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WO2025163665A1 - Compositions pharmaceutiques stables d'abiratérone - Google Patents

Compositions pharmaceutiques stables d'abiratérone

Info

Publication number
WO2025163665A1
WO2025163665A1 PCT/IN2025/050093 IN2025050093W WO2025163665A1 WO 2025163665 A1 WO2025163665 A1 WO 2025163665A1 IN 2025050093 W IN2025050093 W IN 2025050093W WO 2025163665 A1 WO2025163665 A1 WO 2025163665A1
Authority
WO
WIPO (PCT)
Prior art keywords
abiraterone
pharmaceutical composition
stable pharmaceutical
composition according
pharmaceutically acceptable
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/IN2025/050093
Other languages
English (en)
Inventor
Dhananjay Panigrahi
Raju SAKA
HariHaran VENUGOPAL
Anup Avijit Choudhury
Venkat Ramana Naidu
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.)
Dr Reddys Laboratories Ltd
Original Assignee
Dr Reddys Laboratories Ltd
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 Dr Reddys Laboratories Ltd filed Critical Dr Reddys Laboratories Ltd
Publication of WO2025163665A1 publication Critical patent/WO2025163665A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • 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
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K9/141—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
    • 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
    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed

Definitions

  • Abiraterone is an inhibitor of CYP17 (17 ⁇ -hydroxylase/C17,20-lyase). Abiraterone being poorly bioavailable, the prodrug abiraterone acetate is used, which rapidly deacetylates in vivo to abiraterone.
  • Abiraterone acetate is designated chemically as (3 ⁇ )-17­(3-pyridinyl) androsta-5,16-dien-3-yl acetate and its structure is:
  • Abiraterone acetate is marketed under the tradename ZYTIGA® as an immediate-release tablet containing 250 mg or 500 mg of abiraterone acetate and is used to treat metastatic castration-resistant (CRPC) and high-risk castration-sensitive (CSPC) prostate cancer in combination with prednisone.
  • CRPC metastatic castration-resistant
  • CSPC high-risk castration-sensitive
  • Abiraterone acetate is classified as BCS class IV drug having low aqueous solubility and low permeability.
  • the low solubility of abiraterone acetate in water significantly contributes to its low bioavailability.
  • steady-state values (mean ⁇ SD) of Cmax were 226 ⁇ 178 ng/mL and of AUC were 993 ⁇ 639 ng.hr/mL.
  • the absolute bioavailability of abiraterone acetate is reported to be no more than 10%, as the drug is primarily metabolized to abiraterone and subsequently excreted by feces (-88%) and urine (-5%) with a terminal half-life of 12 ⁇ 5 hours. Consequently, from the 4 tablets of 250 mg each (1000 mg)/ 2 tablets of 500 mg each (1000 mg) that a patient must take daily, only 10% of the drug can exert a therapeutic effect.
  • abiraterone acetate is known to exhibit a strong food effect when administered orally.
  • Cmax and AUC0- ⁇ were approximately 7- and 5-fold higher, respectively, when a single dose of abiraterone acetate was administered with a low-fat meal (7% fat, 300 calories) and approximately 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a high-fat (57% fat, 825 calories) meal compared to overnight fasting.
  • abiraterone acetate is labeled to be taken on an empty stomach. Patients must abstain from food for 2 hours prior to dosing and for 1 hour afterward.
  • YONSA® manufactured by Sun Pharmaceutical Industries Ltd. using SoluMatrix particulate technology, is a modified abiraterone acetate tablet designed to enhance the dissolution of abiraterone acetate and improve the oral bioavailability as compared to the original drug ZYTIGA®.
  • the dose of YONSA® is reduced to 500 mg by reduction in the particle size of the drug, it improves the dissolution rate without significantly increasing the permeability of abiraterone acetate through gastrointestinal epithelial cells. Consequently, the oral bioavailability of YONSA® remains very low. Given the recommended dose of 500 mg, patients currently need to take four 125 mg tablets, contributing to the pill burden.
  • US11801252, CN111617258 and CN111617257 discloses tablet containing nanosuspension of abiraterone acetate using absorption enhancers selected from the group consisting of capric acid, sodium or potassium caprate, N- (10- [ 2-hydroxybenzoyl ] amino) capric acid (SNAD), caprylic acid, sodium or potassium caprylate, N- (8- (2-hydroxybenzoyl) amino) caprylic acid (NAC), N- (5-chlorosalicyloyl) -8-aminocaprylic acid (5-CNAC), sodium 8- (salicylamido) caprylate (SNAC) and 8-(salicylamido) caprylic acid.
