CZ2018150A3 - Pharmaceutical compositions for immediate release of drug - Google Patents

Abstract

Disclosed are pharmaceutical compositions for immediate release of a drug comprising a metastable form of a pharmaceutically active agent and / or a pharmaceutically active agent in a form at a higher dissolution rate when administered on an empty stomach than after a meal, and further comprising an ionic polymer that serves to balance the dissolution rate difference a pharmaceutically active substance when choosing a different solid form and / or when administered on an empty stomach or after a meal.

Description

Technical field

The invention relates to immediate release pharmaceutical compositions comprising fast-dissolving (metastable) forms of the active substances and / or the pharmaceutically active substance in a form with a higher dissolution rate in the fasted state than after a meal.

BACKGROUND OF THE INVENTION

The bioavailability of pharmaceutically active substances (APIs) depends primarily on whether the product is crystalline or amorphous. The amorphous product is usually more rapidly soluble, but often it cannot be obtained in an adequate quality and is also less stable physically and chemically. In contrast, the crystalline product is usually stable compared to the amorphous form, easier to obtain, and more slowly to dissolve. Polymorphism, i.e. the ability to form more than one crystalline form, is very common in pharmaceutically active substances. The individual solid forms have different molecular configurations and hence different physicochemical properties. Solvent molecules may also be part of the crystalline lattice, such as hydrated forms (the solvent is water) or solvated (the solvent is another organic substance). Several solid state analytical methods can be used to distinguish them from one another, for example, X-ray powder diffraction, solid state NMR, Raman spectroscopy, as well as thermoanalytical methods.

Because of the too low solubility of the thermodynamically most stable form or other limitations, lower melting point crystalline forms are often used in immediate-release pharmaceutical compositions, where a different crystal arrangement guarantees higher solubility of the crystalline form. However, such crystalline forms may, under certain conditions, be converted to the most stable crystalline form and therefore may be referred to as metastable polymorphic forms. In the same way, an amorphous form can be seen, which can spontaneously convert to a more stable crystalline form.

The solubility of many pharmaceutically active substances and their forms, whether crystalline or amorphous, often depends on pH. Generally, low pH in the stomach increases with food intake, which in some active substances results in a different rate of dissolution from fasting conditions when administered to patients. This effect may be exacerbated by the use of a metastable form of the active ingredient. All this causes a number of problems in the development of the final dosage form, especially with regard to the requirement of bioequivalence of the original and generic product.

Thus, there remains a need in the art for a simple method to compensate for differences in solubility of each form of the same substance, regardless of whether the drug is administered to the patient on an empty stomach or after a meal. It is also desirable to find pharmaceutical formulations which allow the solubility of the pharmaceutically active substance to be adjusted, in particular by retarding the dissolution of the metastable solid form of the pharmaceutically active substance, so as to achieve comparable properties to the reference preparation (bioequivalence).

SUMMARY OF THE INVENTION

Surprisingly, it has been found within the scope of the present invention that both of these technical problems can be solved by providing an immediate release pharmaceutical composition in which an ionic polymer is used as the filler or one of the fillers in an amount that does not form a matrix system. As shown in the examples, the effect of the ionic polymer is independent of the pharmaceutically active agent.

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The present invention provides an immediate release pharmaceutical composition comprising a metastable form of a pharmaceutically active agent and / or a pharmaceutically active agent in a form with a higher dissolution rate in the fasted state than after a meal in admixture with an ionic polymer.

In the context of the present invention, the term "metastable form" means a solid form of a pharmaceutically active substance having a lower melting point or a higher solubility or dissolution rate than its other solid form. The various solid forms of a single substance include both its crystalline forms, which may be hydrated or solvated, and the amorphous form.

The term "pharmaceutically active substance in a form with a higher dissolution rate when administered in the fasting state than after a meal" means a form of a pharmaceutically active substance which when administered to a patient or undergoing a dissolution test in the absence of an ionic polymer fasting, respectively. at a pH of 1.6 in a dissolution test than when administered after a meal, respectively. at pH 5 in a dissolution test.

Examples of pharmaceutically active substances capable of forming metastable forms include axitinib, apremilast, agomelatine, atorvastatin, baricitinib, canagliflozin, ceritinib, clopidogrel, dapagliflozin, darunavir, elagolix, febuxostat, ibrutinib, imatinib, ivabradine, lesinuret, lesinurad, lesinurad. In a preferred embodiment, the pharmaceutically active agent is axitinib, preferably crystalline form IV of axitinib, or apremilast, preferably amorphous apremilast.

