WO2025163665A1

WO2025163665A1 - Stable pharmaceutical compositions of abiraterone

Info

Publication number: WO2025163665A1
Application number: PCT/IN2025/050093
Authority: WO
Inventors: Dhananjay Panigrahi; Raju SAKA; HariHaran VENUGOPAL; Anup Avijit Choudhury; Venkat Ramana Naidu
Original assignee: Dr Reddys Laboratories Ltd
Current assignee: Dr Reddys Laboratories Ltd
Priority date: 2024-01-29
Filing date: 2025-01-28
Publication date: 2025-08-07
Anticipated expiration: 2026-07-29

Abstract

The present invention relates to a stable pharmaceutical composition of abiraterone or pharmaceutically acceptable salt thereof. Specifically, it relates to a stable pharmaceutical composition comprising a nanosuspension of abiraterone or pharmaceutically acceptable salt thereof that reduces the dose, lessen the pill burden, enhance the bioavailability of abiraterone in fasting conditions and reduce the food effect as compared to commercial products. A method of preparation of the said composition is also disclosed. Additionally, the invention pertains to the methods of treating certain cancers in mammalian subjects using the said composition.

Description

STABLE PHARMACEUTICAL COMPOSITIONS OF ABIRATERONE

CROSS REFERENCE

This application claims priority from Indian Patent Application No. 202441005734 filed on January 29, 2024.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions of abiraterone or pharmaceutically acceptable salt thereof and a method of preparing the same. Additionally, the invention pertains to the methods of treating certain cancers in mammalian subjects using the said composition.

BACKGROUND OF THE INVENTION

Abiraterone is an inhibitor of CYP17 (17α-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 (3β)-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. A daily dose of 1000 mg abiraterone acetate is administered once daily.

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. According to the approved prescribing information, at the dose of 1,000 mg daily in patients with metastatic CRPC, 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.

Further, according to the approved prescribing information abiraterone acetate is known to exhibit a strong food effect when administered orally. In healthy subjects abiraterone 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. To control the drug uptake, 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®. Although 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.

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 comprising 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.

Despite numerous efforts to address the issues associated with current commercial products, there remains a need to develop an improved formulation of abiraterone acetate. Specifically, there is a need for formulations that reduce the dose, lessen the pill burden, enhance the bioavailability of abiraterone in fasting conditions, reduce the food effect and minimize high intra- and inter-subject variability.

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.

In certain embodiments, the stable pharmaceutical composition for oral administration comprises the nanosuspension of abiraterone or pharmaceutically acceptable salt thereof.

In certain embodiments, the stable pharmaceutical composition further comprises a stabilizer.

In certain embodiments, 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.

In certain embodiments, the invention relates to 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.

In certain embodiments, the invention relates to a stable pharmaceutical composition comprising:

a) a nanosuspension containing abiraterone or pharmaceutically acceptable salt thereof 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.

In certain embodiments, 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.

In certain embodiments, the stable pharmaceutical composition comprises abiraterone nanoparticles with an D90 particle size less than about 1000 nm.

In certain embodiments, the composition remains stable for at least 6 months at 40⁰ C/75% RH (“relative humidity”) or 30⁰C/75% RH. Further, the composition also remains stable for at least 6 months at 25⁰ 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.

In certain embodiments, 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.

In certain embodiments, the stable pharmaceutical compositions of abiraterone or pharmaceutically acceptable salt thereof reduces pill burden such that only single unit dose is administered once daily.

In certain embodiments, 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).

DETAILED DESCRIPTION OF INVENTION

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.

Terms:

The term “abiraterone” as used in this specification 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 terms “about” and “approximate,” when used along with a numerical variable, generally means the value of the variable and all the values of the variable within a measurement or an experimental error (e.g., 95% confidence interval for the mean) or within a specified range (e.g., ±20%, ±10%, ±5%). For instance, 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. Preferably, the term “about” refers to ±20%, preferably ±10%, and more preferably ±5% of the value or range it refers to.

The term “comprising” as used herein is synonymous with "including", "containing", or "characterized by" and is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.

