WO2022147183A1 - Pharmaceutical extended release suspensions of riociguat - Google Patents

Pharmaceutical extended release suspensions of riociguat Download PDF

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Publication number
WO2022147183A1
WO2022147183A1 PCT/US2021/065589 US2021065589W WO2022147183A1 WO 2022147183 A1 WO2022147183 A1 WO 2022147183A1 US 2021065589 W US2021065589 W US 2021065589W WO 2022147183 A1 WO2022147183 A1 WO 2022147183A1
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WO
WIPO (PCT)
Prior art keywords
dosage form
extended release
suspension
riociguat
amount
Prior art date
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PCT/US2021/065589
Other languages
French (fr)
Inventor
Indranil Nandi
Tusharmouli Mukherjee
Dinesh Kumar
Rakesh Kumar Singh
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Jubilant Pharma Holdings Inc.
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Publication of WO2022147183A1 publication Critical patent/WO2022147183A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches

Definitions

  • the present invention relates to orally administered extended release pharmaceutical suspensions of riociguat.
  • the extended release suspensions are in the form of ready to use suspension and suspension powder for reconstitution. It also relates to the processes for the preparation of said extended release suspensions. It further relates to the use of extended release pharmaceutical suspensions for the treatment of hypertension and related disorders.
  • Riociguat is an antihypertensive drug. It is chemically known as methyl 4,6- diamino-2- [ 1 -(2-fluorobenzy 1)- 1 H-pyrazolo [3,4-b]pyridin-3 -y 1] -5- pyrimidinyl(methyl)carbamate and is represented by the following formula as:
  • Riociguat is marketed in the U.S. as an immediate-release tablet in 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg strengths under the brand name Adempas® by Bayer Healthcare Pharmaceuticals.
  • the marketed solid dosage form of riociguat is indicated for the treatment of persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH) to improve exercise capacity.
  • CTEPH chronic thromboembolic pulmonary hypertension
  • PAH pulmonary arterial hypertension
  • U.S. Patent Nos. 10,087,183 and 10,662,188 assigned to Bayer Healthcare, discloses various polymorphs of riociguat such as modification I, modification II, mono- DMSO solvate, sesqui-DMSO solvate, ' i-ethyl acetate solvate and pharmaceutical compositions thereof.
  • Difficulty in swallowing solid oral dosage forms such as tablets and capsules is a problem for many patients and can induce significant non-compliance with the prescribed treatment regimens.
  • Adolescents, children, and the elderly are particularly vulnerable population groups that are more likely than adults to experience difficulty in swallowing tablets or capsules.
  • the prescribing information of Adempas® tablet mentions that the riociguat tablets may be crushed and mixed with water or soft foods for patients who have difficulty swallowing. In addition, the tablet has to be administered three times a day owing to short half-life of the drug.
  • a particular challenge in the development of extended release suspension dosage form is the prevention of a premature release of drug from the suspended particles during the shelflife of the suspension dosage form prior to ingestion by a patient. Additionally, the maintenance of the desired dissolution profile, as well as the desired dose uniformity of the suspension dosage form throughout its shelf life, are additional challenges to be addressed in formulating an oral, extended release suspension product.
  • the inventors of the present invention have developed extended release suspension dosage forms of riociguat with an objective to minimize swallowing difficulties and to provide a simpler dosage regimen by once daily or twice daily administration. This improves patient compliance by reducing dysphagia-related adverse events and providing a more convenient and less cumbersome dosage regimen.
  • the inventors have developed ready-to- use extended release suspension and extended release suspension powder for reconstitution, which are convenient for administration by paediatric and geriatric patients and even by adults, easy to manufacture, functionally reproducible, provide ease of dose adjustment and are bioequivalent to the marketed tablet.
  • the extended release suspension dosage form exhibits desirable technical attributes such as pourability, viscosity, pH, dissolution, re-suspendability, assay and stability.
  • the extended release suspension dosage form of the present invention is in the form of ready- to-use extended release suspension and extended release suspension powder for reconstitution.
  • It is another object of the present invention to provide a ready -to-use extended release suspension comprising riociguat or its pharmaceutically acceptable esters, salts, solvates, polymorphs, enantiomers or mixtures thereof with at least one or more pharmaceutically acceptable excipients and process for their preparation.
  • It is another object of the present invention to provide an extended release suspension powder for reconstitution comprising riociguat or its pharmaceutically acceptable esters, salts, solvates, polymorphs, enantiomers or mixtures thereof with at least one or more pharmaceutically acceptable excipients and process for their preparation.
  • It is another object of the present invention to provide an extended release suspension dosage form comprising riociguat or its pharmaceutically acceptable esters, salts, solvates, polymorphs, enantiomers or mixtures thereof, in an amount of about 0.01% to about 30% by weight, wherein the suspension dosage form exhibits desirable technical attributes like pourability, viscosity, dissolution, stability, re-suspendability and a process for preparing the same.
  • a pharmaceutical extended release suspension dosage form comprising riociguat or its pharmaceutically acceptable esters, salts, solvates, polymorphs, enantiomers or mixtures thereof, for use in the treatment of hypertension, pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, persistent/recurrent chronic thromboembolic pulmonary hypertension, heart failure, arrhythmia, high blood pressure, angina pectoris, myocardial infarction, stroke, transient ischaemic attacks, arteriosclerosis, erectile dysfunction, osteoporosis, Alzheimer's disease, Parkinson's disease, multiple sclerosis, depression, schizophrenia, bipolar disorder and migraine.
  • composition or “formulation” or “dosage form”, as in pharmaceutical composition is intended to encompass a drug product comprising riociguat or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, and other inert ingredient(s) (pharmaceutically acceptable excipients).
  • Such pharmaceutical compositions are synonymous with “formulation” and “dosage form”.
  • Pharmaceutical suspension dosage form of the invention includes, but is not limited to ready to use extended release suspension, extended release powder for suspension, extended release granules, pellets, beads, multiparticulates, microspheres, and microcapsules, and the like.
  • the pharmaceutical composition refers to extended release powder, granules, pellets, beads, multiparticulates, microspheres, and microcapsules and the like, filled into capsules or sachets and ready to use suspension.
  • the extended release suspension powder for reconstitution comprises granules, cores, pellets, beads, spheroids, multiparticulates, microspheres, and microcapsules of riociguat.
  • the term “ready to use suspension” means a pre-constituted suspension that can be administered as such.
  • the “powder for suspension” or “suspension powder for reconstitution” or “dry suspension” are synonymous and are reconstituted with a liquid carrier to form a suspension.
  • riociguat is used in broad sense to include not only “riociguat” per se but also its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, derivatives, isomers, polymorphs, prodrugs thereof, and also its various crystalline and amorphous forms.
  • Riociguat is present in an amount from about 0.01% w/w to about 70% w/w of the extended release suspension dosage form, particularly from about 0.01% w/w to about 30% w/w, from about 0.01% w/w to about 20% w/w, from about 0.01% w/w to about 10% w/w, from about 0.01% w/w to about 5% w/w, from about 0.01% w/w to about 3% w/w of the suspension dosage form.
  • extended release refers to a release profile to effect delivery of riociguat over an extended period of time, as being between about 1 hour to about 2, 4, 6, 8, 12, 16 or 24 hours.
  • extended release encompasses controlled release, sustained release, modified release, prolonged release, programmed release, pulsatile release, delayed release, and the like and mean broadly that the active agent is released at a predetermined rate that is different or slower than immediate release.
  • An extended release composition is one for which the drug release characteristics of time course are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as solutions or promptly dissolving dosage forms e.g., immediate release tablets.
  • inert particle refers to a particle made from a sugar sphere also known as a non-pareil seed, a microcrystalline cellulose sphere, a dibasic calcium phosphate bead, a mannitol bead, a silica bead, a tartaric acid pellet, a wax-based pellet, and the like.
  • drug resin particle refers to a drug-containing ion-exchange resin particle in which there is an ionic bond between drug and the ion-exchange resin particle.
  • excipient means a pharmacologically inactive component such as a suspending agent, pH adjusting agent/buffering agent, release-controlling agent, diluent, carrier, anticaking agent, antifoaming agent, antioxidant, sweetening agent, vehicle, solvent, flavoring agent, surfactant/solubilizer/wetting agent, buffer, glidant, lubricant, and preservative and mixtures thereof.
  • a suspending agent such as a suspending agent, pH adjusting agent/buffering agent, release-controlling agent, diluent, carrier, anticaking agent, antifoaming agent, antioxidant, sweetening agent, vehicle, solvent, flavoring agent, surfactant/solubilizer/wetting agent, buffer, glidant, lubricant, and preservative and mixtures thereof.
  • Reference to an excipient includes both one and more than one such excipient.
  • Co-processed excipients are also covered under the scope of present invention. Combination of excipient
  • the term “about,” as used herein, means ⁇ approximately 10% of the indicated value, such that “about 10 percent” indicates approximately 8 to 12 percent.
  • the term “substantially similar,” as used herein, means ⁇ approximately 25% of the indicated value.
  • the ratio represented here may be referred as any ratio as known in the art, preferably as “weight ratio”.
  • stable refers to chemical stability, wherein not more than 5% w/w of total related substances are formed on storage at 40°C and 75% relative humidity (R.H.) or at 25°C and 60% R.H. for a period of at least 1 week, for a period of at least one month, particularly for a period of two months, and more particularly for a period of at least three months.
  • an extended release suspension dosage form of riociguat comprising riociguat and at least one or more pharmaceutically acceptable excipients.
  • an extended release suspension dosage form of riociguat comprising riociguat, a release controlling agent and at least one or more pharmaceutically acceptable excipients.
  • an extended release suspension dosage form comprising: a) a core comprising riociguat; b) a coating layer over said core comprising a release-controlling agent; and c) at least one or more pharmaceutically acceptable excipients.
  • Another embodiment of the present invention provides an extended release suspension dosage form of riociguat comprising: a) extended release cores of riociguat comprising a release-controlling agent; and b) at least one or more pharmaceutically acceptable excipients.
  • Another embodiment of the present invention provides a ready to use extended release suspension dosage form of riociguat comprising: a) cores of riociguat coated with a release-controlling agent to form the extended release cores; and b) a pharmaceutically acceptable carrier.
  • Another embodiment of the present invention provides an extended release suspension powder for reconstitution of riociguat comprising: a) cores of riociguat coated with a release-controlling agent to form the extended release cores; and b) at least one or more pharmaceutically acceptable excipients.
  • the extended release suspension is an aqueous suspension.
  • Another embodiment of the present invention provides an extended release suspension dosage form of riociguat comprising: a) riociguat; b) a release-controlling agent; c) a suspending agent; and d) one or more pharmaceutically acceptable excipients.
  • Another embodiment of the present invention provides an extended release suspension dosage form of riociguat comprising: a) riociguat; b) a release-controlling agent; c) a suspending agent; d) a pH adjusting agent; and e) one or more pharmaceutically acceptable excipients, wherein the suspension has a pH of about 3 to about 8.
  • Another embodiment of the present invention provides an extended release suspension dosage form of riociguat comprising: a) riociguat; b) a release-controlling agent; c) a suspending agent; d) optionally a pH adjusting agent; and e) one or more pharmaceutically acceptable excipients, wherein the suspension has a viscosity from about 100 cps to 4000 cps.
  • Another embodiment of the present invention provides an extended release suspension dosage form of riociguat comprising: a) riociguat; b) a release-controlling agent; c) a suspending agent; d) optionally a pH adjusting agent; and e) one or more pharmaceutically acceptable excipients, wherein the suspension has a pH of about 3 to about 8 and a viscosity from about 100 cps to 4000 cps.
  • Another embodiment of the present invention provides an extended release suspension dosage form of riociguat comprising: a) riociguat in an amount of about 0.01% to about 10% by weight, b) a release controlling agent; and c) at least one or more pharmaceutically acceptable excipients wherein the suspension has a pH of about 3 to about 8 and ratio of riociguat to release controlling agent in the dosage form is between about 1:0.5 to about 1 : 10.
  • Another embodiment of the present invention provides an extended release suspension dosage form of riociguat comprising: a) riociguat in an amount from about 0.01% to about 30% w/w; b) a release-controlling agent in an amount from about 0.1 % to about 50% w/w; c) a suspending agent in an amount from about 0.05% to about 20% w/w; and d) one or more pharmaceutically acceptable excipients.
  • Another embodiment of the present invention provides an extended release suspension dosage form of riociguat comprising riociguat complexed with ion-exchange resin particles to form drug resin particles, which are coated with an extended release coating comprising a release-controlling agent.
  • Another embodiment of the present invention provides an extended release suspension dosage form of riociguat comprising riociguat complexed with sodium polystyrene sulfonate resin to form drug resin particles, which are coated with an extended release coating comprising a release-controlling agent.
  • an extended release oral suspension dosage form comprising: a) riociguat in an amount of about 0.01% to about 10% by weight, b) an ion-exchange complexing agent selected from sodium polystyrene sulfonate and polacrillin potassium or combination thereof in an amount of about 0.01% to about 10% by weight, and c) a suspending agent selected from the group consisting of xanthan gum, hydroxypropyl methyl cellulose, gellan gum, sodium carboxymethylcellulose, a mixture of carboxymethylcellulose and microcrystalline cellulose, propylene glycol alginate and combinations thereof in an amount from about 0.05% to about 20% w/w.
  • the composition further comprises one or more sweetening agents, preservatives, carrier/vehicle/solvent, and flavoring agents.
  • the ratio of riociguat and ion-exchange complexing agent in the composition is more than 1:1, preferably 1:2, more preferably 1:3.
  • the composition exhibits at least 40% drug release in 12 hours when measured in 900 ml of 6.8 phosphate buffer and 2% KCL using a USP II apparatus (Paddle) at a temperature of 37 ⁇ 0.5°C and a rotation speed of 75 revolutions per minute.
  • an extended release oral suspension dosage form of riociguat comprising: a) riociguat in an amount of about 0.01% to about 10% by weight, b) a release controlling agent selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methaacrylic acid copolymers, ethyl cellulose, cellulose acetate, an ion-exchange resin and combination thereof in an amount of about 0.1% to about 10% by weight, c) a suspending agent selected from the group consisting of xanthan gum, hydroxypropyl methylcellulose, gellan gum, sodium carboxymethylcellulose, a mixture of carboxymethylcellulose and microcrystalline cellulose, propylene glycol alginate and combinations thereof in an amount from about 0.05% to about 20% w/w, d) one or more buffering agents selected from the group consisting of monosodium dibasic phosphate, citric acid, acetic acid, sodium cit
  • the present invention relates to, an extended release oral suspension dosage form of riociguat comprising: a) riociguat in an amount of about 0.01% to about 10% by weight, b) hydroxypropyl methylcellulose, ethyl cellulose, sodium polystyrene sulfonate and combination thereof in an amount of about 0.1% to about 10% by weight, c) xanthan gum, a mixture of carboxymethylcellulose and microcrystalline cellulose, and combinations thereof in an amount from about 0.05% to about 10% w/w, d) citric acid, sodium citrate, and combinations thereof in an amount of about 0.01% w/w to about 5% w/w of the dosage form; and e) at least one or more pharmaceutically acceptable excipients, wherein the suspension has a pH of about 3 to about 8 and the ratio of riociguat to release controlling agent in the dosage form is between about 1:0.5 to about 1:5.