For example, five unsolvated forms (forms I, IV, VI, XXV, XLI), two hydrates, and sixty-five solvated forms have been described for an axitinib molecule (see Campeta et al. J. Pharm. Sci., 99 (9), 2010, 3874 -86). The thermodynamically most stable solid form with the highest melting point is the unsolvated form XLI, all other forms described having a lower melting point and hence higher solubility or dissolution rate, and thus fall within the definition of a metastable polymorphism of the form.

Similarly, for the apremilast molecule, Celgene described in total international patent application WO 2009/120167 a total of seven different crystalline forms, referred to as A-G, and additionally an amorphous form. Form B, which is the unsolvated crystalline form of the free base, is considered to be the most stable form.

Although exemplified herein are pharmaceutically active agents capable of forming metastable forms, the feasibility and effects of the invention are not limited to these pharmaceutically active agents. The feasibility and effects of the invention are not limited to certain structures of pharmaceutically active substances. The present results obtained by the inventors show that the effects of the invention are due to the modification of the pharmaceutical formulation by the presence of an ionic polymer in an amount lower than the amount to form the matrix system, and not caused by the reaction, interaction or structure.

Ionic polymers are polymer chains that contain functional groups that can be protonated or deprotonated depending on the pH of the environment. This ability, among other things, significantly affects the solubility of these polymers throughout the pH range. Pharmaceutically useful ionic polymers include, in particular, cellulose derivatives, polyacrylate and methacrylate copolymers, polyvinyl derivatives. The cellulose derivatives are preferably cellulose esters or hydroxypropylmethyl cellulose esters, more preferably selected from the group comprising cellulose acetate phthalate (CAP); hydroxypropylmethyl cellulose phthalate (HPMCP); hydroxypropylmethyl cellulose acetate succinate (HPMCAS); cellulose acetate butyrate (CAB). The copolymers of polyacrylates or methacrylates are preferably selected from methacrylic acid-methyl methacrylate copolymers, in particular in a ratio of 1: 1 (e.g. the trade name Eudragit L100) or 1: 2 (e.g. the trade name Eudragit S100), cationic copolymers based on dimethylaminoethyl methacrylates, butyl methacrylates and methyl methacrylates, in particular in a 2: 1: 1 ratio (e.g., the trade name Eudragit E100, Eudragit EPO), methacrylic acid copolymer and ethyl acrylate (e.g., the trade name Eudragit LI00-55). In particular, the polyvinyl derivatives include

Polyvinyl acetate esters, preferably polyvinyl acetate phthalate (PVAP).

In a particularly preferred embodiment, the ionic polymer is a cellulose derivative, particularly preferably hydroxypropylmethyl cellulose acetate succinate (HPMCAS), which is commercially available e.g. under the trade names AQOAT, AquaSolve ™ or AFFINISOL ™.

Preferably, the pharmaceutical composition comprises an ionic polymer in an amount of 3 to 33 wt% based on the total weight of the composition. In a preferred embodiment, the pharmaceutical composition comprises an ionic polymer in an amount of 15 to 25% by weight, most preferably less than 20% by weight, based on the total weight of the composition. The particular amount is selected depending on the metastable form of the pharmaceutically active substance used or the form of the pharmaceutically active substance with a higher dissolution rate when administered in the fasting state than after a meal, i.e. the desired rate of dissolution retardation. The only rule is that the polymer is not present in an amount sufficient to form the matrix system.

Preferably, the composition comprises at least one additional pharmaceutically acceptable excipient selected from the group consisting of fillers, binders, disintegrants, lubricants, and flow-enhancing materials. Preferred fillers are potassium carbonate, potassium phosphate, cellulose and its derivatives, lactose, mannitol, starch, sucrose and talc. Preferred binders are potassium carbonate, copovidone, dextrose, ethylcellulose, gelatin, glucose, cellulose derivatives, lactose, povidone, polyethylene oxide, polymethacrylates, povidone, starch and derivatives thereof. Preferred disintegrants are alginic acid, chitosan, colloidal silica, croscarmellose sodium, crospovidone, hydroxyproply cellulose, hydroxypropyl starch, pregelatinized starch, povidone, maltose. Preferred lubricants are potassium stearate, magnesium stearate, mineral oils, palmitic acid, poloxamer, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearate, talc and hydrogenated vegetable oil. Preferred flowability materials are alumina, hypromellose, poloxamer, potassium phosphate, potassium silicate, colloidal silica, magnesium oxide, magnesium silicate, maltodextrin, and talc.

