WO2023084545A1 - Stable pharmaceutical composition of non-steroidal antiandrogens - Google Patents

Stable pharmaceutical composition of non-steroidal antiandrogens Download PDF

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Publication number
WO2023084545A1
WO2023084545A1 PCT/IN2022/051000 IN2022051000W WO2023084545A1 WO 2023084545 A1 WO2023084545 A1 WO 2023084545A1 IN 2022051000 W IN2022051000 W IN 2022051000W WO 2023084545 A1 WO2023084545 A1 WO 2023084545A1
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Prior art keywords
apalutamide
composition
tri
block copolymer
pva
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PCT/IN2022/051000
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French (fr)
Inventor
Nirav Nalinkumar Vyas
Nilesh Dineshbhai Yadav
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Amerise Pharmaceuticals Pvt Ltd.
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Publication date
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Publication of WO2023084545A1 publication Critical patent/WO2023084545A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to pharmaceutical composition of non-steroidal antiandrogens.
  • the present invention relates to pharmaceutical composition of Apalutamide having high drug loading.
  • Apalutamide is BCS Class-II substance and is known to have poor aqueous solubility. Apalutamide is approved as 60mg tablets and, it is to be administered as 240mg (i.e. 4 X 60mg tablets) once daily. Due to its poor solubility,higher amount of Apalutamide could not be loaded per pill and it lead to higher pill burden for the patients.
  • the present invention provides pharmaceutical composition of Apalutamide having high drug loading.
  • a unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide and pharmaceutically acceptable excipient.
  • a stable unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide and pharmaceutically acceptable excipient.
  • a unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer and pharmaceutically acceptable excipient.
  • a stable unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer and pharmaceutically acceptable excipient.
  • a unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer PVC-PVA-PEG, and pharmaceutically acceptable excipient.
  • a stable unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer PVC-PVA-PEG, and pharmaceutically acceptable excipient.
  • a tablet composition comprising 120mg to 240mg Apalutamide and pharmaceutically acceptable excipient.
  • a tablet composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer and pharmaceutically acceptable excipient.
  • a tablet composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer PVC-PVA-PEG, and pharmaceutically acceptable excipient.
  • a unit does pharmaceutical composition comprising 120mg to 240mg Apalutamide, and pharmaceutically acceptable excipient; wherein the unit does pharmaceutical composition provides at least 90% drug release within 15 minutes when measured by USP Apparatus II.
  • a tablet composition comprising 120mg to 240mg Apalutamide, and pharmaceutically acceptable excipient; wherein the tablet composition provides at least 90% drug release within 15 minutes when measured by USP Apparatus II.
  • a unit does pharmaceutical composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer and pharmaceutically acceptable excipient; wherein the unit does pharmaceutical composition provides at least 90% drug release within 15 minutes when measured by USP Apparatus II.
  • a tablet composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer PVC-PVA-PEG, and pharmaceutically acceptable excipient; wherein the tablet composition provides at least 90% drug release within 15 minutes when measured by USP Apparatus II.
  • the values or the range of values described herein with respect to the quantity or concentration of the ingredients are not to be construed as absolute values and the analytical and/or manual errors in measuring, reporting and/or recording such values and non-substantial variations thereof are also included within the expression of the value or the range of values.
  • a variance of +/- 5-10% from the reference value is to be construed as the same as within the described range. e.g. in some embodiment the expression “150 mg” can include 142.5-157.5 mg; and in some embodiment the expression “120-240mg” can include 108-252 mg.
  • tri-block copolymer means an amphiphilic graft co-polymer having a hydrophilic backbone and hydrophobic side chain or having a hydrophobic backbone and hydrophophilic side chain.
  • the amphiphilic graft co-polymer can be selected from a group comprising poly(ethylene oxide)(PEO)-poly( ⁇ -caprolactone), PEO-poly(propylene oxide), PEO-poly(aspartic acid), Poly(ester amide)-Poly(ethylene oxide), poly( ⁇ -caprolactone)- g -poly(ethylene glycol), (PCL- g -PEG) copolymers, and PVC-PVA-PEG co-polymers.
  • PVC-PVA-PEG as used herein means a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer.
  • Soluplus® is a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (PVC-PVA-PEG) graft co-polymer.
  • the present invention provides pharmaceutical composition of Apalutamide having high drug loading.
  • the known arts have prepared amorphous form and amorphous solid dispersion of Apalutamide to improve the solubility and provide better dissolution profile. Even in amorphous form Apalutamide is insoluble in water and in buffer at pH ranging from 1.2 to 8.0. None of the known arts have been able to provide a unit dosage form of apalitamide with a higher drug loadings and with more than 90% drug release within 15 minute.
  • a unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide and pharmaceutically acceptable excipient.
  • a stable unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide and pharmaceutically acceptable excipient.
  • a unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer and pharmaceutically acceptable excipient.
  • a stable unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer and pharmaceutically acceptable excipient.
  • a unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer PVC-PVA-PEG, and pharmaceutically acceptable excipient.
  • a stable unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer PVC-PVA-PEG, and pharmaceutically acceptable excipient.
  • composition of the present invention can be in the form of powder, granules, beads, flakes, film, tablet or capsule.
  • composition of the present invention is preferably tablet or capsule.
  • composition of the invention is tablet composition.
  • composition of the invention is capsule.
  • a tablet composition comprising 120mg to 240mg Apalutamide and pharmaceutically acceptable excipient.
  • a tablet composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer and pharmaceutically acceptable excipient.
  • a tablet composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer PVC-PVA-PEG, and pharmaceutically acceptable excipient.
  • a capsule composition comprising 120mg to 240mg Apalutamide and pharmaceutically acceptable excipient.
  • a capsule composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer and pharmaceutically acceptable excipient.
  • a tablet composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer PVC-PVA-PEG, and pharmaceutically acceptable excipient.
  • the present invention provides a pharmaceutical composition of Apalutamide, comprising more than 60mg to as high as 240mg of Apalutamide in a single unit dosage form, that provides more than 90% drug release within 15 min,equivalent to four 60mg tablets currently approved and marketed under the brand name Erleada®.
  • composition of the present invention allows to reduce the pill burden on the patient and enables to provide a single unit dosage form comprising the entire 240mg dose in a dosage form of comparable size, shape, and/or weight.
  • the attempts to increase the solubility of Apalutamide using polymers have resulted in irregular dissolution or drug release, and reduced permeability too.
  • the present invention provides a composition comprising Apalutamide and amphiphilic graft copolymer with increased solubility and improved dissolution profile to provide more than 90% drug release within 15 min.
  • a unit does pharmaceutical composition comprising 120mg to 240mg Apalutamide, and pharmaceutically acceptable excipient; wherein the unit does pharmaceutical composition provides at least 90% drug release within 15 minutes when measured by USP Apparatus II.
  • a tablet composition comprising 120mg to 240mg Apalutamide, and pharmaceutically acceptable excipient; wherein the tablet composition provides at least 90% drug release within 15 minutes when measured by USP Apparatus II.
  • a unit does pharmaceutical composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer and pharmaceutically acceptable excipient; wherein the unit does pharmaceutical composition provides at least 90% drug release within 15 minutes when measured by USP Apparatus II.
  • the tri-block copolymer is an amphiphilic tri-block copolymer and the amphiphilic tri-block copolymer can be a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (PVC-PVA-PEG) graft co-polymer.
  • PVC-PVA-PEG polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol
  • Soluplus® is a PVC-PVA-PEG graft co-polymer, which can be used as the amphiphilic tri-block copolymer of the present invention.
