STABLE PHARMACEUTICAL COMPOSITIONS OF ABIRATERONE
Background of the invention
Abiraterone acetate is a prodrug of Abiraterone and is rapidly deacetylated to Abiraterone in vivo. Abiraterone is poorly bioavailable and hence the acetate form is used in pharmaceutical formulations.
Abiraterone acetate in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have received prior chemotherapy of docetaxel. Abiraterone acetate is chemically described as (3β)-17-(3-pyridinyl) androsta-5,16-dien-3-yl acetate. Abiraterone is structurally represented as:
Abiraterone acetate is marketed in the US as Zytiga® by Johnson and Johnson. The prescribing information for Zytiga® tablets recommends 1,000 mg (4x250 mg tablets) administered orally once daily in combination with prednisone (5 mg) administered orally twice daily. Zytiga® comprises Abiraterone acetate along with colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate.
U.S patent 5,604,213 to Barrie et al. describes Abiraterone acetate and related analogs and the process of preparation.
U.S. patent 8,822,438 to Auerbach et al. discloses a method of treating prostate cancer in a human by administering a therapeutically effective amount of Abiraterone acetate or a

pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of prednisone.
WO 2013/012959 to Casebier et al. discloses a composition comprising a solid dispersion of Abiraterone and a solid matrix, wherein Abiraterone is dispersed in the solid matrix.
WO 2013/164473 to Grenier et al. discloses Abiraterone acetate dissolved or dispersed in a carrier, wherein the carrier comprises one or more lipid excipients.
WO 2014/145813 to Bosch et al. discloses a method of producing a composition comprising nanoparticles of Abiraterone acetate.
The low solubility of Abiraterone acetate in water is one of the factors leading to low bioavailability of Abiraterone acetate for Zytiga®. The absolute bioavailability of Abiraterone acetate for Zytiga® is reported to be no more than 10%, as the drug is mainly metabolized to Abiraterone and then excreted by feces (88%) and urine (5%) with a terminal half-life of 12±5 hours. Hence to achieve the desired therapeutic effect, the recommended dose of 1000mg is administered as four Zytiga® tablets of 250 mg each.
This situation is unsatisfactory and inconvenient to the patients, particularly in cases where medications usually consist of multiple drug regimen demanding the administration of large number of tablets or capsules. Hence it is desirable to improve the bioavailability of Abiraterone acetate and to reduce the necessary daily dose of Abiraterone acetate.
The inventors have developed improved bioavailable oral formulations of Abiraterone, wherein the daily dose is less than 1000mg.

SUMMARY OF THE INVENTION
The present invention relates to oral pharmaceutical formulations of Abiraterone comprising of solubilizing agents, wherein the formulations show improved bioavailability.
Another aspect of the present invention is to provide oral pharmaceutical formulations of Abiraterone, wherein the daily dose of Abiraterone is less than 1000mg.
Another aspect of the present invention provides oral pharmaceutical formulations of Abiraterone comprising of Abiraterone, cyclodextrins and other pharmaceutically acceptable excipients, wherein the daily dose of Abiraterone is less than 1000mg.
Another aspect of the present invention provides oral pharmaceutical formulations of Abiraterone comprising of Abiraterone, diethylene glycol monoethyl ether (such as transcutol) and/or medium chain triglycerides and other pharmaceutically acceptable excipients, wherein the daily dose of Abiraterone is less than 1000mg.
Yet another aspect of the present invention is to provide oral pharmaceutical formulations of Abiraterone comprising of Abiraterone, lecithin and other pharmaceutically acceptable excipients, wherein the daily dose of Abiraterone is less than 1000mg.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to oral pharmaceutical formulations comprising Abiraterone, solubilizing agents and one or more pharmaceutically acceptable excipients, wherein the daily dose of Abiraterone is less than 1000mg.
In the context of this invention “Abiraterone” refers to the pharmaceutically acceptable derivatives such as salts, solvates, hydrates, polymorphs and prodrugs thereof, preferably Abiraterone or Abiraterone acetate.

