WO2022144930A1 - Pharmaceutical oral suspensions of riociguat - Google Patents

Pharmaceutical oral suspensions of riociguat Download PDF

Info

Publication number
WO2022144930A1
WO2022144930A1 PCT/IN2022/050008 IN2022050008W WO2022144930A1 WO 2022144930 A1 WO2022144930 A1 WO 2022144930A1 IN 2022050008 W IN2022050008 W IN 2022050008W WO 2022144930 A1 WO2022144930 A1 WO 2022144930A1
Authority
WO
WIPO (PCT)
Prior art keywords
dosage form
suspension
amount
riociguat
immediate release
Prior art date
Application number
PCT/IN2022/050008
Other languages
French (fr)
Inventor
Indranil Nandi
Tusharmouli Mukherjee
Dinesh Kumar
Rakesh Kumar Singh
Original Assignee
Jubilant Generics Limited
Jubilant Pharma Holdings Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jubilant Generics Limited, Jubilant Pharma Holdings Inc. filed Critical Jubilant Generics Limited
Publication of WO2022144930A1 publication Critical patent/WO2022144930A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules

Definitions

  • the present invention relates to orally administered, pharmaceutical immediate release suspensions of riociguat.
  • the immediate 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 suspensions. It further relates to the use of 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-[l-(2- fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate and is represented by the following formula as:
  • Riociguat is marketed in the USA 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 No. 10,087,183 assigned to Bayer Healthcare, discloses polymorphs of riociguat such as modification I, modification II, mono-DMSO solvate, sesqui-DMSO solvate, l ⁇ -ethyl acetate solvate and pharmaceutical composition thereof.
  • the publication highlights various polymorphic forms of riocugat and the conversion of these polymorphs into other forms.
  • U.S. Patent No. 9,884,859 assigned to Sunshine Lake Pharma, discloses crystalline form III and form IV of riociguat.
  • Difficulty in swallowing 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.
  • riociguat tablets may be crushed and mixed with water or soft foods for patients who have difficulty in swallowing.
  • an extemporaneously created dispersion of riociguat is physicochemically not stable leading to highly variable riociguat dosing with accompanying unpredictable therapeutic efficacy.
  • the inventors of the present invention have developed a suspension dosage form of riociguat with an objective to minimize swallowing difficulties, which is likely to improve patient compliance by reducing dysphagia-related adverse events and accordingly providing a more convenient and less cumbersome posology.
  • the inventors have developed immediate release, ready to use suspension and/or suspension powder for reconstitution convenient for administration to paediatric and geriatric patients, easy to manufacture, functionally reproducible, and provides ease of dose adjustment.
  • the suspension dosage form exhibits desirable technical attributes such as pourability, viscosity, pH, dissolution, re-suspendability, assay and chemical and physical stability.
  • the suspension dosage form of the present invention is in the form of immediate release ready to use suspension and/or immediate release suspension powder for reconstitution.
  • an immediate release suspension dosage form comprising riociguat 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 composition of the invention includes, but is not limited to immediate release ready to use suspension, powder for suspension, granules for suspension, pellets, beads, multiparticulates, and the like.
  • the pharmaceutical composition refers to powder, granules, pellets, beads, multiparticulates, and the like filled into capsules or sachets, and ready to use suspension.
  • the term “ready to use suspension” means a pre-constituted suspension which can be administered as such to patient.
  • the “powder for suspension” or “suspension powder for reconstitution” or “dry suspension” or “granules for suspension” are synonymous and are reconstituted with a liquid carrier like water to form a suspension.
  • riociguaf is used in broad sense to include not only “riociguaf ’ per se but also its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, derivatives, isomers, polymorphs, stereoisomers, diastereoisomers prodrugs thereof, and also its various crystalline and amorphous forms or mixtures thereof.
  • Riociguat is present in an amount from about 0.01% to about 70% of the suspension dosage form, particularly from about 0.01% to about 30%, from about 0.01% to about 20%, from about 0.01% to about 10%, from about 0.01% to about 5%, from about 0.01% to about 3% w/w or w/v of the suspension dosage form.
  • excipient means a pharmacologically inactive component such as a suspending agent, pH adjusting agent/buffering agent, diluent, carrier, anticaking agent, antifoaming agent, antioxidant, sweetening agent, flavoring agent, surfactant/solubilizer/wetting agent, buffer, glidant, binder, preservative, and the like.
  • 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.
  • immediate release implies that riociguat is released from the composition in an immediate release fashion.
  • Immediate release refers to pharmaceutical compositions that release at least 75% of the active ingredient within a small period of time, typically less than 60 minutes and more particularly in less than 45 minutes and most particularly more than 85% of drug release within 30 minutes.
  • the term “about” means ⁇ approximately 10% of the indicated value, such that “about 10 percent” indicates approximately 08 to 12 percent.
  • the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise.
  • a reference to “a process” includes one or more process, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.
  • 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.
  • weight percentages expressed herein are based on the final weight or volume of the composition or formulation.
  • a stable immediate release oral pharmaceutical suspension dosage form of riociguat comprising riociguat and at least one or more pharmaceutically acceptable excipients.
  • the immediate release oral pharmaceutical suspension dosage form of riociguat is a ready-to-use suspension and suspension powder for reconstitution.
  • an immediate release oral pharmaceutical suspension dosage form of riociguat comprising: a) riociguat; b) a suspending agent; and c) at least one or more pharmaceutically acceptable excipients.
  • an immediate release oral pharmaceutical suspension dosage form of riociguat comprising: a) riociguat from about 0.01% to about 30% w/w; b) a suspending agent from about 0.05% to about 20% w/w; and c) at least one or more pharmaceutically acceptable excipients.
  • an immediate release oral pharmaceutical suspension dosage form of riociguat comprising: a) riociguat from about 0.01% to about 30% w/w; b) a suspending agent from about 0.05% to about 20% w/w; and c) at least one or more pharmaceutically acceptable excipients; wherein the pH of the suspension is from about 3 to about 8.
  • an immediate release ready to use oral pharmaceutical suspension of riociguat comprising: a) riociguat from about 0.01% to about 30% w/w; b) a suspending agent from about 0.05% to about 20% w/w; and c) a pharmaceutically acceptable liquid carrier.
  • an immediate release oral pharmaceutical suspension powder for reconstitution of riociguat comprising: a) riociguat from about 0.01% to about 30% w/w; b) a suspending agent from about 0.05% to about 20% w/w; and c) one or more pharmaceutically acceptable excipients.
  • an immediate release oral pharmaceutical suspension dosage form of riociguat comprising: a) riociguat; b) a suspending agent; and c) at least one or more pharmaceutically acceptable excipients; wherein the dosage form exhibits an in-vitro dissolution rate of more than 50% of drug release within 30 minutes when the said dosage form is placed in a dissolution vessel filled with 900 ml of pH 6.8 phosphate buffer with 0.1% sodium lauryl sulfate (SLS) maintained at 37 ⁇ 0.5°C and stirred at a paddle speed of 75 rpm using a USP Type II (paddle) apparatus.
  • SLS sodium lauryl sulfate
  • an immediate release oral pharmaceutical suspension powder for reconstitution of riociguat comprising riociguat and a suspending agent, wherein the suspending agent is present in an amount ranging from about 0.05% to about 20% w/w in the powder formulation.
  • an immediate release oral pharmaceutical suspension dosage form of riociguat comprising riociguat and a suspending agent, wherein the riociguat and suspending agent have a ratio ranging from about 1 : 0.01 to 1:40 by weight.
  • the riociguat and suspending agent have a ratio ranging from about 1:0.01 to 1:50.
  • the riociguat and suspending agent have a ratio ranging from about 1 : 10 to 1 :50.
  • the riociguat and suspending agent have a ratio ranging from about 1:0.01 to 1:25.
  • the riociguat and suspending agent have a ratio of about 1:25. In a preferred embodiment, the riociguat and suspending agent have a ratio of about 1:22.5. In a preferred embodiment, the riociguat and suspending agent have a ratio of about 1 : 10. In a preferred embodiment, the riociguat and suspending agent have a ratio of about 1:5.
  • an immediate release oral pharmaceutical suspension dosage form of riociguat comprising riociguat and wetting agent, wherein the riociguat and wetting agent have a ratio ranging from about 1 :0.01 to 1 : 10, preferably, ranging from about 1:0.01 to 1:5.
  • the immediate release oral pharmaceutical suspension dosage form of riociguat is a ready-to-use suspension and suspension powder for reconstitution.
  • the immediate release oral pharmaceutical suspension dosage form of riociguat wherein riociguat is present in an amount from about 0.05 mg/mL to about 30 mg/mL and viscosity from about 100 cps to about 4000 cps.
  • the viscosity of the suspension is from about 100 cps to about 3000 cps.
  • the viscosity of the suspension is from about 100 cps to about 1000 cps.
  • the amount of riociguat in the suspension ranges from about 0.05 mg/mL to about 7.5 mg/mL.
  • the amount of riociguat in the suspension ranges from about 0.05 mg/mL to about 5 mg/mL.
  • an immediate release oral pharmaceutical suspension dosage form of riociguat comprising: a) riociguat or its pharmaceutically acceptable salt, ester, hydrate or polymorph thereof; b) a suspending agent; c) a pH adjusting agent; and d) one or more pharmaceutically acceptable excipients.
  • an immediate release oral pharmaceutical suspension dosage form of riociguat comprising: a) riociguat or its pharmaceutically acceptable salt, ester, hydrate or polymorph thereof; b) a suspending agent; c) pH adjusting agent to maintain the pH of the composition in the range of about 3 to about 8; d) optionally a surfactant; e) optionally a preservative; and f) one or more pharmaceutically acceptable excipients.
  • an immediate release oral pharmaceutical suspension dosage form of riociguat comprising: a) riociguat or its pharmaceutically acceptable salt, ester, hydrate or polymorph thereof; b) a suspending agent; c) a pH adjusting agent to maintain the pH of the composition in the range of about 3 to about 8; and d) a diluent or a pharmaceutically acceptable liquid carrier.
  • an immediate release oral pharmaceutical suspension dosage form of riociguat comprising: a) riociguat; b) a suspending agent; c) optionally a pH adjusting agent; and d) one or more pharmaceutically acceptable excipients; wherein the suspending agent is selected from the group comprising of xanthan gum, gellan gum, cellulose and its derivatives, a mixture of carboxymethylcellulose and microcrystalline cellulose, propylene glycol alginate, and combinations thereof.
