Oral formulation of abiraterone acetate and its manufacturing method

Abstract

The present invention relates to an oral suspension dosage form of abiraterone acetate. The present invention also relates to providing an economically and technologically advanced dosage form that is more patient-compatible than existing dosage forms. Furthermore, the solubility and stability of patient-compatible abiraterone acetate formulations prepared according to the present invention have been found to be higher when compared to prior art inventions. Furthermore, the present invention also provides a suspension composition prepared by a relatively simple, commercially easy, and functionally reproducible method.

Description

[Technical Field]

[0001] The present invention relates to an oral liquid formulation of abiraterone acetate as a suspension. Further, the present invention relates to providing a dosage form that is economically and technically advanced over existing dosage forms. [Background technology]

[0002] Abiraterone acetate (CAS: 154229-18-2) is an inhibitor of CYP17 (17α-hydroxylase / C17,20 lyase). Abiraterone acetate is chemically known as 17-(pyridin-3-yl)androsta-5,16-dien-3β-yl acetate and is structurally represented as follows: [ka] U.S. Patent No. 5,629,999 first disclosed abiraterone acetate and analogs (Markush structure) and their use in the treatment of prostate cancer. U.S. Patent No. 5,629,999 further discloses the methanesulfonate salt of abiraterone acetate.

[0003] Abiraterone acetate is currently marketed in the United States under the trade name "ZYTIGA®." The tablet is indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) and metastatic high-risk castration-sensitive prostate cancer (CSPC). The recommended dosage of abiraterone acetate is 1,000 mg (two 500 mg tablets or four 250 mg tablets) orally once daily plus 5 mg of prednisone orally twice daily.

[0004] US Patent No. 5,999,949 claims a method for the treatment of prostate cancer in humans, comprising administering to said human a therapeutically effective amount of abiraterone acetate or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of prednisone.

[0005] US Patent No. 5,929,999 discloses a method for preparing a tablet composition having the same qualitative composition and the same concentration of abiraterone acetate in the tablet as Zytiga tablets.

[0006] US Patent No. 5,929,999 discloses tablets containing a high loading of abiraterone acetate, but the dissolution profile of this composition is slow when compared to the approved Zytiga 250 mg tablets.

[0007] Patent Document 6 discloses abiraterone acetate dissolved or dispersed in a carrier, the carrier comprising one or more lipid excipients.

[0008] Patent Document 7 claims a pharmaceutical formulation containing abiraterone, propylene glycol monocaprylate, and an emulsifier. It discloses a pharmaceutical formulation containing a poorly water-soluble drug such as abiraterone formulated into a capsule, where the drug is solubilized within other components of the pharmaceutical formulation that form a nanoemulsion upon exposure to an aqueous environment.

[0009] Patent Document 8 discloses a nanosuspension comprising particles of abiraterone acetate or a pharmaceutically acceptable salt, hydrate or solvate thereof having a d(0.5) of less than 1000 nm.

[0010] Patent Document 9 discloses a method for producing a composition comprising nanoparticles of abiraterone acetate, the method comprising dry-milling a composition comprising abiraterone acetate, a grindable abrasive compound, an accelerator, and one or both of an antioxidant and a sequestering agent in a mill containing multiple grinding bodies for a time sufficient to produce a composition comprising fine particles of abiraterone acetate, wherein the particle size of the abrasive matrix and the particle size of the abiraterone acetate are reduced by the dry-milling.

[0011] Patent Document 10 discloses tablets containing a high loading of abiraterone acetate (50-80% w / w) and a wetting agent. However, the bioavailability of these compositions is low when compared to the approved Zytiga 250 mg tablets.

[0012] Patent Document 11 discloses a dosage composition of abiraterone acetate in the form of an emulsion, solution, suspension, syrup, or elixir for once-daily administration, wherein the abiraterone particles are nano-sized, having a particle size of less than about 2000 nanometers.

