Claims:We claim:
1. A pharmaceutical solution composition comprising selexipag and its pharmaceutically acceptable salts thereof and a carrier.
2. The pharmaceutical solution composition according to claim 1, wherein the carrier is a mixture of one or more pharmaceutically acceptable excipient selected from the group comprising water, co-solvents, solvents, polymers, additives, antioxidants, microbial preservatives, buffering agents, aromatic agents, sweeteners, flavouring agent or diluents.
3. The pharmaceutical solution composition according to claim 1, wherein the said composition is solid, liquid or a mixture thereof.
4. The pharmaceutical solution composition according to claim 3, wherein the said composition is a solid.
5. The pharmaceutical solution composition according to claim 4, wherein the composition is dissolved in water to prepare liquid solution.
6. The pharmaceutical solution composition according to claim 3, wherein the said composition is a liquid.
7. The pharmaceutical solution composition according to claim 6, wherein the said composition comprises selexipag and its pharmaceutically acceptable salts thereof at a concentration between about 0.01 mg/ml to 10 mg/ml, preferably 0.01 mg/ml to 2 mg/ml, more preferably 0.05 mg/ml to 1 mg/ml of total the pharmaceutical solution.
8. The pharmaceutical solution composition according to claim 6, wherein the pH of the composition is between about 2 to about 9, preferably between about 5 to about 8, more preferably between about 6 to about 7.
9. The pharmaceutical solution composition according to claim 6, wherein the co-solvent is selected from the group propylene glycol, polyethylene alcohol, ethanol, glycerin, propylene glycol esters, glycofural, polyethylene glycol esters ethanol, and mixtures thereof.
10. The pharmaceutical solution composition according to claim 2, wherein the preservative is selected from the group consisting of cresols, phenol, benzyl alcohol, ethanol, chlorobutanol, parabens, imidura, benzalkonium chloride, EDTA or its salt, and a combination thereof. , Description:Selexipag Pharmaceutical Compositions

Technical field of the Invention
The present invention provides pharmaceutical solutions containing selexipag which advantageously avoid swallowing while providing with improved stability. The present invention also relates to methods of using the pharmaceutical solutions containing selexipag for treatment of diseases and disorders such as treat arteriosclerosis obliterans, pulmonary hypertension or Raynaud's disease secondary to systemic sclerosis.

Background of the invention
Orally administered drugs are provided to the patient in many dosage forms, including solid forms such as capsules, caplets or tablets and liquid forms such as solutions, syrups, emulsions or suspensions. Pharmaceutically active agents administered in solid dosage form like tablets and capsules are usually intended to be swallowed whole but many patients including children, older persons and many other persons including disabled or incapacitated patients often have trouble swallowing solid dosage form like tablets or capsules. Often a liquid oral dosage form is preferred over a solid dosage form because of the ease with which it can be swallowed. Additionally, patients may be more inclined to comply with their medication instruction if the dosages are easier to ingest.

Selexipag is an oral, selective, non-prostanoid prostacyclin receptor (IP receptor) agonist which leads to vasodilation of the pulmonary circulation. It is approved in various markets as oral tablets under the brand name UPTRAVI® and is indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH.

The IUPAC name of selexipag is 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}- N(methylsulfonyl) acetamide. Selexipag is represented by the structural Formula I:

Formula I
Selexipag and its salts are disclosed in US7205302B2. It also discloses method of treating pulmonary arterial hypertension. US8791122B2, US9284280B2, US9340516 B2, US9440931B2, WO2017040872A1, WO2016193994A1, WO2017042731A1, WO2017109772A1, WO2018015975A1, WO2018015974A1, WO2018022704A1, and WO2018078383A1 disclose various novel forms of Selexipag and their methods of preparation.

Selexipag is a pale yellow crystalline powder that is poorly soluble in water. It exhibits pH dependent solubility and solubility increases with increase in pH from pH 4.0. Due to the poor solubility of the drug substance, particle size control of the drug is considered the most critical parameter for bioavailability of the tablet and any other solid dosage form.

Selexipag is available as solid tablets in 8 different strengths i.e. 0.2 mg, 0.4 mg, 0.6 mg, 0.8 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg. However, a solid tablet form may be unsuitable for patients who have difficulty swallowing, such as children, elderly patients, stroke patients, many other persons including disabled or incapacitated patients and/or the like. In order to overcome this problem, it would be beneficial to provide a Selexipag containing composition as an oral solution which is palatable, as well as physically and chemically stable.

Summary of the Invention
Provided herein are selexipag solution formulations. In one aspect, the selexipag solution formulation comprises selexipag and its pharmaceutically acceptable salts thereof and a carrier.
In another aspect, selexipag solution formulation is a liquid or solid for reconstitution into liquid. In another aspect, selexipag solution formulation contains a carrier which is a mixture of one or more pharmaceutically acceptable excipient selected from the group comprising water, co-solvents, solvents, polymers, additives, antioxidants, microbial preservatives, buffering agents, aromatic agents, sweeteners, flavouring agent or diluents.

In another aspect, selexipag solution formulations have selexipag concentration between about 0.01 mg/ml to 10 mg/ml, preferably 0.01 mg/ml to 2 mg/ml, more preferably 0.05 mg/ml to 1 mg/ml of total the pharmaceutical solution.

