DESC:CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority to co-pending Indian Provisional Patent Application Serial Number 201921012816 filed on March 30, 2019. This application is incorporated herein by reference, in its entirety.

FIELD OF INVENTION:
The present invention relates to pharmaceutical formulations of Riociguat. Particularly, the present invention relates to oral extended release formulations of riociguat or pharmaceutically acceptable salts thereof and processes for preparing such formulations. Further provided are methods of using such extended release formulation in the treatment of pulmonary hypertension.

BACKGROUND OF INVENTION:
Pulmonary arterial hypertension (PAH) is a chronic, life-threatening disease, characterised by increased pulmonary vascular resistance (PVR) due to progressive vascular remodelling, which can ultimately lead to right heart failure and death. Although several licensed therapies are available, PAH remains an incurable disease and there is a need for additional treatment options. Chronic thromboembolic pulmonary hypertension is characterized by obstruction of the pulmonary vasculature by residual organized thrombi, leading to increased pulmonary vascular resistance, progressive pulmonary hypertension, and right ventricular failure. Patients with chronic thromboembolic pulmonary hypertension have a poor prognosis unless they receive treatment early.

Pulmonary endarterectomy is the standard treatment for chronic thromboembolic pulmonary hypertension and is the only potentially curative treatment. However, surgery is not an option for all patients; some patients are ineligible for surgery owing to the occlusion of distal vessels or coexisting conditions, some decline surgery, and some do not have access to expert surgical centers. Operability should be assessed with the use of high-quality imaging, with each patient undergoing review at an experienced pulmonary-endarterectomy center. Furthermore, some patients who undergo pulmonary endarterectomy have persistent or recurrent pulmonary hypertension after surgery. Since long time pharmacologic therapies have been approved for pulmonary arterial hypertension but not for chronic thromboembolic pulmonary hypertension highlighting a substantial unmet need.

Riociguat is the first approved medication from the novel class of soluble guanylate cyclase (sGC) stimulators and the only agent approved for treating both chronic thromboembolic hypertension (CTEPH) and pulmonary arterial hypertension (PAH). It has a dual mode of action, sensitising sGC to endogenous nitric oxide by stabilising nitric oxide–sGC binding and directly stimulating sGC via a different binding site, independently of nitric oxide . This results in increased production of cyclic GMP (cGMP). Riociguat is the first drug to demonstrate efficacy in two separate pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), and has been approved for the treatment of both indications.

The chemical name of Riociguat is methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1Hpyrazolo [3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate with the following structural formula:

Its molecular has formula is C20H19FN8O2 and has a molecular weight of 422.2 g/mole. The absolute bioavailability of riociguat is 94% and aqueous solubility is 4mg/mL.

US6743798 and US7173037 disclose riociguat , its characteristic, composition and pharmacological effect. WO2017103760 disclose various novel polymorphs of riociguat. WO2016202124 disclose riociguat intermediates and their preparation.

The recommended starting dosage of Adempas is 1 mg taken 3 times a day. For patients who may not tolerate the hypotensive effect of Adempas, consider a starting dose of 0.5 mg taken three times a day. If systolic blood pressure remains greater than 95 mmHg and the patient has no signs or symptoms of hypotension, up-titrate the dose by 0.5 mg taken three times a day. Dose increases should be no sooner than 2 weeks apart. The dose can be increased to the highest tolerated dosage, up to a maximum of 2.5 mg taken three times a day. If at any time, the patient has symptoms of hypotension, decrease the dosage by 0.5 mg taken three times a day.

Thus, with the conventional dosage form of riociguat, there is a problem of medication adherence, which is defined as the degree to which patients follow recommendations on the timing, dosage and frequency of their medications. The need for multiple dosings in a day, present patient compliance problems and also cause fluctuations in serum concentrations of the active agents and toxicity. Poor adherence is associated with worse health outcomes. The prescribed number of dose units of medication daily is an important factor in influencing adherence, with an increasing number of doses associated with poorer adherence.

Extended release formulations generally control the rate of drug absorption, so as to avoid excessive drug absorption while maintaining effective blood concentration of the drug to provide a patient with a consistent therapeutic effect over the extended time. Besides reducing the frequency of dosing and providing a more consistent therapeutic effect, extended released dosage forms generally help reduce side effects caused by a drug and enhance the patient's compliance.
Extended release formulations of riociguat can provide patients stable plasma levels, improved predictability of absorption and reduced inter-individual variability, smooth and stable plasma levels compared to immediate release formulations, improved tolerability for long term administration, improved safety profile, improved long term adherence to therapy and better patient compliance resulting into reduction in adverse events. The pill burden of taking 0.5- 1mg tablet three times a day can be reduced by taking extended release formulation and hence has the potential to increase adherence in the patients.

