WO2018069937A1 - Dispersions solides de sacubitril/valsartan trisodique et procédé de leur préparation - Google Patents

Dispersions solides de sacubitril/valsartan trisodique et procédé de leur préparation Download PDF

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WO2018069937A1
WO2018069937A1 PCT/IN2017/050467 IN2017050467W WO2018069937A1 WO 2018069937 A1 WO2018069937 A1 WO 2018069937A1 IN 2017050467 W IN2017050467 W IN 2017050467W WO 2018069937 A1 WO2018069937 A1 WO 2018069937A1
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Prior art keywords
solid dispersion
mixtures
valsartan
acid
trisodium
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PCT/IN2017/050467
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English (en)
Inventor
Ramakoteswara Rao Jetti
Aggi Ramireddy Bommareddy
Narasimha Murthy PILLI
Arabinda Sahu
Nitin Ashok Shimpi
Anil Kumar Ponnuru
Sachin Gahoi
Haraprasad CHATTERJEE
Sureshreddy JAKKIREDDY
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Mylan Laboratories Limited
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Publication of WO2018069937A1 publication Critical patent/WO2018069937A1/fr

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    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/225—Polycarboxylic acids
    • 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
    • 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
    • A61K9/14—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
    • A61K9/1682—Processes

Definitions

  • the present invention relates generally to active pharmaceutical agents and method for their preparation and more specifically to solid dispersionsof trisodium sacubitril valsartanas well as a process for the preparation thereof.
  • the present invention also relates to a method of preparation of trisodium sacubitril valsartan tablets.
  • Sacubitril valsartan also known as LCZ696, is a co-crystallized complex ofvalsartan and sacubitril in a 1 : 1 molar ratio.
  • valsartan is known as (5)-3-methyl-2-(N- ⁇ [2'-(2H- l,2,3,4-tetrazol-5-yl)biphenyl-4-yl]methyl ⁇ pentanamido)butanoic acid
  • sacubitril is known as 4- ⁇ [(25,4i?)-l-(4-biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentanyl]amino ⁇ -4-oxobutanoic acid.
  • LCZ696 consists of 6 valsartan anions, 6 sacubitril anions, 18 sodium cations, and 15 molecules of water. Sacubitril valsartanis marketed under the trade nameEntresto® by Novartis. The reduced formula of the sacubitril valsartan, as included in the Entresto® product, is shown below as Formula-I as a single valsartan molecule with a single sacubitril molecule together with three sodium anions and 2.5 water molecules.
  • Sacubitril is a neprilysin inhibitor and valsartan is an angiotensin II receptor blocker.
  • Entresto® is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.
  • PCT Publication No. W02007/056546 discloses a combination, more particularly, a supramolecular complex, of two active agents with different mechanisms of action, namely an angiotensin receptor antagonist and a neutral endopeptidase inhibitor. With respect to this disclosed combination, PCT Publication No. W02007/056546 is hereby incorporated by reference.
  • PCT Publication No.WO2016/125123 discloses amorphous trisodium sacubitril valsartan.
  • PCT Publication Nos.WO2017/085573 and WO2017/037596 disclose an amorphous sacubitril- valsartan complex and solid dispersion with a pharmaceutically acceptable carrier.
  • dosage forms of active ingredients include both the active ingredient as well as one or more pharmaceutically acceptable carriers or excipients. These excipients function to improve a variety of pharmaceutically relevant properties during manufacture of the dosage form as well as properties of the final dosage form itself. For example, excipients are carefully selected to improve process dynamics such as flowability, wettability, cohesiveness, and solubility of the API. Excipients may affect final dosage form properties such as bioavailability of the API, dissolution properties of the API (e.g., immediate, extended, continued release profiles), or stability in storage. Coordinating optimal addition and combination of excipients and active ingredients during manufacture is a complex and difficult process, requiring careful planning and execution to produce a dosage form that meets the requirements to be sold in the U.S.
  • Pre-prepared mixtures of active ingredients with excipients may ease some of this burden and difficulty of formulation.
  • WO2017/085573 and WO2017/037596 disclose sacubitril/valsartan with a pharmaceutically acceptable carrier. In this case, it is likely that the solid dispersion with only one class of excipient (i.e., the carrier) would require addition of many other excipients in order to form the final dosage form, and complex planning and implementation would still be required.
  • the present invention provides an enhanced solid dispersion of trisodium sacubitril valsartan together with a pharmaceutically acceptable carrier and with one or more further excipients including anti-tacking agents, glidants, lubricants, and stabilizing agents.
  • the pre-prepared mixture that contains an anti-taking agent, glidant, lubricant, stabilizing agent, or any combination thereof improves stability and handling of the solid dispersion when compared to mixtures without these agents. Further, inclusion of these agents may only require addition of one or two more ingredients to prepare a final dosage form, thus simplifying and streamlining the manufacture process.
  • trisodium [3-((lS, 3R)-l-biphenyl-4-ylmethyl-3- ethoxycarbonyl- 1 -butylcarbamoyl) propionate-(S)-3'-methyl-2'-(pentanoyl ⁇ 2"-(tetrazol-5-ylate) biphenyl-4'-ylmethyl ⁇ amino) butyrate] will be referred to as "trisodium sacubitril valsartan.”
  • the present invention provides a method of preparing a solid dispersion of trisodium sacubitril valsartan.
  • a solid dispersion of trisodium sacubitril valsartan may be prepared by a process which includes the following steps: a) dissolving amorphous trisodium sacubitril valsartan in a solvent to form a solution;
  • the solvent may be an alcohol solvent, a ketone solvent, an ester solvent, a chlorinated solvent, an ether solvent, water, or mixtures thereof.
  • suitable alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, and mixtures thereof.
  • suitable ketone solvents include, but are not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof.
  • suitable ester solvents include, but are not limited to, methyl acetate, ethyl acetate, isopropyl acetate, tert-butyl acetate, and mixtures thereof.
  • suitable chlorinated solvents include, but are not limited to, chloromethane, methylene dichloride, chloroform, and mixtures thereof.
  • suitable ether solvents include, but are not limited to, tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, and mixtures thereof.
  • the present invention provides a solid dispersion of trisodium sacubitril valsartan.
  • the solid dispersion of trisodium sacubitril valsartan includes a solid dispersion agent and an anti-tacking agent.
  • Particularly useful solid dispersion agents include selected from the group consisting of hydroxypropyl methylcellulose, ⁇ -cyclodextrin, a polymer-blend based carriers, a silica based carrier, polyvinylpyrrolidone, and mixtures thereof.
  • Particularly useful processing aids include stearic acid, magnesium stearate, sodium stearyl fumarate, and mixtures thereof.
  • suitable solid dispersion agents include, but are not limited to, saccharides, polysaccharides, polyvinylpyrrolidone,polyvinyl acetate, polyvinyl alcohol, polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinyl pyrrolidone-vinyl acetate copolymers, polyalkylene glycols (e.g., polypropylene glycol or polyethylene glycol), co-block polymers of polyethylene glycol, proprietary polymer blends, optionally substituted cyclodextrins, polysorbates, sorbitan monolaurate, silica-based carriers, and mixtures thereof.
  • saccharides include, but are not limited to, saccharides, polysaccharides, polyvinylpyrrolidone,polyvinyl acetate, polyvinyl alcohol, polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinyl pyrrolidone-vinyl acetate copolymers
  • Suitable saccharides and polysaccharides include, but are not limited to, hydroxypropyl methylcellulose, carboxymethylcellulose and salts thereof, methylcellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, and mixtures thereof.
  • a copolymer of N-vinyl-2-pyrrolidone and vinyl acetate with a mass ratio of 60:40 is used as a solid dispersion agent.
  • processing aids include, but are not limited to, lubricants, glidants, anti-tacking agents, stabilizing agents, and mixtures thereof.
