EP4025191A1

EP4025191A1 - Pharmaceutical compositions of abiraterone acetate

Info

Publication number: EP4025191A1
Application number: EP20714106.0A
Authority: EP
Inventors: Pavel ZVATORA; Josef Beranek; Igor CERNA; Tereza Boleslavska; Ales VOGL; Jan BOSAK
Original assignee: Zentiva KS
Current assignee: Zentiva KS
Priority date: 2019-03-20
Filing date: 2020-03-17
Publication date: 2022-07-13
Also published as: WO2020187343A1; CZ2019168A3

Abstract

The invention provides immediate release pharmaceutical compositions comprising amorphous or predominantly amorphous abiraterone acetate or a salt of abiraterone acetate with a higher solubility and bioavailability, compared to the original dosage form comprising crystalline abiraterone acetate. Improvement in solubility was demonstrated in an in-vitro experiment and in-vivo improvement in bioavailability was demonstrated in rat models and human volunteers.

Description

Pharmaceutical compositions of abiraterone acetate

Field of Art

The invention relates to immediate release pharmaceutical compositions of abiraterone acetate, the absorption of which is independent of whether they are administered after a meal or in the fasting state. This characteristic allows to significantly reduce the therapeutic dose of the drug.

Background Art

Abiraterone acetate is a selective inhibitor of 17a-hydroxylase/C 17,20-lyase (CYP17) and has been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) under the trade name Zytiga^® as a medicament for the treatment of metastatic prostate cancer.

The bioavailability of active pharmaceutical ingredients (APIs) depends primarily on whether the product is crystalline or amorphous. The amorphous product is usually more rapidly soluble, but it is often not obtainable in an adequate quality and it is also less stable physically and chemically. In contrast, the crystalline product is usually stable, easier to obtain in a pure form, and dissolves more slowly than the amorphous form.

During the preparation of dosage forms containing abiraterone acetate with a higher bioavailability based on amorphous API, amorphous solid solutions, amorphous solid dispersions, or significantly amorphous API, a negative effect on the chemical stability of abiraterone acetate was observed.

The original Zytiga^® drug product, which contains crystalline abiraterone acetate, exhibits low drug absorption and a significant pharmacokinetic variability when administered to patients (Clin Pharmacokinet. 2017; 56(7): 803-813). The bioavailability of this drug when administered in the fasting state is approximately 10%. There was a marked increase in pharmacokinetic parameters when administered after a meal: total plasma levels (AUC) increased ten-fold, and maximum plasma concentrations (Cmax) increased 17-fold (Int. J. Pharm. 2017; 532 (1): 427-434).

To ensure that the maximum safe plasma concentration of the drug is not exceeded after administration of the original Zytiga^® product, it must be administered in a fasting state (on an empty stomach).

Currently, there are many formulation approaches and strategies to increase the equilibrium solubility of abiraterone in-vitro and in-vivo, and to reduce the effect of fasting or post-meal administration on the bioavailability of the final dosage form. For example, WO 2016/128891 discloses an amorphous complex of abiraterone acetate with a complexing polymer. This complex was prepared by dissolving/dispersing the components in water, freeze-drying and lyophilization. The preparation uses low temperatures up to room temperature (temperatures up to 40 °C were tested, the temperature for preparation of the solution was 30 °C). WO 2013/012959 discloses a solid dispersion of a drug, which may be abiraterone acetate, in a polymer matrix. However, abiraterone acetate has not actually been tested in any of the examples of WO 2013/012959

In 2018, the FDA, under the trade name Yonsa®, approved a medicinal product containing fine particles of abiraterone acetate. The fine particle formulation was prepared using SoluMatrix Fine Particle Technology™. In this way, bioequivalence (the same therapeutic effect) was achieved using 500 mg of fine particles of abiraterone acetate compared to the original Zytiga^® drug formulation containing 1000 mg of crystalline abiraterone acetate.

However, there still remains a need in the art for a simple method to compensate for differences in solubility of the API, regardless of whether the drug is administered to the patient on an empty stomach (in a fasting state) 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 to increase the solubility and bioavailability, so as to achieve comparable properties to the reference product (bioequivalence) using as low amount of the active ingredient as possible. This approach significantly reduces patient exposure to the active substance, thus reducing the risk of side effects observed in the reference product Zytiga^® 250 mg a 500 mg, such as the frequently occurring muscle weakness, tremor, cardiac palpation, diarrhea, fluid accumulation in the legs and feet, low potassium in the blood, urinary tract infections, high blood pressure, increased bone fragility. Moreover, side effects such as increased fat in the blood, elevated hepatic counts, digestive disorders, blood in urine, chest pain, heart rhythm disorders, heart failure, muscle pain and adrenal disorders may occur (source: Zytiga^® 500 mg film-coated tablets SPC).

Disclosure of the Invention

Surprisingly, it has been found within the framework of the present invention that said technical problems associated with the low bioavailability of abiraterone and its increased oxidative degradation can be solved by providing an immediate release pharmaceutical composition comprising as a filler or as one of the fillers a cellulose derivative, such as hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (HPMC) or cellulose acetate butyrate, and further comprising poloxamer as a lubricant.