Thus, extended release dosage form of riociguat or pharmaceutically acceptable salts thereof are needed that would enable better patient compliance and offer advantages over conventional immediate release formulations. Extended release formulations would also lessen or prevent potentially undesirable effects by reducing peak blood levels (Cmax) and' increase drug efficacy (Cmin) by maintaining desired therapeutic plasma concentrations for longer period.

Need therefore exists to provide oral extended release formulations of riociguat that would enable better patient compliance by reducing the number of dosage, providing increased adherence with regimen and still is bioavailable during an extended period of long hours from its administration effectively optimizing the desired pharmacologic action of riociguat and can be produced by simple manufacturing techniques.

OBJECT OF INVENTION:
An object of the present invention is to provide an extended release pharmaceutical formulation comprising riociguat, at least one release controlling agent and optionally pharmaceutically acceptable excipients capable of advantageous therapeutic actions.

Yet another object of the present invention is to provide an extended release pharmaceutical formulation comprising riociguat, at least one release controlling agent and optionally pharmaceutically acceptable excipients and release active for a longer period of time.

Another object of the present invention is to provide a process for manufacturing a pharmaceutical composition in extended release formulation comprising riociguat, at least one release controlling agent and optionally pharmaceutically acceptable excipients in such a way as to make the drug bioavailable during a prolonged period of time of at least 12 hours from its administration. Thus, the pharmacologic action of riociguat is optimized.

Another object of the present invention is to provide a method for treatment of chronic thromboembolic hypertension (CTEPH) and pulmonary arterial hypertension (PAH). comprising riociguat, at least one release controlling agent and optionally pharmaceutically acceptable excipients.

SUMMARY OF INVENTION:
An aspect of the present invention is to provide an extended release pharmaceutical formulation comprising riociguat, at least one release controlling agent and optionally pharmaceutically acceptable excipients capable of advantageous therapeutic actions.

Yet another aspect of the present invention is to provide an extended release pharmaceutical formulation comprising riociguat, at least one release controlling agent and optionally pharmaceutically acceptable excipients and release active for a longer period of time.

Another aspect of the present invention is to provide a process for manufacturing a pharmaceutical composition in extended release formulation comprising riociguat, at least one release controlling agent and optionally pharmaceutically acceptable excipients in such a way as to make the drug bioavailable during a prolonged period of time of at least 12 hours from its administration. Thus, the pharmacologic action of riociguat is optimized.

Another aspect of the present invention is to provide a method for treatment of chronic thromboembolic hypertension (CTEPH) and pulmonary arterial hypertension (PAH). comprising riociguat, at least one release controlling agent and optionally pharmaceutically acceptable excipients.

DETAILED DESCRIPTION OF INVENTION:
The inventors have now developed a new extended release formulation comprising riociguat or its pharmaceutically acceptable salts or derivatives thereof and pharmaceutically acceptable excipients to enable the patient compliance and simultaneously providing equivalent product as compared to immediate release conventional formulation.

The present inventors provide extended release formulations of riociguat that not only release the active agent continuously in a predetermined manner and lessen the frequency of dosing but also reduce peak-trough fluctuations thereby maintaining desired therapeutic concentrations for longer duration of time and minimizing side effects otherwise associated immediate release tablets. The formulations of the present invention are stable, easy or convenient to prepare, and provide the desired in vitro release and bioavailability.

The term "composition" or "formulation" or "dosage form" has been employed interchangeably for the purpose of the present invention and mean that it is a pharmaceutical composition which is suitable for administration to a patient or subject.

The subject can be an animal, preferably a mammal, more preferably a human. For the purpose of the present invention terms "controlled release" or "sustained release" or
"extended release" or "prolonged release" have been used interchangeably and mean broadly that riociguat is released at a predetermined rate that is slower than the immediate release formulation.

AUC, as used herein, refers to the area under the curve that represents changes in blood concentrations of riociguat over time.

Cmax, as used herein, refers to the maximum value of blood concentration shown on the curve that represents changes in blood concentrations of riociguat over time.

Tmax, as used herein, refers to the time that it takes for riociguat blood concentration to reach the maximum value.

T1/2, as used in this disclosure, refers to the time that it takes for riociguat blood concentration to decline to one-half of the maximum level.

Collectively AUC, Cmax, Tmax, and T1/2 are the principle pharmacokinetic parameters that characterize the pharmacokinetic responses of a particular drug product such as riociguat in an animal or human subject.