  • the suspension has a pH of about 3
  • an extended release oral suspension dosage form of riociguat comprising: i. an inert inner core, ii. optionally a water-soluble seal or seal coating layer consisting essentially of water-soluble polymers, iii. a first coating on top of the inner core comprised of riociguat in an amount of about 0.01% to about 10% by weight and a binder selected from the group consisting of povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, starch, methylcellulose, ethylcellulose, carboxymethyl cellulose, sucrose solution, dextrose solution in an amount of about 0.1% to about 20% by weight, iv.
  • a liquid carrier comprises of: a) a suspending agent selected from the group consisting of xanthan gum, hydroxypropyl methylcellulose, gellan gum, sodium carboxymethylcellulose, a mixture of carboxymethylcellulose and microcrystalline cellulose, propylene glycol alginate and combinations thereof in an amount from about 0.05% to about 20% w/w, b) one or more wetting agents selected from the group consisting of sodium lauryl sulphate, polysorbate, sorbitan monostearate, poloxamers, and combinations thereof in an amount of about 0.01% w/w to about 8% w/w of the dosage form, c) one or more buffering agents selected from the group consisting of monosodium dibasic phosphate, citric acid, acetic acid, sodium citrate, sodium acetate potassium citrate, and potassium
  • vehicle/solvent selected from the group consisting of water, alcohol, polyethylene glycol, propylene glycol, glycerin, hydrochloric acid and combinations thereof.
  • an extended release powder for oral suspension dosage form of riociguat comprising: i. an inert inner core, ii. optionally a water-soluble seal or seal coating layer consisting essentially of water-soluble polymers, iii.
  • a first coating on top of the inner core comprised of riociguat in an amount of about 0.01% to about 10% by weight and a binder selected from the group consisting of povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, starch, methylcellulose, ethylcellulose, carboxymethyl cellulose, sucrose solution, dextrose solution in an amount of about 0.1% to about 20% by weight, iv. optionally a water-soluble seal or seal coating layer consisting essentially of water-soluble polymers, v. an extended coating layer comprises of at least one water-insoluble cellulose derivative; and vi.
  • inactive granules comprise of: a) one or more diluents selected from the group consisting of lactose, cellulose, microcrystalline cellulose, mannitol, dextrose, calcium phosphate, starch, pregelatinized starch, and combination thereof in an amount from about 5% to about 90% w/w, b) a suspending agent selected from the group consisting of xanthan gum, hydroxypropyl methylcellulose, gellan gum, sodium carboxymethylcellulose, a mixture of carboxymethylcellulose and microcrystalline cellulose, propylene glycol alginate and combinations thereof in an amount from about 0.05% to about 20% w/w, c) one or more disintegrants selected from the group consisting of carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, polacrillin potassium, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose, pregelatinized starch, and combinations thereof in an amount from about 0.1% to about 10%
  • the dosage form further comprises one or more wetting agents selected from the group consisting of sodium lauryl sulphate, polysorbate, sorbitan monostearate, poloxamers, and combinations thereof in an amount of about 0.01% w/w to about 8% w/w of the dosage form.
  • the dosage form further comprises one or more sweetening agents selected from the group consisting of sucrose, dextrose, sucralose, sorbitol, fructose, mannitol, saccharin sodium, aspartame, thaumatin and combination thereof in an amount of about 0.1% w/w to about 20% w/w of the dosage form.
  • the dosage form further comprises one or more preservatives selected from the group consisting of parabens such as methylparaben, propylparaben, butylparaben benzoic acid, sodium benzoate, potassium benzoate, butylated hydroxyl toluene (BHT), butylated hydroxyl anisole (BHA), tocopherol, benzalkonium chloride and combinations thereof in an amount of about 0.001% w/w to about 3% w/w of the dosage form.
  • parabens such as methylparaben, propylparaben, butylparaben benzoic acid, sodium benzoate, potassium benzoate, butylated hydroxyl toluene (BHT), butylated hydroxyl anisole (BHA), tocopherol, benzalkonium chloride and combinations thereof in an amount of about 0.001% w/w to about 3% w/w of the dosage form.
  • the dosage form further comprises one or more flavoring agents selected from the group consisting of orange, grape, lime and grapefruit, vanilla, bubble gum, peppermint, tutti-frutti, strawberry, and combinations thereof in an amount of about 0.01% w/w to about 5% w/w of the dosage form.
  • the inner core is an inert non-pareil sugar sphere.
  • the core is devoid of any cellulose-based excipients.
  • the core is devoid of microcrystalline cellulose.
  • the drug and binder in a ratio less than 1:3 or less than 1 :2.
  • the drug and binder is in a ratio of 1 : 1.
  • the controlled release polymer has a viscosity of less than 10 cps.
  • the controlled release polymer has a viscosity of less than 10 cps.
  • the controlled release polymer is ethylcellulose having a viscosity of 7 cps.
  • the controlled release polymer is used in about 20% weight gain or less, about 10% weight gain or less by the total weight of the core or drug layered dosage form. In a preferred embodiment, the controlled release polymer is used in about 5% weight gain or less by the total weight of core or drug layered dosage form. In a preferred embodiment, the dosage form is free of any glidant. In a preferred embodiment, the multi-particulate delivery system contains particles having a mean diameter of about 400 to about 1200 microns.
  • the extended release coating over drug resin particles may be a water-permeable diffusion barrier coating that is insoluble in gastrointestinal fluids and water, thereby providing an extended release of drug under conditions encountered in the gastrointestinal tract or may also include a slow-dissolve polymer coating.
  • Another embodiment of the present invention provides an extended release suspension dosage form of riociguat comprising solid lipid nanoparticles of riociguat.
  • Solid lipid nanoparticles are lipid-based nanocarriers with a size from 10 nmto 1000 nm.
  • the key ingredients of solid lipid nanoparticles formulations include lipid, surfactant/emulsifier, and mixtures thereof, active pharmaceutical ingredient and a solvent.
  • Lipids used in the preparation of solid lipid nanoparticles are selected from the group comprising fatty acids (e.g.
  • dodecanoic acid myristic acid, palmitic acid, stearic acid
  • monoglycerides glyceryl monostearate, glyceryl hydroxy stearate, glyceryl behenate/ Compritol®
  • diglycerides glyceryl palmitostearate, glyceryl dibehenate
  • triglycerides caprylate triglyceride, caprate triglyceride, glyceryl tristearate/tristearate, glyceryl trilaurate/trilaurate glyceryl trimyristate/trimyristin, glyceryl tripalmitate/tripalmitin, glyceryl tribehenate/tribehenin, tristearin glyceride
  • phospholipids waxes (cetyl palmitate, bees wax), liquid lipids (soya bean oil, oleic acid, medium chain triglycerides / caprylic and capric
  • Surfactants used in the preparation of solid lipid nanoparticles are selected from the group comprising ionic surfactants (e.g. sodium cholate, sodium taurocholate, sodium taurodeoxycholate, sodium glucocholate, sodium oleate, sodium dodecyl sulphate), nonionic surfactants (e.g. Tween 20, Tween 80, Tween 85, Span 20, Span 85, Tyloxapol, Poloxamer 188, Poloxamer 407, Poloxamer 908, Brij 78, Solutol, Tego care 450, Pluronic F68, polyethylene glycols such as PEG 400, PEG 2000, PEG 4500), amphoteric surfactants (e.g. egg phosphatidylcholine, soy phosphatidylcholine, hydrogenated egg phosphatidylcholine, hydrogenated soy phosphatidylcholine, Phospholipon), and combinations thereof.
  • ionic surfactants e.
  • solid lipid nanoparticles of riociguat can be prepared prepare using lipid (3.33%), phospholipids (0.6-1.5%), glycerol (2-4%), Poloxamer 188 (1.2-5%), soy phosphatidyl choline (95%), compritol (10%), cetyl palmitate (10%), Tego Care 450 (1.2%), PEG 2000 (0.25%), PEG 4500 (0.5%), PEG 400 (5%), Tween 85 (0.5%), ethyl oleate (30%), sodium alginate (70%), ethanol/butanol (2%), tristearin glyceride (95%), isopropyl myristate (3.60%), Pluronic F 68 (40%), Tween 80 (50%), and mixtures thereof.
  • Another embodiment of the present invention provides an extended release suspension dosage form of riociguat comprising liquid crystals of riociguat.
  • lyotropic liquid crystals are lamellar, hexagonal and cubic.
  • Lipid-based lyotropic liquid crystals are formed by swelling of certain amphiphilic lipids due to their amphiphilic nature containing a polar head group and a hydrophobic tail.
  • amphiphilic lipids When exposed to aqueous environment, amphiphilic lipids spontaneously form thermodynamically stable self-assembled structures and eventually develop into cubic and/or hexagonal liquid crystals depending on temperature and water content.
  • Lyotropic liquid crystal can coat an active to keep it from being destroyed in the digestive tract. The active can then be taken orally, and after it reaches the proper location in the body, the liquid crystal breaks down and the drug is released.
  • Ester groups of fatty acids are able to build liquid crystals that in turn can act as extended release systems. These fatty acids build lyotropic liquid crystalline mesophases in the presence of water at body temperature.
  • the cubic phase favors the controlled release of active agents, because it has a structure made up of tridimensional curved lipid bilayers, separated by congruent water channels. This structure has the appearance of highly viscous transparent gel.
  • Glyceryl monooleate (2,3- dihydroxypropyl oleate), phytantriol (3,7,l l,15-tetramethyl-l,2,3-hexadecanetriol), and other lipids such as mono linolein, monoelaidin, phosphatidylethanolamine, oleoylethanolamide, phospholipids, pegylated phospholipids, alkyl glycerates and glycolipids form cubic phase.
  • glyceryl monooleate and phytantriol are used to form cubic phase liquid crystals.
  • an extended release oral pharmaceutical suspension dosage form of riociguat comprising riociguat and a suspending agent, wherein the riociguat and suspending agent are present in a ratio from about 1: 0.01 to 1 :40 by weight.
  • the riociguat and suspending agent are present in a ratio of at least about 1 : 1.
  • the riociguat and suspending agent are present in a ratio of at least about 1 : 1 or less.
  • the riociguat and suspending agent are present in a ratio of at least about 1 : 1 or more.
  • the riociguat and suspending agent are present in a ratio of at least about 1 :2.
  • the riociguat and suspending agent are present in a ratio of at least about 1 :3.
  • an extended release oral pharmaceutical suspension dosage form of riociguat comprising riociguat and a release controlling agent, wherein the ratio of riociguat to release controlling agent in the composition is from about 1:0.01 to about 1:30 by weight.
  • the ratio of riociguat to release controlling agent in the composition is at least 1 : 1, to at least 1:2.
  • the ratio of riociguat to release controlling agent in the composition is about 1:5, about 1 : 10, or about 1:2 to about 1: 10.
  • the ratio of riociguat : releasecontrolling agent : suspending agent is from about 1:0.5:0.1 to 1 : 10:5.
  • an extended release oral pharmaceutical suspension dosage form of riociguat wherein sucrose has a particle size such that not less than 90% particles are below 200 pm. In particular, sucrose has a particle size such that not less than 90% particles are below 100 pm. This helps in achieving improved uniformity of the drug in the mixture.
  • an extended release suspension comprising riociguat, wherein the amount of riociguat in the suspension ranges from about 0.05 mg/mL to about 30 mg/mL, from about 0.05 mg/mL to 20 mg/mL, particularly from about 0.05 mg/mL to 15 mg/mL, particularly from about 0.05 mg/mL to 10 mg/mL. More particularly, the amount of riociguat in the suspension ranges from about 0.05 mg/mL to 1 mg/mL. More particularly, the amount of riociguat in the suspension ranges from about 3mg/ml and about 3mg/5ml.
  • an extended release suspension comprising riociguat or its pharmaceutically acceptable salts, wherein the pH of suspension is in the range of about 3 to about 9.
  • the pH is in a range of about 3 to about 8.
  • riociguat is the sole active ingredient in the extended release suspension dosage form.
  • the extended release suspension dosage form of riociguat of the present invention is sugar-free.
  • the extended release suspension dosage form of riociguat comprises an immediate release component.
  • the extended release suspension dosage form of riociguat is administered once daily or twice daily, more particularly it is administered once daily.
  • the extended release suspension dosage form of riociguat is bioequivalent to the marketed conventional immediate release composition of riociguat (Adempas®) administered thrice daily.
  • an extended release suspension dosage form of riociguat wherein there is no substantial change in the in-vitro dissolution release profile of the active ingredient upon storage of the extended release suspension composition for at least ten days.
  • the in-vitro dissolution release profile of the extended release suspension composition of the present invention upon storage for at least one month, for at least two months, for at least three months, for at least six months remains substantially similar to initial in-vitro dissolution release profile obtained as soon as practicable after preparation of the extended release suspension composition.
  • an extended release pharmaceutical suspension dosage form comprising riociguat or its pharmaceutically acceptable esters, salts, solvates, polymorphs, enantiomers or mixtures thereof, wherein riociguat has a particle size distribution D90 less than about 200 pm, D50 is less than about 100 pm and D10 is less than about 50 pm.
  • D90 of riociguat ranges about 0.1 pm to 200 pm, particularly from 1 pm to 150 pm, 1 pm to 100 pm, from about 1 pm to about 75 pm, particularly from about 1 pm to about 50 pm, particularly from about 1 pm to about 30 pm, particularly from about 1 pm to about 20 pm, and more particularly from 1 pm to about 10 pm.
  • the particle size of riociguat can be measured by suitable techniques such as Laser light scattering (e.g. Malvern Light Scattering), Coulter counter, microscopy and any other technique known in the art.
  • the riociguat coated core may be further optionally coated with a coating layer comprising a film-forming agent to mask the bitter taste or to improve the stability.
  • the coating layer prevents riociguat release during storage, but is quickly penetrated by gastric fluid allowing rapid release of riociguat.
  • the film-forming agent can have a pH-dependent solubility in which the release of active ingredient is prevented by using a pre-adjusted pH of the liquid composition such that the film-forming agent does not get dissolved in the liquid composition but get dissolved when exposed to the physiological conditions.
  • the suspension powder for reconstitution may be reconstituted with a liquid carrier having suspending agent and one or more pharmaceutically acceptable excipients.
  • suspending agent and at least one or more pharmaceutically acceptable excipients may be premixed with the extended release cores which may be reconstituted with an aqueous vehicle.
  • the average diameter of the extended release cores of the present invention ranges from about 10 pm to about 800 pm, particularly from about 50 pm to 500 pm.
  • the suspending agent enhances the physical stability of the composition by sufficiently increasing the viscosity so that an appropriate dose can be delivered with minimal shaking.
  • Suitable suspending agents/viscosity agents are selected from the group comprising cellulose derivatives such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methylcellulose, carboxymethyl cellulose and its salts/derivatives e.g., carboxymethyl cellulose sodium, microcrystalline cellulose, and coprocessed spray dried forms of microcrystalline cellulose and carboxymethyl cellulose sodium (such as Avicel® RC-501, Avicel® RC-581, Avicel® RC-591, and Avicel®CL-611); carbomers (such as those available under the trade name Carbopol®); gums such as xanthan gum, locust bean gum, tragacanth gum, arabinogalactan gum, agar gum, gellan gum, guar gum, apricot gum, karaya gum, sterculia gum, acacia gum, gum arabic, and carrageenan; pectin; propylene glycol alginate;
  • the suspending agents are present in an amount of about 0.05% w/w to about 20% w/w of the composition. Particularly, the suspending agents are present in an amount of about 0.1% w/w to about 10% w/w, about 0.1% to about 5% w/w and about 0.1% w/w to about 3% w/w of the composition.