[0013] Patent Document 12 discloses lipid compositions for abiraterone acetate, such as lipid multiparticulate formulations containing abiraterone acetate and a lipid matrix, or liquid-filled hard capsules containing abiraterone acetate and a lipid matrix. However, the invention is not considered advantageous because the capsules are affected by relative humidity and microbial contamination.

[0014] Patent Document 13 discloses an oral pharmaceutical formulation containing abiraterone, a solubilizer, and other pharmaceutically acceptable excipients, the oral pharmaceutical formulation containing less than 1000 mg of abiraterone.

[0015] Patent Document 14 discloses an oral emulsion formulation of abiraterone containing abiraterone, polysorbate-80, lecithin, an oil phase, and an aqueous phase.

[0016] US Pat. No. 5,699,499 discloses tablet compositions for oral administration of abiraterone acetate, in particular pharmaceutical granules and tablets that provide immediate release of abiraterone acetate in the stomach.

[0017] Most of the prior art is directed to oral tablet formulations of abiraterone acetate. These tablets are large and must be taken on an empty stomach. Therefore, to overcome the problems of the prior art, there remains a need to find an oral liquid dosage form of abiraterone that is also bioequivalent to the commercially available abiraterone tablet, Zytiga®.

[0018] Note that abiraterone acetate is a difficult process due to its low solubility and poor permeability (a BCS Class IV product), and suspensions are useful drug delivery systems for poorly soluble therapeutic agents. Therefore, drugs with poor wetting and slow dissolution characteristics may be difficult to formulate and manufacture as tablets, where suspensions enhance dissolution and bioavailability, resulting in sufficient and complete drug bioavailability.

[0019] Furthermore, when given in tablet form, they cannot be easily ingested, and some drugs cause stomach irritation, making tablets unsuitable for patients with dysphagia and elderly patients. Furthermore, tablets are unsuitable for unconscious patients. The above limitations have been very effectively identified by the inventors of the present invention, and therefore, a stable and effective oral liquid suspension dosage form has been developed to meet the shortcomings identified in prior art publications.

[0020] The present invention discloses an oral liquid suspension dosage form of abiraterone acetate that does not require sophisticated technology and is economically more affordable than available dosage forms. Furthermore, the oral liquid suspension dosage form prepared according to the present invention provides higher stability. Furthermore, oral liquid dosage forms are most suitable for patients who have difficulty swallowing tablets or capsules, such as patients with swallowing disorders, pediatric patients, or geriatric patients. They are visually appealing and provide beneficial psychological effects.

[0021] A suspension is a heterogeneous mixture containing solid particles large enough to settle. The suspended particles are visible to the naked eye. A suspension is a heterogeneous mixture in which the suspended particles remain suspended throughout the bulk of the liquid medium, but the suspended particles do not dissolve. Generally, the solid portion is dispersed by mechanical agitation using a suspending agent. In contrast, a solution has homogeneously mixed solutes that are dissolved and do not exist as solids.

[0022] The present invention incorporates a suspending agent with a smaller particle size, which increases the solubility of abiraterone acetate by providing a better dissolution profile. Furthermore, the present invention achieves greater stability of abiraterone acetate. Furthermore, the solubility and stability of the patient-compatible abiraterone acetate formulations prepared according to the present invention were found to be higher when compared to prior art inventions.

[0023] Furthermore, the present invention provides suspension compositions prepared by a relatively simple, commercially easy, and functionally reproducible method. Additionally, the suspension compositions of the present invention can incorporate two or more active ingredients. [Prior art documents] [Patent documents]

