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WO2024165966A1 - Compositions de riociguat à libération prolongée et à rétention gastrique - Google Patents

Compositions de riociguat à libération prolongée et à rétention gastrique Download PDF

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Publication number
WO2024165966A1
WO2024165966A1 PCT/IB2024/051021 IB2024051021W WO2024165966A1 WO 2024165966 A1 WO2024165966 A1 WO 2024165966A1 IB 2024051021 W IB2024051021 W IB 2024051021W WO 2024165966 A1 WO2024165966 A1 WO 2024165966A1
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WO
WIPO (PCT)
Prior art keywords
riociguat
composition
extended release
gastroretentive extended
release composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2024/051021
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English (en)
Inventor
Kannan Essakimuthu MUTHAIYYAN
Chetan Rajashekhara Murthy
Vimal Tulsidas KANERIA
Nikalesh Ravindrabhai PATEL
Krunal Dineshbhai PATEL
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Zydus Lifesciences Ltd
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Zydus Lifesciences Ltd
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Publication of WO2024165966A1 publication Critical patent/WO2024165966A1/fr
Anticipated expiration legal-status Critical
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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to gastroretentive extended release compositions of riociguat.
  • the compositions of the invention are stable, possess improved formulation characteristics and also provide extended therapeutically effective plasma levels over twenty four hours time period.
  • the invention also relates to processes of preparing such compositions.
  • Riociguat is a stimulator of soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system and the receptor for nitric oxide (NO) and useful for the treatment of pulmonary hypertension.
  • sGC soluble guanylate cyclase
  • NO nitric oxide
  • U.S. Patent No. 7,173,037 discloses riociguat and its related compounds, along with their pharmaceutically acceptable salts.
  • Riociguat is approved in the US under the brand Adempas as an immediate release tablet form with doses ranging from 0.5 mg to 2.5 mg administered TID (three times a day) for the treatment of chronic-thromboembolic pulmonary hypertension and pulmonary arterial hypertension.
  • Existing marketed tablet formulations of riociguat provide immediate release of the active ingredient once the tablet reaches the stomach.
  • the absolute bioavailability of riociguat is high, about 94% and the peak plasma concentrations are observed within 1.5 hours following drug administration.
  • administration of an immediate -release tablet can lead to greater frequency of adverse pharmacological events due to fast rate of absorption.
  • Another disadvantage of the immediate release tablet dosage form is that the blood plasma concentration achieved with these tablets is cyclical, with peaks occurring after administration of drug followed by troughs occurring before the next administration of drug.
  • a gastroretentive extended release composition comprising riociguat and one or more pharmaceutically acceptable excipients.
  • a gastroretentive extended release composition of riociguat suitable for once-a-day or twice-a-day administration.
  • a stable gastroretentive extended release composition comprising riociguat, at least one swellable polymer and optionally, one or more pharmaceutically acceptable excipients, wherein the composition is stable at 40° C and 75% relative humidity for at least one month.
  • Embodiments of the gastroretentive extended release composition may include one or more of the following features.
  • the pharmaceutically acceptable excipients may include swellable polymers, gas generating agents, release retarding agents, fillers, binders, disintegrants, glidants, lubricants, antiadherents, plasticizers and the like.
  • a method of treating hypertension which comprises orally administering to a patient a therapeutically effective amount of riociguat in the form of a gastroretentive extended release composition comprising riociguat and at least one swellable polymer.
  • composition of the present invention comprises riociguat and one or more pharmaceutically acceptable excipients.
  • riociguat should be understood, unless otherwise indicated herein, to include methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5- pyrimidinyl(methyl)carbamate or any pharmaceutically acceptable salt thereof.
  • Riociguat may be present in crystalline or amorphous form.
  • the pharmaceutical composition of the present invention comprises about 0.5 mg to about 7.5 mg of riociguat. Typically, the composition of the present invention comprises from about 0.5% to 10% by weight of riociguat.
  • composition of the present invention comprises riociguat and one or more pharmaceutically acceptable excipients wherein D90 of said riociguat is less than 20pm, preferably less than 15 pm, more preferably less than 10pm.
  • composition of the present invention comprises riociguat and one or more pharmaceutically acceptable excipients wherein said riociguat is in crystalline form.
  • composition of the present invention comprises crystalline riociguat and one or more pharmaceutically acceptable excipients wherein said riociguat has an X-ray powder diffraction pattern (XRPD) comprising peaks at an angle 20 ⁇ 0.2° of 6.7°, 9.1°, 17.8°, 20.2°, 25.6°, and 27.3°.
