Abiraterone acetate oral preparation and preparation method thereof

Abstract

The invention relates to an oral suspension dosage form of abiraterone acetate. The invention also relates to providing patient compliant, economical and technically advanced dosage forms over existing dosage forms. Besides, compared with the prior art, the abiraterone acetate preparation with patient compliance, which is prepared according to the invention, is proved to have higher solubility and stability. In addition, the present invention provides a suspension composition prepared by a relatively simple, readily commercially producible and functionally reproducible method.

Description

Field of the Invention:

[0001] The present invention relates to an oral liquid formulation of abiraterone acetate as a suspension. In addition, the present invention relates to providing a dosage form that is economical and technologically advanced compared to existing dosage forms. Background of the invention:

[0003] 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-diethylenetriamine-3β-yl acetate, and its structure is shown below:

[0004]

[0005] WO1993 / 20097 first disclosed abiraterone acetate and analogs (Markush structure) and their use in treating prostate cancer. WO2006 / 021776 further disclosed abiraterone acetate mesylate.

[0006] Abiraterone acetate is currently marketed in the United States under the trade name "ZYTIGA". The tablet is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) and metastatic high-risk castration-sensitive prostate cancer (CSPC) in combination with prednisone. The recommended dose of abiraterone acetate is 1000 mg (two 500 mg tablets or four 250 mg tablets) taken orally once daily and prednisone 5 mg taken orally twice daily.

[0007] US8822438 claims a method for treating prostate cancer in a human, comprising administering to the human a therapeutically effective amount of abiraterone acetate or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of prednisone.

[0008] CN102743393 discloses a tablet composition having the same qualitative composition preparation method and the same abiraterone acetate concentration in the tablet as the Zytiga tablet.

[0009] CN102336801 discloses a tablet containing a high level of abiraterone acetate, however the dissolution profile of the composition is slower when compared to the approved Zytiga 250 mg tablet.

[0010] WO2013 / 164473 discloses abiraterone acetate dissolved or dispersed in a carrier, wherein the carrier comprises one or more lipid excipients.

[0011] US9511078 claims a pharmaceutical formulation comprising abiraterone, propylene glycol monocaprylate and an emulsifier. It discloses a pharmaceutical formulation comprising a low water-soluble drug, such as abiraterone formulated in a capsule, wherein the drug is dissolved in the other ingredients of the pharmaceutical formulation and forms a nanoemulsion when exposed to an aqueous environment.

[0012] WO2014 / 009436 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.

[0013] WO2014 / 145813 discloses a method for preparing a composition comprising abiraterone acetate nanoparticles, the method comprising dry milling a composition comprising abiraterone acetate, a grindable grinding compound, an accelerator, and one or both of an antioxidant and a chelating agent in a grinder comprising a plurality of grinding bodies, and continuing the milling for a time sufficient to prepare a composition comprising fine particles of abiraterone acetate, wherein the particle size of the grinding matrix and the particle size of the abiraterone acetate are reduced by dry milling.

[0014] WO2015 / 032873 discloses a tablet comprising high levels of 50% to 80% w / w abiraterone acetate and a wetting agent. However, these compositions have lower bioavailability compared to the approved Zytiga 250 mg tablets.

[0015] WO2015 / 114314 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 with a particle size of less than about 2000 nanometers.

[0016] US10722527 discloses lipid compositions for abiraterone acetate, such as lipid multiparticulate formulations comprising abiraterone acetate and a lipid matrix or liquid-filled hard capsules comprising abiraterone acetate and a lipid matrix. However, the invention is considered to be unfriendly because the capsule is affected by relative humidity and microbial contamination.

[0017] WO2017 / 037647 discloses an oral pharmaceutical formulation comprising abiraterone, a solubilizer and other pharmaceutically acceptable excipients, wherein the formulation contains less than 1000 mg of abiraterone.

[0018] WO2019 / 186444 discloses an oral emulsion formulation of abiraterone, which comprises abiraterone, polysorbate-80, lecithin, an oil phase and an aqueous phase.

[0019] WO2019 / 206472 discloses a tablet composition for oral administration of abiraterone acetate, in particular, drug granules and tablets that immediately release abiraterone acetate in the stomach.

[0020] Most of the prior art is an oral tablet formulation of abiraterone acetate. These tablets are large and need to be taken on an empty stomach. Therefore, in order to overcome the problems of the prior art, it is still necessary to find an oral liquid dosage form of abiraterone that is bioequivalent to the commercially available abiraterone tablet Zytiga.

