EP3512504A1 - Procédé de production d'une formulation solide d'acétate d'abiratérone au moyen du procédé de granulation en lit fluide - Google Patents

Procédé de production d'une formulation solide d'acétate d'abiratérone au moyen du procédé de granulation en lit fluide

Info

Publication number
EP3512504A1
EP3512504A1 EP17771978.8A EP17771978A EP3512504A1 EP 3512504 A1 EP3512504 A1 EP 3512504A1 EP 17771978 A EP17771978 A EP 17771978A EP 3512504 A1 EP3512504 A1 EP 3512504A1
Authority
EP
European Patent Office
Prior art keywords
preparing
accordance
abiraterone acetate
fluid
excipients
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.)
Withdrawn
Application number
EP17771978.8A
Other languages
German (de)
English (en)
Inventor
Pawel STASIAK
Monika Kurkova
Jaroslava SVOBODOVA
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
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Zentiva KS filed Critical Zentiva KS
Publication of EP3512504A1 publication Critical patent/EP3512504A1/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K9/1682—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
    • 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
    • A61K9/20—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

Definitions

  • This invention relates to solid formulations of abiraterone acetate, in particular granules, tablets and capsules prepared using the fluid granulation method. Good dissolution characteristics of such formulations have been proved using an in vitro method.
  • Abiraterone ((3 )-17-(pyridin-3-yl) androsta-5,16-dien-3-ol; CAS: 154229-19-3; formula: C 24 H 31 NO; molar mass: 349.5 g/mol) is an inhibitor of CYP17. It prevents synthesis of androgens in the testicles, adrenal glands and tissue with a prostate tumor.
  • Abiraterone acetate (17-(3-Pyridyl) androsta-5 acetate, CAS #154229-18-2), a prodrug of abiraterone, has been approved for the treatment of castration-resistant prostate carcinoma.
  • Abiraterone acetate is considered to be a substance that is poorly soluble in water (US 20150246060 A).
  • Zytiga® 250 mg tablets are approved in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate carcinoma.
  • the package insert information for Zytiga® tablets recommends 1000 mg (tablets 4x250 mg) administered orally once a day in combination with prednisone (5 mg) administered orally twice a day (US 20150246060A).
  • Granulation is a process wherein small particles are agglomerated to a bigger mass where the original particles still remain identifiable.
  • particles are subjected to spraying to achieve agglomeration of the active substance and excipients during mixing of the binder, usually in a high-speed mixer or a fluid layer. Particles are agglomerated by a combination of capillary and viscose forces until more stable bonds are created after drying. Granulation prevents disintegration of the constituents of a powdery mixture, improves the flow characteristics of the mixture and improves compression into tablets (AAPS PharmSciTech, 15 (4), 2014, 1039-1048).
  • dry powder is stirred in a bowl comprising a stirrer rotating on a horizontal plane and a breaker rotating on a vertical or horizontal plane.
  • a stirrer rotating on a horizontal plane
  • a breaker rotating on a vertical or horizontal plane.
  • the powders are mixed.
  • Granules are produced, liquid drops being dispersed in the powder and growing until the prescribed time has elapsed. Then, granules are removed to the next part of the plant where drying is carried out (AAPS PharmSciTech, 15 (4), 2014, 1039-1048).
  • fluid granulators feature a number of advantages. All the processes, including drying, are carried out in the same device. This saves labor costs, transfer costs and time (AAPS PharmSciTech, 15 (4), 2014, 1039-1048).
  • the original drug Zytiga® is produced with the use of high-speed granulation.
  • granules produced with the use of the high-speed technology have different physical characteristics from granules produced in a fluid granulator. The differences comprise the bulk density, which is generally higher with the use of the high-speed granulation process, and porousness, which is higher with the use of the general fluid granulation process (Int J Pharm, 237, 2002, 1-14).
  • This has an impact on the dissolution behavior of the resulting formulations (e.g. tablets, capsules), which is usually slower in the case of the high-speed granulation process.
  • data from the reference literature indicate that both the technologies ( Int J Pharm, 237, 2002, 1-14) can achieve similar dissolution behavior by optimizing the process parameters.
  • the present invention relates to a solid formulation of abiraterone acetate, in particular granules, tablets and capsules prepared using the fluid granulation method. Since the product Zytiga (Janssen-Cilag), which is commercially available at present, is produced with the use of high-speed technology, another production device for drying of granules is required. Unlike the high number of publications that mention a higher dissolution rate of products made using the fluid granulation technology as compared to the standard granulation method we have found out that dissolution of abiraterone acetate remains on a similar level if fluid granulation and at the same time suitable process parameters are used.
  • abiraterone acetate In addition, due to a low solubility and biological availability, abiraterone acetate must be used in a micronized form.
  • the disadvantage of the fluid granulation method is that micronized materials usually tend to deposit on the device walls. This is manifested in unsatisfactory determination of the content of the active substance in the drug form.
  • elaborate studies dealing with the process parameters of the method have led to generating a robust preparation method with the determination of 95.0 to 105.0% by weight of abiraterone acetate, wherein granules do not settle on the walls, with meets the product specification limits.
  • Our observations have led to the development of a quick preparation method, maintaining the CQA (Critical Quality Attributes).
  • the preparation method in accordance with the invention is well reproducible and provides solid drug forms of abiraterone acetate with the required physical parameters.
  • the method is characterized by the following steps:
  • Abiraterone acetate is mixed with one or more of the following excipients:
  • binders such as, without limitation, povidone, water-soluble cellulose derivatives (preferably methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose), sugar alcohols (preferably mannitol, sorbitol), calcium sulphate, calcium phosphate, starch;
  • fillers such as e.g., without limitation, microcrystalline cellulose, lactose, calcium phosphate, glucose, cellulose and its derivatives, calcium carbonate, starch, mannitol or other sugar alcohols;
  • disintegrants such as, without limitation, sodium croscarmellose, sodium starch glycolate, crospovidone, alginates;
