WO2020026126A1 - Compositions pharmaceutiques stables comprenant de l'acétate d'abiratérone et leur procédé de préparation - Google Patents

Compositions pharmaceutiques stables comprenant de l'acétate d'abiratérone et leur procédé de préparation Download PDF

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WO2020026126A1
WO2020026126A1 PCT/IB2019/056464 IB2019056464W WO2020026126A1 WO 2020026126 A1 WO2020026126 A1 WO 2020026126A1 IB 2019056464 W IB2019056464 W IB 2019056464W WO 2020026126 A1 WO2020026126 A1 WO 2020026126A1
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Prior art keywords
pharmaceutical composition
acetate
abiraterone acetate
pharmaceutically acceptable
composition according
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PCT/IB2019/056464
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English (en)
Inventor
Melinda KONTA
Gergely SZAKONYI
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Richter Gedeon Nyrt.
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Priority to EP19779954.7A priority Critical patent/EP3829542A1/fr
Publication of WO2020026126A1 publication Critical patent/WO2020026126A1/fr

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    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • 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
    • 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
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to a safe manufacturing process for the preparation of stable pharmaceutical compositions comprising abiraterone acetate or pharmaceutically acceptable salts, hydrates or solvates thereof, and to the use of said compositions in the treatment of cancer.
  • Abiraterone is a selective inhibitor of CYP17A1, an enzyme complex, which manifests as two enzymes 17a- hydroxylase and C17, 20-lyase.
  • CYP17A1 is expressed in testicular, adrenal, and prostatic tumor tissues.
  • Said enzyme complex catalyzes the conversion of pregnenolone and progesterone to their 17-a-hydroxy derivatives by its 17 a-hydroxylase activity, and the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, by its C17, 20-lyase activity.
  • DHEA and androstenedione are precursors of testosterone, thus, the inhibition of CYP17A1 activity decreases circulating levels of testosterone and other androgens.
  • Abiraterone acetate is a white to off-white powder practically insoluble in aqueous media (pH range 2.0 to 12.9), very slightly soluble in 0.1N HC1 solution and soluble to freely soluble in organic solvents. Abiraterone acetate is classified as a Class IV compound (low solubility and low permeability) according to the biopharmaceutical classification system (BCS).
  • BCS biopharmaceutical classification system
  • abiraterone acetate is a reproductive toxin.
  • the risk of impaired fertility (R62) and the risk of harm to the unborn child (R63) is possible, as stated in the safety data sheet.
  • Abiraterone acetate was first approved by the FDA in April 2011 for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC), who had received prior chemotherapy. Abiraterone acetate was launched in the USA and in Europe by Johnson & Johnson under the trade name of Zytiga®. Recent clinical trials proved, that abiraterone acetate is also useful in the treatment of advanced and metastatic breast cancer (Bonnefoi et. al Annals of Oncology 27 (2016) 812-818).
  • abiraterone acetate in water is one of the factors leading to the low bioavailability of Zytiga®. Furthermore, it is not well absorbed over the intestinal mucosa, therefore a high variability of systemic exposure is expected in vivo. This means in consequence, that, from the daily dose of 1 g, only 10 % of the drug develops a therapeutic effect. Accordingly, high amount of high potency drug is required for the manufacture of the product, which requires particular care and attention to ensure the safety for those involved in the handling of the materials. High potency drugs are highly selective pharmacologically active ingredients that bind to specific receptors or enzymes and/or could cause cancer, mutations, developmental effects or reproductive toxicity at low doses.
  • an active pharmaceutical ingredient or a finished pharmaceutical composition requires special approaches in facility design, equipment selection, and manufacturing process to achieve the desired levels of containment and minimize operator exposure.
  • the manufacturing process must be designed to protect product quality and patient safety by preventing cross-contamination, and to protect the operators who participate in the manufacturing process by environmental, health, and safety controls.
  • the assessment report of Zytiga® (EMEA/H/C/002321) published by the European Medicines Agency discloses the composition and preparation of abiraterone drug product for use as a medicament treating metastatic advanced prostate cancer (castration resistant prostate cancer) in adult patients who have received prior chemotherapy.
  • Abiraterone acetate tablets represent an immediate- release formulation for oral use packaged in high density polyethylene (HDPE) bottles of 120 tablets with polypropylene child resistant closure and foil induction seal.
