WO2019008426A1 - Novel composition of enzalutamide oral dosage form and method of manufacturing thereof - Google Patents

Novel composition of enzalutamide oral dosage form and method of manufacturing thereof Download PDF

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Publication number
WO2019008426A1
WO2019008426A1 PCT/IB2017/057273 IB2017057273W WO2019008426A1 WO 2019008426 A1 WO2019008426 A1 WO 2019008426A1 IB 2017057273 W IB2017057273 W IB 2017057273W WO 2019008426 A1 WO2019008426 A1 WO 2019008426A1
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Prior art keywords
enzalutamide
dosage form
oral dosage
granules
pharmaceutical composition
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PCT/IB2017/057273
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French (fr)
Inventor
Shah DHARMESH MAHENDRABHAI
Badiger ARAVIND MANAPPA
Choksi RAKSHIT KETANBHAI
Patel BHAVESH NAGINBHAI
Salunkhe PIYUSHA SHARAD
Soni NIRAJ RAMNIVEDAN
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Bdr Pharmaceuticals International Private Limited
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Application filed by Bdr Pharmaceuticals International Private Limited filed Critical Bdr Pharmaceuticals International Private Limited
Priority to RU2020105102A priority Critical patent/RU2020105102A/en
Priority to MX2020000213A priority patent/MX2020000213A/en
Priority to BR112020000207-0A priority patent/BR112020000207A2/en
Publication of WO2019008426A1 publication Critical patent/WO2019008426A1/en
Priority to PH12020500045A priority patent/PH12020500045A1/en
Priority to ZA2020/00609A priority patent/ZA202000609B/en