In another aspect, selexipag solution formulations in form of liquid have pH between about 2 to about 9.0, preferably between about 5 to about 8, more preferably between about 6 to about 7.

In another aspect, selexipag solution formulations have co-solvents selected from the group of propylene glycol, polyethylene alcohol, ethanol, glycerin, propylene glycol esters, glycofural, polyethylene glycol esters ethanol, and mixtures thereof.

In another aspect, selexipag solution formulations have preservatives selected from the group consisting of cresols, phenol, benzyl alcohol, ethanol, chlorobutanol, parabens, imidura, benzalkonium chloride, EDTA or its salt, and a combination thereof.

In another aspect, the selexipag solution formulation comprises (i) selexipag or a pharmaceutically acceptable salt (ii) a co-solvent (iii) a sweetener (iii) a buffer (iv) a preservative and (v) water; wherein the pH of the formulation is between about 6 and about 7.

Detailed description of the invention
Provided herein are selexipag solution formulations. Also provided herein are selexipag solutions in form of solid solution in form of powder or granules formulations for reconstitution for oral liquid administration. Also provided herein are selexipag solutions in form of liquid.

These selexipag formulations described herein are useful for the treatment of treatment of arteriosclerosis obliterans, pulmonary hypertension and Raynaud's disease secondary to systemic sclerosis and related diseases. The formulations are advantageous over conventional solid dosage administration of selexipag ranging from ease of administration, accuracy of dosing, accessibility to additional patient populations such as to children and the elderly, and an increased patient compliance to medication.

It is generally known that certain segments of the population have difficulty ingesting and swallowing solid oral dosage forms such as tablets and capsules. As many as a quarter of the total population has this difficulty. Often, this leads to non-compliance with the recommended medical therapy with the solid dosage forms, thereby resulting in rending the therapy ineffective. Further, solid dosage forms are not recommended for children or elderly due to increased risk in choking.

Furthermore, selexipag is approved in various markets as oral tablets for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH. The recommended starting dose of selexipag is 0.2mg given twice daily. Increase the dose in increments of 0.2mg twice daily, usually at weekly intervals, to the highest tolerated dose up to 1.6mg twice daily. Patient has to swallow selexipag tablets whole without splitting, crushing or chewing. Tolerability may be improved when taken with food.

Current dosage Regimen suggest tittering dose of the therapy according to tolerance of the patient, weekly. Also dose adjustment is required in moderate to severe hepatic impairment. When the dose required is something other than the amount present in one or more intact solid dosage forms, the solid dosage form must be divided to provide the correct dose. This leads to inaccurate dosing when solid dosages forms, such as tablets, are compounded to prepare other formulations for children.
For selexipag, the current solution to overcoming the use of the tablet form is for a compounding pharmacist to pulverize and crush the selexipag tablet(s) into a powder via mortar and pestle and reconstitute the powder in some liquid form. However forming a selexipag oral liquid in this fashion has significant drawbacks including large variability in the actual dosage, incomplete solubilizing of the selexipag tablet in the liquid, rapid instability, inconsistent formulation methods per compounding pharmacy, and a number of other potential issues. The crushed tablet liquid formulation may also be potentially unsafe due to contamination with residual drugs and other substances from the mortar and pestle or other crushing agent.

The present embodiments provide a safe and effective oral administration of selexipag for the treatment of pulmonary hypertension and other disorders. In particular, the embodiments provide stable selexipag solution formulations as well as selexipag powder formulations for reconstitution for oral liquid administration.

As used herein, "selexipag" refers to selexipag base, its salt, or solvate or derivative or isomer or polymorph thereof. Suitable compounds include the free base, the organic and inorganic salts, isomers, isomer salts, solvates, polymorphs, complexes etc. In some embodiments, the selexipag used in the formulations described herein is a selexipag salt. In some instances, the selexipag used in the formulations described herein is a selexipag hydrate. In some instances, the selexipag used in the formulations described herein is selexipag monohydrate. In some instances, the selexipag used in the formulations described herein is selexipag dihydrate.

Oral liquids include, but are not limited to, solutions (both aqueous and nonaqueous), suspensions, emulsions, syrups, slurries, juices, elixirs, dispersions, and the like. It is envisioned that solution/suspensions are also included where certain components described herein are in a solution while other components are in a suspension.

In one aspect, the selexipag solution formulations described herein comprise selexipag and a carrier. The carrier is a mixture of one or more pharmaceutically acceptable excipient selected from the group comprising water, co-solvents, solvents, polymers, additives, antioxidants, microbial preservatives, buffering agents, aromatic agents, sweeteners, flavouring agent or diluents.