  • XRPD X-ray powder diffraction pattern
  • the composition of the present invention comprises riociguat and one or more pharmaceutically acceptable excipients wherein said riociguat dissolves completely at pH less than 6.5, preferably at pH less than 4.5, more preferably at pH less than 1.5.
  • pharmaceutically acceptable excipient also named as “excipients” as used herein, refers to a substance formulated alongside with the active pharmaceutical ingredient of a medicinal product and includes all kind of pharmaceutically acceptable compounds commonly used in pharmaceutical compositions and in particular extended composition or gastroretentive composition.
  • pharmaceutically acceptable excipients comprise diluents, binders, disintegrants, gas generating agents, swelling agents, release retardant agents, lubricants, antiadherents, organic acids, sweeteners, glidants, colorants, flavor agents and the like.
  • composition means that upon oral administration at least a portion of the composition remains in the stomach for a period that is longer than the normal emptying time from the stomach, i.e., longer than about 2 hours, particularly longer than about 3 hours, and more particularly longer than about 4, 6, 8, or 10 hours.
  • extended release refers to riociguat release over a prolonged period of time, e.g., more than about 4, 6, 8, 16, or 24 hours following ingestion.
  • the extended release tablets include, but not limited to, conventional extended release tablets, gastroretentive tablets, two or more layered tablets (including bi-layer, tri-layer), tablet-in-tablets, osmotic tablets, minitablets, or coated tablets (including enteric coating, non-enteric coating).
  • lag time refers to time taken for gastroretentive pharmaceutical composition of riociguat to reach to the surface of gastric juice in stomach of patient(s).
  • method of treatment or “therapy” (as well as different forms thereof) as used herein include preventative (e.g., prophylactic), curative, or palliative treatment.
  • treating includes alleviating or reducing at least one adverse or negative effect or symptom of a condition, disease or disorder.
  • This condition, disease or disorder may refer to pulmonary hypertension, chronic-thromboembolic pulmonary hypertension or pulmonary arterial hypertension.
  • subject or “patient” as used interchangeably herein, and refer to a human, to whom treatment, including prophylactic treatment, with a dosage form described herein, is provided.
  • C max refers to the maximum plasma, serum, or blood concentration of a drug, following administration of the drug.
  • AUC refers to the “area under the curve” and is a measurement for the plasma concentration over the entire dosing interval.
  • swellable polymer refers to a polymer that swells in the presence of a fluid.
  • suitable swellable polymers include, but not limited to, polyethylene oxide, hydroxypropylmethyl cellulose, xanthan gum, and sodium alginate.
  • the swellable polymer may be present in an amount of from about 1 % to about 60% by weight of the composition.
  • the composition of the present invention comprises riociguat, at least one swellable polymer and pharmaceutically acceptable excipients wherein the swellable polymer has viscocity less than 5000 mPa sec, less than 4000 mPa sec, preferably less than 3000 mPa sec, or more preferably less than 2000 mPa sec.
  • release retarding agent refers to any material or substance that slows the release of the drug from the pharmaceutical composition.
  • a release retarding agent can be a polymer or a non-polymer.
  • suitable release retarding agents include, but not limited to, cellulose derivatives such as, ethylcellulose, hydroxypropylmethylcellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate mellitate, cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, and carboxymethyl cellulose ether; polyvinyl acetate phthalate; polyester of styrene and maleic acid copolymer; polyester of vinylether and maleic acid copolymer; vinylacetate and crotonic acid copolymer; copolymers of methacrylic acid and ethylacrylate; copolymers of methacrylic acid and methacrylate; copolymers of methacrylate/
  • composition of the present invention comprises riociguat and one or more pharmaceutically acceptable excipients wherein said composition comprises one or more release retarding agents or one or more swellable polymers or both.
  • composition of the present invention comprises riociguat, one or more release retarding agents, one or more swellable polymers, and one or more pharmaceutically acceptable excipients wherein the swellable polymer or the release retarding agent is hydroxypropylmethylcellulose.
  • the composition of the present invention comprises, riociguat, hydroxypropylmethylcellulose, and one or more pharmaceutically acceptable excipients wherein the hydroxypropylmethylcellulose is hydroxypropylmethylcellulose K15M, hydroxypropylmethylcellulose K100M Premium CR, hydroxypropylmethylcellulose K4M, hydroxypropylmethylcellulose K100LV, or mixture thereof.
  • the erodible or non-erodible polymeric release retardant may be present in an amount of from about 1% to about 70% by weight of the composition, preferably from about 1% to about 50% by weight of the composition, more preferably from about 1% to about 30% by weight of the composition, most preferably from about 1% to about 10% by weight of the composition.