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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • the present invention relates to novel oral dosage composition of enzalutamide as a hard gelatin capsule. Further, the present invention discloses the process for preparing the same. The present invention provides an economical and advanced dosage form over an existing dosage form.
  • Enzalutamide is non-steroidal anti-androgen (NSAA) agent used in the treatment of patients with metastatic castration-resistant prostate cancer. Structurally, enzalutamide is represented as below:
  • Enzalutamide is disclosed in US patent no. 7709517 and is marketed under the brand name of XTANDI ® , which is a liquid-filled soft gelatin capsule for oral administration.
  • the recommended dose of enzalutamide is 160 mg, which should be administered in the form of four capsules of 40 mg, daily.
  • Each capsule contains enzalutamide dissolved in the solvent Labrasol ® ALF, which is reported to contain caprylocaproyl macrogol-8 glycerides (caprylocaproyl polyoxyl-8 glycerides).
  • Labrasol ® ALF solvent
  • caprylocaproyl macrogol-8 glycerides caprylocaproyl polyoxyl-8 glycerides
  • Prostate cancer is reported to grow slowly and can, if detected in an early stadium, be cured by the radical removal of the prostate. However, if not detected early prostate cancer can progress and result in an aggressive prostate cancer and the cancer cells may metastasize to other parts of the body and thus affect vitally important other organs, such the lymph nodes, lungs, bones and the gastrointestinal tract. A possible handling of the disease depends on several individual conditions, such as age, general health, the extent of the cancer and possible metastasis. Thus, the decision whether or not to treat localized prostate cancer with a curative intent is a personal patient trade-off between the expected beneficial and harmful effects in terms of patient survival and the maintenance of a certain quality of life. According to the USFDA, XTANDI ® is a liquid-filled soft gelatin capsule for oral administration comprising enzalutamide. The dosage form is reported to be used for the treatment of patients with metastatic castration- resistant prostate cancer.
  • the dosage form is a capsule, preferably a soft gelatin capsule.
  • PCT publication no. WO 2014/043208 claims a formulation of enzalutamide that contains a spray dried particulate dispersion. Particulate dispersion having diameter of less than 50 ⁇ , are compressed to form a tablet followed by encapsulation of the same.
  • PCT publication no. WO 2015/049650 exemplifies hard gelatin capsule formulation of enzalutamide and optionally in combination with afuresertib. This combination is used in the treatment of cancer.
  • PCT publication no. WO 2014/0378517 reveals a solid dispersion containing formulation to improve solubility and absorption of enzalutamide.
  • the above mentioned invention also discloses that formulation and its method of preparation preferably in the form of tablet. This formulation has rapidly disintegrating property that leads to improvisation of bioavailability by providing the entire daily therapeutic dose of enzalutamide in a single dosage unit.
  • XTANDI ® Present dose of XTANDI ® is 160 mg, and it is administered orally once daily in the form of four capsules each containing 40 mg of active pharmaceutical ingredient, wherein the administration of XTANDI ® is reported to be independent of food uptake.
  • Each capsule contains 40 mg of enzalutamide as a solution, wherein the active pharmaceutical ingredient is dissolved in the solvent Labrasol ® ALF.
  • the Labrasol ® ALF has certain disadvantages since it is used in higher amount.
  • the capsules are reported to be very big due to the higher quantity of Labrasol ® ALF necessary to keep the active pharmaceutical ingredient in solution. Due to its big size and the more number of capsules that has to be taken, this dosage form is difficult to swallow, in particular for older men.
  • Enzalutamide formulation is available in soft gelatin capsule.
  • the present invention discloses a method of manufacturing hard gelatin capsule, which makes manufacturing at commercial scale economic and uncomplicated. It uses reduced quantity of Labrasol ® ALF compared to the existing prior arts. Therefore, it is significantly advanced technically and provides economic improvement over existing prior arts. Further, in existing prior art IIG limit for Labrasol ® ALF is not within range of recommended daily dose by USFDA. This problem is also solved in the present invention, which uses Labrasol ® ALF within IIG limit range.
  • the present invention uses much lesser quantity of Labrasol ® ALF, which is around thirty times lesser as compared to the innovator's product. Therefore, toxicity or side effects associated with Labrasol ® ALF are decreased as well.
  • enzalutamide is adsorbed on the surface of the lactose particles along with the Labrasol ® ALF that provides higher surface area by the simple mixing of the active ingredients and excipients. Solubility of the active ingredient is increased.
  • the present invention resulted in achieving good dissolution profile with minimum use of excipients.
  • the stability of active ingredients in the liquid forms is generally considered less as compared to in the solid form. Stability of dosage forms as per present invention is observed higher than compared to prior art inventions.
  • Soft gelatin capsules pose manufacturing challenges, where in particular, temperature and humidity have to be maintained and such formulations need dedicated manufacturing system.
  • Soft gelatin capsules need special handling procedures during manufacturing, packaging and transporting the material, which makes the entire process more complicated and less economical.
  • Manufacturing of hard gelatin capsules is simpler, easier and more conventional.
  • the primary object of the present invention is to provide to novel oral dosage formulation of enzalutamide as a hard gelatin capsule.
  • Another object of the present invention is to provide an economical and advanced dosage form over existing dosage form.
  • Yet another object of the present invention is to provide formulation of enzalutamide with very less quantity of Labrasol ® ALF.
  • the present invention discloses novel compositions of enzalutamide preferably in hard gelatin capsule dosage form with pharmaceutically acceptable excipients and method of preparation thereof.
  • Enzalutamide is dissolved in the mixture of acetone and Labrasol ® ALF.
  • Labrasol ® ALF improves the solubility and wettability of active pharmaceutical ingredients in-vitro and in-vivo.
  • the solution containing Labrasol ® ALF and enzalutamide is sprayed on lactose anhydrous for surface adsorption during the granulation stage.
  • Granulation is done by using fluidized bed process (FBP) or rapid mixing granulating method (RMG) or any other suitable granulating methods.
  • FBP fluidized bed process
  • RMG rapid mixing granulating method
  • acetone is evaporated in the drying stage of granulation, completing granulation process.
  • Prepared granules are lubricated by microcrystalline cellulose (MCC) and Aerosil ® 200 in the blender and are filled in a capsule.
  • MMC microcrystalline cellulose
  • Aerosil ® 200 in the blender and are filled in a capsule.
  • Hard gelatin capsule formulation of enzalutamide obtained in such a way exhibits superior performance with respect to dissolution data as well as product stability.
  • Figure-1 shows a comparison graph of Enzalutamide dissolution from XTA DI ® (Reference product) and Enzalutamide compositions of the present invention (test);
  • Figure-2 shows a Powder X-Ray diffraction pattern of API Enzalutamide (1) and treated Enzalutamide according to the present invention (2);
  • Figure-3 shows DSC of API Enzalutamide (1) and treated Enzalutamide (2).
  • Enzalutamide is a small molecule with no ionizable groups at biologically relevant pH; therefore, enzalutamide solubility is not affected by pH over the physiological range.
  • Enzalutamide exhibits limited aqueous solubility (2.0 ⁇ g/mL at 1 to 7 pH range), high permeability across CACO-2 monolayers (mean apparent permeability coefficient (31 x 10 "6 cm/sec), and is not a substrate for P-glycoprotein. As it is having low solubility and high permeability, enzalutamide is considered a Biopharmaceutics Classification System (BCS) Class 2 drug substance.
  • BCS Biopharmaceutics Classification System
  • a novel pharmaceutical composition comprising hard gelatin capsule comprising the enzalutamide as an active ingredient and one or more excipients including carriers, surfactants, diluents, disintegrants, binders, lubricants, glidants and solubilizers, but not limited thereof.
  • the novel pharmaceutical composition of enzalutamide oral dosage form of hard gelatin capsule dosage comprises a shell as hard gelatin and a fill matrix comprises the pre-adsorbed enzalutamide mixed or complexed with excipients.
  • the pharmaceutical composition of the present invention comprises enzalutamide in the dosage form in range from 3% w/w to 25%.
  • excipients of hard gelatin capsules are divided in three parts according to their uses in the manufacturing process (A) intra-granular excipients, (B) excipients used in binder solution, and (C) extra-granular ingredients but not limited thereof.
  • A intra-granular excipients
  • B excipients used in binder solution
  • C extra-granular ingredients but not limited thereof.
  • excipients with their ranges are shown below in table:
  • diluents may be selected from the group consisting of cellulose, cellulose acetate, dextrates, dextrin, dextrose, fructose, 1-O-a-D-glucopyranosyl-D- mannitol, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, lactitol, lactose, lactose monohydrate, maltol, mannitol, maltodextrin, maltose, pregelatinized starch, sodium chloride, sorbitol, starches, sucrose, talc and xylitol or a mixture of one or more of said diluents.
  • Surfactants are used for modulating solubility and bioavailability of APIs and increase the stability of active ingredient in the dosage forms.
  • surfactants may be selected from the group consisting of sodium lauryl sulphate, cetyl trimethylammonium bromide (CTAB) / hexadecyltrimethylammonium bromide, caprylocaproyl macrogol-8 glycerides EP (Labrasol ® ALF) or a mixture of one or more of said surfactants.
  • Disintegrants used for the preparation of solid oral dosage form are selected from the group consisting of carboxymethylcellulose, low substituted hydroxypropyl cellulose, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, methylcellulose, polacrilin potassium, sodium alginate and sodium starch glycolate or a mixture of one or more of the said disintegranting agents.
  • Lubricants may be selected from the group consisting of calcium stearate, glyceryl palmitostearate, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate and magnesium stearate and the like or a mixture of one or more of said lubricants.
  • the binders may be selected from the group consisting of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, methylcellulose, gum Arabic, and the like or a mixture thereof.