  • surfactants such as, without limitation, sodium lauryl sulphate, polyoxyethylene sorbitans.
  • the mixture containing abiraterone acetate and excipients is granulated, dried and ground.
  • the granulation method is based on using a fluid granulator.
  • the powdery material is granulated with water or an aqueous solution of suitable excipients as surfactants and binders to a fluid layer of a mixture of abiraterone acetate with the excipients, namely at a temperature of 20 - 60°C, preferably 25 - 50°C and most preferably 30 - 40°C.
  • the granulated material is then dried at a temperature of 20 - 60°C, preferably 25 - 50°C and most preferably 30 - 40°C until the water content of 0.1-5%, preferably 0.5-3% and most preferably 1.0-2.0% by weight is achieved.
  • the dry material is then crushed to granules with the use of sieves of 0.5-1.7 mm, preferably 0.6-1.5 mm and most preferably 0.8-1.25 mm.
  • the crushing method is carried out in such a way for the resulting granules to meet the following parameters:
  • the granules can be possibly mixed with one or more excipients from the following list:
  • disintegrants such as, without limitation, sodium croscarmellose, sodium starch glycolate, crospovidone, alginates;
  • glidants such as, without limitation, colloidal silicon dioxide, corn starch;
  • moisteners such as, without limitation, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, talc, polyethylene oxide;
  • surfactants such as, without limitation, sodium lauryl sulphate.
  • the tabletting matter is compressed with the use of a rotary tabletting press into cores, which may be coated with any type of coating material ensuring immediate releasing.
  • the compression is carried out with the use of the pre-compression force of 0 - 20 kN and compression force of 5 - 40 kN.
  • the tablet cores can be possibly coated with:
  • a film-forming polymer such as, without limitation, hypromellose, polyvinyl alcohol, polyvinylpyrrolidone or their mixtures;
  • plasticizers such as, without limitation, polyethylene glycol (Macrogol), triethyl citrate, dibutyl sebacate;
  • anti-sintering agents such as, without limitation, talc, lactose
  • the entire preparation method defined by the patent claims comprises the following steps: a) mixing of abiraterone acetate with excipients selected from the group comprising fillers, binders, disintegrants, surfactants;
  • excipients selected from the group comprising disintegrants, glidants, surfactants and moisteners;
  • Fig. 1 Dissolution profiles of selected batches (Examples 1-4), acetate buffer solution with pH 4.5, 0.2% by weight, sodium lauryl sulphate, paddle device (30 rpm, 45 min; 150 rpm, 15 min), PEAK beakers.
  • Tablets comprising 250 mg of abiraterone acetate, 200 mg of lactose monohydrate, 140 mg of microcrystalline cellulose, 43 mg of sodium croscarmellose, 36 mg of povidone, 29.0 mg of sodium lauryl sulphate, 7 mg of colloidal anhydrous silicon dioxide and 10 mg of magnesium stearate in the tablet core were produced by fluid granulation of abiraterone acetate with microcrystalline cellulose, lactose monohydrate, a part of sodium croscarmellose, povidone and sodium lauryl sulphate with the use of a Glatt GPCG2 fluid granulator with the following parameters:
  • the granules are dried at the following parameters:
  • the granules are then sieved with the use of an oscillating sieving device 0.8 mm, being mixed with a part of sodium croscarmellose, colloidal anhydrous silicon dioxide and magnesium stearate.
  • the tabletting matter is compressed into tablet cores 715 mg with a rotary tabletting press.
  • Tablets comprising 250 mg of abiraterone acetate, 200 mg of lactose monohydrate, 140 mg of microcrystalline cellulose, 43 mg of sodium croscarmellose, 36 mg of povidone, 29.0 mg of sodium lauryl sulphate, 7 mg of colloidal anhydrous silicon dioxide and 10 mg of magnesium stearate in the tablet core were produced by fluid granulation of abiraterone acetate with microcrystalline cellulose, lactose monohydrate, a part of sodium croscarmellose and povidone with the use of a Glatt GPCG2 fluid granulator at the following parameters:
  • the granules were dried with the use of the following settings:
  • the granules are then dried with the use of an oscillating sieving device 0.8 mm in a mixture with sodium croscarmellose, colloidal anhydrous silicon dioxide and magnesium stearate.
  • the tabletting matter is compressed into tablet cores 715 mg with a rotary tabletting press.
  • Tablets comprising 250 mg of abiraterone acetate, 200 mg of lactose monohydrate, 140 mg of microcrystalline cellulose, 43 mg of sodium croscarmellose, 36 mg of povidone, 29.0 mg of sodium lauryl sulphate, 7 mg of colloidal anhydrous silicon dioxide and 10 mg of magnesium stearate in the tablet core were produced by fluid granulation of abiraterone acetate with microcrystalline cellulose, lactose monohydrate and a part of sodium croscarmellose with the use of a Glatt GPCG2 fluid granulator with the following parameters:
  • the granules were dried at the following parameters:
  • Tablets comprising 250 mg of abiraterone acetate, 200 mg of lactose monohydrate, 140 mg of microcrystalline cellulose, 43 mg of sodium croscarmellose, 36 mg of povidone, 29.0 mg of sodium lauryl sulphate, 7 mg of colloidal anhydrous silicon dioxide and 10 mg of magnesium stearate in the tablet core were produced by high-speed granulation of abiraterone acetate with macrocrystalline cellulose, lactose monohydrate, a part of sodium croscarmellose, povidone and sodium lauryl sulphate with the use of a Glatt VG50 high-speed granulator with the following parameters:
  • the granules are then sieved with the use of an oscillating sieving device 0.8 mm, in a mixture with a part of sodium croscarmellose, colloidal anhydrous silicon dioxide and magnesium stearate.
  • the tabletting matter is compressed into tablet cores 715 mg with a rotary tabletting press.
  • the dissolution test was carried out with an acetate buffer solution with pH 4.5 containing 0.2% by weight of sodium lauryl sulphate with the use of a paddle device (30 rpm, 45 min; 150 rpm, 15 min, Fig. 1).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des formulations solides d'acétate d'abiratérone, en particulier des granules, des comprimés et des capsules préparées à l'aide du procédé de granulation en lit fluide. De bonnes caractéristiques de dissolution de telles formulations ont été démontrées à l'aide d'un procédé in vitro.
EP17771978.8A 2016-09-16 2017-08-30 Procédé de production d'une formulation solide d'acétate d'abiratérone au moyen du procédé de granulation en lit fluide Withdrawn EP3512504A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ2016-573A CZ2016573A3 (cs) 2016-09-16 2016-09-16 Pevná formulace abirateronu acetátu vyráběná technologií fluidní granulace
PCT/CZ2017/000057 WO2018050131A1 (fr) 2016-09-16 2017-08-30 Procédé de production d'une formulation solide d'acétate d'abiratérone au moyen du procédé de granulation en lit fluide