[0021] Abiraterone acetate is challenging to process due to its low solubility and permeability (BCS Class IV product), and it can be noted that suspensions are a useful delivery system for therapeutic agents with low solubility. Thus, drugs with poor wetting and slow dissolution properties may be difficult to formulate and manufacture into tablets with sufficient full drug bioavailability, while suspensions will enhance solubility and bioavailability.

[0022] In addition, tablets are not suitable for patients with dysphagia and elderly patients because they are not easy to take, and some drugs can cause gastric irritation when administered in tablet form. In addition, tablets are not suitable for comatose patients. The inventors of the present invention have very effectively discovered the above limitations and have therefore developed a stable and effective oral liquid suspension dosage form to make up for the deficiencies found in the prior art disclosures.

[0023] The present invention discloses abiraterone acetate in an oral liquid suspension dosage form which does not use complex technology and is economically affordable compared to existing dosage forms. In addition, the formulated oral liquid suspension dosage form prepared according to the present invention provides greater stability. In addition, the oral liquid dosage form is the most suitable dosage form for patients who have difficulty taking tablets or capsules, such as patients with dysphagia, pediatric or elderly patients. They are attractive in appearance and produce beneficial psychological effects.

[0024] A suspension is a heterogeneous mixture that contains solid particles that are large enough to settle. The suspended particles are visible to the naked eye. A suspension is a heterogeneous mixture in which the suspended particles are not dissolved, they remain suspended throughout the liquid medium. Usually, the solid portion is dispersed by mechanical agitation using a suspending agent. In comparison, a solution has dissolved and uniformly mixed solutes, which are not present in solid form.

[0025] The present invention introduces a suspension with a smaller particle size, which increases the solubility of abiraterone acetate by providing a better dissolution profile. In addition, the present invention achieves a higher stability of abiraterone acetate. In addition, when compared with the prior art invention, it can be demonstrated that the solubility and stability of the abiraterone acetate preparation prepared according to the present invention with patient compliance are higher.

[0026] Furthermore, the present invention provides a suspension composition that is prepared by a relatively simple, commercially amenable and functionally reproducible process. In addition, the suspension composition of the present invention can also incorporate two or more other active ingredients.

[0027] Purpose of the invention:

[0028] The main purpose of the present invention is to provide an oral composition of abiraterone acetate or a pharmaceutically acceptable salt thereof and a preparation method thereof, preferably a liquid suspension dosage form having one or more pharmaceutically acceptable excipients.

[0029] In one object of the present invention, the formulated product is a stable suspension.

[0030] In one object of the present invention, the active ingredient incorporated in the pharmaceutical composition comprises a particle size D90 in the range of 0.5 to 50 microns.

[0031] According to another object of the present invention, wherein the formulated product has nano to micron particle size which results in about 80% to 110% enhancement in the in vitro dissolution profile.

[0032] One object of the present invention includes a pharmaceutical composition comprising abiraterone acetate and a pharmaceutically acceptable excipient, but not containing a pH regulator.

[0033] In another object, the pharmaceutical composition manufactured according to the present invention is a suspension. The pharmaceutical composition is manufactured by multiple stages in the manufacturing process, including homogenization, sonication, mixing and / or evaporation by spray drying.

[0034] One object of the present invention may include a pharmaceutical composition comprising about 5% to 60% W / V of abiraterone acetate and a pharmaceutically acceptable excipient, preferably 5% to 45% of abiraterone acetate and a pharmaceutically acceptable excipient, and more preferably 5% to 30% of abiraterone acetate and a pharmaceutically acceptable excipient.

[0035] In another object of the present invention, wherein the pH value of the pharmaceutical composition is in the range of 3.5-6.5.

[0036] Another object of the present invention is that the 1000 mg / 5 ml oral liquid suspension dosage form has super bioavailability when compared to the existing tablet dosage of 2 500 mg tablets and 4 250 mg tablets. Thus, the therapeutic dose can be reduced according to the present invention.

[0037] Another object of the present invention is an abiraterone acetate composition comprising a solubility enhancer and a permeability enhancer which is not part of the dosage form currently available in the market.

[0038] Another object of the present invention is a liquid formulation that is orally administered once a day, whereas in the prior art dosage form, four abiraterone tablets are administered.

