[go: up one dir, main page]

WO2025153768A1 - Composition contenant de l'apalutamide nanométrique cristallin - Google Patents

Composition contenant de l'apalutamide nanométrique cristallin

Info

Publication number
WO2025153768A1
WO2025153768A1 PCT/FI2025/050007 FI2025050007W WO2025153768A1 WO 2025153768 A1 WO2025153768 A1 WO 2025153768A1 FI 2025050007 W FI2025050007 W FI 2025050007W WO 2025153768 A1 WO2025153768 A1 WO 2025153768A1
Authority
WO
WIPO (PCT)
Prior art keywords
apalutamide
crystalline
pvpva
nanosized
hpmc
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
PCT/FI2025/050007
Other languages
English (en)
Inventor
Tatiana DANILOVA
Martti KAASALAINEN
Nikolay HOUBENOV
Tamas Solymosi
Shuddhodana SHUDDHODANA
Petteri HELANDER
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.)
Nanoform Finland Oyj
Original Assignee
Nanoform Finland Oyj
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 Nanoform Finland Oyj filed Critical Nanoform Finland Oyj
Publication of WO2025153768A1 publication Critical patent/WO2025153768A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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
    • A61K9/141—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
    • A61K9/146—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 macromolecular 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure relates to compositions comprising crystalline nanosized apalutamide and one or more polymers, and to methods for producing the same.
  • Apalutamide (4-[7-(6-cyano-5-trifluoromethyl pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methyl benzamide, 1) is marketed by Janssen Biotech under the trade name Erleada® as 60 mg and 240 mg oral tablet in the US and EU for the treatment of patients with non-metastatic castration-resistant prostate cancer.
  • Apalutamide is practically insoluble in aqueous media over a wide range of pH values. Further, it is non-hygroscopic, crystalline solid that remains unionized over the physiologic pH range.
  • the Erleada® tablets include apalutamide as an amorphous solid dispersion (ASD) in hypromellose acetate succinate (HPMCAS).
  • ASDs are susceptible to thermodynamic instability due to the higher free energy associated with the amorphous state. Numerous factors such as the improper selection of formulation components, thermal stress, environmental stress such as humidity, and manufacturing stress contribute to the physical instability of ASD. The proper selection of formulation ingredients, manufacturing process, process parameters, and packaging components are deemed essential to obtain a stable ASD drug product. Furthermore, an ASD dose must include a significant amount of the polymer increasing the dose size.
  • PVPVA polyvinylpyrrolidone/vinyl acetate
  • HPMC hydroxypropyl methyl cellulose
  • PVPVA polyvinylpyrrolidone/vinyl acetate
  • HPMC hydroxypropyl methyl cellulose
  • It is still an object of the present disclosure to provide a pharmaceutical composition comprising an effective amount of a crystalline polymorph of apalutamide characterized by a powder X-ray diffraction pattern having peaks at 25.1 , 28.2, 30.4, and 33.0 ⁇ 0.2 [°20] and at least one pharmaceutically acceptable excipient or carrier. It is still an object of the present disclosure to provide a pharmaceutical composition comprising
  • composition comprising
  • PVPVA polyvinylpyrrolidone/vinyl acetate
  • HPMC hydroxypropyl methyl cellulose
  • Figure 2 depicts the XRD diffractogram of amorphous nanosized apalutamide.
  • the polymer is PVPVA
  • the nanosized crystalline apalutamide of the composition has powder X-ray diffraction pattern having peaks at 25.0, 28.1 , 30.3, and 32.9 ⁇ 0.2 [°20], preferably 18.5, 20.3, 21 .5, 25.0, 28.1 , 30.3, and 32.9 ⁇ 0.2 [°20], more preferably the same as the X-ray powder diffraction pattern shown in Fig 1 B.
  • the present disclosure concerns a method for producing nanoparticles of crystalline apalutamide, the method comprises a) providing solid amorphous nanosized apalutamide, preferably as dry powder; b) providing an aqueous solution comprising PVPVA and/or HPMC; c) contacting the solid amorphous nanosized apalutamide and the aqueous solution comprising PVPVA and/or HPMC to form an admixture wherein content of the amorphous nanosized apalutamide in the admixture is higher than solubility of the amorphous nanosized apalutamide in the aqueous solution, thereby obtaining a suspension comprising nanoparticles of crystalline apalutamide.
  • Particle size growth of apalutamide is inhibited during crystallization, and the resulting particles remain nanoparticles.
  • the average particle size of an amorphous apalutamide is ca. 40 nm average particle size of the apalutamide crystallized using the method of the present disclosure may be ca. 120 nm.
  • the particle size of the crystalline apalutamide would be larger than particle size of amorphous apalutamide, the crystalline apalutamide of the present disclosure is still nanosized and the particle size does not typically grow more than 300%, preferably not more than 100%, more preferably not more than 50%, still even more preferably not more than 25%, most preferably not more than 10% larger upon crystallization.
  • the content of the amorphous nanosized apalutamide in the admixture must be higher, such as at least 10 times higher, preferably at least 50 times, more preferably at least 100 times higher, even more preferably at least 500 times higher than its solubility in the aqueous solution comprising PVPVA or HPMC to form a suspension. Accordingly, the amount of the amorphous apalutamide needed for the method is dependent on its solubility to the aqueous solution comprising PVPVA and/or HPMC.