  • HDPE high density polyethylene
  • the excipients of Zytiga® are: lactose monohydrate and microcrystalline cellulose as diluents, croscarmellose sodium as a disintegrant, povidone as a binder, magnesium stearate as a lubricant, colloidal silicon dioxide as a glidant, and sodium lauryl sulfate as an anionic surfactant and wetting agent.
  • the manufacture of the finished product involves conventional processes including (1) mixing, (2) granulation, (3) wet milling, (4) drying, (5) dry milling, (6) blending, (7) lubrication, (8) tablet compression, and (9) packaging.
  • Abiraterone molecule was first disclosed in the patent application
  • the tablet size is larger than usual, thus, the improvement of the final product cannot be obtained by adding more excipients.
  • There are several different difficulties during the production process for example bad flow properties, unwanted agglomeration and sticking during granulation, and the necessity of wet milling before the drying step.
  • it is difficult to granulate high volumes of micronized active substances because excipients with higher density sediment during the process, which cause problems during the compression, and the inhomogeneous distribution of the excipients decrease the dissolution properties of the tablets. Fluid granulation is not applicable, because abiraterone acetate is a non-fluidizable material.
  • WO 2016/001208 A1 discloses stable pharmaceutical compositions in the form of immediate release tablets comprising abiraterone acetate, characterized by improved solubility resulting in good bioavailability.
  • WO 2014/009437 A1 discloses a process for the preparation of a pharmaceutical composition, in which abiraterone acetate is stabilized against oxidative degradation by the addition of at least one antioxidant, wherein the antioxidant is selected from the group consisting of butylated hydroxytoluene, butylated hydrox anisole , ascorbyl palmitate, propyl gallate, alpha tocopherol or any mixtures thereof in an amount of 0.0001 % to 5 % by weight. Furthermore, the product is stabilized against oxidative degradation by using oxygen barrier packaging material, and by preparation under inert atmosphere.
  • the use of antioxidants in pharmaceutical compositions is not advantageous, as the regulatory requirements increase the cost of the production and patients take unnecessary additives.
  • the application for the registration should contain reason for inclusion for each antioxidant, proof of efficacy, the method of control in finished product, details of the labelling of the finished product and safety information.
  • the prior art discloses several different mechanisms to obtain pharmaceutical compositions with improved quality compared to Zytiga® tablets by different methods.
  • Most of the prior art relates to the improvement of bioavailability in order to decrease the daily dose.
  • products with improved bioavailability are not equivalent to the registered product, thus, this development is not desirable for the patients, as it requires long-term clinical trials, which prolongs the time of launching the product on the market.
  • biologically different formulations can cause undesirable adverse effects during the treatment, because of the much higher bioavailability compared to Zytiga®.
  • Other prior developments aimed to improve the stability of the product in different ways, for example by manufacturing the product under inert atmosphere, and by the addition of at least one antioxidant, or by using oxygen barrier packaging material.
  • compositions with improved stability which can be stored and used at room temperature for more than two years, and which can be stored in climate zones characterized by high temperature or high temperature and high humidity.
  • the objective of the present invention is to provide a safe and economic manufacturing process for an oral pharmaceutical composition
  • an oral pharmaceutical composition comprising abiraterone acetate or its pharmaceutically acceptable salts, hydrates and solvates with at least one organic solvent suitable for granulation of micronized active substance preventing the granules from forming lumps during the manufacturing process, wherein the composition is suitable for geographic regions with high relative humidity or elevated temperatures and in vitro and in vivo similar to Zytiga® tablets.
  • Figure 1 illustrates the comparative dissolution profile of Zytiga® tablets and tablets manufactured by wet granulation based on the process described in the EMEA/H/C/002321 public assessment report.
  • Figure 2 illustrates the comparative dissolution profile of Zytiga® tablets and tablets manufactured by the manufacturing process of the present invention.
  • Figure 3 illustrates the agglomerates and local inhomogeneity of the granules manufactured by wet granulation based on the process described in the EMEA/H/C/002321 public assessment report.
  • the present invention relates to a stable pharmaceutical composition with improved physicochemical characteristics and improved impurity profile comprising abiraterone acetate or pharmaceutically acceptable salts, hydrates or solvates thereof, and at least one pharmaceutically acceptable excipient; wherein said composition possesses the following features: a) an increased stability compared to Zytiga;
  • the present invention provides a process for the preparation of a stable pharmaceutical composition comprising abiraterone acetate or pharmaceutically acceptable salts, hydrates or solvates thereof, said process comprising the steps of: high shear mixing and granulation with a pharmaceutically acceptable solvent or a mixture of solvents with a dielectric constant of about 20 to about 80; drying; blending; and direct compression into tablets.