  • processing aids include, but are not limited to, caprylic acid, capric acid, lauric acid , myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, magnesium stearate, aluminum stearate, calcium stearate, sodium stearate, sodium stearyl fumarate, magnesium carbonate, magnesium oxide, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose, glyceryl behenate, stearic acid, hydrogenated castor oil, glyceryl monostearate, and mixtures thereof.
  • a solid dispersion of trisodium sacubitril valsartan may be prepared by a process which includes the following steps: a) dissolving sacubitril and valsartan in a solvent to form a solution;
  • the solvent may be, for example, ethanol, ethyl acetate, methylene chloride, tetrahydrofuran, or mixtures thereof.
  • suitable solid dispersion agents include, but are not limited to, saccharides, polysaccharides, polyvinylpyrrolidone,polyvinyl acetate, polyvinyl alcohol, polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinyl pyrrolidone-vinyl acetate copolymers, polyalkylene glycols (e.g., polypropylene glycol or polyethylene glycol), co-block polymers of polyethylene glycol, proprietary polymer blends, optionally substituted cyclodextrins, polysorbates, sorbitan monolaurate, silica-based carriers, and mixtures thereof.
  • saccharides include, but are not limited to, saccharides, polysaccharides, polyvinylpyrrolidone,polyvinyl acetate, polyvinyl alcohol, polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinyl pyrrolidone-vinyl acetate copolymers
  • Suitable saccharides and polysaccharides include, but are not limited to, hydroxypropyl methylcellulose, carboxymethylcellulose and salts thereof, methylcellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, and mixtures thereof.
  • a copolymer of N-vinyl-2-pyrrolidone and vinyl acetate with a mass ratio of 60:40 is used as a solid dispersion agent.
  • processing aids include, but are not limited to, lubricants, glidants, anti-tacking agents, stabilizing agents, and mixtures thereof.
  • processing aids include, but are not limited to, caprylic acid, capric acid, lauric acid , myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, magnesium stearate, aluminum stearate, calcium stearate, sodium stearate, sodium stearyl fumarate, magnesium carbonate, magnesium oxide, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose, glyceryl behenate, stearic acid, hydrogenated castor oil, glyceryl monostearate, and mixtures thereof.
  • a solid dispersion of trisodium sacubitril valsartan may be prepared by a process which includes the following steps: a) combining amorphous trisodium sacubitril valsartan, a solid dispersion agent, and a processing aid to form a mixture;
  • suitable solid dispersion agents include, but are not limited to, saccharides, polysaccharides, polyvinylpyrrolidone,polyvinyl acetate, polyvinyl alcohol, polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinyl pyrrolidone-vinyl acetate copolymers, polyalkylene glycols (e.g., polypropylene glycol or polyethylene glycol), co-block polymers of polyethylene glycol, proprietary polymer blends, optionally substituted cyclodextrins, polysorbates, sorbitan monolaurate, silica-based carriers, and mixtures thereof.
  • saccharides include, polysaccharides, polyvinylpyrrolidone,polyvinyl acetate, polyvinyl alcohol, polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinyl pyrrolidone-vinyl acetate copolymers, polyalkylene glycols (e
  • Suitable saccharides and polysaccharides include, but are not limited to, hydroxypropyl methylcellulose, carboxymethylcellulose and salts thereof, methylcellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, and mixtures thereof.
  • a copolymer of N-vinyl-2-pyrrolidone and vinyl acetate with a mass ratio of 60:40 is used as a solid dispersion agent.
  • processing aids include, but are not limited to, lubricants, glidants, anti-tacking agents, stabilizing agents, and mixtures thereof.
  • processing aids include, but are not limited to, caprylic acid, capric acid, lauric acid , myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, magnesium stearate, aluminum stearate, calcium stearate, sodium stearate, sodium stearyl fumarate, magnesium carbonate, magnesium oxide, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose, glyceryl behenate, stearic acid, hydrogenated castor oil, glyceryl monostearate, and mixtures thereof.
  • the solid dispersions of trisodium sacubitril valsartan may be used to prepare pharmaceutical dosage forms, for example, a tablet or a capsule.
  • Figure 1 is apowder X-ray diffraction (PXRD) pattern of a solid dispersion of trisodiumsacubitril valsartan with 40% HPMC and 10% stearic acid, prepared according toExample 16.
  • PXRD apowder X-ray diffraction
  • One aspect of the present invention provides a solid dispersion of trisodiumsacubitril valsartan together with a dispersion agent and aprocessing aid as well as processes for the preparation thereof.
  • the term "about” when modifying an absolute measurement, such as time, mass, or volume, is meant to mean the recited value plus or minus 10% of that value.
  • the term “about” when modifying a temperature measurement is meant to mean the recited temperature plus or minus five degrees.
  • the solid dispersions of the trisodium sacubitril valsartan disclosed herein may be characterized as amorphous by X-ray powder diffraction (PXRD).
  • samples of trisodium sacubitrilvalsartan solid dispersions prepared by methods disclosed herein, were analyzed on a PanalyticalX'pertPro powder X-ray diffractometer equipped with goniometer of ⁇ /2 ⁇ configuration and X'celerator detector.
  • the Cu-anode X-ray tube was operated at 40kV and 30 mA. The experiments were conducted over the 2 ⁇ range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.
  • Figure 1 depicts a PXRD pattern obtained from one such analysis of a solid dispersion of trisodium sacubitril valsartan with 40% HPMC and 10% stearic acid.
  • a solid dispersion of trisodium sacubitril valsartan may be prepared by a process that includes the following steps: a) dissolving amorphoustrisodium sacubitril valsartan in a solvent to form a solution;
  • amorphous or crystalline trisodium sacubitril valsartan may be dissolved in a solvent.
  • suitable solvents include, but are not limited to, alcohol solvents, ketone solvents, ester solvents, chlorinated solvents, ether solvents, water, or mixtures thereof.
  • suitable alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, and mixtures thereof.
  • Suitable ketone solvents include, but are not limited to, acetone, methylethyl ketone, methylisobutyl ketone, and mixtures thereof.
  • suitable ester solvents may be, but are not limited to,methyl acetate, ethyl acetate, isopropyl acetate, tert-butyl acetate, ormixtures thereof.
  • chlorinated solvents include, but are not limited to, chloromethane, methylene dichloride, chloroform, and mixtures thereof.
  • Suitable ether solvents include, but are not limited to, tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, and mixtures thereof.
  • water, ethanol, ethyl acetate, methylene dichloride, and miscible mixtures thereof were each found to be a particularly useful solvent.
  • one or moresolid dispersion agents may be added to the solution.
  • suitable solid dispersion agents include saccharides and polysaccharides, polyvinylpyrrolidone,polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinyl pyrrolidone-vinyl acetate copolymers, polyalkylene glycols (e.g., polypropylene glycol or polyethylene glycol), co-block polymers of polyethylene glycol (especially co-block polymers of polyethylene glycol and polypropylene glycol (such as those sold under the brand name Pluronic ® , Tween ® , Span ® )), proprietary polymer blends (e.g., Eudragit ® E PO, EthocelTM), cyclodextrins (e.g., a-cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl
  • PVAC polyviny
  • Suitable saccharides and polysaccharides include hydroxypropyl methylcellulose (HPMC, for example, those sold under the brand name MethocelTM (e.g., E3 Premium LV and E6 Premium LV) or AffinisolTM (e.g., HPMC-HME)), carboxymethylcellulose (CMC), and salts thereof (especially sodium and calcium salts), methylcellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), microcrystalline cellulose, and mixtures thereof.
  • HPMC hydroxypropyl methylcellulose
  • MethocelTM e.g., E3 Premium LV and E6 Premium LV
  • AffinisolTM e.g., HPMC-HME
  • CMC carboxymethylcellulose
  • salts thereof especially sodium and calcium salts
  • methylcellulose hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC
  • useful polyvinylpyrrolidones are those with K-values ranging from about 12 to about 103, including povidone K-12, povidone K-15, povidone K-17, povidone K-25, povidone K-30, povidone K-90, and mixtures thereof.