  • Glidants if used, may be selected from the group consisting of colloidal silica, hydrophobic colloidal silica, magnesium trisilicate, talc and the like or a mixture thereof; preferably, the glidants are selected from the group consisting of colloidal silica.
  • Solvents may be selected from the group consisting of short chain alcohols, long chain alcohols, acetone, methylene dichloride (MDC) and the like or a mixture thereof.
  • quantity of Labrasol ® ALF is used preferably in the range of 2-24%, which is much lesser as compared to the innovator's product. Therefore, toxicity or side effects associated with Labrasol ® ALF are significantly decreased.
  • enzalutamide is adsorbed on the surface of the lactose particles along with the Labrasol ® ALF which provides higher surface area by the simple mixing of the active ingredients and excipients. Therefore, solubility of the active ingredient is increased.
  • the present invention resulted in achieving good dissolution profile with minimum use of excipients.
  • the stability of active ingredients in the liquid forms is less as compared to in the solid form. As a result, stability of dosage forms of the present invention is quite higher.
  • Another embodiment of the present invention represents the solid pharmaceutical composition of enzalutamide, wherein the unit dosage form of said hard gelatin capsule contains the active ingredient in an amount of from 20 mg to 320 mg, preferably contains the enzalutamide in an amount of from 40 mg to 160 mg.
  • the present invention also discloses method of manufacturing the hard gelatin capsule of enzalutamide. Further, the present invention discloses enhancement of solubility of enzalutamide by adsorption of the drug substance on particles of lactose anhydrous, which is a hydrophilic excipient.
  • Lactose anhydrous is sifted using 20# sieve and transferred to a fluid bed processor or rapid mixer granulator or any other suitable granulator.
  • Enzalutamide is added slowly to the mixture of Labrasol ® ALF and solvent, in which solvent is selected from short chain and long chain alcohols, acetone and methylene di chloride (MDC) preferably acetone with continuous stirring till solution become clear.
  • solvent selected from short chain and long chain alcohols, acetone and methylene di chloride (MDC) preferably acetone with continuous stirring till solution become clear.
  • MDC methylene di chloride
  • MCC and Aerosil ® 200 are sifted from 40# sieve. Granules are lubricated in a blender with sifted MCC and Aerosil ® 200. (e) Filling of Capsule
  • FBP Fluidized Bed Processor
  • Binder solution was prepared by dissolving enzalutamide in the mixture of Acetone and Labrasol ® ALF solution.
  • Granulation was done of lactose anhydrous with binder solution in FBP.
  • Granules were dried in FBP.
  • Granules were sifted after drying from 20# sieve. Then after, granules were lubricated with Aerosil ® 200 and microcrystalline cellulose (MCC PH 200). *Acetone does not retain in significant amount in the finished formulation.
  • FBP Fluidized Bed Processor
  • Binder solution was prepared by dissolving BHT in the mixture of Acetone and Labrasol ® ALF solution and enzalutamide was added in this solution and stirred till solution became clear.
  • Granulation was done of lactose anhydrous with binder solution in FBP.
  • Granules were dried in FBP.
  • Granules were sifted after drying from 20# sieve. Then, granules were lubricated with Aerosil ® 200 and microcrystalline cellulose (MCC PH 200). *Acetone does not retain in significant amount in the finished formulation.
  • FBP Fluidized Bed Processor
  • Binder solution was prepared by dissolving enzalutamide in the mixture of Acetone and Labrasol ® ALF followed by stirring until the solution became clear.
  • Granulation was done of lactose anhydrous with binder solution in FBP.
  • Granules were dried in FBP.
  • Granules were sifted after drying from 20# sieve. Then, granules were lubricated with CTAB and Aerosil ® 200. *Acetone does not retain in significant amount in the finished formulation.
  • FBP Fluidized Bed Processor
  • Binder solution was prepared by dissolving PVPK 30 in ethanol and enzalutamide in Labrasol ® ALF solution. Mixed both solutions and stirred till solution became clear.
  • Granulation was done of lactose anhydrous with binder solution in FBP.
  • Granules were dried in FBP.
  • Granules were sifted after drying from 20# sieve. Then, granules were lubricated with CTAB. *Ethanol does not retain in significant amount in the finished formulation.
  • Binder solution was prepared by dissolving PVPK 30 in ethanol and enzalutamide in Labrasol ® ALF solution. Mixed both solutions and stirred till solution became clear. Granulation was done of dry mixture with binder solution in FBP. Granules were dried in FBP. Granules were sifted after drying from 20# sieve. Then, granules were lubricated with CTAB. *Ethanol does not retain in significant amount in the finished formulation.
  • FBP Fluidized Bed Processor
  • Binder solution was prepared by dissolving PVP K30 and CTAB in ethanol and enzalutamide in acetone. Mixed both solutions and stirred till solution became clear.
  • Granulation was done of dry mixture with binder solution in FBP.
  • Granules were dried in FBP.
  • Granules were sifted after drying from 20# sieve. Then, granules were lubricated with sodium lauryl sulphate, magnesium stearate and CTAB.
  • FBP Fluidized Bed Processor
  • Binder solution was prepared by dissolving PVPK 30 and CTAB in ethanol and enzalutamide in acetone. Mixed both solutions and stirred till solution became clear.
  • Granulation was done of dry mixture with binder solution in FBP.
  • Granules were dried in FBP.
  • Granules were sifted after drying from 20# sieve. Then, granules were lubricated with sodium lauryl sulphate and magnesium stearate.
  • Aerosil ® 200 9.0 mg
  • Previously sifted lactose monohydrate, crospovidone, Aerosil 200 and microcrystalline cellulose (MCC PH 101) from 20# sieve were placed in FBP (Fluidized Bed Processor). Binder solution was prepared by dissolving PVP K25 in ethanol and enzalutamide in acetone. Mixed both solutions and stirred till solution became clear. Granulation was done of dry mixture with binder solution in FBP. Granules were dried in FBP. Granules were sifted after drying from 20# sieve. Then after, granules were lubricated with sodium lauryl sulphate and magnesium stearate.
  • FBP Fluidized Bed Processor
  • Previously sifted lactose monohydrate, crospovidone and microcrystalline cellulose (MCC PH 101) from 20# sieve were placed in FBP (Fluidized Bed Processor).
  • Binder solution was prepared by dissolving PVP K25 in ethanol and enzalutamide in acetone. Mixed both solutions and stirred till solution became clear.
  • Granulation was done of dry mixture with binder solution in FBP.
  • Granules were dried in FBP.
  • Granules were sifted after drying from 20# sieve. Then after, granules were lubricated with sodium lauryl sulphate and magnesium stearate.
  • Previously sifted lactose monohydrate, crospovidone and microcrystalline cellulose (MCC PH 101) from 20# sieve were placed in FBP (Fluidized Bed Processor).
  • Binder solution was prepared by dissolving PVP K25 in ethanol and enzalutamide in acetone. Mixed both solutions and stirred till solution became clear.
  • Granulation was done of dry mixture with binder solution in FBP.
  • Granules were dried in FBP.
  • Granules were sifted after drying from 20# sieve. Then, granules were lubricated with crospovidone and magnesium stearate.
  • FBP Fluidized Bed Processor
  • Binder solution was prepared by dissolving enzalutamide in acetone and Labrasol ® ALF. Granulation was done of dry mixture with binder solution in FBP. Granules were dried in FBP. Granules were sifted after drying from 20# sieve. Then, granules were lubricated with Aerosil ® 200 and CTAB. * Acetone does not retain
  • enzalutamide of 80 mg and 160 mg exhibited similar dissolution profile as described in the table 14 and 15.
  • Experiments with increase in concentration of Labrasol ® ALF at a level from 30 mg to 120 mg are also under the scope of this invention.
  • the later inventions largely meet the patient compliance and avoid the exposure of patients to additional amount of Labrasol ® ALF and other excipients at higher levels.
  • Lactose anhydrous, sifted from 20# sieve was placed in FBP (Fluidized Bed Processor). Binder solution was prepared by dissolving enzalutamide in the mixture of Acetone and Labrasol ® ALF. Granulation was done of lactose anhydrous with binder solution in FBP. Granules were dried in FBP. Granules were sifted after drying from 20# sieve. Then, granules were lubricated with Aerosil ® 200 and microcrystalline cellulose PH 102. * Acetone does not retain in significant amount in the finished formulation.
  • FBP Fluidized Bed Processor
  • Lactose anhydrous, sifted from 20# sieve was placed in FBP (Fluidized Bed Processor). Binder solution was prepared by dissolving enzalutamide in the mixture of Acetone and Labrasol ® ALF. Granulation was done of lactose anhydrous with binder solution in FBP. Granules were dried in FBP. Granules were sifted after drying from 20# sieve. Then, granules were lubricated with Aerosil ® 200 and microcrystalline cellulose PH 102. * Acetone does not retain in significant amount in the finished formulation.
  • FBP Fluidized Bed Processor
  • Comparative dissolution profile of the product of present invention with a reference product was studied.
  • Dissolution study of the pharmaceutical dosage the present invention was carried out by FIPLC.
  • Dissolution profile of the pharmaceutical dosage form as per the present invention was carried out using USP apparatus type II (paddle) with sinker.
  • CTAB cetyltrimethyl ammonium bromide
  • Dissolution media was prepared by adding 8.5 ml concentrated HC1 into 1000 ml of water. In this solution, 3.0 g of CTAB was dissolved and mixed well.
  • Standard solution was prepared by adding about 20 mg of enzalutamide into 50 ml volumetric flask. In that, 25 ml of ACN was dissolved and diluted with ACN to volume. From this solution, 2 ml of solution was transferred to a 100 ml volumetric flask and diluted with dissolution medium to volume. The standard solution was found stable at 25 °C for 27 h. Sample solution was prepared by adding a capsule of the present invention in 900 ml of dissolution medium. Further, 5 ml of this solution was diluted with 25 ml of dissolution medium. The sample solution was observed stable at 25 °C for 27 h.
  • Test samples were collected for analysis under chromatographic conditions by using X-Terra RP 18 (150 mm x 4.6 mm, 3.5 ⁇ ) column at a flow rate of 1 ml/min at column temperature of 25 °C of the injection volume 10 ⁇ and run time of 10 min. Dissolution media was separately injected in equal volume as blank and standard preparation in six replicates and test preparation into the chromatograph. Chromatograms were recorded and responses were measured for major peaks.
  • Dissolution profile of the pharmaceutical dosage form as per the present invention was compared with the reference product. Release rate for both above said formulations was compared ( Figure- 1) at the below mentioned time intervals.
  • the pharmaceutical dosage form prepared as per the present invention studied for its stability under accelerated stability analysis conditions. It was found to be adequately stable, as per general stability requirement under accelerated conditions.