  • a tablet composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer PVC-PVA-PEG, and pharmaceutically acceptable excipient; wherein the tablet composition provides at least 90% drug release within 15 minutes when measured by USP Apparatus II.
  • composition of the present invention can be prepared as a solid dispersion of Apalutamide and the tri-block copolymer.
  • the solid dispersion of Apalutamide and the tri-block copolymer can be prepared by dissolving Apalutamide and the tri-block copolymer in a mixture of water and a water miscible polar solvent and lyophilizing the solution.
  • the solid dispersion of Apalutamide and the tri-block copolymer can also be prepared by dissolving Apalutamide and the tri-block copolymer in a polar solvent optionally mixed with water and spray drying the solution.
  • composition of the present invention can also be prepared by preparing granules comprising Apalutamide and the tri-block copolymer by wet granulation.
  • the granules comprising Apalutamide and the tri-block copolymer can be prepared by mixing Apalutamide and the tri-block copolymer with an organic solvent and water followed by granulation in a granulator.
  • the solid dispersion or granules comprising Apalutamide and the tri-block copolymer can be directly compressed into tablets or can be filled in the capsules.
  • the solid dispersion or granules comprising Apalutamide and the tri-block copolymer can be mixed with other excipients and then compressed into tablets or can be filled in the capsules.
  • the tri-block copolymer is an amphiphilic tri-block copolymer and the amphiphilic tri-block copolymer can be a PVC-PVA-PEG graft co-polymer.
  • the PVC-PVA-PEG graft co-polymer enhances the solubility and dissolution of Apalutamide at a relatively low polymer to drug ratio, which allows encompassing as high as 240mg of Apalutamide in a unit dose form and still having lower weight of the tablet or capsule to ease swallowing.
  • the PVC-PVA-PEG graft co-polymer in addition to increasing solubility and holding higher amount of Apalutamide in the unit dosage form, also provides higher dissolution rate and drug release profile to provide more than 90% drug release within 15 minutes.
  • the tri-block co-polymer can be present in the composition at a concentration of 0.1-70% w/w, more preferably 1-50% w/w, even more preferably 10-40% w/w and most preferably 30-40% w/w – of the composition.
  • composition comprising 120mg to 240mg Apalutamide and 0.1-70% a tri-block copolymer by weight of the composition.
  • a unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide, 0.1-70% a tri-block copolymer by weight of the composition and pharmaceutically acceptable excipient.
  • composition comprising 120mg to 240mg Apalutamide and 10-40% a tri-block copolymer by weight of the composition.
  • unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide, 10-40% a tri-block copolymer by weight of the composition and pharmaceutically acceptable excipient.
  • composition comprising 120mg to 240mg Apalutamide and 30-40% a tri-block copolymer by weight of the composition.
  • a unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide, 30-40% a tri-block copolymer by weight of the composition and pharmaceutically acceptable excipient.
  • composition comprising 120mg to 240mg Apalutamide and 0.1-70% PVC-PVA-PEG graft co-polymer by weight of the composition.
  • a unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide, 0.1-70% PVC-PVA-PEG graft co-polymer by weight of the composition and pharmaceutically acceptable excipient.
  • composition comprising 120mg to 240mg Apalutamide and 10-40% PVC-PVA-PEG graft co-polymer by weight of the composition.
  • a unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide, 10-40% PVC-PVA-PEG graft co-polymer by weight of the composition and pharmaceutically acceptable excipient.
  • composition comprising 240mg Apalutamide and 20-40% PVC-PVA-PEG graft co-polymer by weight of the composition.
  • a unit dose pharmaceutical composition comprising 240mg Apalutamide, 30-40% PVC-PVA-PEG graft co-polymer by weight of the composition and pharmaceutically acceptable excipient.
  • the tri-block co-polymer can be present in the composition at a ratio of 1:0.1 to 1:10, preferably from 1:0.25 to 1:5, more preferably from 1:0.5 to 1:3, even more preferably from 1:0.75 to 1:2 and most preferably from 1:0.8 to 1:1.5, compared to Apalutamide.
  • composition comprising Apalutamide and tri-block co-polymer at ratio of 1:0.1 to 1:10
  • composition comprising Apalutamide and tri-block co-polymer at ratio of 1:0.1 to 1:10 and pharmaceutically acceptable excipient
  • composition comprising Apalutamide and tri-block co-polymer at ratio of 1:0.25 to 1:3
  • composition comprising Apalutamide and PVC-PVA-PEG graft co-polymer at ratio of 1:0.25 to 1:3 and pharmaceutically acceptable excipient.
  • composition comprising Apalutamide and PVC-PVA-PEG graft co-polymer at ratio of 1:0.5 to 1:2
  • composition comprising Apalutamide and PVC-PVA-PEG graft co-polymer at ratio of 1:0.5 to 1:2 and pharmaceutically acceptable excipient
  • composition comprising Apalutamide and PVC-PVA-PEG graft co-polymer at ratio of 1:0.75 to 1:1.5
  • composition comprising Apalutamide and PVC-PVA-PEG graft co-polymer at ratio of 1:0.75 to 1:1.5 and pharmaceutically acceptable excipient.
  • composition comprising 240mg Apalutamide and 20-2400mg tri-block copolymer.
  • composition comprising 240mg Apalutamide, 20-2400mg tri-block copolymer and pharmaceutically acceptable excipient.
  • composition comprising 240mg Apalutamide and 60-1200mg tri-block copolymer.
  • composition comprising 240mg Apalutamide, 60-1200mg tri-block copolymer and pharmaceutically acceptable excipient.
  • composition comprising 240mg Apalutamide and 120-720mg tri-block copolymer.
  • composition comprising 240mg Apalutamide, 120-720mg tri-block copolymer and pharmaceutically acceptable excipient.
  • composition comprising 240mg Apalutamide and 150-480mg tri-block copolymer.
  • composition comprising 240mg Apalutamide, 150-480mg tri-block copolymer and pharmaceutically acceptable excipient.
  • composition comprising 240mg Apalutamide and 200-260mg tri-block copolymer.
  • composition comprising 240mg Apalutamide, 200-260mg tri-block copolymer and pharmaceutically acceptable excipient.
  • composition comprising 240mg Apalutamide and 20-2400mg PVC-PVA-PEG graft copolymer.
  • composition comprising 240mg Apalutamide, 20-2400mg PVC-PVA-PEG graft copolymer and pharmaceutically acceptable excipient.
  • composition comprising 240mg Apalutamide and 200-260mg PVC-PVA-PEG graft copolymer.
  • composition comprising 240mg Apalutamide, 200-260mg PVC-PVA-PEG graft copolymer and pharmaceutically acceptable excipient.
  • composition of the present invention in addition to Apalutamide and tri-block copolymer may further comprise one or more of surfactant, solubility enhancing polymer and vegetable oil.
  • the surfactant can be cationic, anionic, zwitterionic, or non-ionic surfactant.
  • the surfactant can be selected from a group comprising sodium lauryl sulfate, sodium dodecyl sulfate, fatty acid esters of sorbitan (generally referred to as Spans) and their ethoxylated derivatives (generally referred to as Tweens), Polyoxyethylene 15 hydroxy stearate, Polyoxyethylene castor oil derivatives, Polyoxyethylene stearates, Polyoxyethylene alkyl ethers and Polyoxyethylenenonylphenol ether.