  • absorption enhancers selected from the group consisting of capric acid, sodium or potassium caprate, N- (10- [ 2-hydroxybenzoyl ] amino) capric acid (SNAD), caprylic acid, sodium or potassium caprylate, N- (8- (2-hydroxybenzoyl) amino) cap
  • WO2014009436 teaches that the stability of tablets containing nanosuspension of abiraterone acetate can be improved with the addition of a non-reducing sugar, sucrose, when HPMC is used as the stabilizing agent or with pH adjustment using buffer when other stabilizing agents are used.
  • CN111110646 discloses a low-specification nanoparticles containing 125mg of abiraterone acetate containing a surfactant, hydrophilic polymer, antioxidant, co-stabilizer, diluent, disintegrant and lubricant.
  • WO2015114314 discloses low dose orally dispersible composition of abiraterone nanoparticles.
  • CN112933053 discloses abiraterone acetate nanocrystals prepared by freeze drying.
  • WO2014145813 discloses abiraterone acetate nanoparticles containing antioxidant and/or sequestering agent and is prepared by dry milling method.
  • WO2013164473 discloses pharmaceutical composition
  • abiraterone acetate dissolved or dispersed in a pharmaceutically acceptable carrier wherein the pharmaceutically acceptable carrier comprises one or more lipid excipients, selected from the group consisting of fatty acid esters, phospholipids, phosphatidyl compounds, glycosylceramides, fatty acids, non-ionic surfactants, vitamin E tocopheryl succinate polyethylene glycol, glycerides, derivatives thereof, and mixtures thereof.
  • the present invention provides improved formulations of abiraterone or pharmaceutically acceptable salt thereof that allow for a reduced dosage strength and total daily dose while achieving more predictable and consistent plasma exposure. As a result, they exhibit a reduced or no food effect.
  • the stable pharmaceutical composition for oral administration comprises the nanosuspension of abiraterone or pharmaceutically acceptable salt thereof.
  • the stable pharmaceutical composition further comprises a stabilizer.
  • the invention relates to stable nanosuspensions comprising: (a) abiraterone or pharmaceutically acceptable salt thereof; (b) a stabilizer comprising a combination of a cellulose derivative and a non-ionic surfactant; and (c) optionally, one or more other pharmaceutically acceptable excipients.
  • the invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a nanosuspension comprising abiraterone or pharmaceutically acceptable salt thereof and stabilizer comprising a combination of a cellulose derivative and a non-ionic surfactant at the ratio from about 5:1 to about 1:5.
  • the invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising:
  • the present invention also provides a process for the preparation of stable pharmaceutical composition for oral administration comprising the nanosuspension of abiraterone or pharmaceutically acceptable salt thereof.
  • the stable pharmaceutical composition comprises abiraterone nanoparticles with an D90 particle size less than about 1000 nm.
  • the composition remains stable for at least 6 months at 40 0 C/75% RH (“relative humidity”) or 30 0 C/75% RH. Further, the composition also remains stable for at least 6 months at 25 0 C/60% RH.
  • the main aspect of the present invention is to provide pharmaceutical compositions of abiraterone or pharmaceutically acceptable salt thereof that exhibits enhanced bioavailability compared to the currently marketed formulations. Due to the increased bioavailability or absorption, the dosage according to the invention can be lower than the conventional dose typically required to produce equal or higher therapeutic effects.
  • the stable pharmaceutical compositions of abiraterone or pharmaceutically acceptable salt thereof exhibit a reduced food effect as compared to ZYTIGA® and YONSA® when administered with a high fat meal.
  • the stable pharmaceutical compositions of abiraterone or pharmaceutically acceptable salt thereof reduces pill burden such that only single unit dose is administered once daily.
  • the present invention also provides a stable pharmaceutical composition of abiraterone or pharmaceutically acceptable salt thereof used in, combination with prednisone, for the treatment of Metastatic castration-resistant prostate cancer (CRPC) and Metastatic high-risk castration-sensitive prostate cancer (CSPC).
  • CRPC Metastatic castration-resistant prostate cancer
  • CSPC Metastatic high-risk castration-sensitive prostate cancer
  • the main aspect of the present invention is to provide pharmaceutical compositions of abiraterone or pharmaceutically acceptable salt thereof, that exhibit enhanced bioavailability compared to the currently marketed formulations. Due to the increased bioavailability, the dosage strength and total daily dose is reduced while achieving more predictable and consistent plasma exposure. As a result, they exhibit a reduced or no food effect.