  • povidone K-12, povidone K-15, povidone K-17, povidone K-25, povidone K-30, povidone K-90, and mixtures thereof are those with K-values ranging from about 12 to about 103, including povidone K-12, povidone K-15, povidone K-17, povidone K-25, povidone K-30, povidone K-90, and mixtures thereof.
  • povidone K-15 povidone K-17
  • povidone K-25 povidone K-25
  • povidone K-30 povidone K-90
  • a copolymer of N-vinyl-2- pyrrolidone and vinyl acetate with a mass ratio of 60:40 for example, Plasdone S-630 or Kollidon ® VA 64, is used as a solid dispersion agent.
  • the solid dispersion agent may be present in a solid dispersion of trisodium sacubitril valsartan at concentrations of between 15% w/w and 90% w/w, which includes 15-80%, 15-70%, 15-60%, 15-50%, 15-50%, 15-40%, 15-30%, 15-20%, 20- 90%, 20-80%, 20-70%, 20-60%, 20-50%, 20-40%, 20-30%, 30-90%, 30-80%, 30-70%, 30-60%, 30-50%, 30-40%, 40-90%, 40-80%, 40-70%, 40-60%, 40-50%, 50-90%, 50-80%, 50-70%, 50- 60%, 60-90%, 60-80%, 60-70%, 70-90%, 70-80%, and 80-90%.
  • one or more processing aids may be added to the solution.
  • examples of processing aids include lubricants, glidants, anti-tacking agents, and stabilizing agents.
  • Specific examples include, but are not limited to, caprylic acid, capric acid, lauric acid , myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, magnesium stearate, aluminum stearate, calcium stearate, sodium stearate, sodium stearyl fumarate, magnesium carbonate, magnesium oxide, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose, glyceryl behenate, stearic acid, hydrogenated castor oil, glyceryl monostearate, and mixtures thereof.
  • the process enhancer may be present in the solid dispersion of trisodium sacubitril valsartan at a ratio ranging from 2% to 20%, which includes 2- 18%, 2-16%, 2-14%, 2-12%, 2-10%, 2-8%, 2-6%, 2-4%, 4-20%, 4-18%, 4-16%, 4-12%, 4-10%, 4-8%, 4-6%, 6-20%, 6-18%, 6-16%, 6-14%, 6-12%, 5-10%, 6-8%, 8-20%, 8-18%, 8-16%, 8- 14%, 8-12%, 8-10%, 10-20%, 10-18%, 10-16%, 10-14%, 10-12%, 12-20%, 12-18%, 12-16%, 12-14%, 14-20%, 14-18%, 14-16%, 16-20%, 16-18%, and 18-20%.
  • a solid dispersion is prepared with a combination of one or more of the following solid dispersion agents:
  • hydroxypropyl methylcellulose e.g., EthocelTM E3 Premium LV, EthocelTM E6 Premium L V, or AffinisolTM HPMC-HME 15LV;
  • polymer-blend based carriers e.g., Eudragit® E PO, Plasdone S-630;
  • silica based carriers e.g., Aeroperl® 300 or Syloid® AL-I FP
  • polyvinylpyrrolidone e.g., povidone K30
  • anti-tacking agents e.g., povidone K30
  • each of the first three steps a), b) and c) involving dissolution of trisodium sacubitril valsartan, the solid dispersion agent, and processing aid( "ingredients") may be carried out individually in any order, or two or more ingredients may be added simultaneously and dissolved simultaneously.
  • a solid dispersion of trisodium sacubitril valsartan together with hydroxypropyl methylcellulose and steric acid is used.
  • hydroxypropyl methylcellulose (HPMC) and steric acid are present in the solid dispersion at a ratio of 1: 1, 5.5:4.5, 6:4, 6.5:3.5, 7:3, 7.5:2.5, 8:2, 8.5: 1.5, 9: 1, 9.5:0.5, 9.7:0.3, 9.8:0.2, or 9.9:0.1 (HPMC:stearic acid).
  • a solid dispersion of trisodium sacubitril valsartan together with hydroxypropyl methylcellulose and sodium stearyl fumarate is used.
  • hydroxypropyl methylcellulose (HPMC) and sodium stearyl fumarate are present in the solid dispersion at a ratio of 1: 1, 5.5:4.5, 6:4, 6.5:3.5, 7:3, 7.5:2.5, 8:2, 8.5: 1.5, 9: 1, 9.5:0.5, 9.7:0.3, 9.8:0.2, 9.9:0.1 (HPMOsodiumstearyl fumarate).
  • a solid dispersion of trisodium sacubitril valsartan together with Plasdone S6-30 and sodium stearyl fumarate is used.
  • Plasdone S6-30 and sodium stearyl fumarate are present in the solid dispersion at a ratio of 1: 1, 5.5:4.5, 6:4, 6.5:3.5, 7:3, 7.5:2.5, 8:2, 8.5: 1.5, 9: 1, 9.5:0.5, 9.7:0.3, 9.8:0.2, 9.9:0.1 (Plasdone S- 630:sodiumstearyl fumarate).
  • the solvent may be removed to isolate a solid dispersion of trisodium sacubitril valsartan. This may be achieved by methods well known in the art, for example, by evaporation, distillation, spray drying, lyophilization, or agitated thin film drying.
  • trisodium valsartan sacubitril may be prepared in situ and not isolated prior to preparing a solid dispersion of trisodium valsartan sacubitril.
  • this may be carried out by a process that includes the following steps: a) dissolving sacubitril and valsartan in a solvent to form a solution;
  • sacubitril and valsartan may be dissolved in a solvent to form a solution.
  • suitable solvents include, but are not limited to, ethanol, ethyl acetate, methylene chloride, tetrahydrofuran,and mixtures thereof.
  • sodium hydroxide may be added to the solution.
  • sodium hydroxide is added to provide sodium cations to form the trisodium valsartan sacubitril complex.
  • One of skill in the art would be able to calculate the amount of sodium hydroxide required based on the amount of sacubitril and valsartan used.
  • one or moresolid dispersion agents may be added to the solution.
  • suitable solid dispersion agents include saccharides and polysaccharides, polyvinylpyrrolidone,polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates,polysorbates (e.g., Tween® 80), sorbitan monolaurate (e.g., Span® 20), vinyl pyrrolidone-vinyl acetate copolymers (e.g., Kollidon® and PlasdoneTM), polyalkylene glycols (for example polypropylene glycol or polyethylene glycol), co-block polymers of polyethylene glycol, especially co-block polymers of polyethylene glycol and polypropylene glycol (such as those sold under the brand name Pluronic ® ), proprietary polymer blends (e.g., Eudragit ® E PO, EthocelTM), silica or silicon dioxide (e.g., Aeroperl
  • Suitable saccharides and polysaccharides include hydroxypropyl methylcellulose (HPMC, for example, those sold under the brand name MethocelTM (e.g., E3 Premium LV and E6 Premium LV) or AffinisolTM (e.g., HPMC-HME)), carboxymethylcellulose (CMC), and salts thereof (especially sodium and calcium salts), methylcellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), microcrystalline cellulose, and mixtures thereof.
  • HPMC hydroxypropyl methylcellulose
  • MethocelTM e.g., E3 Premium LV and E6 Premium LV
  • AffinisolTM e.g., HPMC-HME
  • CMC carboxymethylcellulose
  • salts thereof especially sodium and calcium salts
  • methylcellulose hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC
  • useful polyvinylpyrrolidones are those with K-values ranging from about 12 to about 103, including povidone K-12, povidone K-15, povidone K-17, povidone K-25, povidone K-30, povidone K-90, and mixtures thereof.
  • povidone K-12, povidone K-15, povidone K-17, povidone K-25, povidone K-30, povidone K-90, and mixtures thereof are those with K-values ranging from about 12 to about 103, including povidone K-12, povidone K-15, povidone K-17, povidone K-25, povidone K-30, povidone K-90, and mixtures thereof.