  • the solubility can be measured by any method known in the art.
  • the contacting is at 15-40 °C, preferably at 20-40 °C, such as at 30 °C.
  • the contacting comprises mixing the suspension.
  • the mixing is performed preferably for at least 10 h, more preferably for 16 h still more preferably for at least 24 h. Relatively long mixing time is preferable to achieve complete wetting and good dispersion.
  • the mixing can be done e.g. by shaking, stirring, or using a spatula.
  • the mixing and wetting can be facilitated by ultrasonication. However, high-intensity ultrasound is not needed.
  • the contacting is performed preferably for at least 24 h.
  • Apalutamide : polymer ratio is typically from 10:1 to 1 :10, more preferably from 5:1 to 1 :5, most preferably from 3:1 to 1 :1 , such as 2:1 or 1 :1 wherein amount of apalutamide is calculated as mg/mL of the suspension and amount of the polymer is calculated as weight-% of the suspension. For example, 25 mg/mL of amorphous nanosized apalutamide with 1 :1 API : PVPVA and/or HPMC ratio produces desired crystals in 24 h at 20 °C.
  • Too high polymer content may lead to slow crystal formation.
  • the optimal polymer content is dependent on the polymer.
  • the copolymer is PVPVA.
  • Content of PVPVA in the aqueous solution is typically 0.2-50 % by weight, such as 0.2 - 40% by weight, preferably from 10 wt.-% to 45 wt.-%.
  • the polymer is HPMC. Content of HPMC in the aqueous solution is typically 0.2-5 % by weight.
  • the aqueous solution comprises one or more surfactants.
  • surfactants suitable for the method are sodium lauryl sulfate (SLS) Tween 80, Tween 20, dioctyl sulfosuccinate sodium salt (DOSS), and tocofersolan (TPGS).
  • SLS sodium lauryl sulfate
  • DOSS dioctyl sulfosuccinate sodium salt
  • TPGS tocofersolan
  • the overall content of the one or more surfactants in the aqueous solution is preferably 0.0025-1 .5% by weight.
  • a particular surfactant is SLS. The surfactants enhance the wetting efficiency.
  • the suspension is dried to give a solid product comprising crystalline nanosized apalutamide and PVPVA and/or HPMC.
  • the drying can be done by using methods known in the art. Exemplary drying methods comprise heating, evaporating, vacuum drying, using a fluidized bed dryer, and freeze drying. A particular drying is evaporating. Crushing of the solid product using e.g. a mortar produces a powder ready for tableting. The crushing has no effect on the particle size.
  • the method includes removing the polymer from the suspension e.g., by filtering with hydrophilic filter or centrifuging and subsequently discarding the supernatant with PVPVA and/or HPMC solution. After this the material can be washed e.g., with water and repeating the filtering or centrifugation step. This can be repeated as many times as needed.
  • Another aspect of the present disclosure relates to a process for the preparation of pharmaceutical dosage form, the process comprising
  • composition comprising crystallized nanosized apalutamide obtained by the process of the present disclosure with one or more pharmaceutical excipients;
  • the amorphous nanosized apalutamide was prepared from bulk crystalline apalutamide purchased from Habotech using the process disclosed in US 10,098,842. XRD diffractogram of amorphous nanosized apalutamide is shown in figure 2.
  • Apalutamide loading of 20% w/w was used and tablet compression parameters (e.g., die cavity height, compression force, ejection force, strokes/min) were kept constant to investigate the impact of excipients on the tablet properties.
  • Figure 5 shows SGF-FaSSIF dissolution profiles of compositions comprising nanocrystalline apalutamide and PVPVA included 0.2 wt.-% SLS (apalutamide: polymer ratio 2:1 , w/w) prepared according to the method of the present disclosure and commercial Erleada® tablet i.e. an amorphous solid dispersion comprising apalutamide and HPMCAS. Also, SGF-FaSSIF dissolution profile of bulk apalutamide is disclosed. As seen from the figure dissolution of the composition of the present disclosure is significantly less pH sensitive than that of the amorphous solid dispersion.
  • the apalutamide compositions of the present disclosure have higher AUC than the commercial amorphous solid dispersion.
  • Compositions comprising nanocrystalline apalutamide and PVPVA or HPMC prepared according to the present disclosure were stable under accelerated conditions (40 °C/ 75% RH) up to tested 30 days as verified by HPLC and XRD analysis.
  • the nanosized crystalline apalutamide of the present does not need to be supersaturated by the polymer for stabilization. Accordingly, the amount of the polymer and/or copolymer in the dose can be reduced compared to a corresponding dose including apalutamide in amorphous form. Furthermore, the method of the present disclosure has an advantage that it does not include organic solvents which may not be completely removable by practical manufacturing techniques. Also, subjecting apalutamide to significant mechanical force for breaking apalutamide particles into smaller ones can be avoided.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La divulgation concerne une composition contenant des nanoparticules d'apalutamide cristallin et de polyvinylpyrrolidone/acétate de vinyle (PVPVA) et/ou d'hydroxypropyl méthylcellulose (HPMC). La divulgation concerne également un procédé de production de la composition.
PCT/FI2025/050007 2024-01-18 2025-01-09 Composition contenant de l'apalutamide nanométrique cristallin Pending WO2025153768A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FI20245042 2024-01-18
FI20245042 2024-01-18

