-1288).

Pathologies associated with increased production of TNF are widespread and often fatal. This fact encourages researchers to develop new substances - TNF inhibitors. It is widely known (L. G. Corral, et al., Ann. Rheum. Dis. 58:(Suppl I), 1107-1113 (1999)) that thalidomide (2-(2,6-dioxopiperidin-3-yl)isoindol-1 ,3-dione) and lenalidomide (3-(4-amino-1-oxo-1,3dihydro-2H-isoindol-2-yl)piperidine-2,6-dione) have an inhibitory ability against TNF without immunosuppressive action. Despite the above fact, one of the urgent problems in the treatment of diseases associated with excessive production of TNF remains the development of drug resistance. Disease progression may occur after response to any type of therapy. Pomalidomide (4-amino-2-(2,6-dioxopiperidin-3-yl)isoindol-1,3-dione), the structural formula of which is presented below, is an immunomodulator - a third-generation TNF inhibitor. Pomalidomide was first described in an article by J0nsson, Acta Pharma. Suecica, 9, 521-542 (1972). In the patent literature, a method for the synthesis of pomalidomide is disclosed, for example, in US patent No. US 5635517:

NH ₂ o

[I \ V ^x0 λ—ΝΗ

Oh Oh

Structural formula of pomalidomide

Pomalidomide has a complex mechanism of action: immunomodulatory, antitumor, inhibiting TNF and suppressing angiogenesis.

The only drug with INN pomalidomide was registered in Russia in May 2015 under the trade name Imnovid (registration certificate number LP-002985; issue date 05/07/2015) for the treatment of adult patients with relapsed and refractory multiple myeloma who received at least two previous treatment regimens, including both lenalidomide and bortezomib, and who experienced disease progression during the last therapy. However, despite this, there is a constant need in the pharmaceutical industry to work on expanding the arsenal of means and methods for prescribing the drug, which includes the development of new various pharmaceutical compositions that positively affect the dissolution profile of the drug, bioavailability, bioequivalence, stability, etc. ., ensuring the therapeutic success of the drug.

When developing a formulation of a medicinal product containing pomalidomide, the reactivity of the main component should be taken into account. Having in its composition amino groups, pomalidomide

- 1 039874 exhibits potential reactivity towards excipients such as maltose, lactose, trehalose or glucose, for example mono- or disaccharides, by the Maillard reaction. In addition, free amino groups of pomalidomide can undergo acid hydrolysis, this fact should also be taken into account when choosing excipients. Thus, it is necessary to select excipients that not only do not destroy pomalidomide, but also additionally stabilize it, providing the necessary level of bioavailability.

US Pat. No. 8,158,653 discloses formulations containing pomalidomide:

tablets (50 and 100 mg) containing pomalidomide in an amount of about 40%, lactose - about 40%, other auxiliary components - in the required amount;

tablets for chewing 75 mg containing pomalidomide in the amount of 15%, mannitol - 46%, lactose - 30%, the remaining components - in the required amount;

10 mg tablets containing pomalidomide in an amount of 2.7%, lactose - 84%, other auxiliary components - in the required amount;

granules for hard gelatin capsules 100 mg containing pomalidomide in the amount of 71%, microcrystalline cellulose - 21.4%, other auxiliary components - in the required amount;

0.2% injection containing pomalidomide, sodium chloride, phosphate buffer solution.

In the description of the patent RU 2479307, the composition of the drug containing pomalidomide is disclosed, and the claims are protected in the form of hard gelatin capsules, covering the composition of the original drug Imnovid:

Table 1

Compositions of pomalidomide compositions according to patent RU 2479307

Component amount (mg per capsule) amount (mg per capsule) amount (mg per capsule) amount (mg per capsule) Pomalidomide 1,000 2,000 3,000 4,000 pregelatinized starch 70.00 140.00 100.80 134.40 Sodium fumarate 0.32 0.64 0.45 0.60 Mannitol (spray dried) 53.68 107.36 75.75 101.00 Capsule content weight 125.00 250.00 180.00 240.00

CN104042590 discloses a capsule formulation containing pomalidomide, lactose anhydrous, dextrin, croscarmellose sodium and polyethylene glycol 4000. It describes the use of two general mixtures: one mixture for 1 and 2 mg capsules and a second general mixture for 3 and 4 capsules/mg.

International application publication WO 2018/024646 discloses pharmaceutical compositions containing pomalidomide, maltodextrin and excipient, where the mass ratio of maltodextrin and excipient is in the range from 1:1 to 1:2.

table 2

Compositions of pomalidomide compositions according to the application WO 2018/024646

Component amount (mg per capsule) amount (mg per capsule) amount (mg per capsule) amount (mg per capsule) Pomalidomide 1,000 2,000 3,000 4,000 Microcrystalline cellulose 26,600 53,200 79,800 106.400 Maltodextrin 19.781 39.563 59.344 79.125 Sodium fumarate 0.119 0.238 0.356 0.475 Capsule content weight 47,500 95,000 142.500 190,000

Table 3

Compositions of pomalidomide compositions according to the application WO 2018/024646

Component amount (mg per capsule) amount (mg per capsule) amount (mg per capsule) amount (mg per capsule) Pomalidomide 1,000 2,000 3,000 4,000 Calcium lactate pentahydrate 25.89 51.78 77.66 103.550 Maltodextrin 19.07 38.14 57.21 76.275 Sodium croscarmellose 1.425 2,850 4.275 5,700 Sodium fumarate 0.119 0.238 0.356 0.475 Capsule content weight 47,500 95,000 142,500 190,000

International application publication WO 2018/150435 discloses a pharmaceutical composition containing pomalidomide and a binder or excipient in an amount of at most about 89%.