[0039] Embodiments of the pharmaceutical composition may include abiraterone acetate as an active ingredient and one or more pharmaceutically acceptable excipients selected from diluent carriers, stabilizers / antioxidants, suspending agents / thickeners, chelating agents / complexing agents, solubilizers, penetration enhancers, preservatives, glidants, active carriers, sweeteners, anti-caking agents, wetting agents, preservatives, buffers, flavoring agents, and the like. Summary of the invention:

[0041] One aspect of the present invention relates to a method for preparing an oral liquid pharmaceutical composition according to the present invention, comprising the following steps:

[0042] (a) adding a diluent carrier to purified water;

[0043] (b) adding a co-solvent and homogenizing;

[0044] (c) adding a solubilizing agent and homogenizing;

[0045] (d) adding abiraterone acetate and homogenizing to obtain a uniform suspension;

[0046] (e) adding a sweetener to the suspension prepared above, and mixing by vortexing or high-speed homogenizer or mechanical or ultrasonic or shear stress to obtain a uniform suspension dosage form;

[0047] (f) adding flavoring agent and homogenizing;

[0048] (g) dissolving the suspending agent and thickening agent in purified water;

[0049] (h) adding the solution of step (g) to step (h) to provide a suitable viscosity, and making up the volume of the suspension with an aqueous carrier. The details of one or more embodiments of the present invention are set forth in the following description. Other features of the present invention will become apparent through the description.

[0050] Detailed description of the invention:

[0051] The invention will now be disclosed by describing certain preferred and alternative embodiments to facilitate its various aspects.

[0052] Abiraterone acetate (CAS: 154229-18-2), chemical name, 17-(pyridin-3-yl)androstane-5,16-diethylenetriamine-3β-yl acetate, has a molecular weight of 391.55 g / mol. Due to its poor solubility in water and low lipid permeability, abiraterone acetate is considered a Class IV drug in the Biopharmaceutics Classification System (BCS).

[0053] According to the present invention, the pharmaceutical composition comprises abiraterone acetate as an active ingredient and a pharmaceutically acceptable excipient. The term "pharmaceutically acceptable excipient" used herein refers to an excipient conventionally used in a pharmaceutical composition. Pharmaceutically acceptable excipients may include diluent carriers, stabilizers / antioxidants, suspending agents / thickeners, chelating agents / complexing agents, solubilizers, preservatives, glidants, sweeteners, anti-caking agents, wetting agents, preservatives, buffers, flavoring agents and combinations thereof. The following table lists the excipients used, but is not limited to the excipients.

[0054] Suitable diluent carriers may include one or more of aqueous carriers, sugars, methylcellulose gel, citric acid, sucrose, sorbitol solution, sodium carboxymethylcellulose solution, xanthan gum solution, non-aqueous carriers such as refined fractionated coconut oil, hydrogenated castor oil, lecithin, aluminum stearate, and the like.

[0055] Suitable solubilizers may include one or more from Emulsifier 80, Soluplus, polyoxyl 40 hydrogenated castor oil, capryloyl polyoxyl-8 glyceride, lauroyl polyoxyl-6 glyceride, lauroyl polyoxyl-32 glyceride, castor oil polyoxyl ether, lecithin, and the like.

[0056] Suitable suspending agents or thickening agents may include one or more of sodium alginate, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone K120, colloidal silicon dioxide, carboxymethylcellulose, sodium carboxymethylcellulose, gum arabic, tragacanth gum, xanthan gum, carbomer, carrageenan, gelatin, and the like.

[0057] Suitable cosolvents may include one or more of ethanol, propylene glycol, glycerol, glycine furan, polyethylene glycol, etc. Suitable wetting agents may include one or more materials selected from anionic, cationic, nonionic or zwitterionic surfactants or combinations thereof. Suitable examples of wetting agents are sodium lauryl sulfate, heptadecyl trimethylamine bromide, polyethylene glycol, polyoxyethylene-polyoxypropylene block copolymers such as poloxamer, polyglycerol fatty acid esters such as decaglycerol monolaurate and decaglycerol monomyristate, sorbitan fatty acid esters such as sorbitan monostearate, polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monooleate, polyethylene glycol fatty acid esters such as polyoxyethylene monostearate, polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether, polyoxyethylene castor oil, etc.