  • the solubility enhancing polymer can be selected from a group comprising polyethylene glycols, polyvinyl pyrrolidone, polyvinyl alcohol, lactose, chitosan, ⁇ -cyclodextrin, poloxamer and hydroxypropyl methylcellulose.
  • composition of the present invention comprising and tri-block copolymer may also comprise one or more of glident, binder, diluents and disintegrant.
  • the composition of the present invention can be used for the treatment of cancer.
  • the composition of the present invention can be used for the treatment of prostate cancer.
  • the composition of the present invention can be used for the treatment of non-metastatic prostate cancer.
  • the composition of the present invention can be used for the treatment of castration-resistant non-metastatic prostate cancer.
  • a method of treatment of cancer comprising administration of a composition comprising 120-240mg Apalutamide and tri-block copolymer.
  • a method of treatment of non-metastatic prostate cancer comprising administration of a composition comprising 120-240mg Apalutamide and PVC-PVA-PEG graft copolymer.
  • a method of treatment of prostate cancer comprising administration of a composition comprising 240mg Apalutamide and 20-2400 tri-block copolymer.
  • a method of treatment of castration-resistant non-metastatic prostate cancer comprising administration of a composition comprising 240mg Apalutamide and 200-260mg PVC-PVA-PEG graft copolymer.
  • Example - 1 Apalutamide capsule 240mg Ingredient Quantity/ 05 capsule Apalutamide 1.2 g PVC-PVA-PEG graft co-polymer (Soluplus®) 2.4 g Methanol 50 mL Purified Water 150 mL Problend (Silicified Microcrystalline Cellulose USP-NF) 3.9 g Process of preparation:
  • Soluplus® polymer was dissolved in purified water and Apalutamide was dissolved in methanol. Apalutamide solution was added to polymer solution with continuous stirring for 30 minute. The resulting solution was lyophilized. The lyophilized powder was sieved, mixed with Problend and filled in capsules.
  • Problend is Silicified Microcrystalline Cellulose USP-NF consist of diluent, Filler, Binder, Disintegrants in granulated form to be mixed with API for filling in capsule and Direct Compression.
  • Example – 2 Apalutamide capsule 240mg Ingredient Quantity/05 capsule Apalutamide 1.2 g PVC-PVA-PEG graft co-polymer (Soluplus®) 2.4 g Mannitol 1.4 g Methanol 45 mL Purified Water 150 mL
  • Soluplus® polymer was dissolved in purified water and Apalutamide was dissolved in methanol. Apalitamide solution was added to polymer solution with continuous stirring for 30 minutes. Mannitol was added and stirred to dissolve it. The resulting solution was lyophilized. The lyophilized powder was sieved and filled in capsules.
  • Example – 3 Apalutamide capsule 240mg Ingredient Quantity/ 05 capsule Apalutamide 1.2 g PVC-PVA-PEG graft co-polymer (Soluplus®) 2.4 g Purified Water 150 mL Problend 3.9 g
  • Soluplus® polymer and Apalutamide were dissolved in purified water and homogenized using a homogenizer for 30 minute. Mannitol was added and stirred to dissolve. The resulting solution was lyophilized. The lyophilized powder was sieved, mixed with Problend and filled in capsules.
  • Example - 4 Apalutamide capsule 240mg Ingredient Quantity/10 capsule Apalutamide 2.4 g PVC-PVA-PEG graft co-polymer (Soluplus®) 4.8 g Mannitol 2.0 g PVP-K-17 700 mg Croscarmellose sodium 500 mg Methanol 90 mL Purified Water 300 mL
  • Soluplus® polymer was dissolved in purified water and Apalutamide was dissolved in Methanol. Apalutamdie solution was added tothe polymer solution with continuous stirring for 30 minute. Mannitolwas added and stirred to dissolve. The resulting solution was lyophilized. The lyophilized powder was sieved to obtain the drug-polymer powder. The drug-polymer powder was mixed with croscarmellose sodium and was granulated using 10% solution of PVP-K-17. The granules were dried, sieved and filled in capsules.
  • Example - 5 Apalutamide capsule 240mg Ingredient Quantity/02 capsule Apalutamide 480 mg Gelucire® 50/13 960mg
  • Gelucire® 50/13 was heated to 40-45 oC and Apalutamide was added and mixed well for 05-15 min at 40o C. The mixture was cooled down to 5oC. The resultant mass was scrapped, sieved and filled in capsules.
  • Example – 6 Apalutamide Granules Ingredient Quantity Apalutamide 6.0 g PVC-PVA-PEG graft co-polymer (Soluplus®) 12.0 g Mannitol 6.25 g PVP-K-17 2.5 g Croscarmellose sodium 1250 mg Methanol 225 mL Purified Water 750 mL
  • Soluplus® polymer was dissolved in purified water and Apalutamide was dissolved in Methanol. Apalutamide solution was added to polymer solution with continuous stirring for 30 minute. Mannitolwas added and stirred to dissolve. The resulting solution was lyophilized and sieved to obtain drug-polymer powder. The drug-polymer powder was mixed with croscarmellose sodium and was granulated using 10% solution of PVP-K-17. The granules were dried and sieved
  • Example 6 The granules obtained following the process as discussed in Example 6 were filled in capsules to obtain Apalutamide 240mg capsule.
  • Example – 7 Apalutamide Granules Ingredient Quantity Apalutamide 6.0 g PVC-PVA-PEG graft co-polymer (Soluplus®) 6.0 g Mannitol 6.25 g Methanol 225 mL Purified Water 750 mL
  • Soluplus® polymer was dissolved in purified water and Apalutamide was dissolved in Methanol. Apalutamide solution was added to polymer solution with continuous stirring for 30 minute. Mannitol was added and stirred to dissolve. The resulting solution was lyophilized and sieved to obtain drug-polymer powder.
  • Example – 7.1 Apalutamide capsules 240mg Ingredient Quantity Lyophilized powder of drug and polymer 9.125 g PVP-k-17 1.25 g Croscarmellose sodium 625 mg The drug-polymer powder was mixed with croscarmellose sodium and was granulated using 10% solution of PVP-K-17. The granules were dried, sieved and filled in capsules.
