Classifications

• • 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
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
• • 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
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone

Definitions

• the present invention relates to amorphous solid dispersions comprising of Elacestrant dihydrochloride which is represented by the following structural formula- la and one or more pharmaceutically acceptable excipients and processes for preparation thereof.
• Elacestrant dihydrochloride is chemically known as (6R)-6-(2-(N-(4-(2- (ethylamino) ethyl)benzyl)-N-ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydro naphthalen-2-ol dihydrochloride of formula- la, which was approved in US under the brand name of ORSERDUTM for the treatment of postmenopausal women or adult men, with ER-positive, HER2-negative, ESRI -mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.
• US patent number US7612114B2 describes the process for the preparation of Elacestrant dihydrochloride.
• US patent number US10385008B2 describes Form 1, Form 2, Form 3 and mixture of Form 2 and Form 3.
• US patent number US11643385B2 describes Form IB.
• W02022056100A1 describes the co-crystal of Elacestrant dihydrochloride and urea (form A); Elacestrant base (Form Bl), Elacestrant monohydrochloride salt (Form Hl), crystalline Elacestrant dihydrochloride Form 6 (DMSO solvate), crystalline Elacestrant dihydrochloride Form 7 (1 -propanol solvate), crystalline Elacestrant dihydrochloride Form 9.
• WO2023227029A1 describes Elacestrant dihydrochloride anhydrous crystalline form (CSII).
• solid state study of an active pharmaceutical ingredient aims to widen the variety of polymorphs that a formulation scientist has available for designing a pharmaceutical dosage form with desired characteristics.
• the present inventors after significant efforts have surprisingly found amorphous solid dispersions of Elacestrant dihydrochloride which are useful for the preparation of various pharmaceutical compositions.
• the first embodiment of the present invention provides amorphous solid dispersions comprising Elacestrant dihydrochloride of formula- la and one or more pharmaceutically acceptable excipients.
• the second embodiment of the present invention provides a process for the preparation of amorphous solid dispersions comprising Elacestrant dihydrochloride of formula- la and one or more pharmaceutically acceptable excipients.
• Figure-1 Illustrates the powder X-Ray diffraction ⁇ PXRD ⁇ pattern of amorphous solid dispersion comprising Elacestrant dihydrochloride and Povidone K-30.
• Figure-2 Illustrates the PXRD pattern of amorphous solid dispersion comprising Elacestrant dihydrochloride and HPMCP-50.
• Figure-3 Illustrates the PXRD pattern of amorphous solid dispersion comprising Elacestrant dihydrochloride and HPMC-E5.
• Figure-4 Illustrates the PXRD pattern of amorphous solid dispersion comprising Elacestrant dihydrochloride and HPMC-AS.
• Figure-5 Illustrates the PXRD pattern of amorphous solid dispersion comprising Elacestrant dihydrochloride and HPC-EF.
• the first embodiment of the present invention provides amorphous solid dispersion comprising Elacestrant dihydrochloride and one or more pharmaceutically acceptable excipients.
• the “excipient” is selected from but not limited to polyvinylpyrrolidone (povidone or PVP), polyvinyl polypyrrolidone, polysorbate, copovidone, cross linked polyvinyl pyrrolidone (crospovidone), polyethylene glycol (macrogol or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethylethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose (hypromellose or HPMC), hydroxy
• the excipients are preferably chosen from Povidone (Povidone K-30), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose (HPMC) E5, hydroxypropyl methylcellulose (HPMC) AS, hydroxypropyl cellulose (HPC) EF, and their respective grades which are deemed more suitable for oral bioavailability.
• the ratio of the weight of Elacestrant dihydrochloride to the weight of the excipient(s) within the solid dispersion ranges from about 1:0.05 to about 1:5, but is not limited to this range.
• first embodiment of the present invention provides a stable amorphous solid dispersion of Elacestrant dihydrochloride which is suitable for pharmaceutical preparations with having greater stability.
• the amorphous solid dispersion is stable at 25-30°C. In the sixth aspect of first embodiment, wherein the amorphous solid dispersion is stable at 0-5 °C.
• the amorphous solid dispersion is stable at 0-5 °C when stored at this temperature for a period of 12 months.
• the second embodiment of the present invention provides a process for the preparation of amorphous solid dispersion comprising Elacestrant dihydrochloride and one or more pharmaceutically acceptable excipients, comprising: a) providing a solution of Elacestrant dihydrochloride and one or more excipients in a solvent or a mixture of solvents, b) isolating amorphous solid dispersion comprising Elacestrant dihydrochloride and the corresponding excipient(s).