  • the present invention provides a pharmaceutical composition
  • abiraterone acetate or pharmaceutically acceptable salts, hydrates or solvates thereof obtained by a process comprising the steps of: high shear mixing and granulation with a pharmaceutically acceptable solvent or a mixture of solvents with a dielectric constant of about 20 to about 80; drying; blending; and direct compression into tablets.
  • the present invention provides a pharmaceutical composition with improved physicochemical characteristics and improved impurity profile comprising abiraterone acetate or pharmaceutically acceptable salts hydrates or solvates thereof, and at least one pharmaceutically acceptable excipient; wherein said composition possesses one or more of the following features: a) an increased stability compared to Zytiga;
  • the present invention provides a stable pharmaceutical composition with improved physicochemical characteristics and improved impurity profile comprising abiraterone acetate or pharmaceutically acceptable salts, hydrates or solvates thereof, and at least one pharmaceutically acceptable excipient; wherein said composition possesses one or more of the following features: a) it has an increased stability compared to Zytiga;
  • the pharmaceutical composition has a lower abiraterone acetate related impurity level than Zytiga.
  • the pharmaceutical composition has a lower abiraterone acetate related impurity level than Zytiga, wherein, the abiraterone acetate related impurities are selected from the group of 7-ketoabiraterone acetate, a-epoxyabiraterone acetate, b-epoxyabiraterone acetate and abiraterone.
  • Table 1 The USP acceptance criteria of impurities for abiraterone acetate
  • the 7-ketoabiraterone acetate impurity level of the composition is about zero to about 0.5 % within 30 months of storage of the final pharmaceutical composition at 25 °C/65 % RH or 30 °C/65 % RH or 30 °C/75 % RH.
  • the abiraterone impurity level of the composition is about zero to about 0.4 % within 30 months of storage of the final pharmaceutical composition at 25 °C/65 % RH or 30 °C/65 % RH or 30 °C/75 % RH.
  • the a-epoxyabiraterone acetate impurity level is about zero to about 0.8 % within 30 months of storage of the final pharmaceutical composition at 25 °C/65 % RH or 30 °C/65 % RH or 30 °C/75 % RH.
  • the b-epoxyabiraterone acetate impurity level is about zero to about 0.8 % within 30 months of storage of the final pharmaceutical composition at 25 °C/65 % RH or 30 °C/65 % RH or 30 °C/75 % RH.
  • the abiraterone acetate related unspecified impurity level is about zero to about 0.2 % within 30 months of storage of the final pharmaceutical composition at 25 °C/65 % RH or 30 °C/65 % RH or 30 °C/75 % RH.
  • the abiraterone acetate related total impurity level is about zero to about 2.0 % within 30 months of storage of the final pharmaceutical composition at 25 °C/65 % RH or 30 °C/65 % RH or 30 °C/75 % RH.
  • the 7-ketoabiraterone acetate impurity level of the composition is about zero to about 0.5 % within 36 months of storage of the final pharmaceutical composition at 25 °C/65 % RH or 30 °C/65 % RH or 30 °C/75 % RH.
  • the abiraterone impurity level of the composition is about zero to about 0.4 % within 36 months of storage of the final pharmaceutical composition at 25 °C/65 % RH or 30 °C/65 % RH or 30 °C/75 % RH.
  • the a-epoxyabiraterone acetate impurity level is about zero to about 0.8 % within 36 months of storage of the final pharmaceutical composition at 25 °C/65 % RH or 30 °C/65 % RH or 30 °C/75 % RH.
  • the b-epoxyabiraterone acetate impurity level is about zero to about 0.8 % within 36 months of storage of the final pharmaceutical composition at 25 °C/65 % RH or 30 °C/65 % RH or 30 °C/75 % RH.
  • the abiraterone acetate related unspecified impurity level is about zero to about 0.2 % within 36 months of storage of the final pharmaceutical composition at 25 °C/65 % RH or 30 °C/65 % RH or 30 °C/75 % RH.
  • the abiraterone acetate related total impurity level is about zero to about 2.0 % within 36 months of storage of the final pharmaceutical composition at 25 °C/65 % RH or 30 °C/65 % RH or 30 °C/75 % RH.
  • the pharmaceutical composition is stabilized against oxidative degradation without the use of a special package and/or storage conditions.