In a preferred embodiment, the pharmaceutical composition of the invention comprises 0.5 to 50 wt. % of the metastable form of the active substance or the form of the pharmaceutically active substance with a higher dissolution rate when administered in the fasting state than after a meal; % filler, 5 to 20 wt. % disintegrant, 0 to 15 wt. % binder, and 0 to 2 wt. lubricant. The ionic polymer is present as part of the filler in the abovementioned amount of 3 to 33% by weight, based on the total weight of the composition.

In the context of the present invention, the pharmaceutical composition is a solid dosage form for oral administration. Examples of such dosage forms include tablets, capsules, powders, pellets or granules. A preferred dosage form is a capsule or tablet.

An immediate release (IR) pharmaceutical composition is generally understood to mean a composition in which the release of the active ingredient occurs immediately after administration of the formulation. As defined by the European Medicines Agency, immediate release means that at least 75% of the active substance is released within 45 minutes under defined conditions (see Reflection on the dissolution specification for generic solid immediate release products with systemic action, http: //www.ema). .europa.eu / docs / en_GB / document_library / Scientific_guideline / 2017/08 / WC5002 33571.pdf). In contrast, modified release (MR) medicines only release API after drug administration for a certain period of time, for extended periods of time or at a specific site.

The pharmaceutical compositions of the present invention can be prepared by methods known in the art, for example by mixing, compacting, dry or wet granulation, fluid granulation or spray drying. The granules can be filled into capsules or tableted into immediate release tablets. The formulation process may include grinding, blending, sieving,

A3 compacting, dry or wet granulation, tabletting or capsule filling.

The tablets may advantageously be coated with a functional coating protecting the active substance from light. The functional coating may comprise at least one excipient from the group of polymers (e.g. hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, methylcellulose, ethylcellulose), plasticizers (e.g. polyethylene glycol, triacetin, triethyl citrate or mineral oil) and other additives such as fillers and glidants (e.g. talc, kaolin, lecithin), surfactants (eg, sodium lauryl sulfate, polysorbates), dispersing agents (eg, xanthan gum). Conventionally pharmaceutically acceptable pigments (e.g. iron oxides, talc, aluminum compounds, titanium dioxide) or other suitable natural and synthetic dyes, mordants and pigments may be advantageously used to prepare the light-protective coating. The tablet cores may preferably be coated with a functional coating with a 2 to 6% weight gain.

The film coating may contain a binder, preferably in an amount of 50 to 70% by weight, a plasticizer preferably in an amount of 3 to 14% by weight, a colorant, preferably in an amount of 15 to 25% by weight, a pigment, preferably in an amount of 0.1 to 1%. % And a sliding agent, preferably in an amount of 8.5 to 10% by weight;

The final product in capsule or tablet form may be further packaged in a protective container such as a blister or vial. If desired, the protective coating may be provided with a desiccant, an oxygen absorber, or an inert atmosphere (e.g. nitrogen) protection.

The present invention provides a new type of immediate release pharmaceutical composition in which an ionic polymer is used as a filler, which affects the dissolution behavior of the pharmaceutically active agent at an acidic pH. HPMCAS appears to be a particularly preferred polymer. This is commonly used in the pharmaceutical industry to improve the solubility of poorly water-soluble substances by forming amorphous solid solutions or dispersions and to prepare acid-resistant coatings, or as a matrix polymer for the preparation of sustained release tablets.

It has surprisingly been found that ionic polymers can be used to retard the dissolution of metastable forms of pharmaceutically active agents so as to be bioequivalent to compositions comprising a thermodynamically more stable solid form. The ionic polymer is only used as a filler in the pharmaceutical composition in an amount which is not sufficient to form a controlled release matrix system. It is therefore a further object of the invention to use an ionic polymer as a filler in a pharmaceutical composition comprising a pharmaceutically active agent for reducing the dissolution rate of the pharmaceutically active agent. As a result, the difference in dissolution rate of the two different solid forms of the pharmaceutically active substance can be compensated as needed.