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. In certain aspects, the bioavailability (e.g., AUC, Cmax and/or Tmax) 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.

The term “lowering of dosage” as used in this specification 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®).

The terms “pharmaceutical composition,” “pharmaceutical product,” “pharmaceutical dosage form,” “dosage form,” “composition” or “formulation” refer 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.

The term “pharmaceutically acceptable” as used in this specification 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.

The term “reducing the food effect” as used herein 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.

The term "salts" as used in this specification include derivatives of an active agent modified by making acid or base addition salts thereof. Examples of 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. For example, 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.

The term “stabilizer(s)” as used herein 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.

The term “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.

In certain embodiments, the invention relates to a stable nanosuspension comprising abiraterone or pharmaceutically acceptable salt thereof and a stabilizer.

a) abiraterone or pharmaceutically acceptable salt thereof,

b) cellulose derivative,

c) non-ionic surfactant, and

d) one or more other pharmaceutically acceptable excipients,

wherein the composition can be administered with or without food.

In certain embodiments, the invention relates to a a stable pharmaceutical composition comprising:

a) a nanosuspension comprising abiraterone or pharmaceutically acceptable salt thereof and stabilizer, and

b) one or more other pharmaceutically acceptable excipients, wherein the composition can be administered with or without food.

In certain embodiments, 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.

The choice of a stabilizer for abiraterone is non-trivial. After extensive experimentation, the inventors of present application discovered that 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. In one of the embodiments of the invention, the non-ionic surfactant is poloxamer.

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.

In certain embodiments, the invention relates to 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. In one of the embodiments of the invention, the weight ratio is about 2.5:1.

After extensive experimentation, the inventors of the present application have discovered that preferably, maintaining the ratio of HPMC (Hydroxypropylmethylcellulose) to poloxamer in the range of about 5:1 to about 1:5 results in a stable formulation with an improved dissolution profile. A high concentration of HPMC enhances binding, leading to lesser dissolution and increased disintegration time. It also results in heavier tablets with dimensions beyond acceptable values. On the other hand, reduction in HPMC content lowers nanosuspension stability, adversely affecting the dissolution rate.

Similarly, high concentration of 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.

In certain embodiments, the invention relates to 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. Preferably, the ratio is about 3:1.

In certain embodiments, the invention relates to 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.

In certain embodiments, the invention relates to 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.

Other pharmaceutically acceptable excipients 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. In one of the embodiments of the invention, the diluent is microcrystalline cellulose, mannitol and lactose monohydrate.

In certain embodiments, 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. Preferably, 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. In one of the embodiments of the invention, 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. In one of the embodiments of the invention, the disintegrant is croscarmellose sodium.

In certain embodiments, disintegrant is included either in nanosuspension or extra-granular material or both. The concentration of disintegrant ranges from about 1% to about 10% w/w of total composition. Preferably, the disintegrant 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, capric acid, sodium or potassium caprate, caprylic acid, sodium or potassium caprylate, dioctyl sodium sulfosuccinate or a mixtures thereof. In one of the embodiments of the invention, the ionic surfactant is sodium lauryl sulphate. The concentration of surfactant ranges from about 0.1% to about 5% w/w of total composition.

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. In one of the embodiments of the invention, 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. In one of the embodiments of the invention, 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. In one of the embodiments of the invention, 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. In one of the embodiments of the invention, 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. In one of the embodiments of the invention, 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. The concentration of film coating used in present invention ranges from about 0.1% to about 5% (w/w) to the total concentration.

In certain embodiments, 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.

In another embodiment, the pharmaceutical 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.

In certain embodiments, the present invention provides a process for the preparation of stable pharmaceutical composition for oral administration comprising following steps:

(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.

(a) adding the cellulose derivative and ionic surfactant to the purified water in a suitable container,

(b) adding abiraterone to step (a) and stirring continuously to obtain abiraterone dispersion,

(c) homogenizing the above abiraterone dispersion to obtain abiraterone slurry,

(d) nano-sizing abiraterone slurry in a ball-mill chamber to obtain desired particle size of abiraterone,

(e) adding redispersing agent, ionic surfactant, non-ionic surfactant and part of disintegrant to obtain nano-suspension,

(f) spraying the nanosuspension onto the diluent and dried,

(g) adding remaining amount of disintegrant, diluent, glidant, lubricant and blended produce a final blend suitable for encapsulating or tableting.