[0058] Suitable penetration enhancers may include one or more selected from the group consisting of alcohols, polyols, short chain glycerides, amines, amides, cyclodextrins, fatty acids, pyrrolidines, azos, sulfoxides, surfactants, terpenes, and the like.

[0059] Suitable surfactants or co-surfactants may include one or more anionic, cationic, nonionic or amphoteric surfactants. Non-limiting examples of surfactants may include polyoxyethylene-polyoxypropylene copolymers and block copolymers, ethoxylated cholesterol, vitamin derivatives, such as vitamin E derivatives, such as tocopherol polyethylene glycol succinate (TPGS), sodium lauryl sulfate or sodium lauryl sulfate; bile acid or its salt, such as cholic acid, glycolic acid or its salt; etc.

[0060] Suitable sweeteners may include, but are not limited to, one or more selected from sucralose, saccharin, neotame, aspartic acid, sodium cyclamate, glycyrrhizin, sucrose, molasses, glucose, fructose, mannitol, sorbitol, xylitol, erythritol, isomalt, maltotriol, lactitol, hydrogenated starch, etc.

[0061] Suitable flavoring agents may include one or more selected from mint, grapefruit, orange, lime, lemon, tangerine, pineapple, strawberry, raspberry, mango, passion fruit, kiwi, apple, pear, peach, apricot, cherry, grape, banana, cranberry, blueberry, black currant, red currant, gooseberry, willowberry, cumin, thyme, basil, Camille, valerian, fennel, parsley, chamomile, tarragon, lavender, dill, bagamo, sage, aloe balm, spearmint, piperine, eucalyptus, etc.

[0062] Suitable solubilizers may include one or more substances selected from the group consisting of surfactants, such as (1) nonionic, such as polyoxyethylene sorbitan fatty acid esters, sorbitan esters, polyoxyethylene ethers, (2) anionic, such as sodium lauryl sulfate, sodium laurate, sodium dialkyl sulfosuccinate, especially 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) zwitterionic / amphoteric surfactants; fatty alcohols, such as lauryl alcohol, cetyl alcohol and stearyl alcohol; glycerides, such as naturally occurring monoglycerides, diglycerides and triglycerides; fatty acid esters of fatty alcohols and other alcohols such as propylene glycol, polyethylene glycol; sucrose; polymers, such as poloxamers, polyvinyl pyrrolidone; glycerides, such as glyceryl triacetate, glyceryl monocaprylate, glyceryl monooleate, glyceryl monostearate; diethylene glycol monoethyl ether; and the like.

[0063] One embodiment of the present invention may include a pharmaceutical composition comprising about 5% to 60% W / V of abiraterone acetate and a pharmaceutically acceptable excipient, preferably 5% to 45% of abiraterone acetate and a pharmaceutically acceptable excipient, and more preferably 5% to 30% of abiraterone acetate and a pharmaceutically acceptable excipient.

[0064] Another embodiment of the present invention includes a pharmaceutical composition comprising abiraterone acetate and a pharmaceutically acceptable excipient without a pH adjuster.

[0065] In one embodiment of the present invention, the active ingredient incorporated into the pharmaceutical composition comprises a particle size D90 in the range of 0.5 to 50 microns.

[0066] In another embodiment according to the present invention, the formulated product is a stable suspension.

[0067] In another embodiment of the present invention, the pharmaceutical composition prepared therein is a suspension, which can enhance the in vitro dissolution profile.

[0068] According to another embodiment of the present invention, wherein the formulated product has a particle size of nano to micrometers which results in an in vitro dissolution profile of about 80% to 110%.

[0069] In another embodiment of the present invention, the pharmaceutical composition is prepared by multiple stages including homogenization, sonication, mixing and / or spray drying evaporation.

[0070] In another embodiment, the pharmaceutical composition of the present invention comprises abiraterone acetate or a pharmaceutically acceptable salt thereof.

[0071] Another embodiment of the present invention is directed to a 1000 mg / 5 ml oral liquid suspension dosage form having super bioavailability when compared to the prior art tablet dosage of 2 500 mg tablets and 4 250 mg tablets. Thus, the therapeutic dose can be reduced according to the present invention.

[0072] In another embodiment of the present invention, the composition of abiraterone acetate comprises a solubility enhancer and a permeability enhancer which are not part of the currently marketed dosage form.