In some embodiments, selexipag is present in about 0.005 mg/ml to about 10 mg/ml in the liquid formulation. In other embodiments, selexipag is present in about 0.005 mg/ml, about 0.01 mg/ml, about 0.015 mg/ml, about 0.02 mg/ml, about 0.025 mg/ml, about 0.03 mg/ml, about 0.035 mg/ml, about 0.04 mg/ml, about 0.045 mg/ml, about 0.05 mg/ml, about 0.055 mg/ml, about 0.06 mg/ml, about 0.065 mg/ml, about 0.07 mg/ml, about 0.075 mg/ml, about 0.08 mg/ml, about 0.085 mg/ml, about 0.09 mg/ml, about 0.095 mg/ml, about 0.1 mg/ml, about 0.15 mg/ml, about 0.2 mg/ml, about 0.25 mg/ml, about 0.3 mg/ml, about 0.35 mg/ml, about 0.4 mg/ml, about 0.45 mg/ml, about 0.5 mg/ml, about 0.55 mg/ml, about 0.6 mg/ml, about 0.65 mg/ml, about 0.7 mg/ml, about 0.75 mg/ml, about 0.8 mg/ml, about 0.85 mg/ml, about 0.9 mg/ml, about 0.95 mg/ml, about 1.0 mg/ml, about 1.25 mg/ml, about 1.5, mg/ml, about 1.75 mg/ml, about 2.0 mg/ml, about 2.25 mg/ml, about 2.5 mg/ml, about 2.75 mg/ml, about 3.0 mg/ml, about 3.5 mg/ml, about 4.0 mg/ml, about 4.5 mg/ml, about 5.0 mg/ml, about 5.5 mg/ml, about 6.0 mg/ml, about 6.5 mg/ml, about 7.0 mg/ml, about 7.5 mg/ml, about 8.0 mg/ml, about 8.5 mg/ml, about 9.0 mg/ml, about 9.5 mg/ml, or about 10 mg/ml in the liquid formulation.

In some embodiments, selexipag is present in about 0.1% w/w to about 90% w/v of the total the pharmaceutical solid solution. In other embodiments, Selexipag is present in about 0.1% w/w, about 0.5% w/w, about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 15% w/w, about 20% w/w, about 25% w/w, about 30% w/w, about 35% w/w, about 40% w/w, about 45% w/w, about 50% w/w, about 60% w/w, about 70% w/w, about 80% w/w, or about 90% w/w of the total the pharmaceutical solid solution. In other embodiments, selexipag solid solution is in form of powder or granules formulations for reconstitution for oral liquid administration.

In some embodiments, selexipag is present about 0.005 mg/ml to about 10 mg/ml in reconstituted liquid prepared from powder or granules of selexipag solid solution. In other embodiments, selexipag is present in about 0.005 mg/ml, about 0.01 mg/ml, about 0.015 mg/ml, about 0.02 mg/ml, about 0.025 mg/ml, about 0.03 mg/ml, about 0.035 mg/ml, about 0.04 mg/ml, about 0.045 mg/ml, about 0.05 mg/ml, about 0.055 mg/ml, about 0.06 mg/ml, about 0.065 mg/ml, about 0.07 mg/ml, about 0.075 mg/ml, about 0.08 mg/ml, about 0.085 mg/ml, about 0.09 mg/ml, about 0.095 mg/ml, about 0.1 mg/ml, about 0.15 mg/ml, about 0.2 mg/ml, about 0.25 mg/ml, about 0.3 mg/ml, about 0.35 mg/ml, about 0.4 mg/ml, about 0.45 mg/ml, about 0.5 mg/ml, about 0.55 mg/ml, about 0.6 mg/ml, about 0.65 mg/ml, about 0.7 mg/ml, about 0.75 mg/ml, about 0.8 mg/ml, about 0.85 mg/ml, about 0.9 mg/ml, about 0.95 mg/ml, about 1.0 mg/ml, about 1.25 mg/ml, about 1.5, mg/ml, about 1.75 mg/ml, about 2.0 mg/ml, about 2.25 mg/ml, about 2.5 mg/ml, about 2.75 mg/ml, about 3.0 mg/ml, about 3.5 mg/ml, about 4.0 mg/ml, about 4.5 mg/ml, about 5.0 mg/ml, about 5.5 mg/ml, about 6.0 mg/ml, about 6.5 mg/ml, about 7.0 mg/ml, about 7.5 mg/ml, about 8.0 mg/ml, about 8.5 mg/ml, about 9.0 mg/ml, about 9.5 mg/ml, or about 10 mg/ml in reconstituted liquid prepared from powder or granules of selexipag solid solution.

In some embodiments, the selexipag solution formulation described herein comprises a solvent. A suitable solvent system comprises an acetone, methylenechloride, an alcohol or a mixture thereof. An alcohol is preferably ethanol which may be denatured, for example, with butanone. Other suitable alcohols include, but are not limited to, methanol, propanol (e.g., isopropyl alcohol), butanol such as tert-butyl, etc., including mixtures thereof. Any suitable acetone may be used to carry out the present invention, such as Pharmacopeial or USP grade acetone. Acetone and water may be used individually or combined as a solvent, and when combined may be used in any suitable ratio. In one embodiment, water alone without acetone is employed as the solvent. Other organic solvent systems encompass a wide variety of organic solvents (examples: tert butyl alcohol, ethanol, n-propanol, n-butanol, iso-propanol, ethyl acetate, acetone, methyl acetate, methanol, carbon tetrachloride, dimethylsulfoxide, chlorobutanol, cyclohexane, and acetic acid).
In some embodiments, the selexipag solution formulation described herein comprises a co-solvent. The term "co-solvent" relates to a substance that is miscible with water and gastrointestinal fluid and increases the solubility and dissolution rate of selexipag in aqueous solutions and gastrointestinal fluids. For example, the co-solvent may include one or more of propylene glycol, polyethylene alcohol, ethanol, glycerin, propylene glycol esters, glycofural, polyethylene glycol esters ethanol, and mixtures thereof. The concentration of co-solvent may be between 1% to 10% w/w of the total weight of the composition.