"Abiraterone" as used herein means abiraterone acetate or a salt of abiraterone acetate such as hydrochloride. They are used in the form of amorphous particles which contain, in addition to the active ingredient, at least one cellulose derivative and optionally at least one poloxamer. The particles may further comprise other excipients. Cellulose derivatives are selected from the group consisting of cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and esters thereof.

The pharmaceutical composition may preferably comprise a cellulose derivative in a weight ratio to abiraterone acetate or a salt thereof, e.g., abiraterone acetate hydrochloride, 0.9:1 to 4:1, and a poloxamer in a weight ratio to abiraterone acetate or a salt thereof, e.g., abiraterone acetate hydrochloride, 0.05:1 to 0.2:1.

Unexpectedly, it has been found that a mixture of amorphous or predominantly amorphous abiraterone and a polymer with a resulting particle size below 250 pm is particularly useful for achieving the desired dissolution effect.

Preferably, spray drying can be used to prepare such particles, which provides uniform particle size distribution, is suitable for thermally and oxidatively sensitive components, and ensures sufficient homogeneity of the prepared sample.

Accordingly, the present invention also provides a process for preparing a pharmaceutical composition of abiraterone, said process comprising the steps of

a) dissolving abiraterone acetate or abiraterone acetate salt,

b) adding at least one cellulose derivative,

c) drying the mixture, preferably by spray drying, and

d) granulating the dried mixture with at least one additional excipient, wherein the said at least one additional excipient comprises a poloxamer.

The present invention further provides a process for preparing a pharmaceutical composition of abiraterone, said process comprising the steps of

a) dissolving the abiraterone acetate or abiraterone acetate salt,

b) adding at least one cellulose derivative and at least one poloxamer, and

c) drying the mixture, preferably by spray drying.

Suitable solvents for dissolving abiraterone acetate or a salt thereof may be, for example, alcohols, chlorinated solvents, and mixtures thereof.

Some excipients, such as antioxidants, may only be present in the dosage form at a low concentration. The use of antioxidants in the food, pharmaceutical and cosmetic industries is regulated by the relevant authorities. Examples of excipients used as antioxidants: vitamin E, ascorbic acid, citric acid, butylated hydroxytoluene, fumaric acid, butylated hydroxytoluene and butylated hydroxyanisole. Antioxidants can be used as protectives in the formulations of the present invention, for example in concentrations of 0.0009 to 0.9% by weight, relative to the total weight of the formulation. In order to achieve an optimal effect of these substances, it is advantageous when their low concentration is homogeneously distributed in the formulation. This can also advantageously be achieved by means of spray drying, when the active ingredient (abiraterone) is dissolved together with the antioxidant, thus ensuring a homogeneous mixing of the two components in the liquid phase.

The pharmaceutical composition of the invention preferably comprises a mixture of amorphous or predominantly amorphous abiraterone in an amount of 1 to 20% by weight, relative to the total weight of the composition, with at least one cellulose derivative, preferably selected from hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetate succinate, hydroxypropyl methylcellulose, cellulose acetate butyrate, in an amount of 10 to 75% by weight, relative to the total weight of the composition. In a preferred embodiment, the pharmaceutical composition comprises a cellulose derivative in an amount of 15 to 45% by weight, relative to the total weight of the composition.

The term "predominantly amorphous" refers to a substance that is predominantly in an amorphous state but contains a crystalline impurity that is reflected in XRPD spectra. The proportion of the crystalline admixture in the total amount of this substance is, for example, less than 20%, or less than 10%, or less than 2%.

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, cellulose derivatives, lactose, mannitol, starch, sucrose and talc. Preferred binders are potassium carbonate, copovidone, dextrose, ethylcellulose, gelatin, glucose, cellulose derivatives, lactose, povidone, polyethylene oxide, polymethacrylates, starch and derivatives thereof. Preferred disintegrants are alginic acid, chitosan, colloidal silica, croscarmellose sodium, crospovidone, hydroxypropyl 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, or hydrogenated vegetable oil. Preferred flow enhancing materials are alumina, hypromellose, poloxamer, potassium phosphate, potassium silicate, colloidal silica, magnesium oxide, magnesium silicate, maltodextrin, or talc.

In an embodiment, the pharmaceutical composition of the invention comprises 15 to 50 wt. % of amorphous or predominantly amorphous abiraterone, 15 to 45 wt. % of filler, 5 to 20 wt. % of disintegrant, 0 to 15 wt. % of binder, and 0 to 2 wt. % of lubricant, and optionally 3 to 10 wt. % of a wetting agent and 0 to 2 wt. % of an antioxidant.

In an embodiment, the pharmaceutical composition of the invention comprises 15 to 50 wt. % of amorphous or predominantly amorphous abiraterone, 15 to 55 wt. % of filler, 5 to 20 wt. % of disintegrant, 0 to 15 wt. % of binder, and 0 to 5 wt. % of lubricant, and optionally 3 to 10 wt. % of a wetting agent and 0 to 2 wt. % of an antioxidant. 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 a tablet.