Publications (1)

Publication Number Publication Date
WO2025153768A1 true WO2025153768A1 (fr) 2025-07-24

Family

ID=94323021

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/FI2025/050007 Pending WO2025153768A1 (fr) 2024-01-18 2025-01-09 Composition contenant de l'apalutamide nanométrique cristallin

Country Status (1)

Country Link
WO (1) WO2025153768A1 (fr)

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013184681A1 (fr) * 2012-06-07 2013-12-12 Aragon Pharmaceuticals, Inc. Formes cristallines d'un modulateur du récepteur des androgènes
WO2016090098A1 (fr) * 2014-12-05 2016-06-09 Aragon Pharmaceuticals, Inc. Compositions anti-cancéreuses
WO2016124149A1 (fr) * 2015-02-06 2016-08-11 苏州晶云药物科技有限公司 Nouvelle forme cristalline d'un médicament anti-androgène destiné à traiter le cancer de la prostate, et procédé de préparation de la nouvelle forme cristalline
US10098842B2 (en) 2014-10-06 2018-10-16 Nanoform Finland Oy Method and a device for producing nanoparticles
WO2020049598A2 (fr) * 2018-09-08 2020-03-12 Cipla Limited Polymorphes d'apalutamide
WO2020234817A1 (fr) * 2019-05-21 2020-11-26 Laurus Labs Limited Formes polymorphes d'apalutamide et leur préparation
WO2022166701A1 (fr) * 2021-02-06 2022-08-11 广东东阳光药业有限公司 Composition et procédé de préparation correspondant
WO2024153857A1 (fr) * 2023-01-18 2024-07-25 Nanoform Finland Oyj Procédé de cristallisation d'ingrédients pharmaceutiques actifs