  • the suspension is easily pourable and when shaken has a viscosity in the range of 100 cps (centipoise) to 10000 cps at 25°C.
  • the viscosity is in the range of 100 cps to 5000 cps at 25°C, 100 cps to 2500 cps at 25°C, 100 cps to 1500 cps at 25°C, 300 cps to 4000 cps at 25°C. More particularly, the viscosity is in the range of 100 cps to 4000 cps at 25°C.
  • shaken refers to shaken prior to use, e.g. by a patient, e.g. vigorously shaken, e.g. by hand, e.g. for 5 to 60 seconds.
  • the viscosity can be measured by using a suitable instrument such as Brookfield viscometer, Haake VT 550 viscometer at room temperature (25°C).
  • pH adjusting agent/buffering agents include, but are not limited to, citrate buffers, phosphate buffers, or any other suitable buffer known in the art including monosodium dibasic phosphate, gluconic acid, lactic acid, citric acid, acetic acid, sodium gluconate, sodium lactate, sodium citrate, sodium acetate potassium citrate, sodium bicarbonate, potassium bicarbonate, sodium dihydrogen phosphate and potassium dihydrogen phosphate, and combinations thereof.
  • the pH adjusting agents are present in an amount of about 0.5% w/w to about 8% w/w of the composition.
  • the release-controlling agent is selected from the group comprising a pH-dependent release-controlling agent, a pH-independent release-controlling agent, and mixtures thereof.
  • the release-controlling agent is present in an amount of about 0.1% w/w to about 60% w/w of the composition.
  • the release-controlling agent is present particularly in an amount of about 0.1% w/w to about 30% w/w of the composition, particularly in an amount of about 0.1% w/w to about 20% w/w of the composition, particularly in an amount of about 0.1% w/w to about 10% w/w of the composition.
  • Suitable pH-dependent release-controlling agents are selected from the group comprising acrylic copolymers such as methacrylic acid and methyl methacrylate copolymers, e.g., Eudragit® L 100 and Eudragit® S 100, dimethylaminoethyl methacrylate and butyl methacrylate and methyl methacrylate copolymers e.g., Eudragit® E 100, Eudragit® E PO, methacrylic acid and ethyl acrylate copolymers, e.g., Eudragit® LI 00-55 and Eudragit® L30 D-55, methyl acrylate and methacrylic acid and octyl acrylate copolymers, styrene and acrylic acid copolymers, butyl acrylate and styrene and acrylic acid copolymers, and ethylacrylate-methacrylic acid copolymer; cellulose acetate phthalate; cellulose acetate succinate
  • Suitable pH-independent release-controlling agents are selected from the group comprising cellulosic polymers such as methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose, cellulose acetate, ethyl cellulose, and carboxy methylcellulose; acrylic copolymers such as methacrylic acid copolymers, e.g., Eudragit® RS, Eudragit® RL, Eudragit® NE 30 D; gums e.g., guar gum, locust bean gum, tragacanth, carrageenan, alginic acid, gum acacia, gum arabic, gellan gum; triglycerides; polyethylene derivatives e.g., polyethylene glycol and polyethylene oxide; polyvinyl alcohol; polyvinyl acetate; waxes, e.g., glyceryl behenate (Compritol®), Lubritab®
  • Various useful fillers or diluents include, but are not limited to sucrose, sugar alcohols, mannitol, sorbitol, xylitol, erythritol, starch, modified starches, pregelatinized starch, calcium carbonate, calcium phosphate, dibasic anhydrous, calcium phosphate, dibasic dihydrate, calcium phosphate tribasic, calcium sulphate, cellulose powdered, silicified microcrystalline cellulose, cellulose acetate, lactose, magnesium carbonate, magnesium oxide, maltodextrin, microcrystalline cellulose, polydextrose, sodium alginate, sodium chloride and or mixtures thereof.
  • Sucrose as a diluent has a particle size such that not less than 90% of particles are below 200 pm.
  • sucrose has a particle size such that not less than 90% of particles are below 100 pm. This helps in achieving improved uniformity of the drug in the mixture.
  • the diluent is present in an amount of 5% w/w to 99% w/w of the total composition.
  • Carrier/vehicle/solvent used in the extended release suspension of the present invention include aqueous and non-aqueous carriers but are not limited to water, alcohol, polyethylene glycol, propylene glycol or glycerin buffers, oil, or combinations thereof.
  • Oils include peanut oil, soy bean oil, com oil, sesame oil, cottonseed oil, acetylated glycerides, ethyl oleate, mineral oil, fatty acid esters, mono- or di- fatty acid esters of polyethylene glycols, or glyceryl mono-oleate.
  • the suspensions are aqueous based.
  • aqueous carrier is meant a suspension comprising water, or a combination of water and a water-miscible organic solvent or solvents.
  • Water-miscible solvents include but are not limited to propylene glycol, polyethylene glycol and ethanol.
  • non-aqueous carrier is meant a suspension in which the carrier does not include water.
  • the carrier can also include one more pharmaceutically acceptable excipients which can be in dissolved or dispersed form.
  • the carrier is present in an amount from about 10% w/w to about 99% w/w, particularly from about 40% w/w to about 95% w/w.
  • antioxidants include, but are not limited to, ascorbic acid, tertbutylhydroquinone, sodium pyrosulfite, glutathione, sodium bisulfite, sodium sulfite, a- tocopherol, a-tocopherol acetate, monothioglycerol, cysteine, ascorbyl palmitate, acetylcysteine, dithiothreitol, sodium metabisulfite, thiourea, sodium thiosulfate, butylated hydroxy anisole (BHA), butylated hydroxy toluene (BHT) and propyl gallate.
  • the antioxidant is present in an amount from 0% w/w to about 20% w/w, from about 0.001% w/w to about 5% w/w.
  • anticaking agents/ glidants include but are not limited to, colloidal silica and/or colloidal silicon dioxide (e.g. Aerosil® 200), magnesium trisilicate, calcium phosphate tribasic, magnesium oxide, magnesium silicate, calcium silicate, talc and combinations thereof.
  • the anticaking agents are present in an amount of about 0. 1% w/w to about 10% w/w of the composition. More particularly, the anticaking agents are present in an amount of about 0.5% w/w to about 7% w/w of the composition.
  • sweetening agents include, but are not limited to, sugar or a sugar alcohol such as sucrose, dextrose, sucralose, sorbitol, fructose, mannitol and invert sugar and sugar substitutes such as saccharin sodium, aspartame and/or thaumatin.
  • Sugar or sugar alcohol can also act as filler.
  • the sweetening agent used is sorbitol, sucralose, thaumatin or a combination thereof.
  • the sweetening agents are present in an amount of 0% w/w to about 90% w/w of the composition, particularly in an amount of about 0.1% w/w to about 90% w/w of the composition.
  • Various useful flavoring agents include but are not limited to, flavors such as banana, lemon, orange, grape, lime and grapefruit, vanilla, bubble gum, peppermint, tutti-frutti, and fruit essence, including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plant leaves, flowers, fruits such as cinnamon oil, oil of wintergreen, peppermint oils, clove oil, citrus oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almonds, and cassia oil, maltitol, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid and combinations thereof.
  • the flavoring agents are present in an amount of about 0.1% w/w to about 5% w/w of the composition.
  • the amount of surfactant or wetting agent should be sufficient to facilitate the dispersion of riociguat in the suspension. At the same time, it should provide improved wettability of the riociguat.
  • Suitable surfactant or wetting agents are selected from the group comprising non-ionic, anionic, cationic, or zwitterionic surfactants, and combinations thereof.
  • surfactants are sodium lauryl sulphate; cetrimide; polyethylene glycols; polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate; sorbitan fatty acid esters such as sorbitan monostearate; polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monooleate; polyoxyethylene alkyl ether such as polyoxyethylene lauryl ether; polyoxyethylene castor oil; polyoxyethylene- polyoxypropylene block copolymers such as poloxamers (e.g. Poloxamer 188); and combinations thereof.
  • surfactant or wetting agents are non-ionic.
  • the surfactant or wetting agents are present in an amount of about 0.01% to about 8% w/w of the composition. Particularly, the surfactant or wetting agents are present in an amount of about 0.01% w/w to about 3% w/w, and more particularly from about 0.01% w/w to about 1% w/w of the composition.
  • Suitable preservatives include, but are not limited to, parabens such as methylparaben, propylparaben, butyl paraben and their salts, sorbic acid, sodium sorbate, potassium sorbate, calcium sorbate, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, methyl hydroxybenzoate, ethyl para- hydroxybenzoate, sodium ethyl para-hydroxybenzoate, sodium metabisulphite, chlorhexidine, diazolidinyl urea, sodium citrate, butylated hydroxyl toluene (BHT), butylated hydroxyl anisole (BHA), tocopherol, ethylenediamine tetraacetic acid, propyl gallate, quaternary compounds, e.g.
  • the preservative is selected from benzoic acid and its salts and parabens.
  • the preservative is present in an amount of about 0.001% w/w to about 3% w/w of the composition.
  • Various useful lubricants include, but are not limited to magnesium stearate, calcium stearate, stearic acid, and sodium stearyl fumarate.
  • the lubricants are present in an amount of about 0.1% w/w to about 5% w/w based on the total weight of the powder formulation.
  • Various useful taste masking agents include, but are not limited to, water-soluble and/or insoluble polymeric excipient, water-insoluble non-polymeric excipient, adsorbent, ion exchange resin, carbomer, alkali metal chlorides or an alkaline earth metal chlorides or a derivative thereof.
  • Suitable antifoaming agents include, but are not limited to simethicone.
  • Suitable coloring agents are selected from the group comprising FD&C (Federal Food, Drug and Cosmetic Act) approved coloring agents; natural coloring agents; natural juice concentrates; pigments such as iron oxide, titanium dioxide, and zinc oxide; and combinations thereof.
  • FD&C Food, Drug and Cosmetic Act
  • Suitable binders are selected from the group comprising gums such as guar gum, acacia, alginic acid, sodium alginate; carbomers; dextrin; maltodextrin; celluloses e.g., methylcellulose, ethyl cellulose, hydroxethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethylmethyl cellulose, carboxymethyl cellulose sodium; povidone; dextrose; polydextrose, starch, pregelatinized starch, microcrystalline cellulose, polymethacrylates including acrylic copolymers, gelatin, and mixtures thereof.
  • the binder is present in an amount of about 0.1% w/w to about 30% w/w of the composition.
  • Suitable disintegrants are selected from the group comprising carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, polacrillin potassium, sodium starch glycolate, alginic acid, sodium alginate, microcrystalline cellulose, silicified microcrystalline cellulose, guar gum, colloidal silicon dioxide, docusate sodium, low substituted hydroxypropyl cellulose, magnesium aluminium silicate, methyl cellulose, starch, pregelatinized starch, and combinations thereof.
  • the disintegrant is present in an amount of about 0.1% w/w to about 30% w/w of the composition.
  • Extended release powder/granules for oral suspension can be reconstituted using water or powder/granules for oral suspension can be administered by sprinkling the extended release powder/granules on soft food e.g. yoghurt, applesauce or empty granules into a small cup or teaspoon containing apple juice, etc.
  • the extended release oral pharmaceutical suspension dosage form is prepared by mixing, blending, dry granulation, wet granulation, spheronization extrusion process, hot melt extrusion process, extrusion spheronization, fluidized bed granulation, melt-granulation, dispersion, drug-ion exchange resin complexation, homogenization, and combinations thereof.
  • the cores of riociguat can be prepared by any method known in the art, e.g., extrusion-spheronization, wet granulation, dry granulation, hot-melt extrusion granulation, spray drying, spray congealing, and the like.
  • riociguat can be layered onto an inert particle to form the core.
  • riociguat can be directly coated with a release-controlling agent to form the microparticles or microcapsules.
  • the microparticles or microcapsules can be prepared by a process of homogenization, solvent evaporation, coacervation phase separation, spray drying, spray congealing, polymer precipitation, or supercritical fluid extraction.
  • the extended release cores can be optionally mixed with at least one or more pharmaceutically acceptable excipients to form the suspension powder for reconstitution which can be reconstituted with a suitable pharmaceutically acceptable carrier/vehicle.
  • Extended release suspension of riociguat can be prepared by (i) preparing cores comprising riociguat and at least one or more pharmaceutically acceptable excipients; (ii) dissolving/dispersing a release-controlling agent and at least one or more pharmaceutically acceptable coating excipients in a suitable solvent; (iii) applying the coating composition of step (ii) over the cores of step (i); (iv) dissolving/dispersing at least one or more pharmaceutically acceptable excipients in a pharmaceutically acceptable vehicle to form a pharmaceutically acceptable carrier; and (v) dispersing the coated cores of step (iii) in the carrier of step (iv) to obtain the extended release suspension.
  • a process for preparing an extended release suspension dosage form of riociguat comprises the following steps: a) blending riociguat with at least one or more pharmaceutically acceptable excipients, b) granulating the blend, c) further coating the granules of step b) with a rate controlling agent, d) drying and lubricating the granules of step c), e) blending the granules with at least one or more pharmaceutically acceptable excipients, f) filling into suitable bottle/sachet/pouch.
  • the extended release coated cores can be optionally mixed with at least one or more pharmaceutically acceptable excipients to form the suspension powder for reconstitution which can be reconstituted with a suitable pharmaceutically acceptable carrier/vehicle.
  • Riociguat can also be present in complexed form with ion-exchange resins which are coated with an extended release coating comprising a release-controlling agent to form the extended release core.
  • the extended release cores are optionally mixed with at least one or more pharmaceutically acceptable excipients to form the extended release suspension powder for reconstitution.
  • the extended release cores are dispersed in a pharmaceutically acceptable carrier to form ready to use extended release liquid composition.
  • Ion-exchange resins are cross-linked, water-insoluble, high molecular-weight polyelectrolytes that can reversibly exchange their mobile ions of equal charge with the surrounding medium stoichiometrically.
  • the ion-exchange resins useful in the extended release compositions of the present invention comprise of a pharmacologically inert organic or inorganic matrix containing covalently bound functional groups that are ionic or capable of being ionized under the appropriate conditions of pH.
  • the organic matrix may be synthetic (e.g., polymers or copolymers of acrylic acid, methacrylic acid, sulfonated styrene, sulfonated divinylbenzene), or partially synthetic (e.g., modified cellulose and dextrans).
  • the inorganic matrix preferably comprises silica gel modified by the addition of ionic groups. Covalently bound ionic groups may be strongly acidic (e.g., sulfonic acid, phosphoric acid), weakly acidic (e.g., carboxylic acid), strongly basic (e.g., primary amine), weakly basic (e.g. quaternary ammonium), or a combination of acidic and basic groups.
  • charged groups can also be used, including any organic group that bears an acidic or a basic functional group, for example, an amine, imine, imidazoyl, guanidine, pyridinyl, quaternary ammonium, or other basic groups, or a carboxylic, phosphoric, phenolic, sulfuric, sulfonic or other acidic groups.
  • Suitable ion exchange resins are also sold under the trade names Amberlite, Amberlyst and Dowex.