The pharmaceutical compositions of the present invention may be prepared by methods known in the art, for example by mixing, compacting, dry or wet granulation, fluid granulation or spray drying. The granules may be filled into capsules or tableted into immediate release tablets. The formulation process may include grinding, mixing, sieving, compacting, dry or wet granulation, tableting 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 (e.g., sodium lauryl sulfate, polysorbates), dispersing agents (e.g., xanthan gum). Preferably, conventional pharmaceutically acceptable pigments (e.g., iron oxides, talc, aluminium compounds, titanium dioxide) or other suitable natural and synthetic dyes, mordants and pigments may be used to prepare the light-protective coating. The tablet cores may preferably be coated with a functional coating in an amount of 2 to 6%, relative to the weight of the tablet core.

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% by weight, and a glidant, preferably in an amount of 8.5 to 10% by weight.

The final product in the form of capsules or tablets can be further packaged in a protective container such as a blister or a 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 of abiraterone acetate regardless of whether the formulation is administered on an empty stomach or after a meal. In the new composition, a cellulose derivative is used as a filler and a poloxamer as a lubricant. Both components influence the dissolution behavior of the pharmaceutically active ingredient. HPMCAS appears to be a particularly preferred cellulose derivative.

The inventors have surprisingly found that a particle size of d(0.9) < 250 mpi is preferable to achieve the desired dissolution effect in the pharmaceutical composition comprising amorphous or predominantly amorphous abirateone acetate or a salt thereof, and the cellulose derivativessuch as hydroxypropyl cellulose, hydroxypropyl methylcellulose, hypromellose acetate succinate.“d(0.9)” means that 90% of the particles are within the stated size range. Furthermore, it has been found that the spray drying process is an ideal industrially applicable method by which such particles can be prepared along with the possibility of homogeneous distribution of low content excipients (such as antioxidants) in the final pharmaceutical composition. The compositions thus prepared can completely eliminate the difference in the dissolution rates of abiraterone acetate or a salt thereof when administered on an empty stomach and after a meal.

Brief Description of Drawings

Figure 1 : Precipitation experiment.

Figure 2: X-ray powder spectrum of amorphous abiraterone acetate with Soluplus.

Figure 3: Comparison of solubility of crystalline abiraterone acetate and amorphous abiraterone acetate with soluplus and sodium deoxycholate.

Figure 4: X-ray powder record of amorphous abiraterone acetate F1C1 with F1PMCAS prepared in-situ. Figure 5: Comparison of solubility of crystalline abiraterone acetate and amorphous abiraterone acetate F1C1 with F1PMCAS.

Figure 6: X-ray powder spectrum of crystalline abiraterone acetate (Form I).

Figure 7: X-ray powder spectrum of crystalline abiraterone acetate (Form II).

Figure 8: X-ray powder spectrum of a pharmaceutical composition comprising crystalline abiraterone acetate F1C1 (Form I) - top. X-ray powder spectrum of crystalline abiraterone acetate F1C1 (Form I) - bottom.

Figure 9: Comparison of the solubilities of crystalline abiraterone acetate F1C1 (reference) and crystalline abiraterone acetate F1C1 in a pharmaceutical composition with F1PMC.

Figure 10: X-ray powder spectrum of a pharmaceutical composition comprising amorphous abiraterone acetate F1C1.

Figure 11 : Comparison of solubility of crystalline abiraterone acetate F1C1 (reference) and amorphous abiraterone acetate F1C1 in pharmaceutical composition with F1PMC.

Figure 12: X-ray powder spectrum of a pharmaceutical composition containing predominantly amorphous abiraterone acetate stabilized with hydroxypropyl methylcellulose (top). X-ray powder spectrum of crystalline mannitol (bottom).

Figure 13: Comparison of solubility of crystalline abiraterone acetate (reference) and predominantly amorphous abiraterone acetate in the pharmaceutical composition with F1PMC.

Figure 14: X-ray powder spectrum of a pharmaceutical composition comprising amorphous abiraterone acetate stabilized with hydroxypropyl methylcellulose with an antioxidant.

Figure 15: Comparison of solubility of crystalline abiraterone acetate (reference) and predominantly amorphous abiraterone acetate in the pharmaceutical composition with F1PMC. Figure 16: X-ray powder spectrum of a pharmaceutical composition containing predominantly amorphous abiraterone acetate stabilized by HPMCAS. X-ray powder spectrum of crystalline mannitol (bottom).

Figure 17: Comparison of solubility of crystalline abiraterone acetate (reference) and predominantly amorphous abiraterone acetate in the pharmaceutical composition with HPMCAS.

Figure 18: X-ray powder spectrum of a pharmaceutical composition comprising amorphous abiraterone acetate stabilized by HPMCAS with an antioxidant. X-ray powder spectrum of crystalline mannitol (bottom).

Figure 19: Comparison of solubility of crystalline abiraterone acetate (reference) and amorphous abiraterone acetate in the pharmaceutical composition with HPMCAS.

Figure 20: Box graphs for Cmax and AUCo4_h parameters for the individual preparations tested. Medians are indicated by a dashed line inside the individual box sections, the lower and upper edges of which indicate the 25th and 75th percentiles. The bars represent 1.5 times the interquartile variance. Data points outside these values are indicated by triangle, square, or circle symbols.