  • the stable pharmaceutical compositions are suitable for oral administration.
  • the present invention relates to the process for the preparation of a stable pharmaceutical composition with improved stability profile comprising abiraterone acetate or pharmaceutically acceptable salts, hydrates, or solvates thereof, comprising the steps of: high shear mixing and granulation with a pharmaceutically acceptable solvent or a mixture of solvents with a dielectric constant of about 20 to about 80; drying; blending; and direct compression into tablets.
  • the process is performed in a high-shear granulator without wet milling.
  • the process comprises the steps of:
  • step (3) adding the granulation solution obtained in step (2) to the blend obtained in step (1) and kneading;
  • step (4) blending colloidal silicon dioxide with the granules obtained in step (4) in a blender and/or a high shear granulator;
  • the pharmaceutically acceptable solvents are selected from the group of acetone, acetonitrile, dimethyl-sulfoxide, ethyl acetate, ethanol, isopropanol, n-propanol, methanol, methylene chloride, tetrahydrofuran, and water or any mixtures thereof.
  • the dielectric constant of the applied solvent or solvent mixture is about 20 to about 80.
  • the dielectric constant of the applied solvent or solvent mixture is about 25 to about 75. In another embodiment, the dielectric constant of the applied solvent or solvent mixture is about 25 to about 70.
  • the dielectric constant of the applied solvent or solvent mixture is about 25 to about 65. In another embodiment, the dielectric constant of the applied solvent or solvent mixture is about 25 to about 60.
  • the dielectric constant of the applied solvent or solvent mixture is about 25 to about 55.
  • the dielectric constant of the applied solvent or solvent mixture is about 30 to about 55.
  • the dielectric constant of the applied solvent or solvent mixture is about 30 to about 50.
  • the pharmaceutically acceptable solvent mixture comprises purified water and at least one other pharmaceutically acceptable solvent selected from the group of acetone, acetonitrile, dimethyl-sulfoxide, ethyl acetate, ethanol, isopropanol, n-propanol, methanol, methylene chloride, and tetrahydrofuran.
  • the pharmaceutically acceptable solvent mixture comprising water and at least one other pharmaceutically acceptable solvent, is characterized by a ratio of 6: 1 % w/w, and a dielectric constant of approximately 65-75.
  • the pharmaceutically acceptable solvent mixture comprising water and at least one other pharmaceutically acceptable solvent, is characterized by a ratio of 4: 1 % w/w, and a dielectric constant of approximately 60-70.
  • the pharmaceutically acceptable solvent mixture comprising water and at least one other pharmaceutically acceptable solvent, is characterized by a ratio of 2 : 1 % w/ w, and a dielectric constant of approximately
  • the pharmaceutically acceptable solvent mixture comprising water and at least one other pharmaceutically acceptable solvent, is characterized by a ratio of 1 : 1 % w/ w, and a dielectric constant of approximately
  • the pharmaceutically acceptable solvent mixture comprising water and at least one other pharmaceutically acceptable solvent, is characterized by a ratio of 1:2 % w/w, and a dielectric constant of approximately 35-45.
  • the pharmaceutically acceptable solvent mixture comprising water and at least one other pharmaceutically acceptable solvent, is characterized by a ratio of 1 :4 % w/w, and a dielectric constant of approximately
  • the granules obtained in step (3) are dried in a high shear granulator at a temperature of approximately 5 to 50 °C. In another embodiment, the granules obtained in step (3) are dried in a high shear granulator at a temperature of approximately 5 to 45 °C.
  • the granules obtained in step (3) are dried in a high shear granulator at a temperature of approximately 5 to 40 °C.
  • the granules obtained in step (3) are dried in a high shear granulator at a temperature of approximately 5 to 35 °C.
  • the granules obtained in step (3) are dried in a high shear granulator at a temperature of approximately 5 to 30 °C.
  • the granules obtained in step (3) are dried in a high shear granulator under vacuum. In one embodiment, the granules obtained in step (3) are dried in a high shear granulator under vacuum and/or using microwave energy and/or bowl heating.
  • the present invention relates to a process for the preparation of pharmaceutical compositions, in which abiraterone acetate or pharmaceutically acceptable salts, hydrates or solvates thereof is manufactured in an economical and safe way.
  • the granules remain in the high shear equipment until the end of the process.