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Table 4

Compositions of pomalidomide compositions according to the application WO 2018/150435

Component amount (mg per capsule) amount (mg per capsule) amount (mg per capsule) amount (mg per capsule) Pomalidomide 1,000 2,000 3,000 4,000 Mannitol 40.00 80.00 60.00 80.00 Pre-desired starch 53.50 107.0 78.75 105.0 Sodium croscarmellose 15.00 30.00 22.50 30.00 Sodium fumarate 0.5 1,000 0.750 1,000 Capsule content weight 110.0 220.0 165.0 220.0

CN107982233 discloses a composition of controlled release tablets containing 1 to 10% pomalidomide, 50 to 90% hydrophobic matrix (glyceride, microcrystalline cellulose, wax, PEG), 1 to 5% binder and 0.5 to 5% lubricant. %.

CN107875128 discloses a composition in the form of an orodispersible tablet containing pomalidomide from 0.1 to 10%, from 20 to 90% of the filler, which is a mixture of lactose with mannitol or mannitol with xylitol in a ratio of from 2:1 to 6:1, disintegrant and fragrance.

Despite the disclosure in the patent literature of a large number of examples of pomalidomide compositions, only one drug with INN pomalidomide (Imnovid) is registered on the world market. In this regard, in order to expand the arsenal of drugs and methods for the treatment of multiple myeloma, as well as other diseases and disorders associated with increased TNF production, there is a need for new compositions of pomalidomide, which have no less high stability and improved bioavailability, in comparison with Imnovid ( INN pomalidomide).

Disclosure of invention

In the present invention, the authors unexpectedly found that the use of sodium starch glycolate together with pomalidomide or a pharmaceutically acceptable salt thereof allows the preparation of pharmaceutical compositions for the treatment of diseases and disorders associated with increased production of TNF (tumor necrosis factor). Moreover, the resulting compositions are characterized by no less high stability and improved bioavailability in comparison with Imnovid (INN pomalidomide, No. RU LP-002985 of 07.05.2015).

In this regard, the present invention is directed to a composition for the treatment of diseases and disorders associated with increased production of TNF, containing pomalidomide or its pharmaceutically acceptable salt in an amount of from 0.1 to 10% of the total weight of the composition, sodium starch glycolate in an amount of from 20 to 50% of the total weight of the composition and pharmaceutically acceptable auxiliary compounds in an amount of from 40 to 79.9% of the total weight of the composition.

In one embodiment of the invention, the composition contains, as pharmaceutically acceptable excipients, the usual pharmaceutically acceptable excipients adopted in drug preparation technology, such as binders, excipients, preservatives, flow regulators, softeners, wetting agents, dispersants, emulsifiers, solvents, antioxidants and / or propellants, action prolongators (Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgard, 1991; Handbook of Pharmaceutical Excipients, Pharmaceutical Press, 6th ^edition , 2009).

In another embodiment of the invention, the composition as pharmaceutically acceptable auxiliary compounds contains at least one filler selected from the group including wheat, potato, corn, rice starch, pregelatinized starch (for example, pregelatinized starch 1500), basic magnesium carbonate, magnesium oxide, sodium chloride, sodium bicarbonate, white clay, gelatin, microcrystalline cellulose, methylcellulose, sodium carboxymethylcellulose, calcium carbonate, calcium hydrogen phosphate dihydrate, calcium hydrogen phosphate anhydrous, glycine, dextrin, amylopectin, ultraamyl pectin, sorbitol, mannitol and pectin, and at least one anti-friction additive selected from the group including starches, talc, colloidal silicon dioxide, macrogol 4000 and 6000, stearic acid, magnesium and calcium stearates, sodium stearyl fumarate, sodium lauryl sulfate.

In a more preferred embodiment of the invention, the composition contains at least one filler, which is calcium hydrogen phosphate dihydrate, as well as at least one antifriction additive, which is colloidal silicon dioxide or sodium stearyl fumarate.

In the most preferred embodiment of the invention, the composition contains pomalidomide or its pharmaceutically acceptable salt in an amount of 0.6 to 4% of the total weight of the composition, sodium starch glycolate in an amount of 22 to 47% of the total weight of the composition, calcium hydrogen phosphate dihydrate in an amount of 45 to 70% of the total weight of the composition, colloidal silicon dioxide in an amount of 1 to 3% of the total weight of the composition and sodium stearyl fumarate in an amount of 0.5 to 1.5% of the total weight of the composition.