  • an immediate release oral pharmaceutical suspension dosage form of riociguat comprising: a) riociguat or its pharmaceutically acceptable salt, ester, hydrate or polymorph thereof a) a suspending agent; b) a surfactant; c) optionally a preservative; d) optionally an antioxidant; e) pH adjusting agent in sufficient amounts to maintain the pH of the composition in the range of about 3 to about 8; and f) a diluent or a pharmaceutically acceptable liquid carrier.
  • an immediate release oral pharmaceutical suspension dosage form of riociguat or its pharmaceutically acceptable salt, ester, hydrate or polymorph thereof with one or more pharmaceutically acceptable excipients comprising riociguat from about 0.05 mg/mL to about 30 mg/mL, wherein the pH of the composition is from about 3 to about 8.
  • an immediate release oral pharmaceutical suspension dosage form comprising: a) riociguat in an amount of about 0.01 % to about 30% w/v of the dosage form; b) a suspending agent selected from xanthan gum, mixture of microcrystalline cellulose and sodium carboxymethyl cellulose, propylene glycol alginate, and gellan gum in an amount from about 0.05% to about 20% w/v of the dosage form; c) a wetting agent selected from poloxamer, polysorbate, polyoxyethylene stearate and combination thereof in an amount from about 0.01% to about 5% w/v of the dosage form; d) pH adjusting agent or buffering agent selected from citric acid, trisodium citrate, citrate buffer, monosodium dibasic phosphate, tribasic sodium phosphate and combination thereof in an amount from about 0.01% to about 5% w/v of the dosage form; e) a pharmaceutically acceptable liquid carrier selected from water,
  • an immediate release oral pharmaceutical suspension dosage form comprising: a) riociguat in an amount of about 0.01% to about 5% w/v of the dosage form; b) a suspending agent selected from xanthan gum, mixture of microcrystalline cellulose and sodium carboxymethyl cellulose, propylene glycol alginate, and gellan gum in an amount from about 0.05% to about 3% w/v of the dosage form; c) a wetting agent selected from poloxamer, polysorbate, polyoxyethylene stearate and combination thereof in an amount from about 0.01% to about 2% w/v of the dosage form; d) liquid carrier selected from water, glycerin and combination thereof in an amount from about 10% to about 95% w/v of the dosage form; and e) at least one or more other pharmaceutically acceptable excipients; wherein the pH of the suspension is from 3 to 6 and suspension exhibits an in-vitro dissolution rate of more than 85%
  • an immediate release oral pharmaceutical suspension dosage form comprising: a) riociguat in an amount of about 0.01% to about 5% w/v of the dosage form; b) a suspending agent selected from xanthan gum, mixture of microcrystalline cellulose and sodium carboxymethyl cellulose, propylene glycol alginate, and gellan gum in an amount from about 0.05% to about 3% w/v of the dosage form; c) a wetting agent selected from poloxamer, polysorbate, polyoxyethylene stearate and combination thereof in an amount from about 0.01% to about 2% w/v of the dosage form; d) citric acid in an amount from about 0.01% to about 2% w/v of the dosage form; e) trisodium citrate in an amount from about 0.01% to about 2% w/v of the dosage form; f) sorbitol in an amount from about 0.01% to about 11% w/v of the dosage form;
  • an immediate release oral pharmaceutical suspension dosage form comprising: a) riociguat in an amount of about 0.01% to about 5% w/v of the dosage form, b) xanthan gum in an amount from about 0.05% to about 3% w/v of the dosage form; c) polysorbate 80 in an amount from about 0.01 % to about 2% w/v of the dosage form; d) citric acid in an amount from about 0.01 % to about 2% w/v of the dosage form, e) trisodium citrate in an amount from about 0.01% to about 2% w/v of the dosage form; f) sorbitol in an amount from about 0.01% to about 11% w/v of the dosage form; g) sodium benzoate in an amount from about 0.01% to about 1% w/v of the dosage form; h) thaumatin in an amount from about 0.01% to about 2% w/v of
  • an immediate release oral pharmaceutical suspension dosage form comprising: a) riociguat in an amount of about 0.05 mg/mL to about 7.5 mg/mL of the dosage form; b) a suspending agent selected from xanthan gum, mixture of microcrystalline cellulose and sodium carboxymethyl cellulose, propylene glycol alginate, and gellan gum in an amount from about 0.1 mg/ml to about 10 mg/ml of the dosage form; c) a wetting agent selected from poloxamer, polysorbate, polyoxyethylene stearate and combination thereof in an amount about 0.01 mg/ml to about 5 mg/ml of the dosage form; d) pH adjusting agent or buffering agent selected from citric acid, trisodium citrate, citrate buffer, monosodium dibasic phosphate, tribasic sodium phosphate and combination thereof in an amount from about 0.01 mg/ml to about 5 mg/ml of the dosage form; and e) a suspending agent selected from xanthan gum, mixture of
  • an immediate release oral pharmaceutical suspension dosage form which exhibits an in-vitro dissolution rate of more than 85% of drug release within 30 minutes, when measured in 900 ml of 6.8 phosphate buffer and 0.1% sodium lauryl sulfate (SLS) using a USP II apparatus (Paddle) at a temperature of 37 ⁇ 0.5°C and a rotation speed of 75 revolutions
  • an immediate release oral pharmaceutical suspension dosage form 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 or w/v of the dosage form.
  • an immediate release oral pharmaceutical suspension dosage form 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 or w/v of the dosage form.
  • 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 or w/v of the dosage form.
  • an immediate release oral pharmaceutical suspension dosage form 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.
  • the dosage form comprises one or more flavoring agents in an amount from about 0.01% to about 1% w/w or w/v of the dosage form.
  • an immediate release oral pharmaceutical suspension dosage form of riociguat comprising riociguat from about 0.05 mg/mL to about 30 mg/mL, wherein the pH of the composition is from about 3 to about 8 and viscosity from about 100 cps to about 4000 cps.
  • an immediate release oral pharmaceutical suspension dosage form of riociguat comprising riociguat about lmg/5 mL.
  • an immediate release oral pharmaceutical suspension dosage form of riociguat comprising riociguat about 1 mg/mL.
  • an immediate release oral pharmaceutical suspension dosage form of riociguat wherein the composition is free from other polymorphic forms.
  • a suspension powder for reconstitution of riociguat comprising riociguat and at least one or more pharmaceutically acceptable excipients selected from the group comprising a suspending agent, pH adjusting agent/buffer, antioxidant, anticaking agent, antifoaming agent, coloring agent, sweetening agent, flavouring agent, surfactant/wetting agent, diluent, carrier, glidant, binder, and preservative.
  • a ready to use suspension of riociguat comprising riociguat, a pharmaceutically acceptable carrier and at least one or more pharmaceutically acceptable excipients selected from the group comprising of: suspending agent, antioxidant, anticaking agent, antifoaming agent, pH adjusting agent/buffer, coloring agent, sweetening agent, flavouring agent, surfactant/wetting agent, diluent, glidant, binder, and preservative.
  • a dry powder for suspension compositions of riociguat suitable for use as a liquid suspension for children or elderly patients.
  • an immediate release oral pharmaceutical suspension dosage form of riociguat which is stable.
  • a process for the preparation of a ready to use suspension of riociguat comprising combining various components using conventional equipment such as overhead stirrers, ultrasonifiers, mills, homogenizers. Many different orders of addition of components can be employed.
  • a process for the preparation of a suspension powder for reconstitution of riociguat comprising admixing riociguat granules with at least one or more pharmaceutically acceptable excipients selected from the group comprising of suspending agent, pH adjusting agent/buffer, diluent, carrier, antioxidant, anticaking agent, antifoaming agent, coloring agent, sweetening agent, flavoring agent, surfactant/solubilizer/wetting agent, preservative, glidant, binder, disintegrant, antioxidant, and mixtures thereof to form a dry admixture, and transferring the dry admixture to a sealable storage container.
  • suspending agent pH adjusting agent/buffer, diluent, carrier, antioxidant, anticaking agent, antifoaming agent, coloring agent, sweetening agent, flavoring agent, surfactant/solubilizer/wetting agent, preservative, glidant, binder, disintegrant, antioxidant, and mixtures thereof to form
  • a pharmaceutical suspension dosage form of riociguat wherein riociguat has a particle size distribution D90 less than about 200 pm, D50 is less than about 100 pm and Dio 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, more particularly from 1 pm to about 10 pm, and more particularly from 1 pm to about 6.7 pm.
  • D50 ranges from about 1 pm to about 100 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.
  • an immediate release pharmaceutical suspension dosage form comprising riociguat for use in the treatment of hypertension, persistent/recurrent chronic thromboembolic pulmonary hypertension, pulmonary arterial hypertension, 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.
  • an immediate release oral pharmaceutical suspension dosage form of riociguat wherein the pH of the suspension is in the range of about 3-9.
  • the pH is in a range of about 3 to about 8. More preferably, the pH is in a range of about 3 to about 6. More preferably, the pH is in a range of about 3 to about 5.5.
  • an immediate release oral pharmaceutical suspension dosage form of riociguat wherein the suspension dosage form comprises less than 2% of total impurities, preferably less than 1% of total impurities.
  • the dosage form comprises less than 0.5% of carbamate impurity.
  • the dosage form comprises less than 0.5% of des-fluoro impurity.
  • the dosage form comprises less than 0.5% of dimethyl impurity.
  • the dosage form comprises less than 0.5% of methyl isopropyl impurity.
  • the immediate release pharmaceutical suspension dosage form comprises less than 2% of total impurities and less than 0.5% of carbamate impurity.
  • riociguat is the sole active ingredient in the suspension dosage form.
  • the suspension dosage form of riociguat of the present invention is sugar free.
  • the suspension dosage form of riociguat is microbiologically stable.
  • an immediate release suspension dosage form comprising riociguat, wherein the suspension is a ready to use suspension packaged in a bottle.
  • an immediate release suspension dosage form comprising riociguat, wherein the suspension is a powder for suspension packaged in a bottle or a sachet.
  • a process for the preparation of a suspension dosage form comprising riociguat, wherein the process utilized is mixing, blending, dry granulation, wet granulation, hot-melt extrusion process, extrusion spheronization, fluidized bed granulation, dispersion, homogenization or the like.
  • a process for preparation of a ready to use suspension of riociguat comprising the following steps: (i) dissolving/dispersing one or more pharmaceutically acceptable excipients in a portion of water;
  • step (ii) dispersing riociguat in the mixture of step (i) to form a dispersion
  • step (iv) adding the mixture of step (iii) to the dispersion of step (ii);
  • step (v) optionally adding one or more pharmaceutically acceptable excipients to the dispersion of step (iv);
  • step (vi) optionally homogenizing the mixture of step (iv) to form a suspension.