  • abiraterone refers to the active ingredient in various forms, including the free base form, acid form, salt form, polymorphic crystalline or amorphous form, solvates, hydrates, ethers and esters. Also the term “abiraterone” and “abiraterone acetate” used herein is the same and can be used interchangeably unless specifically suggested otherwise.
  • the term “about” typically means a value falling within an accepted standard of error of the mean, as considered by one of ordinary skill in the art.
  • the term “about” refers to ⁇ 20%, preferably ⁇ 10%, and more preferably ⁇ 5% of the value or range it refers to.
  • the term “enhanced bioavailability” as used in this specification refers to an increase in the concentration of the active ingredient in the body fluid provided by the compositions of the present invention compared to the concentration obtained from ZYTIGA® under identical conditions.
  • the bioavailability e.g., AUC, Cmax and/or Tmax
  • the bioavailability of abiraterone when formulated as described herein, is enhanced at least 15%, but may be greater, reaching 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375% or 400% of the dose administered when compared to ZYTIGA® under identical conditions.
  • lowering of dosage may mean that the dose of abiraterone in the nanosuspension or pharmaceutical composition of the present disclosure can be 80% less, or 75% less, or 70% less, or 65% less, or 60% less, or 55% less, or 50% less, or 45% less, or 40% less, or 35% less, or 30% less, or 25% less, or 20% less, as compared to the commercially available reference drug products (such as ZYTIGA®).
  • composition refers to a pharmaceutical composition administered to a patient in need of treatment. This includes, but is not limited to tablet, hard-gelatin capsule, soft-gelatin capsule, oral suspension, oral solution, enteric coated hard-gelatin capsule, enteric coated soft-gelatin capsule, cores, coated cores, pellets, micro pellets, pills, compressed tablets, granules, spheres, capsules and the like.
  • pharmaceutically acceptable refers to substances that are suitable to be in contact with a tissue of a patient without inappropriate toxicity, irritation, allergic response or other adverse effects. These substances have a reasonable balance between advantages and disadvantages and can be applied effectively to their intended use.
  • reducing the food effect refers to narrowing the difference in pharmacokinetic parameters, e.g., AUC0- ⁇ , AUC0-t and/or Cmax for a drug administered under fasted state compared to fed state.
  • salts include derivatives of an active agent modified by making acid or base addition salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid addition salts of basic residues such as amines; alkali or organic addition salts of acidic residues; and the like, or a combination comprising one or more of these salts.
  • the pharmaceutically acceptable salts also include quaternary ammonium salts of the active agent.
  • acid salts may be derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like.
  • Other acceptable inorganic salts include metal salts such as sodium, potassium, cesium salt, as well as alkaline earth metal salts, such as calcium and magnesium salts, or a combination of these.
  • the preferred salt used in the present invention is acetate.
  • stabilizer(s) includes, but not limited to, crystal growth inhibitors, excipients capable of preventing aggregation/flocculation or physical degradation, including chemical degradation (for example, autolysis, deamination, oxidation, etc.) in an aqueous state and/or when stored for pharmaceutically acceptable duration of time.
  • the stabilizers also include the excipients that adsorb on drug particle surfaces and reduce the interfacial tension between the drug particles thereby preventing aggregation or degradation.
  • stable as used herein in the context of stable abiraterone particles, stable abiraterone nanosuspensions or stable nanoparticulate abiraterone, means that the particles do not appreciably flocculate or agglomerate due to interparticle attractive forces or otherwise increase in particle size during and after preparation of the nanosuspension.
  • the nanosuspension was stable in dispersed phase for more than 10 days before processing into tablets. Additionally, the finished formulations are chemically stable, with no more than 2% of total impurities are present when stored at accelerated (40°C/75%RH) and long term (30oC/75% RH) storage conditions for at least 6 months. Further, the composition also remains stable for at least 6 months at 250 C/60% RH.
  • the invention relates to a stable nanosuspension comprising abiraterone or pharmaceutically acceptable salt thereof and a stabilizer.
  • the invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising:
  • composition can be administered with or without food.
  • the invention relates to a a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising:
  • a) a nanosuspension comprising abiraterone or pharmaceutically acceptable salt thereof and stabilizer
  • composition can be administered with or without food.
  • the invention relates to a stable nanosuspension comprising: (a) abiraterone or pharmaceutically acceptable salt thereof (b) a stabilizer comprising a combination a cellulose derivative and a non-ionic surfactant.