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Abstract

The present invention relates to novel composition of oral dosage forms of enzalutamide with pharmaceutically acceptable excipients and method of manufacturing thereof. The invention provides economical and advanced dosage form.

Description

NOVEL COMPOSITION OF ENZALUTAMIDE ORAL DOSAGE FORM AND
METHOD OF MANUFACTURING THEREOF
FIELD OF THE INVENTION:
The present invention relates to novel oral dosage composition of enzalutamide as a hard gelatin capsule. Further, the present invention discloses the process for preparing the same. The present invention provides an economical and advanced dosage form over an existing dosage form.
BACKGROUND OF THE INVENTION:
Enzalutamide is non-steroidal anti-androgen (NSAA) agent used in the treatment of patients with metastatic castration-resistant prostate cancer. Structurally, enzalutamide is represented as below:
Figure imgf000003_0001
ENZALUTAMIDE
Enzalutamide is disclosed in US patent no. 7709517 and is marketed under the brand name of XTANDI®, which is a liquid-filled soft gelatin capsule for oral administration. The recommended dose of enzalutamide is 160 mg, which should be administered in the form of four capsules of 40 mg, daily. Each capsule contains enzalutamide dissolved in the solvent Labrasol® ALF, which is reported to contain caprylocaproyl macrogol-8 glycerides (caprylocaproyl polyoxyl-8 glycerides). With daily dosing regimen, steady state of enzalutamide is achieved after 28 days. Prostate cancer is a common cancer in men, especially in the US and in Europe. Prostate cancer is reported to grow slowly and can, if detected in an early stadium, be cured by the radical removal of the prostate. However, if not detected early prostate cancer can progress and result in an aggressive prostate cancer and the cancer cells may metastasize to other parts of the body and thus affect vitally important other organs, such the lymph nodes, lungs, bones and the gastrointestinal tract. A possible handling of the disease depends on several individual conditions, such as age, general health, the extent of the cancer and possible metastasis. Thus, the decision whether or not to treat localized prostate cancer with a curative intent is a personal patient trade-off between the expected beneficial and harmful effects in terms of patient survival and the maintenance of a certain quality of life. According to the USFDA, XTANDI® is a liquid-filled soft gelatin capsule for oral administration comprising enzalutamide. The dosage form is reported to be used for the treatment of patients with metastatic castration- resistant prostate cancer.
PCT publication no. WO 2015/022349 discloses a formulation that contains enzalutamide in dissolved form. Further, invention uses a solvent that have HLB value responsible for forming water-in-oil type of emulsion. In preferred embodiment, the dosage form is a capsule, preferably a soft gelatin capsule.
PCT publication no. WO 2014/043208 claims a formulation of enzalutamide that contains a spray dried particulate dispersion. Particulate dispersion having diameter of less than 50 μπι, are compressed to form a tablet followed by encapsulation of the same. PCT publication no. WO 2015/049650 exemplifies hard gelatin capsule formulation of enzalutamide and optionally in combination with afuresertib. This combination is used in the treatment of cancer.
PCT publication no. WO 2014/0378517 reveals a solid dispersion containing formulation to improve solubility and absorption of enzalutamide. The above mentioned invention also discloses that formulation and its method of preparation preferably in the form of tablet. This formulation has rapidly disintegrating property that leads to improvisation of bioavailability by providing the entire daily therapeutic dose of enzalutamide in a single dosage unit.
Present dose of XTANDI® is 160 mg, and it is administered orally once daily in the form of four capsules each containing 40 mg of active pharmaceutical ingredient, wherein the administration of XTANDI® is reported to be independent of food uptake. Each capsule contains 40 mg of enzalutamide as a solution, wherein the active pharmaceutical ingredient is dissolved in the solvent Labrasol® ALF. The Labrasol® ALF has certain disadvantages since it is used in higher amount. The capsules are reported to be very big due to the higher quantity of Labrasol® ALF necessary to keep the active pharmaceutical ingredient in solution. Due to its big size and the more number of capsules that has to be taken, this dosage form is difficult to swallow, in particular for older men. This results in a poor patient compliance, especially in this important patient group. Enzalutamide formulation is available in soft gelatin capsule. The present invention discloses a method of manufacturing hard gelatin capsule, which makes manufacturing at commercial scale economic and uncomplicated. It uses reduced quantity of Labrasol® ALF compared to the existing prior arts. Therefore, it is significantly advanced technically and provides economic improvement over existing prior arts. Further, in existing prior art IIG limit for Labrasol® ALF is not within range of recommended daily dose by USFDA. This problem is also solved in the present invention, which uses Labrasol® ALF within IIG limit range.
The present invention uses much lesser quantity of Labrasol® ALF, which is around thirty times lesser as compared to the innovator's product. Therefore, toxicity or side effects associated with Labrasol® ALF are decreased as well. In present invention, enzalutamide is adsorbed on the surface of the lactose particles along with the Labrasol® ALF that provides higher surface area by the simple mixing of the active ingredients and excipients. Solubility of the active ingredient is increased. The present invention resulted in achieving good dissolution profile with minimum use of excipients. The stability of active ingredients in the liquid forms is generally considered less as compared to in the solid form. Stability of dosage forms as per present invention is observed higher than compared to prior art inventions.
Soft gelatin capsules pose manufacturing challenges, where in particular, temperature and humidity have to be maintained and such formulations need dedicated manufacturing system. Soft gelatin capsules need special handling procedures during manufacturing, packaging and transporting the material, which makes the entire process more complicated and less economical. Manufacturing of hard gelatin capsules, on the other hand, is simpler, easier and more conventional.
OBJECTIVE OF THE INVENTION
The primary object of the present invention is to provide to novel oral dosage formulation of enzalutamide as a hard gelatin capsule.
Another object of the present invention is to provide an economical and advanced dosage form over existing dosage form.
Yet another object of the present invention is to provide formulation of enzalutamide with very less quantity of Labrasol® ALF.
Yet another object of the present invention is to provide a process for preparation of oral dosage formulation of enzalutamide as a hard gelatin capsule. Yet another objective of the present invention is to provide enzalutamide oral dosage form with enhanced dissolution profile.
SUMMARY OF THE INVENTION
The present invention discloses novel compositions of enzalutamide preferably in hard gelatin capsule dosage form with pharmaceutically acceptable excipients and method of preparation thereof. Enzalutamide is dissolved in the mixture of acetone and Labrasol® ALF. Labrasol® ALF improves the solubility and wettability of active pharmaceutical ingredients in-vitro and in-vivo. The solution containing Labrasol® ALF and enzalutamide is sprayed on lactose anhydrous for surface adsorption during the granulation stage. Granulation is done by using fluidized bed process (FBP) or rapid mixing granulating method (RMG) or any other suitable granulating methods. The remaining acetone is evaporated in the drying stage of granulation, completing granulation process. Prepared granules are lubricated by microcrystalline cellulose (MCC) and Aerosil® 200 in the blender and are filled in a capsule. Hard gelatin capsule formulation of enzalutamide obtained in such a way exhibits superior performance with respect to dissolution data as well as product stability.
BRIEF DESCRIPTION OF THE DRAWINGS:
Figure-1: shows a comparison graph of Enzalutamide dissolution from XTA DI® (Reference product) and Enzalutamide compositions of the present invention (test);
Figure-2: shows a Powder X-Ray diffraction pattern of API Enzalutamide (1) and treated Enzalutamide according to the present invention (2);
Figure-3: shows DSC of API Enzalutamide (1) and treated Enzalutamide (2).
DETAILED DESCRIPTION OF THE INVENTION:
The present invention will now be disclosed by describing certain preferred and optional embodiments, to facilitate various aspects thereof.
Enzalutamide is a small molecule with no ionizable groups at biologically relevant pH; therefore, enzalutamide solubility is not affected by pH over the physiological range. Enzalutamide exhibits limited aqueous solubility (2.0 μg/mL at 1 to 7 pH range), high permeability across CACO-2 monolayers (mean apparent permeability coefficient (31 x 10"6 cm/sec), and is not a substrate for P-glycoprotein. As it is having low solubility and high permeability, enzalutamide is considered a Biopharmaceutics Classification System (BCS) Class 2 drug substance.
In accordance with the present invention, a novel pharmaceutical composition comprising hard gelatin capsule comprising the enzalutamide as an active ingredient and one or more excipients including carriers, surfactants, diluents, disintegrants, binders, lubricants, glidants and solubilizers, but not limited thereof.
The novel pharmaceutical composition of enzalutamide oral dosage form of hard gelatin capsule dosage comprises a shell as hard gelatin and a fill matrix comprises the pre-adsorbed enzalutamide mixed or complexed with excipients. The pharmaceutical composition of the present invention comprises enzalutamide in the dosage form in range from 3% w/w to 25%.
The excipients of hard gelatin capsules are divided in three parts according to their uses in the manufacturing process (A) intra-granular excipients, (B) excipients used in binder solution, and (C) extra-granular ingredients but not limited thereof. For the solid dosage composition of enzalutamide of the present invention, excipients with their ranges are shown below in table:
1. Related practical data with different percentages of excipients range.
A) Excipient used in intra-granular part:
Figure imgf000007_0001
Sr. No. Name Range
8. Sorbitol powder 58% -75%
9. Tween 80 6% - 25 %
10. Cetyl trimethylammonium bromide 1% - 6% (CTAB)
11. Caprylocaproyl macrogol-8 glycendes EP 2% - 60% (Labrasol® ALF)
12. Poly vinyl pyrollidone K-30 3% -6% sed in binder preparation:
Figure imgf000008_0001
C) Excipients used in extra-granular part:
Figure imgf000009_0001
The excipients used as listed in above tables are only indicative and are not limited to thereof. In further aspect of present invention diluents may be selected from the group consisting of cellulose, cellulose acetate, dextrates, dextrin, dextrose, fructose, 1-O-a-D-glucopyranosyl-D- mannitol, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, lactitol, lactose, lactose monohydrate, maltol, mannitol, maltodextrin, maltose, pregelatinized starch, sodium chloride, sorbitol, starches, sucrose, talc and xylitol or a mixture of one or more of said diluents. Surfactants are used for modulating solubility and bioavailability of APIs and increase the stability of active ingredient in the dosage forms. In the present invention, surfactants may be selected from the group consisting of sodium lauryl sulphate, cetyl trimethylammonium bromide (CTAB) / hexadecyltrimethylammonium bromide, caprylocaproyl macrogol-8 glycerides EP (Labrasol® ALF) or a mixture of one or more of said surfactants. Disintegrants used for the preparation of solid oral dosage form are selected from the group consisting of carboxymethylcellulose, low substituted hydroxypropyl cellulose, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, methylcellulose, polacrilin potassium, sodium alginate and sodium starch glycolate or a mixture of one or more of the said disintegranting agents.
Lubricants may be selected from the group consisting of calcium stearate, glyceryl palmitostearate, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate and magnesium stearate and the like or a mixture of one or more of said lubricants.
The binders may be selected from the group consisting of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, methylcellulose, gum Arabic, and the like or a mixture thereof. Glidants, if used, may be selected from the group consisting of colloidal silica, hydrophobic colloidal silica, magnesium trisilicate, talc and the like or a mixture thereof; preferably, the glidants are selected from the group consisting of colloidal silica.
Solvents may be selected from the group consisting of short chain alcohols, long chain alcohols, acetone, methylene dichloride (MDC) and the like or a mixture thereof. In the present invention, quantity of Labrasol® ALF is used preferably in the range of 2-24%, which is much lesser as compared to the innovator's product. Therefore, toxicity or side effects associated with Labrasol® ALF are significantly decreased. In present invention, enzalutamide is adsorbed on the surface of the lactose particles along with the Labrasol® ALF which provides higher surface area by the simple mixing of the active ingredients and excipients. Therefore, solubility of the active ingredient is increased. The present invention resulted in achieving good dissolution profile with minimum use of excipients. The stability of active ingredients in the liquid forms is less as compared to in the solid form. As a result, stability of dosage forms of the present invention is quite higher.
Another embodiment of the present invention represents the solid pharmaceutical composition of enzalutamide, wherein the unit dosage form of said hard gelatin capsule contains the active ingredient in an amount of from 20 mg to 320 mg, preferably contains the enzalutamide in an amount of from 40 mg to 160 mg.
The present invention also discloses method of manufacturing the hard gelatin capsule of enzalutamide. Further, the present invention discloses enhancement of solubility of enzalutamide by adsorption of the drug substance on particles of lactose anhydrous, which is a hydrophilic excipient.
The method of the preparation of hard gelatin capsule of enzalutamide is divided in different steps as following: (a) Sifting
Lactose anhydrous is sifted using 20# sieve and transferred to a fluid bed processor or rapid mixer granulator or any other suitable granulator.
(b) Binder solution preparation
Enzalutamide is added slowly to the mixture of Labrasol® ALF and solvent, in which solvent is selected from short chain and long chain alcohols, acetone and methylene di chloride (MDC) preferably acetone with continuous stirring till solution become clear. Prepared solution is stirred for 5 to 15 minutes preferably 10 minutes on a stirrer.
(c) Granulation, Drying and Sizing
During the granulation stage, spraying of binder solution prepared in stage (b) is sprayed on the lactose anhydrous in a fluidized bed processor (FBP) at 30-60°C or spraying the binder solution on lactose anhydrous of step a) in rapid mixer granulator (RMG) at slower speed of impeller followed by slower speed of chopper. Top spray technique is used for the spraying method in the FBP. After completing, the said process granules are dried in the fluidized bed processor at inlet air temperature 45 to 65°C and product temperature at around 30 to 60°C till loss on drying (LOD) of blend reaches to less than 2.5% W/W at 105°C. Solvent is evaporated during the drying stage. Dried granules are sifted through sieve 20# or 30# or 40#, preferably sieve 20#.
(d) Lubrication
MCC and Aerosil® 200 are sifted from 40# sieve. Granules are lubricated in a blender with sifted MCC and Aerosil® 200. (e) Filling of Capsule
Above prepared granules are filled in capsules (size "00") as per target fill weight.
The invention will be further described with respect to the following examples; however, the scope of the invention is not limited thereby. All percentages stated in this specification are by weight, unless otherwise specified. EXAMPLES:
Example: 1 Enzalutamide formulation preparation 1
Table: 1 Enzalutamide capsule formula: 1
Ingredients Quantity per Capsule
Intra-granular
Lactose anhydrous 507.0 mg
Binder solution
Enzalutamide 40.0 mg
Acetone* 0.1 ml
Labrasol® ALF 30.0 mg
Extra-granular
Aerosil® 200 7.5 mg
MCC PH 200 57.5 mg