  • Weak cation acid ion exchange resins such as Indion 204, Indion 214, Indion 224, polacrillin potassium as well as a strong cation acid resin such as PuroliteClOOCaMR, Amberlite IRP-69 and Dowex-50 can also be used.
  • the ion-exchange resin used is sodium polystyrene sulfonate (Amberlite IRP-69).
  • the size of the ion-exchange particles is from about 30 microns to about 500 microns, preferably the particle size is within the range of about 30 microns to about 150 microns for extended release suspension dosage form of the present invention.
  • Binding of drug to resin can be accomplished by the following ways. In the case of a basic drug, these are: (a) resin (Na-form) plus drug (salt form); (b) resin (Na-form) plus drug (as free base); (c) resin (H-form) plus drug (Salt form), and (d) resin (H- form) plus drug (as free base).
  • Coating may be applied by employing solution, suspension or powder blend using any conventional coating technique known in the art such as spray coating, dip coating or compression coating.
  • Suitable solvents used for granulation or forming a solution or dispersion for coating are selected from the group comprising water, ethyl alcohol, isopropyl alcohol, acetone, methanol, methylene chloride, and mixtures thereof.
  • the coating additives used in the present invention are selected from the group comprising plasticizers, opacifiers, surfactants, anti-tacking agents, coloring agents and mixtures thereof.
  • Suitable plasticizers are selected from the group comprising dibutyl sebacate, triethyl citrate, tributyl citrate, triacetin, acetylated triacetin, glyceryl tributyrate, diacetylated monoglyceride, rapeseed oil, olive oil, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, glycerin, diethyl oxalate, diethyl phthalate, diethyl malate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, and mixtures thereof.
  • Suitable opacifiers are selected from the group comprising titanium dioxide, manganese dioxide, iron oxide, silicon dioxide, and mixtures thereof.
  • the extended release pharmaceutical composition of the present invention can be packaged in a suitable pack/container such as amber colored polyethylene terephthalate (PET) bottle, glass bottle, vials, high density polyethylene (HDPE) bottle, low density polyethylene (LDPE) bottle, polypropylene (PP) bottle, packets, pouches, sachets and the like.
  • a suitable pack/container such as amber colored polyethylene terephthalate (PET) bottle, glass bottle, vials, high density polyethylene (HDPE) bottle, low density polyethylene (LDPE) bottle, polypropylene (PP) bottle, packets, pouches, sachets and the like.
  • the glass or plastic bottle may be provided with a child proof closure.
  • the package can include a syringe (marked in mL) for ease of dosing.
  • the extended release suspension powder formulation can be for a single dose or multiple doses after reconstitution with a carrier.
  • the container such as bottle has a fill volume of, e.g., from about 30 mL to about 300 mL comprising riociguat suspension.
  • Pack chosen are made of material which is non- reactive with the extended release ready to use suspension and suspension powder for reconstitution.
  • Containers for use in the storage of the extended release oral suspensions may be used to administer a multiple dose of riociguat.
  • the extended release pharmaceutical dosage form of the present invention can be provided in a kit comprising (a) extended release suspension powder for reconstitution of riociguat and (b) a pharmaceutically acceptable carrier.
  • the extended release suspensions of the present invention provide predictable riociguat release throughout the shelf life.
  • Ethyl cellulose and dibutyl sebacate were dispersed in a mixture of acetone and purified water.
  • step 4 The drug layered cores of step 2 were coated with the coating dispersion of step 3.
  • Xanthan gum microcrystalline cellulose-sodium carboxymethyl cellulose, xylitol/sorbitol, citric acid - monosodium dibasic phosphate (if present), sucralose (if present), saccharin sodium (if present), and orange flavor were mixed in purified water.
  • Ethyl cellulose and dibutyl sebacate were dispersed in a mixture of acetone and purified water.
  • step 4 The drug layered cores of step 2 were coated with the coating dispersion of step 3.
  • Xanthan gum, microcrystalline cellulose-sodium carboxymethyl cellulose, sucralose, xylitol/sorbitol, citric acid - monosodium dibasic phosphate (if present), saccharin sodium (if present), sucralose (if present), and orange flavor were mixed with coated cores of step 4 to prepare extended release suspension powder for reconstitution of riociguat.
  • Extended release suspension powder for reconstitution of riociguat was reconstituted with required amount of liquid carrier e.g. water when required to form the extended release suspension.
  • step 3 The slurry of step 2 was filtered to collect resin particles and washed with pre-heated deionized water.
  • step 4 The resulting drug-resin complex of step 3 was dried in an oven at 45°C.
  • a coating dispersion was prepared by dispersing ethyl cellulose and dibutyl sebacate in a mixture of acetone and water.
  • Microcrystalline cellulose-sodium carboxymethyl cellulose, xanthan gum, sucralose, xylitol, and bubble gum flavor were mixed in purified water.
  • step 3 The blend of step 1 was granulated with the solution of step 2 and dried.
  • Xanthan gum, microcrystalline cellulose-sodium carboxymethyl cellulose, xylitol/sorbitol, citric acid - monosodium dibasic phosphate (if present), saccharin sodium (if present) and strawberry flavor were mixed with extended release granules of step 3 to prepare extended release suspension powder for reconstitution of riociguat.
  • Extended release suspension powder for reconstitution of riociguat was reconstituted with required amount of liquid carrier e.g. water when required to form the extended release suspension.
  • step 2 Sodium polystyrene sulfonate was added in the solution of step 1 and the dispersion was stirred for a suitable time period (4-5 hours).
  • step 3 The solution of step 2 was filtered through wattman filter paper. The filtrate and resinate were separated.
  • the resinate was dried in a suitable dryer (such as a tray dryer) at 60°C for a suitable time period (6-8 hours).
  • Sorbitol was added to the purified water and stirred until a clear solution was obtained. 2. Glycerin was heated at 80°C in another beaker and methyl paraben and propyl paraben were added and stirred to dissolve completely.
  • step 2 was added into step 1 with stirring.
  • Xanthan gum was added into the solution of step 4 and stirred for a suitable time (about 30 minutes).
  • step 5 The dispersion of step 5 was homogenized for a suitable time (about 30 minutes).
  • step 8 Resinate was added into the solution of step 7 and stirred the suspension for a suitable time (about 30 minutes) to form a homogeneous suspension.
  • Drug solution was prepared by adding povidone and riociguat in methanol and was stirred until a clear solution was obtained.
  • step 2 Drug solution of step 1 was sprayed over MCC spheres/sugar spheres to obtain the desired weight gain.
  • Extended release coating solution was prepared by dissolving ethyl cellulose in methanol and stirred until a clear solution formed.
  • step 4 The drug layered pellets of step 2 were coated with the extended release coating solution of step 3 to obtain the desired weight gain.
  • step 6 The solution of step 6 was added into step 5 under stirring.
  • Xanthan gum was added under stirring into the solution of step 8 and was further stirred for 30 minutes.
  • step 9 The dispersion of step 9 was homogenized for 30 minutes.
  • step 11 Strawberry flavor was added into the solution of step 10 and the volume was made-up with water.
  • step 4 Ethylcellulose coated pellets of step 4 were added into the suspension of step 11 and the suspension was stirred for 30 min to form a smooth homogeneous suspension.
  • Drug solution was prepared by adding povidone and riociguat in methanol and was stirred until a clear solution was obtained.
  • step 2 Drug solution of step 1 was sprayed over MCC spheres/sugar spheres to obtain the desired weight gain.
  • Extended release coating solution was prepared by dissolving ethyl cellulose in methanol and stirred until a clear solution formed.
  • step 4 The drug layered pellets of step 2 were coated with the extended release coating solution of step 3 to obtain the desired weight gain.
  • Dextrose, xanthan gum, and crospovidone were sifted through a suitable mesh.
  • Citric acid was dissolved in isopropyl alcohol and the blend of step 5 was granulated.
  • step 6 The blend of step 6 was dried at 50°C ⁇ 10°C for a suitable period of time.
  • step 8 The extended release pellets of step 4 and inactive granules of step 7 were filled in a suitable sachet/bottle.
  • results The dissolution, and assay of dosage forms prepared using quantitative formula (Examples 28-30), is given below.
  • the dissolution profile was measured in 900 ml of 6.8 phosphate buffer and 0.1% SLS using a USP II apparatus (Paddle) at a temperature of 37 ⁇ 0.5°C and a rotation speed of 100 revolutions per minute.

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Abstract

The present invention relates to orally administered extended release pharmaceutical suspensions of riociguat. The extended release suspensions are in the form of ready to use suspension and suspension powder for reconstitution. It also relates to the processes for the preparation of said extended release suspensions. It further relates to the use of extended release pharmaceutical suspensions for the treatment of hypertension and related disorders. The prepared compositions are useful in patients having difficulties in swallowing tablets and provide enhanced patient compliance over conventional tablet dosage form.

Description

PHARMACEUTICAL EXTENDED RELEASE SUSPENSIONS OF RIOCIGUAT
FIELD OF THE INVENTION
The present invention relates to orally administered extended release pharmaceutical suspensions of riociguat. The extended release suspensions are in the form of ready to use suspension and suspension powder for reconstitution. It also relates to the processes for the preparation of said extended release suspensions. It further relates to the use of extended release pharmaceutical suspensions for the treatment of hypertension and related disorders.
BACKGROUND OF THE INVENTION
Riociguat is an antihypertensive drug. It is chemically known as methyl 4,6- diamino-2- [ 1 -(2-fluorobenzy 1)- 1 H-pyrazolo [3,4-b]pyridin-3 -y 1] -5- pyrimidinyl(methyl)carbamate and is represented by the following formula as:
Figure imgf000002_0001
Riociguat is marketed in the U.S. as an immediate-release tablet in 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg strengths under the brand name Adempas® by Bayer Healthcare Pharmaceuticals. The marketed solid dosage form of riociguat is indicated for the treatment of persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH) to improve exercise capacity.
U.S. Patent No. 7,173,037, assigned to Bayer Healthcare, discloses riociguat as a new compound. This patent also discloses the use of riociguat in the treatment of hypertension.
U.S. Patent Nos. 10,087,183 and 10,662,188, assigned to Bayer Healthcare, discloses various polymorphs of riociguat such as modification I, modification II, mono- DMSO solvate, sesqui-DMSO solvate, ' i-ethyl acetate solvate and pharmaceutical compositions thereof.
Difficulty in swallowing solid oral dosage forms such as tablets and capsules is a problem for many patients and can induce significant non-compliance with the prescribed treatment regimens. Adolescents, children, and the elderly are particularly vulnerable population groups that are more likely than adults to experience difficulty in swallowing tablets or capsules.
The prescribing information of Adempas® tablet mentions that the riociguat tablets may be crushed and mixed with water or soft foods for patients who have difficulty swallowing. In addition, the tablet has to be administered three times a day owing to short half-life of the drug.
Till date, no extended release suspension formulation of riociguat is commercially available. There remains an unmet need in the art for an extended release suspension dosage form of riociguat which is suitable for administration for fewer times a day and which also obviates swallowing difficulty associated with the marketed tablet dosage form.
A particular challenge in the development of extended release suspension dosage form is the prevention of a premature release of drug from the suspended particles during the shelflife of the suspension dosage form prior to ingestion by a patient. Additionally, the maintenance of the desired dissolution profile, as well as the desired dose uniformity of the suspension dosage form throughout its shelf life, are additional challenges to be addressed in formulating an oral, extended release suspension product.
The inventors of the present invention have developed extended release suspension dosage forms of riociguat with an objective to minimize swallowing difficulties and to provide a simpler dosage regimen by once daily or twice daily administration. This improves patient compliance by reducing dysphagia-related adverse events and providing a more convenient and less cumbersome dosage regimen. The inventors have developed ready-to- use extended release suspension and extended release suspension powder for reconstitution, which are convenient for administration by paediatric and geriatric patients and even by adults, easy to manufacture, functionally reproducible, provide ease of dose adjustment and are bioequivalent to the marketed tablet. Further, the extended release suspension dosage form exhibits desirable technical attributes such as pourability, viscosity, pH, dissolution, re-suspendability, assay and stability. SUMMARY OF THE INVENTION
It is a principal object of the present invention to provide a stable extended release oral pharmaceutical suspension dosage form of riociguat comprising riociguat and at least one or more pharmaceutically acceptable excipients and processes for its preparation. The extended release suspension dosage form of the present invention is in the form of ready- to-use extended release suspension and extended release suspension powder for reconstitution.
It is another object of the present invention to provide an extended release oral pharmaceutical suspension dosage form of riociguat comprising riociguat or its pharmaceutically acceptable esters, salts, solvates, polymorphs, enantiomers or mixtures thereof with at least one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients are selected from the group consisting of suspending agent, buffer/pH adjusting agent, release-controlling agent, diluent, carrier, vehicle, antioxidant, anticaking agent, antifoaming agent, coloring agent, sweetening agent, flavoring agent, surfactant/solubilizer/wetting agent, preservative, glidant, lubricant, binder, disintegrant, ion-exchange resins, plasticizers, opacifiers, solvents, and mixtures thereof.
It is another object of the present invention to provide a ready -to-use extended release suspension comprising riociguat or its pharmaceutically acceptable esters, salts, solvates, polymorphs, enantiomers or mixtures thereof with at least one or more pharmaceutically acceptable excipients and process for their preparation.
It is another object of the present invention to provide an extended release suspension powder for reconstitution comprising riociguat or its pharmaceutically acceptable esters, salts, solvates, polymorphs, enantiomers or mixtures thereof with at least one or more pharmaceutically acceptable excipients and process for their preparation.
It is another object of the present invention to provide an extended release suspension dosage form comprising riociguat or its pharmaceutically acceptable esters, salts, solvates, polymorphs, enantiomers or mixtures thereof, in an amount of about 0.01% to about 30% by weight, wherein the suspension dosage form exhibits desirable technical attributes like pourability, viscosity, dissolution, stability, re-suspendability and a process for preparing the same.
In accordance with still another embodiment of the present invention, there is provided a pharmaceutical extended release suspension dosage form comprising riociguat or its pharmaceutically acceptable esters, salts, solvates, polymorphs, enantiomers or mixtures thereof, for use in the treatment of hypertension, pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, persistent/recurrent chronic thromboembolic pulmonary hypertension, heart failure, arrhythmia, high blood pressure, angina pectoris, myocardial infarction, stroke, transient ischaemic attacks, arteriosclerosis, erectile dysfunction, osteoporosis, Alzheimer's disease, Parkinson's disease, multiple sclerosis, depression, schizophrenia, bipolar disorder and migraine.
DETAILED DESCRIPTION OF THE INVENTION
The present invention can be more readily understood by the following detailed description of the invention and study of the included examples.
As used herein, the term “composition or “formulation” or “dosage form”, as in pharmaceutical composition, is intended to encompass a drug product comprising riociguat or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, and other inert ingredient(s) (pharmaceutically acceptable excipients). Such pharmaceutical compositions are synonymous with “formulation” and “dosage form”. Pharmaceutical suspension dosage form of the invention includes, but is not limited to ready to use extended release suspension, extended release powder for suspension, extended release granules, pellets, beads, multiparticulates, microspheres, and microcapsules, and the like. Particularly, the pharmaceutical composition refers to extended release powder, granules, pellets, beads, multiparticulates, microspheres, and microcapsules and the like, filled into capsules or sachets and ready to use suspension.