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In yet another embodiment of the invention, the composition is in the form of gelatin capsules, preferably containing gelatin, titanium dioxide and at least one colorant.

Brief description of figures and drawings

The figure shows the average release profiles of the active substance of the compositions of pomalidomide from the composition of the drug Imnovid 4 mg (Manufacturer Celgene International Sarl., Switzerland, Series C2168A) and the drug composition (pomalidomide 4 mg) described in example 3 (composition No. 003082018) of the present invention in the test comparative dissolution kinetics. Dissolution medium - 0.1 M hydrochloric acid solution. The time range for studying the release of the active substance is from 10 to 60 minutes.

Implementation of the invention

The claimed invention relates to a composition with the active substance pomalidomide, characterized by high stability of the active substance and higher bioavailability than the only registered drug Imnovid known in the prior art (INN pomalidomide, No. RU LP-002985 dated 07.05.2015).

The implementation of the present invention consists in the use of starch glycolate in the composition together with pomalidomide or its pharmaceutically acceptable sodium salt. Sodium starch glycolate unexpectedly stabilized the pomalidomide molecule in the composition, and also made it possible to provide pomalidomide in the composition with a bioavailability that exceeds the bioavailability of the known drug Imnovid. The discovery of the mentioned properties of sodium starch glycolate in relation to pomalidomide is not known from the prior art and was a complete surprise for the authors of the claimed invention, because the use of lactose, microcrystalline cellulose, povidone and maltodextrin instead of sodium starch glycolate had previously failed.

This invention relates to a composition for the treatment of diseases and disorders associated with increased production of TNF, containing pomalidomide or its pharmaceutically acceptable salt in an amount of from 0.1 to 10% of the total weight of the composition, sodium starch glycolate in an amount of from 20 to 50% of the total weight of the composition and pharmaceutically acceptable auxiliary compounds in an amount of from 40 to 79.9% of the total weight of the composition. At the above mass contents of sodium starch glycolate had a stabilizing effect on pomalidomide, and also ensured high bioavailability of pomalidomide in the composition.

Preferably, the composition may be in the form of tablets (enteric, modified release), combination tablets, capsules, dragees, coated granules, suppositories, suspensions. Dosage forms can be made in the traditional way (Pharmaceutical technology. Technology of dosage forms, 2nd ed., M., 2006).

Tablets and capsules are the most preferred forms of the composition due to the ease of administration to the body and the ease of implementation of the technical manufacturing process. In order to avoid the effect of water on the composition, the finished dosage form is produced in an anhydrous way. Also, in order to exclude side reactions between the active ingredient and auxiliary compounds, compounds that are sugars (lactose, glucose, sucrose) are not used as the latter or are used in sufficiently small quantities.

Preferably, the composition of the present invention is in the form of gelatin capsules, most preferably containing gelatin, titanium dioxide and at least one color.

The composition of the invention may be administered orally or parenterally in the usual manner. The dosage depends on the age, condition and weight of the patient, as well as on the type of administration.

The pomalidomide molecule, as well as the method for its preparation, is described in US Pat. No. US5,635,517. Dosages of pomalidomide in the composition of the present invention can be from 0.1 to 10 mg per unit composition. The most preferred dosages of pomalidomide may be from 1 to 4 mg per unit composition.

As pharmaceutically acceptable salts of pomalidomide, suitable acid addition salts containing the anion of a pharmaceutically acceptable acid, as defined in the USP, may be selected. For example, pomalidomide hydrochloride or pomalidomide sulfate can be selected as pharmaceutically acceptable salts of pomalidomide. Pharmaceutically acceptable acid additive salts of pomalidomide, as well as methods for their preparation, are disclosed in the publication of international application WO 2011/050962 dated 05.05.2011.

Sodium Starch Glycolate can be used in all available brands (Primojel, Vivastar, Explosol, Explotab) and meet USP or EP requirements as defined in the relevant article for this excipient (Handbook of Pharmaceutical Excipients, Pharmaceutical Press, 6th ^edition , 2009 , pp. 663-666).

As pharmaceutically acceptable excipients, the composition of the present invention may contain conventional pharmaceutically acceptable excipients adopted in drug preparation technology, such as binders, fillers, preservatives, flow regulators, anti-friction additives, softeners, wetting agents, dispersants, emulsifiers, solvents, antioxidants. and/or propellants, action prolongators (Sucker et al.:

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Pharmazeutische Technologie, Thieme-Verlag, Stuttgard, 1991; Handbook of Pharmaceutical Excipients,

Pharmaceutical Press, 6th ^edition , 2009).