In addition, ionic polymers suppress differences in the solubility (bioavailability) of a pharmaceutically active agent under the post-meal and fasting conditions of the medicinal product. Yet another object of the invention is the use of an ionic polymer as a filler in a pharmaceutical composition comprising a pharmaceutically active agent to suppress the difference in solubility of the pharmaceutically active agent when administered in the fasted state and after a meal. Thus, the difference in dissolution rate of the pharmaceutically active substance when administered on an empty stomach and after a meal can be completely eliminated.

Clarification of drawings

Figure 1: Dissolution curve: a) Inlyta 7 mg axitinib reference formulation (Form XLI); b) granulate containing 7 mg axitinib (form IV) and HPMCAS wet granulation (VG) polymer; c) granules containing 7 mg of axitinib (Form IV) and HPMCAS polymer briquetting preparation; d) granulate containing 7 mg axitinib (Form IV) and Kollidon, wet granulation preparation; (e) granules containing 7 mg of axitinib (form

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IV) and Methocel, wet granulation preparation; f) granules containing 7 mg axitinib (Form IV) and Eudragit, wet granulation preparation; in solution at pH = 2.

Figure 2: Dissolution curve: a) amorphous apremilast 30 mg; b) a granulate containing 30 mg of amorphous apremilast and Eudragit; c) a granulate containing 30 mg of amorphous apremilast and HPMCAS; d) granules containing 30 mg of amorphous apremilast and Methocel; in solution at pH = 2.

Figure 3: Dissolution curve of a) Inlyta reference formulation (7 mg axitinib form XLI); b) a granulate containing 7 mg axitinib form IV and 18 wt. % HPMCAS under conditions simulating gastric binder condition (FeSSGF).

Figure 4: Dissolution curve of a) Inlyta reference formulation (7 mg axitinib form XLI); b) a granulate containing 7 mg axitinib form IV and 18 wt. % HPMCAS in conditions simulating a simulated stomach condition "fasting" (FaSSGF).

Figure 5: Dissolution curve of a) Inlyta reference formulation (1 mg axitinib form XLI); b) prepared film-coated immediate release tablets (FCIR tablets) containing 1 mg axitinib (Form IV) and 18 wt. % HPMCAS; in solution at pH = 2.

Figure 6: Dissolution curve a) of the reference preparation Inlyta (7 mg axitinib form XLI); b) prepared FCIR tablets containing 7 mg axitinib (Form IV) and 18 wt. % HPMCAS; in solution at pH = 2.

Figure 7: Dissolution curve of a) Inlyta reference formulation (7 mg axitinib form XLI); b) prepared FCIR tablets containing 7 mg of axitinib without ionic polymer (Form IV); c) prepared FCIR tablets containing 7 mg axitinib (Form IV) and 18 wt. % HPMCAS; in solution at pH = 2.

DETAILED DESCRIPTION OF THE INVENTION

The invention is illustrated by the following examples. These examples serve only to illustrate and explain the invention, and are not intended in any way to limit the scope of protection, which is limited only by the wording of the claims.

Example 1

Study of influence of dissolution rate of axitinib form IV with selected polymers by wet granulation

Axitinib is a non-hygroscopic weak base compound that is classified as a Group II substance (low solubility and good permeability across biological membranes) in the Bio-Pharmaceutical Classification System (BCS). The thermodynamically most stable solid form of axitinib with the highest melting point and slowest dissolution rate is Form XLI. Moreover, the solubility of this substance, and hence its bioavailability, is dependent on the pH of the environment, which poses a challenge in its formulation in terms of both efficacy and patient safety.

In the preparation of Inlyta, pharmaceutical compositions containing different polymorphic forms of axitinib were prepared in clinical trials and bioequivalence studies and tested in different administration regimens (fasting and after meals). Prototypes containing 5 mg axitinib form IV prepared by wet or dry granulation were bioequivalent to the post-meal administration regimen but were not bioequivalent when administered in the fasted state. For the preparation of axirinib immediate release (FCIR) film-coated tablets

Form IV, the mean peak C max and _m was 39% to 57% lower when administered after a meal than when administered in the fasted state. The mean AUC 0, after administration after meals was 7% to 36% lower than in the fasted state. No clinically relevant changes in blood plasma concentrations of this drug (C _ma x) after administration (Inlyta: EPAR - Public assessment report) were observed when using FCIR containing polymorphic form of axitinib XLI.