  • povidone K-15 povidone K-17
  • povidone K-25 povidone K-25
  • povidone K-30 povidone K-90
  • a suitable vinylpyrrolidone-vinyl acetate copolymer contains N-vinyl-2- pyrrolidone and vinyl acetate with a mass ratio of 60:40 (such as those sold under the brand name Kollidon and Plasdone (e.g., KollidonVA64 and Plasdone S-630).
  • the solid dispersion agent may be present in a solid dispersion of trisodium sacubitril valsartan at concentrations of between 15% w/w and 90% w/w, which includes 15-80%, 15-70%, 15-60%, 15-50%, 15-50%, 15-40%, 15-30%, 15-20%, 20- 90%, 20-80%, 20-70%, 20-60%, 20-50%, 20-40%, 20-30%, 30-90%, 30-80%, 30-70%, 30-60%, 30-50%, 30-40%, 40-90%, 40-80%, 40-70%, 40-60%, 40-50%, 50-90%, 50-80%, 50-70%, 50- 60%, 60-90%, 60-80%, 60-70%, 70-90%, 70-80%, and 80-90%.
  • examples of processing aids include lubricants, glidants, anti-tacking agents, and stabilizing agents.
  • Specific examples include, but are not limited to, caprylic acid, capric acid, lauric acid , myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, magnesium stearate, aluminum stearate, calcium stearate, sodium stearate, sodium stearyl fumarate, magnesium carbonate, magnesium oxide, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose, glyceryl behenate, stearic acid, hydrogenated castor oil, glyceryl monostearate, and mixtures thereof.
  • the process enhancer may be present in the solid dispersion of trisodium sacubitril valsartan at a ratio ranging from 2% to 20%, which includes 2- 18%, 2-16%, 2-14%, 2-12%, 2-10%, 2-8%, 2-6%, 2-4%, 4-20%, 4-18%, 4-16%, 4-12%, 4-10%, 4-8%, 4-6%, 6-20%, 6-18%, 6-16%, 6-14%, 6-12%, 5-10%, 6-8%, 8-20%, 8-18%, 8-16%, 8- 14%, 8-12%, 8-10%, 10-20%, 10-18%, 10-16%, 10-14%, 10-12%, 12-20%, 12-18%, 12-16%, 12-14%, 14-20%, 14-18%, 14-16%, 16-20%, 16-18%, and 18-20%.
  • the solvent may be removed to isolate a solid dispersion of trisodium sacubitril valsartan. This may be carried out by methods well known in the art, for example, by evaporation, distillation, spray drying, lyophilization, or agitated thin film drying.
  • a solid dispersion of trisodium sacubitril valsartan may be prepared by a process that includes the following steps: a) combining amorphous trisodium sacubitril valsartan, a solid dispersion agent, and a
  • amorphous or crystalline trisodium sacubitril amorphous or crystalline trisodium sacubitril
  • valsartan may first be mixed with one or moresolid dispersion agent and a processing aid to form a mixture.
  • suitable solid dispersion agents include saccharides and polysaccharides, polyvinylpyrrolidone,polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, polysorbates (e.g., Tween® 80), sorbitan monolaurate (e.g., Span® 20), vinyl pyrrolidone-vinyl acetate copolymers (e.g., Kollidon® and PlasdoneTM), polyalkylene glycols (for example polypropylene glycol or polyethylene glycol), co-block polymers of polyethylene glycol, especially co-block polymers of polyethylene glycol and polypropylene glycol (such as those sold under the brand name Pluronic ® ), proprietary polymer blends (e.g., Eu
  • Suitable saccharides and polysaccharides include hydroxypropyl methylcellulose (HPMC, for example, those sold under the brand name MethocelTM (e.g., E3 Premium LV and E6 Premium LV) or AffinisolTM (e.g., HPMC-HME)), carboxymethylcellulose (CMC), and salts thereof (especially sodium and calcium salts), methylcellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), microcrystalline cellulose, and mixtures thereof.
  • HPMC hydroxypropyl methylcellulose
  • MethocelTM e.g., E3 Premium LV and E6 Premium LV
  • AffinisolTM e.g., HPMC-HME
  • CMC carboxymethylcellulose
  • salts thereof especially sodium and calcium salts
  • methylcellulose hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC
  • useful polyvinylpyrrolidones are those with K-values ranging from about 12 to about 103, including povidone K-12, povidone K-15, povidone K-17, povidone K-25, povidone K-30, povidone K-90, and mixtures thereof.
  • povidone K-12, povidone K-15, povidone K-17, povidone K-25, povidone K-30, povidone K-90, and mixtures thereof are those with K-values ranging from about 12 to about 103, including povidone K-12, povidone K-15, povidone K-17, povidone K-25, povidone K-30, povidone K-90, and mixtures thereof.
  • povidone K-15 povidone K-17
  • povidone K-25 povidone K-25
  • povidone K-30 povidone K-90
  • a suitable vinylpyrrolidone-vinyl acetate copolymer contains N-vinyl-2- pyrrolidone and vinyl acetate with a mass ratio of 60:40 (such as those sold under the brand name Kollidon ® and Plasdone ® (e.g., KollidonVA64 and Plasdone S-630).
  • the solid dispersion agent may be present in a solid dispersion of trisodium sacubitril valsartan at concentrations of between 15% w/w and 90% w/w, which includes 15-80%, 15-70%, 15-60%, 15-50%, 15-50%, 15-40%, 15-30%, 15-20%, 20- 90%, 20-80%, 20-70%, 20-60%, 20-50%, 20-40%, 20-30%, 30-90%, 30-80%, 30-70%, 30-60%, 30-50%, 30-40%, 40-90%, 40-80%, 40-70%, 40-60%, 40-50%, 50-90%, 50-80%, 50-70%, 50- 60%, 60-90%, 60-80%, 60-70%, 70-90%, 70-80%, and 80-90%.
  • examples of processing aids include lubricants, glidants, anti-tacking agents, and stabilizing agents.
  • Specific examples include, but are not limited to, caprylic acid, capric acid, lauric acid , myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, magnesium stearate, aluminum stearate, calcium stearate, sodium stearate, sodium stearyl fumarate, magnesium carbonate, magnesium oxide, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose, glyceryl behenate, stearic acid, hydrogenated castor oil, glyceryl monostearate, and mixtures thereof.
  • the process enhancer may be present in the solid dispersion of trisodium sacubitril valsartan at a ratio ranging from 2% to 20%, which includes 2- 18%, 2-16%, 2-14%, 2-12%, 2-10%, 2-8%, 2-6%, 2-4%, 4-20%, 4-18%, 4-16%, 4-12%, 4-10%, 4-8%, 4-6%, 6-20%, 6-18%, 6-16%, 6-14%, 6-12%, 5-10%, 6-8%, 8-20%, 8-18%, 8-16%, 8- 14%, 8-12%, 8-10%, 10-20%, 10-18%, 10-16%, 10-14%, 10-12%, 12-20%, 12-18%, 12-16%, 12-14%, 14-20%, 14-18%, 14-16%, 16-20%, 16-18%, and 18-20%.
  • Particularly useful solid dispersion agents and process enhancers have a melting point of about 50 °C to about 200 °C.
  • the solid dispersion agents and process enhancers have a
  • the mixture may then be heated.
  • heating will melt the mixture.
  • This may be carried out by processes known in the art, for example, by hot melt extrusion.
  • One of skill in the art would recognize appropriate parameters and conditions required to heat the mixture by hot melt extrusion.
  • the following Zone temperatures are used: Zone 1: 60 °C; Zone 2: 90 °C; Zone 3: 100 °C; Exit temperature: 100 °C.
  • the following Zone temperatures are used: Zone 1: 110 °C; Zone 2: 135 °C; Zone 3: 145 °C; Exit temperature: 160 °C.