As pharmaceutically acceptable auxiliary compounds, for example, sugars and their derivatives (lactose, modified lactose, sucrose, glucose, mannitol, modified mannitol, sorbitol, fructose), polysaccharides (cellulose and its derivatives, starch, modified starch, dextrin, dextrose) can be used. , dextrate, maltodextrin, calcium salts (phosphates, carbonates, chlorides), magnesium compounds (oxide, carbonate, stearate), crospovidone, copovidones, cyclodextrins, alginic acid and its salts, saccharin and its salts, sodium salts (chloride, citrate, fumarate , carbonate), aspartame, lactic acid and its salts, succinic acid, ascorbic acid, tartaric acid, colloidal silicon dioxide, cyclamate, benzoic acid and its salts, parabens and their salts, low-substituted hyprolose (hydroxypropyl cellulose), cellulose ethers (alkyl esters celluloses such as ethylcellulose, ethylmethylcellulose, ethylpropylcellulose, isopropylcellulose, butylcellulose, etc.;aralkyl ethers celluloses such as benzylcellulose and the like; cyanoalkyl cellulose ethers such as cyanoethyl cellulose and the like), cellulose esters (esters of cellulose and organic acids such as cellulose acetate butyrate, cellulose acetate, cellulose propionate, cellulose butyrate, cellulose acetate propionate and the like), copolymers methacrylic acid-acrylic acid, polysorbate 80 (for example, TWEEN-80 brand polysorbate), macrogol 6000 (polyethylene glycol 6000) and many others.

Preferably, the total content of the above pharmaceutically acceptable auxiliary compounds in the composition of the present invention is from 40 to 79.9% of the total weight of the composition.

In a preferred embodiment, the composition of the present invention contains, as pharmaceutically acceptable auxiliary compounds, at least one filler selected from the group including wheat, potato, corn, rice starch, basic magnesium carbonate, pregelatinized starch (for example, pregelatinized starch 1500), magnesium oxide , sodium chloride, sodium bicarbonate, white clay, gelatin, microcrystalline cellulose, methyl cellulose, sodium carboxymethyl cellulose, calcium carbonate, calcium hydrogen phosphate dihydrate, calcium hydrogen phosphate anhydrous, glycine, dextrin, amylopectin, ultraamyl pectin, sorbitol, mannitol and pectin.

Preferably, the content of fillers in the composition is from 28 to 75% of the total weight of the composition.

The most preferred excipient is calcium hydrogen phosphate dihydrate, which is a highly stable and non-hygroscopic material, which is important in the production of preparations with moisture sensitive active ingredients, has excellent flowability and is suitable as a capsule filler.

In a preferred embodiment, the composition of the present invention contains, as pharmaceutically acceptable auxiliary compounds, at least one antifriction additive selected from the group including starches, talc, colloidal silicon dioxide, macrogol 4000 and 6000, stearic acid, magnesium and calcium stearates, sodium stearyl fumarate , sodium lauryl sulfate.

Preferably, the content of anti-friction additives in the composition is from 0.2 to 4.5% of the total weight of the composition.

In a more preferred embodiment of the invention, the composition contains at least one filler, which is calcium hydrogen phosphate dihydrate, as well as at least one antifriction additive, which is colloidal silicon dioxide or sodium stearyl fumarate.

In the most preferred embodiment of the invention, the composition contains pomalidomide or its pharmaceutically acceptable salt in an amount of 0.6 to 4% of the total weight of the composition, sodium starch glycolate in an amount of 22 to 47% of the total weight of the composition, calcium hydrogen phosphate dihydrate in an amount of 45 to 70% of the total weight of the composition, colloidal silicon dioxide in an amount of 1 to 3% of the total weight of the composition and sodium stearyl fumarate in an amount of 0.5 to 1.5% of the total weight of the composition.

Ethyl alcohol, starch paste, solutions of carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, povidone, alginic acid, sodium alginate, gelatin, etc. can be used as binders.

Wheat starch, potato starch, corn starch, rice starch, pectin, gelatin, crystalline microcellulose, sodium carboxymethylcellulose, amylopectin, ultramylopectin, agar-agar, alginic acid, potassium and sodium alginate, a mixture of sodium bicarbonate with citric or tartaric acid, polysorbates.

As antifriction additives, it is advisable to introduce the following components: starches, talc, colloidal silicon dioxide (Aerosil), macrogol 4000 and 6000, stearic acid, magnesium and calcium stearates, sodium stearyl fumarate, sodium lauryl sulfate.

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It is preferable to use sodium stearyl fumarate as antifriction additives, since, compared to others, it significantly increases the ejection force and the disintegration time of the active component from the finished dosage form, which improves the characteristics of the drug, such as solubility and bioavailability. The content of sodium stearyl fumarate in the finished dosage form is usually not more than 4%.

Xylitol, mannitol, erythritol, glycine, essential oils, menthol, vanillin, ethylvanillin, fruit essences, dyes, pigments, plasticizers (glycerin, polysorbates, vaseline oil, oleic acid, propylene glycol), prolongators (wax, vegetable oil) can be used as flavoring agents. , monopalmitin, trilaurin, paraffin), as well as solvents (purified water, ethyl alcohol, acetone, chloroform, ammonia, hydrochloric acid).