The term riociguat as employed herein refers is used in broad sense to include not only “riociguat free base” per se but also its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable esters, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable complexes etc.

The term "salt" as used herein, refers to salts derived from inorganic or organic acids.
Examples of suitable salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, carbonates, bicarbonates, hydrobromide, hydrolodide, 2-hydroxy-ethanesulfonate, lactate, maleate, mandelate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 2-phenylpropionate, picrate, pivalate, propionate, salicylate, succinate, sulfate, nitrates, tartrate, sulfonates, thiocyanate, tosylate, mesylate, and undecanoate.

Pharmaceutically effective amount of riociguat is employed in the composition of the present invention. The term "effective amount" refers to an amount effective to achieve desired preventive, therapeutic and/or beneficial effect. In one embodiment the amount of riociguat in the composition can vary from about 0.01 weight % to about 90 weight %, based on the total weight of the composition. In another embodiment the amount of riociguat in the composition can vary from about 0.02 weight % to about 85 weight %, based on the total weight of the composition. In still another embodiment, the amount of riociguat in the composition can vary from about 0.05 weight % to about 80 weight %, based on the total weight of the composition, most preferably from about 0.5% to about 20% weight based on the total weight of composition. In one embodiment the compositions of the present invention may be administered at a dose of about 0.25 mg to about 10 mg of riociguat once – thrice in a day, more preferably, 1.5 mg to 7.5 mg dose of composition administered once a day.

In one embodiment, the riociguat employed for present invention is in the form of free acid or free base or pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts, pharmaceutically acceptable salts of prodrugs, active metabolites, polymorphs, solvates, hydrates, enantiomers, optical isomers, tautomers or racemic mixtures thereof.
The extended release compositions of the present invention comprise along with riociguat comprises of at least one release controlling agent. The term "release controlling agent" as used herein means any excipient that can retard the release of active agent and includes, but is not limited to, polymeric release controlling agent, nonpolymeric release controlling agent or combinations thereof.

Suitable polymeric release controlling agent may be employed in the compositions of the present invention. In an embodiment, the polymeric release controlling agent employed in the compositions of the present invention may be swelling or non-swelling. In a further embodiment, polymeric release controlling agents that may be employed in the compositions of the present invention include, but are not limited to, cellulose derivatives, saccharides or polysaccharides, poly(oxyethylene)-poly(oxypropylene) block copolymers (poloxamers), vinyl derivatives or polymers or copolymers thereof, polyalkylene oxides and derivatives thereof, maleic copolymers, acrylic acid derivatives or the like or any combinations thereof.

Cellulose derivatives include, but are not limited to, ethyl cellulose, methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl ethylcellulose, carboxymethylethyl cellulose, carboxy ethylcellulose, carboxymethyl hydroxyethylcellulose, hydroxyethylmethyl carboxymethyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose, methylhydroxyethyl cellulose, methylhydroxypropyl cellulose, carboxymethyl sulfoethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethyl ethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose acetate trimelliate, cellulose benzoate phthalate, cellulose propionate phthalate, methylcellulose phthalate, ethylhydroxy ethylcellulose phthalate, or combinations thereof.
Saccharides or polysaccharides include, but are not limited to, guar gum, xanthan gum, gum arabic, tragacanth or combinations thereof. Vinyl derivatives, polymers and copolymers thereof include, but are not limited to, polyvinylacetate aqueous dispersion (Kollicoat® SR 30D , copolymers of vinyl pyrrolidone, copolymers of polyvinyl alcohol, mixture of polyvinyl acetate and polyvinylpyrrolidone (e.g. Kollidon® SR), polyvinyl alcohol phthalate, polyvinylacetal phthalate, polyvinyl butylate phthalate, polyvinylacetoacetal phthalate, polyvinylpyrrolidone (PVP), or combinations thereof. Acrylic acid derivatives include, but are not limited to, methacrylic acids, poiymethacrylic acids, polyacrylates, especially polymethacrylates like a) copolymer formed from monomers selected from methacrylic acid, methacrylic acid esters, acrylic acid and acrylic acid esters b) copolymer formed from monomers selected from butyl methacrylate, (2-dimethylaminoethyl)methacrylate and methyl methacrylate c) copolymer formed from monomers selected from ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride or d) copolymers of acrylate and methacrylates with/without quarternary ammonium group in combination with sodium carboxymethylcellulose, e.g. those available from Rohm GmbH under the trademark Eudragit ® like Eudragit EPO (dimethylaminoethyl methacrylate copolymer; basic butylated methacrylate copolymer), Eudragit RL and RS (trimethylammonioethyl methacrylate copolymer), Eudragit NE30D and Eudragit NE40D (ethylacrylate methymethacrylate copolymer), Eudragit® L 100 and Eudragit® S (methacrylic acid'methyl methacrylate copolymer), Eudragit® L 100-55 (methacrylic acid'ethyl acrylate copolymer), Eudragit RD 100 (ammoniomethacrylate copolymer with sodium carboxymethylcellulose); or the like or any combinations thereof. Maleic copolymer based polymeric release controlling agent includes, but is not limited to, vinylacetate maleic acid anhydride copolymer, styrene maleic acid anhydride copolymer, styrene maleic acid monoester copolymer, vinylmethylether maleic acid anhydride copolymer, ethylene maleic acid anhydride copolymer, vinylbutylether maleic acid anhydride copolymer, acrylonitrile methyl acrylate maleic acid anhydride copolymer, butyl acrylate styrene maleic acid anhydride copolymer and the like, or combinations thereof. In one embodiment, polymers with low viscosity are employed in the compositions of the present invention as release controlling agent such as, but not limited to, Methocel K4M, and the like or combinations.