  • the release retardant polymer is present in an amount of from about 1% to about 5% by weight of the composition.
  • the composition of the present invention in addition to the release retarding agents, may also include one or more pharmaceutically acceptable excipients like diluents, binders, gas generating agents, swellable polymers, disintegrants, glidants, lubricants, antiadherents, plasticizers, or mixture thereof.
  • Suitable diluents include, but not limited to, powdered sugar, calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, lactose, mannitol, kaolin, sodium chloride, dry starch, and sorbitol.
  • the diluent may be present in an amount of from 5% to 90% by weight of the composition.
  • Suitable binders include, but are not limited to, polyvinylpyrrolidone, xanthan gum, cellulose derivatives such as carboxymethylcellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, gelatin, starch, and pregelatinized starch.
  • the binder may be present in an amount of from 1% to 20% by weight of the composition.
  • suitable gas generating agents include, but are not limited to, carbonates such as sodium carbonate, potassium carbonate, calcium carbonate; amino acid-alkali metal carbonate derivatives; bicarbonates such as sodium or potassium bicarbonate; sulfites such as sodium sulfite, sodium bisulfite, or sodium metabisulfite, and the like.
  • the gas generating agent may be present in an amount of from about 1% to about 50% by weight of the composition, more preferably from about 1% to about 15% by weight of the composition.
  • These agents may be used alone or in combination with one or more acid sources.
  • the acid source may be an organic acid, a salt of an organic acid, or mixtures thereof.
  • organic acids examples include citric acid, malic acid, succinic acid, tartaric acid, fumaric acid, maleic acid, ascorbic acid, glutamic acid, and their salts, and mixtures thereof.
  • the acid source may be present in an amount of from about 1% to about 50% by weight of the composition.
  • Suitable disintegrants include, but are not limited to, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethyl cellulose, pregelatinized starch, low- substituted hydroxypropylcellulose, and sodium starch glycolate.
  • the disintegrant may be present in an amount of from 0.5% to 20% by weight of the composition.
  • Suitable lubricants or glidants include, but are not limited to, talc, colloidal silicon dioxide, stearic acid, vegetable oil, calcium stearate, zinc stearate, and magnesium stearate.
  • the lubricant may be present in an amount of from 0.1% to 10% by weight of the composition.
  • antiadherents examples include, but are not limited to, silicon dioxide, calcium silicate, salts of stearic acid or sodium stearyl fumarate, talc, leucine, starch, cellulose, and talc.
  • the antiadherent may be present in an amount of from 0.1% to 5% by weight of the composition.
  • plasticizers include, but are not limited to, dibutyl phthalate, dibutyl sebacate, diethyl phthalate, dimethyl phthalate, triethyl citrate, benzyl benzoate, butyl and glycol esters of fatty acids, mineral oil, oleic acid, stearic acid, cetyl alcohol, stearyl alcohol, castor oil, corn oil, coconut oil, and camphor oil.
  • the plasticizer may be present in an amount of from 0.01% to 20% by weight of the composition.
  • excipients that can be incorporated into the composition include, but are not limited to, preservatives, antioxidants, or any other excipient commonly used in the pharmaceutical industry or general state of art.
  • riociguat is embedded into an erodible or non-erodible polymeric matrix.
  • An erodible matrix includes a matrix which is either erodible or dissolvable in aqueous medium in presence or absence of an acid or base to ionize the polymeric matrix sufficiently to cause erosion or dissolution.
  • polymers used for preparation of erodible, or soluble matrix include but not limited to, naturally occurring polysaccharides such as chitin, chitosan, dextran and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, guar gum, xanthan gum and scleroglucan; starches such as dextrin and maltodextrin; hydrophilic colloids such as pectin; alginates such as ammonium alginate, sodium, potassium or calcium alginate, propylene glycol alginate; gelatin; collagen; and cellulosics such as methylethyl cellulose, carboxymethyl cellulose, carboxymethylethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl
  • riociguat is distributed in an inert matrix.
  • the drug is released by diffusion through the inert matrix.
  • materials suitable for the inert matrix include, but not limited to, copolymers of ethylene and vinyl acetate, methyl acrylate-methyl methacrylate copolymers, polyacrylamide, polyvinyl chloride, and polyethylene; ethyl cellulose, cellulose acetate, crosslinked polyvinylpyrrolidone, and fatty compounds, such as carnauba wax, microcrystalline wax, and triglycerides.