  • Plasdone S-630, Tween ® 80, Span ® 20, or mixtures thereof were found to be particularly useful solid dispersion agents.
  • the heated mixture may be cooled, for example, to room temperature.
  • the mixture may then be further processed to provide a solid dispersion of trisodium sacubitril valsartan with properties as desired.
  • the mixture may be milled.
  • solid dispersions of trisodium sacubitril valsartan contain and are prepared using a vinylpyrrolidone-vinyl acetate copolymer, a polyvinylpyrrolidone, or a cyclodextrin as the solid dispersion agent.
  • solid dispersions where a processing aid is used, it may be particularly useful to use an anti- tacking agent as said processing aid.
  • a solid dispersion is prepared with a combination of one or more of the following solid dispersion agents:
  • hydroxypropyl methylcellulose e.g., EthocelTM E3 Premium LV, EthocelTM E6 Premium L V, or AffinisolTM HPMC-HME 15LV;
  • polymer-blend based carriers e.g., Eudragit® E PO, Plasdone S-630;
  • silica based carriers e.g., Aeroperl® 300 or Syloid® AL-I FP
  • polyvinylpyrrolidone e.g, povidone K30
  • anti-tacking agents e.g, povidone K30
  • the solid dispersion agent is hydroxypropyl methylcellulose
  • magnesium stearate, sodium stearyl fumarate, or stearic acid is often used.
  • magnesium stearate or sodium stearyl fumarate is combined with hydroxypropyl methylcellulose to prepare a solid dispersion of trisodium sacubitril valsartan.
  • solid dispersions disclosed herein may be combined with further pharmaceutically acceptable excipients to prepare a final dosage form, for example, a solid oral dosage form.
  • pharmaceutically acceptable excipients are inert ingredients that are used in the manufacture of solid oral dosage forms and that are combined with an active ingredient, a pre-prepared mixture (e.g., a solid dispersion) containing the active ingredient during dosage formulation.
  • a pre-prepared mixture e.g., a solid dispersion
  • pharmaceutically acceptable excipients include, but are not limited to, solid dispersion agents, anti-tacking agents, glidants, lubricants, stabilizing agents,binders, disintegrants, fillers, and diluents.
  • pharmaceutically acceptable binders include, but are not limited to, starches, celluloses, and derivatives thereof.
  • celluloses and their derivatives include hydroxypropyl methylcellulose, carboxymethylcellulose, and salts thereof (especially sodium and calcium salts), methylcellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (high or low substituted), hydroxylethyl cellulose, microcrystalline cellulose, sucrose, dextrose, corn syrup, polysaccharides, gelatin, and mixtures thereof.
  • low substituted hydroxypropyl cellulose is used.
  • the binder may be present in the final dosage form at a concentration from about 1% to 10 % w/w, which includes 1-9%, 1-8%, 1-7%, 1-6%, 1-5%, 1- 4%, 1-3%, 1-2%, 2-10%, 2-9%, 2-8%, 2-7%, 2-6%, 2-5%, 2-4%, 2-3%, 3-10%, 3-9%, 3-8%, 3- 7%, 3-6%, 3-5%, 3-4%, 4-10%, 4-9%, 4-8%, 4-7%, 4-6%, 4-5%, 5-10%, 5-9%, 5-8%, 5-7%, 5- 6%, 6-10%, 6-9%, 6-8%, 6-7%, 7-10%, 7-9%, 7-8%, 8-10%, 8-9%, and 9-10% w/w.
  • the binder is present at a concentration of about 3% to 5% w/w.
  • disintegrants examples include, but are not limited to, starches clays, celluloses, alginates, gums (e.g., guar), cross-linked polymers (e.g., crospovidone such as Polyplasdone XL andPolyplasdoneXL-10), croscarmellose sodium, (e.g., AC-DI- SOL),croscarmellose calcium, soy polysaccharides, and mixtures thereof.
  • crospovidone is used as a disintegrant.
  • the disintegrant may be present in the final dosage form at a concentration from about 1% to 10 % w/w which includes 1-9%, 1-8%, 1-7%, 1-6%, 1-5%, 1-4%, 1-3%, 1-2%, 2-10%, 2- 9%, 2-8%, 2-7%, 2-6%, 2-5%, 2-4%, 2-3%, 3-10%, 3-9%, 3-8%, 3-7%, 3-6%, 3-5%, 3-4%, 4- 10%, 4-9%, 4-8%, 4-7%, 4-6%, 4-5%, 5-10%, 5-9%, 5-8%, 5-7%, 5-6%, 6-10%, 6-9%, 6-8%, 6- 7%, 7-10%, 7-9%, 7-8%, 8-10%, 8-9%, and 9-10% w/w.
  • the disintegrant is present at a concentration of about 3% to 5% w/w.
  • pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants include, but are not limited to, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose, glyceryl behenate, stearic acid, hydrogenated castor oil, glyceryl monostearate, sodium stearyl fumarate, and mixtures thereof.
  • magnesium stearate is used as a lubricant and colloidal silica is used as a glidant.
  • the lubricant may be present in the final dosage form at a concentration from aboutO.01% to 5% w/w, which also includes 0.05-5%, 0.5-4%, 0.5-3%, 0.5-2%, 0.5-1%, 1-5%, 1-4%, 1-3%, 1-2%, 2-5%, 2-4%, 2-4%, 3-5%, 3-4%, and 4-5%.
  • the lubricant is present at a concentration of about 0.5% to 1 % w/w.
  • the glidant may be present in the final dosage form at a concentration from aboutO.01% to 5% w/w, which also includes 0.05-5%, 0.5- 4%, 0.5-3%, 0.5-2%, 0.5-1%, 1-5%, 1-4%, 1-3%, 1-2%, 2-5%, 2-4%, 2-4%, 3-5%, 3-4%, and 4- 5%.
  • the glidant is present at a concentration of about 0.5% to 1 % w/w.
  • Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, and mixtures thereof. In particularly useful embodiments, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose, or mixtures thereof are used.
  • microcrystalline cellulose is used.
  • the filler/diluent may be present in the final dosage form at a concentration from aboutl% to 10% which includes 1-9%, 1-8%, 1-7%, 1-6%, 1-5%, 1-4%, 1-3%, 1-2%, 2-10%, 2-9%, 2-8%, 2-7%, 2-6%, 2-5%, 2-4%, 2-3%, 3-10%, 3-9%, 3-8%, 3-7%, 3-6%, 3-5%, 3-4%, 4-10%, 4-9%, 4-8%, 4-7%, 4-6%, 4-5%, 5-10%, 5-9%, 5-8%, 5-7%, 5-6%, 6-10%, 6-9%, 6-8%, 6-7%, 7-10%, 7-9%, 7-8%, 8-10%, 8-9%, and 9-10% w/w.
  • the filler/diluent is present at a concentration of about 5% to 7% w/w.
  • Solid oral dosage forms for example, tablets or capsules, may be further coated with suitable coating agents by methods well-known to a person skilled in the art.
  • suitable coating agents include, but are not limited to, Opadry AMB-II, Opadry white, Opadry yellow, Opadry red, Opadry black, and Aquarius.
  • a solid dosage form of trisodium sacubitril valsartan may be prepared by mixing a solid dispersion of trisodium sacubitril valsartan with one or more pharmaceutical excipients as outlined above and compressing the mixture into tablets, which may then be optionally coated.
  • a solid dosage form of trisodium sacubitril valsartan may be prepared by mixing amorphous sacubitril valsartan with pharmaceutical excipients and compressing the mixture into tablets, which may then be optionally coated.
  • Amorphous trisodium sacubitril valsartan may be prepared by processes disclosed in PCT PublicationNo. WO 2016/125123.
  • the tablet composition of present invention can be prepared by any known techniques known in the art, for example, direct compression, dry granulation, and roller compression.
  • solid dispersions containing trisodium sacubitril valsartan together with a solid dispersion agent and an anti-tacking agent may be realized with the stability of solid dispersions that include the anti-tacking agent.