  • the concentration of abiraterone or pharmaceutically acceptable salt thereof used in the present invention ranges from about 5% to about 50% (w/w) of the total weight of the composition. Preferably, the concentration ranges from about 15% to about 35% (w/w) of the total weight of the composition. More preferably, the concentration of active ingredient is about 24% to about 27% (w/w) of the total weight of the composition.
  • a stabilizer for abiraterone is non-trivial.
  • a nanosuspension comprising, preferably a combination of a cellulose derivative and a non-ionic surfactant as the stabilizer results in substantially no abiraterone degradation product and a reduced amount of total impurities as compared to the commercially available tablets.
  • Suitable “cellulose derivative” may be selected from the group consisting of hydroxypropylmethylcellulose (HPMC), methylcellulose, hydroxypropylcellulose (HPC), hydroxyethylcellulose, sodium carboxymethylcellulose, or mixtures thereof. In one of the embodiments of the invention, the cellulose derivative is hydroxypropyl methylcellulose (HPMC).
  • Suitable “non-ionic surfactant” may be selected from the group consisting of polyoxyethylene aliphatic alcohol ester, span, polyoxyethylene sorbitol fatty acid esters (tween), sorbitol ester, glyceride, polyethylene glycol, spermol, cetyl stearyl alcohol, stearyl alcohol, poloxamer, polyoxypropylene-polyoxyethylene copolymer, castor oil derivatives (Cremophor), vitamin E or derivatives thereof (vitamin E TPGS), PEG fatty acid glyceride such as PEG-8 glycerol caprylate/decanoin, PEG-4 glycerol caprylate/decanoin, PEG-32 glycerol monolaurate, PEG-6 glycerin mono-fatty acid ester, PEG-6 glycerol linoleate, diethylene glycol monoethyl ether, or mixtures thereof.
  • the non-ionic surfactant may
  • the concentration of stabilizer used in the present invention ranges from about 10% to about 30% of the total weight of the composition. Preferably, the concentration ranges from about 5% to about 15% (w/w) of the total weight of the composition. More preferably, the concentration of active ingredient is about 10% (w/w) of the total weight of the composition.
  • the invention relates to a stable pharmaceutical composition
  • a nanosuspension comprising abiraterone or pharmaceutically acceptable salt thereof and stabilizer comprising a combination of a cellulose derivative and a non-ionic surfactant at the ratio from about 5:1 to about 1:5.
  • the weight ratio is about 2.5:1.
  • HPMC Hydrophilicitypropylmethylcellulose
  • non-ionic surfactant like poloxamer can cause processing issues during granulation at optimal spray rates, increasing processing time.
  • Poloxamer have a low melting point ( ⁇ 57°C), which aligns with granulation process temperatures. Excessive poloxamer can alter granule morphology, leading to aggregates or waxy melt granules.
  • the invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a nanosuspension comprising abiraterone or pharmaceutically acceptable salt thereof and stabilizer at the ratio from about 1:4 to about 4:1.
  • the ratio is about 3:1.
  • the invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a nanosuspension comprising abiraterone or pharmaceutically acceptable salt thereof and stabilizer comprising a combination of a cellulose derivative and a non-ionic surfactant, wherein the ratio of abiraterone or pharmaceutically acceptable salt thereof and stabilizer ranges from about 1:4 to about 4:1. Preferably, the ratio is about 3:1.
  • the invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising (a) a nanosuspension containing abiraterone acetate and a stabilizer, which is a combination of a cellulose derivative and a non-ionic surfactant at the ratio from about 5:1 to about 1:5 and (b) optionally, one or more other pharmaceutically acceptable excipients.
  • compositions used in the present invention may include, but are not limited to, diluents, binders, disintegrants, surfactants, redispersing agents, lubricants, glidants, chelating agents, antioxidants, coating agents or mixtures thereof.
  • Suitable diluents include, one or more of, but not limited to microcrystalline cellulose, silicified microcrystalline cellulose, calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose monohydrate, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners and the like.
  • the diluent is microcrystalline cellulose, mannitol and lactose monohydrate.
  • diluent is included either in intra-granular material or extra-granular material or both.
  • the diluent concentration ranges from about 10% to about 60% w/w of total composition.
  • the diluent concentration in the intra-granular material ranges from about 15% to about 25% w/w of total composition and the concentration in the extra-granular material ranges from about 20% to about 30% w/w of total composition.
  • Suitable binders include, one or more of, but not limited to methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinyl pyrrolidone, microcrystalline cellulose, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol and the like.