  • the erodible or non-erodible polymeric release retardant may be present in an amount of from about 1% to about 70% by weight of the composition.
  • composition of the present invention can be in the form of granules, tablets, or granules filled in capsules.
  • composition of the present invention may be in the form of a tablet wherein said tablet comprises riociguat, one or more diluents, one or more disintegrants, one or more effervescent agents, one or more binders, one or more swellable polymer, one or more release retarding agents, one or more glidants, one or more lubricants, one or more colorants or mixture thereof, wherein said tablet is an extended release tablet.
  • composition of the present invention may be in the form of a tablet wherein said tablet comprises riociguat, microcrystalline cellulose, lactose monohydrate, hydroxypropyl methylcellulose, sodium bicarbonate, povidone, magnesium stearate, or mixture thereof, wherein said tablet is an extended release tablet.
  • the composition of the present invention may be in the form of a tablet, wherein said tablet is a bilayer or multilayer tablet, optionally said tablet is an extended release tablet.
  • composition of the present invention may be a bilayer tablet wherein said bilayer tablet comprises an immediate release layer, an extended release layer, or a combination of both the layers.
  • composition of the present invention may be a bilayer tablet wherein said bilayer tablet comprises an immediate release layer, comprising riociguat, one or more diluents, one or more disintegrants, one or more gas generating agents, one or more binders, one or more glidants, one or more lubricants, one or more colorants or mixture thereof.
  • composition of the present invention can be in form bilayer tablet wherein said bilayer tablet comprises an extended release layer comprising riociguat, one or more diluents, one or more disintegrants, one or more effervescent agents, one or more binders, one or more swellable polymers, one or more release retarding agents, one or more glidants, one or more lubricants, one or more colorants, or mixture thereof.
  • composition of the present invention can be in form of a bilayer tablet, wherein said bilayer tablet comprises an immediate release layer, an extended release layer, or combination of both the layers, wherein said immediate release layer comprises riociguat, one or more diluents, one or more disintegrants, one or more effervescent agents, one or more binders, one or more glidants, one or more lubricants, one or more colorants, or mixture thereof, and wherein said extended release layer comprises riociguat, one or more diluents, one or more disintegrants, one or more gas generating agents, one or more binders, one or more swellable polymer, one or more release retarding agents, one or more glidants, one or more lubricants, one or more colorants, or mixture thereof.
  • composition of the present invention can be a bilayer tablet, wherein said bilayer tablet comprises an immediate release layer, an extended release layer, or combination of both the layers, wherein said immediate release layer comprises microcrystalline cellulose, lactose monohydrate, ferric oxide, povidone, magnesium stearate, or mixture thereof, and wherein said extended release layer comprises riociguat, microcrystalline cellulose, lactose monohydrate, one or more swellable polymer, one or more release retarding agents, sodium bicarbonate, povidone, magnesium stearate, or mixture thereof.
  • composition of the present invention can be a bilayer tablet wherein said bilayer tablet comprises an immediate release layer and an extended release layer, wherein said immediate release layer comprises microcrystalline cellulose, lactose monohydrate, ferric oxide, povidone, magnesium stearate, or mixture thereof, and wherein said extended release layer comprises riociguat, microcrystalline cellulose, lactose monohydrate, hydroxypropyl methylcellulose, sodium bicarbonate, povidone, magnesium stearate, or mixture thereof.
  • composition of the present invention may be generally prepared using standard techniques well known in the art. Typically, they may be prepared by blending one or more swellable polymers, one or more release retarding agents, riociguat, and other excipients followed by granulating the mixture using a solvent until proper granulation is obtained.
  • the wet granules may be dried in a fluid bed dryer, sifted and ground to an appropriate size.
  • Lubricating agents may be mixed with the dried granules to obtain the final dosage form. Alternatively, the granules can be filled into a hard gelatin capsule or compressed into a tablet.
  • the tablets may be prepared using direct compression of a powdered or granular composition containing riociguat, alone or in combination with one or more release retarding agents, one or more swellable polymers and one or more pharmaceutically acceptable excipients.
  • the term “external water” as used herein, refers to the aqueous solvent which is added during the manufacturing steps of granules that can be filled into a hard gelatin capsule or compressed into a tablet.
  • the pharmaceutical composition of the present invention is prepared by a process known in general state of art including direct compression, wet granulation or dry granulation, wherein said process is devoid of addition of external water.
  • a stable gastroretentive extended release composition comprising riociguat, at least one swellable polymer and one or more pharmaceutically acceptable excipients.