  • the present invention provides a pharmaceutical composition with improved physicochemical characteristics and improved impurity profile comprising abiraterone acetate or pharmaceutically acceptable salts hydrates or solvates thereof, and at least one pharmaceutically acceptable excipient; wherein said composition possesses the following features: a) an increased stability compared to Zytiga;
  • cancer preferably early stage or metastatic prostate cancer or breast cancer.
  • the dielectric constant of the solvent or solvent mixture is critical during the granulation of abiraterone acetate, as it has the tendency to separate from polar granulating solvents. Therefore - especially in the case of micronized abiraterone acetate - agglomeration occurs during solvent feeding, which deteriorates the granulation process and causes local inhomogeneity. Granulating with solvents or solvent mixtures with too low dielectric constants are also not preferable, because of their inability to dissolve the granulating polymer (e.g., PVP, HPMC, etc.).
  • the use of a solvent or solvent mixture with a dielectric constant of 20-80 prevents lump formation within the granules, thus, the wet milling step used by the originator is not required.
  • the oxidative degradation of abiraterone acetate is prevented by the manufacturing process, therefore, the use of any antioxidants in the pharmaceutical compositions of the present invention is not necessary. Furthermore, there is no need to manufacture the pharmaceutical compositions of the present invention under inert gas atmosphere, and there is no need to use oxygen scavengers/ absorbers in the package.
  • compositions of the present invention maintain their stability in regions with high relative humidity and/or elevated temperatures for more than two years, without the addition of at least one antioxidant or without the preparation under inert gas atmosphere, and maintain their stability in regions with high relative humidity and / or elevated temperatures for more than two years.
  • Reproductive toxicity includes adverse effects on sexual function and fertility in adult males and females, as well as developmental toxicity in the offspring.
  • The“Biopharmaceutics Classification System” is a system to differentiate the drugs on the basis of their solubility and permeability. This system restricts the prediction using the parameters solubility and intestinal permeability.
  • the solubility classification is based on a United States Pharmacopoeia (USP) aperture.
  • USP United States Pharmacopoeia
  • the intestinal permeability classification is based on a comparison to the intravenous injection. Class IV compounds have low permeability and low solubility, thus they have poor bioavailability. Usually they are not well absorbed over the intestinal mucosa and a high variability is expected.
  • “Micronisation” is the process of reducing the average diameter of a solid material's particles. Traditional techniques for micronisation focus on mechanical means, such as milling and grinding. Modem techniques make use of the properties of supercritical fluids and manipulate the principles of solubility. The term micronisation usually refers to the reduction of average particle diameters to the micrometer range, but can also describe further reduction to the nano
  • composition refers to a finished dosage formulation, which contains the active agent abiraterone acetate or pharmaceutically acceptable salts, hydrates or solvates thereof and in the form in which it can be marketed.
  • inert atmosphere relates to a substantially oxygen free environment, e.g. nitrogen or argon atmosphere.
  • the term graspert gas is a gas which does not undergo chemical reactions under a set of given conditions, e.g. nitrogen or argon.
  • pharmaceutically acceptable describes an ingredient that is useful in preparing a pharmaceutical composition, is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes those acceptable for human pharmaceutical use.
  • salt means an ionic compound that can be formed by the neutralization reaction of an acid and a base.
  • the salts include, but not limited to tartaric, acetic, malic, methanesulfonic, trifluoromethanesulfonic, ditoluoyl tartaric, hydrochloric, sulphuric, benzenesulfonic, p-toluenesulfonic and fumaric acid salts.
  • hydrate means non-covalent combinations between water and solute.
  • solvent means non-covalent combinations between solvent and solute.
  • Solvents include, but are not limited to, ethanol, acetone, 2-propanol, acetonitrile and tetrahydrofuran.
  • ком ⁇ онент means an inorganic or an organic liquid used as a vehicle for the preparation of solutions or suspensions in the synthesis of a new drug substance or the manufacture of a new drug product (ICH Topic Q 6 A, CPMP/ICH/367/96).
  • dielectric constant or relative permittivity is a property of materials. It is associated with the polarity of the solvent in the case of liquid materials. Usually, the higher the dielectric constant of a solvent the more polar it is. For example, water is very polar and has a dielectric constant at room temperature around 80, while n-hexane is non-polar and has a dielectric constant around 2.
  • release testing means a series of tests to ensure active ingredients are free of contaminants, is present in an appropriate amount and demonstrate compliance with regulatory guidelines.
  • shelf life means the length of time that a pharmaceutical product retains the functionality, effectiveness and safety.