[0024] [Patent Document 1] International Publication No. 1993 / 20097 [Patent Document 2] International Publication No. 2006 / 021776 [Patent Document 3] U.S. Patent No. 8,822,438 [Patent Document 4] Chinese Patent No. 102743393 [Patent Document 5] Chinese Patent No. 102336801 [Patent Document 6] International Publication No. 2013 / 164473 [Patent Document 7] U.S. Patent No. 9,511,078 [Patent Document 8] International Publication No. 2014 / 009436 [Patent Document 9] International Publication No. 2014 / 145813 [Patent Document 10] International Publication No. 2015 / 032873 [Patent Document 11] International Publication No. 2015 / 114314 [Patent Document 12] U.S. Patent No. 10,722,527 [Patent Document 13] International Publication No. 2017 / 037647 [Patent Document 14] International Publication No. 2019 / 186444 [Patent Document 15] International Publication No. 2019 / 206472 Summary of the Invention [Problem to be solved by the invention]

[0025] The primary object of the present invention is to provide oral compositions, preferably liquid suspension dosage forms, of abiraterone acetate or pharmaceutically acceptable salts thereof, comprising one or more pharmaceutically acceptable excipients, and methods for preparing the same.

[0026] In one aspect of the present invention, the formulated product is a stabilized suspension.

[0027] In one object of the present invention, the active ingredient incorporated into the pharmaceutical composition is a granular material having a particle size D in the range of 0.5 to 50 microns. 90 Includes:

[0028] Another object according to the present invention wherein the formulated product has particle size in the nanometer to micrometer range and results in an improved in vitro dissolution profile of about 80% to 110%.

[0029] One object of the present invention includes a pharmaceutical composition comprising abiraterone acetate together with pharmaceutically acceptable excipients, but without a pH adjusting agent.

[0030] In yet another aspect, the pharmaceutical composition produced according to the present invention is a suspension. The pharmaceutical composition is produced by several steps of the manufacturing process including homogenization, sonication, mixing and / or evaporation by spray drying.

[0031] One object of the present invention may include a pharmaceutical composition comprising about 5% to 60% w / v abiraterone acetate together with a pharmaceutically acceptable excipient, preferably 5% to 45% abiraterone acetate and a pharmaceutically acceptable excipient, and more preferably 5% to 30% abiraterone acetate and a pharmaceutically acceptable excipient.

[0032] In yet another object of the present invention, the pH of the pharmaceutical composition is in the range of 3.5 to 6.5.

[0033] Another object of the present invention is to provide a super-bioavailable 1000 mg / 5 mL oral liquid suspension dosage form compared to the existing tablet dosage of two 500 mg tablets and four 250 mg tablets, thus allowing for a reduced therapeutic dose.

[0034] In yet another object of the present invention, the composition of abiraterone acetate includes solubility enhancers and permeability enhancers that are not part of the current dosage forms available on the market.

[0035] Another object of the present invention is that the liquid formulation is administered orally once daily, while the existing dosage form is administered as four abiraterone tablets.

[0036] Embodiments of the pharmaceutical composition may include abiraterone acetate as the active ingredient along with one or more pharmaceutically acceptable excipients selected from similar diluent vehicles, stabilizers / antioxidants, suspending / thickening agents, chelating / complexing agents, solubility enhancers, permeability enhancers, preservatives, glidants, active carriers, sweeteners, anti-caking agents, humectants, preservatives, buffers, flavoring agents, and the like. [Means for solving the problem]

[0037] One aspect of the present invention is a method for producing a method for manufacturing a semiconductor device comprising the steps of: (a) adding a dilution vehicle to purified water; (b) adding a co-solvent and homogenizing; (c) adding a solubilizer and homogenizing; (d) adding abiraterone acetate and homogenizing to obtain a homogenous suspension; (e) adding a sweetener to the suspension prepared above and mixing it by vortex or high speed homogenizer or mechanical stress or ultrasonic stress or shear stress to obtain a uniform suspension formulation; (f) adding flavoring agents and homogenizing; (g) dissolving a suspending agent and a thickening agent in purified water; (h) adding the solution of step (g) to step (h) and making up the volume of the suspension with purified water to obtain the appropriate viscosity. The present invention relates to a method for the preparation of an oral liquid pharmaceutical composition according to the present invention, comprising:

[0038] The details of one or more embodiments of the invention are set forth in the description below. Other features of the invention will become apparent from the description.