  • the stability of solid dispersions that include the anti-tacking agent is improved when compared to similar solid dispersions prepared without anti-tacking agents, which tend to be highly hygroscopic.
  • Hygroscopic formulations become gummy and more viscous upon storage in an environment that contains water vapor, significant chemical degradation of the formulation often occurs.
  • PXRD and stability data indicate that chemical degradation is avoided.
  • stability during storage was thus measured by PXRD and HPLC.
  • HPLC analyses were performed previously described. HPLC analyses were performed by routine methods well known in the art, for example, on anXB ridge C18 column (150 mm x 4.5 mm, 3 ⁇ ), using a UV detector set at 210 nm with a column oven temperature of about 30 °C. A flow rate of 1.5 ml/min with an injection volume of 10 ⁇ L ⁇ may be used, with a run time of approximately 45 minutes. The mobile phase was a ratio of 95:50:25 (by volume) acetonitrile : water : tetrahydrofur an .
  • trisodium sacubitril valsartan solid dispersions and pharmaceutical tablet compositions prepared therefrom according to the present invention contain trisodium sacubitril valsartan at a HPLC purity of more than 99%.
  • a compound or pharmaceutical composition is considered “stable” when the HPLC purity of the compound or solid dispersion changes by less than about 1 % when stored at 5 ⁇ 3 °C and/or at 25 °C/60% and 40 °C/75% relative humidity (RH).
  • Dosage forms that include the trisodium sacubitril valsartan and solid dispersions thereof may be useful for reducing the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure and reduced ejection fraction.
  • oral dosage forms include sacubitril from about 24 mg to about 97 mg.
  • oral dosage forms include valsartan from about 26 mg to about 103 mg.
  • oral dosage forms 24 mg of sacubitril and 26 mg of valsartan; 49 mg of sacubitril and 51 mg of valsartan; or 97 mg of sacubitril and 103 mg of valsartan.
  • Example 1 Preparation of a solid dispersion of trisodium sacubitril valsartan with 50% w/w HPMC
  • Amorphous trisodium sacubitril valsartan (8 g) was dissolved in water (40 ml) at 25 ⁇ 2°C.
  • hydroxypropyl methylcellulose (8 g) was dissolved in water (160 ml) at 25 ⁇ 2°C.
  • the two solutions were combined to make one solution which was then filtered through Hyflo to remove any undissolved particulate.
  • the solution was then subjected to spray drying in laboratory spray dryer (Model Buchi-290) with inlet temperature at 100°C and 100% aspiration to yield a solid dispersion oftrisodium sacubitril valsartan with 50% w/w HPMC.
  • Amorphous trisodium sacubitril valsartanamorphous form (8 g) and Plasdone S-630 (8 g) were dissolved in ethanol (80 ml) at 25 ⁇ 2°C.
  • the resulting clear solution was filtered through Hyfloto remove any undissolved particulate.
  • the solution was then subjected to spray drying in a laboratory spray dryer (Model Buchi-290) with inlet temperature at 80 °C and 100% aspiration to yield a solid dispersion oftrisodium sacubitril valsartan with 50% w/w Plasdone S-630.
  • Example 3 Preparation of a solid dispersion of trisodium sacubitril valsartan with 50% w/w povidone K30
  • Amorphous trisodium sacubitril valsartan (8 g) and Povidone K30 (8 g) were dissolved in ethanol (80 ml) at 25 ⁇ 2°C.
  • the resulting clear solution was filtered through Hyflo to remove any undissolved particulate.
  • the solution was then subjected to spray drying in a laboratory spray dryer (Model Buchi-290) with inlet temperature at 80 °C and with 100% aspiration to yield a solid dispersion oftrisodium sacubitril valsartan with 50% w/w povidone K30.
  • Example 4 Preparation of a solid dispersion of trisodium sacubitril valsartan with 50% w/w ⁇ -cyclodextrin ⁇ -cyclodextrin (10 g) was dissolved in a mixture of water (150 ml) and ethanol (50 ml) at 75 ⁇ 5 °C. The solution was then cooled to 25 ⁇ 5°C and amorphous trisodium sacubitril valsartan (10 g) was added. The mixture was stirred for 15-30 minutes and the resulting solution was filtered through Hyflo to remove any undissolved particulate.
  • Example 5 Preparation of a solid dispersion of trisodium sacubitril valsartan with 50% w/w hydroxypropyl-P-cyclodextrin
  • Amorphous trisodium sacubitril valsartan (10 g) and hydroxypropyl-P-cyclodextrin (10 g) were dissolved in ethanol (200 ml) at 65 ⁇ 5°C.
  • the resulting solution was filtered through Hyflo to remove any undissolved particulate and the filtrate was subjected to spray drying in a laboratory spray dryer (Model Buchi-290) with inlet temperature at 80 °C and with 100% aspiration to yield a solid dispersion oftrisodium sacubitril valsartan with 50% w/w hydroxypropyl-P-cyclodextrin.
  • Example 6 Preparation of a solid dispersion of trisodium sacubitril valsartan with 50% HPMC-HME Amorphous trisodium sacubitril valsartan (9 g) was dissolved in ethanol (25 ml) at 25 ⁇ 2°C. In another flask, hydroxyl propyl methylcellulose (HPMC-HME 15LV, 9 g) was dissolved in ethanol (200 ml) at 75 ⁇ 5°C and cooled to 25 ⁇ 2°C.
  • HPMC-HME 15LV hydroxyl propyl methylcellulose
  • Example 7 Preparation of a solid dispersion of trisodium sacubitril valsartan with 50% Plasdone S-630 by hot melt-extrusion
  • Amorphous trisodium sacubitril valsartan (10 g) andPlasdone S-630 (10 g) were passed through a 40mesh sieve and subjected to melt extrusion on hot melt extruder instrument (Make: Leistritz, model: Nanol6) with following experimental conditions: Zone-1 temperature: 110°C, Zone-2 temperature: 135°C, Zone-3 temperature: 145°C and exit zone temperature of 160°C.
  • the product was milled the product at 25 ⁇ 2°C. Characterization by PXRD showed it to beamorphous.
  • Example 8 Preparation of a solid dispersion of trisodium sacubitril valsartan with 40% w/w Plasdone S-630 and 10% Tween 80 by hot melt-extrusion
  • a mixture of amorphous trisodium sacubitril valsartan (10 g), Plasdone S-630 (8 g), and Tween 80 (2 g) was prepared. The mixture was then milled and passed through 40mesh sieve. The homogeneous mixture was then subjected to melt extrusion on hot melt extruder instrument (Make: Leistritz, model: Nanol6) with following experimental conditions: Zone-1 temperature: 60°C, Zone-2 temperature: 90°C, Zone-3 temperature: 100 °C and exit zone temperature of 100 °C. The product obtained was milled at 25 ⁇ 2°C. Characterization by PXRD revealed the final product to be amorphous.
  • Example 9 Preparation of a solid dispersion of trisodium sacubitril valsartanwith 40% w/w Plasdone S-630 and 10% Span 20 by hot melt-extrusion
  • a mixture of amorphous trisodium sacubitril valsartan amorphous form (10 g), Plasdone S-630 (8 g), and Span 20 (2 g) was prepared. The mixture was milled and passed through 40mesh sieve. The homogeneous mixture was subjected to melt extrusion on hot melt extruder instrument (Make: Leistritz, model: Nanol6) with following experimental conditions: Zone-1 temperature: 60°C, Zone-2 temperature: 90°C, Zone-3 temperature: 100°C and exit zone temperature of 100°C. The product obtained was milled at 25 ⁇ 2°C and characterizedby PXRD as amorphous.
  • Example 10 Preparation of a solid dispersion of trisodium sacubitril valsartan with 50% w/w Eudragit E PO
  • Sacubitril (25 g) and valsartan (26.4 g) were dissolved in ethanol (150 ml).