  • process for preparation of a suspension powder for reconstitution of riociguat comprising the following steps:
  • step (ii) granulating the mixture of step (i) using a solvent
  • step (iii) drying the granulated mixture of step (ii);
  • step (iv) milling the mixture of step (iii) to form granules
  • step (v) mixing the granules of step (iv) optionally with one or pharmaceutically acceptable excipients to form the suspension powder for reconstitution.
  • step (ii) compacting the mixture of step (i) to form slugs
  • step (iii) milling the slugs of step (ii) to form granules
  • step (iv) mixing the granules of step (iii) optionally with one or pharmaceutically acceptable excipients to form the suspension powder for reconstitution.
  • powder/granules for oral suspension can be reconstituted using water or powder/granules for oral suspension can be administered by sprinkling the powder/granules on soft food like yoghurt, applesauce or empty granules into a small cup or teaspoon containing apple juice, etc.
  • suspension dosage form of the present invention is bioequivalent to the immediate release marketed tablet of riociguat (Adempas® tablet).
  • the suspension of the present invention provides advantages such as the absence of lumps even after long storage when the composition is shaken as well as good pourability.
  • the suspension of the invention has good physical stability properties such as a low level of sedimentation (reduced or no caking) and easy re-dispersion on agitation. Moreover, it provides dose uniformity during each administration.
  • the present inventors have observed that in the development of immediate release suspension dosage form of riociguat, the amount and ratio of drug, suspending agents, wetting agents and buffering agents are critical. Following are the key observations by the present inventors: a) for a successful immediate release suspension dosage form of riociguat, it is necessary to use the drug and suspending agent in specific ratio ranges i.e. from about 1:0.01 to 1:50. b) use the drug and wetting agent in a specific ratio range i.e. 1:2 or less, c) use the drug and buffering agents in specific ratio ranges i.e. 1: 10 or less.
  • the drug and buffering agents is used in a specific ratio ranges from about 1 :0.01 to 1:5.
  • the immediate release suspension dosage form of riociguat failed to achieve the desired assay and drug release and other technical attributes when ratios from about 1: 100 (drug and suspending agent); 1:3 (drug and wetting agent) and 1: 11 or more (drug and buffering agents) were used in test formulations.
  • Carrier/vehicle/solvent used in the suspension of the present invention includes aqueous and non-aqueous carriers but are not limited to water, alcohol, polyethylene glycol, propylene glycol, glycerin, oil, or combinations thereof.
  • Oils include peanut oil, soy bean oil, corn 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 aqueousbased.
  • 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 comprises 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 5% to about 99%, particularly from about 40% to about 95% w/w or w/v.
  • 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, hydroxypropylmethyl cellulose, methylcellulose, carboxymethyl cellulose and its salts/derivatives, e.g., carboxymethyl cellulose sodium, microcrystalline cellulose, and co-processed 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 (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
  • the suspending agents are present in an amount of about 0.05% to about 20% w/w or w/v of the composition. Particularly, the suspending agents are present in an amount of about 0.1% to about 10%, about 0.1% to about 5% and about 0.1% to about 3% w/w or w/v 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).
  • Suitable fillers or diluents include, but are not limited to sugars (e.g. sucrose, dextrose, fructose, lactose, maltose, invert sugar), sugar alcohols (e.g. sorbitol, mannitol, xylitol, lactitol, erythritol, maltodextrin, maltitol, isomaltitol, isomalt, maltulose, isomaltulose, lactulose, threitol, arabitol, ribitol, galactitol), starch, pregelatinized starch, calcium carbonate, calcium phosphate, dibasic anhydrous, calcium phosphate, dibasic dihydrate, calcium phosphate tribasic, calcium sulphate, cellulose powdered, silicified microcrystalline cellulose, cellulose acetate, magnesium carbonate, magnesium oxide, microcrystalline cellulose, polydextrose, sodium alginate, sodium
  • sucrose 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.
  • 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.
  • the pH adjusting agents are present in an amount of about 0.1% to about 8% w/w or w/v 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; polysorbates (such as polysorbate 80); polyoxyethylene alkyl ether such as polyoxyethylene lauryl ether; polyoxyethylene castor oil; polyoxyethylene -polyoxypropylene block copolymers such as poloxamers (e.g.
  • Poloxamer 188 polyoxyethylene stearate such as polyoxy 100 stearate (Myrj® 59P) as the wetting agent 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 or w/v of the composition.
  • the surfactant or wetting agents are present in an amount of about 0.01% to about 3%, and more particularly from about 0.01% to about 1% w/w or w/v of the composition.
  • Suitable preservatives include, but are not limited to, parabens such as methylparaben, propylparaben, butylparaben 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% to about 3% w/w or w/v of the composition.
  • 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% to about 10% w/w of the composition. More particularly, the anticaking agents are present in an amount of about 0.5% to about 7% w/w of the composition.
  • 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 hydroxyl anisole (BHA), butylated hydroxytoluene (BHT) and propyl gallate
  • BHA butylated hydroxyl anisole
  • BHT butylated hydroxytoluene
  • the antioxidant is present in an amount from 0% to about 20%, from about 0.001% to about 5% w/w or w/v.
  • Various useful sweetening agents include, but are not limited to, sugars such as sucrose, dextrose, fructose, lactose, maltose, invert sugar, sugar alcohols such as sorbitol, mannitol, xylitol, lactitol, erythritol, maltodextrin, maltitol, isomaltitol, isomalt, maltulose, isomaltulose, lactulose, threitol, arabitol, ribitol, galactitol, and sugar substitutes such as saccharin sodium, aspartame, acesulfame, and sucralose.
  • sugars such as sucrose, dextrose, fructose, lactose, maltose, invert sugar
  • sugar alcohols such as sorbitol, mannitol, xylitol, lactitol, erythritol, malto
  • Sugar or a sugar alcohol can also act as a filler.
  • the sweetening agents are present in an amount of 0% to about 90% w/w or w/v of the composition, particularly in an amount of about 0.1% to about 90% w/w or w/v of the composition, more particularly in an amount of about 0.1% to about 30% w/w or w/v of the composition.
  • 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; maltol, 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% to about 5% w/w or w/v 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% to about 5% w/w based on the total weight of the powder formulation.
  • 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 mixture thereof.
  • the binder is present in an amount of about 0.1% w/w to about 30% w/w of the composition.
  • Suitable 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
  • the 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 is provided with a child proof closure.
  • the package can include a syringe (marked in mL) for ease of dosing.
  • the 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 20 mL to about 300 mL comprising riociguat suspension.
  • Pack chosen are made of material which is non-reactive with the suspension and suspension powder for reconstitution.
  • Containers for use in the storage of the oral suspensions may be used to administer a multiple dose of riociguat.
  • the suspension powder for reconstitution can be provided in a kit comprising (a) suspension powder for reconstitution of riociguat and (b) a pharmaceutically acceptable carrier.
  • a suspension comprising riociguat
  • the suspension is provided in a kit comprising: (a) an immediate release oral pharmaceutical ready to use suspension comprising riociguat, and (b) a dosing syringe for administering the suspension.
  • the suspensions of the present invention are homogenous and deliver the desired dose of riociguat in every use without any risk of overdosing or underdosing.
  • the compositions provide predictable riociguat release throughout the shelf life. pH Measurement: pH values are determined using potentiometry using USP ⁇ 791>.
  • Viscosity Measurement The viscosity can be measured by using a suitable instrument such as Brookfield viscometer, Haake VT 550 viscometer at room temperature (25°C).
  • the powder for suspension was evaluated for in-vitro riociguat release.
  • the in-vitro dissolution is determined using a USP type II apparatus at 75 rpm in 900 mL of pH 6.8 phosphate buffer with 0.1% sodium lauryl sulfate at 37 ⁇ 0.5°C by HPLC method.
  • Example 6-11 Suspension powder for reconstitution of riociguat
  • the suspension powder for reconstitution is reconstituted with a suitable carrier such as water when required.
  • a suitable carrier such as water when required.
  • Example 12-15 Ready-To-Use Suspension of riociguat
  • Suitable sweetener/diluent was added to the purified water and was stirred to get a clear solution.
  • Suitable suspending agent was added to the solution and was stirred for a suitable time (30 minutes).
  • a suitable buffer solution was prepared by adding pH-adjusting agents in purified water and was added to the dispersion.
  • Suitable wetting agents and riociguat were added in the dispersion and were stirred for a suitable time period.
  • Suitable preservatives methylparaben and propylparaben
  • a suitable carrier such as glycerin (heated at 80°C) and were cooled at room temperature and were added to the suspension (example 13-14) or sodium benzoate was added in to the suspension (example 15).
  • Suitable sweetening and flavoring agents were added to the suspension and were stirred for a suitable time. Suspension was homogenized for a suitable time period. Volume of suspension was adjusted with a suitable liquid carrier and was stirred the final suspension for a suitable time (30 minutes). The suspension was filled into a suitable container closure system.
  • results The dissolution, pH and assay of dosage forms prepared using quantitative formula is given below.
  • the dissolution profile was measured in 900 ml of 6.8 phosphate buffer and 0.1% sodium lauryl sulfate (SLS) using a USP II apparatus (Paddle) at a temperature of 37 ⁇ 0.5°C and a rotation speed of 75 revolutions per minute.
  • SLS sodium lauryl sulfate
  • the test examples exhibited desired pharmaceutical formulation technical attributes such as dissolution profile, pH, and assay.
  • Test formulations pH was determined in the range of 3-7.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Dispersion Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention relates to orally administered immediate release pharmaceutical suspensions of riociguat. The immediate release suspensions are in the form of ready to use suspension. It also relates to the processes for the preparation of said suspensions. The present invention provides suspensions of riociguat which are expected to exhibit desired technical attributes such as viscosity, pH, dissolution, assay and stability. The prepared compositions are useful in patients having difficulties in swallowing tablets and provide enhanced patient compliance over conventional tablet dosage form.