Total Weight 642.0 mg
Previously sifted lactose anhydrous from 20# sieve was placed in FBP (Fluidized Bed Processor). Binder solution was prepared by dissolving enzalutamide in the mixture of Acetone and Labrasol® ALF solution. Granulation was done of lactose anhydrous with binder solution in FBP. Granules were dried in FBP. Granules were sifted after drying from 20# sieve. Then after, granules were lubricated with Aerosil® 200 and microcrystalline cellulose (MCC PH 200). *Acetone does not retain in significant amount in the finished formulation.
Example: 2 Enzalutamide formulation preparation 2
Table: 2 Enzalutamide capsule formula: 2
Ingredients Quantity per Capsule
Intra-granular
Lactose anhydrous 507.0 mg
Binder solution
Enzalutamide 40.0 mg
Acetone* 0.1 ml
Labrasol® ALF 30.0 mg
BHT 0.3 mg Extra-granular
Aerosil® 200 25.0 mg
CTAB 40.0 mg
Total Weight 642
Previously sifted lactose anhydrous from 20# sieve was placed in FBP (Fluidized Bed Processor). Binder solution was prepared by dissolving BHT in the mixture of Acetone and Labrasol® ALF solution and enzalutamide was added in this solution and stirred till solution became clear. Granulation was done of lactose anhydrous with binder solution in FBP. Granules were dried in FBP. Granules were sifted after drying from 20# sieve. Then, granules were lubricated with Aerosil® 200 and microcrystalline cellulose (MCC PH 200). *Acetone does not retain in significant amount in the finished formulation.
Example: 3 Enzalutamide formulation preparation 3
Table: 3 Enzalutamide capsule formula: 3
Ingredients Quantity per Capsule
Intra-granular
Lactose anhydrous 418.0 mg
Binder solution
Enzalutamide 40.0 mg
Acetone* 0.1 ml
Labrasol® ALF 120.0 mg
Extra-granular
CTAB 40.0 mg
Total Weight 618.0 mg
Previously sifted lactose anhydrous from 20# sieve was placed in FBP (Fluidized Bed Processor). Binder solution was prepared by dissolving enzalutamide in the mixture of Acetone and Labrasol® ALF followed by stirring until the solution became clear. Granulation was done of lactose anhydrous with binder solution in FBP. Granules were dried in FBP. Granules were sifted after drying from 20# sieve. Then after, granules were lubricated with CTAB. * Acetone does not retain in significant amount in the finished formulation. Example: 4 Enzalutamide formulation preparation 4
Table: 4 Enzalutamide capsule formula: 4
Ingredients Quantity per Capsule
Intra-granular
Lactose anhydrous 358.0 mg
Binder solution
Enzalutamide 40.0 mg
Acetone* 0.1 ml
Labrasol® ALF 130.0 mg
Extra-granular
Aerosil®200 50.0 mg
CTAB 40.0 mg
Total Weight 618.0 mg
Previously sifted lactose anhydrous from 20# sieve was placed in FBP (Fluidized Bed Processor). Binder solution was prepared by dissolving enzalutamide in the mixture of Acetone and Labrasol® ALF followed by stirring until the solution became clear. Granulation was done of lactose anhydrous with binder solution in FBP. Granules were dried in FBP. Granules were sifted after drying from 20# sieve. Then, granules were lubricated with CTAB and Aerosil® 200. *Acetone does not retain in significant amount in the finished formulation.
Example: 5 Enzalutamide Formulation preparation 5
Table: 5 Enzalutamide capsule formula: 5
Ingredients Quantity per Capsule
Intra-granular
Lactose anhydrous 418.0 mg
Binder solution
Enzalutamide 40.0 mg
PVP K30 80.0 mg
Labrasol® ALF 40.0 mg
Ethanol* 0.150 ml Extra-granular
CTAB 40.0 mg
Total Weight 618.0 mg
Previously sifted lactose anhydrous from 20# sieve was placed in FBP (Fluidized Bed Processor). Binder solution was prepared by dissolving PVPK 30 in ethanol and enzalutamide in Labrasol® ALF solution. Mixed both solutions and stirred till solution became clear. Granulation was done of lactose anhydrous with binder solution in FBP. Granules were dried in FBP. Granules were sifted after drying from 20# sieve. Then, granules were lubricated with CTAB. *Ethanol does not retain in significant amount in the finished formulation.
Example: 6 Enzalutamide formulation preparation 6
Enzalutamide capsule formula: 6
Ingredients Quantity per Capsule
Intra-granular
Sorbitol 378.0 mg
Tween 80 40.0 mg
Binder solution
Enzalutamide 40.0 mg
Labrasol® ALF 30.0 mg
PVP K30 120.0 mg
Ethanol* 0.150 ml
Extra-granular
CTAB 40.0 mg
Total Weight 648
Previously sifted sorbitol and Tween 80 were placed in FBP (Fluidized Bed Processor). Binder solution was prepared by dissolving PVPK 30 in ethanol and enzalutamide in Labrasol® ALF solution. Mixed both solutions and stirred till solution became clear. Granulation was done of dry mixture with binder solution in FBP. Granules were dried in FBP. Granules were sifted after drying from 20# sieve. Then, granules were lubricated with CTAB. *Ethanol does not retain in significant amount in the finished formulation. Example: 7 Enzalutamide formulation preparation 7
Enzalutamide capsule formula: 7
Ingredients Quantity per Capsule
Intra-granular
Lactose monohydrate 309.0 mg
Crospovidone 36.0 mg
HPMC 3 CPS 151.0 mg
Binder solution
Enzalutamide 40.0 mg
PVP K30 42.0 mg
Acetone* 0.150 ml
Ethanol* 0.600 ml
CTAB 20.0 mg
Extra-granular
Sodium lauryl sulfate 14.0 mg
Magnesium stearate 5.0 mg
CTAB 20.0 mg
Total Weight 637.0 mg
Previously sifted lactose monohydrate, crospovidone and HPMC 3 CPS from 20# sieve were placed in FBP (Fluidized Bed Processor). Binder solution was prepared by dissolving PVP K30 and CTAB in ethanol and enzalutamide in acetone. Mixed both solutions and stirred till solution became clear. Granulation was done of dry mixture with binder solution in FBP. Granules were dried in FBP. Granules were sifted after drying from 20# sieve. Then, granules were lubricated with sodium lauryl sulphate, magnesium stearate and CTAB.
* Acetone and ethanol do not retain in significant amount in the finished formulation. Example: 8 Enzalutamide formulation preparation 8
Enzalutamide capsule formula: 8
Ingredients Quantity per Capsule
Intra-granular
Lactose monohydrate 309.0 mg
Crospovidone 36.0 mg
HPMC 3 CPS 151.0 mg
Binder solution
Enzalutamide 40.0 mg
PVP K30 42.0 mg
Acetone* 0.150 ml
Ethanol* 0.600 ml
CTAB 20.0 mg
Extra-granular
Sodium lauryl sulfate 14.0 mg
Magnesium stearate 5.0 mg
Total Weight 617.0 mg
Previously sifted lactose monohydrate, crospovidone and HPMC 3 CPS from 20# sieve were placed in FBP (Fluidized Bed Processor). Binder solution was prepared by dissolving PVPK 30 and CTAB in ethanol and enzalutamide in acetone. Mixed both solutions and stirred till solution became clear. Granulation was done of dry mixture with binder solution in FBP. Granules were dried in FBP. Granules were sifted after drying from 20# sieve. Then, granules were lubricated with sodium lauryl sulphate and magnesium stearate.
* Acetone and ethanol do not retain in significant amount in the finished formulation. Example: 9 Enzalutamide formulation preparation 9
Table: 9 Enzalutamide capsule formula: 9
Ingredients Quantity per Capsule
Intra-granular
Lactose monohydrate 420.0 mg
Crospovidone 36.0 mg
Aerosil® 200 9.0 mg
MCC PH 101 51.0 mg
Binder solution
Enzalutamide 40.0 mg
Acetone* 0.150 ml
Ethanol* 0.600 ml
PVP K25 42.0 mg
Extra-granular
Sodium lauryl sulfate 14.0 mg
Magnesium stearate 5.0 mg
Total Weight 617.0 mg
Previously sifted lactose monohydrate, crospovidone, Aerosil 200 and microcrystalline cellulose (MCC PH 101) from 20# sieve were placed in FBP (Fluidized Bed Processor). Binder solution was prepared by dissolving PVP K25 in ethanol and enzalutamide in acetone. Mixed both solutions and stirred till solution became clear. Granulation was done of dry mixture with binder solution in FBP. Granules were dried in FBP. Granules were sifted after drying from 20# sieve. Then after, granules were lubricated with sodium lauryl sulphate and magnesium stearate.
* Acetone and ethanol do not retain in significant amount in the finished formulation. Example: 10 Enzalutamide formulation preparation 10
Figure imgf000019_0001
Ingredients Quantity per Capsule
Intra-granular
Lactose monohydrate 439.0 mg
Crospovidone 36.0 mg
MCC PH 101 51.0 mg
Binder solution
Enzalutamide 40.0 mg
Acetone* 0.150 ml
Ethanol* 0.600 ml
PVP K25 42.0 mg
Extra-granular
Sodium lauryl sulfate 7.0 mg
Magnesium stearate 5.0 mg
Total Weight 620.0 mg