The release controlling agents may be also selected from polyethylene oxides , carbopols and the like. Examples of such substances which can act as release controlling agents are polyethylene oxide, such as POLYOX® WSR 303 (viscosity-average molecular weight: 7,000,000, viscosity: 7,500 to 10,000 cps (aqueous 1% solution at 25°C)), POLYOX® WSR Coagulant (viscosity-average molecular weight: 5,000,000, viscosity: 5,500 to 7,500 cps (aqueous 1% solution at 25°C)), POLYOX® WSR- 301 (viscosity-average molecular weight of 4,000,000, viscosity: 1650-5500 cps (aqueous 1% solution at 25°C)), POLYOX® WSR N-60K (viscosity-average molecular weight: 2,000,000, viscosity: 2,000 to 4,000 cps (2% aqueous solution at 25°C) (all made by Union Carbide), ALKOX® E-75 (viscosity-average molecular weight: 2,000,000 to 2,500,000, viscosity: 40 to 70 cps (aqueous 0.5% solution at 25°C)), ALKOX® E-100 (viscosity-average molecular weight of 2,500,000 to 3,000,000, viscosity: 90 to 110 cps (aqueous 0.5% solution at 25°C)), ALKOX® E-130 (viscosity-average molecular weight: 3,000,000 to 3,500,000, viscosity: 130 to 140 cps (aqueous 0.5% solution at 25°C)), ALKOX® E-160 (viscosity-average molecular weight: 3,600,000 to 4,000,000, viscosity: 150 to 160 cps (aqueous 0.5% solution at 25°C)), ALKOX® E-240 (viscosity-average molecular weight: 4,000,000 to 5,000,000, viscosity: 200 to 240 cps (aqueous 0.5% solution at 25°C)) (all made by Meisei Kagaku Co., Ltd.), PEO-8 (viscosity-average molecular weight: 1,700,000 to 2,200,000, viscosity: 20 to 70 cps (aqueous 0.5% solution at 25°C)), PEO-15 (viscosity-average molecular weight: 3,300,000 to 3,800,000, viscosity: 130 to 250 cps (aqueous 0.5% solution at 25°C)), PEO-18 (viscosity- average molecular weight: 4,300,000 to 4,800,000, viscosity: 250 to 480 cps (aqueous 0.5% solution at 25°C)) (all made by Seitetsu Kagaku Kogyo Co., Ltd.), etc. Preferably, polyethylene oxide derivatives of desired molecular weight and grade when act as release controlling agents ae included at an amount from about 20% to about 80% of total weight of formulation, preferably from about 30% to about 70% of total weight of formulation, most preferably from about 40% to about 60% of total weight of formulation.

Further, release controlling agents of such as Polyethylene oxide derivatives, carbopols may play role as swelling agents. The polyethylene oxides swell in size and in combination with other polymeric release controlling agent such as cellulose derivatives aid in extended release of drug in gastrointestinal tract. When the dosage form swell, it remains in the tract for longer time while the drug is released at controlled rate. Such release controlling agents which may also act as swelling agent are included in the dosage form in such an optimum quantity which should not lead to burst of dosage form leading to rapid drug release and showing burst effect. Thus, choosing optimum amount of particular grade of swelling agent which in combination with release controlling agent provide desired release of drug for prolonged time.