Description

PHARMACEUTICAL ORAL SUSPENSIONS OF RIOCIGUAT
FIELD OF THE INVENTION
The present invention relates to orally administered, pharmaceutical immediate release suspensions of riociguat. The immediate 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 suspensions. It further relates to the use of 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-[l-(2- fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate and is represented by the following formula as:
Figure imgf000002_0001
Riociguat is marketed in the USA 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 No. 10,087,183, assigned to Bayer Healthcare, discloses polymorphs of riociguat such as modification I, modification II, mono-DMSO solvate, sesqui-DMSO solvate, l^-ethyl acetate solvate and pharmaceutical composition thereof. The publication highlights various polymorphic forms of riocugat and the conversion of these polymorphs into other forms. U.S. Patent No. 9,884,859, assigned to Sunshine Lake Pharma, discloses crystalline form III and form IV of riociguat.
U.S. Patent No. 10,414,766, assigned to Alembic Pharmaceuticals, discloses crystalline form AL of riociguat.
Difficulty in swallowing 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 in swallowing. However, an extemporaneously created dispersion of riociguat is physicochemically not stable leading to highly variable riociguat dosing with accompanying unpredictable therapeutic efficacy.
Till date, no suspension formulation of riociguat is commercially available. There is an unmet need in the art to provide immediate release suspension dosage forms of riociguat which are stable, no conversion into undesirable polymorphs, provide ease of administration, ease of dose adjustment, and enhanced patient compliance.
The inventors of the present invention have developed a suspension dosage form of riociguat with an objective to minimize swallowing difficulties, which is likely to improve patient compliance by reducing dysphagia-related adverse events and accordingly providing a more convenient and less cumbersome posology. The inventors have developed immediate release, ready to use suspension and/or suspension powder for reconstitution convenient for administration to paediatric and geriatric patients, easy to manufacture, functionally reproducible, and provides ease of dose adjustment. Further, the suspension dosage form exhibits desirable technical attributes such as pourability, viscosity, pH, dissolution, re-suspendability, assay and chemical and physical stability.
SUMMARY OF THE INVENTION
It is a principal object of the present invention to provide a stable immediate release oral pharmaceutical suspension dosage form of riociguat comprising riociguat and at least one or more pharmaceutically acceptable excipients and a process for its preparation. The suspension dosage form of the present invention is in the form of immediate release ready to use suspension and/or immediate release suspension powder for reconstitution. It is another object of the present invention to provide an immediate release oral pharmaceutical suspension dosage form of riociguat comprising riociguat and at least one or more pharmaceutically acceptable excipients; wherein the one or more pharmaceutically acceptable excipients are selected from the group comprising of suspending agent, buffer/pH adjusting agent, diluent, carrier, antioxidant, anticaking agent, antifoaming agent, coloring agent, sweetening agent, flavoring agent, surfactant/solubilizer/wetting agent, preservative, glidant, binder, and mixtures thereof.
It is another object of the present invention to provide an immediate release, ready to use suspension comprising riociguat and at least one or more pharmaceutically acceptable excipients and a process for its preparation.
It is another object of the present invention to provide an immediate release suspension powder for reconstitution comprising riociguat and at least one or more pharmaceutically acceptable excipients and a process for its preparation.
It is another object of the present invention to provide an immediate release suspension dosage form comprising riociguat 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 (physical, chemical and polymorph stability), re-suspendability and a process for preparing the same.
In accordance with still another embodiment of the present invention, there is provided an immediate release suspension dosage form comprising riociguat 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 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 composition of the invention includes, but is not limited to immediate release ready to use suspension, powder for suspension, granules for suspension, pellets, beads, multiparticulates, and the like. Particularly, the pharmaceutical composition refers to powder, granules, pellets, beads, multiparticulates, and the like filled into capsules or sachets, and ready to use suspension.
As used herein, the term “ready to use suspension” means a pre-constituted suspension which can be administered as such to patient. The “powder for suspension” or “suspension powder for reconstitution” or “dry suspension” or “granules for suspension” are synonymous and are reconstituted with a liquid carrier like water to form a suspension.
As used herein, the term “riociguaf ’ is used in broad sense to include not only “riociguaf ’ per se but also its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, derivatives, isomers, polymorphs, stereoisomers, diastereoisomers prodrugs thereof, and also its various crystalline and amorphous forms or mixtures thereof. Riociguat is present in an amount from about 0.01% to about 70% of the suspension dosage form, particularly from about 0.01% to about 30%, from about 0.01% to about 20%, from about 0.01% to about 10%, from about 0.01% to about 5%, from about 0.01% to about 3% w/w or w/v of the suspension dosage form.
The term “excipient” means a pharmacologically inactive component such as a suspending agent, pH adjusting agent/buffering agent, diluent, carrier, anticaking agent, antifoaming agent, antioxidant, sweetening agent, flavoring agent, surfactant/solubilizer/wetting agent, buffer, glidant, binder, preservative, and the like. 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 “immediate release,” as used herein, implies that riociguat is released from the composition in an immediate release fashion. Immediate release refers to pharmaceutical compositions that release at least 75% of the active ingredient within a small period of time, typically less than 60 minutes and more particularly in less than 45 minutes and most particularly more than 85% of drug release within 30 minutes.
As used herein, the term “about” means ± approximately 10% of the indicated value, such that “about 10 percent” indicates approximately 08 to 12 percent. As used in this specification, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to “a process” includes one or more process, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.
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 or volume 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 of the present invention, there is provided a stable immediate release oral pharmaceutical suspension dosage form of riociguat comprising riociguat and at least one or more pharmaceutically acceptable excipients.
In accordance with another embodiment of the present invention, the immediate release oral pharmaceutical suspension dosage form of riociguat is a ready-to-use suspension and suspension powder for reconstitution.
In accordance with another embodiment of the present invention, there is provided an immediate release oral pharmaceutical suspension dosage form of riociguat comprising: a) riociguat; b) a suspending agent; and c) at least one or more pharmaceutically acceptable excipients.
In accordance with another embodiment of the present invention, there is provided an immediate release oral pharmaceutical suspension dosage form of riociguat comprising: a) riociguat from about 0.01% to about 30% w/w; b) a suspending agent from about 0.05% to about 20% w/w; and c) at least one or more pharmaceutically acceptable excipients.
In accordance with another embodiment of the present invention, there is provided an immediate release oral pharmaceutical suspension dosage form of riociguat comprising: a) riociguat from about 0.01% to about 30% w/w; b) a suspending agent from about 0.05% to about 20% w/w; and c) at least one or more pharmaceutically acceptable excipients; wherein the pH of the suspension is from about 3 to about 8.
In accordance with another embodiment of the present invention, there is provided an immediate release ready to use oral pharmaceutical suspension of riociguat comprising: a) riociguat from about 0.01% to about 30% w/w; b) a suspending agent from about 0.05% to about 20% w/w; and c) a pharmaceutically acceptable liquid carrier.
In accordance with another embodiment of the present invention, there is provided an immediate release oral pharmaceutical suspension powder for reconstitution of riociguat comprising: a) riociguat from about 0.01% to about 30% w/w; b) a suspending agent from about 0.05% to about 20% w/w; and c) one or more pharmaceutically acceptable excipients.
In accordance with another embodiment of the present invention, there is provided an immediate release oral pharmaceutical suspension dosage form of riociguat comprising: a) riociguat; b) a suspending agent; and c) at least one or more pharmaceutically acceptable excipients; wherein the dosage form exhibits an in-vitro dissolution rate of more than 50% of drug release within 30 minutes when the said dosage form is placed in a dissolution vessel filled with 900 ml of pH 6.8 phosphate buffer with 0.1% sodium lauryl sulfate (SLS) maintained at 37±0.5°C and stirred at a paddle speed of 75 rpm using a USP Type II (paddle) apparatus.
In accordance with another embodiment of the present invention, there is provided an immediate release oral pharmaceutical suspension powder for reconstitution of riociguat comprising riociguat and a suspending agent, wherein the suspending agent is present in an amount ranging from about 0.05% to about 20% w/w in the powder formulation.