In some embodiments, the selexipag solution formulation described herein comprises a sweetening agent. Sweeteners or sweetening agents include any compounds that provide a sweet taste. This includes natural and synthetic sugars, natural and artificial sweeteners, natural extracts and any material that initiates a sweet sensation in a subject. In some embodiments, a solid/powder sweetener is used in the solution formulation described herein. In other embodiments, a liquid sweetener is used in the solution formulation described herein.

Sugars illustratively include glucose, fructose, sucrose, xylitol, tagatose, sucralose, maltitol, isomaltulose, hydrogenated isomaltulose, lactitol, sorbitol, erythritol, trehalose, maltodextrin, polydextrose, and the like. Other sweeteners illustratively include glycerin, inulin, erythritol, maltol, acesulfame and salts thereof, e.g., acesulfame potassium, alitame, aspartame, neotame, sodium cyclamate, saccharin and salts thereof, e.g., saccharin sodium or saccharin calcium, neohesperidin dihydrochalcone, stevioside, thaumatin, and the like. Sweeteners can be used in the form of crude or refined products. Sweeteners can be used singly or in combinations of two or more. Suitable concentrations of different sweeteners can be selected based on published information, manufacturers' data sheets and by routine testing.

In some embodiments, the sweetening agent is sucralose. In some embodiments, sucralose is present in about 0.5 mg/ml to about 3 mg/ml in the liquid formulation. In some embodiments, the sweetening agent is xylitol. In some embodiments, xylitol is present in about 50 mg/ml to about 250 mg/ml in the solution formulation. In some embodiments, the sweetener is saccharin. In some embodiments, saccharin is present in about 1 mg/ml to about 3 mg/ml in the solution formulation. In some embodiments, the sweetening agent is sorbitol. In some embodiments, sorbitol is present in about 50 mg/ml to about 250 mg/ml in the solution formulation.

In some embodiments, the selexipag solution formulation described herein comprises a preservative. Preservatives include anti-microbials, anti-oxidants, and agents that enhance sterility. Exemplary preservatives include ascorbic acid, ascorbyl palmitate, tocopherols, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), citric acid, erythorbic acid, fumaric acid, malic acid, propyl gallate, tertiary butylhydroquinone, sodium ascorbate, sodium bisulfate, sodium metabisulfite, sodium sulfite, parabens (such as methylparaben, ethylparaben, propylparaben, butylparaben and their salts), benzoic acid, sodium benzoate, potassium sorbate, vanillin, and the like.

In some embodiments, the preservative is a paraben. In some embodiments, the paraben or mixture of parabens is present in about 0.1 mg/ml to about 2 mg/ml in the solution formulation. In some embodiments, a paraben is present in about 0.01% w/w to about 5% w/w of the solid solution formulation. In some embodiments, the preservative is sodium benzoate. In some embodiments, sodium benzoate is present in about 0.5 mg/ml to about 1.2 mg/ml in the liquid solution formulation. In some embodiments, sodium benzoate is present in about 0.01% w/w to about 5% w/w of the solid solution formulation. In some embodiments, the preservative is ascorbic acid. In some embodiments, the ascorbic acid is present in about 0.1 mg/ml to about 2 mg/ml in the solution formulation.

In some embodiments, the selexipag solution formulation described herein does not comprise a preservative. In further embodiments, the selexipag solution described herein does not comprise a paraben preservative. In further embodiments, the selexipag solution described herein does not comprise a paraben preservative when the formulation also comprises a sugar or sugar alcohol.
In some embodiments, the pH of the selexipag liquid solution formulation or liquid prepared by reconstitution of solid solution described herein is between about 2.0 to about 9.0. In some embodiments, the pH of the selexipag liquid solution formulation or liquid prepared by reconstitution of solid solution described herein is between about 2.0 to about 9.0. In some embodiments, the pH of the selexipag liquid solution formulation or liquid prepared by reconstitution of solid solution described herein is between about 4 and about 8. In some embodiments, the pH of the selexipag liquid solution formulation or liquid prepared by reconstitution of solid solution described herein is about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8.0, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5, about 8.6, about 8.7, about 8.8, about 8.9 or about 9.0.

In some embodiments, the selexipag solution formulation described herein comprises a buffer. Buffering agents maintain the pH of the selexipag solution formulation described herein. Non-limiting examples of buffering agents include, but are not limited to sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium glucomate, aluminium hydroxide, aluminium hydroxide/sodium bicarbonate co-precipitate, mixture of an amino acid and a buffer, a mixture of aluminium glycinate and a buffer, a mixture of an acid salt of an amino acid and a buffer, and a mixture of an alkali salt of an amino acid and a buffer. Additional buffering agents include citric acid, sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts. Some buffering agents also impart effervescent qualities when a powder is reconstituted in a solution. In some embodiments, the buffer concentration is between about 5 mM and about 50 mM.

In some embodiments, the buffer in the selexipag solution formulation described herein comprises citric acid. In some embodiments, citric acid is present in about 0.50 mg/ml to about 5.5 mg/ml in the solution formulation. In some embodiments, the buffer in the selexipag solution formulation described herein comprises citric acid and sodium citrate. In some embodiments, sodium citrate is present in about 1.2 mg/ml to about 8.8 mg/ml in the solution formulation.