Colloidal silicon dioxide is preferred as an anti-adherent agent, being an inert compound and providing a sliding and loosening effect, and also facilitates the granulation process by improving the fluidity of the mass. The content of silicon dioxide in the finished form is usually not more than 5%.

The qualitative and quantitative composition of the claimed pharmaceutical composition is determined experimentally and is optimal. The finished dosage form demonstrates the rapid and complete release of the active substance.

The pharmaceutical composition obtained according to the invention, containing pomalidomide as an active substance, is intended for the treatment of diseases caused by a violation of the production of TNF, which include, but are not limited to, the following: cancer, disorders associated with angiogenesis, pain, including complex regional pain syndrome, macular degeneration and related syndromes, skin diseases, asbestos-related diseases, parasitic diseases, immunodeficiencies, CNS disorders, CNS damage, atherosclerosis and related disorders, sleep disorder and related disorders, hemoglobinopathies and related disorders (eg anemia), arthritis, arthrosis , Alzheimer's disease and other TNF-related disorders and disorders.

Examples

The examples below illustrate (without limiting the scope of claims) the most preferred embodiments of the invention, and also confirm the possibility of obtaining the claimed pharmaceutical composition of pomalidomide and achieving the indicated technical results for it.

Example 1. Technology for obtaining capsules containing pomalidomide.

Pre-weighed raw materials are loaded into the mixing tank of the gravity mixer in the following sequence: sodium starch glycolate, pomalidomide (or its salt), binders, lubricants (for example, sodium stearyl fumarate, magnesium stearate and other surfactants), anti-friction additives (for example, silicon dioxide colloidal or talc). Next, stirring is carried out for 5 minutes at a speed of 30 rpm. The required amount of filler(s) (eg calcium hydrogen phosphate dihydrate, calcium carbonate, microcrystalline cellulose) is then added to the resulting mixture and mixed again for 3 minutes at a speed of 30 rpm. The resulting mixture is sieved through a sieve with a nominal opening size of 5 mm. The sifted mixture is loaded back into the capacity of the gravity mixer and mixed for 3-5 minutes at a speed of 30 rpm. The resulting mixture was filled into hard gelatin capsules (eg No. 2 or 3).

Example 2. Technology for obtaining tablets containing pomalidomide.

Pomalidomide was micronized in a water–alcohol (1:1) solution of the necessary binders, flow regulators, wetting agents, antioxidants, and action prolongators for 10 min. The resulting suspension was mixed with the necessary fillers. The resulting granulate was dried at a temperature of 45°C in a spray dryer to a residual moisture content of not more than 2.0%. The dried granulate was calibrated through a vibrating sieve, for example 30 mesh, mixed and powdered in a cone mixer until smooth. From the powdered granulate, tablet cores were obtained. The tablets were then, if necessary, film-coated in a coating plant by spraying an aqueous film coating dispersion at a temperature of 50°C.

Example 3 Compositions of pomalidomide in the form of capsules.

Based on the procedure for obtaining the composition of pomalidomide in the form of capsules from example 1, the following compositions were obtained.

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Table 5

Compositions of pomalidomide compositions No. 001082018, 002082018 and 003082018___________

Component №001082018, mg (%) №002082018, mg (%) №003082018, mg (%) Pomalidomide 1 (0.8) 3(2,3) 4(3.1) Calcium hydrogen phosphate dihydrate 79.6 (61.2) 77.6 (59.7) 76.6 (58.9) sodium starch glycolate 45.5 (35) 45.5 (35) 45.5 (35) Silicon dioxide colloidal 2.6(2) 2.6(2) 2.6(2) Sodium stearyl fumarate 1.3 (1) 1.3 (1) 1.3 (1) Capsule content weight 130.0 130.0 130.0

Table 6 Composition of pomalidomide No. 004082018

Component mg (%) Pomalidomide 10(10) calcium carbonate 38.5 (38.5) sodium starch glycolate 50(50) Sodium stearyl fumarate 1.5 (1.5) Capsule content weight 100.0

Table 7 Composition of pomalidomide No. 013072018

Component mg (%) Pomalidomide 0.5 (0.2) Calcium hydrogen phosphate dihydrate 93.8 (40.8) sodium starch glycolate 115 (50) Talc 2.3(1) Croscarmellose sodium 16.1 (7) Sodium stearyl fumarate 2.3(1) Capsule content weight 230.0

Example 4 Compositions of pomalidomide in the form of capsules.

Based on the procedure for preparing the composition of pomalidomide in the form of capsules and example 1, the following formulations were obtained containing pomalidomide in an amount of 4 mg.