  • a stable gastroretentive extended release composition comprising riociguat, wherein said composition provides lag time of less than 60 seconds, preferably less than 45 seconds, more preferably less than 30 seconds.
  • a stable gastroretentive extended release composition comprising riociguat, wherein said composition has floating time of at least about 16 hours, preferably at least about 12 hours, more preferably at least about 10 hours.
  • a stable gastroretentive extended release composition comprising riociguat, wherein said composition has water content not more than 0.5% w/w.
  • stable means retaining substantially the same properties and characteristics of the active ingredient throughout its period of storage and use that it possessed at the time of its manufacture, such that the composition provides substantially the same therapeutic benefit to the patient over the period of time that the composition is stored and delivered.
  • composition described herein retains at least 80% of the potency of riociguat after storage at 40 °C and 75% relative humidity for at least 1 month, for example, for 3 months, 6 months, 12 months, 24 months.
  • the present invention provides a gastroretentive extended release pharmaceutical composition of riociguat, wherein said composition has water content not more than 0.5% w/w after storage at 40 °C and 75% relative humidity for at least 1 month.
  • impurity means unwanted chemicals that remain with the active pharmaceutical ingredients (APIs), or develop during formulations, or upon degradation of API and/or formulations.
  • the present invention provides a gastroretentive extended release pharmaceutical composition of riociguat, wherein said composition comprises individual impurity including, but not limited to, methyl 4,6-diamino-2-(l-(2-fluorobenzyl)-lH- pyrazolo[3,4-b]pyridin-3-yl) pyrimidin-5-ylcarbamat, methyl (4,6-diamino-2-(l-benzyl-lH- pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-yl)(methyl)carbamate, methyl (4-amino-2-(l-(2- fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)-6-(methylamino)pyrimidin-5- yl)(methyl)carbamate, isopropyl (4,6-diamino-2-(l-(2-fluorobenzyl)
  • the present invention provides a gastroretentive extended release pharmaceutical composition of riociguat, wherein total impurity content of said composition is not more than about 0.50% by weight of the composition.
  • the present invention provides a gastroretentive extended release pharmaceutical composition of riociguat, wherein said composition has individual impurity content not more than about 0.15% by weight of composition after storage at 40 °C and 75% relative humidity for at least 1 month, for example, for 3 months, 6 months, 12 months, 24 months.
  • the present invention provides a gastroretentive extended release pharmaceutical composition of riociguat, wherein said composition has total impurity content of not more than about 0.50% by weight of composition after storage at 40 °C and 75% relative humidity for at least 1 month, for example, for 3 months, 6 months, 12 months, 24 months.
  • the present invention provides a gastroretentive extended release pharmaceutical composition of riociguat, wherein said composition releases not more than about 40% of riociguat in 1 hour, when subjected to a test medium comprising 900 mL of 0.1 N HC1 at 37 °C in a standard USP basket apparatus at 100 rpm.
  • the present invention provides a gastroretentive extended release pharmaceutical composition of riociguat, wherein said composition releases not more than about 70% of riociguat within 4 hours, when subjected to a test medium comprising 900 mL of 0.1 N HC1 at 37 °C in a standard USP basket apparatus at 100 rpm.
  • the present invention provides a gastroretentive extended release pharmaceutical composition of riociguat, wherein said composition releases not less than about 80% of riociguat within 12 hours, when subjected to a test medium comprising 900 mL of 0.1 N HC1 at 37 °C in a standard USP basket apparatus at 100 rpm.
  • the present invention provides a gastroretentive extended release pharmaceutical composition of riociguat, wherein said composition releases not more than about 40 % of riociguat within 1 hour, not more than about 70% of riociguat within 4 hours, and not less than about 80% of riociguat within 12 hours, when subjected to a test medium comprising 900 mL of 0.1 N HC1 at 37° C in a standard USP basket apparatus at 100 rpm.
  • the present invention provides a gastroretentive extended release pharmaceutical composition of riociguat, wherein said composition releases not more than about 40% of riociguat in 1 hour, when subjected to a test medium comprising 900 mL of 0.1 N HC1 at 37 °C in a standard USP basket apparatus at 100 rpm, wherein said composition provides said release profile after storage at 40 °C and 75% relative humidity for at least 1 month, for example, for 3 months, 6 months, 12 months, 24 months.
  • the present invention provides a gastroretentive extended release pharmaceutical composition of riociguat, wherein said composition releases not more than about 70% of riociguat within 4 hours, when subjected to a test medium comprising 900 mL of 0.1 N HC1 at 37 °C in a standard USP basket apparatus at 100 rpm, wherein said composition provides said release profile after storage at 40 °C and 75% relative humidity for at least 1 month, for example, for 3 months, 6 months, 12 months, 24 months.