The extended release suspension powder for reconstitution comprises granules, cores, pellets, beads, spheroids, multiparticulates, microspheres, and microcapsules of riociguat.
As used herein, the term “ready to use suspension” means a pre-constituted suspension that can be administered as such. The “powder for suspension” or “suspension powder for reconstitution” or “dry suspension” are synonymous and are reconstituted with a liquid carrier to form a suspension.
As used herein, the term “riociguat” is used in broad sense to include not only “riociguat” per se but also its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, derivatives, isomers, polymorphs, prodrugs thereof, and also its various crystalline and amorphous forms. Riociguat is present in an amount from about 0.01% w/w to about 70% w/w of the extended release suspension dosage form, particularly from about 0.01% w/w to about 30% w/w, from about 0.01% w/w to about 20% w/w, from about 0.01% w/w to about 10% w/w, from about 0.01% w/w to about 5% w/w, from about 0.01% w/w to about 3% w/w of the suspension dosage form.
The term “extended release” as used herein, refers to a release profile to effect delivery of riociguat over an extended period of time, as being between about 1 hour to about 2, 4, 6, 8, 12, 16 or 24 hours. The terms “extended release” encompasses controlled release, sustained release, modified release, prolonged release, programmed release, pulsatile release, delayed release, and the like and mean broadly that the active agent is released at a predetermined rate that is different or slower than immediate release. An extended release composition is one for which the drug release characteristics of time course are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as solutions or promptly dissolving dosage forms e.g., immediate release tablets.
The term “inert particle,” as used herein, refers to a particle made from a sugar sphere also known as a non-pareil seed, a microcrystalline cellulose sphere, a dibasic calcium phosphate bead, a mannitol bead, a silica bead, a tartaric acid pellet, a wax-based pellet, and the like.
The term “drug resin particle,” or “drug resin complex” as used herein, refers to a drug-containing ion-exchange resin particle in which there is an ionic bond between drug and the ion-exchange resin particle.
The term “excipient” means a pharmacologically inactive component such as a suspending agent, pH adjusting agent/buffering agent, release-controlling agent, diluent, carrier, anticaking agent, antifoaming agent, antioxidant, sweetening agent, vehicle, solvent, flavoring agent, surfactant/solubilizer/wetting agent, buffer, glidant, lubricant, and preservative and mixtures thereof. Reference to an excipient includes both one and more than one such excipient. Co-processed excipients are also covered under the scope of present invention. Combination of excipients performing the same function may also be used to achieve desired formulation characteristics.
The term “about,” as used herein, means ± approximately 10% of the indicated value, such that “about 10 percent” indicates approximately 8 to 12 percent. The term “substantially similar,” as used herein, means ± approximately 25% of the indicated value. The ratio represented here may be referred as any ratio as known in the art, preferably as “weight ratio”.
The term “stable,” as used herein, refers to chemical stability, wherein not more than 5% w/w of total related substances are formed on storage at 40°C and 75% relative humidity (R.H.) or at 25°C and 60% R.H. for a period of at least 1 week, for a period of at least one month, particularly for a period of two months, and more particularly for a period of at least three months.
Unless otherwise stated the weight percentages expressed herein are based on the final weight of the composition or formulation.
The following embodiments further describe the objects of the present invention in accordance with the best mode of practice, however, disclosed invention is not restricted to the particular embodiments hereinafter described.
In accordance with one embodiment, there is provided an extended release suspension dosage form of riociguat comprising riociguat and at least one or more pharmaceutically acceptable excipients.
In accordance with one embodiment, there is provided an extended release suspension dosage form of riociguat comprising riociguat, a release controlling agent and at least one or more pharmaceutically acceptable excipients.
In accordance with one embodiment, there is provided an extended release suspension dosage form comprising: a) a core comprising riociguat; b) a coating layer over said core comprising a release-controlling agent; and c) at least one or more pharmaceutically acceptable excipients.
Another embodiment of the present invention provides an extended release suspension dosage form of riociguat comprising: a) extended release cores of riociguat comprising a release-controlling agent; and b) at least one or more pharmaceutically acceptable excipients.
Another embodiment of the present invention provides a ready to use extended release suspension dosage form of riociguat comprising: a) cores of riociguat coated with a release-controlling agent to form the extended release cores; and b) a pharmaceutically acceptable carrier.
Another embodiment of the present invention provides an extended release suspension powder for reconstitution of riociguat comprising: a) cores of riociguat coated with a release-controlling agent to form the extended release cores; and b) at least one or more pharmaceutically acceptable excipients.
According to another embodiment, the extended release suspension is an aqueous suspension.
Another embodiment of the present invention provides an extended release suspension dosage form of riociguat comprising: a) riociguat; b) a release-controlling agent; c) a suspending agent; and d) one or more pharmaceutically acceptable excipients.
Another embodiment of the present invention provides an extended release suspension dosage form of riociguat comprising: a) riociguat; b) a release-controlling agent; c) a suspending agent; d) a pH adjusting agent; and e) one or more pharmaceutically acceptable excipients, wherein the suspension has a pH of about 3 to about 8.
Another embodiment of the present invention provides an extended release suspension dosage form of riociguat comprising: a) riociguat; b) a release-controlling agent; c) a suspending agent; d) optionally a pH adjusting agent; and e) one or more pharmaceutically acceptable excipients, wherein the suspension has a viscosity from about 100 cps to 4000 cps.
Another embodiment of the present invention provides an extended release suspension dosage form of riociguat comprising: a) riociguat; b) a release-controlling agent; c) a suspending agent; d) optionally a pH adjusting agent; and e) one or more pharmaceutically acceptable excipients, wherein the suspension has a pH of about 3 to about 8 and a viscosity from about 100 cps to 4000 cps.
Another embodiment of the present invention provides an extended release suspension dosage form of riociguat comprising: a) riociguat in an amount of about 0.01% to about 10% by weight, b) a release controlling agent; and c) at least one or more pharmaceutically acceptable excipients wherein the suspension has a pH of about 3 to about 8 and ratio of riociguat to release controlling agent in the dosage form is between about 1:0.5 to about 1 : 10.
Another embodiment of the present invention provides an extended release suspension dosage form of riociguat comprising: a) riociguat in an amount from about 0.01% to about 30% w/w; b) a release-controlling agent in an amount from about 0.1 % to about 50% w/w; c) a suspending agent in an amount from about 0.05% to about 20% w/w; and d) one or more pharmaceutically acceptable excipients.
Another embodiment of the present invention provides an extended release suspension dosage form of riociguat comprising riociguat complexed with ion-exchange resin particles to form drug resin particles, which are coated with an extended release coating comprising a release-controlling agent.
Another embodiment of the present invention provides an extended release suspension dosage form of riociguat comprising riociguat complexed with sodium polystyrene sulfonate resin to form drug resin particles, which are coated with an extended release coating comprising a release-controlling agent.
In another embodiment, the present invention relates to, an extended release oral suspension dosage form comprising: a) riociguat in an amount of about 0.01% to about 10% by weight, b) an ion-exchange complexing agent selected from sodium polystyrene sulfonate and polacrillin potassium or combination thereof in an amount of about 0.01% to about 10% by weight, and c) a suspending agent selected from the group consisting of xanthan gum, hydroxypropyl methyl cellulose, gellan gum, sodium carboxymethylcellulose, a mixture of carboxymethylcellulose and microcrystalline cellulose, propylene glycol alginate and combinations thereof in an amount from about 0.05% to about 20% w/w. In an embodiment, the composition further comprises one or more sweetening agents, preservatives, carrier/vehicle/solvent, and flavoring agents. In an embodiment, the ratio of riociguat and ion-exchange complexing agent in the composition is more than 1:1, preferably 1:2, more preferably 1:3. In an embodiment, the composition exhibits at least 40% drug release in 12 hours when measured in 900 ml of 6.8 phosphate buffer and 2% KCL using a USP II apparatus (Paddle) at a temperature of 37±0.5°C and a rotation speed of 75 revolutions per minute.
In another embodiment, the present invention relates to, an extended release oral suspension dosage form of riociguat comprising: a) riociguat in an amount of about 0.01% to about 10% by weight, b) a release controlling agent selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methaacrylic acid copolymers, ethyl cellulose, cellulose acetate, an ion-exchange resin and combination thereof in an amount of about 0.1% to about 10% by weight, c) a suspending agent selected from the group consisting of xanthan gum, hydroxypropyl methylcellulose, gellan gum, sodium carboxymethylcellulose, a mixture of carboxymethylcellulose and microcrystalline cellulose, propylene glycol alginate and combinations thereof in an amount from about 0.05% to about 20% w/w, d) one or more buffering agents selected from the group consisting of monosodium dibasic phosphate, citric acid, acetic acid, sodium citrate, sodium acetate potassium citrate, and potassium dihydrogen phosphate, and combinations thereof in an amount of about 0.01% w/w to about 8% w/w of the dosage form; and e) at least one or more other pharmaceutically acceptable excipients, wherein the suspension has a pH of about 3 to about 8. In another embodiment, the present invention relates to, an extended release oral suspension dosage form of riociguat comprising: a) riociguat in an amount of about 0.01% to about 10% by weight, b) hydroxypropyl methylcellulose, ethyl cellulose, sodium polystyrene sulfonate and combination thereof in an amount of about 0.1% to about 10% by weight, c) xanthan gum, a mixture of carboxymethylcellulose and microcrystalline cellulose, and combinations thereof in an amount from about 0.05% to about 10% w/w, d) citric acid, sodium citrate, and combinations thereof in an amount of about 0.01% w/w to about 5% w/w of the dosage form; and e) at least one or more pharmaceutically acceptable excipients, wherein the suspension has a pH of about 3 to about 8 and the ratio of riociguat to release controlling agent in the dosage form is between about 1:0.5 to about 1:5. Preferably, the suspension has a pH of about 3 to about 5.5.
In another embodiment, the present invention relates to, an extended release oral suspension dosage form of riociguat comprising: i. an inert inner core, ii. optionally a water-soluble seal or seal coating layer consisting essentially of water-soluble polymers, iii. a first coating on top of the inner core comprised of riociguat in an amount of about 0.01% to about 10% by weight and a binder selected from the group consisting of povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, starch, methylcellulose, ethylcellulose, carboxymethyl cellulose, sucrose solution, dextrose solution in an amount of about 0.1% to about 20% by weight, iv. optionally a water-soluble seal or seal coating layer consisting essentially of water-soluble polymers, v. an extended coating layer comprises of at least one water-insoluble cellulose derivative; and vi. a liquid carrier comprises of: a) a suspending agent selected from the group consisting of xanthan gum, hydroxypropyl methylcellulose, gellan gum, sodium carboxymethylcellulose, a mixture of carboxymethylcellulose and microcrystalline cellulose, propylene glycol alginate and combinations thereof in an amount from about 0.05% to about 20% w/w, b) one or more wetting agents selected from the group consisting of sodium lauryl sulphate, polysorbate, sorbitan monostearate, poloxamers, and combinations thereof in an amount of about 0.01% w/w to about 8% w/w of the dosage form, c) one or more buffering agents selected from the group consisting of monosodium dibasic phosphate, citric acid, acetic acid, sodium citrate, sodium acetate potassium citrate, and potassium dihydrogen phosphate, and combinations thereof in an amount of about 0.01% w/w to about 8% w/w of the dosage form, d) one or more sweetening agents selected from the group consisting of sucrose, dextrose, sucralose, sorbitol, fructose, mannitol, saccharin sodium, aspartame, thaumatin and combination thereof in an amount of about 0.1% w/w to about 20% w/w of the dosage form, e) one or more preservatives selected from the group consisting of parabens such as methylparaben, propylparaben, butylparaben benzoic acid, sodium benzoate, potassium benzoate, butylated hydroxyl toluene (BHT), butylated hydroxyl anisole (BHA), tocopherol, benzalkonium chloride and combinations thereof in an amount of about 0.001% w/w to about 3% w/w of the dosage form;
1) one or more vehicle/solvent selected from the group consisting of water, alcohol, polyethylene glycol, propylene glycol, glycerin, hydrochloric acid and combinations thereof.
In another embodiment, the present invention relates to, an extended release powder for oral suspension dosage form of riociguat comprising: i. an inert inner core, ii. optionally a water-soluble seal or seal coating layer consisting essentially of water-soluble polymers, iii. a first coating on top of the inner core comprised of riociguat in an amount of about 0.01% to about 10% by weight and a binder selected from the group consisting of povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, starch, methylcellulose, ethylcellulose, carboxymethyl cellulose, sucrose solution, dextrose solution in an amount of about 0.1% to about 20% by weight, iv. optionally a water-soluble seal or seal coating layer consisting essentially of water-soluble polymers, v. an extended coating layer comprises of at least one water-insoluble cellulose derivative; and vi. inactive granules comprise of: a) one or more diluents selected from the group consisting of lactose, cellulose, microcrystalline cellulose, mannitol, dextrose, calcium phosphate, starch, pregelatinized starch, and combination thereof in an amount from about 5% to about 90% w/w, b) a suspending agent selected from the group consisting of xanthan gum, hydroxypropyl methylcellulose, gellan gum, sodium carboxymethylcellulose, a mixture of carboxymethylcellulose and microcrystalline cellulose, propylene glycol alginate and combinations thereof in an amount from about 0.05% to about 20% w/w, c) one or more disintegrants selected from the group consisting of carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, polacrillin potassium, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose, pregelatinized starch, and combinations thereof in an amount from about 0.1% to about 10% w/w; and d) one or more buffering agents selected from the group consisting of monosodium dibasic phosphate, citric acid, acetic acid, sodium citrate, sodium acetate potassium citrate, and potassium dihydrogen phosphate, and combinations thereof in an amount of about 0.01% w/w to about 8% w/w of the dosage form.
In an embodiment, the dosage form further comprises one or more wetting agents selected from the group consisting of sodium lauryl sulphate, polysorbate, sorbitan monostearate, poloxamers, and combinations thereof in an amount of about 0.01% w/w to about 8% w/w of the dosage form. In an embodiment, the dosage form further comprises one or more sweetening agents selected from the group consisting of sucrose, dextrose, sucralose, sorbitol, fructose, mannitol, saccharin sodium, aspartame, thaumatin and combination thereof in an amount of about 0.1% w/w to about 20% w/w of the dosage form. In an embodiment, the dosage form further comprises one or more preservatives selected from the group consisting of parabens such as methylparaben, propylparaben, butylparaben benzoic acid, sodium benzoate, potassium benzoate, butylated hydroxyl toluene (BHT), butylated hydroxyl anisole (BHA), tocopherol, benzalkonium chloride and combinations thereof in an amount of about 0.001% w/w to about 3% w/w of the dosage form. In an embodiment, the dosage form further comprises one or more flavoring agents selected from the group consisting of orange, grape, lime and grapefruit, vanilla, bubble gum, peppermint, tutti-frutti, strawberry, and combinations thereof in an amount of about 0.01% w/w to about 5% w/w of the dosage form.