Preferably, polyethylene oxide of desired molecular weight and grade as swelling agents when act in combination of cellulose derivatives are incorporated at an amount of from about 5% to about 75% by total weight of formulation. Most preferably, polyethylene oxide of desired molecular weight and grade in combination with cellulose derivatives are incorporated at an amount of from about 10% to about 60% by total weight of formulation.

The term "non-polymeric release controlling agent" as used herein refers to any excipient that can retard the release of an active agent and that does not comprise of repeating units of monomers. Suitable non-polymeric release controlling agents employed in the present invention include, but are not limited to, fatty acids, long chain alcohols, fats and oils, waxes, phospholipids, eicosonoids, terpenes, steroids, resins and the like or combinations thereof. Fatty acids are carboxylic acids derived from or contained in an animal or vegetable fat or oil. Fatty acids are composed of a chain of alkyl groups containing from 4 to 22 carbon atoms and are characterized by a terminal carboxyl group. Fatty acids that may be employed in the present invention include, but are not limited to, hydrogenated palm kernel oil, hydrogenated peanut oil, hydrogenated palm oil, hydrogenated rapeseed oil, hydrogenated rice bran oil, hydrogenated soybean oil, hydrogenated sunflower oil, hydrogenated castor oil, hydrogenated cottonseed oil, and the like, and mixtures thereof. Other fatty acids include, but are not limited to, decenoic acid, docosanoic acid, stearic acid, palmitic acid, lauric acid, myristic acid, and the like, and mixtures thereof. In one embodiment, the fatty acids employed include, but are not limited to, hydrogenated palm oil, hydrogenated castor oil, stearic acid, hydrogenated cottonseed oil, palmitic acid, and mixtures thereof. Suitable long chain monohydric alcohols include, but are not limited to, cetyl alcohol, stearyl alcohol or mixtures thereof.

Waxes are esters of fatty acids with long chain monohydric alcohols. Natural waxes are often mixtures of such esters, and may also contain hydrocarbons. Waxes are low melting organic mixtures or compounds having a high molecular weight and are solid at room temperature. Waxes may be hydrocarbons or esters of fatty acids and alcohols.

Waxes that may be employed in the present invention include, but are not limited to, natural waxes, such as animal waxes, vegetable waxes, and petroleum waxes (i.e., paraffin waxes, microcrystalline waxes, petrolatum waxes, mineral waxes), and synthetic waxes. Specific examples include, but are not limited to, spermaceti wax, carnauba wax, Japan wax, bayberry wax, flax wax, beeswax, Chinese wax, shellac wax, lanolin wax, sugarcane wax, candelilla wax, paraffin wax, microcrystalline wax, petrolatum wax, carbowax, and the like, or mixtures thereof. Mixtures of these waxes with the fatty acids may also be used. Waxes are also monoglyceryl esters, diglyceryl esters, or triglyceryl esters (glycerides) and derivatives thereof formed from a fatty acid having from about 10 to about 22 carbon atoms and glycerol, wherein one or more of the hydroxy! groups of glycerol is substituted by a fatty acid. Glycerides that may be employed in the present invention include, but are not limited to, glyceryl monostearate, glyceryl distearate, glyceryl tristearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monopalmitate, glyceryl dilaurate, glyceryl trilaurate, glyceryl monolaurate, glyceryl didocosanoate, glyceryl tridocosanoate, glyceryl monodocosanoate, glyceryl monocaproate, glyceryl dicaproate, glyceryl tricaproate, glyceryl monomyristate, glyceryl dimyristate, glyceryl trimyristate, glyceryl monodecenoate, glyceryl didecenoate, glyceryl tridecenoate, glyceryl behenate, polyglyceryl diisostearate, lauroyl macrogolglycerides, oleyl macrogolglycerides, stearoyl macrogolglycerides, and the like, or mixtures thereof.

Resins employed in the compositions of the present invention include, but are not limited to, shellac and the like or any combinations thereof. In one embodiment the non-polymeric release controlling agent employed includes, but is not limited to, Cutina® (Hydrogenated castor oil), Hydrobase® (Hydrogenated soybean oil), Castorwax® (Hydrogenated castor oil, Croduret® (Hydrogenated castor oil), Carbowax®, Compritol® (Glyceryl behenate), Sterotex® (Hydrogenated cottonseed oil), Lubritab® (Hydrogenated cottonseed oil), Apifil® (Wax yellow), Akofine® (Hydrogenated cottonseed oil), Softisan® (Hydrogenated palm oil), Hydrocote® (Hydrogenated soybean oil), Corona® (Lanolin), Gelucire® (Macrogolglycerides Lauriques), Precirol® (Glyceryl Palmitostearate), Emulcire™ (Cetyl alcohol), Plurol® diisostearique (Polyglyceryl Diisostearate), Geleol® (Glyceryl Stearate), and mixtures thereof.