  • Example –7.2 Apalutamide tablets 240mg :
  • Example 7 & Example 7.1 The granules obtained following the process as discussed in Example 7 & Example 7.1 were compressed to obtain Apalutamide 240mg tablets
  • Example –7.3 Apalutamide capsules 240mg : Ingredient Quantity Lyophilized powder of drug and polymer 9.125 g PVP VA 64 1.25 g Croscarmellose sodium 625 mg
  • the drug-polymer powder was mixed with croscarmellose sodium and was granulated using 10% solution of PVP VA 64. The granules were dried, sieved and filled in capsules
  • Example –7.4 Apalutamide tablets 240mg :
  • Example –8 Apalutamide tablets 240mg : Ingredient Quantity/ 25 Tablets Apalutamide 6.0 g Sodium lauryl sulfate 2.5 g Magnesium aluminometasilicate 10.0 g Croscarmellose sodium 2.5 g
  • Example –8.1 Apalutamide tablets 240mg : Ingredient Quantity/ 25 Tablets Apalutamide 6.0 g Sodium lauryl sulfate 5 g Magnesium aluminometasilicate 10.0 g Croscarmellose sodium 2.5 g
  • Example –9 Apalutamide capsule 240mg : Ingredient Quantity/10 capsule Apalutamide 2.4 g PVC-PVA-PEG graft co-polymer (Soluplus®) 1.2 g Mannitol 1.5 g Sodium lauryl sulfate 1.0 g Magnesium aluminometasilicate 3.4 g Croscarmellose sodium 1 g Acetone 20 mL Purified Water 100 mL
  • Soluplus® polymer and Sodium lauryl sulfate were dissolved in purified water and Apalutamide was dissolved in Acetone. Apalutamide solution was added to polymer solution with continuous stirring for 30 minute. Mannitolwas added and stirred to dissolve. The resulting mixture was lyophilized and sieved to obtain drug-polymer powder. The drug-polymer powder was mixed with magnesium aluminometasilicate and croscarmellose sodium, and the resultant mix was compressed in to scored tablets
  • Example 1 Medium 1 NA NA 68.6 NA 96.4 77.4
  • Example 2 Medium 1 91.3 56.0 54.5 53.9 51.0 48.5
  • Example 3 Medium 1 85.4 36 33.9 31.5 30.1 28.2
  • Example 4 Medium 1 96.1 35.1 43.5 NA NA NA NA
  • Example 4 Medium 2 96.1 108.6 105 NA NA NA NA
  • Example 4 Medium 3 96.1 97.2 98 NA NA NA NA
  • Example 4 Medium 4 96.1 100.7 95.8 NA NA NA NA
  • Example 5 Medium 1 NA 4.0 0.1 NA NA 26.7
  • Example 6.1 Medium 2 NA 89 93.9 NA NA 89.8
  • Example 6.2 Medium 2 NA 8.1 20.1 NA 24.9 34.2
  • Example 7 Medium 2 NA 89.0 93.9 NA NA 89.8
  • Example 7.1 Medium 2 NA 99.1 99.8 NA NA 98.5
  • Example 7.2 Medium 2 NA 12.7 23.4 NA 44.1 57.0
  • Example 7.3 Medium 2 NA 73.6 90.8 NA NA 96.9
  • Example 7.4 Medium 2 NA 5.4 9.4
  • Example –10.0 Comparative Drug Release Profiles : Ingredients Ex-10.1 Ex-10.2 Apalutamide 240mg 240mg Eudragit® RL PO 480 mg -- Hydroxypropyl methyl acetate succinate -- 480 mg Acetone q.s. q.s. Microcrystalline cellulose ( PH 101 ) 800 mg 800 mg Silicon dioxide 64 mg 64 mg Talc 50 mg 50 mg
  • Solid dispersion of Apalutamide and the polymer was prepared and the dried powder was mixed with silicon dioxide, talc and microcrystalline cellulose (PH 101) and sifted through sieve.
  • Example 10.3 Ingredients Qty % Apalutamide 10 Hydroxypropyl methyl cellulose 5 Sodium lauryl sulphate 2 Lecithin 2 Sucrose 10 Purified water Q.S
  • Apalutamide nanosuspension was prepared as per above composition and then sprayed on lactose and the powder is then granulated
  • Example 10.4 Sr. No. Ingredients Qty./Unit 1 Apalutamide 240mg 2 Soluplus® 240mg 3 Mannitol 100 mg 4 Cross carmellose sodium (intragranular) 35 mg 5 Cross carmellose sodium (extragranular) 35 mg

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Abstract

The present invention provides pharmaceutical composition of non-steroidal antiandrogens. The present invention provides pharmaceutical composition of non-steroidal antiandrogens having high drug loading. The present invention provides a stable unit dose pharmaceutical composition Apalutamide and pharmaceutically acceptable excipients. The present invention provides a stable unit dose pharmaceutical composition Apalutamide, copolymer and pharmaceutically acceptable excipients.

Description

Stable Pharmaceutical Composition of Non-steroidal Antiandrogens FIELD OF THE INVENTION
The present invention relates to pharmaceutical composition of non-steroidal antiandrogens. In particular, the present invention relates to pharmaceutical composition of Apalutamide having high drug loading.
 BACKGROUND OF THE INVENTION
Apalutamide is BCS Class-II substance and is known to have poor aqueous solubility. Apalutamide is approved as 60mg tablets and, it is to be administered as 240mg (i.e. 4 X 60mg tablets) once daily. Due to its poor solubility,higher amount of Apalutamide could not be loaded per pill and it lead to higher pill burden for the patients. There have been some attempts to increase the solubility of Apalutamide by making an amorphous form or amorphous solid dispersion of Apalutamide or by making a mixture of Apalutamide with polymers, but permeability decreases with increase in solubility; see especially, WO 2016/090098 A1, WO 2016/060105 A1, WO 2019/016747 A1, EP 3811932 A1, US 2020/0397756 A1 and Journal of Molecular Liquids, Volume 322, 15 January 2021, 114937, disclose and/or discusses.
There is a need to provide a composition of Apalutamide that can have higher drug loading than 60mg per unit dosage form and thereby reduce the pill burden for the patients.
The present invention provides pharmaceutical composition of Apalutamide having high drug loading.
In one embodiment, there is provided a unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide and pharmaceutically acceptable excipient.
In another embodiment, there is provided a stable unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide and pharmaceutically acceptable excipient.
In another embodiment, there is provided a unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer and pharmaceutically acceptable excipient.
In another embodiment, there is provided a stable unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer and pharmaceutically acceptable excipient.
In another embodiment, there is provided a unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer PVC-PVA-PEG, and pharmaceutically acceptable excipient.
In another embodiment, there is provided a stable unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer PVC-PVA-PEG, and pharmaceutically acceptable excipient.
In another embodiment, there is provided a tablet composition comprising 120mg to 240mg Apalutamide and pharmaceutically acceptable excipient.
In another embodiment, there is provided a tablet composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer and pharmaceutically acceptable excipient.
In another embodiment, there is provided a tablet composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer PVC-PVA-PEG, and pharmaceutically acceptable excipient.
In another embodiment, there is provided a unit does pharmaceutical composition comprising 120mg to 240mg Apalutamide, and pharmaceutically acceptable excipient; wherein the unit does pharmaceutical composition provides at least 90% drug release within 15 minutes when measured by USP Apparatus II.
In another embodiment, there is provided a tablet composition comprising 120mg to 240mg Apalutamide, and pharmaceutically acceptable excipient; wherein the tablet composition provides at least 90% drug release within 15 minutes when measured by USP Apparatus II.
In another embodiment, there is provided a unit does pharmaceutical composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer and pharmaceutically acceptable excipient; wherein the unit does pharmaceutical composition provides at least 90% drug release within 15 minutes when measured by USP Apparatus II.
In another embodiment, there is provided a tablet composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer PVC-PVA-PEG, and pharmaceutically acceptable excipient; wherein the tablet composition provides at least 90% drug release within 15 minutes when measured by USP Apparatus II.
DETAILED DESCRIPTION OF THE INVENTION
Various generic and specific embodiments of the invention are discussed herein and further non-limiting specific embodiments are described in detail. The specific embodiments and the examples, described hereinafter, are exemplary and in no way limits the scope of the invention to expressly or specifically disclosed embodiments only; and variations and/or modifications thereof that are apparent to-, and obvious for-, a person skilled in the art are also included within the scope of the invention.
Unless otherwise defined, all the technical and scientific terms used herein shall bear the meaning as ordinarily understood by a person skilled in the field of the invention. Processes, methods and techniques, which are commonly used and routinely practiced in the field of the invention and/or easily understood by a person skilled in the art, are not described in detail, for the sake of brevity.