In accordance with another embodiment of the present invention, there is provided an immediate release oral pharmaceutical suspension dosage form of riociguat comprising riociguat and a suspending agent, wherein the riociguat and suspending agent have a ratio ranging from about 1 : 0.01 to 1:40 by weight. In a preferred embodiment, the riociguat and suspending agent have a ratio ranging from about 1:0.01 to 1:50. In a preferred embodiment, the riociguat and suspending agent have a ratio ranging from about 1 : 10 to 1 :50. In a preferred embodiment, the riociguat and suspending agent have a ratio ranging from about 1:0.01 to 1:25. In a preferred embodiment, the riociguat and suspending agent have a ratio of about 1:25. In a preferred embodiment, the riociguat and suspending agent have a ratio of about 1:22.5. In a preferred embodiment, the riociguat and suspending agent have a ratio of about 1 : 10. In a preferred embodiment, the riociguat and suspending agent have a ratio of about 1:5.
In accordance with another embodiment of the present invention, there is provided an immediate release oral pharmaceutical suspension dosage form of riociguat comprising riociguat and wetting agent, wherein the riociguat and wetting agent have a ratio ranging from about 1 :0.01 to 1 : 10, preferably, ranging from about 1:0.01 to 1:5.
In accordance with another embodiment of the present invention, the immediate release oral pharmaceutical suspension dosage form of riociguat is a ready-to-use suspension and suspension powder for reconstitution.
In accordance with another embodiment of the present invention, the immediate release oral pharmaceutical suspension dosage form of riociguat, wherein riociguat is present in an amount from about 0.05 mg/mL to about 30 mg/mL and viscosity from about 100 cps to about 4000 cps. In a preferred embodiment, the viscosity of the suspension is from about 100 cps to about 3000 cps. In a preferred embodiment, the viscosity of the suspension is from about 100 cps to about 1000 cps. In a preferred embodiment, the amount of riociguat in the suspension ranges from about 0.05 mg/mL to about 7.5 mg/mL. In a preferred embodiment, the amount of riociguat in the suspension ranges from about 0.05 mg/mL to about 5 mg/mL.
In accordance with another embodiment of the present invention, there is provided an immediate release oral pharmaceutical suspension dosage form of riociguat comprising: a) riociguat or its pharmaceutically acceptable salt, ester, hydrate or polymorph thereof; b) a suspending agent; c) a pH adjusting agent; and d) one or more pharmaceutically acceptable excipients.
In accordance with another embodiment of the present invention, there is provided an immediate release oral pharmaceutical suspension dosage form of riociguat comprising: a) riociguat or its pharmaceutically acceptable salt, ester, hydrate or polymorph thereof; b) a suspending agent; c) pH adjusting agent to maintain the pH of the composition in the range of about 3 to about 8; d) optionally a surfactant; e) optionally a preservative; and f) one or more pharmaceutically acceptable excipients.
In accordance with another embodiment of the present invention, there is provided an immediate release oral pharmaceutical suspension dosage form of riociguat comprising: a) riociguat or its pharmaceutically acceptable salt, ester, hydrate or polymorph thereof; b) a suspending agent; c) a pH adjusting agent to maintain the pH of the composition in the range of about 3 to about 8; and d) a diluent or a pharmaceutically acceptable liquid carrier.
In accordance with another embodiment of the present invention, there is provided an immediate release oral pharmaceutical suspension dosage form of riociguat comprising: a) riociguat; b) a suspending agent; c) optionally a pH adjusting agent; and d) one or more pharmaceutically acceptable excipients; wherein the suspending agent is selected from the group comprising of xanthan gum, gellan gum, cellulose and its derivatives, a mixture of carboxymethylcellulose and microcrystalline cellulose, propylene glycol alginate, and combinations thereof.
In accordance with another embodiment of the present invention, there is provided an immediate release oral pharmaceutical suspension dosage form of riociguat comprising: a) riociguat or its pharmaceutically acceptable salt, ester, hydrate or polymorph thereof a) a suspending agent; b) a surfactant; c) optionally a preservative; d) optionally an antioxidant; e) pH adjusting agent in sufficient amounts to maintain the pH of the composition in the range of about 3 to about 8; and f) a diluent or a pharmaceutically acceptable liquid carrier.
In accordance with another embodiment of the present invention, there is provided an immediate release oral pharmaceutical suspension dosage form of riociguat or its pharmaceutically acceptable salt, ester, hydrate or polymorph thereof with one or more pharmaceutically acceptable excipients comprising riociguat from about 0.05 mg/mL to about 30 mg/mL, wherein the pH of the composition is from about 3 to about 8.
In accordance with another embodiment of the present invention, there is provided an immediate release oral pharmaceutical suspension dosage form comprising: a) riociguat in an amount of about 0.01 % to about 30% w/v of the dosage form; b) a suspending agent selected from xanthan gum, mixture of microcrystalline cellulose and sodium carboxymethyl cellulose, propylene glycol alginate, and gellan gum in an amount from about 0.05% to about 20% w/v of the dosage form; c) a wetting agent selected from poloxamer, polysorbate, polyoxyethylene stearate and combination thereof in an amount from about 0.01% to about 5% w/v of the dosage form; d) pH adjusting agent or buffering agent selected from citric acid, trisodium citrate, citrate buffer, monosodium dibasic phosphate, tribasic sodium phosphate and combination thereof in an amount from about 0.01% to about 5% w/v of the dosage form; e) a pharmaceutically acceptable liquid carrier selected from water, glycerin, propylene glycol, aqueous sorbitol solution, aqueous buffer solution and combination thereof in an amount from about 10% to about 95% w/v of the dosage form; and f) at least one or more other pharmaceutically acceptable excipients; wherein the pH of the suspension is from 3 to 7. Preferably, the pH of the suspension is from 4 to 6. In another embodiment, riociguat has a particle size distribution D90 less than about 20 pm, preferably 10 pm and more preferably 6.7 pm.
In accordance with another embodiment of the present invention, there is provided an immediate release oral pharmaceutical suspension dosage form comprising: a) riociguat in an amount of about 0.01% to about 5% w/v of the dosage form; b) a suspending agent selected from xanthan gum, mixture of microcrystalline cellulose and sodium carboxymethyl cellulose, propylene glycol alginate, and gellan gum in an amount from about 0.05% to about 3% w/v of the dosage form; c) a wetting agent selected from poloxamer, polysorbate, polyoxyethylene stearate and combination thereof in an amount from about 0.01% to about 2% w/v of the dosage form; d) liquid carrier selected from water, glycerin and combination thereof in an amount from about 10% to about 95% w/v of the dosage form; and e) at least one or more other pharmaceutically acceptable excipients; wherein the pH of the suspension is from 3 to 6 and suspension exhibits an in-vitro dissolution rate of more than 85% of drug release within 30 minutes when measured in 900 ml of 6.8 phosphate buffer and 0.1% sodium lauryl sulfate using a USP II apparatus (Paddle) at a temperature of 37±0.5°C and a rotation speed of 75 revolutions.
In accordance with another embodiment of the present invention, there is provided an immediate release oral pharmaceutical suspension dosage form comprising: a) riociguat in an amount of about 0.01% to about 5% w/v of the dosage form; b) a suspending agent selected from xanthan gum, mixture of microcrystalline cellulose and sodium carboxymethyl cellulose, propylene glycol alginate, and gellan gum in an amount from about 0.05% to about 3% w/v of the dosage form; c) a wetting agent selected from poloxamer, polysorbate, polyoxyethylene stearate and combination thereof in an amount from about 0.01% to about 2% w/v of the dosage form; d) citric acid in an amount from about 0.01% to about 2% w/v of the dosage form; e) trisodium citrate in an amount from about 0.01% to about 2% w/v of the dosage form; f) sorbitol in an amount from about 0.01% to about 11% w/v of the dosage form; g) methylparaben and propylparaben in an amount from about 0.01% to about 1% w/v of the dosage form; and h) liquid carrier selected from water, glycerin and combination thereof in an amount from about 10% to about 95% w/v of the dosage form; wherein the pH of the suspension is from 3 to 6 and the riociguat and suspending agent have a ratio ranging from about 1:0.01 to 1:25.
In accordance with another embodiment of the present invention, there is provided an immediate release oral pharmaceutical suspension dosage form comprising: a) riociguat in an amount of about 0.01% to about 5% w/v of the dosage form, b) xanthan gum in an amount from about 0.05% to about 3% w/v of the dosage form; c) polysorbate 80 in an amount from about 0.01 % to about 2% w/v of the dosage form; d) citric acid in an amount from about 0.01 % to about 2% w/v of the dosage form, e) trisodium citrate in an amount from about 0.01% to about 2% w/v of the dosage form; f) sorbitol in an amount from about 0.01% to about 11% w/v of the dosage form; g) sodium benzoate in an amount from about 0.01% to about 1% w/v of the dosage form; h) thaumatin in an amount from about 0.01% to about 2% w/v of the dosage form; i) liquid carrier selected from water, glycerin and combination thereof in an amount from about 10% to about 95% w/v of the dosage form; wherein the pH of the suspension is from 3 to 8.
In accordance with another embodiment of the present invention, there is provided an immediate release oral pharmaceutical suspension dosage form comprising: a) riociguat in an amount of about 0.05 mg/mL to about 7.5 mg/mL of the dosage form; b) a suspending agent selected from xanthan gum, mixture of microcrystalline cellulose and sodium carboxymethyl cellulose, propylene glycol alginate, and gellan gum in an amount from about 0.1 mg/ml to about 10 mg/ml of the dosage form; c) a wetting agent selected from poloxamer, polysorbate, polyoxyethylene stearate and combination thereof in an amount about 0.01 mg/ml to about 5 mg/ml of the dosage form; d) pH adjusting agent or buffering agent selected from citric acid, trisodium citrate, citrate buffer, monosodium dibasic phosphate, tribasic sodium phosphate and combination thereof in an amount from about 0.01 mg/ml to about 5 mg/ml of the dosage form; and e) a pharmaceutically acceptable liquid carrier selected from water, glycerin and combination thereof in an amount up to 1ml for 1ml suspension dosage form; wherein the pH of the suspension is from 3 to 6 and wherein riociguat has a particle size distribution D90 less than about 20 pm.