The term "pharmaceutical formulations" includes dosage forms, such as but not limited to, tablets, soft gelatin capsules, hard gelatin capsules, dispersible tablets, granules and sachets. Powder filled sachet formulation of Abiraterone could be easily dispersed in water and hence provides a convenient method of administration, particularly for the elderly.
The present invention provides oral pharmaceutical formulation comprising Abiraterone with one or more pharmaceutically acceptable excipients wherein the said formulation is formulated to provide a total daily dose of Abiraterone of less than 1000 mg, preferably less than 800 mg.
An embodiment of the present invention is to provide oral pharmaceutical formulations of Abiraterone comprising of: i. Abiraterone ii. solubilizing agents.
iii. other pharmaceutically acceptable excipients, wherein the daily dose of Abiraterone is less than 1000mg.
A preferred embodiment of the present invention is to provide oral pharmaceutical formulations of Abiraterone comprising of: i. Abiraterone ii. solubilizing agents selected from cyclodextrins, diethylene glycol monoethyl
ether (such as transcutol), medium chain triglycerides and lecithin iii. other pharmaceutically acceptable excipients, wherein the daily dose of Abiraterone is less than 1000mg.
The inventors of the present invention surprisingly found that the presence of certain excipients such as solubilizing agents in the formulation resulted in improved bioavailable formulation of Abiraterone.
Solubilizing agents for use according to the invention include, but not limited to cyclodextrins such as α, β, and γ-cyclodextrin and cyclodextrins modified with alkyl-,

hydroxyalkyl-, dialkyl, and sulfoalkyl-ether modified cyclodextrins such as methyl or hydroxypropyl β-cyclodextrins (HPCD), sulfobutylether-β-cyclodextrin (SBECD) and the like; glycol ethers such as diethylene glycol monoethyl ether (e.g. Transcutol HP) medium-chain triglycerides, maltodextrins and surfactants. Suitable surfactants include amphoteric, non-ionic, cationic or anionic surfactants such as sodium lauryl sulfate (Kolliphor), polyoxyethylene alkylaryl ethers, polyethylene glycol fatty acid esters, polyoxyethylene- polyoxypropyl ene block co-polymers, polyoxyethylene sorbitan fatty acid ester such as polysorbate, sorbitan fatty acid mono esters, polyoxyethylene castor oil derivates such as polyoxyl castor oil, polyoxyl hydrogenated castor oil, monooleate, monolaurate, monopalmitate, monostearate, dioctyl sulfosuccinate, lecithin, polyoxyethylene fatty acid glycerides, poloxamer, cremophor, cetrimide and the like. Preferred solubilizing agents are cyclodextrins, diethylene glycol monoethyl ether, medium chain triglycerides, phospholipids and lecithin.
Suitable excipients that may be used for formulating the pharmaceutical dosage forms of the invention include disintegrants, diluents, binders, glidants, lubricants, plasticizers, sweeteners, flavoring agents, antioxidants, stabilizers, viscosity modifying agents, polymers, channeling agents, emulsifiers, surfactants, buffering agents, coloring agents and the like.
Examples of fillers are sucrose, glucose, lactose (lactochem), mannitol, xylitol, dextrates, dextrin, dextrose, trehalose, erythritol, ethylcellulose, fructose, glyceryl palmitostearate, hydrogenated vegetable oil type I, isomalt, kaolin, lactitol, magnesium carbonate, magnesium oxide, maltodextrin, polydextrose, cellulose, cellulose acetate, microcrystalline cellulose, coprocessed microcrystalline celluloses (such as various grades of Avicel), silicified microcrystalline cellulose, maltose, sorbitol, calcium phosphate, calcium sulphate, carrageenan, chitosan, pectinic acid, sodium alginate, magnesium aluminium silicate, calcium carbonate and the like.
Examples of binders include, but are not limited to, celluloses such as microcrystalline cellulose, modified celluloses such as low substituted hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose,