In some embodiments, the buffer in the selexipag solution formulation described herein comprises phosphoric acid. In some embodiments, the buffer in the selexipag solution formulation described herein comprises sodium phosphate.

In some embodiments, modulation of the pH is desired to provide the lowest impurity profile. In some embodiments, modulation of the pH is desired to provide increase the solubility of the solution.

In further embodiments, the selexipag solution formulation described herein comprises additional excipients including, but not limited to, glidants, flavouring agents, colouring agents and thickeners. Additional excipients such as bulking agents, tonicity agents and chelating agents are within the scope of the embodiments.

Glidants are substances that improve flowability of a powder. Suitable glidants include, but are not limited to, calcium phosphate tribasic, calcium silicate, cellulose (powdered), colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, silicon dioxide, starch, talc and the like. In some embodiments, the selexipag powder formulations described herein comprise a glidant.

In another embodiment, the selexipag solution formulation described herein comprises a flavouring agent or flavorant to enhance the taste or aroma of the formulation in liquid form. Suitable natural or synthetic flavouring agents can be selected from standard reference books, for example Fenaroli's Handbook of Flavour Ingredients, 3rd edition (1995). Non-limiting examples of suitable natural flavours, some of which can readily be simulated with synthetic agents or combinations thereof, include almond, anise, apple, apricot, bergamot, blackberry, blackcurrant, blueberry, cacao, caramel, cherry, cinnamon, clove, coffee, coriander, cranberry, cumin, dill, eucalyptus, fennel, fig, ginger, grape, grapefruit, guava, hop, lemon, licorice, lime, malt, mandarin, molasses, nutmeg, mixed berry, orange, peach, pear, peppermint, pineapple, raspberry, rose, spearmint, strawberry, tangerine, tea, vanilla, wintergreen, etc. Also useful, particularly where the formulation is intended primarily for pediatric use, is tutti-frutti or bubblegum flavor, a compounded flavouring agent based on fruit flavours. Presently preferred flavoring agents include anise, cinnamon, cacao, orange, peppermint, cherry (in particular wild cherry), grape, bubblegum, vanilla, and mixed berry. Flavoring agents can be used singly or in combinations of two or more.

In further embodiments, the selexipag solution formulation described herein comprises a colouring agent for identity and/or aesthetic purposes. Suitable colouring agents illustratively include FD&C Red No. 3, FD&C Red No. 20, FD&C Red No. 40, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, caramel, ferric oxide and mixtures thereof.

In further embodiments, the selexipag solution formulation described herein comprises a thickener. Thickeners impart viscosity or weight to the resultant liquid forms from the selexipag formulation described herein. Exemplary thickeners include dextrin, cellulose derivatives (ethylcellulose, hydroxyethyl cellulose, methylcellulose, hypromellose, and the like) starches, pectin, polyethylene glycol, polyethylene oxide, trehalose and certain gums (xanthan gum, locust bean gum, etc.). In certain embodiments, the selexipag solution formulations comprise a thickener.

Additional excipients are contemplated in the selexipag solution formulation embodiments. These additional excipients are selected based on function and compatibility with the selexipag solution formulations described herein and may be found, for example in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, (Easton, Pa.: Mack Publishing Co 1975); Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms (New York, N.Y.: Marcel Decker 1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed (Lippincott Williams & Wilkins 1999), herein incorporated by reference in their entirety.

In one embodiment, the sweetening agent is xylitol. In some embodiments, the sweetening agent is sucralose. In some embodiments, the sweetener is saccharin. In another embodiment, the preservative is sodium benzoate. In yet another embodiment, the preservative is one or more paraben preservatives. In yet another embodiment, the buffer comprises citric acid. In yet another embodiment, the buffer comprises citric acid and sodium citrate. In yet another embodiment, the buffer comprises phosphoric acid or salts thereof. In one aspect, the selexipag solution formulation described herein comprises selexipag, xylitol, sodium citrate, citric acid, sodium benzoate, and water. In some embodiments, the selexipag solution formulation herein further comprises a flavouring agent.

Preparation of the selexipag solution formulation described herein includes any known pharmaceutical method. In one embodiment, the selexipag solution formulation described herein is prepared by dissolving the selexipag in co-solvent, and adding the solution to a solution of buffer, the preservative, and the sweetener in water and adjusting the pH as needed with sodium hydroxide or hydrochloric acid. In one embodiment, the selexipag solution formulation described herein is prepared by dissolving the buffer, the preservative, selexipag, and the sweetener in water and adjusting the pH as needed with sodium hydroxide or hydrochloric acid. In one embodiment, the oral selexipag solution formulation described herein is prepared by dissolving citric acid anhydrous, sodium citrate anhydrous, sodium benzoate, selexipag, and xylitol in water and adjusting the pH as needed with sodium hydroxide or hydrochloric acid. In some embodiments, the order of addition does not matter. In some embodiments, the pH does not need to be adjusted with sodium hydroxide or hydrochloric acid.