Unless specifically described otherwise, the values or the range of values described herein with respect to the quantity or concentration of the ingredients are not to be construed as absolute values and the analytical and/or manual errors in measuring, reporting and/or recording such values and non-substantial variations thereof are also included within the expression of the value or the range of values. In general, a variance of +/- 5-10% from the reference value is to be construed as the same as within the described range. e.g. in some embodiment the expression “150 mg” can include 142.5-157.5 mg; and in some embodiment the expression “120-240mg” can include 108-252 mg.
The term “tri-block copolymer” as used herein, means an amphiphilic graft co-polymer having a hydrophilic backbone and hydrophobic side chain or having a hydrophobic backbone and hydrophophilic side chain. The amphiphilic graft co-polymer can be selected from a group comprising poly(ethylene oxide)(PEO)-poly(ε-caprolactone), PEO-poly(propylene oxide),  PEO-poly(aspartic acid), Poly(ester amide)-Poly(ethylene oxide), poly(ε-caprolactone)-g-poly(ethylene glycol), (PCL-g-PEG) copolymers, and PVC-PVA-PEG co-polymers.
The term “PVC-PVA-PEG” as used herein means a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer. e.g. Soluplus® is a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (PVC-PVA-PEG) graft co-polymer.
The present invention provides pharmaceutical composition of Apalutamide having high drug loading.
The known arts have prepared amorphous form and amorphous solid dispersion of Apalutamide to improve the solubility and provide better dissolution profile. Even in amorphous form Apalutamide is insoluble in water and in buffer at pH ranging from 1.2 to 8.0. None of the known arts have been able to provide a unit dosage form of apalitamide with a higher drug loadings and with more than 90% drug release within 15 minute.
In one embodiment, there is provided a unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide and pharmaceutically acceptable excipient.
In another embodiment, there is provided a stable unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide and pharmaceutically acceptable excipient.
In another embodiment, there is provided a unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer and pharmaceutically acceptable excipient.
In another embodiment, there is provided a stable unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer and pharmaceutically acceptable excipient.
In another embodiment, there is provided a unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer PVC-PVA-PEG, and pharmaceutically acceptable excipient.
In another embodiment, there is provided a stable unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer PVC-PVA-PEG, and pharmaceutically acceptable excipient.
The composition of the present invention can be in the form of powder, granules, beads, flakes, film, tablet or capsule.
The composition of the present invention is preferably tablet or capsule.
In one embodiment the composition of the invention is tablet composition.
In another embodiment, the composition of the invention is capsule.
In another embodiment, there is provided a tablet composition comprising 120mg to 240mg Apalutamide and pharmaceutically acceptable excipient.
In another embodiment, there is provided a tablet composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer and pharmaceutically acceptable excipient.
In another embodiment, there is provided a tablet composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer PVC-PVA-PEG, and pharmaceutically acceptable excipient.
In another embodiment, there is provided a capsule composition comprising 120mg to 240mg Apalutamide and pharmaceutically acceptable excipient.
In another embodiment, there is provided a capsule composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer and pharmaceutically acceptable excipient.
In another embodiment, there is provided a tablet composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer PVC-PVA-PEG, and pharmaceutically acceptable excipient.
The present invention provides a pharmaceutical composition of Apalutamide, comprising more than 60mg to as high as 240mg of Apalutamide in a single unit dosage form, that provides more than 90% drug release within 15 min,equivalent to four 60mg tablets currently approved and marketed under the brand name Erleada®.
The ability of the composition of the present invention to provide higher drug loading compared to the marketed Erleada® tablets, allows to reduce the pill burden on the patient and enables to provide a single unit dosage form comprising the entire 240mg dose in a dosage form of comparable size, shape, and/or weight.
The attempts to increase the solubility of Apalutamide using polymers have resulted in irregular dissolution or drug release, and reduced permeability too. The present invention provides a composition comprising Apalutamide and amphiphilic graft copolymer with increased solubility and improved dissolution profile to provide more than 90% drug release within 15 min.
In another embodiment, there is provided a unit does pharmaceutical composition comprising 120mg to 240mg Apalutamide, and pharmaceutically acceptable excipient; wherein the unit does pharmaceutical composition provides at least 90% drug release within 15 minutes when measured by USP Apparatus II.
In another embodiment, there is provided a tablet composition comprising 120mg to 240mg Apalutamide, and pharmaceutically acceptable excipient; wherein the tablet composition provides at least 90% drug release within 15 minutes when measured by USP Apparatus II.
In another embodiment, there is provided a unit does pharmaceutical composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer and pharmaceutically acceptable excipient; wherein the unit does pharmaceutical composition provides at least 90% drug release within 15 minutes when measured by USP Apparatus II.
The tri-block copolymer is an amphiphilic tri-block copolymer and the amphiphilic tri-block copolymer can be a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (PVC-PVA-PEG) graft co-polymer. e.g. Soluplus® is a PVC-PVA-PEG graft co-polymer, which can be used as the amphiphilic tri-block copolymer of the present invention.
In another embodiment, there is provided a tablet composition comprising 120mg to 240mg Apalutamide, a tri-block copolymer PVC-PVA-PEG, and pharmaceutically acceptable excipient; wherein the tablet composition provides at least 90% drug release within 15 minutes when measured by USP Apparatus II.
In another embodiment, there is provided process for preparation of a composition comprising 120-240mg Apalutamide and tri-block copolymer.
The composition of the present invention can be prepared as a solid dispersion of Apalutamide and the tri-block copolymer.
The solid dispersion of Apalutamide and the tri-block copolymer can be prepared by dissolving Apalutamide and the tri-block copolymer in a mixture of water and a water miscible polar solvent and lyophilizing the solution.
The solid dispersion of Apalutamide and the tri-block copolymer can also be prepared by dissolving Apalutamide and the tri-block copolymer in a polar solvent optionally mixed with water and spray drying the solution.
The composition of the present invention can also be prepared by preparing granules comprising Apalutamide and the tri-block copolymer by wet granulation.
The granules comprising Apalutamide and the tri-block copolymer can be prepared by mixing Apalutamide and the tri-block copolymer with an organic solvent and water followed by granulation in a granulator.
The solid dispersion or granules comprising Apalutamide and the tri-block copolymer can be directly compressed into tablets or can be filled in the capsules.
The solid dispersion or granules comprising Apalutamide and the tri-block copolymer can be mixed with other excipients and then compressed into tablets or can be filled in the capsules.
The tri-block copolymer is an amphiphilic tri-block copolymer and the amphiphilic tri-block copolymer can be a PVC-PVA-PEG graft co-polymer.
The PVC-PVA-PEG graft co-polymer enhances the solubility and dissolution of Apalutamide at a relatively low polymer to drug ratio, which allows encompassing as high as 240mg of Apalutamide in a unit dose form and still having lower weight of the tablet or capsule to ease swallowing. The PVC-PVA-PEG graft co-polymer, in addition to increasing solubility and holding higher amount of Apalutamide in the unit dosage form, also provides higher dissolution rate and drug release profile to provide more than 90% drug release within 15 minutes.
The tri-block co-polymer can be present in the composition at a concentration of 0.1-70% w/w, more preferably 1-50% w/w, even more preferably 10-40% w/w and most preferably 30-40% w/w – of the composition.
In another embodiment, there is provided a composition comprising 120mg to 240mg Apalutamide and 0.1-70% a tri-block copolymer by weight of the composition.
In another embodiment, there is provided a unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide, 0.1-70% a tri-block copolymer by weight of the composition and pharmaceutically acceptable excipient.