hydroxyethyl methylcellulose, ethyl cellulose, cellulose gum, xanthan gum, sugars such
as sucrose, glucose, amylose, maltodextrin, dextrose and the like, starches such as corn
or potato starch partially pregelatinized starches, polyvinyl acetate, polyvinyl alcohol-
polyethylene glycol graft copolymer, copovidone, povidone, cross-linked
polyvinylpyrrolidone, acrylic acid polymer, poloxamer, polycarbophil, polyethylene
oxide, polyethylene glycol or a combination of suitable binders.
Examples of disintegrants that may be used include starches, partially or completely pregelatinized starches, sodium starch glycolate, pregelatinized starch, alginic acid, calcium alginate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, powdered cellulose, chitosan, croscarmellose sodium, polyvinylpyrrolidones, including modified polyvinylpyrrolidones such as crospovidone, docusate sodium, guar gum, hydroxypropyl methyl cellulose, low substituted hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, polacrilin, sodium alginate or a combination of suitable disintegrants.
Examples of glidants include calcium phosphate, calcium silicate, powdered cellulose, magnesium stearate, magnesium trisilicate, talc, silicon dioxide, colloidal silica and colloidal silica anhydrous.
Examples of lubricants include canola oil, hydroxyethyl cellulose, lauric acid, leucine, poloxamers, polyvinyl alcohol, oxtyldodecanol, sodium hyaluronate, maize starch, triethanolamine, calcium stearate, magnesium stearate, sodium stearyl fumarate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil type I, light mineral oil, magnesium lauryl sulfate, mineral oil, myristic acid, palmitic acid, polyethylene glycol, potassium benzoate, sodium benzoate, sodium lauryl sulfate, stearic acid, talc and zinc stearate.
Carriers such as magnesium aluminometasilicate (various grades of Neusilin) which act as adsorbents for drugs which are in liquid or solution form may also be used. Wetting agents such as glycerol, gelatin can also be used in the formulation.

Suitable flavouring agents and sweetening agents may be used in the pharmaceutical formulation of the present invention.
Suitable antioxidants which may be used in the pharmaceutical formulation of the present invention include, but are not limited to, tocopherols, ascorbic acid, sodium ascorbate, sodium pyrosulfite, butylhydroxytoluene, butylated hydroxyanisole, edetic acid, and edetate salts, or mixtures. Suitable texture enhancers which may be used in the pharmaceutical formulation of the present invention include, but are not limited to, pectin, polyethylene oxide and carrageenan or mixtures.
The following examples further describe certain specific aspects and embodiments of the present invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.
Manufacturing process
Abiraterone acetate was dissolved in transcutol HP at room temperature by stirring. Medium chain triglyceride was added to the above solution and homogenized. Solution obtained after homogenization was filled in oblong 20 size soft gelatin capsules.
Manufacturing process
Abiraterone acetate was dissolved in transcutol HP at room temperature by stirring. Medium chain triglyceride was added to the above solution and homogenized. The obtained solution was adsorbed on to the magnesium aluminometasilicate. The final blend was filled into ’0’ size hard gelatin capsule.
Manufacturing process
Sulfobutyl ether β cyclodextrin / hydroxy propyl β cyclodextrin was dissolved in required quantity of water. Abiraterone acetate was dissolved in the above solution by stirring. The pH of the solution was adjusted to about 4 to 5 with hydrochloric acid. Maltodextrin /mannitol was dissolved in required quantity of water and added to the above drug solution and homogenized. Final concentration was adjusted with water and subjected for spray drying. The spray dried powder was then blended with sweetener/flavor. The final blend equivalent to 100 mg of Abiraterone acetate was filled hermetically in a sachet.
The formulation was tested for dissolution in water. The results in comparison with the dissolution of the active ingredient are tabulated below in table 1:

Manufacturing process
Abiraterone acetate was dissolved in transcutol HP at room temperature by stirring. Medium chain triglyceride was added to the above solution and homogenized. The above

solution was adsorbed on to the magnesium aluminometasilicate. Microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, sodium starch glycolate, sodium lauryl sulfate and L-hydroxy propyl cellulose were co-sifted and blended with the drug adsorbed magnesium aluminometasilicate mixture. The blend was then pre-lubricated with colloidal silicon dioxide. Lubrication was done with Magnesium stearate. The lubricated blend was compressed in to oblong tablets (19 X 10 mm).
Manufacturing process
Maltodextrin, lactose and sodium ascorbate were dissolved in water (solution A). Gelatin was dissolved in water at 40°C (solution B). Lecithin was dissolved in water at 40°C (solution C). Abiraterone acetate was dispersed in solution B by homogenization. Solution A and solution C were added to the above dispersed solution and homogenized. Final concentration was adjusted with water and subjected for spray drying. The above spray dried powder was blended with a mixture of cosifted sodium starch glycolate, sodium lauryl sulfate and microcrystalline cellulose. The final blend was compressed in to oval tablets (15.8 X 9.5 mm).