  • acceptance criteria means numerical limits, ranges, or other suitable measures for acceptance of the results of analytical procedures (ICH Topic Q 6 A, CPMP/ICH/367/96).
  • degradation product means a molecule resulting from a chemical change in the drug molecule brought about over time and/or by the action of e.g., light, temperature, pH, water, or by reaction with an excipient and / or the immediate container/ closure system. Also called decomposition product (ICH Topic Q 6 A, CPMP/ICH/367/96).
  • impurity means any component of the drug substance which is not the chemical entity defined as the drug substance and any component of the pharmaceutical composition which is not the chemical entity defined as the drug substance or an excipient in the pharmaceutical composition (ICH Topic Q 6 A, CPMP/ICH/367/96).
  • room temperature denotes a temperature in the range from 20°C to 25°C.
  • quantitation limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be quantitatively determined with suitable precision and accuracy.
  • the quantitation limit is a parameter of quantitative assays for low levels of compounds in sample matrices, and is used particularly for the determination of impurities and / or degradation products (ICH Topic Q2(R1), CPMP/ICH281/95).
  • composition of the Zytiga® 250 mg tablet is composition of the Zytiga® 250 mg tablet
  • Table 3 composition of the formulation containing micronized abiraterone acetate
  • Example 1 Granulation of abiraterone acetate with purified water
  • the process comprises the steps of:
  • step (2) aqueous povidone solution is prepared; (3) the granulation solution prepared in step (2) is slowly added to the blend of step (1) and the blend is granulated to form a wet mass;
  • the dried granules are homogenously mixed with sieved colloidal silicon dioxide, and lubricated with magnesium stearate to prepare the final blend;
  • the product manufactured by the above described manufacturing process exhibits an in vitro release profile, wherein on average less than about 80 % of the total abiraterone acetate is released within 30 minutes in a standard dissolution test.
  • the Zytiga® tablet exhibits a faster in vitro release profile wherein, on average more than about 80 % of the total abiraterone acetate is released within 45 minutes in a standard dissolution test.
  • Dissolution method Apparatus nr. 2 (paddle); Medium - 900 ml pH 4.5 phosphate buffer + 0.25 % sodium lauryl sulphate (SLS) - Run time 8 hours; Temperature: 37 ⁇ 0.5 °C; Stirring rate: 50 rpm.
  • SLS sodium lauryl sulphate
  • Example 2 The effect of the granulation solution’s composition on the final product
  • the granulation solution and the manufacturing process were modified in order to avoid the unwanted agglomeration and slow dissolution.
  • the immediate release composition (see Table 3) was prepared by mixing abiraterone acetate with suitable excipients, high shear granulation with water miscible solvents and/or a mixture of water miscible solvents, vacuum and/or microwave drying and/or bowl heating, regranulation, homogenization with the external phase and compression of the mixture to tablets.
  • the process comprises the steps of:
  • step (3) the granulation liquid prepared in step (2) is slowly added to the blend of step (1) and the blend is granulated to form a wet mass;
  • the granules are homogenously mixed with sieved colloidal silicon dioxide and croscarmellose sodium then lubricated with magnesium stearate to prepare the final blend;
  • the final blend is compressed into tablets with a tableting press equipment.
  • the product manufactured by the above described manufacturing process exhibits an in vitro release profile wherein on average more than about 80 % of the total abiraterone acetate is released within 45 minutes in a standard dissolution test.
  • Dissolution method Apparatus nr. 2 (paddle); Medium - 900 ml pH 4.5 phosphate buffer + 0.25 % SLS - Run time 8 hours; Temperature: 37 ⁇ 0.5 °C; Stirring rate: 50 rpm.
  • the process comprises the steps of:
  • step (3) the granulation liquid prepared in step (2) is slowly added to the blend of step
  • the granules are homogenously mixed with sieved colloidal silicon dioxide and croscarmellose sodium then lubricated with magnesium stearate to prepare the final blend;
  • the final blend is compressed into tablets with a tableting press equipment.
  • Dissolution method Apparatus nr. 2 (paddle); Medium - 900 ml pH 4.5 phosphate buffer + 0.25 % SLS - Run time 8 hours; Temperature: 37 ⁇ 0.5 °C; Stirring rate: 50 rpm.