In certain embodiments, 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. Preferably, the D90 particle size is equal to or less than about 200 nm.

In certain embodiments, 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. Preferably, the D50 particle size is equal to or less than about 100 nm.

In certain embodiments, 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. Preferably, 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.

In certain embodiments, 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.

In certain embodiments, 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.

In certain embodiments, 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.

Furthermore, it has been found that using 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 (40⁰C/75%RH) and long term (30⁰C/75% RH) or (25⁰ C/60% RH) storage conditions for at least 6 months.

In certain embodiments, the present invention relates to a stable nanosuspension comprising abiraterone or pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention relates to stable pharmaceutical composition for oral administration comprising the nanosuspension of abiraterone or pharmaceutically acceptable salt thereof.

In certain embodiments, 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.

In one embodiment, 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.

In yet another embodiment, 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.

In certain embodiments, dose modification is required in case of patients with hepatic impairment and hepatotoxicity.

In certain embodiments, the stable pharmaceutical compositions of abiraterone or pharmaceutically acceptable salt thereof reduces pill burden such that only single unit dose of about 300 mg is to be administered once daily.

Effect of poloxamer on in-vitro dissolution and bioavailability was studied. 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.

Further, the composition of present invention containing poloxamer also showed significant improvement in bioavailability as compared to ZYTIGA under fasting condition.

In certain embodiments, 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,

b) stabilizer, and

c) one or more pharmaceutically acceptable excipients,

wherein upon administration, the said composition exhibits one or more of the following pharmacokinetic parameter;

i) a maximum plasma concentration (Cmax) of about 81.21± 56.13 ng/mL to about 124.06± 106.60 ng/mL of abiraterone;

ii) 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.

In certain embodiments, the pharmaceutical compositions described herein reduce or eliminate the food effect. Thus, 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. Hence, the pharmaceutical compositions according to the present invention can be administered with or without food.

In certain embodiments, the present invention provides a stable nanosuspension composition comprising:

a) abiraterone or pharmaceutically acceptable salt thereof in an amount of about 300 mg equivalent to free base;

b) stabilizer, and

c) one or more pharmaceutically acceptable excipients,

wherein upon administration with food, the said composition exhibits one or more of the following pharmacokinetic parameter;

i) a maximum plasma concentration (Cmax) of about 475.09 ± 353.78 ng/mL of abiraterone;

ii) an area under the plasma concentration-time curve (AUC0-t) of about 1069.48 ± 569.44 ng.hr/mL; and

wherein 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.

In certain embodiments, 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). Further, the aforementioned pharmaceutical composition is used in combination with a glucocorticoid, preferably prednisone, prednisolone or methylprednisolone. Preferably, the pharmaceutical composition is used in combination with prednisone.

The following examples are exemplary and not intended to be limiting. The above disclosure provides many different embodiments for implementing the features of the invention, and the following examples describe certain embodiments. It will be appreciated that other modifications and methods known to one of ordinary skill in the art can also be applied to the following experimental procedures, without departing from the scope of the invention.

EXAMPLES

Example 1: Abiraterone tablet composition using nanosuspension

Ingredients	Ex 1a	Ex 1b	Ex 1c	Ex 1d	Ex 1e
Ingredients	%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:

Cellulose derivative and ionic surfactant were dissolved in purified water,
Abiraterone acetate was added to solution in step a) and homogenized,
Slurry obtained in step b) was subjected to nano-sizing in a ball-mill chamber to obtain desired particle size of abiraterone,
Redispersing agent, ionic surfactant, non-ionic surfactant and part of disintegrant are added to obtain nano-suspension,
Suspension of step d) was sprayed onto the diluent and dried,
Extragranular phase was prepared by mixing remaining amount of disintegrant, diluent, glidant, lubricant and blended with dried mixture obtained in step e),
Mixture obtained in step f) was compressed to get abiraterone acetate tablet and packaged in HDPE bottle pack.