Previously sifted lactose monohydrate, crospovidone and microcrystalline cellulose (MCC PH 101) from 20# sieve were placed in FBP (Fluidized Bed Processor). Binder solution was prepared by dissolving PVP K25 in ethanol and enzalutamide in acetone. Mixed both solutions and stirred till solution became clear. Granulation was done of dry mixture with binder solution in FBP. Granules were dried in FBP. Granules were sifted after drying from 20# sieve. Then after, granules were lubricated with sodium lauryl sulphate and magnesium stearate.
* Acetone and ethanol do not retain in significant amount in the finished formulation.
Example: 11 Enzalutamide formulation preparation 11
Table: 11 Enzalutamide capsule formula: 11
Ingredients Quantity per Capsule
Intra-granular
Lactose monohydrate 446.0 mg
Crospovidone 27.0 mg
MCC PH 101 51.0 mg Binder solution
Enzalutamide 40.0 mg
PVP K25 42.0 mg
Ethanol* 0.150 ml
Acetone* 0.600 ml
Extra-granular
Crospovidone 9.0 mg
Magnesium stearate 5.0 mg
Total Weight 620.0 mg
Previously sifted lactose monohydrate, crospovidone and microcrystalline cellulose (MCC PH 101) from 20# sieve were placed in FBP (Fluidized Bed Processor). Binder solution was prepared by dissolving PVP K25 in ethanol and enzalutamide in acetone. Mixed both solutions and stirred till solution became clear. Granulation was done of dry mixture with binder solution in FBP. Granules were dried in FBP. Granules were sifted after drying from 20# sieve. Then, granules were lubricated with crospovidone and magnesium stearate.
* Acetone and ethanol do not retain in significant amount in the finished formulation.
Example: 12 Enzalutamide formulation preparation 12
Table: 12 Enzalutamide capsule formula: 12
Ingredients Quantity per Capsule
Intra-granular
Lactose anhydrous 495.0 mg
Binder solution
Enzalutamide 40.0 mg
Acetone* 0.1 ml
Labrasol® ALF 45.0 mg
Extra-granular
Aerosil® 200 25.0 mg
CTAB 40.0 mg
Total Weight 645.0 mg Lactose anhydrous, sifted from 20# sieve was placed in FBP (Fluidized Bed Processor). Binder solution was prepared by dissolving enzalutamide in acetone and Labrasol® ALF. Granulation was done of dry mixture with binder solution in FBP. Granules were dried in FBP. Granules were sifted after drying from 20# sieve. Then, granules were lubricated with Aerosil® 200 and CTAB. * Acetone does not retain in significant amount in the finished formulation.
Example: 13 Enzalutamide formulation preparation 13
Table: 13 Enzalutamide capsule formula: 13
Ingredients Quantity per Capsule
Intra-granular
Lactose anhydrous 510.0 mg Binder solution
Enzalutamide 40.0 mg
Acetone* 0.1 ml
Labrasol® ALF 30.0 mg
Extra-granular
Aerosil® 200 7.5 mg
Microcrystalline cellulose PH 102 57.5 mg
Total Weight 645.0 mg Lactose anhydrous, sifted from 20# sieve was placed in FBP (Fluidized Bed Processor). Binder solution was prepared by dissolving enzalutamide in the mixture of Acetone and Labrasol® ALF. Granulation was done of lactose anhydrous with binder solution in FBP. Granules were dried in FBP. Granules were sifted after drying from 20# sieve. Then, granules were lubricated with Aerosil® 200 and microcrystalline cellulose PH 102. * Acetone does not retain in significant amount in the finished formulation.
In another embodiment of the present invention, enzalutamide of 80 mg and 160 mg exhibited similar dissolution profile as described in the table 14 and 15. Experiments with increase in concentration of Labrasol® ALF at a level from 30 mg to 120 mg are also under the scope of this invention. The later inventions largely meet the patient compliance and avoid the exposure of patients to additional amount of Labrasol® ALF and other excipients at higher levels. Example: 14 Enzalutamide formulation preparation 14
Table: 14 Enzalutamide capsule formula: 14
Ingredients Quantity per Capsule
Intra-granular
Lactose anhydrous 510.0 mg Binder solution
Enzalutamide 80.0 mg
Acetone* 0.2 ml
Labrasol® ALF 30.0 mg
Extra-granular
Aerosil® 200 7.5 mg
Microcrystalline cellulose PH 102 57.5 mg
Total Weight 685.0 mg
Lactose anhydrous, sifted from 20# sieve was placed in FBP (Fluidized Bed Processor). Binder solution was prepared by dissolving enzalutamide in the mixture of Acetone and Labrasol® ALF. Granulation was done of lactose anhydrous with binder solution in FBP. Granules were dried in FBP. Granules were sifted after drying from 20# sieve. Then, granules were lubricated with Aerosil® 200 and microcrystalline cellulose PH 102. * Acetone does not retain in significant amount in the finished formulation.
Example: 15 Enzalutamide formulation preparation 15
Table: 15 Enzalutamide capsule formula: 15
Ingredients Quantity per Capsule
Intra-granular
Lactose anhydrous 480.0 mg
Binder solution
Enzalutamide 80.0 mg
Acetone* 0.2 ml
Labrasol® ALF 60.0 mg Extra-granular
Aerosil® 200 7.5 mg
Microcrystalline cellulose PH 102 57 5 mg
Total Weight 685 0 mg
Lactose anhydrous, sifted from 20# sieve was placed in FBP (Fluidized Bed Processor). Binder solution was prepared by dissolving enzalutamide in the mixture of Acetone and Labrasol® ALF. Granulation was done of lactose anhydrous with binder solution in FBP. Granules were dried in FBP. Granules were sifted after drying from 20# sieve. Then, granules were lubricated with Aerosil® 200 and microcrystalline cellulose PH 102. * Acetone does not retain in significant amount in the finished formulation.
The clinical studies reported for enzalutamide have exhibited the adverse reaction as largely attributed to the effects of Placebo to an extent of 20% of population. Converting the approved liquid filled soft gelatin to powder filled hard gelatin can increase the safety compliance aspect of treatment.
DISSOLUTION STUDY
Comparative dissolution profile of the product of present invention with a reference product (soft gelatin capsule) was studied. Dissolution study of the pharmaceutical dosage the present invention was carried out by FIPLC.
Dissolution profile of the pharmaceutical dosage form as per the present invention was carried out using USP apparatus type II (paddle) with sinker.
In this, 0.3% cetyltrimethyl ammonium bromide (CTAB) in 0.1 N HC1 of 900 ml was used as dissolution media at 50 RPM for 45 min of time duration at (37 ± 0.5) °C. In this acetonitrile (ACN), orthophosphoric acid and dihydrogen potassium phosphate were used as reagents.
Dissolution media was prepared by adding 8.5 ml concentrated HC1 into 1000 ml of water. In this solution, 3.0 g of CTAB was dissolved and mixed well.
Standard solution was prepared by adding about 20 mg of enzalutamide into 50 ml volumetric flask. In that, 25 ml of ACN was dissolved and diluted with ACN to volume. From this solution, 2 ml of solution was transferred to a 100 ml volumetric flask and diluted with dissolution medium to volume. The standard solution was found stable at 25 °C for 27 h. Sample solution was prepared by adding a capsule of the present invention in 900 ml of dissolution medium. Further, 5 ml of this solution was diluted with 25 ml of dissolution medium. The sample solution was observed stable at 25 °C for 27 h.
For preparation of buffer, 1.36 g of KH2PO4 was dissolved in 1000 ml water and pH was adjusted to 2.8 with orthophosphoric acid. Mobile Phase was prepared by adding above prepared buffer: ACN by 1 : 1 v/v.
Test samples were collected for analysis under chromatographic conditions by using X-Terra RP 18 (150 mm x 4.6 mm, 3.5 μιη) column at a flow rate of 1 ml/min at column temperature of 25 °C of the injection volume 10 μιη and run time of 10 min. Dissolution media was separately injected in equal volume as blank and standard preparation in six replicates and test preparation into the chromatograph. Chromatograms were recorded and responses were measured for major peaks.
Dissolution profile of the pharmaceutical dosage form as per the present invention was compared with the reference product. Release rate for both above said formulations was compared (Figure- 1) at the below mentioned time intervals.
Figure imgf000024_0001
Stability Data for the product of the present invention
The pharmaceutical dosage form prepared as per the present invention studied for its stability under accelerated stability analysis conditions. It was found to be adequately stable, as per general stability requirement under accelerated conditions.
Figure imgf000025_0001
The invention described herein comprises in various objects as mentioned above and their description in relation to characteristics, compositions and process adopted. While these aspects are emphasised in the invention, any variations of the invention described above are not to be regarded as departure from the spirit and scope of the invention as described.