  • the binder is polyvinyl pyrrolidone.
  • the concentration of binder ranges from about 1% to about 20% w/w of total composition, preferably about 5% to about 10% w/w.
  • Suitable disintegrants include, one or more of, but not limited to croscarmellose sodium, low substituted hydroxypropyl cellulose (L-HPC), sodium starch glycollate, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, starch, crystalline cellulose, hydroxypropyl starch, pregelatinized starch, and the like.
  • the disintegrant is croscarmellose sodium.
  • disintegrant is included either in nanosuspension or extra-granular material or both.
  • concentration of disintegrant ranges from about 1% to about 10% w/w of total composition.
  • concentration in the nanosuspension ranges from about 1% to about 5% w/w of total composition and the concentration in the extra-granular material ranges from about 5% to about 10% w/w of total composition.
  • Suitable surfactants include, one or more of, but not limited to non-ionic surfactant or an ionic surfactant.
  • Surfactant may be selected from, the group consisting of sodium lauryl sulphate, polyoxyethylene products of hydrogenated vegetable oils, sodium taurocholate, polyoxyethylated castor oils or polyethoxylated hydrogenated castor oil, polyoxyethylene-sorbitan-fatty acid esters, polyoxyethylene castor oil derivatives, sorbitan esters, sucrose esters, polyoxamers, poloxamers, polyglycolyzed glycerides (as caprylocaproly macrogol glyceride (Labrasol), linoleaoyl macrogol glycerides (Labrafil), polyglyceryl oleate (Plurol)), gelucires, sodium dodecyl sulfate (SDS), sodium cholate, sodium glycolcholate, saccharose monostearate, lecithin,
  • Suitable redispersing agents include, one or more of, but not limited to reducing and non-reducing sugars and sugar alcohols.
  • Redispersing agent may be selected from, but not limited to the group consisting of glucose, galactose, lactose, maltose, sucrose, trehalose xylitol, mannitol, sorbitol and isomalt.
  • the redispersing agent is mannitol.
  • the concentration of redispersing agent ranges from about 1% to about 30% (w/w) to the total concentration. Preferably, the concentration ranges from about 5% to about 10% (w/w) to the total concentration.
  • Suitable lubricants or glidants include, one or more of, but not limited to colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like.
  • the lubricant or glidants is colloidal silicon dioxide and magnesium stearate.
  • the concentration of lubricant or glidant ranges from about 0.5% to about 5% w/w of total composition.
  • Suitable chelating agents include, one or more of, but not limited to ethylenediaminetetraacetic acid (EDTA), disodium EDTA and derivatives thereof, citric acid and derivatives thereof, niacinamide and derivatives thereof, and sodium desoxycholate and the like.
  • the chelating agent is EDTA.
  • the concentration of chelating agent ranges from about 0.1% to about 1% w/w of total composition.
  • Suitable antioxidants include, one or more of, but not limited to a-tocopherol, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tert-butylhydroquinone (TBHQ), propyl gallate (PG) and the like.
  • BHT butylated hydroxytoluene
  • BHA butylated hydroxyanisole
  • TBHQ tert-butylhydroquinone
  • PG propyl gallate
  • the antioxidant is BHA and/or BHT.
  • the concentration of antioxidant ranges from about 0.1% to about 1% w/w of total composition.
  • Suitable solvent includes, one or more of, but not limited to, purified water, dichloromethane, acetone.
  • the solvent is purified water.
  • Suitable coating includes, one or more of, but not limited to, opadry film coating, hydroxypropyl cellulose, hypromellose, eudragit coating agents. Most preferable is opadry film coating.
  • concentration of film coating used in present invention ranges from about 0.1% to about 5% (w/w) to the total concentration.
  • the pharmaceutical compositions comprising nano-sized abiraterone or pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients are prepared by wet granulation, which process comprises mixing nanosuspension of abiraterone with intra-granular excipients.
  • the mixed granules were dried and sieved.
  • the dried intra-granular granules were mixed with extra-granular excipients and the resultant mixture is either compressed to tablet or filled in hard gelatin capsules.
  • compositions comprising nano-sized abiraterone or pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients are prepared using dry granulation, which process comprises mixing nano-suspension of abiraterone and pharmaceutically acceptable excipients, and the resultant mixture is either compressed to tablet or filled in hard gelatin capsules.