Example 2: Effect of poloxamer on bioavailability of the composition

To study the effect of poloxamer on the bioavailability of the composition in the present invention, two 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.

Ingredients	Formulation 2a	Formulation 2b
Ingredients	(%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:

Formulation 2a: D90 is about 184 nm; D50 is about 60.3 nm; D4,3 is about 88.9 nm.

Formulation 2b: D90 is about 159 nm; D50 is about 54.1 nm; D4,3 is about 75.8 nm.

Dissolution study:

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 (min)	Formulation 2a (300 mg)	Formulation 2b (300 mg)	Zytiga (1000 mg)	Yonsa (500 mg)
Time (min)	% Drug release
0	0	0	0	0
15	98	102	33	92
30	98	102	39	94
60	100	103	42	95
90	100	103	42	96
120	100	104	42	95
Dissolved (mg)	300mg	300mg	420mg	475mg

Similarly, the in vitro dissolution rate was determined in 900 mL pH 4.5 + 0.06% SLS using an USP Apparatus II at 75 RPM. The dissolution profile of the test formulations 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.

Pharmacokinetic Study:

A study was conducted to test the pharmacokinetics and bioavailability of composition 2a and 2b, in healthy adult, human volunteers, under fasting condition.

This study was open label, balanced, randomized, single-dose, three-treatment, three-sequence, three-period, six-sequence, crossover, oral bioavailability study of comparative bioavailability of abiraterone acetate tablets, 300mg (Test formulations), compared with that of the reference product ZYTIGA® Tablets (500 mg x 2 tablets), in normal, healthy, adult, male human subjects under fasting conditions. Table-5 represents the results of the study.

Table 5: Statistical Summary for Abiraterone tablets 300 mg Fasting Study

Parameter	Arithmetic Mean		Ratio (T/R) %	90% Confidence Limits (%)		Power (%)	ISCV (%)
Parameter	Test	Reference	Ratio (T/R) %	Lower	Upper	Power (%)	ISCV (%)
Formulation 2a (N = 22)
Cmax (ng/mL)	81.21± 56.13	110.30± 78.05	75.19	55.63	101.63	32.94	62.30
AUC0-t (ng.hr/mL)	317.34 ± 158.68	471.69 ± 301.94	72.55	57.81	91.04	48.83	45.24
AUC0-inf (ng.hr/mL)	326.22 ± 159.19	485.69 ± 303.79	72.28	58.41	89.46	53.19	42.23
Formulation 2b (N = 23)
Cmax (ng/mL)	124.06± 106.60	110.30± 78.05	108.75	82.62	143.15	37.45	58.10
AUC0-t (ng.hr/mL)	400.82 ± 219.34	471.69 ± 301.94	91.38	78.29	106.68	77.28	31.07
AUC0-inf (ng.hr/mL)	412.01 ± 221.10	485.69 ± 303.79	90.67	78.28	105.03	80.88	29.46

From the data shown in Table 5, it is apparent that improved bioavailability was observed in the case of test formulation 2b compared to the reference product ZYTIGA®.

Example 3: Food effect study

Based on above results, 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.

Table 6: Statistical Summary for Abiraterone tablets 300 mg Fed Vs Fasting Study (TFE Vs TFA)

Parameter	Arithmetic Mean		Ratio (TFE/TFA) %	90% Confidence Limits (%)		Power (%)	ISCV (%)
Parameter	Test FE	Test FA	Ratio (TFE/TFA) %	Lower	Upper	Power (%)	ISCV (%)
(N = 19)
Cmax (ng/mL)	475.09 ± 353.78	176.49 ± 106.60	237.06	151.31	371.40	19.69	93.78
AUC0-t (ng.hr/mL)	1069.48 ± 569.44	541.00 ± 264.72	195.84	155.23	247.07	47.29	42.92
AUC0-inf (ng.hr/mL)	1084.03 ± 573.73	550.49 ± 266.47	194.72	154.95	244.70	48.41	42.13

From the data shown in Table 6, it is apparent that test formulation 2b showed a 2.4-fold increase in Cmax and a 2-fold increase in AUC compared to overnight fasting. Hence, the pharmaceutical compositions according to the present invention exhibit a reduction of the positive food effect and can be administered with or without food.

