EP4025191A1 - Compositions pharmaceutiques d'acétate d'abiratérone - Google Patents

Compositions pharmaceutiques d'acétate d'abiratérone

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Publication number
EP4025191A1
EP4025191A1 EP20714106.0A EP20714106A EP4025191A1 EP 4025191 A1 EP4025191 A1 EP 4025191A1 EP 20714106 A EP20714106 A EP 20714106A EP 4025191 A1 EP4025191 A1 EP 4025191A1
Authority
EP
European Patent Office
Prior art keywords
abiraterone acetate
pharmaceutical composition
cellulose
amorphous
acetate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP20714106.0A
Other languages
German (de)
English (en)
Inventor
Pavel ZVATORA
Josef Beranek
Igor CERNA
Tereza Boleslavska
Ales VOGL
Jan BOSAK
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zentiva KS
Original Assignee
Zentiva KS
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Filing date
Publication date
Application filed by Zentiva KS filed Critical Zentiva KS
Publication of EP4025191A1 publication Critical patent/EP4025191A1/fr
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Definitions

  • 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.
  • 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.
  • FDA Food and Drug Administration
  • EMA European Medicines Agency
  • the bioavailability of active pharmaceutical ingredients 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.
  • the crystalline product is usually stable, easier to obtain in a pure form, and dissolves more slowly than the amorphous form.
  • 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%.
  • 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
  • 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.
  • a cellulose derivative such as hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (HPMC) or cellulose acetate butyrate
  • 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.
  • 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
  • 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.
  • 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.
  • the present invention also provides a process for preparing a pharmaceutical composition of abiraterone, said process comprising the steps of
  • the present invention further provides a process for preparing a pharmaceutical composition of abiraterone, said process comprising the steps of
  • Suitable solvents for dissolving abiraterone acetate or a salt thereof may be, for example, alcohols, chlorinated solvents, and mixtures thereof.
  • excipients such as antioxidants
  • antioxidants may only be present in the dosage form at a low concentration.
  • 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.
  • the pharmaceutical composition comprises a cellulose derivative in an amount of 15 to 45% by weight, relative to the total weight of the composition.
  • crystalline admixture 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%.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • polymers e.g. hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, methylcellulose, ethylcellulose
  • plasticizers e.g. polyethylene glycol, triacetin, triethyl citrate or mineral oil
  • other additives such as fillers and gli
  • conventional pharmaceutically acceptable pigments e.g., iron oxides, talc, aluminium compounds, titanium dioxide
  • 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.
  • 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
  • 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.
  • a protective container such as a blister or a vial.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • BCS Biopharmaceutical Classification System
  • 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).
  • 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.
  • 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.
  • HPC hydroxypropyl cellulose
  • HPMCAS hypromellose acetate succinate
  • HPMCP hypromellose phthalate
  • Soluplus 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.
  • 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.
  • 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)
  • 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.
  • FIG. 1 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.
  • 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
  • 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)
  • 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 -
  • 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
  • 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.
  • 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
  • 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.
  • Plasma 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.
  • 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.
  • 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.
  • 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 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 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).
  • Plasma samples were 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.
  • 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
  • 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.
  • the measurement was performed on a flat sample, which was applied to a Si plate.
  • 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.
  • 0.02 rad Sober orifice plates and 5.0 mm anti-scattering orifice plate were used.
  • 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.

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Abstract

L'invention concerne des compositions pharmaceutiques à libération immédiate comprenant de l'acétate d'abiratérone amorphe ou majoritairement amorphe ou un sel d'acétate d'abiratérone présentant une solubilité et une biodisponibilité supérieures, par rapport à la forme posologique d'origine comprenant de l'acétate d'abiratérone cristallin. L'amélioration de la solubilité a été démontrée dans une expérience in vitro et une amélioration in vivo de la biodisponibilité a été démontrée dans des modèles de rat et des volontaires humains.
EP20714106.0A 2019-03-20 2020-03-17 Compositions pharmaceutiques d'acétate d'abiratérone Pending EP4025191A1 (fr)

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CZ2019-168A CZ2019168A3 (cs) 2019-03-20 2019-03-20 Farmaceutická kompozice obsahující abirateron acetát
PCT/CZ2020/050014 WO2020187343A1 (fr) 2019-03-20 2020-03-17 Compositions pharmaceutiques d'acétate d'abiratérone

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AU2012284053A1 (en) 2011-07-18 2014-01-23 Tokai Pharmaceuticals, Inc. Novel compositions and methods for treating prostate cancer
WO2014009437A1 (fr) * 2012-07-11 2014-01-16 Sandoz Ag Stabilité d'oxydation d'acétate d'abiratérone
WO2014009436A1 (fr) * 2012-07-11 2014-01-16 Sandoz Ag Nanosuspension d'acétate d'abiratérone
CN105596303A (zh) * 2014-11-03 2016-05-25 重庆安格龙翔医药科技有限公司 一种稳定的醋酸阿比特龙片剂及其制备方法
HUP1500055A1 (hu) 2015-02-09 2016-08-29 Druggability Technologies Ip Holdco Ltd Abirateron acetát komplexei, eljárás elõállításukra, és az azokat tartalmazó gyógyászati készítmények
CN108785256B (zh) * 2017-04-28 2021-06-29 江苏恒瑞医药股份有限公司 一种固体分散体及其制备方法
JP2020530461A (ja) * 2017-08-09 2020-10-22 ナンジェネックス ナノテクノロジー インコーポレーテッドＮａｎｇｅｎｅｘ Ｎａｎｏｔｅｃｈｎｏｌｏｇｙ Ｉｎｃｏｒｐｏｒａｔｅｄ 酢酸アビラテロン及びダルロタミドを含む医薬組成物

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