  • the present invention provides a process for the preparation of stable pharmaceutical composition for oral administration comprising following steps:
  • step (a) preparing a nanosuspension containing abiraterone or pharmaceutically acceptable salt thereof, stabilizer, surfactant, redispersing agent and part of disintegrant, (b) spraying the above nanosuspension onto the diluent and drying to form granules, (c) preparing extragranular phase by mixing remaining amount of disintegrant, diluent, glidant, lubricant and blending with dried mixture obtained, and (d) compressing the blend of step (c) into tablet, and optionally coating the tablet.
  • the present invention provides a process for the preparation of stable pharmaceutical composition for oral administration comprising following steps:
  • step (b) adding abiraterone to step (a) and stirring continuously to obtain abiraterone dispersion
  • the invention relates to pharmaceutical compositions comprising abiraterone nanoparticles and at least one pharmaceutically acceptable excipient, wherein the abiraterone nanoparticles have an D90 particle size less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm or less than about 100 nm.
  • the D90 particle size is equal to or less than about 200 nm.
  • the invention relates to pharmaceutical compositions comprising abiraterone nanoparticles and at least one pharmaceutically acceptable excipient, wherein the abiraterone nanoparticles have an D50 particle size less than about 150 nm, less than about 140 nm, less than about 130 nm, less than about 120 nm, less than about 100 nm, less than about 90 nm, less than about 80 nm, less than about 70 nm, less than about 60 nm or less than about 50 nm.
  • the D50 particle size is equal to or less than about 100 nm.
  • the invention relates to pharmaceutical compositions comprising abiraterone nanoparticles and at least one pharmaceutically acceptable excipient, wherein the abiraterone nanoparticles have an D4,3 particle size less than about 150 nm, less than about 140 nm, less than about 130 nm, less than about 120 nm, less than about 100 nm, less than about 90 nm, less than about 80 nm, less than about 70 nm, less than about 60 nm or less than about 50 nm.
  • the D4,3 particle size is equal to or less than about 100 nm.
  • the particle size can be measured by a dynamic light scattering method, laser diffraction method, microscopy, photon correlation spectroscopy or other appropriate methods known in the art.
  • the invention relates to stable nanosuspension comprising: (a) abiraterone or pharmaceutically acceptable salt thereof; and (b) a stabilizer comprising a combination a cellulose derivative and a non-ionic surfactant; wherein the abiraterone particles have an D90 particle size less than about 200 nm.
  • the invention relates to stable nanosuspension comprising: (a) abiraterone or pharmaceutically acceptable salt thereof; and (b) a stabilizer comprising a combination a cellulose derivative and a non-ionic surfactant; wherein the abiraterone particles have an D50 particle size less than about 100 nm.
  • the invention relates to stable nanosuspension comprising: (a) abiraterone or pharmaceutically acceptable salt thereof; and (b) a stabilizer comprising a combination a cellulose derivative and a non-ionic surfactant; wherein the abiraterone particles have an D4,3 particle size less than about 100 nm.
  • a combination of a cellulose derivative, specifically HPMC, and a non-ionic surfactant, particularly poloxamer, as the stabilizer also enhances the stability of the nanosuspension upon storage. Notably, no significant increase in degradation products has been observed when stored at accelerated (40 0 C/75%RH) and long term (30 0 C/75% RH) or (25 0 C/60% RH) storage conditions for at least 6 months.
  • the present invention relates to a stable nanosuspension comprising abiraterone or pharmaceutically acceptable salt thereof.
  • the present invention relates to stable pharmaceutical composition for oral administration comprising the nanosuspension of abiraterone or pharmaceutically acceptable salt thereof.
  • the present invention provides abiraterone or pharmaceutically acceptable salt thereof for use in the treatment of prostate cancer, wherein the total daily dose administered is less than about 1000 mg, preferably less than about 500mg, and more preferably about 300mg once daily.
  • the present invention provides a pharmaceutical composition containing about 500 mg of abiraterone or pharmaceutically acceptable salt thereof, wherein said composition provide a pharmacokinetic profile comparable to commercially available immediate release formulations.
  • the present invention provides, a pharmaceutical composition containing about 300 mg of abiraterone or pharmaceutically acceptable salt thereof, wherein said composition provide a pharmacokinetic profile comparable to commercially available immediate release formulations.
  • dose modification is required in case of patients with hepatic impairment and hepatotoxicity.