  • the present invention provides a gastroretentive extended release pharmaceutical composition of riociguat, wherein said composition releases not less than about 80% of riociguat within 12 hours, when subjected to a test medium comprising 900 mL of 0.1 N HC1 at 37 °C in a standard USP basket apparatus at 100 rpm, wherein said composition provides said release profile after storage at 40 °C and 75% relative humidity for at least 1 month, for example, for 3 months, 6 months, 12 months, 24 months.
  • the present invention provides a gastroretentive extended release pharmaceutical composition of riociguat, wherein said composition releases not more than about 40 % of riociguat within 1 hour, not more than about 70% of riociguat within 4 hours, and not less than about 80% of riociguat within 12 hours, when subjected to a test medium comprising 900 mL of 0.1 N HC1 at 37° C in a standard USP basket apparatus at 100 rpm, wherein said composition provides said release profile after storage at 40 °C and 75% relative humidity for at least 1 month, for example, for 3 months, 6 months, 12 months, 24 months.
  • a stable gastroretentive extended release composition comprising riociguat, wherein said composition provides lag time of less than 60 seconds, preferably less than 45 seconds, more preferably less than 30 seconds, after storage at 40 °C and 75% relative humidity for at least 1 month, for example, for 3 months, 6 months, 12 months, 24 months.
  • a stable gastroretentive extended release composition comprising riociguat, wherein said composition has floating time of at least about 16 hours, preferably at least about 12 hours, more preferably at least about 10 hours after storage at 40 °C and 75% relative humidity for at least 1 month, for example, for 3 months, 6 months, 12 months, 24 months.
  • a stable gastroretentive extended release composition comprising riociguat, wherein said composition has water content not more than 0.5% w/w after storage at 40 °C and 75% relative humidity for at least 1 month, for example, for 3 months, 6 months, 12 months, 24 months.
  • the present invention provides a kit comprising gastroretentive extended release pharmaceutical composition of riociguat.
  • the present invention provides a kit comprising gastroretentive extended release pharmaceutical composition of riociguat, wherein said composition is packed in child resistant container, aluminum - aluminum packing, or aluminum-plastic packing.
  • the present invention provides a gastroretentive extended release pharmaceutical composition of riociguat, wherein said composition is packed in child resistant container, aluminum - aluminum packing, or aluminum-plastic packing.
  • the pharmaceutical composition of the present invention provides an in vivo plasma riociguat concentration profile having a C max from 3 ng/mL to 300 ng/mL, preferably from 10 ng/mL to 250 ng/mL, more preferably from 20 ng/mL to 200 ng/mL.
  • the pharmaceutical composition of the present invention provides an in vivo plasma riociguat concentration profile having AUC from 50 ng/mL*hr to 5000 ng/mL*hr, preferably from 100 ng/mL to 4000 ng/mL, more preferably from 200 ng/mL to 3000 ng/mL.
  • the pharmaceutical composition of the present invention provides an in vivo plasma riociguat concentration profile having AUC0-24 from 50 ng/mL*hr to 5000 ng/mL*hr, preferably from 100 ng/mL to 4000 ng/mL, more preferably from 200 ng/mL to 3000 ng/mL.
  • the pharmaceutical composition of the present invention provides an in vivo plasma riociguat concentration profile having T max median of at least about 5 hours.
  • the pharmaceutical composition of the present invention comprises riociguat and one or more pharmaceutically acceptable excipients, wherein the composition is administered to a patient in need thereof as a single dose which provides a C max between about 3 ng/mL and about 300 ng/mL, an in vivo plasma profile with an AUC between 50 ng/mL*hr and 5000 ng/mL*hr or both.
  • the gastroretentive extended release composition comprises riociguat and one or more pharmaceutically acceptable excipients, wherein the composition releases not less than about 80% of riociguat within 12 hours, when subjected to a test medium comprising 900 mL of 0.1 N HC1 at 37 °C in a standard USP basket apparatus at 100 rpm; and wherein the said composition provides in vivo plasma profile with a C max from 3 ng/mL to 300 ng/mL when administered as a single dose to a patient in need thereof.
  • the gastroretentive extended release composition comprises riociguat and one or more pharmaceutically acceptable excipients, wherein the composition releases not less than about 80% of riociguat within 12 hours, when subjected to a test medium comprising 900 mL of 0.1 N HC1 at 37 °C in a standard USP basket apparatus at 100 rpm; and wherein the said composition provides in vivo plasma profile with an AUC from 50 ng/mL*hr to 5000 ng/mL*hr when administered as a single dose to a patient in need thereof.