The invention is further illustrated by the following examples. These examples serve only to illustrate and explain the invention, and should not be construed as limiting the scope of protection, which is determined solely by the claims.

Example 1: Choosing a polymer for stabilizing abiraterone acetate

Abiraterone acetate is a non-hygroscopic weakly basic compound that is classified as a Group IV substance (low solubility and low permeability across biological membranes) in the Biopharmaceutical Classification System (BCS). The thermodynamically most stable solid unsolvated form of free abiraterone acetate is the crystalline form I. The solubility of this substance, and hence its bioavailability, is also dependent on the pH of the environment, which poses a challenge in its formulation in terms of both efficacy and patient safety.

The original Zytiga® drug product, which contains crystalline abiraterone acetate, has been shown to exhibit low drug absorption and marked pharmacokinetic variability when administered to patients (Clin Pharmacokinet. 2017; 56(7): 803-813).

Thus, the present inventors faced the problem of how to prepare immediate release drug tablets with higher solubility and bioavailability of abiraterone acetate, which would exhibit identical pharmacokinetic parameters, both when administered on an empty stomach and after a meal.

An experiment was conducted to identify polymers potentially suitable for retarding crystallization and precipitation of dissolved abiraterone acetate due to the changing environment (pH) in the gastrointestinal tract. Precipitation kinetics of abiraterone acetate was monitored by a precipitation experiment, where the precipitation rate and induction time in the presence of polymers were monitored. Abiraterone acetate was dissolved in DMSO and injected into 40 mL FaSSIF (Fasted State Simulated Intestinal Fluid) containing a polymer (no polymer was present in the control sample). The initial concentration of the sample in the solution was approximately 80 mg/L, which is a 4-fold higher concentration than the equilibrium solubility of crystalline abiraterone acetate in FaSSIF. The precipitation and the amount of dissolved abiraterone acetate, respectively, were monitored over time using a UV/Vis probe.

Figure 1 shows the recording of a precipitation experiment with the polymers: hydroxypropyl cellulose (HPC), hypromellose acetate succinate (HPMCAS), hypromellose phthalate (HPMCP) and Soluplus. In all cases except hypromellose phthalate (HPMCP), the induction time (the time when abiraterone acetate begins to crystallize) was prolonged. The individual polymers further differ in the precipitation kinetics of abiraterone acetate, with best results being obtained using the polymers soluplus, hypromellose acetate succinate and hydroxypropyl cellulose.

Example 2: Preparation of amorphous abiraterone acetate with soluplus (comparative example)

Amorphous form of abiraterone acetate was prepared by reproducing the process disclosed in WO 2016/128891.

Figure 2 shows a powder X-ray diffraction pattern of the material prepared by the reproduction of the above process. A fully amorphous solid solution of abiraterone acetate, soluplus and sodium deoxycholate was prepared as described.

The composition prepared according to the procedure described in the patent application WO 2016/128891 was used as a positive reference in a Pharmacokinetic study in rats (see Example 13). The sample was labeled as Test 1. Improvement of solubility, bioavailability, and elimination of the post-meal vs. fasting effects has been demonstrated in a study in the International Journal of Pharmaceutics 532 (2017) 427-434.

Figure 3 shows a comparison of the solubility of crystalline abiraterone acetate and amorphous abiraterone acetate with soluplus and sodium deoxycholate, in which case the solubility of abiraterone acetate increased more than 2.5 times.

Example 3: In-situ preparation of abiraterone acetate HC1 (reference example)

A solid solution containing abiraterone acetate HC1 was prepared by spray drying. 3.8 g of abiraterone acetate free base was dissolved in 145 ml of dichloromethane/tetrahydrofuran (5: 1). To this solution was added, with stirring, 2 ml of hydrochloric acid in isopropyl alcohol (c = 6 mol/1). This solution was stirred at room temperature for 30 min. To this solution was added 3.8 g of HPMCAS with stirring, and after dissolution of the polymer, the solution was allowed to stir at room temperature for 30 minutes. The solvent was removed using a Biichi B-290 spray dryer with a peristaltic pump performance of 20%; inlet temperature 84 °C; outlet temperature 62 °C; aspirator performance 100%; cooling loop temperature -20 °C.

Figure 4 shows the X-ray powder diffraction pattern of amorphous abiraterone acetate HC1 obtained as described above. A fully amorphous solid solution of abiraterone acetate HC1 with HPMCAS was prepared.

Figure 5 shows comparison of the solubility of crystalline abiraterone acetate and of amorphous abiraterone acetate HC1 with HPMCAS, in which case the solubility of abiraterone acetate increased by about 2-fold.