In preferred embodiment, the formulation of present invention is a polymeric rate controlling agent.

The amount of release controlling agent used in the sustained release formulations of the present invention may vary depending upon the degree of controlled or sustained release desired. In an embodiment, release controlling agent is present in the composition in an amount from about 10% to about 90% by weight of the dosage form. In another embodiment, release controlling agent is present in the formulation in an amount from about 20% to about 80% by weight of the dosage form.

In one embodiment, riociguat is in the form of, but not limited to, powder, granules, pellets, beads, minitablets or the like is treated with at least one release controlling agent. In a further embodiment the active agent may be in micronized form. The active ingredient may be treated by any of the techniques known in the art such as,but not limited to, melt granulation, hot melt extrusion, fluid bed coating, wet granulation, spray drying, extrusion-spheronization, dry granulation or roll compaction. In an embodiment, riociguat is blended or physically mixed with release controlling agent.

In addition to the above discussed excipients, the controlled release compositions of the present invention comprises at least one pharmaceutically acceptable excipients, such as, but not limited to lubricants, diluents, disintegrants, glidants, stabilizers, preservatives, colorants and the like or combinations thereof.

Examples of suitable diluents include, but are not limited to, starch, dicalcium phosphate, lactose monohydrate, dextrate hydrated calcium carbonate, calcium phosphate, tribasic calcium sulfate and polyvinylpyrrolidone and so on dextrin derivatives, dextrin, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrins, maltose, sorbitol, starch, sucrose, sugar, and xylitol, microcrystalline cellulose and the like. Most preferably, lactose monohydrate and microcrystalline cellulose are used as diluent at an amount of from about 10% to about 30% by weight of the dosage form. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, talc, and sodium stearyl fumarate. Most preferably, magnesium stearate is used as lubricant is present at an amount of from about 0.25 % to about 15% by weight of the formulation.

Compositions of the present invention may also include a glidant such as, but not limited to, colloidal silica, silica gel, precipitated silica, or combinations thereof. Most preferably, colloidal silica is used as lubricant is present at an amount of from about 0.5% to about 15% by weight of the dosage form. Suitable disintegrants may optionally be employed in the compositions of the present invention include croscarmellose sodium, crospovidone, sodium starch glycolate, starch or combinations thereof.

The formulation of present invention comprising riociguat, at least one release controlling agent and optionally pharmaceutically acceptable excipient is in the form of tablet. In another embodiment according to the invention, the extended release formulation may be optionally coated. Surface coatings may be employed for aesthetic purposes or for dimensionally stabilizing the dosage form or functional coating. The coating may be carried out using any conventional technique employing conventional ingredient. A surface coating can, for example, be obtained using a quick-dissolving film using conventional polymers such as, but not limited to, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, ethyl cellulose, polyvinyl alcohol, poly methacrylates or the like or combinations thereof. Tablets of the present invention may vary in shape including, but not limited to, oval, triangle, almond, peanut, parallelogram, pentagonal. It is contemplated within the scope of the invention that the dosage form can be encapsulated. Tablets in accordance with the present invention may be manufactured using conventional techniques of common tableting methods known in the art such as direct compression, dry granulation, wet granulation and extrusion/ melt granulation.

The present invention also provides a method of treating chronic thromboembolic hypertension (CTEPH) and pulmonary arterial hypertension (PAH) which method comprises administration of a therapeutically effective amount of a pharmaceutical composition according to the present invention.

The present invention also provides a use of the pharmaceutical composition in the manufacture of a medicament for the treatment of chronic thromboembolic hypertension (CTEPH) and pulmonary arterial hypertension (PAH).

The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.

Example 1: Preparation of Riociguat extended release formulation by direct compression method

Table 1: composition of riociguat ER tablet
Sr. No. Ingredient Mg/tab
1 Riociguat 7.50
2 Lactose monohydrate 30.00
3 Microcrystalline cellulose 70.25
4 Hydroxypropyl methylcellulose 70.00
5 Colloidal silicon dioxide 0.75
6 Magnesium stearate 1.50
Total weight of tablet 160.00

Manufacturing process: All the material were sifted through selected sieve.
Blended the drug with intra-granular material using octagonal blender.
Lubricated the blend using magnesium stearate and compressed the lubricated blend into tablets using compression machine.