  • the gastroretentive extended release composition comprises riociguat and one or more pharmaceutically acceptable excipients, wherein the composition releases not more than about 40 % of riociguat within 1 hour, not more than about 70% of riociguat within 4 hours, and not less than about 80% of riociguat within 12 hours, when subjected to a test medium comprising 900 mL of 0.1 N HC1 at 37° C in a standard USP basket apparatus at 100 rpm; and wherein the said composition provides in vivo plasma profile with a C max from 3 ng/mL to 300 ng/mL when administered as a single dose to a patient in need thereof.
  • the gastroretentive extended release composition comprises riociguat and one or more pharmaceutically acceptable excipients, wherein the composition releases not more than about 40 % of riociguat within 1 hour, not more than about 70% of riociguat within 4 hours, and not less than about 80% of riociguat within 12 hours, when subjected to a test medium comprising 900 mL of 0.1 N HC1 at 37° C in a standard USP basket apparatus at 100 rpm; and wherein the said composition provides in vivo plasma profile with an AUC from 50 ng/mL*hr to 5000 ng/mL*hr when administered as a single dose to a patient in need thereof.
  • the pharmaceutical composition of the present invention is used for the treatment of patients having pulmonary hypertension including chronic-thromboembolic pulmonary hypertension or pulmonary arterial hypertension or both.
  • the pharmaceutical composition of the present invention is used for the treatment of patients in need thereof, either alone or in combination with other anti -hypertensive agents known in the art.
  • the pharmaceutical composition of the present invention is used for the treatment of patients in need thereof, either in a single dose or in divided doses.
  • the pharmaceutical composition of the present invention according to any one of the embodiments disclosed herein, is administered with food.
  • the pharmaceutical composition of the present invention according to any one of the embodiments disclosed herein, is administered under fasting conditions.
  • the invention provides a method of treating pulmonary hypertension in a subject in need thereof comprising orally administering to the subject a gastroretentive extended release composition according to any one of the embodiments of the invention wherein single dose administration of the extended release composition provides an in vivo plasma profile with an AUC from 50 ng/mL*hr to 5000 ng/mL*hr, preferably from 100 ng/mL to 4000 ng/mL, more preferably from 200 ng/mL to 3000 ng/mL.
  • the invention provides method of treating pulmonary hypertension in a subject in need thereof comprising orally administering to the subject a gastroretentive extended release composition according to any one of the embodiments of the invention wherein single dose administration of the composition provides an in vivo plasma profile with an AUC0-24 from 50 ng/mL*hr to 5000 ng/mL*hr, preferably from 100 ng/mL to 4000 ng/mL, more preferably from 200 ng/mL to 3000 ng/mL.
  • the invention provides methods of treating pulmonary hypertension in a subject in need thereof comprising orally administering to the subject a gastroretentive extended release composition according to any one of the embodiments of the invention wherein single dose administration of the composition provides an in vivo plasma profile with a C max from 3 ng/mL to 300 ng/mL, preferably from 10 ng/mL to 250 ng/mL, more preferably from 20 ng/mL to 200 ng/mL.
  • the invention provides methods of treating pulmonary hypertension in a subject in need thereof comprising orally administering to the subject a gastroretentive extended release composition according to any one of the embodiments of the invention wherein single dose administration of the composition provides a C max from 3 ng/mL to 300 ng/mL, an in vivo plasma profile with an AUC from 50 ng/mL*hr to 5000 ng/mL*hr or both.
  • the invention provides methods of treating pulmonary hypertension in a subject in need thereof comprising orally administering to the subject a gastroretentive extended release composition according to any one of the embodiments of the invention wherein the composition releases not less than about 80% of riociguat within 12 hours, when subjected to a test medium comprising 900 mL of 0.1 N HC1 at 37 °C in a standard USP basket apparatus at 100 rpm; and wherein the composition provides in vivo plasma profile with a C max from 3 ng/mL to 300 ng/mL when administered as a single dose to a patient in need thereof.
  • the invention provides methods of treating pulmonary hypertension in a subject in need thereof comprising orally administering to the subject a gastroretentive extended release composition according to any one of the embodiments of the invention wherein the composition releases not less than about 80% of riociguat within 12 hours, when subjected to a test medium comprising 900 mL of 0.1 N HC1 at 37 °C in a standard USP basket apparatus at 100 rpm; and wherein the composition provides in vivo plasma profile with an AUC from 50 ng/mL*hr to 5000 ng/mL*hr when administered as a single dose to a patient in need thereof.