In accordance with another embodiment of the present invention, there is provided an immediate release oral pharmaceutical suspension dosage form which exhibits an in-vitro dissolution rate of more than 85% of drug release within 30 minutes, when measured in 900 ml of 6.8 phosphate buffer and 0.1% sodium lauryl sulfate (SLS) using a USP II apparatus (Paddle) at a temperature of 37±0.5°C and a rotation speed of 75 revolutions
In accordance with another embodiment of the present invention, there is provided an immediate release oral pharmaceutical suspension dosage form 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 or w/v of the dosage form.
In accordance with another embodiment of the present invention, there is provided an immediate release oral pharmaceutical suspension dosage form 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 or w/v of the dosage form.
In accordance with another embodiment of the present invention, there is provided an immediate release oral pharmaceutical suspension dosage form 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. Preferably, the dosage form comprises one or more flavoring agents in an amount from about 0.01% to about 1% w/w or w/v of the dosage form.
In accordance with another embodiment of the present invention, there is provided an immediate release oral pharmaceutical suspension dosage form of riociguat comprising riociguat from about 0.05 mg/mL to about 30 mg/mL, wherein the pH of the composition is from about 3 to about 8 and viscosity from about 100 cps to about 4000 cps.
In a preferred embodiment, there is provided an immediate release oral pharmaceutical suspension dosage form of riociguat comprising riociguat about lmg/5 mL. In a preferred embodiment, there is provided an immediate release oral pharmaceutical suspension dosage form of riociguat comprising riociguat about 1 mg/mL. In accordance with still another embodiment of the present invention, there is provided an immediate release oral pharmaceutical suspension dosage form of riociguat, wherein the composition is free from other polymorphic forms.
In accordance with another embodiment of the present invention, there is provided a suspension powder for reconstitution of riociguat comprising riociguat and at least one or more pharmaceutically acceptable excipients selected from the group comprising a suspending agent, pH adjusting agent/buffer, antioxidant, anticaking agent, antifoaming agent, coloring agent, sweetening agent, flavouring agent, surfactant/wetting agent, diluent, carrier, glidant, binder, and preservative.
In accordance with another embodiment of the present invention, there is provided a ready to use suspension of riociguat comprising riociguat, a pharmaceutically acceptable carrier and at least one or more pharmaceutically acceptable excipients selected from the group comprising of: suspending agent, antioxidant, anticaking agent, antifoaming agent, pH adjusting agent/buffer, coloring agent, sweetening agent, flavouring agent, surfactant/wetting agent, diluent, glidant, binder, and preservative.
In accordance with another embodiment of the present invention, there is provided a dry powder for suspension compositions of riociguat suitable for use as a liquid suspension for children or elderly patients.
In accordance with still another embodiment of the present invention, there is provided a process for the preparation of an immediate release oral pharmaceutical suspension dosage form of riociguat comprising riociguat in micronized form.
In accordance with one embodiment of the present invention, there is provided an immediate release oral pharmaceutical suspension dosage form of riociguat which is stable.
In accordance with still another embodiment of the present invention, there is provided a process for the preparation of a ready to use suspension of riociguat comprising combining various components using conventional equipment such as overhead stirrers, ultrasonifiers, mills, homogenizers. Many different orders of addition of components can be employed.
In accordance with still another embodiment of the present invention, there is provided a process for the preparation of a suspension powder for reconstitution of riociguat comprising admixing riociguat granules with at least one or more pharmaceutically acceptable excipients selected from the group comprising of suspending agent, pH adjusting agent/buffer, diluent, carrier, antioxidant, anticaking agent, antifoaming agent, coloring agent, sweetening agent, flavoring agent, surfactant/solubilizer/wetting agent, preservative, glidant, binder, disintegrant, antioxidant, and mixtures thereof to form a dry admixture, and transferring the dry admixture to a sealable storage container.
In accordance with still another embodiment of the present invention, there is provided a pharmaceutical suspension dosage form of riociguat, wherein riociguat has a particle size distribution D90 less than about 200 pm, D50 is less than about 100 pm and Dio 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, more particularly from 1 pm to about 10 pm, and more particularly from 1 pm to about 6.7 pm. D50 ranges from about 1 pm to about 100 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.
In accordance with another embodiment of the present invention, there is provided an immediate release pharmaceutical suspension dosage form comprising riociguat for use in the treatment of hypertension, persistent/recurrent chronic thromboembolic pulmonary hypertension, pulmonary arterial hypertension, 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.
In accordance with another embodiment of the present invention, there is provided a method of treating hypertension, persistent/recurrent chronic thromboembolic pulmonary hypertension, pulmonary arterial hypertension, 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 by administering an immediate release oral pharmaceutical suspension dosage form of riociguat of the present invention.
In accordance with another embodiment of the present invention, there is provided an immediate release oral pharmaceutical suspension dosage form of riociguat, wherein the pH of the suspension is in the range of about 3-9. Preferably, the pH is in a range of about 3 to about 8. More preferably, the pH is in a range of about 3 to about 6. More preferably, the pH is in a range of about 3 to about 5.5.
In accordance with another embodiment of the present invention, there is provided an immediate release oral pharmaceutical suspension dosage form of riociguat, wherein the suspension dosage form comprises less than 2% of total impurities, preferably less than 1% of total impurities. In another embodiment, the dosage form comprises less than 0.5% of carbamate impurity. In another embodiment, the dosage form comprises less than 0.5% of des-fluoro impurity. In another embodiment, the dosage form comprises less than 0.5% of dimethyl impurity. In another embodiment, the dosage form comprises less than 0.5% of methyl isopropyl impurity. In another embodiment, the immediate release pharmaceutical suspension dosage form comprises less than 2% of total impurities and less than 0.5% of carbamate impurity.
In accordance with other embodiment, riociguat is the sole active ingredient in the suspension dosage form.
In accordance with other embodiment, the suspension dosage form of riociguat of the present invention is sugar free.
In accordance with other embodiment, the suspension dosage form of riociguat is microbiologically stable.
In accordance with other embodiment of the present invention, there is provided an immediate release suspension dosage form comprising riociguat, wherein the suspension is a ready to use suspension packaged in a bottle.
In accordance with yet another embodiment of the present invention, there is provided an immediate release suspension dosage form comprising riociguat, wherein the suspension is a powder for suspension packaged in a bottle or a sachet.
In accordance with one embodiment of the present invention, there is provided a process for the preparation of a suspension dosage form comprising riociguat, wherein the process utilized is mixing, blending, dry granulation, wet granulation, hot-melt extrusion process, extrusion spheronization, fluidized bed granulation, dispersion, homogenization or the like.
In accordance with one embodiment of the present invention, there is provided a process for preparation of a ready to use suspension of riociguat, wherein the process comprises the following steps: (i) dissolving/dispersing one or more pharmaceutically acceptable excipients in a portion of water;
(ii) dispersing riociguat in the mixture of step (i) to form a dispersion;
(iii) mixing suspending agent in another portion of water;
(iv) adding the mixture of step (iii) to the dispersion of step (ii); and
(v) optionally adding one or more pharmaceutically acceptable excipients to the dispersion of step (iv); and
(vi) optionally homogenizing the mixture of step (iv) to form a suspension.
In accordance with other embodiment of the present invention, there is provided a process for preparation of a suspension powder for reconstitution of riociguat wherein process comprises the following steps:
(i) mixing riociguat with one or more pharmaceutically acceptable excipients;
(ii) granulating the mixture of step (i) using a solvent;
(iii) drying the granulated mixture of step (ii);
(iv) milling the mixture of step (iii) to form granules; and
(v) mixing the granules of step (iv) optionally with one or pharmaceutically acceptable excipients to form the suspension powder for reconstitution.
In accordance with other embodiment of the present invention, there is provided a process for preparation of a suspension powder for reconstitution of riociguat, wherein the process comprises the following steps:
(i) mixing riociguat with one or more pharmaceutically acceptable excipients;
(ii) compacting the mixture of step (i) to form slugs;
(iii) milling the slugs of step (ii) to form granules; and
(iv) mixing the granules of step (iii) optionally with one or pharmaceutically acceptable excipients to form the suspension powder for reconstitution.
In accordance with other embodiment of the present invention, there is provided a process for preparation of a suspension powder for reconstitution of riociguat, wherein the process comprises the following steps:
(i) mixing riociguat with one or more pharmaceutically acceptable excipients; and