Publications (1)

Publication Number Publication Date
EP3512504A1 true EP3512504A1 (fr) 2019-07-24

Family

ID=59955309

Family Applications (1)

Application Number Title Priority Date Filing Date
EP17771978.8A Withdrawn EP3512504A1 (fr) 2016-09-16 2017-08-30 Procédé de production d'une formulation solide d'acétate d'abiratérone au moyen du procédé de granulation en lit fluide

Country Status (4)

Country Link
EP (1) EP3512504A1 (fr)
CZ (1) CZ2016573A3 (fr)
RU (1) RU2019110098A (fr)
WO (1) WO2018050131A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020126017A1 (fr) * 2018-12-20 2020-06-25 Pharmaceutical Oriented Services Ltd Forme posologique contenant de l'acétate d'abiratérone

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB201207886D0 (en) 2012-05-04 2012-06-20 Jagotec Ag Improvements in or relating to organic compounds
WO2014009436A1 (fr) * 2012-07-11 2014-01-16 Sandoz Ag Nanosuspension d'acétate d'abiratérone
CN105007898A (zh) * 2012-12-19 2015-10-28 卡希夫制药有限责任公司 难溶性药物的过饱和的稳定纳米颗粒
US20150246060A1 (en) 2013-03-15 2015-09-03 Iceutica Inc. Abiraterone Acetate Formulation and Methods of Use
WO2015032873A1 (fr) * 2013-09-06 2015-03-12 Synthon B.V. Compositions pharmaceutiques à charge élevée comprenant de l'acétate d'abiratérone
AU2017275396A1 (en) 2016-06-03 2018-11-22 Aragon Pharmaceuticals, Inc. Anticancer compositions

Also Published As

Publication number Publication date
RU2019110098A (ru) 2020-10-16
CZ2016573A3 (cs) 2018-03-28
WO2018050131A1 (fr) 2018-03-22
RU2019110098A3 (fr) 2020-10-16

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