Table 8

Compositions of pomalidomide compositions No. 005082018,

006082018 and 007082018

Component №005082018, mg (%) №006082018, mg (%) №007082018, mg (%) Pomalidomide 4 (3.3) 4 (3.3) 4(3,3) sodium starch glycolate 24 (20) 48 (40) 42 (35) Mannitol 88.4 (73.7) 63.8 (53.2) 70.4 (58.7) Silicon dioxide colloidal 2.4(2) 3(2.5) 3 (2.5) magnesium stearate 1.2(1) 1.2(1) 0.6 (0.5) Capsule content weight 120.0 120.0 120.0

Table 9

Compositions of pomalidomide compositions No. 001072018, 02072018 and 03072018

Component Pomalidomide Sodium Starch Glycolate Xylitol No. 001072018, mg (%) 4(2.7) 70.5 (47) 66.5 (44.3) №002072018, mg (%) 4(3.3) 48 (40) №003072018, mg (%) 4 (3.3) 36 (30) Microcrystalline cellulose - 62.6 (52.2) 74.6 (62.2) Silicon dioxide colloidal 3(2) 2.4(2) 2.4(2) Stearic acid 6(4) 3 (2.5) 3(2.5) Capsule content weight 150.0 120.0 120.0

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Table 10

Compositions of compositions of pomalidomide No. 004072018, 005072018 and 006072018

Component No. 004042018, MG(%) №005072018, mg (%) No. 006072018, MG (%) Pomalidomide 4(3.1) 4(3.1) 4(3.1) sodium starch glycolate 45.5 (35) 26 (20) 65(50) Starch 1500 pregelatinized 76.6 (58.9) 94.8 (72.9) 57.1 (43.9) Talc 2.6(2) 3.25 (2.5) 2.6(2) Sodium stearyl fumarate 1.3 (1) 1.95 (1.5) 1.3 (1) Capsule content weight 130.0 130.0 130.0

Table 11

Compositions of pomalidomide compositions No. 007072018, 008072018 and 009072018

Component №007072018, mg (%) №008072018, mg (%) №009072018, mg (%) Pomalidomide 4(2.7) 4(2.7) 4 (2.7) sodium starch glycolate 49.5 (33) 52.5 (35) 37.5 (25) Potato starch 83 (55.3) 82.25 (54.8) 97.25 (64.8) Polyvinylpyrrolidone 10.5 (7) 6.75 (4.5) 6.75 (4.5) Silicon dioxide colloidal 1.5(1) 3(2) 3(2) Sodium stearyl fumarate 1.5(1) 1.5(1) 1.5(1) Capsule content weight 150.0 150.0 150.0

Table 12

Compositions of compositions of pomalidomide No. 010072018, 011072018 and 012072018

Component №010072018, mg (%) No. 011072018, MG (%) №012072018, mg (%) Pomalidomide 4 (2.7) 4 (2.7) 4 (2.7) sodium starch glycolate 75(50) 70.5 (47) 33 (22) Magnesium carbonate basic 62 (41.3) - 96.5 (64.3) Sorbitol - 68 (45.3) - Sodium salt of carboxymethyl cellulose - - 7.5 (5) Silicon dioxide colloidal 3(2) 4.5(3) 4.5(3) Sodium stearyl fumarate 6(4) 3(2) 4.5(3) Capsule content weight 150.0 150.0 150.0

Table 13

Compositions of compositions of pomalidomide No. 014072018, 015072018 and 016072018

Component №014072018, mg (%) №015072018, mg (%) №016072018, mg (%) Pomalidomide 4(3,3) 4(3,3) 4 (3.3) sodium starch glycolate 60(50) 48(40) 42 (35) Mannitol 88.4 (73.7) 63.8 (53.2) 70.4 (58.7) Silicon dioxide colloidal 2.4(2) 1.2 (1) 3.6(3) Sodium stearyl fumarate 1.2(1) 1.8 (1.5) 0.6 (0.5) Capsule content weight 120.0 120.0 120.0

- 8 039874

Table 14

Compositions of compositions of pomalidomide No. 017072018 and 018072018

Component №017072018, mg (%) №018072018, mg (%) Pomalidomide 4(3.1) 4(3.1) Calcium hydrogen phosphate dihydrate 94.15 (72.4) 65.55 (50.4) sodium starch glycolate 26 (20) 58.5 (45) Silicon dioxide colloidal 3.9(3) 1.3 (1) Sodium stearyl fumarate 1.95 (1.5) 0.65 (0.5) Capsule content weight 130.0 130.0

Table 15

Compositions of compositions of pomalidomide No. 019072018 and 020072018

Component №019072018, mg (%) №020072018, mg (%) Pomalidomide 4(3.1) 4(3.1) Calcium hydrogen phosphate dihydrate 59.05 (45.4) (58.9) sodium starch glycolate 65 (50) 52 (40) Silicon dioxide colloidal 1.3(1) 2.6(2) Sodium stearyl fumarate 0.65 (0.5) 1.3(1) Capsule content weight 130.0 130.0

Example 5 Compositions of pomalidomide in the form of tablets.

Based on the procedure for obtaining the composition of pomalidomide in the form of tablets from example 2, the following compositions were obtained.