In a preferred embodiment, the inner core is an inert non-pareil sugar sphere. In a preferred embodiment, the core is devoid of any cellulose-based excipients. In a preferred embodiment, the core is devoid of microcrystalline cellulose. In a preferred embodiment, the drug and binder in a ratio less than 1:3 or less than 1 :2. Preferably the drug and binder is in a ratio of 1 : 1. In a preferred embodiment, the controlled release polymer has a viscosity of less than 10 cps. In a preferred embodiment, the controlled release polymer has a viscosity of less than 10 cps. Preferably, the controlled release polymer is ethylcellulose having a viscosity of 7 cps. In a preferred embodiment, the controlled release polymer is used in about 20% weight gain or less, about 10% weight gain or less by the total weight of the core or drug layered dosage form. In a preferred embodiment, the controlled release polymer is used in about 5% weight gain or less by the total weight of core or drug layered dosage form. In a preferred embodiment, the dosage form is free of any glidant. In a preferred embodiment, the multi-particulate delivery system contains particles having a mean diameter of about 400 to about 1200 microns.
The extended release coating over drug resin particles may be a water-permeable diffusion barrier coating that is insoluble in gastrointestinal fluids and water, thereby providing an extended release of drug under conditions encountered in the gastrointestinal tract or may also include a slow-dissolve polymer coating.
Another embodiment of the present invention provides an extended release suspension dosage form of riociguat comprising solid lipid nanoparticles of riociguat.
Solid lipid nanoparticles are lipid-based nanocarriers with a size from 10 nmto 1000 nm. The key ingredients of solid lipid nanoparticles formulations include lipid, surfactant/emulsifier, and mixtures thereof, active pharmaceutical ingredient and a solvent. Lipids used in the preparation of solid lipid nanoparticles are selected from the group comprising fatty acids (e.g. dodecanoic acid, myristic acid, palmitic acid, stearic acid), monoglycerides (glyceryl monostearate, glyceryl hydroxy stearate, glyceryl behenate/ Compritol®), diglycerides (glyceryl palmitostearate, glyceryl dibehenate), triglycerides (caprylate triglyceride, caprate triglyceride, glyceryl tristearate/tristearate, glyceryl trilaurate/trilaurate glyceryl trimyristate/trimyristin, glyceryl tripalmitate/tripalmitin, glyceryl tribehenate/tribehenin, tristearin glyceride), phospholipids, waxes (cetyl palmitate, bees wax), liquid lipids (soya bean oil, oleic acid, medium chain triglycerides / caprylic and capric triglycerides, alpha-tocopherol/vitamin E, squalene hydroxy octa-cosanyl, hydroxy stearate isopropyl myristate), cationic lipids (stearyl amine, benzalkonium chloride, cetrimide, cetyl pyridinium chloride, dimethyl dioctadecyl ammonium bromide).
Surfactants used in the preparation of solid lipid nanoparticles are selected from the group comprising ionic surfactants (e.g. sodium cholate, sodium taurocholate, sodium taurodeoxycholate, sodium glucocholate, sodium oleate, sodium dodecyl sulphate), nonionic surfactants (e.g. Tween 20, Tween 80, Tween 85, Span 20, Span 85, Tyloxapol, Poloxamer 188, Poloxamer 407, Poloxamer 908, Brij 78, Solutol, Tego care 450, Pluronic F68, polyethylene glycols such as PEG 400, PEG 2000, PEG 4500), amphoteric surfactants (e.g. egg phosphatidylcholine, soy phosphatidylcholine, hydrogenated egg phosphatidylcholine, hydrogenated soy phosphatidylcholine, Phospholipon), and combinations thereof.
In another embodiment, solid lipid nanoparticles of riociguat can be prepared prepare using lipid (3.33%), phospholipids (0.6-1.5%), glycerol (2-4%), Poloxamer 188 (1.2-5%), soy phosphatidyl choline (95%), compritol (10%), cetyl palmitate (10%), Tego Care 450 (1.2%), PEG 2000 (0.25%), PEG 4500 (0.5%), PEG 400 (5%), Tween 85 (0.5%), ethyl oleate (30%), sodium alginate (70%), ethanol/butanol (2%), tristearin glyceride (95%), isopropyl myristate (3.60%), Pluronic F 68 (40%), Tween 80 (50%), and mixtures thereof.
Another embodiment of the present invention provides an extended release suspension dosage form of riociguat comprising liquid crystals of riociguat.
The different mesophases of lyotropic liquid crystals are lamellar, hexagonal and cubic. Lipid-based lyotropic liquid crystals are formed by swelling of certain amphiphilic lipids due to their amphiphilic nature containing a polar head group and a hydrophobic tail. When exposed to aqueous environment, amphiphilic lipids spontaneously form thermodynamically stable self-assembled structures and eventually develop into cubic and/or hexagonal liquid crystals depending on temperature and water content. Lyotropic liquid crystal can coat an active to keep it from being destroyed in the digestive tract. The active can then be taken orally, and after it reaches the proper location in the body, the liquid crystal breaks down and the drug is released. Ester groups of fatty acids, such as glyceryl monooleate and glyceryl monolinoleate, are able to build liquid crystals that in turn can act as extended release systems. These fatty acids build lyotropic liquid crystalline mesophases in the presence of water at body temperature. The cubic phase favors the controlled release of active agents, because it has a structure made up of tridimensional curved lipid bilayers, separated by congruent water channels. This structure has the appearance of highly viscous transparent gel. Glyceryl monooleate (2,3- dihydroxypropyl oleate), phytantriol (3,7,l l,15-tetramethyl-l,2,3-hexadecanetriol), and other lipids such as mono linolein, monoelaidin, phosphatidylethanolamine, oleoylethanolamide, phospholipids, pegylated phospholipids, alkyl glycerates and glycolipids form cubic phase. In particular, glyceryl monooleate and phytantriol are used to form cubic phase liquid crystals.
In accordance with another embodiment of the present invention, there is provided an extended release oral pharmaceutical suspension dosage form of riociguat comprising riociguat and a suspending agent, wherein the riociguat and suspending agent are present in a ratio from about 1: 0.01 to 1 :40 by weight. Preferably, the riociguat and suspending agent are present in a ratio of at least about 1 : 1. Preferably, the riociguat and suspending agent are present in a ratio of at least about 1 : 1 or less. Preferably, the riociguat and suspending agent are present in a ratio of at least about 1 : 1 or more. Preferably, the riociguat and suspending agent are present in a ratio of at least about 1 :2. Preferably, the riociguat and suspending agent are present in a ratio of at least about 1 :3.
In accordance with another embodiment of the present invention, there is provided an extended release oral pharmaceutical suspension dosage form of riociguat comprising riociguat and a release controlling agent, wherein the ratio of riociguat to release controlling agent in the composition is from about 1:0.01 to about 1:30 by weight. Preferably, the ratio of riociguat to release controlling agent in the composition is at least 1 : 1, to at least 1:2. Preferably, the ratio of riociguat to release controlling agent in the composition is about 1:5, about 1 : 10, or about 1:2 to about 1: 10. In an embodiment, the ratio of riociguat : releasecontrolling agent : suspending agent is from about 1:0.5:0.1 to 1 : 10:5. In accordance with another embodiment of the present invention, there is provided an extended release oral pharmaceutical suspension dosage form of riociguat, wherein sucrose has a particle size such that not less than 90% particles are below 200 pm. In particular, sucrose has a particle size such that not less than 90% particles are below 100 pm. This helps in achieving improved uniformity of the drug in the mixture.
In accordance with other embodiment of the present invention, there is provided an extended release suspension comprising riociguat, wherein the amount of riociguat in the suspension ranges from about 0.05 mg/mL to about 30 mg/mL, from about 0.05 mg/mL to 20 mg/mL, particularly from about 0.05 mg/mL to 15 mg/mL, particularly from about 0.05 mg/mL to 10 mg/mL. More particularly, the amount of riociguat in the suspension ranges from about 0.05 mg/mL to 1 mg/mL. More particularly, the amount of riociguat in the suspension ranges from about 3mg/ml and about 3mg/5ml.
In accordance with other embodiment of the present invention, there is provided an extended release suspension comprising riociguat or its pharmaceutically acceptable salts, wherein the pH of suspension is in the range of about 3 to about 9. Preferably, the pH is in a range of about 3 to about 8.
In accordance with other embodiment, riociguat is the sole active ingredient in the extended release suspension dosage form.
In accordance with other embodiment, the extended release suspension dosage form of riociguat of the present invention is sugar-free.
According to another embodiment of the present invention, the extended release suspension dosage form of riociguat comprises an immediate release component.
According to another embodiment of the present invention, the extended release suspension dosage form of riociguat is administered once daily or twice daily, more particularly it is administered once daily.
According to another embodiment of the present invention, the extended release suspension dosage form of riociguat is bioequivalent to the marketed conventional immediate release composition of riociguat (Adempas®) administered thrice daily.
In accordance with another embodiment of the present invention, there is provided an extended release suspension dosage form of riociguat, wherein there is no substantial change in the in-vitro dissolution release profile of the active ingredient upon storage of the extended release suspension composition for at least ten days. Particularly, the in-vitro dissolution release profile of the extended release suspension composition of the present invention upon storage for at least one month, for at least two months, for at least three months, for at least six months, remains substantially similar to initial in-vitro dissolution release profile obtained as soon as practicable after preparation of the extended release suspension composition.
In accordance with still another embodiment of the present invention, there is provided an extended release pharmaceutical suspension dosage form comprising riociguat or its pharmaceutically acceptable esters, salts, solvates, polymorphs, enantiomers or mixtures thereof, wherein riociguat has a particle size distribution D90 less than about 200 pm, D50 is less than about 100 pm and D10 is less than about 50 pm. D90 of riociguat ranges about 0.1 pm to 200 pm, particularly from 1 pm to 150 pm, 1 pm to 100 pm, from about 1 pm to about 75 pm, particularly from about 1 pm to about 50 pm, particularly from about 1 pm to about 30 pm, particularly from about 1 pm to about 20 pm, and more particularly from 1 pm to about 10 pm. The particle size of riociguat can be measured by suitable techniques such as Laser light scattering (e.g. Malvern Light Scattering), Coulter counter, microscopy and any other technique known in the art.
The riociguat coated core may be further optionally coated with a coating layer comprising a film-forming agent to mask the bitter taste or to improve the stability. The coating layer prevents riociguat release during storage, but is quickly penetrated by gastric fluid allowing rapid release of riociguat. The film-forming agent can have a pH-dependent solubility in which the release of active ingredient is prevented by using a pre-adjusted pH of the liquid composition such that the film-forming agent does not get dissolved in the liquid composition but get dissolved when exposed to the physiological conditions.
The suspension powder for reconstitution may be reconstituted with a liquid carrier having suspending agent and one or more pharmaceutically acceptable excipients. Alternatively, suspending agent and at least one or more pharmaceutically acceptable excipients may be premixed with the extended release cores which may be reconstituted with an aqueous vehicle.
The average diameter of the extended release cores of the present invention ranges from about 10 pm to about 800 pm, particularly from about 50 pm to 500 pm. The suspending agent enhances the physical stability of the composition by sufficiently increasing the viscosity so that an appropriate dose can be delivered with minimal shaking. Suitable suspending agents/viscosity agents are selected from the group comprising cellulose derivatives such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methylcellulose, carboxymethyl cellulose and its salts/derivatives e.g., carboxymethyl cellulose sodium, microcrystalline cellulose, and coprocessed spray dried forms of microcrystalline cellulose and carboxymethyl cellulose sodium (such as Avicel® RC-501, Avicel® RC-581, Avicel® RC-591, and Avicel®CL-611); carbomers (such as those available under the trade name Carbopol®); gums such as xanthan gum, locust bean gum, tragacanth gum, arabinogalactan gum, agar gum, gellan gum, guar gum, apricot gum, karaya gum, sterculia gum, acacia gum, gum arabic, and carrageenan; pectin; propylene glycol alginate; dextran; gelatin; polyethylene glycols; polyvinyl compounds such as polyvinyl acetate, polyvinyl alcohol, and polyvinyl pyrrolidone; maltodextrin, starch; and mixtures thereof. The suspending agents are present in an amount of about 0.05% w/w to about 20% w/w of the composition. Particularly, the suspending agents are present in an amount of about 0.1% w/w to about 10% w/w, about 0.1% to about 5% w/w and about 0.1% w/w to about 3% w/w of the composition.
The suspension is easily pourable and when shaken has a viscosity in the range of 100 cps (centipoise) to 10000 cps at 25°C. Particularly, the viscosity is in the range of 100 cps to 5000 cps at 25°C, 100 cps to 2500 cps at 25°C, 100 cps to 1500 cps at 25°C, 300 cps to 4000 cps at 25°C. More particularly, the viscosity is in the range of 100 cps to 4000 cps at 25°C.
The term “shaken” as used herein refers to shaken prior to use, e.g. by a patient, e.g. vigorously shaken, e.g. by hand, e.g. for 5 to 60 seconds.
The viscosity can be measured by using a suitable instrument such as Brookfield viscometer, Haake VT 550 viscometer at room temperature (25°C).
Various useful pH adjusting agent/buffering agents include, but are not limited to, citrate buffers, phosphate buffers, or any other suitable buffer known in the art including monosodium dibasic phosphate, gluconic acid, lactic acid, citric acid, acetic acid, sodium gluconate, sodium lactate, sodium citrate, sodium acetate potassium citrate, sodium bicarbonate, potassium bicarbonate, sodium dihydrogen phosphate and potassium dihydrogen phosphate, and combinations thereof. The pH adjusting agents are present in an amount of about 0.5% w/w to about 8% w/w of the composition.
The release-controlling agent is selected from the group comprising a pH-dependent release-controlling agent, a pH-independent release-controlling agent, and mixtures thereof. The release-controlling agent is present in an amount of about 0.1% w/w to about 60% w/w of the composition. Particularly, the release-controlling agent is present particularly in an amount of about 0.1% w/w to about 30% w/w of the composition, particularly in an amount of about 0.1% w/w to about 20% w/w of the composition, particularly in an amount of about 0.1% w/w to about 10% w/w of the composition.
Suitable pH-dependent release-controlling agents are selected from the group comprising acrylic copolymers such as methacrylic acid and methyl methacrylate copolymers, e.g., Eudragit® L 100 and Eudragit® S 100, dimethylaminoethyl methacrylate and butyl methacrylate and methyl methacrylate copolymers e.g., Eudragit® E 100, Eudragit® E PO, methacrylic acid and ethyl acrylate copolymers, e.g., Eudragit® LI 00-55 and Eudragit® L30 D-55, methyl acrylate and methacrylic acid and octyl acrylate copolymers, styrene and acrylic acid copolymers, butyl acrylate and styrene and acrylic acid copolymers, and ethylacrylate-methacrylic acid copolymer; cellulose acetate phthalate; cellulose acetate succinates; hydroxyalkyl cellulose phthalates such as hydroxypropylmethyl cellulose phthalate; hydroxyalkyl cellulose acetate succinates such as hydroxypropylmethyl cellulose acetate succinate, vinyl acetate phthalates; vinyl acetate succinate; cellulose acetate trimelliate, polyvinyl derivatives such as polyvinyl acetate phthalate, polyvinyl alcohol phthalate, polyvinyl butylate phthalate, and polyvinyl acetoacetal phthalate, zein, shellac, and mixtures thereof.