  • sodium hydroxide (7.25 g) dissolved in water (20 mL) then diluted with ethanol (50 ml).
  • the sodium hydroxide solution was added to the above solution of sacubitril and valsartan to form a reaction mass, which was stirred for 90-120 minutes at 25-30°C and concentrated under vacuum. Traces of water were removed using ethanol (3x75 ml) until the moisture level of the resulting residue dropped to less than 0.5%.
  • Ethyl acetate (150 ml) was added to the residue and the mixture was stirred at 40-45 °C until a clear solution was formed.
  • Example 11 Preparation of a solid dispersion of trisodium sacubitril valsartan with 50% w/w Ethocel Sacubitril (5 g) and valsartan (5.3 g) were dissolved in ethanol (30 ml).
  • Ethocel Sacubitril 5 g
  • valsartan 5.3 g
  • ethanol 30 ml
  • sodium hydroxide 1.25g was dissolved in water (4 ml) then diluted with ethanol (10 ml).
  • the sodium hydroxide solution was added to the above clear solution of sacubitril and valsartan to form a reaction mass, which was stirred for 30 minutes at 25-30°C and concentrated under vacuum. Traces of water were removed using ethanol(3xl5 ml) until the moisture level of the residue was to less than 0.5%.
  • Example 12 Preparation of a solid dispersion of trisodium sacubitril valsartan with 50% Aeroperl 300 Sacubitril (5 g) and valsartan (5.3 g) were dissolved in ethanol (30 ml). In another flask,sodium hydroxide (1.425 g) was dissolved in water (4 ml) then diluted with ethanol (10 ml). This sodium hydroxide solution was then added to the above clear solution of sacubitril and valsartan to form a reaction mass. The reaction mass was stirred for 30 minutes at 25-30°C andconcentrated under vacuum. Traces of water were removed using ethanol(3xl5 ml) until the moisture level of the residue fell below 0.5%.
  • Example 13 Preparation of a solid dispersionof trisodium sacubitril valsartan with 50% w/w Aeroperl
  • Sacubitril (10 g) and valsartan (10.6 g) were dissolved in ethanol (60 ml).
  • sodium hydroxide (2.9 g) was dissolved in water (8 ml) then diluted with ethanol (20 ml).
  • Thesodium hydroxide solution was added to the above clear solution of sacubitril and valsartan to form a reaction mass.
  • the reaction mass was stirred for 90 minutes at 25-30°C then concentrated under vacuum maintaining the temperature below 60°C.
  • Methylene dichloride (150 ml) was charged to the reaction mass and water was removed azeotropically from the reaction mass until the moisture content dropped below 0.20%.
  • the reaction mass was cooled to 25-30°C and Aeroperl 300 (20 g) was added.
  • Example 14 Preparation of a solid dispersion of trisodium sacubitril valsartan with 50% Syloid AL-I FP
  • Sacubitril (5 g) and valsartan (5.3 g) were dissolved in ethanol (30 ml).
  • sodium hydroxide (1.425 g) was dissolved in water (4 ml) then diluted with ethanol (10 ml).
  • Thesodium hydroxide solution was added to the above clear solution of sacubitril and valsartan to form a reaction mass.
  • the reaction mass was stirred for 30 minutes at 25-30°C then concentrated under vacuum. Traces of water were removed using ethanol (3x15 ml) until the moisture level of the residue dropped below 0.5%.
  • Ethyl acetate (30 ml) was added to the residue and the resulting mixture was stirred at 40-45 °C until it became clear solution.
  • Example 15 Preparation of a solid dispersion of trisodium sacubitril valsartan with 40% HPMC and 10 % stearic acid
  • Amorphous trisodium sacubitril valsartan (5 g), hydroxypropyl methylcellulose (E6 Premium LV) (4g) and stearic acid (lg) were suspended in mixture of water (60 ml) and ethanol (120 ml) at 25-30°C. The reaction mass was heated to 75-85°C to obtain aclear solution. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate.
  • the clear solution was re -heated to 55-65°C and subjected to spray-drying in a laboratory spray dryer (Model Buchi-290) with inlet temperature at 100 °C and a flow rate of 5ml/minute to yield a solid dispersion of trisodium sacubitril valsartan with 40% w/w HPMC and 10% w/w stearic acid.
  • Example 16 Preparation of a solid dispersion of trisodium sacubitril valsartan with 40% HPMC and 10% stearic acid
  • Sacubitril (5 g) and valsartan (5.3 g) were dissolved in ethanol (30 ml).
  • sodium hydroxide (1.425g) was dissolved in water (4ml) then diluted with ethanol (10ml). This sodium hydroxide solution was added to the above clear solution of sacubitril and valsartan to form a reaction mass.
  • the reaction mass was stirred for 30 minutes at 25-30°C then concentrated under vacuum. Traces of water were removed using ethanol (3x15ml) until the moisture level of the resulting residue dropped below 0.5%.
  • Example 17 Preparation of a solid dispersion of trisodium sacubitril valsartan with 40% HPMC and 10% sodium stearyl fumarate
  • Amorphous trisodium sacubitril valsartan (5 g), hydroxypropyl methylcellulose (E6 Premium LV) (4g) and sodium stearyl fumarate (lg) were suspended in a mixture of water (60 ml) and ethanol (120 ml) at 25-30°C. The reaction mass was heated to 75-85°C to obtain a clear solution. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate.
  • the clear solution was re -heated to 55-65°C and subjected to spray-drying in a laboratory spray dryer (Model Buchi-290) with inlet temperature at 100 °C and flow rate of 5 ml/minute to yield a solid dispersion of trisodium sacubitril valsartan with 40% HPMC and 10% sodium stearyl fumarate.
  • Example 18 Preparation of a solid dispersion of trisodium sacubitril valsartan with 45% HPMC and 5% magnesium stearate
  • Amorphous trisodium sacubitril valsartan (5 g) was dissolved in ethyl acetate (50 ml). The reaction mass was heated to 50-55°C. Hydroxy propyl methylcellulose (4.5 g) and magnesium stearate (0.5g) were charged to the solution. The reaction mass was stirred at 50-55 °C for 15-30 minutes. The reaction mass was concentrated under vacuum maintaining the temperature below 60°C. Traces of water were removed using isopropyl ether (50 ml). Isopropyl ether (50 ml) was again charged to the reaction mass which was cooled to 25-30°C then stirred for 30 minutes.
  • Example 19 Preparation of a solid dispersion of trisodium sacubitril valsartan with 45% HPMC and 5% sodium stearyl fumarate
  • Amorphous trisodium sacubitril valsartan (5 g) was dissolved in ethyl acetate (50 ml). The reaction mass was heated at 50-55 °C to dissolve the solids. Hydroxypropyl methylcellulose (4.5 g) and sodium stearyl fumarate (0.5 g) were charged to the solution which was then stirred at 50-55 °C for 15-30 minutes. The reaction mass was concentrated under vacuum maintaining the temperature below 60°C. Traces of water were removed using isopropyl ether (50 ml). Isopropyl ether (50 ml) was again charged to the reaction mass which was then cooled to 25- 30 °C and stirred for 30 minutes.
  • reaction mass was then filtered and the obtained solid was washed with isopropyl ether (10 ml).
  • the solid was then dried in under vacuum oven to get 9.6 g of a solid dispersion of trisodium sacubitril valsartan with 45% HPMC and 5% sodium stearyl fumarate.
  • Example 20 Preparation of a solid dispersion of trisodium sacubitril valsartan with 40% HPMC and 10% sodium stearyl fumarate
  • Amorphous trisodium sacubitril valsartan (25g), hydroxypropyl methylcellulose (E6 Premium LV, 20g), and sodium stearyl fumarate (5g) were suspended in a mixture of water (300 ml) and ethanol (600 ml) at 25-30°C. The reaction mass was heated to 75-85°C to obtain a clear solution. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate and washed with mixture of water and ethanol (1:2 ratio, 50 ml).