  • the tablets containing poloxamer prepared using nano-suspension of abiraterone or pharmaceutically acceptable salt thereof of the present invention demonstrated improved in vitro dissolution such that 100% drug is released within 15min in 6.8 pH Phosphate Buffer with 0.5% SLS, 900 mL, USP type II apparatus, 75 rpm and more than 90% drug is released within 30min in 4.5 pH Phosphate Buffer with 0.06% SLS, 900 mL, USP type II apparatus, 75 rpm.
  • composition of present invention containing poloxamer also showed significant improvement in bioavailability as compared to ZYTIGA under fasting condition.
  • the present invention provides a stable pharmaceutical composition comprising:
  • a) a nanosuspension comprising abiraterone or pharmaceutically acceptable salt thereof in an amount of about 300 mg equivalent to free base
  • the said composition upon administration, exhibits one or more of the following pharmacokinetic parameter
  • Cmax a maximum plasma concentration of about 81.21 ⁇ 56.13 ng/mL to about 124.06 ⁇ 106.60 ng/mL of abiraterone
  • AUC0-t an area under the plasma concentration-time curve (AUC0-t) of about 317.34 ⁇ 158.68 ng.hr/mL to about 400.82 ⁇ 219.34 ng.hr/mL.
  • the pharmaceutical compositions described herein reduce or eliminate the food effect.
  • a pharmaceutical composition as described herein upon oral administration of a pharmaceutical composition as described herein to a mammal in need, there is no significant food effect.
  • the inventors of the present invention unexpectedly discovered that when a single unit dose of about 300mg of abiraterone or pharmaceutically acceptable salt thereof was administered to healthy subjects with a high-fat meal (1000 calories), the increase in Cmax and AUC was only about 2.4 and about 2 fold, respectively, compared to overnight fasting.
  • the pharmaceutical compositions according to the present invention can be administered with or without food.
  • the present invention provides a stable nanosuspension composition comprising:
  • abiraterone or pharmaceutically acceptable salt thereof in an amount of about 300 mg equivalent to free base
  • the said composition upon administration with food, the said composition exhibits one or more of the following pharmacokinetic parameter
  • the said composition exhibits an increase in the maximum plasma concentration (Cmax) that is not more than 3 fold higher, and the area under the plasma concentration-time curve (AUC0-t) that is not more than 2 fold higher, as compared to when the said composition is administered after an overnight fasting.
  • the present invention also provides a stable pharmaceutical composition of abiraterone or pharmaceutically acceptable salt thereof used in the treatment of Metastatic castration-resistant prostate cancer (CRPC) and Metastatic high-risk castration-sensitive prostate cancer (CSPC).
  • abiraterone or pharmaceutically acceptable salt thereof used in the treatment of Metastatic castration-resistant prostate cancer (CRPC) and Metastatic high-risk castration-sensitive prostate cancer (CSPC).
  • the aforementioned pharmaceutical composition is used in combination with a glucocorticoid, preferably prednisone, prednisolone or methylprednisolone.
  • the pharmaceutical composition is used in combination with prednisone.
  • Example 1 Abiraterone tablet composition using nanosuspension Ingredients Ex 1a Ex 1b Ex 1c Ex 1d Ex 1e %w/w %w/w %w/w %w/w %w/w Abiraterone acetate 26.43 27.52 24.21 25.68 27.52 Hydroxypropyl methyl cellulose 6.5 6.75 6.05 6.86 13.75 Poloxamer 2.5 2.75 3.2 2.5 -- Sodium lauryl sulphate 1.35 1.35 1.75 1.10 1.35 Mannitol 15.7 14.1 17.25 17.16 12.1 Vitamin E TPGS 0.66 0.55 - 0.85 0.55 Microcrystalline cellulose 38.5 31.5 32.22 32.14 29.25 Lactose monohydrate - 6.8 5.25 6.42 6.8 Croscarmellose sodium 6.6 6.8 8.47 5.25 6.8 Colloidal silicon dioxide 0.88 0.94 0.8 1.02 0.94 Magnesium stearate 0.88 0.94 0.8 1.02 0.94 Process for preparation:
  • test formulations (2a and 2b) were prepared following the process described in Example 1. These formulations were evaluated for in vitro dissolution and pharmacokinetic study against commercially available reference drug products.
  • Formulation 2a (%w/w) (%w/w) Abiraterone acetate 24.10 25.75 Hydroxypropyl methyl cellulose 12.05 6.44 Poloxamer - 2.58 Sodium lauryl sulphate 1.2 1.29 Mannitol 14.05 15.02 Vitamin E TPGS 0.48 0.52 Microcrystalline cellulose 32.94 32.19 Lactose monohydrate 6.02 6.44 Croscarmellose sodium 7.55 8.07 Colloidal silicon dioxide 0.88 0.86 Magnesium stearate 0.88 0.86 Particle size : The particle size of the abiraterone acetate nanoparticles in the composition, measured by laser diffraction method, is as below:
  • D90 is about 184 nm; D50 is about 60.3 nm; D4,3 is about 88.9 nm.