[0073] Another embodiment of the present invention is a liquid formulation that is orally administered once a day, while the existing dosage form is administered in four tablets of abiraterone. Tablets are not suitable for elderly patients because they are not easy to take, and some drugs can cause gastric irritation when administered in tablet form. In addition, tablets are not suitable for comatose patients. In addition, cancer patients are usually treated with multiple drugs and need to take a large number of tablets or capsules, usually accompanied by intravenous treatment. Considering the bioavailability of the administered drug, the compliance of the patient in this regimen can be solved by reducing the number of tablets or capsules administered and the type of dosage form administered. The bioavailability of the drug cannot be compromised in order to meet the compliance of the patient.

[0074] Animal pharmacokinetic studies were conducted on the compositions prepared according to the present invention to determine the absorption by the oral route, and it was observed that the extent of absorption after oral administration ranged from 5% to 90%. In addition, the pharmaceutical compositions made according to the present invention are suspensions. Suspensions facilitate the administration of low-solubility therapeutic agents. Low-solubility therapeutic agents can be administered via suspensions. However, they require large amounts of solvents. This volume can compromise the storage of the reagents when precipitation issues are involved.

[0075] Furthermore, suspensions help in the dispersion of bitter tasting drugs. Not all drugs given to patients have a sweet taste. Most of them are bitter, especially when given to children who may do everything in their power to resist these drugs. With suspensions, the bitter taste is reduced using masking agents such as sweeteners and flavorings, making the final formulation palatable. This is also an alternative method of administering drugs to patients who have difficulty swallowing solid drugs.

[0076] In addition, the suspension also increases the bioavailability of the drug dose. Most drug doses may only be available in one form, such as a capsule. This form may limit the way the drug is administered to a particular patient. This challenge can be addressed by using a suspension. In another embodiment of the present invention, the pH of the pharmaceutical composition is in the range of 3.5-6.5.

[0077] In one embodiment, the preparation method of the oral liquid pharmaceutical composition of the present invention comprises the following steps:

[0078] (a) adding a diluent carrier to purified water;

[0079] (b) adding a co-solvent and homogenizing;

[0080] (c) adding a solubilizing agent and homogenizing;

[0081] (d) adding abiraterone acetate and homogenizing to obtain a uniform suspension;

[0082] (e) adding a sweetener to the suspension prepared above, and mixing by vortexing or high-speed homogenizer or mechanical or ultrasonic or shear stress to obtain a uniform suspension dosage form;

[0083] (f) adding flavoring agent and homogenizing;

[0084] (g) dissolving the suspending agent and thickening agent in purified water;

[0085] (h) adding the solution of step (g) to step (h) to provide suitable viscosity, and replenishing the volume of the suspension with an aqueous carrier. The present invention will be further described with reference to the following examples. However, the scope of the present invention is not limited thereto. Unless otherwise indicated, all percentages described in this specification are weight percentages. Although the present invention has been described in detail according to its specific embodiments, it is obvious to those skilled in the art that some modifications and equivalents are included in the scope of the present invention.

[0086] Example 1:

[0087] Table 1 – Recipe

[0088]

[0089] Table 2 – Results

[0090] Serial number parameter result 1 Content determination 99.5％ 2 Dissolved (10 minutes) 98.5％

[0091] Example 2:

[0092] Table 3 – Recipe

[0093]

[0094]

[0095] Table 4 – Results

[0096] Serial number parameter result 1 Content determination 101.1％ 2 Dissolved (10 minutes) 100.4％

[0097] Example 3:

[0098] Table 5 – Recipe

[0099]

[0100] Table 6 – Results

[0101] Serial number parameter result 1 Content determination 98.7％ 2 Dissolved (10 minutes) 97.2％

[0102] Example 4:

[0103] Table 7 – Recipe

[0104]

[0105] Table 8 – Results

[0106] Serial number parameter result 1 Content determination 104.12％ 2 Dissolved (10 minutes) 99.60％

[0107] Example 5:

[0108] Table 9 – Recipe

[0109]

[0110]

[0111] Table 10 – Results

[0112] Serial number parameter result 1 Content determination 104.12％ 2 Dissolved (10 minutes) 99.60％

[0113] Example 6:

[0114] Table 11 – Recipe

[0115]

[0116] Table 12 – Results

[0117] Serial number parameter result 1 Content determination 101.4％ 2 Dissolved (10 minutes) 95.6％

[0118] Example 7:

[0119] Table 13 – Recipe

[0120]

[0121]

[0122] Table 14 – Results

[0123] Serial number parameter result 1 Content determination 102.6％ 2 Dissolved (10 minutes) 96.4％

[0124] Example 8:

[0125] Table 15 – Recipe

[0126]

[0127] Table 16 – Results

[0128] Serial number parameter result 1 Content determination 102.1％ 2 Dissolved (10 minutes) 103.5％

[0129] Example 9:

[0130] Table 17 – Recipe

[0131]

[0132] Table 18 – Results

[0133] Serial number parameter result 1 Content determination 100.9％ 2 Dissolved (10 minutes) 100.4％

[0134] Example 10:

[0135] Table 19 – Recipe

[0136]

[0137]

[0138] Table 20 – Results

[0139] Serial number parameter result 1 Content determination 97.9％ 2 Dissolved (10 minutes) 95.6％

[0140] Example 11:

[0141] Table 21 – Recipe

[0142]

[0143] Table 22 – Results

[0144]

[0145]

[0146] Common manufacturing process of Examples 1-11:

[0147] 1.Put pure water (half amount) into a container.

[0148] 2. Add sorbitol to step 1 under stirring and mix with the aid of a homogenizer for 10 minutes.

[0149] 3. Add polyethylene glycol 400 to the solution in step 2 under homogenization and continue homogenization for 10 minutes.

[0150] 4. Add emulsifier 80 / Soluplus / polyoxyethylene 40 hydrogenated castor oil / octanoyl polyoxyethylene-8 glyceride / lauroyl polyoxyethylene-6 glyceride / lauroyl polyoxyethylene-32 glyceride to the solution in step 3 under homogenization and continue homogenization for 10 minutes.

[0151] 5. Add abiraterone acetate API to the mixture in step 4 under homogenizing conditions and continue homogenizing for 1 hour to obtain a uniform homogenous suspension.

[0152] 6. Add sucralose to the suspension from step 5 while homogenizing and continue homogenizing for 10 minutes.

[0153] 7. Add strawberry flavor to the suspension from step 6 while homogenizing and continue homogenizing for 10 minutes.

[0154] 8. Under homogenization conditions, dissolve hydroxypropyl methylcellulose (HPMC K4M) / hydroxypropyl cellulose (HPC-M) / povidone K120 / colloidal silicon dioxide / xanthan gum in purified water and continue homogenization for 30 minutes.

[0155] 9. Under homogenization conditions, add the solution in step 8 to step 7 to make up the volume and continue homogenization for 60 minutes.

[0156] 10. Wet mill the above suspension using DYNO-MILL with the required parameters.

[0157] 11. Collect the wet grinding suspension in a container.

[0158] Stages: Wet grinding with a DYNO grinder:

[0159]

[0160]

[0161] Accelerated stability reporting;

[0162] Assay, pH and dissolution studies were performed under different conditions and time periods to evaluate stability up to 6 months. Dissolution profile studies were observed in a medium defined by the United States Food and Drug Administration USFDA with 50 rpm in 900 ml of pH 4.5 buffer and 0.25% sodium lauryl sulfate in 56.5 mM phosphate buffer. For this stability study, an oral liquid suspension composition prepared according to Example-11 was observed.

[0163] Test Example 1:

[0164] Stability studies were performed on all samples under accelerated conditions of 40±2°C and 75±5% RH and the chemical parameters were evaluated initially, after 1 month, after 3 months and after 6 months. The results obtained are reported in the following table:

[0165] Table 23

[0166]

[0167] Test Example 2:

[0168] Stability studies were performed on all samples under accelerated conditions of 30±2°C and 75±5% RH and the chemical parameters were evaluated initially, after 1 month, after 3 months and after 6 months. The results obtained are reported in the following table:

[0169] Table 24

[0170]

[0171]

[0172] Test Example 3:

[0173] Stability studies were performed on all samples under accelerated conditions of 25 ± 2 °C and 60 ± 5% RH and the chemical parameters were evaluated initially, after 1 month, after 3 months and after 6 months. The results obtained are reported in the following table:

[0174] Table 25

[0175]

[0176] According to the above test examples, there are clear signs that the assay, pH and dissolution curve studies of the composition according to the present invention are stable for up to 6 months. Therefore, it is not necessary to add a pH regulator to the final formulation to adjust the pH. Therefore, the above results show that the present invention surprisingly produces better results and proves its creativity through technological progress.