Table 16

Compositions of pomalidomide compositions No. 021072018, 022072018 and 023072018

Component №021072018, mg (%) №022072018, mg (%) №023072018, mg (%) Pomalidomide 1 (0.7) 3 (2.1) 4.0 (2.8) Calcium hydrogen phosphate dihydrate 79.6 (54.9) 77.6 (53.5) 76.6 (52.8) sodium starch glycolate 45.5 (31.4) 45.5 (31.4) 45.5 (31.4) Povidone 8.3 (5.7) 8.3 (5.7) 8.3 (5.7) Silicon dioxide colloidal 2.6 (1.8) 2.6 (1.8) 2.6 (1.8) Sodium stearyl fumarate 1.3 (0.9) 1.3 (0.9) 1.3 (0.9) Opadry shell (orange) 6.7 (4.6) 6.7 (4.6) 6.7 (4.6) Capsule content weight 145.0 145.0 145.0

Example 6 Comparative dissolution kinetics study.

A comparative dissolution kinetics test was carried out using capsule formulations containing 4 mg of pomalidomide (Formulation No. 003082018 from Example 3 and all formulations from Example 4) of the present invention and Imnovid 4 mg manufactured by Celgene International Sarl., Switzerland, Series C2168A (No. RU LP-002985 dated 07.05.2015). The study was carried out according to the General Pharmacopoeia. 1.4.2.0014.15 Dissolution for solid dosage forms on an ERWEKA DT 820 paddle mixer at a rotation speed of 50 rpm at a temperature of 37±0.5°C. Dissolution medium - 0.1 M hydrochloric acid solution. The volume of the dissolution medium is 900 ml. Sampling time points: 10, 15, 20, 30, 45 and 60 min. The released pomalidomide was quantified by HPLC.

According to the test results, it was found that the release of at least 90% of the active substance from the compositions of the present invention occurs over a period of time not exceeding 30 minutes, while the release of at least 90% of the active substance from the composition of Imnovid 4 mg occurs over a longer period of time - 40 min.

The figure shows the average release profiles of the active substance of the compositions of pomalidomide from the composition of the drug Imnovid 4 mg (Manufacturer Celgene International Sarl., Switzerland, Series C2168A) and the drug composition (pomalidomide 4 mg) described in example 3 (composition No. 003082018) of the present invention in the test comparative dissolution kinetics. Dissolution medium - 0.1 M hydrochloric acid solution. The time range for studying the release of the active substance is from 10 to 60 minutes. The named figure very clearly demonstrates the advantages of the compositions of the present invention in terms of more efficient release of the active substance, namely, according to the presented figure, the release of pomalidomide from the composition according to example 3 (composition No. 003082018) was 65% after 10 minutes, 80% after 15 minutes, 85 % after 20

-9039874 min, 91% after 30 min, 94% after 45 min and 95% after 60 min, while the release of pomalidomide from Imnovid 4 mg was: 62% after 10 min, 77% after 15 min, 83% after min, 88% after 30 min, 91% after 45 min and 92% after 60 min.

In the light of the foregoing, the compositions of the present invention have an advantage in terms of the bioavailability of pomalidomide compared to the registered drug Imnovid (No. RU LP-002985 dated May 07, 2015), since they allow more efficient release of pomalidomide from the lekform, and, consequently, deliver pomalidomide to the patient's body.

Example 7 Comparative Stability Study of Pomalidomide Compositions.

The stability of pomalidomide compositions under accelerated aging conditions was evaluated at 40°C/75% relative humidity and the content of impurities was determined for 0; one; 3 and 6 months (from August 2018 to February 2019). All samples from examples 3, 4 according to the present invention were subjected to the study. As the pomalidomide composition for comparison (comparison composition), Imnovid 4 mg preparation composition (Manufacturer Celgene International Sarl., Switzerland, Series C2168A) was used.

To determine the content of impurities in pomalidomide compositions, HPLC was used under the following conditions:

Speaker

mobile phase

Zorbax SB - CN, 250 x 4.6 mm, particle size 5 µm

Mobile phase A : Mobile phase B = 90 :10

Na octanesulfonate AcN:MeOH =50:50

KH2RO4

As a result of studying the stability of pomalidomide compositions, the impurity values obtained for the pomalidomide compositions of the present invention and the reference composition were below the sensitivity limit of the method during the entire period of the study. The data obtained indicate that the compositions of the present invention are characterized by excellent stability and are not inferior in this indicator to the original registered preparation of pomalidomide Imnovid (No. RU LP-002985 of 05/07/2015). Thus, one of the claimed technical results of the invention is achieved - high stability of pomalidomide compositions, which is not inferior to the original registered drug.

Example 8 Comparative bioavailability study of pomalidomide formulations in healthy volunteers.

Start date of the study: 11/01/2018.

Date of completion of the study: 12/12/2018.

Date of preparation of the study report: 03/07/2019.

Purpose of the study: To compare the bioavailability of the pomalidomide composition of the invention (Example 3, Formulation No. 003082018) and the pomalidomide composition of Imnovid 4 mg (Celgene International Sarl., Switzerland, Series C2168A) in healthy volunteers.

Methodology: Single-centre, randomized, open-label, two-period, two-dose, cross-over comparative bioequivalence study in healthy male volunteers, conducted under fasted medication conditions.