Furthermore, 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
Water content	NMT 5%	3.16	2.74	2.71	2.77	3.07	3.51
Related substances
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 abiraterone acetate	NMT 0.8	BDL	0.071	0.044	0.058	0.032	0.046
Single maximum unknown	NMT 0.2	BDL	BDL	BDL	BDL	BDL	ND
Total impurities	NMT 2	0.09	0.285	0.224	0.455	0.242	0.335

NMT: Not more than; NLT: Not less than, BDL: Below detection limit, BPQL: Below peak quantitation limit

As apparent from the results above, no significant increase in degradation products has been observed when stored at accelerated (40⁰C/75%RH) and long term (30⁰C/75% RH) storage conditions for at least 6 months.

Claims

A stable pharmaceutical composition comprising:
a) abiraterone or pharmaceutically acceptable salt thereof,
b) cellulose derivative,
c) non-ionic surfactant, and
d) one or more other pharmaceutically acceptable excipients,
wherein the composition can be administered with or without food.
A stable pharmaceutical composition comprising:
a) a nanosuspension comprising abiraterone or pharmaceutically acceptable salt thereof and stabilizer, and
b) one or more other pharmaceutically acceptable excipients,
wherein the composition can be administered with or without food.
The stable pharmaceutical composition according to claim 2, wherein the stabilizer is a combination of a cellulose derivative and a non-ionic surfactant.
The stable pharmaceutical composition according to claim 1 or 3, wherein the cellulose derivative is selected from hydroxyl propyl methylcellulose (HPMC), methylcellulose, hydroxypropylcellulose (HPC), hydroxy ethyl cellulose, sodium carboxy methyl cellulose or mixtures thereof and the non-ionic surfactant is selected from 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 stable pharmaceutical composition according to claim 1 or 3, wherein the cellulose derivative is hydroxyl propyl methyl cellulose and the non-ionic surfactant is poloxamer.
The stable pharmaceutical composition according to claim 1 or 3, wherein the ratio of cellulose derivative and a non-ionic surfactant ranges from about 5:1 to about 1:5.
The stable pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutically acceptable excipients are selected from redispersing agent, diluent, disintegrant, lubricant, glidant, surfactant or mixtures thereof.
The stable pharmaceutical composition according to claim 1 or 2, wherein the abiraterone or pharmaceutically acceptable salt thereof is present in amount of about 300 mg equivalent to free base and the composition is administered once daily.
The stable pharmaceutical composition according to claim 1 or 2, wherein the dissolution rate of the abiraterone or pharmaceutically acceptable salt thereof is such that at least 90% of the abiraterone is released within 30min when tested in 900 ml of pH 4.5 phosphate buffer (0.06% SLS) using USP Apparatus II at 75 rpm.
The stable pharmaceutical composition according to claim 1 or 2, wherein upon administration of a single unit dose of about 300 mg abiraterone or pharmaceutically acceptable salt thereof to healthy subjects with a high-fat meal (1000 calories) resulted an increase in Cmax of about 2.4 fold and AUC of about 2 fold compared to overnight fasting.
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,
b) stabilizer, and
c) one or more pharmaceutically acceptable excipients,
wherein upon administration, the said composition exhibits one or more of the following pharmacokinetic parameters;
i) a maximum plasma concentration (Cmax) of about 81.21± 56.13 ng/mL to about 124.06± 106.60 ng/mL of abiraterone;
ii) 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 stable pharmaceutical composition according to claim 11, wherein the stabilizer is a combination of a cellulose derivative and a non-ionic surfactant.
The stable pharmaceutical composition according to claim 12, wherein the cellulose derivative is hydroxyl propyl methyl cellulose and the non-ionic surfactant is poloxamer.
The stable pharmaceutical composition according to claim 12, wherein the ratio of cellulose derivative and a non-ionic surfactant ranges from about 5:1 to about 1:5.