The selexipag solution formulations described herein are stable in various storage conditions including refrigerated, ambient and accelerated conditions. Stable as used herein refer to selexipag solution formulations having about 95% or greater of the initial selexipag amount and about 5% w/w or less total impurities or related substances at the end of a given storage period. The percentage of impurities is calculated from the amount of impurities relative to the amount of selexipag. Stability is assessed by HPLC or any other known testing method. In some embodiments, the stable selexipag solution formulations have about 5% w/w, about 4% w/w, about 3% w/w, about 2.5% w/w, about 2% w/w, about 1.5% w/w, about 1% w/w, or about 0.5% w/w total impurities or related substances. In other embodiments, the stable selexipag solution formulations have about 5% w/w total impurities or related substances. In yet other embodiments, the stable selexipag solution formulations have about 4% w/w total impurities or related substances. In yet other embodiments, the stable selexipag solution formulations have about 3% w/w total impurities or related substances. In yet other embodiments, the stable selexipag solution formulations have about 2% w/w total impurities or related substances. In yet other embodiments, the stable selexipag solution formulations have about 1% w/w total impurities or related substances.

At refrigerated and ambient conditions, the selexipag solution formulations described herein are stable for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months and at least 36 months. At accelerated conditions, the selexipag solution formulations described herein are stable for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months or at least 12 months. Accelerated conditions include temperature and/or relative humidity (RH) that are above ambient levels (e.g. 25±.5°C; 55±10% RH).
Provided herein are various embodiments of selexipag solution formulations. In one aspect, the selexipag solution formulation comprises (i) selexipag or a pharmaceutically acceptable salt (ii) a co-solvent (iii) a sweetener (iii) a buffer (iv) a preservative and (v) water; wherein the pH of the formulation is between about 3 and about 8.

In another aspect, selexipag solid solutions described herein are prepared by the methods known in the art like melt method and the solution method. The excipients are usually polymers, but small molecules such as urea¸ sucrose, dextrose and galactose have been used, as have waxes. In the solution method, selexipag and excipients are co-dissolved in a solvent, which is then removed to form the dosage form. This method is used to form slabs of material which can be ground to powders, and is also the basis of spray drying and emulsification/solvent removal. Spray drying involves forcing an aqueous or organic solution of selexipag and excipients through a nozzle to form an aerosol in an evaporation chamber. The solvent evaporates leaving solid selexipag/excipient particles. The selexipag in the particles can be crystalline, amorphous or can show characteristics of both. Emulsification/solvent-removal involves preparing a solution of selexipag and excipients in a water immiscible solvent which is emulsified into an aqueous surfactant solution. The solvent is removed from the emulsion droplets to form particles. Water insoluble polymers are most commonly used in this process, such as PLA, PLGA, ethyl cellulose, or cellulose acetate phthalate.

In the melt method, selexipag is added to molten excipients and the mixture is then cooled. This method is the basis of spray chilling (spray congealing), melt/emulsification/chill-hardening, hot-melt extrusion and injection molding. Spray chilling is analogous to spray drying, but the selexipag/excipient mixture is molten rather than in solution, and the final particles are formed by solidification of the cooling aerosol droplets rather than by solvent evaporation. Waxy excipients such as Compritol®, Dynasan® and lecithin are especially useful in this method. Melt/emulsification/chill hardening is analogous to emulsification/solvent-removal, except the final particles are formed by cooling of the emulsified melt. Thermoplastic polymers such as polyethylene glycol, polyvinylpyrrolidinone, various lactic acid-glycolic acid copolymers, various acrylates, and poly(vinylcaprolactam-co-vinyl acetate-g-polyethylene glycol)2 are co-melted with the selexipag in a hot-melt extruder and the extrudate is further processed into the powder or granules. Injection molding is used in the manufacture of some drug-eluting devices. The API is mixed with thermoplastic excipients, and injected molten into a mold where the final powder or granules is made on cooling.

In another aspect, selexipag liquid formulations described herein are prepared from the reconstitution of a selexipag solid solution formulation. In some embodiments, the selexipag solid solution formulation comprising selexipag, a sweetener, a preservative, and optionally an excipient is dissolved in water, a buffer, other aqueous solvent, or a liquid to form a selexipag solution formulation. In some embodiments, the selexipag solid solution formulation herein further comprises a flavoring agent.

Various amounts and concentrations of other components (sweeteners, buffers, preservatives, and the like) in the selexipag solid solution formulations are found in the previous section describing the amounts and concentrations for the analogous selexipag solution formulations.

Liquid vehicles suitable for the selexipag solid solution formulations to be reconstituted into a liquid solution described herein are selected for a particular solution formulation (solution, suspension, etc.) as well as other qualities such as clarity, toxicity, viscosity, compatibility with excipients, chemical inertness, palatability, odor, colour and economy. Exemplary liquid vehicles include water, ethyl alcohol, glycerin, propylene glycol, syrup (sugar or other sweetener based, sugar-free flavoured syrup), juices (apple, grape, orange, cranberry, cherry, tomato and the like), other beverages (tea, coffee, soft drinks, milk and the like), oils (olive, soybean, corn, mineral, castor and the like), and combinations or mixtures thereof. Certain liquid vehicles, e.g., oil and water, can be combined together to form emulsions. In some embodiments, water is used for as a vehicle for a selexipag solution formulation. In other embodiments, syrup is used for as a vehicle for a selexipag solution formulation. In yet other embodiments, a juice is used for as a vehicle for a selexipag solution formulation.
In some embodiments, the selexipag solution formulations prepared from the powder formulations described herein are homogenous. Homogenous liquids as used herein refer to those liquids that are uniform in appearance, identity, consistency and drug concentration per volume. Non-homogenous liquids include such liquids that have varied colouring, viscosity and/or aggregation of solid particulates, as well as non-uniform drug concentration in a given unit volume. Homogeneity in liquids are assessed by qualitative identification or appearance tests and/or quantitative HPLC testing or the like. The mixing methods and excipients described herein are selected to impart a homogenous quality to a resultant selexipag solution formulation.