Thus, the present inventors faced the problem of how to prepare immediate release tablets containing a metastable form of axitinib (Form IV) that would be bioequivalent to XLI, both in the fasted state and after a meal.

The inventors of the present invention have prepared a crystalline axitinib free base (Form IV) according to the process disclosed in WO 2006/048751. In order to achieve uniformity of content in the final dosage form, the axitinib thus prepared was adjusted by grinding.

The crystalline axitinib free base (180 mg, Form IV) was mixed with 2820 mg of selected Methocel E5 series polymer in a polyethylene bag; Eudragit L100; Kollidon 90F; HPMCAS-LF (which is HPMC AS) for 5 min. The mixture was transferred to a stainless steel container and again homogenized using a top stirrer and a 3-blade pitched stirrer for 5 min. at 400 rpm. To this mixture, 0.6 ml of water was added dropwise with stirring. The sample was an additional 5 min. homogenized with stirring. The wet sample was allowed to dry in a vacuum oven at 40 ° C and 20 kPa pressure overnight. The next day the sample was sieved through a 0.8 mm sieve. An amount containing 7 mg of axitinib was weighed from the prepared granulate for dissolution measurement. The comparison of the dissolution curves of the individual granules of axitinib (form IV) with the medicinal product Inlyta 7 mg axitinib (form XLI) in the dissolution solution at pH = 2 is shown in Figure 1. In the preparation of granules containing ionic polymers, a pH = 2 a significant reduction in the dissolved amount of axitinib (Form IV). In the case of eudragit, the dissolved amount was at 60 min. 77%. When using HPMCAS, the dissolved amount was at 60 min. 26%. If nonionic polymers were used, the dissolved amount in both cases was 92% at 60 min. This shows that ionic polymers retard the dissolution of the metastable form of the pharmaceutically active agent, and thus the dissolution rate can be adjusted to a rate corresponding to the dissolution rate of the thermodynamically most stable form; while nonionic polymers do not affect the dissolution rate.

Example 2

Study of influence of dissolution rate of axitinib form IV with selected polymers by dry granulation

The crystalline axitinib free base (180 mg, Form IV) was mixed with 2820 mg HPMCAS-LF in a polyethylene bag for 5 min. 300 mg of the prepared mixture was briquetted using a hand press at 26 kN on a 1 cm tablet. The prepared tablets were spread through a 0.8 mm screen. An amount containing 7 mg of axitinib was weighed from the prepared granulate for dissolution measurement. A comparison of the dissolution curves of this axitinib granulate (Form IV) with the medicinal product Inlyta 7 mg axitinib (Form XLI) in a dissolution solution at pH = 2 is shown in Figure 1 c). In the case of HPMCAS briquetting granulates, the pH = 2 solution had a similar decrease in axitinib (Form IV) solubility as in wet granulation to 29% of the total amount in 60 min.

Based on the experiment (Figure 1), it was found that the use of ionic polymers, especially HPMCAS, together with axitinib form IV significantly changes the dissolution behavior of this substance in acidic pH.

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Example 3

Study of influence of dissolution rate of amorphous apremilast with selected polymers by wet granulation

The amorphous form of apremilast was prepared according to the procedure disclosed in patent application WO 2015/173792.

The amorphous apremilast was mixed with selected polymers from the series in a polyethylene bag; HPMCAS-LF; Eudragit L100; methocel (see Table 1) for 5 min. The mixture was transferred to a stainless steel container and again homogenized using a top stirrer and a 3-blade pitched stirrer for 5 min. at 400 rpm. To this mixture was added dropwise 3 ml water while stirring. The sample was an additional 5 min. homogenized with stirring. The wet sample was allowed to dry in a vacuum oven at 40 ° C and 20 kPa pressure overnight. The next day the sample was sieved through a 1 mm sieve. The prepared granulates were compared with the amorphous form of apremilast in a dissolution solution of pH = 2 (see Figure 2).