The stable pharmaceutical composition according to claim 11, wherein the pharmaceutically acceptable excipients are selected from redispersing agent, diluent, disintegrant, lubricant, glidant, surfactant or mixtures thereof.
The stable pharmaceutical composition according to claim 11, wherein upon administration, the said composition exhibits one or more of the following pharmacokinetic parameters;
i) a maximum plasma concentration (Cmax) of about 124.06± 106.60 ng/mL of abiraterone;
ii) an area under the plasma concentration-time curve (AUC0-t) of about 400.82 ± 219.34 ng.hr/mL.
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;
b) stabilizer, and
c) one or more pharmaceutically acceptable excipients,
wherein upon administration with food, the said composition exhibits one or more of the following pharmacokinetic parameters;
i) a maximum plasma concentration (Cmax) of about 475.09 ± 353.78 ng/mL of abiraterone;
ii) an area under the plasma concentration-time curve (AUC0-t) of about 1069.48 ± 569.44 ng.hr/mL; and
wherein 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 stable pharmaceutical composition according to claim 17, wherein the stabilizer is a combination of a cellulose derivative and a non-ionic surfactant.
The stable pharmaceutical composition according to claim 18, wherein the cellulose derivative is hydroxyl propyl methyl cellulose and the non-ionic surfactant is poloxamer.
The stable pharmaceutical composition according to claim 18, wherein the ratio of celllose derivative and a non-ionic surfactant ranges from about 5:1 to about 1:5.
The stable pharmaceutical composition according to claim 17, wherein the pharmceutically acceptable excipients are selected from redispersing agent, diluent, disintegrant, lubricant, glidant, surfactant or mixtures thereof.
A process for the preparation of stable pharmaceutical composition for oral administration comprising following steps:
(a) adding cellulose derivative and ionic surfactant to purified water in a suitable container,
(b) adding abiraterone to step (a) and stirring continuously to obtain abiraterone dispersion,
(c) homogenizing the above abiraterone dispersion to obtain abiraterone slurry,
(d) nano-sizing the abiraterone slurry in a ball-mill chamber to obtain desired particle size of abiraterone,
(e) adding redispersing agent, ionic surfactant, non-ionic surfactant and part of disintegrant to obtain nano-suspension,
(f) spraying the nanosuspension onto diluent and drying,
(g) adding remaining amount of disintegrant, diluent, glidant, lubricant and blending to produce a final blend suitable for encapsulating or tableting.
The process for the preparation of stable pharmaceutical composition according to claim 22, wherein the cellulose derivative is hydroxyl propyl methyl cellulose and non-ionic surfactant is poloxamer.
The process for the preparation of stable pharmaceutical composition according to claim 23, wherein the ratio of hydroxyl propyl methyl cellulose and poloxamer ranges from about 5:1 to about 1:5.
The process for the preparation of stable pharmaceutical composition according to claim 22, wherein the abiraterone particles in nanosuspension have D90 particle size of equal to or less than about 200 nm.
The process for the preparation of stable pharmaceutical composition according to claim 22, wherein the abiraterone particles in nanosuspension have D50 particle size of equal to or less than about 100 nm.
The process for the preparation of stable pharmaceutical composition according to claim 22, wherein the abiraterone particles in nanosuspension have D4,3 particle size of equal to or less than about 100 nm.
The stable pharmaceutical composition according to claim 1 or 2, wherein the composition is used in the treatment of metastatic castration-resistant prostate cancer (CRPC) and metastatic high-risk castration-sensitive prostate cancer (CSPC) in combination with glucocorticoid.
The stable pharmaceutical composition according to claim 28, wherein the glucocorticoid is selected from prednisone, prednisolone and methylprednisolone.
The stable pharmaceutical composition according to claim 1 or 2, wherein the composition remains stable for at least 6 months at accelerated 40⁰ C/75% RH and long term storage conditions 30⁰C/75% RH .