Manufacturing process
Solution adsorbed blend: Abiraterone acetate was dissolved in transcutol HP at room temperature by stirring. Medium chain triglyceride was added to the above solution and homogenized. Solution adsorption blend was prepared by adsorbing the above prepared solution on to magnesium aluminometasilicate.
Spray dried blend: Maltodextrin, lactose and sodium ascorbate was dissolved in water (solution A). Gelatin was dissolved in water at 40°C (solution B). Lecithin was dissolved in water at 40°C (solution C). Abiraterone acetate was dispersed in solution B by homogenization. Solution A and solution C were added to the above dispersion and homogenized. Final concentration was adjusted with water and subjected for spray drying.
Finally solution adsorbed blend equivalent to 50 mg of Abiraterone acetate and spray dried blend equivalent to 75 mg of Abiraterone acetate were blended with co-sifted sodium starch glycolate, sodium lauryl sulfate and microcrystalline cellulose and compressed into oblong tablets.

Manufacturing process
Solution adsorption blend: Abiraterone acetate was dissolved in transcutol HP at room temperature by stirring. Medium chain triglyceride was added to the above solution and homogenized. Solution adsorption blend was prepared by adsorbing the above prepared solution on to magnesium aluminometasilicate.
Spray dried blend: Maltodextrin, and sodium ascorbate was dissolved in water (solution A). Gelatin was dissolved in water at 40°C (solution B). Lecithin was dissolved in water at 40°C (solution C). Abiraterone acetate was dispersed in solution B by homogenization. Solution A and solution C were added to the above dispersion and homogenized. Final concentration was adjusted with water and subjected for spray drying.
Finally, solution adsorbed blend equivalent to 50 mg of Abiraterone acetate and spray dried blend equivalent to 50 mg of Abiraterone acetate were blended with co-sifted sodium starch glycolate, and sodium lauryl sulfate and filled in hard gelatin capsules.

We claim
Claim 1: An oral pharmaceutical formulation comprising Abiraterone, solubilizing agents and other pharmaceutically acceptable excipients, wherein the formulation comprises less than 1000 mg of Abiraterone.
Claim 2: The pharmaceutical formulation of claim 1, wherein the solubilizing agents are selected from the group comprising of cyclodextrins, diethylene glycol monoethyl ether, medium chain triglycerides and surfactants.
Claim 3: The pharmaceutical formulation of claim 2, wherein the cyclodextrins are selected from the group comprising, methyl or hydroxypropyl β-cyclodextrins, methyl or ethyl β-cyclodextrin, sulfoalkylether-substituted β-cyclodextrin, sulfobutylether-β-cyclodextrin.
Claim 4: The pharmaceutical formulation of claim 2, wherein the surfactants are selected from anionic, non-ionic, cationic and amphoteric surfactants.
Claim 5: The pharmaceutical formulation of claim 4, wherein the surfactant is selected from dioctylsulfosuccinate sodium, polyethylene glycol fatty acid esters, sodium lauryl sulphate, polyoxyethylene-polyoxypropylene block co-polymers, polyoxyethylene fatty acid glycerides, polyoxyethylene sorbitan fatty acid esters, polysorbates, polyoxyethylene castor oil derivates, poloxamer, cremophor, cetrimide, phospholipid, lecithin or combinations thereof.
Claim 6: The pharmaceutical formulation of claim 1, wherein the excipients are selected from the group comprising disintegrants, diluents, binders, glidants, lubricants, plasticizers, sweeteners, flavoring agents, antioxidants, stabilizers, viscosity modifying agents, polymers, channeling agents, emulsifiers, surfactants, buffering agents and coloring agents.

Claim 7: The pharmaceutical formulation of claim 6, wherein the formulation additionally comprises carriers and wetting agents.
Claim 8: The pharmaceutical formulation of claim 7, wherein the formulation comprises magnesium aluminometasilicate, glycerol and gelatin.