In another embodiment, there is provided a composition comprising 120mg to 240mg Apalutamide and 10-40% a tri-block copolymer by weight of the composition.In another embodiment, there is provided a unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide, 10-40% a tri-block copolymer by weight of the composition and pharmaceutically acceptable excipient.
In another embodiment, there is provided a composition comprising 120mg to 240mg Apalutamide and 30-40% a tri-block copolymer by weight of the composition.
In another embodiment, there is provided a unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide, 30-40% a tri-block copolymer by weight of the composition and pharmaceutically acceptable excipient.
In another embodiment, there is provided a composition comprising 120mg to 240mg Apalutamide and 0.1-70% PVC-PVA-PEG graft co-polymer by weight of the composition.
In another embodiment, there is provided a unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide, 0.1-70% PVC-PVA-PEG graft co-polymer by weight of the composition and pharmaceutically acceptable excipient.
In another embodiment, there is provided a composition comprising 120mg to 240mg Apalutamide and 10-40% PVC-PVA-PEG graft co-polymer by weight of the composition.
In another embodiment, there is provided a unit dose pharmaceutical composition comprising 120mg to 240mg Apalutamide, 10-40% PVC-PVA-PEG graft co-polymer by weight of the composition and pharmaceutically acceptable excipient.
In another embodiment, there is provided a composition comprising 240mg Apalutamide and 20-40% PVC-PVA-PEG graft co-polymer by weight of the composition.
In another embodiment, there is provided a unit dose pharmaceutical composition comprising 240mg Apalutamide, 30-40% PVC-PVA-PEG graft co-polymer by weight of the composition and pharmaceutically acceptable excipient.
The tri-block co-polymer can be present in the composition at a ratio of 1:0.1 to 1:10, preferably from 1:0.25 to 1:5, more preferably from 1:0.5 to 1:3, even more preferably from 1:0.75 to 1:2 and most preferably from 1:0.8 to 1:1.5, compared to Apalutamide.
In another embodiment, there is provided a composition comprising Apalutamide and tri-block co-polymer at ratio of 1:0.1 to 1:10
In another embodiment, there is provided a composition comprising Apalutamide and tri-block co-polymer at ratio of 1:0.1 to 1:10 and pharmaceutically acceptable excipient
In another embodiment, there is provided a composition comprising Apalutamide and tri-block co-polymer at ratio of 1:0.25 to 1:3
In another embodiment, there is provided a composition comprising Apalutamide and PVC-PVA-PEG graft co-polymer at ratio of 1:0.25 to 1:3 and pharmaceutically acceptable excipient.
In another embodiment, there is provided a composition comprising Apalutamide and PVC-PVA-PEG graft co-polymer at ratio of 1:0.5 to 1:2
In another embodiment, there is provided a composition comprising Apalutamide and PVC-PVA-PEG graft co-polymer at ratio of 1:0.5 to 1:2 and pharmaceutically acceptable excipient
In another embodiment, there is provided a composition comprising Apalutamide and PVC-PVA-PEG graft co-polymer at ratio of 1:0.75 to 1:1.5
In another embodiment, there is provided a composition comprising Apalutamide and PVC-PVA-PEG graft co-polymer at ratio of 1:0.75 to 1:1.5 and pharmaceutically acceptable excipient.
In another embodiment, there is provided a composition comprising 240mg Apalutamide and 20-2400mg tri-block copolymer.
In another embodiment, there is provided a composition comprising 240mg Apalutamide, 20-2400mg tri-block copolymer and pharmaceutically acceptable excipient.
In another embodiment, there is provided a composition comprising 240mg Apalutamide and 60-1200mg tri-block copolymer.
In another embodiment, there is provided a composition comprising 240mg Apalutamide, 60-1200mg tri-block copolymer and pharmaceutically acceptable excipient.
In another embodiment, there is provided a composition comprising 240mg Apalutamide and 120-720mg tri-block copolymer.
In another embodiment, there is provided a composition comprising 240mg Apalutamide, 120-720mg tri-block copolymer and pharmaceutically acceptable excipient.
In another embodiment, there is provided a composition comprising 240mg Apalutamide and 150-480mg tri-block copolymer.
In another embodiment, there is provided a composition comprising 240mg Apalutamide, 150-480mg tri-block copolymer and pharmaceutically acceptable excipient.
In another embodiment, there is provided a composition comprising 240mg Apalutamide and 200-260mg tri-block copolymer.
In another embodiment, there is provided a composition comprising 240mg Apalutamide, 200-260mg tri-block copolymer and pharmaceutically acceptable excipient.
In another embodiment, there is provided a composition comprising 240mg Apalutamide and 20-2400mg PVC-PVA-PEG graft copolymer.
In another embodiment, there is provided a composition comprising 240mg Apalutamide, 20-2400mg PVC-PVA-PEG graft copolymer and pharmaceutically acceptable excipient.
In another embodiment, there is provided a composition comprising 240mg Apalutamide and 200-260mg PVC-PVA-PEG graft copolymer.
In another embodiment, there is provided a composition comprising 240mg Apalutamide, 200-260mg PVC-PVA-PEG graft copolymer and pharmaceutically acceptable excipient.
The composition of the present invention, in addition to Apalutamide and tri-block copolymer may further comprise one or more of surfactant, solubility enhancing polymer and vegetable oil.
The surfactant can be cationic, anionic, zwitterionic, or non-ionic surfactant. The surfactant can be selected from a group comprising sodium lauryl sulfate, sodium dodecyl sulfate, fatty acid esters of sorbitan (generally referred to as Spans) and their ethoxylated derivatives (generally referred to as Tweens), Polyoxyethylene 15 hydroxy stearate, Polyoxyethylene castor oil derivatives, Polyoxyethylene stearates, Polyoxyethylene alkyl ethers and Polyoxyethylenenonylphenol ether.
The solubility enhancing polymer can be selected from a group comprising polyethylene glycols, polyvinyl pyrrolidone, polyvinyl alcohol, lactose, chitosan, β-cyclodextrin, poloxamer and hydroxypropyl methylcellulose.
The composition of the present invention comprising and tri-block copolymer may also comprise one or more of glident, binder, diluents and disintegrant.The composition of the present invention can be used for the treatment of cancer. The composition of the present invention can be used for the treatment of prostate cancer. The composition of the present invention can be used for the treatment of non-metastatic prostate cancer. The composition of the present invention can be used for the treatment of castration-resistant non-metastatic prostate cancer.
In another embodiment, there is provided a method of treatment of cancer comprising administration of a composition comprising 120-240mg Apalutamide and tri-block copolymer.
In another embodiment, there is provided a method of treatment of non-metastatic prostate cancer comprising administration of a composition comprising 120-240mg Apalutamide and PVC-PVA-PEG graft copolymer.
In another embodiment, there is provided a method of treatment of prostate cancer comprising administration of a composition comprising 240mg Apalutamide and 20-2400 tri-block copolymer.
In another embodiment, there is provided a method of treatment of castration-resistant non-metastatic prostate cancer comprising administration of a composition comprising 240mg Apalutamide and 200-260mg PVC-PVA-PEG graft copolymer.
Examples
One or more general or specific embodiments of the invention described in detail in the following examples, are not intended in any way to limit the scope of the invention. The skilled artisan can make certain changes and modifications that are readily apparent in light of the teachings of this invention without departing from the scope of the invention; and such changes and modifications are also to be construed to be included within the scope of the invention.