[0039] The present invention will now be disclosed by describing certain preferred and optional embodiments in order to facilitate its various aspects.

[0040] Abiraterone acetate (CAS: 154229-18-2), chemically known as 17-(pyridin-3-yl)androsta-5,16-dien-3β-yl acetate, has a molecular weight of 391.55 g / mol. Abiraterone acetate is considered a Biopharmaceutics Classification System (BCS) Class IV drug substance due to its low aqueous solubility and poor lipid permeability.

[0041] According to the present invention, the pharmaceutical composition comprises abiraterone acetate as an active ingredient together with pharmaceutically acceptable excipients.

[0042] The term "pharmaceutically acceptable excipient" as used herein refers to an excipient that is routinely used in pharmaceutical compositions. Pharmaceutically acceptable excipients can include diluent vehicles, stabilizers / antioxidants, suspending / thickening agents, chelating / complexing agents, solubility enhancers, preservatives, glidants, sweeteners, anticaking agents, humectants, preservatives, buffers, flavoring agents, and combinations thereof. A list of excipients that can be used is listed in the following table, but is not limited to the excipients.

[0043] Suitable diluent vehicles may include one or more of aqueous vehicles, sugars, methylcellulose gel, citric acid, sucrose, sorbitol solution, sodium carboxymethylcellulose solution, xanthan gum solution, non-aqueous vehicles such as purified fractionated coconut oil, hydrogenated castor oil, lecithin, aluminum stearate, and the like.

[0044] Suitable solubilizers may include one or more of Tween 80, Soluplus, polyoxyl 40 hydrogenated castor oil (Kolliphor® RH 40), caprylocaproyl polyoxyl-8 glyceride (Labrasol ALF), lauroyl polyoxyl-6 glyceride (Labrafil M 2130 CS), lauroyl polyoxyl-32 glyceride (Gelucire 44 / 14), Cremophor, lecithin, and the like.

[0045] Suitable suspending or thickening agents may include one or more of sodium alginate, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone K 120, colloidal silicon dioxide, carboxymethylcellulose, sodium carboxymethylcellulose, acacia, tragacanth, xanthan gum, carbomer, carrageen, gelatin, and the like.

[0046] Suitable co-solvents may include one or more from ethanol, propylene glycol, glycerin, glycofural, polyethylene glycol, and the like.

[0047] Suitable wetting agent can comprise one or more from the group comprising anionic, cationic, nonionic or zwitterionic surfactant, or their combinations.Suitable examples of wetting agent include sodium lauryl sulfate, cetrimide, polyethylene glycol, polyoxyethylene-polyoxypropylene block copolymer, such as poloxamer, polyglycerin fatty acid ester, such as decaglyceryl monolaurate and decaglyceryl monomyristate, sorbitan fatty acid ester, such as sorbitan monostearate, polyoxyethylene sorbitan fatty acid ester, such as polyoxyethylene sorbitan monooleate, polyethylene glycol fatty acid ester, such as polyoxyethylene monostearate, polyoxyethylene alkyl ether, such as polyoxyethylene lauryl ether, polyoxyethylene castor oil etc.

[0048] Suitable permeability enhancers may include one or more from the group including alcohols, polyols, short chain glycerides, amines, amides, cyclodextrins, fatty acids, pyrrolidines, azones, sulfoxides, surfactants, terpenes, and the like.

[0049] Suitable surfactant or co-surfactant can include one or more from anionic, cationic, nonionic or amphoteric surfactant.Non-limiting examples of surfactant can include polyoxyethylene-polyoxypropylene copolymer and block copolymer, ethoxylated cholesterol, vitamin derivatives, for example vitamin E derivatives, for example tocopherol polyethylene glycol succinate (TPGS), sodium dodecyl sulfate or sodium lauryl sulfate; bile acid or its salt, for example cholic acid, glycolic acid or salt; etc.