Suitable pH-independent release-controlling agents are selected from the group comprising cellulosic polymers such as methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose, cellulose acetate, ethyl cellulose, and carboxy methylcellulose; acrylic copolymers such as methacrylic acid copolymers, e.g., Eudragit® RS, Eudragit® RL, Eudragit® NE 30 D; gums e.g., guar gum, locust bean gum, tragacanth, carrageenan, alginic acid, gum acacia, gum arabic, gellan gum; triglycerides; polyethylene derivatives e.g., polyethylene glycol and polyethylene oxide; polyvinyl alcohol; polyvinyl acetate; waxes, e.g., glyceryl behenate (Compritol®), Lubritab®, and Gelucires® lipids; fatty acids or their salts/derivatives; polyvinyl polymers; a mixture of polyvinyl acetate and polyvinyl pyrrolidone, e.g., Kollidon® SR; and mixtures thereof.
Various useful fillers or diluents include, but are not limited to sucrose, sugar alcohols, mannitol, sorbitol, xylitol, erythritol, starch, modified starches, pregelatinized starch, calcium carbonate, calcium phosphate, dibasic anhydrous, calcium phosphate, dibasic dihydrate, calcium phosphate tribasic, calcium sulphate, cellulose powdered, silicified microcrystalline cellulose, cellulose acetate, lactose, magnesium carbonate, magnesium oxide, maltodextrin, microcrystalline cellulose, polydextrose, sodium alginate, sodium chloride and or mixtures thereof. Sucrose as a diluent has a particle size such that not less than 90% of particles are below 200 pm. In particular, sucrose has a particle size such that not less than 90% of particles are below 100 pm. This helps in achieving improved uniformity of the drug in the mixture. The diluent is present in an amount of 5% w/w to 99% w/w of the total composition.
Carrier/vehicle/solvent used in the extended release suspension of the present invention include aqueous and non-aqueous carriers but are not limited to water, alcohol, polyethylene glycol, propylene glycol or glycerin buffers, oil, or combinations thereof. Oils include peanut oil, soy bean oil, com oil, sesame oil, cottonseed oil, acetylated glycerides, ethyl oleate, mineral oil, fatty acid esters, mono- or di- fatty acid esters of polyethylene glycols, or glyceryl mono-oleate. Particularly, the suspensions are aqueous based. By “aqueous carrier” is meant a suspension comprising water, or a combination of water and a water-miscible organic solvent or solvents. Water-miscible solvents include but are not limited to propylene glycol, polyethylene glycol and ethanol. By “non-aqueous carrier” is meant a suspension in which the carrier does not include water. The carrier can also include one more pharmaceutically acceptable excipients which can be in dissolved or dispersed form. The carrier is present in an amount from about 10% w/w to about 99% w/w, particularly from about 40% w/w to about 95% w/w.
Various useful antioxidants include, but are not limited to, ascorbic acid, tertbutylhydroquinone, sodium pyrosulfite, glutathione, sodium bisulfite, sodium sulfite, a- tocopherol, a-tocopherol acetate, monothioglycerol, cysteine, ascorbyl palmitate, acetylcysteine, dithiothreitol, sodium metabisulfite, thiourea, sodium thiosulfate, butylated hydroxy anisole (BHA), butylated hydroxy toluene (BHT) and propyl gallate. The antioxidant is present in an amount from 0% w/w to about 20% w/w, from about 0.001% w/w to about 5% w/w.
Various useful anticaking agents/ glidants include but are not limited to, colloidal silica and/or colloidal silicon dioxide (e.g. Aerosil® 200), magnesium trisilicate, calcium phosphate tribasic, magnesium oxide, magnesium silicate, calcium silicate, talc and combinations thereof. The anticaking agents are present in an amount of about 0. 1% w/w to about 10% w/w of the composition. More particularly, the anticaking agents are present in an amount of about 0.5% w/w to about 7% w/w of the composition.
Various useful sweetening agents include, but are not limited to, sugar or a sugar alcohol such as sucrose, dextrose, sucralose, sorbitol, fructose, mannitol and invert sugar and sugar substitutes such as saccharin sodium, aspartame and/or thaumatin. Sugar or sugar alcohol can also act as filler. Particularly, the sweetening agent used is sorbitol, sucralose, thaumatin or a combination thereof. The sweetening agents are present in an amount of 0% w/w to about 90% w/w of the composition, particularly in an amount of about 0.1% w/w to about 90% w/w of the composition.
Various useful flavoring agents include but are not limited to, flavors such as banana, lemon, orange, grape, lime and grapefruit, vanilla, bubble gum, peppermint, tutti-frutti, and fruit essence, including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plant leaves, flowers, fruits such as cinnamon oil, oil of wintergreen, peppermint oils, clove oil, citrus oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almonds, and cassia oil, maltitol, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid and combinations thereof. The flavoring agents are present in an amount of about 0.1% w/w to about 5% w/w of the composition.
The amount of surfactant or wetting agent should be sufficient to facilitate the dispersion of riociguat in the suspension. At the same time, it should provide improved wettability of the riociguat. Suitable surfactant or wetting agents are selected from the group comprising non-ionic, anionic, cationic, or zwitterionic surfactants, and combinations thereof. Suitable examples of surfactants are sodium lauryl sulphate; cetrimide; polyethylene glycols; polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate; sorbitan fatty acid esters such as sorbitan monostearate; polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monooleate; polyoxyethylene alkyl ether such as polyoxyethylene lauryl ether; polyoxyethylene castor oil; polyoxyethylene- polyoxypropylene block copolymers such as poloxamers (e.g. Poloxamer 188); and combinations thereof. Particularly, surfactant or wetting agents are non-ionic. The surfactant or wetting agents are present in an amount of about 0.01% to about 8% w/w of the composition. Particularly, the surfactant or wetting agents are present in an amount of about 0.01% w/w to about 3% w/w, and more particularly from about 0.01% w/w to about 1% w/w of the composition.
Various useful preservatives include, but are not limited to, parabens such as methylparaben, propylparaben, butyl paraben and their salts, sorbic acid, sodium sorbate, potassium sorbate, calcium sorbate, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, methyl hydroxybenzoate, ethyl para- hydroxybenzoate, sodium ethyl para-hydroxybenzoate, sodium metabisulphite, chlorhexidine, diazolidinyl urea, sodium citrate, butylated hydroxyl toluene (BHT), butylated hydroxyl anisole (BHA), tocopherol, ethylenediamine tetraacetic acid, propyl gallate, quaternary compounds, e.g. benzalkonium chloride and cetylpyridinium chloride, phenyl ethyl alcohol and combinations thereof. In particular, the preservative is selected from benzoic acid and its salts and parabens. The preservative is present in an amount of about 0.001% w/w to about 3% w/w of the composition.
Various useful lubricants include, but are not limited to magnesium stearate, calcium stearate, stearic acid, and sodium stearyl fumarate. The lubricants are present in an amount of about 0.1% w/w to about 5% w/w based on the total weight of the powder formulation.
Various useful taste masking agents include, but are not limited to, water-soluble and/or insoluble polymeric excipient, water-insoluble non-polymeric excipient, adsorbent, ion exchange resin, carbomer, alkali metal chlorides or an alkaline earth metal chlorides or a derivative thereof.
Various useful antifoaming agents include, but are not limited to simethicone.
Suitable coloring agents are selected from the group comprising FD&C (Federal Food, Drug and Cosmetic Act) approved coloring agents; natural coloring agents; natural juice concentrates; pigments such as iron oxide, titanium dioxide, and zinc oxide; and combinations thereof.
Suitable binders are selected from the group comprising gums such as guar gum, acacia, alginic acid, sodium alginate; carbomers; dextrin; maltodextrin; celluloses e.g., methylcellulose, ethyl cellulose, hydroxethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethylmethyl cellulose, carboxymethyl cellulose sodium; povidone; dextrose; polydextrose, starch, pregelatinized starch, microcrystalline cellulose, polymethacrylates including acrylic copolymers, gelatin, and mixtures thereof. The binder is present in an amount of about 0.1% w/w to about 30% w/w of the composition.
Suitable disintegrants are selected from the group comprising carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, polacrillin potassium, sodium starch glycolate, alginic acid, sodium alginate, microcrystalline cellulose, silicified microcrystalline cellulose, guar gum, colloidal silicon dioxide, docusate sodium, low substituted hydroxypropyl cellulose, magnesium aluminium silicate, methyl cellulose, starch, pregelatinized starch, and combinations thereof. The disintegrant is present in an amount of about 0.1% w/w to about 30% w/w of the composition.
Extended release powder/granules for oral suspension can be reconstituted using water or powder/granules for oral suspension can be administered by sprinkling the extended release powder/granules on soft food e.g. yoghurt, applesauce or empty granules into a small cup or teaspoon containing apple juice, etc.
According to another embodiment, the extended release oral pharmaceutical suspension dosage form is prepared by mixing, blending, dry granulation, wet granulation, spheronization extrusion process, hot melt extrusion process, extrusion spheronization, fluidized bed granulation, melt-granulation, dispersion, drug-ion exchange resin complexation, homogenization, and combinations thereof.
The cores of riociguat can be prepared by any method known in the art, e.g., extrusion-spheronization, wet granulation, dry granulation, hot-melt extrusion granulation, spray drying, spray congealing, and the like. Alternatively, riociguat can be layered onto an inert particle to form the core.
Further, riociguat can be directly coated with a release-controlling agent to form the microparticles or microcapsules. The microparticles or microcapsules can be prepared by a process of homogenization, solvent evaporation, coacervation phase separation, spray drying, spray congealing, polymer precipitation, or supercritical fluid extraction.
Alternatively, the extended release cores can be optionally mixed with at least one or more pharmaceutically acceptable excipients to form the suspension powder for reconstitution which can be reconstituted with a suitable pharmaceutically acceptable carrier/vehicle.
Extended release suspension of riociguat can be prepared by (i) preparing cores comprising riociguat and at least one or more pharmaceutically acceptable excipients; (ii) dissolving/dispersing a release-controlling agent and at least one or more pharmaceutically acceptable coating excipients in a suitable solvent; (iii) applying the coating composition of step (ii) over the cores of step (i); (iv) dissolving/dispersing at least one or more pharmaceutically acceptable excipients in a pharmaceutically acceptable vehicle to form a pharmaceutically acceptable carrier; and (v) dispersing the coated cores of step (iii) in the carrier of step (iv) to obtain the extended release suspension.
Alternatively, a process for preparing an extended release suspension dosage form of riociguat comprises the following steps: a) blending riociguat with at least one or more pharmaceutically acceptable excipients, b) granulating the blend, c) further coating the granules of step b) with a rate controlling agent, d) drying and lubricating the granules of step c), e) blending the granules with at least one or more pharmaceutically acceptable excipients, f) filling into suitable bottle/sachet/pouch.
Alternatively, the extended release coated cores can be optionally mixed with at least one or more pharmaceutically acceptable excipients to form the suspension powder for reconstitution which can be reconstituted with a suitable pharmaceutically acceptable carrier/vehicle.
Riociguat can also be present in complexed form with ion-exchange resins which are coated with an extended release coating comprising a release-controlling agent to form the extended release core. The extended release cores are optionally mixed with at least one or more pharmaceutically acceptable excipients to form the extended release suspension powder for reconstitution. Alternatively, the extended release cores are dispersed in a pharmaceutically acceptable carrier to form ready to use extended release liquid composition.
Ion-exchange resins are cross-linked, water-insoluble, high molecular-weight polyelectrolytes that can reversibly exchange their mobile ions of equal charge with the surrounding medium stoichiometrically. The ion-exchange resins useful in the extended release compositions of the present invention comprise of a pharmacologically inert organic or inorganic matrix containing covalently bound functional groups that are ionic or capable of being ionized under the appropriate conditions of pH. The organic matrix may be synthetic (e.g., polymers or copolymers of acrylic acid, methacrylic acid, sulfonated styrene, sulfonated divinylbenzene), or partially synthetic (e.g., modified cellulose and dextrans). The inorganic matrix preferably comprises silica gel modified by the addition of ionic groups. Covalently bound ionic groups may be strongly acidic (e.g., sulfonic acid, phosphoric acid), weakly acidic (e.g., carboxylic acid), strongly basic (e.g., primary amine), weakly basic (e.g. quaternary ammonium), or a combination of acidic and basic groups. Other types of charged groups can also be used, including any organic group that bears an acidic or a basic functional group, for example, an amine, imine, imidazoyl, guanidine, pyridinyl, quaternary ammonium, or other basic groups, or a carboxylic, phosphoric, phenolic, sulfuric, sulfonic or other acidic groups. Suitable ion exchange resins are also sold under the trade names Amberlite, Amberlyst and Dowex. Weak cation acid ion exchange resins such as Indion 204, Indion 214, Indion 224, polacrillin potassium as well as a strong cation acid resin such as PuroliteClOOCaMR, Amberlite IRP-69 and Dowex-50 can also be used. Particularly, the ion-exchange resin used is sodium polystyrene sulfonate (Amberlite IRP-69).
The size of the ion-exchange particles is from about 30 microns to about 500 microns, preferably the particle size is within the range of about 30 microns to about 150 microns for extended release suspension dosage form of the present invention.
Binding of drug to resin can be accomplished by the following ways. In the case of a basic drug, these are: (a) resin (Na-form) plus drug (salt form); (b) resin (Na-form) plus drug (as free base); (c) resin (H-form) plus drug (Salt form), and (d) resin (H- form) plus drug (as free base).
For binding an acidic drug to an anion exchange resin four analogous binding reactions can be carried out. These are: (a) resin (Cl-form) plus drug (Salt form); (b) resin (Cl-form) plus drug (as free acid); (c) resin (as free base) plus drug (salt form), and (d) resin (as free base) plus drug (as free acid).
Coating may be applied by employing solution, suspension or powder blend using any conventional coating technique known in the art such as spray coating, dip coating or compression coating. Suitable solvents used for granulation or forming a solution or dispersion for coating are selected from the group comprising water, ethyl alcohol, isopropyl alcohol, acetone, methanol, methylene chloride, and mixtures thereof. The coating additives used in the present invention are selected from the group comprising plasticizers, opacifiers, surfactants, anti-tacking agents, coloring agents and mixtures thereof.
Suitable plasticizers are selected from the group comprising dibutyl sebacate, triethyl citrate, tributyl citrate, triacetin, acetylated triacetin, glyceryl tributyrate, diacetylated monoglyceride, rapeseed oil, olive oil, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, glycerin, diethyl oxalate, diethyl phthalate, diethyl malate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, and mixtures thereof.
Suitable opacifiers are selected from the group comprising titanium dioxide, manganese dioxide, iron oxide, silicon dioxide, and mixtures thereof.
The extended release pharmaceutical composition of the present invention can be packaged in a suitable pack/container such as amber colored polyethylene terephthalate (PET) bottle, glass bottle, vials, high density polyethylene (HDPE) bottle, low density polyethylene (LDPE) bottle, polypropylene (PP) bottle, packets, pouches, sachets and the like. The glass or plastic bottle may be provided with a child proof closure. The package can include a syringe (marked in mL) for ease of dosing. The extended release suspension powder formulation can be for a single dose or multiple doses after reconstitution with a carrier.
The container such as bottle has a fill volume of, e.g., from about 30 mL to about 300 mL comprising riociguat suspension. Pack chosen are made of material which is non- reactive with the extended release ready to use suspension and suspension powder for reconstitution. Containers for use in the storage of the extended release oral suspensions may be used to administer a multiple dose of riociguat.