Example - 1: Apalutamide capsule 240mg
Ingredient Quantity/ 05 capsule
Apalutamide 1.2 g
PVC-PVA-PEG graft co-polymer (Soluplus®) 2.4 g
Methanol 50 mL
Purified Water 150 mL
Problend (Silicified Microcrystalline Cellulose USP-NF) 3.9 g
Process of preparation:
Soluplus® polymer was dissolved in purified water and Apalutamide was dissolved in methanol. Apalutamide solution was added to polymer solution with continuous stirring for 30 minute. The resulting solution was lyophilized. The lyophilized powder was sieved, mixed with Problend and filled in capsules.
Problend is Silicified Microcrystalline Cellulose USP-NF consist of diluent, Filler, Binder, Disintegrants in granulated form to be mixed with API for filling in capsule and Direct Compression.
Example – 2: Apalutamide capsule 240mg
Ingredient Quantity/05 capsule
Apalutamide 1.2 g
PVC-PVA-PEG graft co-polymer (Soluplus®) 2.4 g
Mannitol 1.4 g
Methanol 45 mL
Purified Water 150 mL
Process of preparation:
Soluplus® polymer was dissolved in purified water and Apalutamide was dissolved in methanol. Apalitamide solution was added to polymer solution with continuous stirring for 30 minutes. Mannitol was added and stirred to dissolve it. The resulting solution was lyophilized. The lyophilized powder was sieved and filled in capsules.
Example – 3: Apalutamide capsule 240mg
Ingredient Quantity/ 05 capsule
Apalutamide 1.2 g
PVC-PVA-PEG graft co-polymer (Soluplus®) 2.4 g
Purified Water 150 mL
Problend 3.9 g
Soluplus® polymer and Apalutamide were dissolved in purified water and homogenized using a homogenizer for 30 minute. Mannitol was added and stirred to dissolve. The resulting solution was lyophilized. The lyophilized powder was sieved, mixed with Problend and filled in capsules.
Example - 4: Apalutamide capsule 240mg
Ingredient Quantity/10 capsule
Apalutamide 2.4 g
PVC-PVA-PEG graft co-polymer (Soluplus®) 4.8 g
Mannitol 2.0 g
PVP-K-17 700 mg
Croscarmellose sodium 500 mg
Methanol 90 mL
Purified Water 300 mL
Soluplus® polymer was dissolved in purified water and Apalutamide was dissolved in Methanol. Apalutamdie solution was added tothe polymer solution with continuous stirring for 30 minute. Mannitolwas added and stirred to dissolve. The resulting solution was lyophilized. The lyophilized powder was sieved to obtain the drug-polymer powder. The drug-polymer powder was mixed with croscarmellose sodium and was granulated using 10% solution of PVP-K-17. The granules were dried, sieved and filled in capsules.
Example - 5: Apalutamide capsule 240mg
Ingredient Quantity/02 capsule
Apalutamide 480 mg
Gelucire® 50/13 960mg
Gelucire® 50/13 was heated to 40-45 ºC and Apalutamide was added and mixed well for 05-15 min at 40º C. The mixture was cooled down to 5ºC. The resultant mass was scrapped, sieved and filled in capsules.
Example – 6: Apalutamide Granules
Ingredient Quantity
Apalutamide 6.0 g
PVC-PVA-PEG graft co-polymer (Soluplus®) 12.0 g
Mannitol 6.25 g
PVP-K-17 2.5 g
Croscarmellose sodium 1250 mg
Methanol 225 mL
Purified Water 750 mL
Soluplus® polymerwas dissolved in purified water and Apalutamide was dissolved in Methanol. Apalutamide solutionwas added to polymer solution with continuous stirring for 30 minute. Mannitolwas added and stirred to dissolve. The resulting solution was lyophilized and sieved to obtain drug-polymer powder. The drug-polymer powder was mixed with croscarmellose sodium and was granulated using 10% solution of PVP-K-17. The granules were dried and sieved
Example – 6.1: Apalutamide capsules 240mg
The granules obtained following the process as discussed in Example 6 were filled in capsules to obtain Apalutamide 240mg capsule.
Example – 6.2: Apalutamide tablets 240mg
The granules obtained following the process as discussed in Example 6 were compressed using to obtain Apalutamide 240mg tablets.
Example – 7: Apalutamide Granules
Ingredient Quantity
Apalutamide 6.0 g
PVC-PVA-PEG graft co-polymer (Soluplus®) 6.0 g
Mannitol 6.25 g
Methanol 225 mL
Purified Water 750 mL
Soluplus® polymer was dissolved in purified water and Apalutamide was dissolved in Methanol. Apalutamide solution was added to polymer solution with continuous stirring for 30 minute. Mannitol was added and stirred to dissolve. The resulting solution was lyophilized and sieved to obtain drug-polymer powder.
Example – 7.1: Apalutamide capsules 240mg
Ingredient Quantity
Lyophilized powder of drug and polymer 9.125 g
PVP-k-17 1.25 g
Croscarmellose sodium 625 mg
The drug-polymer powder was mixed with croscarmellose sodium and was granulated using 10% solution of PVP-K-17. The granules were dried, sieved and filled in capsules.
Example –7.2: Apalutamide tablets 240mg:
The granules obtained following the process as discussed in Example 7 & Example 7.1 were compressed to obtain Apalutamide 240mg tablets
Example –7.3: Apalutamide capsules 240mg:
Ingredient Quantity
Lyophilized powder of drug and polymer 9.125 g
PVP VA 64 1.25 g
Croscarmellose sodium 625 mg
The drug-polymer powder was mixed with croscarmellose sodium and was granulated using 10% solution of PVP VA 64. The granules were dried, sieved and filled in capsules
Example –7.4: Apalutamide tablets 240mg:
The granules obtained following the process as discussed in Example 7 & Example 7.3 were compressed to obtain Apalutamide 240mg tablets
Example –8: Apalutamide tablets 240mg:
Ingredient Quantity/ 25 Tablets
Apalutamide 6.0 g
Sodium lauryl sulfate 2.5 g
Magnesium aluminometasilicate 10.0 g
Croscarmellose sodium 2.5 g
All ingredients were sieved, mixed and compressed to obtain Apalutamide 240mg tablets.
Example –8.1: Apalutamide tablets 240mg:
Ingredient Quantity/ 25 Tablets
Apalutamide 6.0 g
Sodium lauryl sulfate 5 g
Magnesium aluminometasilicate 10.0 g
Croscarmellose sodium 2.5 g
All ingredients were sieved, mixed and compressed to obtain Apalutamide 240mg tablets
Example –9: Apalutamide capsule 240mg:
Ingredient Quantity/10 capsule
Apalutamide 2.4 g
PVC-PVA-PEG graft co-polymer (Soluplus®) 1.2 g
Mannitol 1.5 g
Sodium lauryl sulfate 1.0 g
Magnesium aluminometasilicate 3.4 g
Croscarmellose sodium 1 g
Acetone 20 mL
Purified Water 100 mL
Soluplus® polymer and Sodium lauryl sulfate were dissolved in purified water and Apalutamide was dissolved in Acetone. Apalutamide solutionwas added to polymer solution with continuous stirring for 30 minute. Mannitolwas added and stirred to dissolve. The resulting mixture was lyophilized and sieved to obtain drug-polymer powder. The drug-polymer powder was mixed with magnesium aluminometasilicate and croscarmellose sodium, and the resultant mix was compressed in to scored tablets
Dissolution and Drug Release Profile
Dissolution Media and Parameters:
USP Apparatus = II
Rotation speed = 75 RMP
Medium volume = 900 mL
Temperature = 37 Degree Celsius ± 2 Degree Celsius
Medium 1 = 0.25 SLS in 0.05 M sodium phosphate buffer, pH 4.5
Medium 2 = 0.50 SLS in 0.05 M sodium phosphate buffer, pH 4.5
Medium 3 = 1.0 SLS in 0.05 M sodium phosphate buffer, pH 4.5
Medium 4 = 1.5 SLS in 0.05 M sodium phosphate buffer, pH 4.5
Results
Parameters Assay % Drug Release
15 min 30 min 45 min 60 min Inf.