(ii) optionally lubricating the mixture of step (i) to form the suspension powder for reconstitution. Powder/granules for oral suspension can be reconstituted using water or powder/granules for oral suspension can be administered by sprinkling the powder/granules on soft food like yoghurt, applesauce or empty granules into a small cup or teaspoon containing apple juice, etc.
In yet another embodiment, the suspension dosage form of the present invention is bioequivalent to the immediate release marketed tablet of riociguat (Adempas® tablet).
The suspension of the present invention provides advantages such as the absence of lumps even after long storage when the composition is shaken as well as good pourability. The suspension of the invention has good physical stability properties such as a low level of sedimentation (reduced or no caking) and easy re-dispersion on agitation. Moreover, it provides dose uniformity during each administration.
The present inventors have observed that in the development of immediate release suspension dosage form of riociguat, the amount and ratio of drug, suspending agents, wetting agents and buffering agents are critical. Following are the key observations by the present inventors: a) for a successful immediate release suspension dosage form of riociguat, it is necessary to use the drug and suspending agent in specific ratio ranges i.e. from about 1:0.01 to 1:50. b) use the drug and wetting agent in a specific ratio range i.e. 1:2 or less, c) use the drug and buffering agents in specific ratio ranges i.e. 1: 10 or less. Preferably, the drug and buffering agents is used in a specific ratio ranges from about 1 :0.01 to 1:5. The immediate release suspension dosage form of riociguat failed to achieve the desired assay and drug release and other technical attributes when ratios from about 1: 100 (drug and suspending agent); 1:3 (drug and wetting agent) and 1: 11 or more (drug and buffering agents) were used in test formulations.
Carrier/vehicle/solvent used in the suspension of the present invention includes aqueous and non-aqueous carriers but are not limited to water, alcohol, polyethylene glycol, propylene glycol, glycerin, oil, or combinations thereof. Oils include peanut oil, soy bean oil, corn 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 aqueousbased. 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. “Non-aqueous carrier” comprises 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 5% to about 99%, particularly from about 40% to about 95% w/w or w/v.
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, hydroxypropylmethyl cellulose, methylcellulose, carboxymethyl cellulose and its salts/derivatives, e.g., carboxymethyl cellulose sodium, microcrystalline cellulose, and co-processed 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 (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; starch; and mixtures thereof. The suspending agents are present in an amount of about 0.05% to about 20% w/w or w/v of the composition. Particularly, the suspending agents are present in an amount of about 0.1% to about 10%, about 0.1% to about 5% and about 0.1% to about 3% w/w or w/v 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 fillers or diluents include, but are not limited to sugars (e.g. sucrose, dextrose, fructose, lactose, maltose, invert sugar), sugar alcohols (e.g. sorbitol, mannitol, xylitol, lactitol, erythritol, maltodextrin, maltitol, isomaltitol, isomalt, maltulose, isomaltulose, lactulose, threitol, arabitol, ribitol, galactitol), starch, pregelatinized starch, calcium carbonate, calcium phosphate, dibasic anhydrous, calcium phosphate, dibasic dihydrate, calcium phosphate tribasic, calcium sulphate, cellulose powdered, silicified microcrystalline cellulose, cellulose acetate, magnesium carbonate, magnesium oxide, microcrystalline cellulose, polydextrose, sodium alginate, sodium chloride and or mixtures thereof. The diluent is present in an amount of 5% to 99% w/w of the total composition.
In accordance with another embodiment of the present invention, sucrose 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.
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. The pH adjusting agents are present in an amount of about 0.1% to about 8% w/w or w/v 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; polysorbates (such as polysorbate 80); polyoxyethylene alkyl ether such as polyoxyethylene lauryl ether; polyoxyethylene castor oil; polyoxyethylene -polyoxypropylene block copolymers such as poloxamers (e.g. Poloxamer 188); polyoxyethylene stearate such as polyoxy 100 stearate (Myrj® 59P) as the wetting agent 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 or w/v of the composition. Particularly, the surfactant or wetting agents are present in an amount of about 0.01% to about 3%, and more particularly from about 0.01% to about 1% w/w or w/v of the composition.
Various useful preservatives include, but are not limited to, parabens such as methylparaben, propylparaben, butylparaben 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% to about 3% w/w or w/v of the composition.
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% to about 10% w/w of the composition. More particularly, the anticaking agents are present in an amount of about 0.5% to about 7% w/w of the composition.
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 hydroxyl anisole (BHA), butylated hydroxytoluene (BHT) and propyl gallate The antioxidant is present in an amount from 0% to about 20%, from about 0.001% to about 5% w/w or w/v.
Various useful sweetening agents include, but are not limited to, sugars such as sucrose, dextrose, fructose, lactose, maltose, invert sugar, sugar alcohols such as sorbitol, mannitol, xylitol, lactitol, erythritol, maltodextrin, maltitol, isomaltitol, isomalt, maltulose, isomaltulose, lactulose, threitol, arabitol, ribitol, galactitol, and sugar substitutes such as saccharin sodium, aspartame, acesulfame, and sucralose. Sugar or a sugar alcohol can also act as a filler. The sweetening agents are present in an amount of 0% to about 90% w/w or w/v of the composition, particularly in an amount of about 0.1% to about 90% w/w or w/v of the composition, more particularly in an amount of about 0.1% to about 30% w/w or w/v 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; maltol, 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% to about 5% w/w or w/v 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% to about 5% w/w based on the total weight of the powder formulation.
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 mixture thereof. The binder is present in an amount of about 0.1% w/w to about 30% w/w of the composition.
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.
The 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 is provided with a child proof closure. The package can include a syringe (marked in mL) for ease of dosing. The 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 20 mL to about 300 mL comprising riociguat suspension. Pack chosen are made of material which is non-reactive with the suspension and suspension powder for reconstitution. Containers for use in the storage of the oral suspensions may be used to administer a multiple dose of riociguat.
The suspension powder for reconstitution can be provided in a kit comprising (a) suspension powder for reconstitution of riociguat and (b) a pharmaceutically acceptable carrier.
In accordance with yet another embodiment of the present invention, there is provided a suspension comprising riociguat, wherein the suspension is provided in a kit comprising: (a) an immediate release oral pharmaceutical ready to use suspension comprising riociguat, and (b) a dosing syringe for administering the suspension.
The suspensions of the present invention are homogenous and deliver the desired dose of riociguat in every use without any risk of overdosing or underdosing. The compositions provide predictable riociguat release throughout the shelf life. pH Measurement: pH values are determined using potentiometry using USP <791>.
Viscosity Measurement: The viscosity can be measured by using a suitable instrument such as Brookfield viscometer, Haake VT 550 viscometer at room temperature (25°C).
Dissolution studies
The powder for suspension was evaluated for in-vitro riociguat release. The in-vitro dissolution is determined using a USP type II apparatus at 75 rpm in 900 mL of pH 6.8 phosphate buffer with 0.1% sodium lauryl sulfate at 37±0.5°C by HPLC method.
The invention may be further illustrated by the following examples, which are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.
EXAMPLES
Examples 1-5. Ready to use suspension of riociguat
Figure imgf000023_0001
Figure imgf000024_0001
Process: Dispersion method
Example 6-11. Suspension powder for reconstitution of riociguat
Figure imgf000024_0002
Process: Dry granulation/ Wet granulation/ Dry blending
The suspension powder for reconstitution is reconstituted with a suitable carrier such as water when required. Example 12-15. Ready-To-Use Suspension of riociguat
Figure imgf000025_0001
Procedure: Suitable sweetener/diluent was added to the purified water and was stirred to get a clear solution. Suitable suspending agent was added to the solution and was stirred for a suitable time (30 minutes). A suitable buffer solution was prepared by adding pH-adjusting agents in purified water and was added to the dispersion. Suitable wetting agents and riociguat were added in the dispersion and were stirred for a suitable time period. Suitable preservatives (methylparaben and propylparaben) were added in a suitable carrier such as glycerin (heated at 80°C) and were cooled at room temperature and were added to the suspension (example 13-14) or sodium benzoate was added in to the suspension (example 15). Suitable sweetening and flavoring agents were added to the suspension and were stirred for a suitable time. Suspension was homogenized for a suitable time period. Volume of suspension was adjusted with a suitable liquid carrier and was stirred the final suspension for a suitable time (30 minutes). The suspension was filled into a suitable container closure system.
Results: The dissolution, pH and assay of dosage forms prepared using quantitative formula is given below. The dissolution profile was measured in 900 ml of 6.8 phosphate buffer and 0.1% sodium lauryl sulfate (SLS) using a USP II apparatus (Paddle) at a temperature of 37±0.5°C and a rotation speed of 75 revolutions per minute. The test examples exhibited desired pharmaceutical formulation technical attributes such as dissolution profile, pH, and assay. Test formulations pH was determined in the range of 3-7.
Figure imgf000026_0001