Mixing methods encompass any type of mixing that result in a homogenous selexipag solution formulation. In some embodiments, a quantity of a selexipag powder formulation is added to a liquid vehicle and then mixed by a stirring, shaking, swirling, agitation element or a combination thereof. In certain instances, a fraction of a selexipag powder formulation (i.e., one-half, one-third, one-fourth, etc.) is added to a liquid vehicle, mixed by stirring, shaking, swirling, agitation or a combination thereof, and the subsequent powder fraction(s) is added and mixed. In other embodiments, a liquid vehicle is added to a selexipag solid solution formulation in a container, for example, a bottle, vial, bag, beaker, syringe, or the like. The container is then mixed by stirring, shaking, swirling, agitation, inversion or a combination thereof. In certain instances, a fractional volume of the liquid vehicle (i.e., one-half, one-third, one-fourth volume, etc.) is added to a selexipag powder formulation in a container, mixed by stirring, shaking, swirling, agitation, inversion or a combination thereof; and the subsequent liquid fraction(s) is added and mixed. In certain instances, a one-half fractional volume of the liquid vehicle is added to a selexipag solid solution formulation in a container and mixing by shaking; the other one-half fractional volume of the liquid vehicle is then subsequently added and mixed.

For the selexipag solid solution and liquid formulations described herein, kits and articles of manufacture are also described. Such kits can comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein including a selexipag powder or liquid formulation. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers can be formed from a variety of materials such as glass or plastic.

A kit will typically may comprise one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for a selexipag powder or liquid formulation described herein. Non-limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes, syringe adapter, carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use associated with a selexipag powder or liquid formulation. A set of instructions will also typically be included.

In one aspect, the selexipag solution formulations are used for the treatment of diseases and conditions described herein to a subject. In some embodiments, the selexipag solution formulations described herein treat arteriosclerosis obliterans, pulmonary hypertension or Raynaud's disease secondary to systemic sclerosis. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of selexipag solution formulations in therapeutically effective amounts to said subject.

Dosages of selexipag solution formulations described can be determined by any suitable method. Maximum tolerated doses (MTD) and maximum response doses (MRD) for selexipag can be determined via established animal and human experimental protocols as well as in the examples described herein. For example, toxicity and therapeutic efficacy of selexipag can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. Selexipag dosages exhibiting high therapeutic indices are of interest. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.

In some embodiments, the amount of a given selexipag solution formulation that corresponds to such an amount varies depending upon factors such as the particular selexipag salt or solvate, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but can nevertheless be determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the liquid formulation type, the condition being treated, and the subject or host being treated.

In some embodiments, the selexipag solution formulations described herein are provided in a dose per day from about 0.01 mg to 10 mg, from about 0.05 mg to about 5 mg, from about 0.1 to about 2.5, from about 0.2 mg to about 2 mg of selexipag. In certain embodiments, the selexipag solution formulations described herein are provided in a daily dose of about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg or about 10 mg, or any range derivable therein. The dose per day described herein can be given once per day or multiple times per day in the form of sub-doses given b.i.d., t.i.d., q.i.d., or the like where the number of sub-doses equal the dose per day. In further embodiments, the daily dosages appropriate for the selexipag solution formulations described herein are from about 0.01 to about 1.0 mg/kg per body weight.
In further embodiments, the selexipag solution formulations are provided in a dosage that is similar, comparable or equivalent to a dosage of a known selexipag tablet formulation. In other embodiments, the selexipag solution formulations are provided in a dosage that provides similar, comparable or equivalent pharmacokinetic parameters (e.g., AUC, Cmax, Tmax, Cmax, T1/2) as a dosage of a known selexipag tablet formulation. Similar, comparable or equivalent pharmacokinetic parameters, in some instances, refer to within 80% to 125%, 80% to 120%, 85% to 125%, 90% to 110%, or increments therein, of the given values. It should be recognized that the ranges can, but need not be symmetrical, e.g., 85% to 105%.

In one embodiment, there is provided a selexipag solution formulation wherein the mean plasma concentration of the selexipag after single dose administration exhibits a pharmacokinetic profile which is superior to that attainable by a product that is not a solution formulation.

In one embodiment, there is provided a method for providing a therapeutic blood plasma concentration of selexipag over a period of up to 24 hours resulting in improved pharmacological effect result which comprises administering orally to a patient in need thereof a selexipag solution formulation conducive to pharmacologically effective selexipag blood plasma levels from about half an hour to about 24 hours.