The extended release pharmaceutical dosage form of the present invention can be provided in a kit comprising (a) extended release suspension powder for reconstitution of riociguat and (b) a pharmaceutically acceptable carrier.
The extended release suspensions of the present invention provide predictable riociguat release throughout the shelf life.
The invention may be further illustrated by the following examples, which are for illustrative purposes and should not be construed as limiting the scope of the invention in any way. Examples 1-5. Ready to Use Extended Release Suspension of Riociguat
Figure imgf000028_0001
Procedure:
1. Riociguat and hydroxypropylmethyl cellulose were dissolved in purified water.
2. Microcrystalline cellulose spheres were coated with the solution of step 1.
3. Ethyl cellulose and dibutyl sebacate were dispersed in a mixture of acetone and purified water.
4. The drug layered cores of step 2 were coated with the coating dispersion of step 3.
5. Xanthan gum, microcrystalline cellulose-sodium carboxymethyl cellulose, xylitol/sorbitol, citric acid - monosodium dibasic phosphate (if present), sucralose (if present), saccharin sodium (if present), and orange flavor were mixed in purified water.
6. Coated cores of step 4 were dispersed in dispersion of step 5 to form extended release suspension of riociguat. Examples 6-10. Extended Release Suspension Powder for Reconstitution of Riociguat
Figure imgf000029_0001
Procedure:
1. Riociguat and hydroxypropylmethyl cellulose were dissolved in purified water.
2. Microcrystalline cellulose spheres were coated with the solution of step 1.
3. Ethyl cellulose and dibutyl sebacate were dispersed in a mixture of acetone and purified water.
4. The drug layered cores of step 2 were coated with the coating dispersion of step 3.
5. Xanthan gum, microcrystalline cellulose-sodium carboxymethyl cellulose, sucralose, xylitol/sorbitol, citric acid - monosodium dibasic phosphate (if present), saccharin sodium (if present), sucralose (if present), and orange flavor were mixed with coated cores of step 4 to prepare extended release suspension powder for reconstitution of riociguat.
6. Extended release suspension powder for reconstitution of riociguat was reconstituted with required amount of liquid carrier e.g. water when required to form the extended release suspension.
Examples 11-12. Riociguat-resin complex
Figure imgf000030_0001
Procedure:
1. Amberlite IRP-69 resin was added to previously heated deionized water to 90°C and the resulting slurry was mixed.
2. Riociguat was added to the resin slurry and subjected to mixing at 90°C for 2 hours to allow binding to occur.
3. The slurry of step 2 was filtered to collect resin particles and washed with pre-heated deionized water.
4. The resulting drug-resin complex of step 3 was dried in an oven at 45°C.
Example 13. Preparation of barrier coated Riociguat-resin complex
Figure imgf000030_0002
Procedure:
1. A coating dispersion was prepared by dispersing ethyl cellulose and dibutyl sebacate in a mixture of acetone and water.
2. Riociguat resin complex was coated with a coating dispersion of step 1 to formbarrier coated riociguat-resin complex.
Examples 14-15. Extended Release Suspension of Riociguat with ion-exchange resin
Figure imgf000030_0003
Figure imgf000031_0001
Procedure:
1. Microcrystalline cellulose-sodium carboxymethyl cellulose, xanthan gum, sucralose, xylitol, and bubble gum flavor were mixed in purified water.
2. Barrier coated riociguat resin complex was dispersed in the dispersion of step 1 to form extended release suspension of riociguat.
Examples 16-20. Extended Release Suspension Powder of Riociguat
Figure imgf000031_0002
Procedure: 1. Riociguat and Kollidon® SR were mixed to form a blend.
2. Polyvinylpyrrolidone was dissolved in water to form a solution.
3. The blend of step 1 was granulated with the solution of step 2 and dried.
4. Xanthan gum, microcrystalline cellulose-sodium carboxymethyl cellulose, xylitol/sorbitol, citric acid - monosodium dibasic phosphate (if present), saccharin sodium (if present) and strawberry flavor were mixed with extended release granules of step 3 to prepare extended release suspension powder for reconstitution of riociguat.
5. Extended release suspension powder for reconstitution of riociguat was reconstituted with required amount of liquid carrier e.g. water when required to form the extended release suspension.
Examples 21-22. Extended Release Suspension of Riociguat
Figure imgf000032_0001
Procedure:
A. Drug-Resin Complex Preparation:
1. Riociguat was added in purified water and 0.1 N HCL under stirring.
2. Sodium polystyrene sulfonate was added in the solution of step 1 and the dispersion was stirred for a suitable time period (4-5 hours).
3. The solution of step 2 was filtered through wattman filter paper. The filtrate and resinate were separated.
4. The resinate was dried in a suitable dryer (such as a tray dryer) at 60°C for a suitable time period (6-8 hours).
B. Suspension Carrier Preparation:
1. Sorbitol was added to the purified water and stirred until a clear solution was obtained. 2. Glycerin was heated at 80°C in another beaker and methyl paraben and propyl paraben were added and stirred to dissolve completely.
3. The solution of step 2 was added into step 1 with stirring.
4. Sucralose was added into the solution of step 3.
5. Xanthan gum was added into the solution of step 4 and stirred for a suitable time (about 30 minutes).
6. The dispersion of step 5 was homogenized for a suitable time (about 30 minutes).
7. Strawberry flavor was added into the solution of step 6 and the volume was made up of water.
8. Resinate was added into the solution of step 7 and stirred the suspension for a suitable time (about 30 minutes) to form a homogeneous suspension.
Results: The dissolution, assay and pH of dosage form prepared using quantitative dosage form (Examples 21), is given below. The dissolution profile was measured in 900 ml of 6.8 phosphate buffer and 2% KCL using a USP II apparatus (Paddle) at a temperature of
37±0.5°C and a rotation speed of 75 revolutions per minute.
Figure imgf000033_0001
Examples 23-26. Extended Release Suspension of Riociguat
Figure imgf000033_0002
Figure imgf000034_0001
Procedure:
1. Drug solution was prepared by adding povidone and riociguat in methanol and was stirred until a clear solution was obtained.
2. Drug solution of step 1 was sprayed over MCC spheres/sugar spheres to obtain the desired weight gain.
3. Extended release coating solution was prepared by dissolving ethyl cellulose in methanol and stirred until a clear solution formed.
4. The drug layered pellets of step 2 were coated with the extended release coating solution of step 3 to obtain the desired weight gain.
5. Sorbitol was added to purified water under stirring to obtain a clear solution.
6. Glycerin was heated at 80°C in another beaker and methyl paraben and propyl paraben were added and stirred to dissolve completely.
7. The solution of step 6 was added into step 5 under stirring.
8. Sucralose was added into the solution of step 7.
9. Xanthan gum was added under stirring into the solution of step 8 and was further stirred for 30 minutes.
10. The dispersion of step 9 was homogenized for 30 minutes.
11. Strawberry flavor was added into the solution of step 10 and the volume was made-up with water. 12. Ethylcellulose coated pellets of step 4 were added into the suspension of step 11 and the suspension was stirred for 30 min to form a smooth homogeneous suspension.
Results: The dissolution, and assay of dosage forms prepared using quantitative formula (Examples 24-26) is given below. The dissolution profile was measured in 900 ml of 6.8 phosphate buffer and 0.1 % SLS using a USP II apparatus (Paddle) at a temperature of 37±0.5°C and a rotation speed of 100 revolutions per minute.
Figure imgf000035_0001
Examples 27-30. Extended Release Powder For Suspension of Riociguat
Figure imgf000035_0002
Procedure:
1. Drug solution was prepared by adding povidone and riociguat in methanol and was stirred until a clear solution was obtained.
2. Drug solution of step 1 was sprayed over MCC spheres/sugar spheres to obtain the desired weight gain.
3. Extended release coating solution was prepared by dissolving ethyl cellulose in methanol and stirred until a clear solution formed.
4. The drug layered pellets of step 2 were coated with the extended release coating solution of step 3 to obtain the desired weight gain.
5. Dextrose, xanthan gum, and crospovidone were sifted through a suitable mesh.
6. Citric acid was dissolved in isopropyl alcohol and the blend of step 5 was granulated.
7. The blend of step 6 was dried at 50°C±10°C for a suitable period of time.
8. The extended release pellets of step 4 and inactive granules of step 7 were filled in a suitable sachet/bottle.
Results: The dissolution, and assay of dosage forms prepared using quantitative formula (Examples 28-30), is given below. The dissolution profile was measured in 900 ml of 6.8 phosphate buffer and 0.1% SLS using a USP II apparatus (Paddle) at a temperature of 37±0.5°C and a rotation speed of 100 revolutions per minute.
Figure imgf000036_0001

Claims

WHAT IS CLAIMED:
1. An extended release suspension dosage form of riociguat comprising: a) riociguat in an amount of about 0.01% to about 10% by weight, b) a release controlling agent; and c) at least one or more other pharmaceutically acceptable excipients wherein the suspension has a pH of about 3 to about 8 and ratio of riociguat to release controlling agent in the dosage form is between about 1:0.5 to about 1 : 10.
2. The extended release suspension dosage form of claim 1, wherein the release controlling agent is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methacrylic acid copolymers, ethyl cellulose, cellulose acetate, an ion-exchange resin and combination thereof.
3. The extended release suspension dosage form of claim 2, wherein the ion-exchange resin used is sodium polystyrene sulfonate.
4. The extended release suspension dosage form of claim 1, wherein the one or more other pharmaceutically acceptable excipients are selected from the group consisting of suspending agent, pH adjusting agent/buffer, diluent, carrier, antioxidant, anticaking agent, antifoaming agent, coloring agent, sweetening agent, flavoring agent, wetting agent, preservative, glidant, lubricant, binder, disintegrant, plasticizers, opacifiers, and mixtures thereof.
5. The extended release suspension dosage form of claim 1, wherein the suspension dosage form is a ready to use extended release suspension or extended release suspension powder for reconstitution.
6. The extended release suspension dosage form of claim 1, wherein the suspension has a viscosity from about 100 cps to 4000 cps.
7. The extended release suspension dosage form of claim 1, wherein the riociguat and suspending agent are present in a ratio from about 1:0.01 to 1:40 by weight.
8. The extended release suspension dosage form of claim 1, wherein the ratio of riociguat to release controlling agent in the dosage form is between about 1 :0.5 to about 1 :5.
9. The extended release suspension dosage form of claim 1, wherein the suspension
36 dosage form is administered once daily or twice daily.
10. The extended release suspension dosage form of claim 1, wherein the amount of riociguat in the suspension ranges from about 0.05 mg/mL to about 30 mg/mL.
11. An extended release suspension dosage form of riociguat comprising: a) riociguat in an amount of about 0.01% to about 10% by weight, b) a release controlling agent selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methacrylic acid copolymers, ethyl cellulose, cellulose acetate, an ion-exchange resin and combination thereof in an amount of about 0.1% to about 10% by weight; and c) a suspending agent selected from the group consisting of xanthan gum, hydroxypropyl methylcellulose, gellan gum, sodium carboxymethylcellulose, a mixture of carboxymethylcellulose and microcrystalline cellulose, propylene glycol alginate and combination thereof in an amount from about 0.05% to about 20% w/w, d) one or more buffering agents selected from the group consisting of monosodium dibasic phosphate, citric acid, acetic acid, sodium citrate, sodium acetate potassium citrate, and potassium dihydrogen phosphate, and combination thereof in an amount of about 0.01% w/w to about 8% w/w of the dosage form; and e) at least one or more other pharmaceutically acceptable excipients wherein the suspension has a pH of about 3 to about 8.
12. The extended release suspension dosage form of claim 11, wherein the suspension further comprises one or more diluents selected from the group consisting of lactose, cellulose, microcrystalline cellulose, mannitol, dextrose, calcium phosphate, starch, pregelatinized starch, and combination thereof in an amount from about 5% to about 90% w/w.
13. The extended release suspension dosage form of claim 11, wherein the suspension further comprises one or more wetting agents selected from the group consisting of sodium lauryl sulphate, polysorbate, sorbitan monostearate, poloxamers, and combination thereof in an amount of about 0.01% w/w to about 8% w/w of the dosage form.
37
14. The extended release suspension dosage form of claim 11, wherein the suspension further comprises one or more sweetening agents selected from the group consisting of sucrose, dextrose, sucralose, sorbitol, fructose, mannitol, saccharin sodium, aspartame, thaumatin and combination thereof in an amount of about 0.1% w/w to about 20% w/w of the dosage form.
15. The extended release suspension dosage form of claim 11, wherein the suspension further comprises one or more preservatives selected from the group consisting of parabens such as methylparaben, propylparaben, butylparaben benzoic acid, sodium benzoate, potassium benzoate, butylated hydroxyl toluene, butylated hydroxyl anisole, tocopherol, benzalkonium chloride and combination thereof in an amount of about 0.001% w/w to about 3% w/w of the dosage form.
16. The extended release suspension dosage form of claim 11, wherein the suspension further comprises one or more flavoring agents selected from the group consisting of orange, grape, lime, vanilla, bubble gum, peppermint, tutti-frutti, strawberry, and combination thereof in an amount of about 0.01% w/w to about 5% w/w of the dosage form.
17. The extended release suspension dosage form of claim 11, wherein the suspension further comprises one or more vehicle/solvent selected from the group consisting of water, alcohol, polyethylene glycol, propylene glycol, glycerin, hydrochloric acid and combination thereof.
18. A process for the preparation of extended release oral pharmaceutical suspension dosage form of claim 1, wherein the suspension dosage form is prepared by blending, dry granulation, wet granulation, spheronization extrusion process, hot melt extrusion process, extrusion spheronization, fluidized bed granulation, dispersion, drug-ion exchange resin complexation, homogenization, and combinations thereof.
19. The extended release suspension dosage form of claim 1, wherein the dosage form is provided in a kit comprising (a) extended release suspension powder for reconstitution of riociguat and (b) a pharmaceutically acceptable carrier.
20. An extended release suspension dosage form of riociguat comprising: a) riociguat in an amount of about 0.01% to about 10% by weight, b) a release controlling agent selected from the group consisting of hydroxypropyl methylcellulose, ethyl cellulose, sodium polystyrene sulfonate and combination thereof in an amount of about 0.1% to about 10% by weight, c) xanthan gum, a mixture of carboxymethylcellulose and microcrystalline cellulose, and combination thereof in an amount from about 0.05% to about 10% w/w, d) citric acid, sodium citrate, and combination thereof in an amount of about 0.01% w/w to about 5% w/w of the dosage form; and e) at least one or more other pharmaceutically acceptable excipients wherein the suspension has a pH of about 3 to about 8 and the ratio of riociguat to release controlling agent in the dosage form is between about 1:0.5 to about 1:5.
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Citations (5)

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US20200222421A1 (en) * 2017-09-25 2020-07-16 Jubilant Generics Limited Modified release suspension of eslicarbazepine
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US20150306135A1 (en) * 2012-12-21 2015-10-29 Laboratorios Rubio, S.A. Oral pharmaceutical composition for drugs with a high-dosage regimen
US20200239469A1 (en) * 2013-02-21 2020-07-30 Adverio Pharma Gmbh Forms of methyl {4,6-diamino-2-[1 (2-fluorobenzyl)-1h-pyrazolo[3-4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate
US20200222421A1 (en) * 2017-09-25 2020-07-16 Jubilant Generics Limited Modified release suspension of eslicarbazepine
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