Claims

WHAT IS CLAIMED:
1. An immediate release oral pharmaceutical suspension dosage form comprising: a) riociguat in an amount of about 0.01 % to about 30% w/v of the dosage form; b) a suspending agent selected from xanthan gum, mixture of microcrystalline cellulose and sodium carboxymethyl cellulose, propylene glycol alginate, and gellan gum in an amount from about 0.05% to about 20% w/v of the dosage form; c) a wetting agent selected from poloxamer, polysorbate, polyoxyethylene stearate and combination thereof in an amount from about 0.01% to about 5% w/v of the dosage form; d) pH adjusting agent selected from citric acid, trisodium citrate, citrate buffer, monosodium dibasic phosphate, tribasic sodium phosphate and combination thereof in an amount from about 0.01% to about 5% w/v of the dosage form; e) a pharmaceutically acceptable liquid carrier selected from water, glycerin, and combination thereof in an amount from about 10% to about 95% w/v of the dosage form; and f) at least one or more other pharmaceutically acceptable excipients; wherein the pH of the suspension is from 3 to 7.
2. The immediate release oral pharmaceutical suspension dosage form of claim 1, wherein the viscosity of the suspension is from about 100 cps to about 3000 cps.
3. The immediate release oral pharmaceutical suspension dosage form of claim 1, wherein the suspension dosage form is a ready to use suspension.
4. The immediate release oral pharmaceutical 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.
5. The immediate release oral pharmaceutical suspension dosage form of claim 1, wherein the amount of riociguat in the suspension ranges from about 0.05 mg/mL to about 5 mg/mL.
6. The immediate release oral pharmaceutical suspension dosage form of claim 1, wherein the riociguat and suspending agent have a ratio ranging from about 1:0.01 to 1:40.
7. The immediate release oral pharmaceutical suspension dosage form of claim 1, wherein the riociguat and suspending agent have a ratio ranging from about 1:0.01 to 1:25.
8. The immediate release oral pharmaceutical suspension dosage form of claim 1, wherein the riociguat and wetting agent have a ratio ranging from about 1:0.01 to 1:5.
26
9. The immediate release oral pharmaceutical suspension dosage form of claim 1, wherein the one or more other pharmaceutically acceptable excipients are selected from the group comprising of antioxidant, anticaking agent, antifoaming agent, coloring agent, sweetening agent, flavouring agent, diluent, carrier, glidant, binder, and preservative.
10. The immediate release oral pharmaceutical suspension dosage form of claim 1, wherein the pH of the dosage form is 4 to 6.
11. A process for the preparation of immediate release oral pharmaceutical suspension dosage form of claim 1, wherein the suspension dosage form is prepared by mixing, blending, dry granulation, wet granulation, hot-melt extrusion process, extrusion spheronization, fluidized bed granulation, dispersion or homogenization.
12. The immediate release oral pharmaceutical suspension dosage form of claim 1, wherein 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% to about 20% of the dosage form.
13. The immediate release oral pharmaceutical suspension dosage form of claim 1, wherein 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, butylated hydroxyl anisole, tocopherol, benzalkonium chloride and combination thereof in an amount of about 0.001 % to about 3% of the dosage form.
14. The immediate release oral pharmaceutical suspension dosage form of claim 1, wherein the dosage form 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% to about 5% of the dosage form.
15. The immediate release oral pharmaceutical suspension dosage form of claim 1, wherein the dosage form is provided in a kit comprising (a) a ready to use suspension comprising riociguat, and (b) a dosing syringe for administering the suspension.
16. An immediate release oral pharmaceutical ready to use suspension dosage form comprising: a) riociguat in an amount of about 0.01% to about 5% w/v of the dosage form; b) a suspending agent selected from xanthan gum, mixture of microcrystalline cellulose and sodium carboxymethyl cellulose, propylene glycol alginate, and gellan gum in an amount from about 0.05% to about 3% w/v of the dosage form; c) a wetting agent selected from poloxamer, polysorbate, polyoxyethylene stearate and combination thereof in an amount from about 0.01% to about 2% w/v of the dosage form; d) liquid carrier selected from water, glycerin and combination thereof in an amount from about 10% to about 95% w/v of the dosage form; and e) at least one or more other pharmaceutically acceptable excipients; wherein the pH of the suspension is from 3 to 6 and suspension exhibits an in-vitro dissolution rate of more than 85% of drug release within 30 minutes when measured in 900 ml of 6.8 phosphate buffer and 0.1% sodium lauryl sulfate using a USP II apparatus (Paddle) at a temperature of 37±0.5°C and a rotation speed of 75 revolutions.
17. An immediate release oral pharmaceutical ready to use suspension dosage form comprising: a) riociguat in an amount of about 0.01% to about 5% w/v of the dosage form; b) a suspending agent selected from xanthan gum, mixture of microcrystalline cellulose and sodium carboxymethyl cellulose, propylene glycol alginate, and gellan gum in an amount from about 0.05% to about 3% w/v of the dosage form; c) a wetting agent selected from poloxamer, polysorbate, polyoxyethylene stearate and combination thereof in an amount from about 0.01% to about 2% w/v of the dosage form; d) citric acid in an amount from about 0.01% to about 2% w/v of the dosage form; e) trisodium citrate in an amount from about 0.01% to about 2% w/v of the dosage form; f) sorbitol in an amount from about 0.01% to about 11% w/v of the dosage form; g) methylparaben and/or propylparaben in an amount from about 0.01% to about 1% w/v of the dosage form; and h) liquid carrier selected from water, glycerin and combination thereof in an amount from about 10% to about 95% w/v of the dosage form; wherein the pH of the suspension is from 3 to 6 and the riociguat and suspending agent have a ratio ranging from about 1:0.01 to 1:25.
18. The immediate release oral pharmaceutical ready to use suspension dosage form of claim
17, wherein the dosage form further comprises one or more flavoring agents in an amount from about 0.01 % to about 1 % w/v of the dosage form.
19. An immediate release oral pharmaceutical ready to use suspension dosage form comprising: a) riociguat in an amount of about 0.05 mg/mL to about 7.5 mg/mL of the dosage form; b) a suspending agent selected from xanthan gum, mixture of microcrystalline cellulose and sodium carboxymethyl cellulose, propylene glycol alginate, and gellan gum in an amount from about 0.1 mg/ml to about 10 mg/ml of the dosage form; c) a wetting agent selected from poloxamer, polysorbate, polyoxyethylene stearate and combination thereof in an amount about 0.01 mg/ml to about 5 mg/ml of the dosage form; d) pH adjusting agent selected from citric acid, trisodium citrate, citrate buffer, monosodium dibasic phosphate, tribasic sodium phosphate and combination thereof in an amount from about 0.01 mg/ml to about 5 mg/ml of the dosage form; and e) a pharmaceutically acceptable liquid carrier selected from water, glycerin and combination thereof in an amount up to 1ml for 1ml suspension dosage form; wherein the pH of the suspension is from 3 to 6 and wherein riociguat has a particle size distribution D90 less than about 20 pm. 0. The immediate release oral pharmaceutical ready to use suspension dosage form of claim 19, wherein the suspension comprises less than 2% of total impurities and less than 0.5% of carbamate impurity.
29
PCT/IN2022/050008 2021-01-04 2022-01-04 Pharmaceutical oral suspensions of riociguat WO2022144930A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202163133601P 2021-01-04 2021-01-04
US63/133,601 2021-01-04

Publications (1)

Publication Number Publication Date
WO2022144930A1 true WO2022144930A1 (en) 2022-07-07

Family

ID=82260321

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2022/050008 WO2022144930A1 (en) 2021-01-04 2022-01-04 Pharmaceutical oral suspensions of riociguat

Country Status (1)

Country Link
WO (1) WO2022144930A1 (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104434845A (en) * 2014-11-12 2015-03-25 广东东阳光药业有限公司 Riociguat-containing solid medicinal preparation
CN105596311A (en) * 2015-12-29 2016-05-25 郑州大明药物科技有限公司 Riociguat oral solid preparation and preparing method thereof
CN105878197A (en) * 2016-03-31 2016-08-24 北京万全德众医药生物技术有限公司 Riociguat orally disintegrating tablet and preparation method thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104434845A (en) * 2014-11-12 2015-03-25 广东东阳光药业有限公司 Riociguat-containing solid medicinal preparation
CN105596311A (en) * 2015-12-29 2016-05-25 郑州大明药物科技有限公司 Riociguat oral solid preparation and preparing method thereof
CN105878197A (en) * 2016-03-31 2016-08-24 北京万全德众医药生物技术有限公司 Riociguat orally disintegrating tablet and preparation method thereof

Similar Documents

Publication Publication Date Title
US11642351B2 (en) Eslicarbazepine suspension
KR101632079B1 (en) Pharmaceutical composition containing dihydropyridine calcium channel antagonist and method for the preparation thereof
US20230381194A1 (en) Suspension for oral administration comprising amorphous tolvaptan
US9161913B2 (en) Stabilized pediatric suspension of carisbamate
US20070015841A1 (en) Pharmaceutical propylene glycol solvate compositions
JP2020506245A (en) Lamotrigine suspension dosage form
US11331324B2 (en) Modified release suspension of eslicarbazepine
WO2022144930A1 (en) Pharmaceutical oral suspensions of riociguat
US8492423B2 (en) Pharmaceutical propylene glycol solvate compositions
US11318145B2 (en) Eslicarbazepine suspension
JP2019530727A (en) Powder for oral suspension containing lamotrigine
US20220265552A1 (en) Eslicarbazepine suspension
US9775832B2 (en) Pharmaceutical composition for oral administration
US20220273670A1 (en) Modified release suspension of eslicarbazepine
EP2987482A1 (en) Soluble and dispersible pharamaceutical deferasirox formulation
WO2013109230A1 (en) Pharmaceutical compositions comprising tadalafil
US11890273B2 (en) Losartan liquid formulations and methods of use
HUT77362A (en) Sabeluzole aqueous oral suspensions and process for preparation of them
WO2022147183A1 (en) Pharmaceutical extended release suspensions of riociguat
WO2020049536A1 (en) Pharmaceutical compositions of valacyclovir or its pharmaceutically acceptable salts thereof
WO2023285981A1 (en) Stable pharmaceutical liquid composition of nilotinib
US20230390194A1 (en) Formulations of nebivolol
TW202313007A (en) Oral aqueous suspension formulations comprising carbamate compound
US20230158012A1 (en) Oral liquid formulations of lenvatinib
WO2020212898A1 (en) Pharmaceutical oral liquid solution of ivacaftor

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22734787

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22734787

Country of ref document: EP

Kind code of ref document: A1