Example 4: Preparation of Abiraterone Acetate Hydrochloride Form 1 (Reference Example)

Abiraterone acetate (65 g) was dissolved at room temperature in 300 mL of dichloromethane. To the stirring solution was added 33 mL of a 5-6 M solution of HC1 in isopropanol, and then the reaction mixture was heated to reflux. 80 ml of acetone was added dropwise to the refluxing solution. Shortly after the addition of acetone, the product crystallized gradually. The resulting suspension was stirred at near boiling point for 25 min and 170 ml of acetone was added dropwise to the stirring mixture. The suspension was stirred at near boiling temperature for 15 min and then cooled to 20 °C over lh. The product was isolated by filtration, washed with acetone. 60 g of abiraterone acetate hydrochloride were obtained as white crystals in a yield of 85%. This product was further dried at 50 °C and 15 mbar for at least 20 hours. Figure 6 shows an X-ray powder diffraction pattern of the crystalline Form 1. Characteristic diffraction peaks of the crystalline Form 1 of abiraterone acetate hydrochloride of the present invention using CuKa radiation are: 7.9; 12.5; 16.2; 18.5; 23.5 ± 0.2° 2-theta, other characteristic peaks are: 15.1; 17.3; 19.8; 22.3 ± 0.2° 2-theta. This crystalline form was characterized by a melting point of 191.3 °C.

Example 5: Preparation of Abiraterone Acetate Hydrochloride Form 2 (Reference Example)

Abiraterone acetate (400 g, 99.68% purity) was dissolved in ethyl-methyl-ketone (4000 mL) at 39 °C and stirred for 30 minutes. Subsequently, a solution of hydrogen chloride in isopropyl alcohol (204 ml, 5-6 M) was added dropwise to the solution at 40-44 °C over 1 h. To the resulting suspension was added 400 mL of ethyl-methyl-ketone and further stirred at 39 °C for 2.5 h. The suspension was filtered through a sintered glass and the product washed with ethyl-methyl-ketone (4000 mL). After drying (45 °C, vacuum, 20 h) 352 g of the product was obtained in 80% yield and 99.93% purity. Figure 7 shows an X-ray powder diffraction pattern of the crystalline Form 2. The characteristic diffraction peaks of the crystalline Form 2 of abiraterone acetate hydrochloride of the present invention using CuKa radiation are: 7.8; 13.8; 15.7; 18.9; 24.5 ± 0.2° 2-theta, other characteristic peaks are: 6.2; 16.2; 18.1 ; 20.9 ± 0.2° 2-theta. This crystalline form was characterized by a melting point of 193.9 °C.

Example 6: Pharmaceutical composition containing crystalline abiraterone acetate HC1 (reference example)

Crystalline abiraterone acetate HC1 (Form I) was mixed with HPMC, croscarmellose sodium, lactose monohydrate, and lauryl sulfate sodium. A granulate was prepared by briquetting and sieving through a 1 mm sieve. Magnesium stearate was added to this granulate.

The prepared composition was characterized by X-ray powder diffraction. Figure 8 shows an X-ray powder diffraction pattern of a pharmaceutical composition comprising crystalline abiraterone acetate

HC1.

Figure 9 shows a comparison of the solubility of crystalline abiraterone acetate HC1 (reference) and crystalline abiraterone acetate HC1 in a pharmaceutical composition with HPMC, in which case the solubility of abiraterone increased by 60%.

Example 7: Pharmaceutical composition containing amorphous abiraterone acetate HC1 (comparative example)

Crystalline abiraterone acetate HC1 (Form I) was dissolved in 300 mL of methanol: dichloromethane (2: 1). To this solution was added hydroxypropyl methylcellulose and mannitol. The solvent was removed from the resulting suspension by spray drying. Spray drying parameters: peristaltic pump performance 20%; inlet temperature 80 °C; outlet temperature 60 °C; aspirator performance 100%; cooling loop temperature -20 °C. In this way, particles were obtained with a Malvern particle size distribution: d(0.1) = 3.442 pm; d(0.5) = 12.679 pm; d(0.9) = 130.225 pm. This sample was used in the Pharmacokinetic study in rats (see Example 13). The sample is labeled Test 2.

The prepared composition was characterized by X-ray powder diffraction. Figure 10 shows an X-ray powder diffraction pattern of a pharmaceutical composition comprising amorphous abiraterone acetate HC1.

Figure 11 shows a comparison of the solubility of crystalline abiraterone acetate HC1 (reference) and amorphous abiraterone acetate HC1 in a pharmaceutical composition with HPMC.

Example 8: Pharmaceutical composition of predominantly amorphous abiraterone acetate and methocel

Crystalline abiraterone acetate (Form I) was dissolved in 1000 mL of methanol: dichloromethane (2:1). To this solution was added hydroxypropyl methylcellulose and poloxamer. The solvent was removed from the resulting solution by spray drying. Spray drying parameters: peristaltic pump performance 20%; inlet temperature 80 °C; outlet temperature 60 °C; aspirator performance 100%; cooling loop temperature -20 °C.

Croscarmellose sodium, aerosil, lactose monohydrate and prosolv were weighed into the spray-dried powder and the mixture was homogenized. A granulate was prepared by briquetting and sieving through a 1 mm sieve. This granulate was mixed with mannitol and hydroxypropyl cellulose.

The prepared composition was characterized by X-ray powder diffraction. Figure 12 shows an X-ray powder diffraction pattern of a pharmaceutical composition containing predominantly amorphous abiraterone acetate (top) and an X-ray powder diffraction pattern of crystalline abiraterone acetate (bottom).

Figure 13 shows a comparison of the solubility of crystalline abiraterone acetate (reference) and predominantly amorphous abiraterone acetate in the pharmaceutical composition with HPMC, in which case solubility increases 2-fold.