  • Example 4 The effect of intra- granular position of the superdisintegrant
  • the process comprises the steps of:
  • step (3) the granulation liquid prepared in step (2) is slowly added to the blend of step (1) and the blend is granulated to form a wet mass; (4) the wet mass is dried by using vacuum and microwave energy;
  • the granules are homogenously mixed with sieved colloidal silicon dioxide, then lubricated with magnesium stearate to prepare the final blend;
  • the final blend is compressed into tablets with a tableting press equipment.
  • the product manufactured by the above described manufacturing process exhibits an in vitro release profile wherein on average more than about 80 % of the total abiraterone acetate is released within 45 minutes in a standard dissolution test.
  • Dissolution method Apparatus nr. 2 (paddle); Medium - 900 ml pH 4.5 phosphate buffer + 0.25 % SLS - Run time 8 hours; Temperature: 37 ⁇ 0.5 °C; Stirring rate: 50 rpm.
  • Example 5 The effect of intra- and extra- granular position of the superdisintegrant
  • the process comprises the steps of:
  • step (3) the granulation liquid prepared in step (2) is slowly added to the blend of step (1) and the blend is granulated to form a wet mass;
  • the granules are homogenously mixed with sieved colloidal silicon dioxide and the half amount of croscarmellose sodium, then lubricated with magnesium stearate to prepare the final blend;
  • the final blend is compressed into tablets with a tableting press equipment.
  • the product manufactured by the above described manufacturing process exhibits an in vitro release profile wherein on average more than about 80 % of the total abiraterone acetate is released within 45 minutes in a standard dissolution test.
  • Dissolution method Apparatus nr. 2 (paddle); Medium - 900 ml pH 4.5 phosphate buffer + 0.25 % SLS - Run time 8 hours; Temperature: 37 ⁇ 0.5 °C; Stirring rate: 50 rpm.
  • Example 6 Product dried using vacuum and microwave energy - Tablet 7683
  • the process comprises the steps of:
  • step (3) the granulation liquid prepared in step (2) is slowly added to the blend of step (1) and the blend is granulated to form a wet mass;
  • the granules are lubricated with magnesium stearate to prepare the final blend.
  • Example 7 Product dried by using vacuum and intense (60 °C) bowl heating - Tablet
  • the process comprises the steps of:
  • step (3) the granulation liquid prepared in step (2) is slowly added to the blend of step (1) and the blend is granulated to form a wet mass;
  • Example 8 Pharmaceutical compositions (Tablet 6975 and Tablet 6673) for the comparative stability study of Zytiga® and the pharmaceutical composition of the present invention
  • Example 9 Manufacture of abiraterone acetate tablets of example 8 by high shear granulation in a closed system The process comprises the steps of:
  • step (3) the granulation solution prepared in step (2) is added to the blend obtained in step (1) and kneaded;
  • step (3) the granules obtained in step (3) are dried in a high shear granulator at approximately 10°C to approximately 40°C;
  • step (4) the colloidal silicon dioxide is blended with the granules obtained in step (4) in a blender;
  • step (5) the granules obtained in step (5) are regranulated
  • magnesium stearate is sieved and blended with the granules from step (6) in a high shear granulator;
  • Example 10 comparative stability study of Tablet 6975 and Zytiga®
  • the reference composition was stored at room conditions (25 °C/65 % RH) prior to the investigation.
  • Degradation profile of the pharmaceutical composition of the present invention (Tablet 1 1) was examined under storage at room conditions (25 °C/65 % RH).
  • the Zytiga® product showed higher impurity level and degradation, stored under identical conditions.
  • the stability test with the reference Zytiga® tablets started 12 months after their manufacture, therefore, at the end of the test, the stored samples reached the shelf life of the Zytiga® product (24 months).
  • the b-epoxyabiraterone-acetate and abiraterone acetate related total impurity levels of Zytiga® are close to the USP acceptance criteria (see Table 12).
  • the pharmaceutical composition of the present invention did not show any degradation during the 12 months of the stability study (30 °C/65 % RH), as the abiraterone acetate related impurity level is under the quantitation limit.
  • the Zytiga® product showed higher impurity level and degradation stored under identical conditions. There was a significant increase in the amount of total degradation, and new impurities also appeared, which were not present at the beginning of the stability test.
  • ICH Harmonised Tripartite guideline ICH HARMONISED TRIPARTITE GUIDELINE EVALUATION FOR STABILITY DATA Q 1E
  • ICH HARMONISED TRIPARTITE GUIDELINE EVALUATION FOR STABILITY DATA Q 1E ICH Harmonised Tripartite guideline
  • Justification can include a discussion of the change pattern or lack of change, relevance of the accelerated data, mass balance, and/or other supporting data as described in the parent guideline. Extrapolation of the retest period or shelf life beyond the period covered by long-term data can be proposed.