[0050] Suitable sweeteners include, but are not limited to, one or more of sucralose, saccharin, neotame, asparmate, cyclamate, glycerin, sucrose, molase, glucose, fructose, mannitol, sorbitol, xylitol, erythritol, isomalt, maltol, lactol, hydrogenated starch, and the like.

[0051] Suitable flavoring agents may include one or more from the group consisting of peppermint, grapefruit, orange, lime, lemon, mandarin, pineapple, strawberry, raspberry, mango, passion fruit, kiwi, apple, pear, peach, apricot, cherry, grape, banana, cranberry, blueberry, blackcurrant, redcurrant, gooseberry, lingonberry, cumin, thyme, basil, camille, valerian, fennel, parsley, chamomile, tarragon, lavender, dill, bergamot, salvia, aloe vera balsam, spearmint, piperine, eucalyptus, and the like.

[0052] Suitable solubility enhancers include (1) nonionic, such as polyoxyethylene sorbitan fatty acid esters, sorbitan esters, and polyoxyethylene ethers; (2) anionic, such as sodium lauryl sulfate, sodium laurate, sodium dialkyl sulfosuccinates, particularly sodium bis-(2-ethylhexyl) sulfosuccinate, sodium stearate, potassium stearate, and sodium oleate; (3) cationic, such as benzalkonium chloride, cetylpyridinium chloride, and benzethonium chloride; and (4) surfactants, such as zwitterionic / amphoteric surfactants. fatty alcohols such as lauryl alcohol, cetyl alcohol, and stearyl alcohol; glyceryl esters such as naturally occurring mono-, di-, and tri-glycerides; fatty acid esters of fatty alcohols and other alcohols such as propylene glycol, polyethylene glycol; sucrose; polymers such as poloxamer, polyvinylpyrrolidone, glycerides such as triacetin, glyceryl monocaprylate, glyceryl monooleate, glyceryl monostearate; diethylene glycol monoethyl ether; and the like.

[0053] One embodiment of the present invention may include a pharmaceutical composition comprising approximately 5% to 60% W / V abiraterone acetate together with a pharmaceutically acceptable excipient, preferably 5% to 45% abiraterone acetate together with a pharmaceutically acceptable excipient, and more preferably 5% to 30% abiraterone acetate together with a pharmaceutically acceptable excipient.

[0054] Another embodiment of the present invention includes a pharmaceutical composition comprising abiraterone acetate together with a pharmaceutically acceptable excipient, but without a pH adjusting agent.

[0055] In one embodiment of the present invention, the active ingredient incorporated into the pharmaceutical composition is a granular material having a particle size D in the range of 0.5 to 50 microns. 90 Includes:

[0056] An additional embodiment according to the present invention is that the formulated product is a stabilized suspension.

[0057] In yet another embodiment of the present invention, the pharmaceutical composition produced is a suspension and has an improved in vitro dissolution profile.

[0058] Another embodiment according to the present invention in which the formulated product has a particle size in the nanometer to micrometer range results in an in vitro dissolution profile of about 80% to 110%.

[0059] In yet another embodiment of the present invention, the pharmaceutical composition is prepared by several steps including homogenization, sonication, mixing and / or evaporation by spray drying.

[0060] In another embodiment, a pharmaceutical composition according to the present invention comprises abiraterone acetate or a pharmaceutically acceptable salt thereof.

[0061] Another embodiment of the present invention is intended to be super-bioavailable when compared to existing tablet dosages of two 500 mg tablets and four 250 mg tablets for a 1000 mg / 5 mL oral liquid suspension dosage form, thus allowing for a reduced therapeutic dose.

[0062] In yet another embodiment of the present invention, the composition of abiraterone acetate includes a solubility enhancer and a permeability enhancer that are not part of the current dosage form available on the market.