• providing a solution of Elacestrant dihydrochloride and excipient(s) in step-a) of the above process can be carried out by combining Elacestrant dihydrochloride and excipient(s) selected from those defined above with a solvent or mixture of solvents at a temperature ranging from about 25 °C to reflux temperature of the solvent used (or) solution in step-a) can also be obtained from the synthetic process in which Elacestrant dihydrochloride is prepared and further combining with the excipient.
• the excipients are same as defined above; preferably chosen from Povidone (Povidone K-30), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose (HPMC) E5, hydroxypropyl methylcellulose (HPMC) AS, hydroxypropyl cellulose (HPC) EF, and their respective grades which are deemed more suitable for oral bioavailability.
• the solvent is selected from methanol, dichloromethane or mixture thereof.
• the isolation of amorphous solid dispersion in step-b) can be done by removing the solvent from the mixture or solution by the suitable techniques which includes but not limited to decantation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, distillation under reduced pressure, distillation by using a rotational distillation device such as buchi rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying or by any other suitable techniques known in the art.
• Elacestrant dihydrochloride used as an input for the preparation of amorphous solid dispersion of Elacestrant dihydrochloride obtained according to the present invention is prepared by any of the process disclosed in US 7612114 B2 or other references.
• the amorphous solid dispersions of the present invention have a purity greater than about 98%, preferably greater than about 99%, more preferably greater than about 99.5% as determined by HPLC.
• amorphous solid dispersions of the present invention are useful for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used.
• the third embodiment of the present invention provides the use amorphous solid dispersions of the present invention for the preparation of pharmaceutical formulations.
• the fourth embodiment of the present invention provides pharmaceutical composition comprising amorphous solid dispersions of the present invention and at least one additional pharmaceutically acceptable excipient.
• pharmaceutical compositions or “pharmaceutical formulations” include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
• the additional pharmaceutically acceptable excipient(s) selected from povidone, polyvinyl polypyrrolidone, polysorbate, copovidone, cross linked polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate, methyl cellulose, carboxymethyl cellulose, carboxymethylethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose phthalate
• the fifth embodiment of the present invention provides a method of treating a patient in need thereof comprising administering to the said patient a therapeutically effective amount of amorphous solid dispersion of the present invention.
• the solid dispersions produced by various processes of the present invention can be further micronized or milled to get desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
• Techniques that may be used for particle size reduction includes but not limited to single or multi-stage micronization using cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills. Milling/micronization may be performed before drying or after drying of the product.
• Example 1 Preparation of amorphous solid dispersion comprising Elacestrant dihydrochloride of formula- la and Povidone K-30.
• Example 2 Preparation of amorphous solid dispersion comprising Elacestrant dihydrochloride of formula-la and HPMCP HP-50. Dissolved Elacestrant dihydrochloride (200 mg) in methanol (10 ml) at 25-30°C. HPMC HP-50 (200 mg) added to the obtained solution at 25-30°C. Further, dichloromethane (10 ml) was added to the above mixture and stirred at the same temperature. Filtered the obtained solution. Distilled off the solvent completely from the filtrate and dried to get title compound.
• Example 3 Preparation of amorphous solid dispersion comprising Elacestrant dihydrochloride of formula-la and HPMC-E5.
• Example 4 Preparation of amorphous solid dispersion comprising Elacestrant dihydrochloride of formula-la and HPMC-AS.
• Example 5 Preparation of amorphous solid dispersion comprising Elacestrant dihydrochloride of formula- la and HPC-EF.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical & Material Sciences (AREA)
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• Engineering & Computer Science (AREA)
• Emergency Medicine (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 2024
  • 2024-02-26 IN IN202441013791A patent/IN202441013791A/en unknown
• 2025
  • 2025-02-25 WO PCT/IN2025/050280 patent/WO2025181825A2/en active Pending

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