  • test results obtained in the 18 months comparative stability study (Tablet 6975) can be extrapolated to 30 months, and the test results obtained in the 20 months stability study (Tablet 6673) can be extrapolated to 32 months. However, considering that there is no change during the storage, it is also suitable for up to 36 months shelf life without any restrictions on storage.
  • the predicted shelf life of the pharmaceutical composition of the present invention is at least 30 months, but rather 36 months which are both longer than the shelf life of the Zytiga® product (2 years).

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Abstract

La présente invention concerne un procédé de fabrication sûr pour la préparation de compositions pharmaceutiques stables comprenant de l'acétate d'abiratérone ou des sels, hydrates ou solvates pharmaceutiquement acceptables de celui-ci, et l'utilisation desdites compositions dans le traitement du cancer.
PCT/IB2019/056464 2018-07-31 2019-07-30 Compositions pharmaceutiques stables comprenant de l'acétate d'abiratérone et leur procédé de préparation WO2020026126A1 (fr)

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993020097A1 (fr) 1992-03-31 1993-10-14 British Technology Group Ltd. Steroïdes substitues-17 utiles pour le traitement du cancer
WO1995009178A1 (fr) 1993-09-30 1995-04-06 British Technology Group Limited Synthese de steroides a base de 17-(3-pyridyl)
WO2006021777A1 (fr) 2004-08-24 2006-03-02 Btg International Limited Procede de preparation de 17-0-vinyltriflates comme intermediaires
WO2014009437A1 (fr) 2012-07-11 2014-01-16 Sandoz Ag Stabilité d'oxydation d'acétate d'abiratérone
WO2014145813A1 (fr) * 2013-03-15 2014-09-18 Iceutica Inc. Formulation d'acétate d'abiratérone
EP2792682A1 (fr) * 2013-04-19 2014-10-22 Zach System Procédé pour la préparation d'un forme solide de l'actetate de l'abiraterone
WO2015032873A1 (fr) * 2013-09-06 2015-03-12 Synthon B.V. Compositions pharmaceutiques à charge élevée comprenant de l'acétate d'abiratérone
US20150246060A1 (en) * 2013-03-15 2015-09-03 Iceutica Inc. Abiraterone Acetate Formulation and Methods of Use
WO2016001208A1 (fr) 2014-06-30 2016-01-07 Galenicum Health S.L. Compositions pharmaceutiques stables sous forme de comprimés à libération immédiate

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993020097A1 (fr) 1992-03-31 1993-10-14 British Technology Group Ltd. Steroïdes substitues-17 utiles pour le traitement du cancer
WO1995009178A1 (fr) 1993-09-30 1995-04-06 British Technology Group Limited Synthese de steroides a base de 17-(3-pyridyl)
WO2006021777A1 (fr) 2004-08-24 2006-03-02 Btg International Limited Procede de preparation de 17-0-vinyltriflates comme intermediaires
WO2014009437A1 (fr) 2012-07-11 2014-01-16 Sandoz Ag Stabilité d'oxydation d'acétate d'abiratérone
WO2014145813A1 (fr) * 2013-03-15 2014-09-18 Iceutica Inc. Formulation d'acétate d'abiratérone
US20150246060A1 (en) * 2013-03-15 2015-09-03 Iceutica Inc. Abiraterone Acetate Formulation and Methods of Use
EP2792682A1 (fr) * 2013-04-19 2014-10-22 Zach System Procédé pour la préparation d'un forme solide de l'actetate de l'abiraterone
WO2015032873A1 (fr) * 2013-09-06 2015-03-12 Synthon B.V. Compositions pharmaceutiques à charge élevée comprenant de l'acétate d'abiratérone
WO2016001208A1 (fr) 2014-06-30 2016-01-07 Galenicum Health S.L. Compositions pharmaceutiques stables sous forme de comprimés à libération immédiate

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Title
ALEXANDER T FLORENCEDAVID ATTWOOD: "Physicochemical Principles of Pharmacy: In Manufacture, Formulation and Clinical Use", 2016, PHARMACEUTICAL PRESS, article "Biopharmaceutical importance of particle size"
BONNEFOI, ANNALS OF ONCOLOGY, vol. 27, 2016, pages 812 - 818

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