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013184681A1 (fr) * 2012-06-07 2013-12-12 Aragon Pharmaceuticals, Inc. Formes cristallines d'un modulateur du récepteur des androgènes
US10098842B2 (en) 2014-10-06 2018-10-16 Nanoform Finland Oy Method and a device for producing nanoparticles
WO2016090098A1 (fr) * 2014-12-05 2016-06-09 Aragon Pharmaceuticals, Inc. Compositions anti-cancéreuses
WO2016124149A1 (fr) * 2015-02-06 2016-08-11 苏州晶云药物科技有限公司 Nouvelle forme cristalline d'un médicament anti-androgène destiné à traiter le cancer de la prostate, et procédé de préparation de la nouvelle forme cristalline
WO2020049598A2 (fr) * 2018-09-08 2020-03-12 Cipla Limited Polymorphes d'apalutamide
WO2020234817A1 (fr) * 2019-05-21 2020-11-26 Laurus Labs Limited Formes polymorphes d'apalutamide et leur préparation
WO2022166701A1 (fr) * 2021-02-06 2022-08-11 广东东阳光药业有限公司 Composition et procédé de préparation correspondant
WO2024153857A1 (fr) * 2023-01-18 2024-07-25 Nanoform Finland Oyj Procédé de cristallisation d'ingrédients pharmaceutiques actifs

Similar Documents

Publication Publication Date Title
Liu et al. Mechanism of dissolution enhancement and bioavailability of poorly water soluble celecoxib by preparing stable amorphous nanoparticles
JP4065640B2 (ja) 医薬用固体分散物
JP6192244B2 (ja) 改良されたバイオアベイラビリティを有する薬学的組成物
RU2461382C2 (ru) Содержащая ревапразан твердая дисперсия и способ ее получения
JP2010526848A (ja) 難溶性薬物用の医薬組成物
JP2013510813A (ja) プロパン−１−スルホン酸｛３−［５−（４−クロロ−フェニル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３−カルボニル］−２，４−ジフルオロ−フェニル｝−アミド組成物とその用途
JP2001527044A (ja) イトラコナゾール（ｉｔｒａｃｏｎａｚｏｌｅ）経口用製剤及びその製造方法
EP1530457B1 (fr) Compositions pharmaceutiques de medicaments à structure semi-ordonnée et de polymères
Alanazi et al. Improvement of albendazole dissolution by preparing microparticles using spray-drying technique
JP2012522825A (ja) 固体支持体に吸着された原薬
WO2010133611A1 (fr) Dispersions médicamenteuses solides
PT2165702E (pt) Composições estáveis e rapidamente dissolvidas de candesartan cilexetil preparadas com granulação húmida
JP7716600B2 (ja) 医薬品有効成分の結晶化のための方法
Miao et al. Investigation of nanosized crystalline form to improve the oral bioavailability of poorly water soluble cilostazol
WO2025153768A1 (fr) Composition contenant de l'apalutamide nanométrique cristallin
WO2007007182A2 (fr) Formes galeniques solides d'agent antiepileptique
WO2025262137A1 (fr) Formulations comprenant de l'encorafénib nanométrique cristallin
EP1207855A1 (fr) Composition pharmaceutique comprenant du nabumetone
CN115551488A (zh) 纳米颗粒组合物
JPWO2017209216A1 (ja) 難溶性薬物の微粒子を含有する医薬組成物の製造方法
EP4651860A1 (fr) Nanoparticules cristallines comprenant de l'enzalutamide
WO2004105728A2 (fr) Dispersions solides de cefpodoxime-proxetil et leurs procedes de preparation
WO2024249660A1 (fr) Compositions comprenant du sotorasib
EP4531815A1 (fr) Composition pharmaceutique améliorée contenant du tadalafil et procédé de nanobroyage pour sa préparation
EP4267109A1 (fr) Composition non micronisée de bilastine

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25700383

Country of ref document: EP

Kind code of ref document: A1