Example 9: A pharmaceutical composition comprising amorphous abiraterone acetate with hydroxypropyl methylcellulose and an antioxidant Crystalline abiraterone acetate (Form I) was dissolved in 1000 mL of methanol: dichloromethane (2:1). To this solution was added hydroxypropyl methylcellulose and butylated hydroxyanisole. Dissolution of the API together with butylated hydroxyanisole in an organic solvent ensures their contact and homogeneous distribution at the molecular level. The solvent was removed from the resulting solution by spray drying. Spray drying parameters: peristaltic pump performance 20%; inlet temperature 80 °C; outlet temperature 60 °C; aspirator performance 100%; cooling loop temperature -

20 °C.

Poloxamer, sodium croscarmellose, aerosil, lactose monohydrate and prosolv were added to the prepared spray-dried powder and this mixture was homogenized. A granulate was prepared by briquetting and sieving through a 1 mm sieve. This granulate was mixed with mannitol and hydroxypropyl cellulose.

The prepared composition was characterized by X-ray powder diffraction. Figure 14 shows an X-ray powder diffraction pattern of a pharmaceutical composition comprising amorphous abiraterone acetate.

Figure 15 shows a comparison of the solubility of crystalline abiraterone acetate (reference) and predominantly amorphous abiraterone acetate in the pharmaceutical composition with HPMC, in which case solubility increases 2-fold.

Example 10: A pharmaceutical composition comprising predominantly amorphous abiraterone acetate and HPMCAS

Crystalline abiraterone acetate (Form I) was dissolved in 600 mL of methanol: dichloromethane (5:1). To this solution was added the HPMCAS, poloxamer, croscarmellose sodium, lactose monohydrate and hydroxypropyl cellulose. The solvent was removed from the resulting suspension by spray drying. Spray drying parameters: peristaltic pump performance 20%; inlet temperature 80 °C; outlet temperature 60 °C; aspirator performance 100%; cooling loop temperature -20 °C. Particles were obtained with a particle size distribution according to Malvern: d(0.1) = 5.909 pm; d(0.5) = 30,327 mpi; d(0.9) = 113.643 mpi. This sample was used in the Pharmacokinetic study in rats (see Example

13). The sample is labeled Test 3.

The prepared composition was characterized by X-ray powder diffraction. Figure 16 shows a powder X-ray diffraction pattern of a pharmaceutical composition containing predominantly amorphous abiraterone acetate (top) and a powder X-ray diffraction pattern of crystalline abiraterone acetate (bottom).

Figure 17 shows a comparison of the solubility of crystalline abiraterone acetate (reference) and predominantly amorphous abiraterone acetate in the pharmaceutical composition with HPMCAS, in which case the solubility increases 2-fold.

Example 11: A pharmaceutical composition comprising amorphous abiraterone acetate with HPMCAS and an antioxidant

Crystalline abiraterone acetate (Form I) was dissolved in 600 mL of methanol :dichloromethane (5:1). To this solution was added HPMCAS and butylated hydroxy anisole. Dissolution of the API together with butylated hydroxyanisole in an organic solvent ensures their contact and homogeneous distribution at the molecular level. The solvent was removed from the resulting suspension by spray drying. Spray drying parameters: peristaltic pump performance 20%; inlet temperature 80 °C; outlet temperature 60 °C; aspirator performance 100%; cooling loop temperature -20 °C.

To the prepared spray-dried powder was added croscarmellose sodium, poloxamer, prosolv, and the resulting mixture was homogenized. A granulate was prepared by briquetting and sieving through a 1 mm sieve. This granulate was mixed with mannitol and hydroxypropyl cellulose.

The prepared composition was characterized by X-ray powder diffraction. Figure 18 shows an X-ray powder diffraction pattern of a pharmaceutical composition containing predominantly amorphous abiraterone acetate (top) and an X-ray powder diffraction pattern for crystalline mannitol (bottom). Figure 19 shows a comparison of the solubility of crystalline abiraterone acetate (reference) and amorphous abiraterone acetate in the pharmaceutical composition with F1PMCAS, in which case the solubility increases 2.5 -fold.

Example 12: A pharmacokinetic study in rats assessing abiraterone acetate formulations

Four different formulations containing abiraterone acetate or a salt thereof were tested in a preclinical study in Wister male rats in the fasted state to assess the relative bioavailability. In this single -dose cross-over study, 4 tested formulation were used in 4 sequences, 4 groups and 3 periods. The sequences were designed using the principle of balanced incomplete block design (see Table I). This study was exploratory and was not conducted in line with a good laboratory practice rules.

A minimum of 6 individuals were used in each group of animals. The animals were cannulated at least 3 days prior to the first administration of the test preparations. The animals did not have access to food for at least 2 hours prior to administration and 4 hours after administration of the test preparations; access to water was not restricted. The test preparations were administered by oral gavage in the form of a suspension which was prepared immediately prior to the administration. The time between administration of 2 preparations was at least 48 hours.

Table I: Sequences of Administration for Individual Groups of Rats. R = Reference, T1 = Test 1 (Example 2), T2 = Test 2 (Example 7), T3 = Test 3 (Example 10).