Dissolution profile: the results of dissolution profile of above formulation is presented in table 2:
Table 2
Time (hrs) Drug released (%)
2 5
4 16
8 44
10 58
12 70
16 87
20 91
24 93

Example 2: Preparation of Riociguat extended release formulation by dry granulation method
Table 3
Sr. No. Ingredient Mg/tab
1 Riociguat 7.50
2 Lactose monohydrate 30.00
3 Microcrystalline cellulose 50.25
4 Polyethylene oxide 85.00
5 Colloidal silicon dioxide 0.75
6 Magnesium stearate 1.50
Total weight of tablet 175.00

Manufacturing process:
All the materials were sifted through selected sieve. The intra-granular material was dry granulated using Roller compactor to form uniform ribbons. The above ribbons were milled through suitable screen attached to integrated mill to obtain uniform sized granules. The sized granules were blended with extra-granular material using octagonal blender. Lubricated the above blend using Magnesium stearate. Compressed the lubricated blend into tablets using compression machine.

Dissolution profile: the results of dissolution profile of above formulation is presented in table 4:
Table 4
Time (hrs) Drug released (%)
2 3
4 8
8 22
10 30
12 38
16 53
20 69
24 89

Example 3: Preparation of Riociguat extended release formulation by Direct Compression
Table 5
Sr. No. Ingredient Mg/tab
1 Riociguat 7.50
2 Lactose monohydrate 20.00
3 Microcrystalline cellulose 60.25
4 Polyethylene oxide 75.00
5 Colloidal silicon dioxide 0.75
6 Magnesium stearate 1.50
Total weight of tablet 165.00

Manufacturing process: All the materials were sifted through selected sieve. Blended the drug with intra-granular material using octagonal blender. Lubricated the above blend using Magnesium stearate. Compressed the above lubricated blend into tablets using compression machine.

Dissolution profile: the results of dissolution profile of above formulation is presented in table 6:
Table 6
Time (hrs) Drug released (%)
2 11
4 30
8 66
10 85
12 95
16 96
20 94
24 95

Example 4: Preparation of Riociguat extended release formulation by dry granulation

Table 7
Sr. No. Ingredient Mg/tab
1 Riociguat 7.50
2 Lactose monohydrate 40.00
3 Microcrystalline cellulose 40.25
4 Hydroxypropyl methylcellulose 95.00
5 Colloidal silicon dioxide 0.75
6 Magnesium stearate 1.50
Total weight of tablet 185.00

Manufacturing process:
All the materials were sifted through selected sieve. The intra-granular material was dry granulated using Roller compactor to form uniform ribbons. The ribbons were milled through suitable screen attached to integrated mill to obtain uniform sized granules. The sized granules were blended with extra-granular material using octagonal blender. The blend using was lubricated with Magnesium stearate. Compressed the lubricated blend into tablets using compression machine.

Example 5: Preparation of Riociguat extended release formulation by wet granulation
Table 8
Sr. No. Ingredient Mg/tab
1 Riociguat 7.50
2 Lactose monohydrate 35.00
3 Microcrystalline cellulose 45.25
4 Hydroxypropyl methylcellulose 75.00
5 Polyethylene oxide 25.00
6 Colloidal silicon dioxide 0.75
7 Magnesium stearate 1.50
Total weight of tablet 190.00

Manufacturing process:
All the material was sifted through selected sieve. The intra-granular material was granule using Rapid mixer Granulation. The granules were dried in Fluidized Bed Processor and the dried granules were milled through suitable screen. The dried granules were blended with extra-granular material using octagonal blender. The above blend was lubricated using Magnesium stearate. The above lubricated blend was compressed into tablets using compression machine.

Example 6: Preparation of Riociguat extended release formulation Hot melt Granulation
Table 9
Sr. No. Ingredient Mg/tab
1 Riociguat 7.50
2 Microcrystalline cellulose 50.25
3 Hydroxypropyl methylcellulose 75.00
4 Polyethylene oxide 25.00
5 Colloidal silicon dioxide 0.75
6 Magnesium stearate 1.50
Total weight of tablet 160.00

Manufacturing process:
All the material was sifted through selected sieve. The drug and polymer were granulated using Hot Melt Extruder to form granules. The above granules were dried and milled through suitable screen to get uniform sized granules. The sized granules were blended with extra-granular material using octagonal blender. The blend was lubricated using Magnesium stearate. The above lubricated blend was compressed into tablets using compression machine.