[0063] In another embodiment of the present invention, the liquid formulation is administered orally once daily, while the existing dosage form is administered as four abiraterone tablets. Tablets are not suitable for elderly patients because they are difficult to ingest and some drugs cause gastric irritation when given in tablet form. Furthermore, tablets are not suitable for unconscious patients. Furthermore, cancer patients typically receive multiple drug regimens, often with intravenous treatment, requiring the administration of multiple tablets or capsules. Patient compliance with such regimens can be addressed by reducing the number of tablets or capsules administered and the type of dosage form administered, taking into account the bioavailability of the administered drugs. Drug bioavailability cannot be compromised to meet patient compliance.

[0064] The compositions prepared according to the present invention have been subjected to animal pharmacokinetic studies to establish absorption by the oral route, and the extent of absorption after oral administration is observed to be in the range of 5% to 90%. Furthermore, the pharmaceutical compositions prepared according to the present invention are suspensions.

[0065] Suspensions facilitate the delivery of poorly soluble therapeutic agents. Low-solubility therapeutic agents can be administered via suspensions. However, they require large volumes of solvent. This volume can compromise drug preservation due to precipitation issues.

[0066] Furthermore, suspensions facilitate the dispersion of bitter drugs. Not all drugs administered to patients have a sweet taste. Most of them have a bitter taste, especially when administered to children who may avoid using drugs at all costs. With suspensions, the bitterness is reduced by the use of masking agents such as sweeteners and flavoring agents, so that the final formulation is palatable. It is also an alternative method of administering drugs to patients who have difficulty swallowing solid drugs.

[0067] Furthermore, suspensions also increase the bioavailability of drug dosages. Most drug dosages can only be presented in one form, such as capsules. This form can limit the way drugs are administered to specific patients. The suspension form can solve this problem.

[0068] In yet another embodiment of the present invention, the pH of the pharmaceutical composition is in the range of 3.5 to 6.5.

[0069] In one embodiment, the method for the preparation of an oral liquid pharmaceutical composition according to the present invention comprises the following steps: (a) adding a dilution vehicle to purified water; (b) adding a co-solvent and homogenizing; (c) adding a solubilizer and homogenizing; (d) adding abiraterone acetate and homogenizing to obtain a homogenous suspension; (e) adding a sweetener to the suspension prepared above and mixing it by vortex or high speed homogenizer or mechanical stress or ultrasonic stress or shear stress to obtain a uniform suspension formulation; (f) adding flavoring agents and homogenizing; (g) dissolving a suspending agent and a thickening agent in purified water; (h) adding the solution of step (g) to step (h) and making up the volume of the suspension with purified water to obtain the appropriate viscosity. Includes:

[0070] The present invention will be further described with reference to the following examples. However, the scope of the present invention is not limited thereto. All percentages described herein are by weight unless otherwise specified. Although the present invention has been described with reference to specific embodiments thereof, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

[0071] Example 1: [Table 1]

[0072] [Table 2]

[0073] Example 2: [Table 3]

[0074] [Table 4]

[0075] Example 3: [Table 5]

[0076] [Table 6]

[0077] Example 4: [Table 7]

[0078] [Table 8]

[0079] Example 5: [Table 9]

[0080] [Table 10]

[0081] Example 6: [Table 11]

[0082] [Table 12]

[0083] Example 7: [Table 13]

[0084] [Table 14]

[0085] Example 8: [Table 15]

[0086] [Table 16]

[0087] Example 9: [Table 17]

[0088] [Table 18]

[0089] Example 10: [Table 19]

[0090] [Table 20]

[0091] Example 11: [Table 21]

[0092] [Table 22]