  • the clear solution was re-heated to 55-65°C and subjected to spray-drying in a laboratory spray dryer (Model Buchi-290) with inlet temperature at 100 °C and flow rate of 5ml/minute to yield a solid dispersion of trisodium sacubitril valsartan with 40% HPMC and 10% sodium stearyl fumarate.
  • Example 21 Preparation of a solid dispersion of trisodium sacubitril valsartan with 18% HPMC and 2% sodium stearyl fumarate
  • Amorphous trisodium sacubitrilvalsartan (50g), hydroxypropylmethylcellulose (E6 Premium LV, 11.25g) and sodium stearyl fumarate (1.25g) were suspended in a mixture of water (300 ml) and ethanol (900 ml) at 25-30 °C. The reaction mass was heated to 75-85 °C to obtain a clear solution. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate and washed with mixture of water and ethanol (1:2 ratio, 50 ml).
  • Example 22 Preparation of a solid dispersion of trisodium sacubitril valsartan with 18% HPMC and 2% sodium stearyl fumarate
  • Amorphous trisodium sacubitril valsartan (25g), hydroxypropyl methylcellulose (E3 Premium LV, 5.625g) and sodium stearyl fumarate (0.625g) were suspended in a mixture of water (150 ml) and ethanol (450 ml) at 25-30°C. The reaction mass was heated to 75-85°C to obtain a clear solution. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate and washed with mixture of water and ethanol (1:2 ratio, 50 ml).
  • Example 23 Preparation of a solid dispersion of trisodium sacubitril valsartan with 18% Plasdone S-630 and 2% sodium stearyl fumarate
  • Amorphous trisodium sacubitrilvalsartan (50g), Plasdone S-630 (11.25g), and sodium stearyl fumarate (1.25g) were dissolved in ethanol (950 ml) at 75-85°C. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate and washed with ethanol (50 ml).
  • the clear solution was re-heated to 55-65°C and subjected to spray-drying in a laboratory spray dryer (Model Buchi-290) with inlet temperature at 70 °C and flow rate of 5ml/minute to yield a solid dispersion of trisodium sacubitrilvalsartan with 18% Plasdone S-630 and 2% sodium stearyl fumarate.
  • Example 24 Preparation of a solid dispersion of trisodium sacubitril valsartan with 26.7% HPMC and 7% sodium stearyl fumarate
  • Amorphous trisodium sacubitrilvalsartan (5g), hydroxypropyl methylcellulose (E6 Premium LV) (2g) and sodium stearyl fumarate (0.5g) were suspended in a mixture of water (60 ml) and ethanol (133 ml) at 25-30°C. The reaction mass was heated to 70-75°C to obtain a clear solution. The resulting clear solution was filtered through Hyflo to remove any undissolved particulate and washed with mixture of water and ethanol (1:2 ratio, 15 ml).
  • the clear solution was re-heated to 55-65°C and subjected to spray-drying in a laboratory spray dryer (Model Buchi-290) with inlet temperature at 100°C and flow rate of 5ml/minute to yield a solid dispersion of trisodium sacubitrilvalsartan with 26.7% HPMC and 7% sodium stearyl fumarate.
  • Example 25 Tablet formulation containing 200mg equivalent of sacubitril-valsartan prepared using a solid dispersion of trisodium sacubitril valsartan with 18% HPMC and 2% sodium stearyl fumarate
  • a solid dispersion of trisodium sacubitril valsartan amorphous, microcrystalline cellulose, low substituted hydroxypropylcellulose, crospovidone, and colloidal silicon dioxide were sifted together through a suitable sieve.
  • Magnesium stearate (intragranular) and magnesium stearate (extragranular) were sifted separately through a suitable sieve.
  • Step No. 3 The sifted material in Step No. 1 was charged into a low shear bin blender and blended for a suitable time.
  • Step No.4 Magnesium stearate (intragranular) of Step No.2 was added to Step 3 blend and blended for a suitable time. 5 Step No.4 blend was compacted using roll compactor.
  • Step No.5 compacts were milled through a suitable screen.
  • Step No. 6 The milled material of Step No. 6 was sifted through ASTM 25 mesh (710 microns) and the retained portion and passing portion were collected separately.
  • Step no. 2 Magnesium stearate (extragranular) of Step no. 2 was added to the blended material of Step no.7 and blended for a suitable time.
  • Crospovidone and colloidal silicon dioxide were added to the material of Step no.8 and blended for a suitable time.
  • a coating dispersion of PVA-based coating (Opadry AMB-II) white in purified water was prepared and the tablets were coated in a perforated coating pan.
  • Example 26 Tablet formulation containing 200 mg equivalent of sacubitril-valsartan prepared using a solid dispersion of trisodium sacubitril valsartan with 18% Plasdone S- 630 and 2% sodium stearyl fumarate
  • Example 27 Tablet formulation containing 200 mg equivalent of sacubitril-valsartan prepared using an amorphous trisodium sacubitril valsartan

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Abstract

La présente invention concerne des dispersions solides de sacubitril/valsartan trisodique. Ces dispersions solides peuvent être utiles dans la fabrication de formes posologiques pharmaceutiques.
PCT/IN2017/050467 2016-10-13 2017-10-12 Dispersions solides de sacubitril/valsartan trisodique et procédé de leur préparation WO2018069937A1 (fr)

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WO2018178295A1 (fr) * 2017-03-31 2018-10-04 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Extrudat thermofusible stable contenant du valsartan et du sacubitril
WO2019239432A1 (fr) * 2018-06-14 2019-12-19 Cipla Limited Complexe de valsartan et de sacubitril trisodique et composition pharmaceutique extrudée à chaud comprenant celui-ci
WO2020039386A1 (fr) 2018-08-23 2020-02-27 Novartis Ag Nouvelle utilisation pharmaceutique pour le traitement d'une insuffisance cardiaque
WO2020039394A1 (fr) 2018-08-24 2020-02-27 Novartis Ag Nouvelles combinaisons de médicaments
WO2021172960A1 (fr) * 2020-02-26 2021-09-02 에리슨제약(주) Préparation à libération prolongée pour traiter une insuffisance cardiaque, comprenant du sacubitril et du valsartan, préparation complexe à libération multiple comprenant celle-ci et procédé de préparation associé
EP4268806A1 (fr) * 2022-04-26 2023-11-01 Sanovel Ilac Sanayi Ve Ticaret A.S. Comprimé comprenant du sacubitril et du valsartan traité par granulation sèche
WO2023211412A1 (fr) * 2022-04-26 2023-11-02 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Comprimé comprenant du sacubitril et du valsartan traité par granulation sèche

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018178295A1 (fr) * 2017-03-31 2018-10-04 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Extrudat thermofusible stable contenant du valsartan et du sacubitril
WO2019239432A1 (fr) * 2018-06-14 2019-12-19 Cipla Limited Complexe de valsartan et de sacubitril trisodique et composition pharmaceutique extrudée à chaud comprenant celui-ci
WO2020039386A1 (fr) 2018-08-23 2020-02-27 Novartis Ag Nouvelle utilisation pharmaceutique pour le traitement d'une insuffisance cardiaque
WO2020039394A1 (fr) 2018-08-24 2020-02-27 Novartis Ag Nouvelles combinaisons de médicaments
WO2021172960A1 (fr) * 2020-02-26 2021-09-02 에리슨제약(주) Préparation à libération prolongée pour traiter une insuffisance cardiaque, comprenant du sacubitril et du valsartan, préparation complexe à libération multiple comprenant celle-ci et procédé de préparation associé
EP4268806A1 (fr) * 2022-04-26 2023-11-01 Sanovel Ilac Sanayi Ve Ticaret A.S. Comprimé comprenant du sacubitril et du valsartan traité par granulation sèche
WO2023211412A1 (fr) * 2022-04-26 2023-11-02 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Comprimé comprenant du sacubitril et du valsartan traité par granulation sèche

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