Example 7: Preparation of Riociguat extended release Matrix tablet with functional coat
Table 10
Sr. No. Ingredient Mg/tab
1 Riociguat 7.50
2 Lactose monohydrate 10.00
3 Microcrystalline cellulose 40.25
4 Hydroxypropyl methylcellulose 75.00
5 Ethylcellulose 37.00
6 Hydroxypropyl cellulose 5.00
7 Polyethylene glycol 3.00
8 Colloidal silicon dioxide 0.75
9 Magnesium stearate 1.50
Total weight of tablet 180.00

Manufacturing process:
All the material was sifted through selected sieve. The drug was blended with intra-granular material using octagonal blender. The above blend was lubricated using Magnesium stearate. The above lubricated blend was compressed into tablets using compression machine. The above tablets were coated using polymer solution to get coated tablets.

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.

It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of “including,” “comprising,” or “having” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to a "cosolvent" refers to a single cosolvent or to combinations of two or more cosolvents, and the like.
,CLAIMS:
1. An extended release pharmaceutical formulation comprising riociguat or its pharmaceutically acceptable salt thereof, at least one release controlling agent and pharmaceutically acceptable excipients thereof.

2. The formulation as claimed in claim 1 wherein riociguat or its therapeutically acceptable excipient is present in an amount from about 0.5% to about 20% by total weight of the formulation.

3. The formulations of claim 1 wherein the release controlling agent is selected from cellulose derivatives, saccharides, cellulose derivatives, saccharides or polysaccharides, poly(oxyethylene)-poly(oxypropylene) block copolymers (poloxamers), vinyl derivatives or polymers or copolymers thereof, polyalkylene oxides and derivatives thereof, maleic copolymers, acrylic acid derivatives and combinations thereof.

4. The formulation as claimed in claim 1, wherein the release controlling agents are selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl ethylcellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose, methylhydroxyethyl cellulose, methylhydroxypropyl cellulose, carboxymethyl sulfoethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropylmethylcellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, hydroxymethyl ethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose acetate trimelliate, cellulose benzoate phthalate, cellulose propionate phthalate, methylcellulose phthalate, ethylhydroxy ethylcellulose phthalate , polyethylene oxide , Carbopol and combination thereof.

5. The formulation as claimed in claim 1, wherein the release controlling agent is present at an amount of from about 20% to 80% by weight of the formulation.

6. The formulation as claimed in claim 1, wherein the formulation comprises of swelling agent in combination with release controlling agent.

7. The formulation as claimed in claim 1, wherein the pharmaceutically acceptable excipients are selected from lubricants, diluents, disintegrants, glidants, stabilizers, preservatives, colorants and combinations thereof.

8. The formulation as claimed in claim 8, wherein the diluents selected from lactose monohydrate, dextrate hydrated calcium carbonate, calcium phosphate, tribasic calcium sulfate, polyvinylpyrrolidone , dextrin derivatives, magnesium carbonate, magnesium oxide, and the combination thereof are present in an amount of from about 10% to about 30% by weight of the formulation.

9. The formulation as claimed in claim 8, wherein the glidants selected from colloidal silica, silica gel, precipitated silica and combinations thereof are present at an amount of from about 0.5% to about 15% by weight of the formulation.

10. The formulation as claimed in claim 8, wherein the disintegrants selected from croscarmellose sodium, crospovidone, sodium starch glycolate, starch and combinations thereof is present in amount of about 0.5% to about 15% by weight of the formulation.

11. The formulation as claimed in claim 8, wherein the lubricants selected from magnesium stearate, calcium stearate, stearic acid, talc, sodium stearyl fumarate and the combinations thereof present in amount from about 0.5% to about 15% by weight of the formulation.

12. The extended release formulation of claim 1 is in the form of a tablet.

13. An extended release pharmaceutical formulation comprising
a) riociguat or its pharmaceutically acceptable salt thereof present in an amount from about 1% to about 20% by total weight of formulation;
b) release controlling agent selected from hydroxypropyl methylcellulose, ethyl cellulose, or combination thereof present in an amount from about 20% to about 80% by total weight of formulation;
c) lactose monohydrate, microcrystalline cellulose and combination thereof present in amount from about 10% to about 30% by weight of total formulation
d) silicon dioxide present in amount from about 1% to about 5% by total weight of formulation;
e) magnesium stearate present in amount from about from about 0.25% to about 15% by weight of the dosage form.
f) optionally, swelling agent selected from polyethylene oxide derivatives , carbopol derivatives present in an amount from about 5% to about 50% by total weight of formulation.

14. The formulation as claimed in claim 1 wherein the formulation is prepared by direct compression method, dry granulation method, wet granulation method, hot melt granulation method, or the combination thereof.

15. The formulation as claimed in claim 1, wherein the formulation is used for the treatment of chronic thromboembolic hypertension (CTEPH) and pulmonary arterial hypertension.