Table 1: Composition of individual granulates and amount of solvent used

Polymer apremilast weight (g) weight polymer (G) Water volume (ml) HPMCAS-LF 2.84 2.83 3.00 Eudragit LI00 4.05 0.95 3.00 K100 LV methocel 2.78 2.77 2.8

On the basis of the experiment (Figure 2), it was found that the use of ionic polymers together with the amorphous form of apremilast resulted in a change in the dissolution behavior of this substance in acidic pH. In the preparation of granules containing ionic polymers there was a significant reduction in the dissolved amount of amorphous apremilast in the solution at pH = 2. In the case of eudragit, the dissolved amount was at 60 min. 69%. When using HPMCAS, the dissolved amount was at 60 min. 56%. If nonionic polymers were used, the dissolved amount was 60% at 60 min. Thus, the solubility of apremilast in acidic pH has been reduced by the ionic polymer in the pharmaceutical composition.

Example 4

Preparation of granules and tablet cores containing 7 mg axitinib (Form IV)

The weights for the preparation of the granulate and the tablet are shown in Table 2. The granulate was prepared by weighing axitinib, HPMCAS, lactose, microcrystalline cellulose and one third of magnesium stearate with gradual homogenization of the individual mixtures. The resulting mixture was compacted on a Powtec compactor. The prepared granulate was tested in dissolution medium simulating gastric state "after meal" (FeSSGF - see Figure 3) and medium simulating gastric state "on an empty stomach" (FaSSGF - see Figure 4).

Table 2: Composition • For Axitinib formulation (Form IV)

Weighed content (% by weight) of quantity (g)

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axitinib (form IV) 140.00 1.43 HPMCAS-LF 1764,00 18.00 microcrystalline cellulose 3642,76 37.17 lactose 3885,70 39.65 magnesium stearate 73.50 0.75 croscarmellose sodium 294.00 3.00

The required amount of magnesium stearate and croscarmellose sodium was imported to the prepared granulate. The prepared mixture was homogenized and tableted to white to off-white cores weighing 490 mg. The prepared cores were coated with red lacquer according to the procedure of Example 8.

Example 5

Preparation of granules and tablet cores containing 1 mg axitinib (Form IV)

The weights for the preparation of the granulate and the tablet are shown in Table 2 of Example 4. The granulate was prepared by weighing axitinib, HPMCAS, lactose, microcrystalline cellulose and one third of magnesium stearate with gradual homogenization of the individual mixtures. The resulting mixture was compacted on a Powtec compactor. The prepared granulate was tested in dissolution medium simulating gastric state "after meal" (FeSSGF) and medium simulating gastric state "fasting" (FaSSGF) with similar results as in Example 4.

The remaining amount of magnesium stearate and croscarmellose sodium were imported to the prepared granulate. The prepared mixture was homogenized and tableted to white to off-white cores weighing 70 mg. The prepared cores were coated with a red lacquer according to the example

8.

Examples 4 and 5 show the use of an ionic polymer in a pharmaceutical composition in the preparation of a proportional biowaiver model for immediate release drug coated tablets (FCIR) containing 1 mg and 7 mg axitinib (Form IV). The prepared granulate achieved an identical dissolution profile of 7 mg axitinib form IV compared to the reference product Inlyta (7 mg axitinib form XLI) using an ionic polymer under conditions simulating gastric state after meals (FeSSGF- see Figure 3) and fasting (FaSSGF- see Figure 4).

Example 6

Preparation of granules and tablet cores containing 7 mg axitinib (Form IV)

The weights for the preparation of the granulate and the tablet are shown in Table 3. The granulate was prepared by weighing axitinib, HPMCAS, lactose, microcrystalline cellulose and a portion of magnesium stearate with gradual homogenization of the individual mixtures. The resulting mixture was compacted on a Powtec compactor.

The required amount of magnesium stearate and croscarmellose sodium was imported to the prepared granulate. The prepared mixture was homogenized and tableted to white to off-white cores weighing 245 mg. The prepared cores were coated with red lacquer according to the procedure of Example 8.

Table 3: Granulate and tablet composition for Axitinib formulation (Form IV)

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Quantity to be weighed (g) content (% by weight) axitinib (form IV) 70,00 2.86 HPMCAS-LF 441,00 18.00 microcrystalline cellulose 910.69 37.17 Lactose 936.44 38.22 magnesium stearate 18.38 0.75 croscarmellose sodium 73.50 3.00

Example 7 (comparative example)

Preparation of granules and tablet cores containing 7 mg axitinib (Form IV) without ionic polymer

The weights for the preparation of the granulate and the tablet are shown in Table 4. The granulate was prepared by weighing axitinib, lactose, microcrystalline cellulose and a portion of magnesium stearate with gradual homogenization of the individual mixtures. The resulting mixture was compacted on a Powtec compactor.