Blood samples were collected from cannulated animals prior to the administration of the tested formulation (0 hours), and then 0.5; 1; 1.5; 2; 2.5; 3 and 4 hours after the administration. The samples were processed and the plasma concentration of abiraterone was determined by LC -MS/MS method. The concentration data was normalized to the weight of the particular animal at the beginning of each period. Primary pharmacokinetic parameters, the maximum concentration (Cmax) and the area under the curve from 0 to 4 hours (AUCo4_h), were calculated by non-compartmental analysis using Phoenix® WinNonlin® version 8.1 software (Pharsight Corporation, Mountain View, California, USA). AUCo 4_h was estimated using a trapezoidal rule. The bioequivalence calculation was performed using the same software, using data of those animals from which all samples from at least 2 periods were obtained. From the exponential difference of the primary parameter (Cmax or AUC0-4h) after transformation by natural logarithm between the individual Tests and Reference, the difference of the least squares geometric mean (point estimate) and the corresponding 90% confidence interval for each Test were calculated.

The pharmacokinetic parameter values and the results of the bioequivalence assessment are shown in Fig. 20 and Table II. The medians for Cmax and AUCo 4_h show increasing values for products in the order of Reference < Test 1 < Test 2 < Test 3. The bioequivalence calculation demonstrates the higher bioavailability of all tested formulations, compared to Reference (100%), namely an increase in bioavailability to 129.90% for Test 1, 196.45% for Test 2 and 248.23% for Test 3.

Table II: Bioequivalence results for individual Tests, compared to Reference, namely point estimates and confidence intervals for Cmax and AUCo 4_h

Example 13: A pharmaceutical composition comprising amorphous abiraterone acetate with HPMCAS and an antioxidant for a pharmacokinetic study in healthy human volunteers

Crystalline abiraterone acetate (Form I) was dissolved in 3 390 mL of methanol. To this solution was added HPMCAS and butylated hydroxyanisole. Dissolution of the API together with butylated hydroxyanisole in an organic solvent ensures their contact and homogeneous distribution at the molecular level. The solvent was removed from the resulting suspension by spray drying. Spray drying parameters: peristaltic pump performance 35 %; inlet temperature 109 °C; outlet temperature 45 °C; aspirator performance 100%; cooling loop temperature -20 °C.

To the prepared spray-dried powder was added croscarmellose sodium, poloxamer, prosolv, and the resulting mixture was homogenized. A granulate was prepared by briquetting and sieving through a 1 mm sieve. This granulate was mixed with mannitol and hydroxypropyl cellulose. Tablet labelet„Test“ containing 100 mg of Abiraterone acetate were prepared on StyOne single puch press.

Spray dried particles in all examples showing the composition of the invention had a d(0.9) < 250 pm.

Example 14: A pharmacokinetic study in healthy human volunteers assessing abiraterone acetate formulations

Pharmacokinetics parameters of formulation (Example 13) were compared with reference drug product Zytiga® in fed (after meal) and fasted (on an empty stomach) state. The formulation was formulated as tablets with the API content of 100 mg, and it is labeled as Test in this example.

The study was performed in two parts in cross-over design, with dosing at the same time. The first part involved 21 volunteers, which take the prototype (Test) in 500 mg final dose (dosing 5x 100 mg tablet) or Zytiga (Reference) in 1000 mg final dose (dosing 2x 500 mg tablet).

In the second part, the influence of the dosing after a meal was tested. This part involved 12 volunteers which take the prototype formulation (Test) in 800 mg total dose (dosing 8x 100 mg tablet), wherein the formulation is administered on an empty stomach or after a high-fat meal in cross-over design study.

Blood sampling was carried out in both parts of the study 0; 0.33; 0.67; 1; 1.33; 1.67; 2; 2.33; 2.67; 3; 3.5; 4; 5; 6; 8; 12; a 24 hours after the administration of the formulation. Samples were analysed by LC-MS/MS using a validated analytical method. The abiraterone concentration in blood was determined in the samples. Primary pharmacokinetic parameters are maximum concentration (Cmax) and area under the curve from 0 to 24 hours (AUCo 24_h). The primary pharmacokinetic parameters were calculated by non-compartment analysis with software Phoenix® WinNonlin® version 8.1 (Pharsight Corporation, Mountain View, Kalifornie,USA).

AUCo 24_h estimate was obtained by the use of trapezoid rule. Calculation of bioequivalence was performed using the same software. From the exponential difference of the primary parameter (Cmax or AUCo 24_h) after logarithmic transformation between the Test and the Reference, or between the Test administered on an empty stomach and the Test administered after a meal, respectively the difference of the least squares geometric mean (point estimate) and the corresponding 90% confidence interval were calculated.

Results of bioequivalence for both parts of the study are shown in Table III. Briefly, in the first part it was found that Cmax for the Test represents 62% of the Cmax for the Reference (100%) and AUCo -24_h for the Test represents 64% of the value for the Reference. After the normalization to the dose, the values for the Test (relative to the Reference) are 124% for Cmax and 128% for AUCo -m. It can thus be concluded that the tested prototype has 28% higher bioavailability than the Reference (Zytiga).