[0093] Common manufacturing process for Examples 1 to 11: 1. Place half of the purified water in a container. 2. Add sorbitol to step 1 under stirring and mix with the help of homogenizer for 10 minutes. 3. Add the polyethylene glycol 400 to the solution from step 2 while homogenizing and continue homogenizing for 10 minutes. 4. Add Tween 80 / Soluplus / Polyoxyl 40 Hydrogenated Castor Oil (Kolliphor® RH 40) / Caprylocaproyl Polyoxyl-8 Glycerides (Labrasol ALF) / Lauroyl Polyoxyl-6 Glycerides (Labrafil M 2130 CS) / Lauroyl Polyoxyl-32 Glycerides (Gelucire 44 / 14) to the solution from step 3 while homogenizing and continue homogenizing for 10 minutes. 5. Add abiraterone acetate API to the mixture from step 4 while homogenizing and continue homogenization for 1 hour to obtain a uniform homogenous suspension. 6. Add sucralose to the suspension from step 5 while homogenizing and continue homogenizing for 10 minutes. 7. Add the strawberry flavor to the suspension from step 6 while homogenizing and continue homogenizing for 10 minutes. 8. Dissolve hydroxypropyl methylcellulose (HPMC K4M) / hydroxypropyl cellulose (HPC-M) / povidone K120 / colloidal silicone dioxide / xanthan gum in purified water while homogenizing, and continue homogenizing for 30 minutes. 9. Add the solution from step 8 to step 7 while homogenizing to make up the volume and continue homogenizing for 60 minutes. 10. Wet mill the suspension through a DYNO®-MILL at the desired parameters. 11. Collect the wet-milled suspension in a container.

[0094] TIFF2025526498000024.tif100157

[0095] Acceleration Stability Report: Assay, pH and dissolution profile studies were incorporated at various conditions and durations to assess stability for up to 6 months.

[0096] The dissolution profile study was observed in a medium defined by USFDA at 50 rpm in 900 mL of pH 4.5 buffer containing 0.25% sodium lauryl sulfate in 56.5 mM phosphate buffer.

[0097] In this stability study, oral liquid suspension compositions prepared according to Example 11 were observed.

[0098] Test Example 1: All samples were submitted for stability study at accelerated conditions of 40±2°C and 75±5% RH and chemical parameters were evaluated initially, after 1 month, after 3 months and after 6 months. The results obtained are reported in the following table: [Table 23]

[0099] Test Example 2: All samples were submitted for stability testing at accelerated conditions of 30±2°C and 75±5% RH and chemical parameters were evaluated initially, after 1 month, after 3 months and after 6 months. The results obtained are reported in the following table: [Table 24]

[0100] Test Example 3:

[0101] All samples were submitted for stability study at accelerated conditions of 25±2°C and 60±5% RH and chemical parameters were evaluated initially, after 1 month, after 3 months and after 6 months. The results obtained are reported in the following table: [Table 25]

[0102] According to the above test examples, the assay, pH and dissolution profile study of the composition of the present invention clearly show that it is stable for up to 6 months.Therefore, there is no need to add a pH adjuster to adjust the pH in the final formulation.Therefore, the above results demonstrate that the novel invention surprisingly achieves better results and proves its inventiveness through technical advancement. Comparative research report:

[0103] Assays and dissolution profile studies were evaluated to establish the equivalence of compositions prepared according to the present invention to commercially available formulations (Zytiga® 250 mg and 500 mg). Dissolution profile studies were observed in media defined by the USFDA.

[0104] [Table 26]

[0105] [Table 27]

[0106] The above comparison clearly shows dissolution of 1000 mg / 5 mL of suspension (by using 2 x 500 mg tablets) versus 1000 mg of Zytiga®, with only incomplete release observed for the innovator product, indicating that the suspension has good solubility in the existing medium and the rate of solubilization is fast over the long term compared to the initial period. Considering the dissolution profile, it can be concluded that the suspension formulation has fast absorption and extent of absorption when administered in vivo.

[0107] The invention described herein includes the various objects mentioned above, as well as descriptions thereof with respect to the properties, compositions, and processes employed. While these aspects are emphasized in the present invention, any variation of the invention described above should not be considered a departure from the spirit and scope of the invention as described.

[0108] The above examples are provided for illustrative purposes only and are not intended to limit the invention in any way.

Claims

1. 1. A pharmaceutical liquid suspension formulation suitable for oral administration comprising abiraterone acetate or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

2. 10. The liquid suspension of claim 1, comprising abiraterone acetate or a pharmaceutically acceptable salt in the form of solid particles having a particle size distribution with a D90 in the range of 0.5 to 50 microns.