Example 1
Medium 1		 NA NA 68.6 NA 96.4 77.4
Example 2
Medium 1		 91.3 56.0 54.5 53.9 51.0 48.5
Example 3
Medium 1		 85.4 36 33.9 31.5 30.1 28.2
Example 4
Medium 1		 96.1 35.1 43.5 NA NA NA
Example 4
Medium 2		 96.1 108.6 105 NA NA NA
Example 4
Medium 3		 96.1 97.2 98 NA NA NA
Example 4
Medium 4		 96.1 100.7 95.8 NA NA NA
Example 5
Medium 1		 NA 4.0 0.1 NA NA 26.7
Example 6.1
Medium 2		 NA 89 93.9 NA NA 89.8
Example 6.2
Medium 2		 NA 8.1 20.1 NA 24.9 34.2
Example 7
Medium 2		 NA 89.0 93.9 NA NA 89.8
Example 7.1
Medium 2		 NA 99.1 99.8 NA NA 98.5
Example 7.2
Medium 2		 NA 12.7 23.4 NA 44.1 57.0
Example 7.3
Medium 2		 NA 73.6 90.8 NA NA 96.9
Example 7.4
Medium 2		 NA 5.4 9.4 NA 15.7 19.1
Example –10.0: Comparative Drug Release Profiles:
Ingredients Ex-10.1 Ex-10.2
Apalutamide 240mg 240mg
Eudragit® RL PO 480 mg --
Hydroxypropyl methyl acetate succinate -- 480 mg
Acetone q.s. q.s.
Microcrystalline cellulose ( PH 101 ) 800 mg 800 mg
Silicon dioxide 64 mg 64 mg
Talc 50 mg 50 mg
Solid dispersion of Apalutamide and the polymer was prepared and the dried powder was mixed with silicon dioxide, talc and microcrystalline cellulose (PH 101) and sifted through sieve.
Example 10.3:
Ingredients Qty %
Apalutamide 10
Hydroxypropyl methyl cellulose 5
Sodium lauryl sulphate 2
Lecithin 2
Sucrose 10
Purified water Q.S
Apalutamide nanosuspension was prepared as per above composition and then sprayed on lactose and the powder is then granulated
Example 10.4:
Sr. No. Ingredients Qty./Unit
1 Apalutamide 240mg
2 Soluplus® 240mg
3 Mannitol 100 mg
4 Cross carmellose sodium (intragranular) 35 mg
5 Cross carmellose sodium (extragranular) 35 mg
Solid dispersion of Apalutamide and Soluplus® was mixed with mannitol and cross carmellose sodium and granulated
Drug release profile of the granules obtained as per Examples 10.1 to 10.4 were compared with the drug release profile of 4X60mg ERLEADA® tablets are shown in table 2.
Time (min) % Drug release
Ex-10.1 Ex 10.2 Ex 10.3 Ex 10.4 4X60mg ERLEADA
0 0 0 0 0 0
15 60.6 50.6 54.4 104.7 81.0
30 64.8 55.5 56.2 107 89.0
Inf 68.7 56.4 56.5 107.4 100.0
.

Claims (23)

  1. A composition comprising 120 mg to 240 mg Apalutamide, and pharmaceutically acceptable excipient; wherein the composition provides at least 90% drug release within 15 minutes when measured by USP Apparatus II.
  2. The composition according to claim 1, wherein the composition is a unit dosage form.
  3. The composition according to claim 1, wherein the composition comprises a tri-block copolymer.
  4. The composition according to claim 3, wherein the tri-block copolymer is selected from a group comprising poly(ethylene oxide)-poly(ε-caprolactone), poly(ethylene oxide)-poly(propylene oxide),  poly(ethylene oxide)-poly(aspartic acid), Poly(ester amide)-Poly(ethylene oxide), poly(ε-caprolactone)-g-poly(ethylene glycol), (PCL-g-PEG) copolymers, and PVC-PVA-PEG co-polymers.
  5. The composition according to claim 3, wherein the tri-block copolymer is PVC-PVA-PEG co-polymer.
  6. The composition according to claim 3, wherein the tri-block copolymer is present in the composition at a concentration of 0.1-70% w/w.
  7. The composition according to claim 3, wherein the tri-block copolymer is present in the composition at a concentration of 10-40% w/w.
  8. The composition according to claim 3, wherein the tri-block copolymer is present in the composition at a ratio of 1:0.1 to 1:10 compared to Apalutamide.
  9. The composition according to claim 3, wherein the tri-block copolymer is present in the composition at a ratio of 1:0.5 to 1:1.5 compared to Apalutamide.
  10. The composition according to claim 1, wherein the composition comprises 20-2400mg tri-block copolymer.
  11. The composition according to claim 1, wherein the composition comprises 200-260mg tri-block copolymer.
  12. The composition according to claim 1, wherein the composition is powder, granules, beads, flakes, film, tablet or capsule.
  13. A composition comprising 120mg to 240mg Apalutamide and 20mg to 2400mg tri-block copolymer.
  14. The composition according to claim 13, wherein composition provides at least 90% drug release within 15 minutes when measured by USP Apparatus II.
  15. The composition according to claim 13, wherein composition comprises 60 mg to 1200mg tri-block copolymer.
  16. The composition according to claim 13, wherein composition comprises 150mg to 480mg tri-block copolymer.
  17. The composition according to claim 13, wherein the tri-block copolymer is PVC-PVA-PEG graft copolymer.
  18. A pharmaceutical composition comprising 120mg to 240mg Apalutamide and 20mg to 2400mg PVC-PVA-PEG graft copolymer.
  19. A pharmaceutical composition comprising 240mg Apalutamide and 200mg to 260mg PVC-PVA-PEG graft copolymer.
  20. A pharmaceutical composition comprising 120mg to 240mg Apalutamide, 20mg to 2400mg PVC-PVA-PEG graft copolymer and pharmaceutically acceptable excipient.
  21. A pharmaceutical composition comprising 240mg Apalutamide and 200mg to 260mg PVC-PVA-PEG graft copolymer and pharmaceutically acceptable excipient.
  22. A method of treatment of prostate cancer comprising administration of a composition according to claim 1.
  23. A method of treatment of prostate cancer comprising administration of a composition according to claim 13.
PCT/IN2022/051000 2021-11-15 2022-11-14 Stable pharmaceutical composition of non-steroidal antiandrogens WO2023084545A1 (en)

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IN202121052192 2021-11-15

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016192680A1 (en) * 2015-06-03 2016-12-08 Triastek, Inc. Dosage forms and use thereof
WO2019016747A1 (en) * 2017-07-20 2019-01-24 Dr. Reddy's Laboratories Limited Amorphous solid dispersions of apalutamide and process for the preparation thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016192680A1 (en) * 2015-06-03 2016-12-08 Triastek, Inc. Dosage forms and use thereof
WO2019016747A1 (en) * 2017-07-20 2019-01-24 Dr. Reddy's Laboratories Limited Amorphous solid dispersions of apalutamide and process for the preparation thereof

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