In the second part it was found that in comparison to administration on an empty stomach (fasted state; 100%), the value of the primary pharmacokinetic parameters at administration after a meal corresponded to 314% for Cmax and 401% for AUCo -24_h- These values are significantly lower than the values observed for the reference drug product Zytiga, wherein administration after a meal results in 17-fold increase of the Cmax (therefore 1700%) a 10-fold increase of the AUCo -24_h (therefore 1000%).

Table III: Bioequivalence results for the Test in comparison with Reference or different conditions of administration of the Test, respectively Cmax a AUCo 24_h

Measuring methods

Dissolution of abiraterone acetate in dissolution medium pH = 2 by suspension dissolution method

Tested samples were weighed to give 20 mg of the active ingredient. The powder was suspended in 5 ml, of demineralized water and then transferred to a dissolution vessel. The dissolution rate of all tested forms was measured using Sotax AT -7 dissolution apparatus using mini-paddles. Dissolution test was carried out in 200 ml of a pH 2.0 solution (10 mM HC1), at a constant rate of 125 RPM until the 45th minute of the experiment and at an increased speed of 250 RPM until the 60th minute. Samples were taken at 5-minute intervals and the dissolved abiraterone acetate concentration was determined using a Jena Analytik UV/Vis spectrophotometer at 270 nm in 5mm cuvettes.

X-ray powder diffraction (XRPD)

Diffractograms were obtained using X'PERT PRO MPD PANalytical powder diffractometer, CuKa radiation (l = 1.542 A), excitation voltage: 45 kV, anode current: 40 mA, measuring range: 2 - 40° 2Q, step size: 0.02° 2Q. The measurement was performed on a flat sample, which was applied to a Si plate. For the primary beam correction, 0.02 rad Soller orifice plates, a 10 mm mask, and a 1/4° fixed anti scattering orifice plate were used. The irradiated area of the sample is 10 mm, programmable divergence screens were used. For the correction of the secondary beam, 0.02 rad Sober orifice plates and 5.0 mm anti-scattering orifice plate were used.

Differential Scanning Calorimetry (DSC)

DSC spectra of crystalline forms of abiraterone acetate HC1 were measured using Discovery DSC apparatus from TA Instruments. 4-5 mg of the sample was weighed into a standard A1 crucible (40 pL) and a heating rate was 5 °C/min. The temperature program that was used consists of 1 stabilization minute at 0 °C and then heating to 250 °C at a heating rate of 5 °C/min (amplitude = 0.8 °C and period = 60 s). 5.0 N2 at a bow rate of 50 ml /min was used as the carrier gas.

Malvern - particle size measurement

Particle size measurements were performed using Malvern Mastersizer 2000 using a Hydro 2000S unit. The sample weight corresponding to 75 mg API was suspended in 30 ml of water with stirring followed by sonication for 1 min to achieve homogeneity. The dispersion was filled into the reservoir until the detector response (5% - 10%) was achieved.

Stirring was maintained at 1500 rpm for the duration of the measurement, and data was recorded every 30 seconds. All spray-dried compositions of the invention had a particle size satisfying the condition d (0.9) < 250 pm.

Claims

1. An immediate -release pharmaceutical composition, characterized in that it comprises particles containing amorphous or predominantly amorphous abiraterone acetate or a salt of abiraterone acetate, and at least one polymer selected from the group of cellulose derivatives, and the composition further comprises a poloxamer.

2. The pharmaceutical composition according to claim 1 , wherein the cellulose derivatives are selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulose and esters thereof.

3. The pharmaceutical composition according to claim 1 or 2, wherein the cellulose derivatives are selected from the group consisting of hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, cellulose acetate butyrate.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the particles comprise amorphous or predominantly amorphous abiraterone acetate or abiraterone acetate hydrochloride, at least one cellulose derivative and a poloxamer.

5. The pharmaceutical composition according to any one of claims 1 to 4, comprising a cellulose derivative in a weight ratio to abiraterone acetate or to a salt of abiraterone acetate ranging from 0.9:1 to 4:1, and a poloxamer in a weight ratio to abiraterone acetate or to a salt of abiraterone acetate ranging from 0.05:1 to 0.2:1.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the particles are obtainable by spray drying.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the particles have a particle size d(0.9) < 250 pm.

8. The pharmaceutical composition according to any one of claims 1 to 7, comprising an antioxidant in an amount ranging from 0.0009 to 0.9% by weight, based on the total weight of the formulation.

9. The pharmaceutical composition according to any one of claims 1 to 8, which is in the form of a tablet, capsule, powder, pellet or granule.

10. A process for preparing a pharmaceutical composition according to claim 1, wherein the abiraterone acetate or the salt of abiraterone acetate is dissolved, at least one cellulose derivative is added, the mixture is dried, preferably by spray drying, and then the mixture is granulated with the addition of at least one additional excipient, wherein said at least one additional excipient comprises a poloxamer.

11. A process for preparing a pharmaceutical composition according to claim 1, wherein the abiraterone acetate or the salt of abiraterone acetate is dissolved, at least one cellulose derivative and a poloxamer are added, and the mixture is dried, preferably by spray drying.