3. 10. The liquid suspension of claim 1, comprising about 5% W / V to 60% W / V abiraterone acetate together with one or more pharmaceutically acceptable excipients.

4. 10. The liquid suspension of claim 1, wherein the pharmaceutically acceptable excipients are selected from similar diluent vehicles, stabilizers / antioxidants, suspending / thickening agents, chelating / complexing agents, solubility enhancers, permeability enhancers, preservatives, glidants, active carriers, sweeteners, anti-caking agents, humectants, preservatives, buffers, and flavoring agents.

5. (a) 5% W / V to 60% W / V abiraterone acetate (b) Dilution vehicle of 15% W / V to 70% W / V (c) 0.05% W / V to 5% W / V of a solubilizing agent (d) 0.1% W / V to 10% W / V of a co-solvent (e) 0.001% W / V to 1% W / V of a sweetener (f) 0.025% W / V to 2.5% W / V of a thickener (g) 0.001% W / V to 1% W / V of a flavoring agent 2. The liquid suspension of claim 1, comprising:

6. (a) abiraterone acetate in a concentration of about 5% to about 60% by weight of the composition; (b) a diluent vehicle component at a concentration of about 15% to about 70% by weight of the composition, comprising at least one diluent vehicle component selected from the group consisting of aqueous vehicles, sugars, methylcellulose gel, citric acid, sucrose, sorbitol solution, sodium carboxymethylcellulose solution, xanthan gum solution, non-aqueous vehicles such as refined fractionated coconut oil, hydrogenated castor oil, lecithin, and aluminum stearate; (c) a solubilizer component in a concentration of about 0.05% to about 100% by weight of the composition, the solubilizer component comprising at least one solubilizer selected from the group consisting of Tween 80, Soluplus, polyoxyl 40 hydrogenated castor oil (Kolliphor® RH 40), caprylocaproyl polyoxyl-8 glyceride (Labrasol ALF), lauroyl polyoxyl-6 glyceride (Labrafil M 2130 CS), lauroyl polyoxyl-32 glyceride (Gelucire 44 / 14), Cremophor, and lecithin; (d) a co-solvent component at a concentration of about 0.1% to about 10% by weight of the composition, the co-solvent component comprising at least one co-solvent selected from the group consisting of ethanol, propylene glycol, glycerin, glycofural, and polyethylene glycol; (e) a sweetener component at a concentration of about 0.001% to about 1% by weight of the composition, the sweetener component comprising at least one pharmaceutically acceptable sweetener; (f) a thickener component at a concentration of about 0.025% to about 2.5% by weight of the composition, comprising at least one thickener selected from the group consisting of sodium alginate, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone K 120, colloidal silicon dioxide, carboxymethylcellulose, sodium carboxymethylcellulose, acacia, tragacanth, xanthan gum, carbomer, carrageen, and gelatin; and (g) a flavoring component at a concentration of about 0.001% to about 1% by weight of said composition, said flavoring component comprising at least one pharmaceutically acceptable flavoring agent.

2. The liquid suspension of claim 1, comprising:

7. The following steps: (a) adding a sorbitol solution to purified water; (b) adding polyethylene glycol and homogenizing; (c) adding Tween 80 and homogenizing; (d) adding abiraterone acetate and homogenizing to obtain a homogenous suspension; (e) adding a sweetener to the suspension prepared above and mixing it by vortex or high speed homogenizer or mechanical or ultrasonic or shear stress to obtain a uniform suspension formulation; (f) adding flavoring agents and homogenizing; (g) dissolving xanthan gum in purified water; (h) adding the solution of step (g) to step (h) and making up the volume of the suspension with purified water to obtain the appropriate viscosity; 10. The liquid suspension of claim 1, comprising a pharmaceutical composition manufactured by

8. 10. The liquid suspension of claim 1, wherein the pH of the pharmaceutical composition is in the range of 3.5 to 6.5.

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