  • D90 is about 159 nm; D50 is about 54.1 nm; D4,3 is about 75.8 nm.
  • the in vitro dissolution rate was determined in 900mL pH 6.8 + 0.5% SLS using an USP Apparatus II at 75 RPM (Rotation Per Minute).
  • the dissolution profile of the test formulations 2a and 2b and reference formulations are shown as below.
  • Time Formulation 2a (300 mg) Formulation 2b (300 mg) Zytiga (1000 mg) Yonsa (500 mg) 0 0 0 0 0 10 66 64 30 63 30 85 92 38 67 60 93 93 38 66 90 92 93 39 67 120 92 94 40 67 Dissolved (mg) 276mg 282mg 400mg 335mg
  • the above results demonstrate that the test formulation 2b containing poloxamer exhibits an improved dissolution profile compared to reference products.
  • composition 2a and 2b were tested for their pharmacokinetics and bioavailability of composition 2a and 2b, in healthy adult, human volunteers, under fasting condition.
  • formulation 2b was further selected for evaluating the food effect.
  • This study was open-label, balanced, randomized, single dose, single treatment, two period, two sequence cross-over study to evaluate the effect of food on exposure of test product abiraterone acetate Tablets 300mg when given under fasting and fed condition (high-calories (nearly 1000 calories) in Normal, Healthy, Adult, Male Human Subjects.
  • Table 6 represents the results of the study.
  • formulation 2b was subjected to a stability study at 30°C/75% RH and 40°C/75% RH. The results of the study are presented in Table 7.
  • Table 7 Stability Data of abiraterone acetate tablet prepared using nano-suspension of the present invention according to Formulation 2b (Storage Condition: 30°C/75% RH and 40°C/75% RH) Parameters Specification 40C/75% RH 30C/75% RH
  • Initial 1M 3M 6M 3M 6M Description White to off white oval shaped tablets plain on both sides
  • Assay 90-110% 100.73 100.86 101.52 97.22 101.92 101.61
  • 7-keto abiraterone acetate NMT 0.5 0.0525 0.0257 BPQL 0.1037 0.0857 0.2009 Abiraterone NMT 0.4 BDL ND BPQL BPQL BPQL BPQL Alpha-epoxy abiraterone acetate NMT 0.8 0.031 0.049 0.050 0.116 0.039 0.05 Beta-epoxy abirater

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Abstract

La présente invention concerne une composition pharmaceutique stable d'abiratérone ou un sel pharmaceutiquement acceptable associé. En particulier, l'invention concerne une composition pharmaceutique stable comprenant une nanosuspension d'abiratérone ou d'un sel pharmaceutiquement acceptable associé qui réduit la dose, diminue la charge médicamenteuse, améliore la biodisponibilité de l'abiratérone dans des conditions de jeûne et réduit l'effet alimentaire par comparaison avec des produits commerciaux. Un procédé de préparation desdites compositions est également divulgué. De plus, l'invention concerne les méthodes de traitement de certains cancers chez des sujets mammifères à l'aide de ladite composition.
PCT/IN2025/050093 2024-01-29 2025-01-28 Compositions pharmaceutiques stables d'abiratérone Pending WO2025163665A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014009436A1 (fr) * 2012-07-11 2014-01-16 Sandoz Ag Nanosuspension d'acétate d'abiratérone
CN111110646A (zh) * 2020-02-19 2020-05-08 纳兰迦(上海)生物医药科技有限公司 一种低规格醋酸阿比特龙口服制剂的处方及制备方法
JP2023103410A (ja) * 2013-03-15 2023-07-26 サン ファーマシューティカル インダストリーズ リミテッド アビラテロン酢酸エステル製剤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014009436A1 (fr) * 2012-07-11 2014-01-16 Sandoz Ag Nanosuspension d'acétate d'abiratérone
JP2023103410A (ja) * 2013-03-15 2023-07-26 サン ファーマシューティカル インダストリーズ リミテッド アビラテロン酢酸エステル製剤
CN111110646A (zh) * 2020-02-19 2020-05-08 纳兰迦(上海)生物医药科技有限公司 一种低规格醋酸阿比特龙口服制剂的处方及制备方法

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