[0177] Comparative Research Report:

[0178] Assay and dissolution profile studies were evaluated and determined to be comparable between the compositions prepared according to the present invention and the commercially available formulations (Zytiga 250 mg and 500 mg). The dissolution profiles were observed in media defined by the US Food and Drug Administration.

[0179] Table 26

[0180]

[0181] Table 27

[0182]

[0183] Based on the above comparison, there is a clear indication that the solubility of the 1000 mg / 5 mL suspension compared to Zytiga 1000 mg (by using 500 mg x 2 tablets), incomplete release was observed in the innovator product, indicating that the suspension has good solubility in the existing medium and a higher dissolution rate from the initial to extended time periods. Considering the dissolution profile, it can be concluded that the suspension formulation has a higher rate and extent of absorption when administered in vivo.

[0184] The invention described herein includes various objects as described above and descriptions thereof about features, compositions and methods adopted. Although these aspects are emphasized in the present invention, any changes of the above-mentioned present invention are not considered to be deviating from the spirit and scope of the present invention. The above examples are only for illustrative purposes and are not intended to limit the present invention.

Claims

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

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

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

4. The liquid suspension according to claim 1, comprising a pharmaceutically acceptable excipient selected from diluent carriers, stabilizers / antioxidants, suspending agents / thickeners, chelating agents / complexing agents, solubility enhancers, permeability enhancers, preservatives, glidants, active carriers, sweeteners, anti-caking agents, wetting agents, preservatives, buffers, flavoring agents.

5. The liquid suspension according to claim 1, comprising (a) 5% to 60% W / V abiraterone acetate (b) 15% to 70% W / V of diluent carrier (c) 0.05% to 5% W / V of a solubilizing agent (d) 0.1% to 10% W / V of cosolvent (e) 0.001% to 1% W / V sweetener (f) 0.025% to 2.5% W / V thickener (g) 0.001% to 1% W / V flavoring agent 6. The liquid suspension of claim 1, comprising: (a) abiraterone acetate at a concentration of about 5% to about 60% by weight of the composition; (b) a diluent carrier component at a concentration of about 15% to about 70% by weight of the composition, the diluent carrier component comprising at least one diluent carrier component selected from aqueous carriers, sugars, methylcellulose gel, citric acid, sucrose, sorbitol solution, sodium carboxymethylcellulose solution, xanthan gum solution, non-aqueous carriers such as refined fractionated coconut oil, hydrogenated castor oil, lecithin, aluminum stearate; (c) a solubilizer component at a concentration of about 0.05% to about 0.05% by weight of the composition, the solubilizer component comprising at least one solubilizer selected from the group consisting of Emulsifier 80, Soluplus, Polyoxyl 40 Hydrogenated Castor Oil, Capryloyl Polyoxyl-8 Glyceride, Lauroyl Polyoxyl-6 Glyceride, Lauroyl Polyoxyl-32 Glyceride, Castor Oil Polyoxyl Ether, 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 ethanol, propylene glycol, glycerol, glycyrrhizin, polyethylene glycol; (e) a sweetener component comprising at least one pharmaceutically acceptable sweetener at a concentration of about 0.001% to about 1% by weight of the composition; (f) a thickener component at a concentration of about 0.025% to about 2.5% by weight of the composition, the thickener component 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, gum arabic, tragacanth gum, xanthan gum, carbomer, carrageenan, and gelatin; and (g) a flavoring component at a concentration of about 0.001% to about 1% by weight of the composition, the flavoring component comprising at least one pharmaceutically acceptable flavoring agent.

7. The liquid suspension according to claim 1, comprising a pharmaceutical composition manufactured by the following steps: (a) adding sorbitol solution into purified water; (b) adding polyethylene glycol and homogenizing; (c) adding emulsifier 80 and homogenizing; (d) adding abiraterone acetate and homogenizing to obtain a uniform suspension; (e) adding a sweetener to the suspension prepared above, and mixing by vortexing or high-speed homogenizer or mechanical or ultrasonic or shear stress to obtain a uniform suspension dosage form; (f) adding flavoring agent and homogenizing; (g) dissolving xanthan gum in purified water; (h) The solution from step (g) is added to step (h) to provide a suitable viscosity and the volume of the suspension is made up with purified water.

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

Images