Number of patients: Screened - 34; randomized - 30; received the drug in the period I - 30; received the drug in period II - 29; excluded - 0; dropped out - 1; completed - 29; included in the pharmacological analysis - 29; included in the statistical analysis - 29.

Diagnosis and main criteria for inclusion of volunteers in the study: All volunteers included in the study were found to be healthy according to the results of a standard clinical and laboratory examination and met all inclusion / exclusion criteria.

Criteria for inclusion of volunteers.

1. Healthy non-smoking male volunteers aged 18 to 45 inclusive.

The concept of healthy is defined as the absence of abnormalities identified from the medical history, as well as during standard clinical, laboratory and instrumental examinations.

2. Availability of a signed and dated clinical study participant information sheet with an informed consent form.

3. Body mass index from 18.5 to 30 kg / m ²

Flow rate Column temperature Detector Sample volume ml/min °C spectrophotometric 210 nm µl

Chromatography time 50 min

4. Male volunteers must agree to use double barrier methods of contraception throughout the study and for 7 days after the last dose.

Duration of use: The total duration of the volunteer's participation in the study, including the screening period, was no more than 25 days. There were two periods of about an hour each (Day 0/Day 7 (hospitalization at least 12 hours prior to taking one of the study drugs) and ending on Day 3/Day 10 (48 hours after taking the drug). Washout period between days taking the drug was 7 days.

Analytical methods: Method - HPLC-MS; analyte - Pomalidomide; calibration curve range - 0.5-200 ng/ml.

Sampling: In each period, blood samples were collected in a volume of -5 ml, in the amount of 15 samples according to the scheme: 0 h, 0.5 h (30 min), 1 h, 1.5 h (1 h 30 min), 2 h, 2.5 h (2 h 30 min), 3 h, 3.5 h (3 h 30 min), 4 h, 6 h, 8 h, 10 h, 12 h, 24 h, 48 h from the moment of administration drug.

Pharmacokinetic analysis: based on the obtained data on the concentration of pomalidomide at various time points (curves of concentration-time), the following bioavailability parameters were determined: AUC _0-t , AUC _0-/ , AUC _extrap %.

Study Results: The table below summarizes the bioavailability parameters of the studied pomalidomide formulations.

Table 17

Generalized Bioavailability Parameters of Pomalidomide Compositions

Parameter Unit. Composition No. 003082018 N=29 Imnovid* 4mg N=29 AU Co-t ^a nghh/ml 301.7874177.47717 291.9333166.49478 AUCo- ^a nghh/ml 323.4321186.19586 306.3437169.43613 AUCextrap/%' % 6.4213.044 4.7012.250 a - presented as MiSD, M - arithmetic mean, SD - standard deviation

According to the results of the study of the bioavailability of the composition of pomalidomide from example 3 (composition No. 003082018) according to the present invention (test drug) in comparison with the composition of the drug Imnovid pomalidomide 4 mg (comparator drug), the bioavailability of the study drug is at least 3% higher than the bioavailability of the comparator drug. In this regard, the present invention provides pomalidomide compositions that are not inferior in bioavailability to the well-known registered drug Imnovid pomalidomide (No. RU LP-002985 dated May 07, 2015), and even slightly surpass it. Thus, one of the claimed technical results of the invention is achieved - an increase in the bioavailability of pomalidomide in the compositions.

CLAIM

Claims (3)

CLAIM 1. Pharmaceutical composition for the treatment of diseases and disorders associated with increased production of tumor necrosis factor (TNF) in the human body, containing pomalidomide or its pharmaceutically acceptable salt in an amount of 0.1 to 10% of the total mass of the composition, sodium starch glycolate in an amount from 20 to 50% of the total weight of the composition, pharmaceutically acceptable auxiliary compounds containing at least one excipient selected from the group including wheat, potato, corn, rice starch, pregelatinized starch, basic magnesium carbonate, magnesium oxide, microcrystalline cellulose, methylcellulose , sodium salt of carboxymethylcellulose, calcium carbonate, calcium hydrogen phosphate dihydrate, calcium hydrogen phosphate anhydrous, sorbitol, xylitol, mannitol, polyvinylpyrrolidone, and at least one anti-friction additive selected from the group including talc, colloidal silicon dioxide, stearic acid, magnesium and calcium stearates , sodium stearyl fum arate, sodium lauryl sulfate, in an amount of 40 to 79.9% of the total weight of the composition. 2. The composition according to claim 1, which contains pomalidomide or its pharmaceutically acceptable salt in an amount of from 0.6 to 4% of the total weight of the composition, sodium starch glycolate in an amount of from 22 to 47% of the total weight of the composition, calcium hydrogen phosphate dihydrate in the amount of from 45 to 70% of the total weight of the composition, colloidal silicon dioxide in an amount of 1 to 3% of the total weight of the composition and sodium stearyl fumarate in an amount of 0.5 to 1.5% of the total weight of the composition. 3. Composition according to any one of claims 1, 2, which is made in the form of gelatin capsules containing gelatin, titanium dioxide and at least one dye.