In another embodiment, the selexipag solution formulation provides a mean AUC of plasma lurasidone in the subject which is greater than the mean AUC of plasma lurasidone provided by an selexipag tablet, wherein the dose of selexipag in the solution formulation is the same as or less than the dose in the tablet dosage form. In another embodiment, the mean AUC of plasma selexipag is about 10% to 50%, about 15% to about 30%, about 5% to 15%, about 5% to 20%, about 10% to 20%, about 10% to 25%, about 15% to 25%, about 20% to 25%, about 20% to 30%, about 20% to 40%, or about 30% to 40% greater than the AUC of plasma selexipag provided by administration of the tablet dosage form to the subject. In another embodiment, the mean AUC of plasma selexipag is about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more than about 50% greater than the mean AUC of plasma selexipag provided by administration of the tablet dosage form to the subject.

In another embodiment, the gastro-retentive dosage form of selexipag shows enhanced bioavailability. In another embodiment, the selexipag solution formulation shows a reduced "food effect" as compared to selexipag non-solution compositions. The compositions exhibit substantially similar oral bioavailability in fed and fasted subjects.

Additional agents for use in combination with a selexipag solution formulation described herein.

Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments described herein, certain preferred methods, devices, and materials are now described.

As used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" is a reference to one or more excipients and equivalents thereof known to those skilled in the art, and so forth.

The term "about" is used to indicate that a value includes the standard level of error for the device or method being employed to determine the value. The use of the term "or" in the claims is used to mean "and/or" unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and to "and/or." The terms "comprise," "have" and "include" are open-ended linking verbs. Any forms or tenses of one or more of these verbs, such as "comprises," "comprising," "has," "having," "includes" and "including," are also open-ended. For example, any method that "comprises," "has" or "includes" one or more steps is not limited to possessing only those one or more steps and also covers other unlisted steps.

EXAMPLES
Example 1
Sr. No. Ingredient Function Quantity (mg/ml)
1 Selexipag Active 0.2
2 Ethanol Co solvent 3.0
3 Propylene glycol Solubilizer 0.5
4 Hydroxypropyl Methyl Cellulose Viscosity building 3.0
5 pH 7.0 citric acid phosphate buffer Buffer 3.5
6 Sodium chloride Thermo reversibility 0.021
7 Ascorbic acid Anti-oxidant 0.1
8 Methyl paraben Preservatives 0.18
9 Propyl paraben Preservatives 0.02
10 Flavour Flavour 0.01
11 Purified water Base q.s.

Procedure:
1. Dissolve Selexipag in ethanol
2. Dissolve parabens in Propylene glycol
3. Dissolve ascorbic acid, sodium chloride and HPMC in pH 7.0 citrate buffer.
4. Add step 2 in step 1
5. Add step 3 in step 4
6. Make up volume.
Example 2
Sr. No. Ingredient Function Quantity (mg/ml)
1 Selexipag Active 0.2
2 Ethanol Co solvent 3.0
3 Propylene glycol Solubilizer 0.5
4 Hydroxypropyl Methyl Cellulose Viscosity building 3.0
5 Sodium citrate Buffer 0.01
6 Ascorbic acid Anti-oxidant 0.1
7 Methyl paraben Preservatives 0.18
8 Propyl paraben Preservatives 0.02
9 Flavour Flavour 0.01
10 Purified water base q.s.

Procedure:
1. Dissolve Selexipag in ethanol
2. Dissolve parabens in Propylene glycol
3. Dissolve ascorbic acid and HPMC in purified water.
4. Add step 2 in step 1
5. Add step 3 in step 4
6. Adjust pH to 7.0 using sodium citrate solution.
7. Make up volume.
Example 3
Sr. No. Ingredient function Quantity (mg/ml)
1 Selexipag Active 0.2
2 Ethanol Co solvent 3.0
3 Propylene glycol Solubilizer 0.5
4 Hydroxypropyl Methyl Cellulose Viscosity building 3.0
5 Hydroxypropyl Beta Cyclodextrin Stabilizer 0.8
6 Ascorbic acid Anti-oxidant 0.1
7 Methyl paraben Preservatives 0.18
8 Propyl paraben Preservatives 0.02
9 Flavour Flavour 0.01
10 Purified water Base. q.s.

Procedure:
1. Dissolve Selexipag in ethanol
2. Dissolve parabens in Propylene glycol
3. Dissolve HPBCD and HPMC in purified water.
4. Add step 2 in step 1
5. Add step 3 in step 4
6. Make up volume.
Example 4
Sr. No. Ingredient function Quantity (mg/ml)
1 Selexipag Active 0.2
2 Ethanol Co solvent 3.0
3 Hydroxypropyl Methyl Cellulose Viscosity building 3.0
4 Ascorbic acid Anti-oxidant 0.1
5 Methyl Paraben Preservatives 0.18
6 Propyl Paraben Preservatives 0.02
7 Purified water Base. q.s.

Procedure:
1. Dissolve Selexipag in ethanol
2. Dissolve parabens in hot water.
3. Dissolve HPMC and Ascorbic acid in purified water.
4. Add Step 2 in step 1
5. Add Step 3 in step 4
6. Make up volume.

Example 5
Sr. No. Ingredient function Quantity (mg/ml)
1 Selexipag Active 0.2
2 Ethanol Co solvent 3.0
3 Hydroxypropyl Methyl Cellulose Viscosity building 3.0
4 Ascorbic acid Anti-oxidant 0.1
5 Purified water Base. q.s.

Procedure:
1. Dissolve Selexipag in ethanol
2. Dissolve HPMC and Ascorbic acid in purified water.
3. Add Step 2 in step 1
4. Add Step 3 in step 4
5. Make up volume.

While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.