Claims

Claim:
A novel pharmaceutical composition of enzalutamide oral dosage form comprising enzalutamide or pharmaceutically acceptable salt or polymorph or solvate or hydrate or complex thereof and one or more pharmaceutically acceptable excipients selected from carriers, surfactants, binders, diluents, disintegrants, glidants, lubricants and solubilizers.
The novel pharmaceutical composition of enzalutamide oral dosage form as claimed in claim
1, wherein the composition is solid dosage form selected from capsule, tablet, mups, powder, granules, pellets, preferably hard gelatin capsule.
The novel pharmaceutical composition of enzalutamide oral dosage form as claimed in claim
2, wherein the hard gelatin capsule dosage form comprising,
a) a shell as hard gelatin and
b) pre-adsorbed enzalutamide mixed or complexed with excipients.
The novel pharmaceutical composition of enzalutamide oral dosage form as claimed in claim
3, wherein the content of enzalutamide in the dosage form is in range from 3% w/w to 25% w/w.
The novel pharmaceutical composition of enzalutamide oral dosage form as claimed in claim 3, wherein the excipients are divided in three parts including (A) intra-granular excipients, (B) excipients used in binder solution, and (C) extra-granular excipients.
The novel pharmaceutical composition of enzalutamide oral dosage form as claimed in claim 3, wherein enzalutamide as a solution in pharmaceutically acceptable carrier along with one or more surfactant is adsorbed on the surface of the pharmaceutically acceptable excipients.
The novel pharmaceutical composition of enzalutamide oral dosage form as claimed in claim 6, wherein pharmaceutically acceptable carrier is organic solvent and pharmaceutically acceptable excipient is hydrophilic excipient selected from lactose anhydrous, lactose monohydrate, mannitol, sorbitol, sucrose; preferably lactose anhydrous.
8. The novel pharmaceutical composition of enzalutamide oral dosage form as claimed in claim 6, wherein the surfactant is selected from sodium lauryl sulphate, cetyl trimethylammonium bromide (CTAB), caprylocaproyl macrogol-8 glycerides/ caprylocaproyl polyoxyl-8 glycerides (Labrasol® ALF), benzalkonium chloride but not poloxamer.
9. The novel pharmaceutical composition of enzalutamide oral dosage form as claimed in claim 1-3, wherein the dosage form is showing a dissolution of at least 70%, preferably 80%, after 10 minutes, determined according to USP type II paddle, with 0.3% CTAB in 0.1 N HC1 as dissolution media.
10. The novel pharmaceutical composition of enzalutamide oral dosage form as claimed in claim 1-3, wherein the dosage strength of the formulation is 40 mg or 80 mg or 160 mg per capsule.
11. A process for preparation of a novel pharmaceutical composition of enzalutamide oral dosage form comprising the following steps:
(1) Sifting:
a) Sifting of lactose anhydrous using 20# sieve and transferring to a fluid bed processor (FBP) or rapid mixer granulator or any other suitable granulator.
(2) Preparation of binder solution:
b) Addition of enzalutamide slowly to mixture of surfactant and solvent, in which solvent is selected from short chain alcohols, long chain alcohols, acetone and methylene dichloride (MDC), preferably acetone, with continuous stirring till solution becomes clear;
c) Stirring of the solution prepared in step b) for 5 to 15 minutes, preferably 10 minutes.
(3) Granulation, Drying and Sifting:
d) Spraying of binder solution prepared in step c) on the lactose anhydrous of step a) in a fluidized bed processor (FBP) at 30-60°C, preferably using top spray technique; or spraying the binder solution on lactose anhydrous of step a) in rapid mixer granulator (RMG) at slower speed of impeller followed by slower speed of chopper; e) After completing the process of step d), drying of the prepared granules in the fluidized bed processor (FBP) at inlet air temperature 45 to 65°C and product temperature at around 30 to 60°C temperature till loss on drying (LOD) of blend reaches to less than 2.5% WAV at 105°C; f) Dried granules are sifted through sieve 20# or 30# or 40#, preferably 20#.
(4) Lubrication:
g) Sifting of microcrystalline cellulose (MCC) and Aerosil® 200 using 40# sieve;
h) Lubricating the granules with sifted microcrystalline cellulose (MCC) and Aerosil® 200 in a blender.
(5) Filling of capsule:
i) Filling of the granules prepared in step h) in suitably sized capsule as per target fill weight.
PCT/IB2017/057273 2017-07-04 2017-11-21 Novel composition of enzalutamide oral dosage form and method of manufacturing thereof WO2019008426A1 (en)

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MX2020000213A MX2020000213A (en) 2017-07-04 2017-11-21 Novel composition of enzalutamide oral dosage form and method of manufacturing thereof.
BR112020000207-0A BR112020000207A2 (en) 2017-07-04 2017-11-21 pharmaceutical composition of oral enzalutamide dosage form and process for preparing the pharmaceutical composition of oral enzalutamide dosage form
PH12020500045A PH12020500045A1 (en) 2017-07-04 2020-01-03 Novel composition of enzalutamide oral dosage form and method of manufacturing thereof
ZA2020/00609A ZA202000609B (en) 2017-07-04 2020-01-29 Novel composition of enzalutamide oral dosage form and method of manufacturing thereof

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Publication number Priority date Publication date Assignee Title
WO2021229278A1 (en) * 2020-05-13 2021-11-18 Novocap S.A Concentrated liquid non-steroidal antiandrogen solution and method for preparing the solution
US12150930B2 (en) 2021-07-07 2024-11-26 BDR Pharmaceuticals Int'l Pvt. Ltd. Oral liquid compositions of Enzalutamide and method of manufacturing thereof

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Publication number Priority date Publication date Assignee Title
US20160346207A1 (en) * 2014-02-05 2016-12-01 Lek Pharmaceuticals D.D. Solid Pharmaceutical Compositions Of Androgen Receptor Antagonists
IN2015CH04824A (en) * 2015-09-10 2017-03-17

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160346207A1 (en) * 2014-02-05 2016-12-01 Lek Pharmaceuticals D.D. Solid Pharmaceutical Compositions Of Androgen Receptor Antagonists
IN2015CH04824A (en) * 2015-09-10 2017-03-17

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021229278A1 (en) * 2020-05-13 2021-11-18 Novocap S.A Concentrated liquid non-steroidal antiandrogen solution and method for preparing the solution
US12150930B2 (en) 2021-07-07 2024-11-26 BDR Pharmaceuticals Int'l Pvt. Ltd. Oral liquid compositions of Enzalutamide and method of manufacturing thereof

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