The required amount of magnesium stearate and croscarmellose sodium was imported to the prepared granulate. The prepared mixture was homogenized and tableted to white to off-white cores weighing 245 mg. The prepared cores were coated with red lacquer according to the procedure of Example 8.

Table 4: Granulate and tablet composition for Axitinib formulation (Form IV)

Quantity to be weighed (g) content (% by weight) axitinib (form IV) 70,00 2.86 microcrystalline cellulose 1504.03 61.39 Lactose 784,00 32,00 magnesium stearate 18.47 0.75 croscarmellose sodium 73.50 3.00

Example 8

Coating of axitinib tablets (Form IV)

The cores prepared according to Example 4 (7mg) and Example 5 (1mg) were coated with a red lacquer in increments of 4% by weight. The coating composition of the tablet coating is shown in Table 5. The prepared mixture was suspended in 320 ml of water.

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Table 5: Coating composition for tablet coating

Quantity to be weighed (g) content (% by weight) hypromellosis 45,60 63.33 polyethylene glycol 4.80 6.67 titanium dioxide 14.40 20,00 iron oxide 0.12 0.17 talc 7.08 9.83

Coated tablets containing 1 mg and 7 mg axitinib (Form IV) were tested in a dissolution solution at pH = 2 (see Figures 5, 6 and 7).

The solubility of FCIR tablets was tested at pH = 2, which simulates the stomach condition on an empty stomach. Figure 5 shows the solubility comparison of FCIR tablets containing 1 mg axitinib (metastable form IV) with the reference Inlyta (1 mg axitinib form XLI) at pH = 2. Figure 6 shows a solubility comparison of FCIR tablets containing 7 mg axitinib (form IV ) with the reference product Inlyta (7 mg axitinib form XLI) at pH = 2. In all tested cases, the prepared tablets containing axitinib (form IV) were in agreement with the reference product Inlyta (axitinib form XLI). Figure 7 shows the dissolution of tablets containing 7 mg axitinib (form IV), with or without an ionic polymer, compared to the reference formulation of Inlyta (7 mg axitinib form XLI) in a pH = 2 solution.

The results show that the use of an ionic polymer as a filler suppresses the differences in solubility and hence the bioavailability of the metastable form of the active substance at acidic pH or under fasting conditions.

Description of methods used

Dissolution of Axitinib polymorph form IV in dissolution medium pH = 2 by powder dissolution method

The dissolution rate of the tested forms of axitinib in a pH = 2 solution was measured on a Sotax AT-7 dissolution apparatus using paddles (USP 2). Dissolution was carried out in 200 ml of a pH 2.0 solution (10 mM HCl), at a constant rate of 75 RPM (RPM = rpm) until 45 minutes of the experiment and at an increased speed of 150 RPM until 60 minutes. Samples were taken at 5 minute intervals and the dissolved axitinib concentration was determined using a Jena Analytik UV / Vis spectrophotometer at 360 nm in 5 mm cuvettes.

Dissolution of Apremilast in Dissolution Medium pH = 2 by Powder Dissolution

The dissolution rate of the tested forms of apremilast in a pH = 2 solution was measured on a Sotax AT-7 dissolution apparatus using paddles (USP 2). Dissolution was performed in 900 ml of a pH 2.0 solution (10 mM HCl) containing 0.2 wt. % sodium dodecyl sulphate (SDS), at a constant rate of 75 RPM until the 45th minute of the experiment and at an increased speed of 150 RPM until the 60th minute. Samples were taken at 5 minute intervals and the dissolved apremilast concentration was determined using a Jena Analytik UV / Vis spectrophotometer at 231 nm in 5 mm cuvettes.

Dissolution of Axitinib polymorphic form IV in dissolution medium simulating the stomach state "fasting" (FaSS GF)

The granulate was analyzed in 200 ml of FaSSGF, prepared by mixing 0.4 g of NaCl and using

The pH of the HCl addition was adjusted to 1.6, followed by the addition of 12 mg of SIF powder at 125 RPM for 45 min, after which the speed was increased up to 150 RPM. Samples were taken at 5 minute intervals and the dissolved axitinib concentration was determined using a Jena Analytik UV / Vis spectrophotometer at 360 nm in 5 mm cuvettes.