  • the invention provides methods of treating pulmonary hypertension in a subject in need thereof comprising orally administering to the subject a gastroretentive extended release composition according to any one of the embodiments of the invention wherein the composition releases not more than about 40 % of riociguat within 1 hour, not more than about 70% of riociguat within 4 hours, and not less than about 80% of riociguat within 12 hours, when subjected to a test medium comprising 900 mL of 0.1 N HC1 at 37° C in a standard USP basket apparatus at 100 rpm; and wherein the composition provides in vivo plasma profile with a C max from 3 ng/mL to 300 ng/mL when administered as a single dose to a patient in need thereof.
  • the invention provides methods of treating pulmonary hypertension in a subject in need thereof comprising orally administering to the subject a gastroretentive extended release composition according to any one of the embodiments of the invention wherein the composition releases not more than about 40 % of riociguat within 1 hour, not more than about 70% of riociguat within 4 hours, and not less than about 80% of riociguat within 12 hours, when subjected to a test medium comprising 900 mL of 0.1 N HC1 at 37° C in a standard USP basket apparatus at 100 rpm; and wherein the composition provides in vivo plasma profile with an AUC from 50 ng/mL*hr to 5000 ng/mL*hr when administered as a single dose to a patient in need thereof.
  • Riociguat, microcrystalline cellulose, povidone K30 and polyethylene oxide were co-sifted and granulated using isopropyl alcohol.
  • the granules prepared above were dried, milled and sifted with hydroxypropyl methylcellulose K4M to get appropriate dimension granules, lubricated with magnesium stearate and compressed to provide a tablet.
  • Dissolution data were determined using in vitro dissolution testing apparatus using dissolution conditions given below.
  • the binder solution was prepared by dissolving Povidone K 30 in isopropyl alcohol.
  • the granules were prepared by adding said binder solution to co-sifted powder. The said granules were dried, sifted to get appropriate dimension. The granules were lubricated with magnesium stearate.
  • Dissolution data of example 4 were determined using in vitro dissolution testing apparatus at dissolution conditions given below.
  • Riociguat, microcrystalline cellulose 101, lactose monohydrate, hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose KI OOM and sodium bicarbonate were co-sifted and granulated using a binder solution containing povidone K30 dissolved in isopropyl alcohol.
  • the granules prepared above were dried, sifted to get appropriate dimension granules, lubricated with magnesium stearate and compressed to provide a tablet.
  • Dissolution data were determined using in vitro dissolution testing apparatus at dissolution conditions given below.
  • ratio of AUCQ-24 of test to reference is 80% under fasting conditions.
  • Pharmacoscintigraphic evaluation was performed on radio labelled tablets of riociguat of the present invention under fed conditions and the highest intensity of tracer activity in stomach was observed up to 10 hours. The tablet remains intact in stomach and drug release from tablets up to 10 hours in stomach.

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Abstract

La présente invention concerne des compositions de riociguat à libération prolongée et à rétention gastrique. Les compositions de l'invention sont stables, possèdent des caractéristiques de formulation améliorées et fournissent également des niveaux de plasma thérapeutiquement efficaces sur une période de vingt-quatre heures. L'invention concerne également des procédés de préparation de telles compositions.
PCT/IB2024/051021 2023-02-07 2024-02-05 Compositions de riociguat à libération prolongée et à rétention gastrique Ceased WO2024165966A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119499187A (zh) * 2024-12-20 2025-02-25 杭州成邦医药科技有限公司 一种利奥西呱固体分散体组合物、缓释组合物及其制备方法和应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021111419A1 (fr) * 2019-12-05 2021-06-10 Cadila Healthcare Limited Compositions pharmaceutiques à libération modifiée de riociguat
US20220202698A1 (en) * 2020-12-28 2022-06-30 Jubilant Pharma Holdings Inc. Extended release pharmaceutical compositions of riociguat

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021111419A1 (fr) * 2019-12-05 2021-06-10 Cadila Healthcare Limited Compositions pharmaceutiques à libération modifiée de riociguat
US20220202698A1 (en) * 2020-12-28 2022-06-30 Jubilant Pharma Holdings Inc. Extended release pharmaceutical compositions of riociguat

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119499187A (zh) * 2024-12-20 2025-02-25 杭州成邦医药科技有限公司 一种利奥西呱固体分散体组合物、缓释组合物及其制备方法和应用

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