Dissolution of Axitinib polymorphic form IV in dissolution medium simulating gastric state "after meals" (FeSSGF)

The granulate was analyzed in 200 ml of FeSSGF, prepared by mixing FeSSIF buffer pH 5 with 5% Capmul at 125 RPM for 45 min, after which the speed was increased up to 150 RPM. During dissolution, samples were taken at regular intervals and the amount of axitinib in the aqueous phase was determined by liquid chromatography.

Axitinib content was determined by liquid chromatography (UPLC):

Apparatus: Waters Acquity UPLC, PDA detection Column: - size: l = 100mm, 0 = 2.1mm stationary phase: Waters CSH Phenyl-Hexyl; 1.7 µm particles column temperature: 40 ° C. Mobile phase: A: Borate buffer pH 9.3 B: acetonitrile R

Gradient elution:

Time (min) Flow rate (ml / min) % A % B 0 0.3 50 50 1 0.3 40 60 3 0.3 20 May 80 3.5 0.3 20 May 80 4 0.3 50 50 4,5 0.3 50 50

Detection: spectrophotometer 331.9 nm Injection. 10 μΐ Sample temperature: Deň: 18 ° C

PATENT CLAIMS

Claims (10)

A pharmaceutical immediate release pharmaceutical composition comprising - 11 GB 2018 - 150 A3 - a metastable form of the pharmaceutically active substance and / or a pharmaceutically active substance in a form having a higher dissolution rate in the fasted state than after a meal, and - an ionic polymer. The pharmaceutical composition of claim 1, wherein the ionic polymer is selected from the group consisting of cellulose derivatives, polyacrylate and / or methacrylate copolymers and polyvinyl derivatives; preferably, the ionic polymer is selected from the group consisting of cellulose or hydroxypropylmethyl cellulose esters, polyacrylate and / or methacrylate copolymers, and polyvinyl esters. The pharmaceutical composition of claim 1 or 2, wherein the ionic polymer is selected from the group consisting of cellulose acetate phthalate; hydroxypropylmethyl cellulose phthalate; hydroxypropylmethyl cellulose acetate succinate; cellulose acetate butyrate; copolymers of methacrylic acid with methyl methacrylate, in particular in a ratio of 1: 1 or 1: 2; cationic copolymers based on dimethylaminoethyl methacrylates, butyl methacrylates and methyl methacrylates, in particular in a 2: 1: 1 ratio; methacrylic acid-ethyl acrylate copolymers; polyvinyl acetate phthalate. The pharmaceutical composition of any one of claims 1 to 3, wherein the ionic polymer is hydroxypropylmethyl cellulose acetate succinate. A pharmaceutical composition according to any one of claims 1 to 4, which comprises the ionic polymer in an amount of 3 to 33% by weight, based on the total weight of the composition. A pharmaceutical composition according to any one of claims 1 to 5, which comprises 0.5 to 50 wt. % of the metastable form of the pharmaceutically active substance and / or the pharmaceutically active substance in a form having a higher dissolution rate in the fasted state than after a meal; % filler, 5 to 15 wt. binder, 5 to 20 wt. % of disintegrant and 0.5 to 2 wt. % of the lubricant, wherein the ionic polymer is present as part of the filler and is present in an amount of 3 to 33% by weight, based on the total weight of the composition. Pharmaceutical composition according to claim 5 or 6, which comprises an ionic polymer in an amount of 15 to 25% by weight, preferably 15 to 20% by weight, based on the total weight of the composition. Pharmaceutical composition according to any one of claims 1 to 7, in the form of a tablet, capsule, powder, pellet or granule. Use of an ionic polymer as a filler in a pharmaceutical immediate release composition comprising a pharmaceutically active agent, preferably a metastable form of a pharmaceutically active agent, to reduce the dissolution rate of the pharmaceutically active agent. Use of an ionic polymer as a filler in a pharmaceutical immediate release pharmaceutical composition comprising a pharmaceutically active agent in a form with a higher dissolution rate when administered in the fasted state than after a meal, to suppress the difference in solubility of the pharmaceutically active agent when administered fasted and after a meal.