This application claims the benefit of priority of our Indian patent application number 202241024179 filed on April 25, 2022 which is incorporated herein by reference.

Field of the Invention:

The present invention relates to liquid injectable and/or lyophilized compositions, that comprise selexipag or pharmaceutically acceptable salts thereof, which is efficacious, chemically stable and physiologically balanced for safety and efficacy. The said invention is used for treatment of pulmonary arterial hypertension (PAH) to delay disease progression and reduce the risk of hospitalization for PAH. Further the invention relates to the process for preparation of said liquid injectable and/or lyophilized composition.

Background of the Invention:

Selexipag acts as a selective, orally bioavailable, non-prostanoid IP receptor agonist with a long-half-life, selectivity for the IP receptor minimizing off-target effects especially in the gastrointestinum and a lack of IP receptor desensitization processes which avoids the development of tachyphylaxis. Selexipag was shown to be beneficial in the treatment of pulmonary arterial hypertension. In clinical trial, among patients with pulmonary arterial hypertension, the risk of the primary composite end point of death or a complication related to PAH was significantly lower among patients who received selexipag than among who received placebo.

The chemical name of the active substance selexipag is 2-{4-[(5,6-diphenylpyrazin-2- yl) (isopropyl) amino] butoxy} -N-(methylsulfonyl) acetamide, corresponding to the molecular formula C26H32N4O4S and has a relative molecular mass 496.62 g/mol. It appears as a pale yellow crystalline powder, non-hygroscopic powder that is practically insoluble in water. Selexipag shows different solubility characteristics in aqueous solutions and is insoluble at pH 2 to 4, freely soluble at pH 8 and very soluble from pH 9 to pH 12. The chemical structure of Selexipag is as:

CAS: 475086-01-2

US patent no US7205302 B2 discloses selexipag or pharmaceutically acceptable salts.

Selexipag first approved in United States in Dec 2015 as oral tablet dosage form with orphan drug status for PAH, and is currently approved in Europe, Canada, Australia and Japan etc... and in July 2021 another dosage form as powder injection is approved in United States. Approved indication include the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH.

It is generally known that certain segments of the population have difficulty in 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 and are in urgent care. Furthermore, treatment of certain diseases may only require short term treatment or a treatment comprising alternative periods of treatment / non-treatment, in which case solid dosage forms could be inappropriate. Therefore there is a need to develop a stable and reproducible i.v. formulation.

Further, development of i.v. formulation of selexipag has facing some difficulties / complications like solubility of selexipag in solutions varies irregularly and unpredictably as function of small changes in temperature and pH. Further selexipag requires very low doses likely to be in the micrograms to single digit milligrams range per day.

Development of such a very small doses of drugs in i.v. formulation facing more issues like adsorption of active ingredient on syringes or tubing may have an impact on the suitability of a selexipag i.v. formulation.

In addition, during development the inventors of instant invention have unexpectedly found that by the nature of selexipag being a hydrolysable prodrug, premature hydrolysis (Hydrolysis is a chemical process in which a water molecule is added to a substance resulting in the split of that substance into two parts. One fragment of the target molecule (or parent molecule) gains a hydrogen ion (H+) from the split water molecule. The other portion of the target molecule collects the hydroxyl group (OH-) of the split water molecule. In effect an acid and a base are formed) to the active metabolite should be prevented in such i.v. formulation.

Technical problem:

An objective of the present invention is to provide a stabilized liquid dosage form or lyophilized powder dosage form of selexipag. Here, the term stability means both the physical stability and chemical stability. Physical stability means solubility of selexipag in pre-lyophilized solvent and reproducibility into reconstituted solvent like WFI or saline. Chemical stability means decrease in the content of selexipag contained in the liquid preparation due to decomposition (Hydrolysis) thereof is suppressed.

Solution to problem

Therefore, looking at the need existing in the art the primary objective of the inventors of present invention is to develop ready-to-use liquid pharmaceutical compositions of selexipag or lyophilized powder pharmaceutical compositions of selexipag. However, stability storage tests have shown that aqueous solutions of selexipag lead to hydrolysis degradation. After several unsuccessful attempts, surprisingly the inventors of the present invention have found shelf stable and do not cause unwanted degradation product by carefully balancing selexipag concentration in the formulation, and selection of an appropriate pH or appropriate pH adjusting agents for the final formulation.

Summary of the Invention:

The present invention relates to stable dosage forms comprising parenteral dosage forms like and not limited to i.v. lyophilized powder formulation or i.v. injectable solution formulation of selexipag, for the treatment of pulmonary arterial hypertension (PAH) to delay disease progression and reduce the risk of hospitalization for PAH.

First embodiment of the present invention is to provide a stable dosage forms comprising parenteral dosage forms like and not limited to i.v. lyophilized powder formulation, or i.v. injectable solution formulation of selexipag or pharmaceutically acceptable salts, solvates, hydrates thereof based on weight of free base.

First aspect of first embodiment of the present invention is to provide a parenteral pharmaceutical composition prepared as i.v. liquid injection.

Second aspect of first embodiment of the present invention is to provide a parenteral pharmaceutical composition prepared by specialized techniques like and not limited to “Lyophilization” or “Freeze drying”.

Second embodiment of the present invention is to provide a parenteral pharmaceutical composition comprising selexipag in free base form, which may be used for the preparation of the present invention in amorphous, or in one or more crystalline forms, or in mixture of amorphous and crystalline form (s). Crystalline forms may be anhydrous, or solvate or hydrate forms.

Third embodiment of the present invention is to provide a stable dosage forms comprising parenteral dosage forms like and not limited to i.v. lyophilized powder formulation, or i.v. injectable solution formulation of selexipag or pharmaceutically acceptable salts, solvates, hydrates thereof based on weight of free base, wherein selexipag is present in the composition from about 0.1 g/kg to about 1 g/kg with respect to total weight of composition, preferably from about 0.5 g/kg.

Fourth embodiment of the present invention is to provide a stable dosage forms comprising parenteral dosage forms like and not limited to i.v. lyophilized powder formulation, or i.v. injectable solution formulation of selexipag or pharmaceutically acceptable salts, solvates, hydrates thereof based on weight of free base, wherein selexipag of purity (according to HPLC) of more than 99.7% or 99.8% or 99.9%, comprising not more than 0.1 % of hydrolysis product of selexipag. First aspect of fourth embodiment of the present invention is to provide a stable dosage forms comprising parenteral dosage forms like and not limited to i.v. lyophilized powder formulation, or i.v. injectable solution formulation of selexipag or pharmaceutically acceptable salts, solvates, hydrates thereof based on weight of free base, wherein selexipag of purity (according to HPLC) of more than 99%, comprising not more than 0.5 % of hydrolysis product of selexipag.

Fifth embodiment of the present invention is to provide a stable dosage forms comprising parenteral dosage forms like and not limited to i.v. lyophilized powder formulation, or i.v. injectable solution formulation of selexipag or pharmaceutically acceptable salts, solvates, hydrates thereof and one or more pharmaceutically acceptable excipients; wherein said excipients are those which improve the solubility and stability of the said pharmaceutical composition.

First aspect of fifth embodiment of the present invention is to provide a stable dosage forms comprising parenteral dosage forms like and not limited to i.v. lyophilized powder formulation, or i.v. injectable solution formulation of selexipag or pharmaceutically acceptable salts, solvates, hydrates thereof, wherein, said solubility and stability improving excipients are one or more selected from, but not limited to a buffering agent, chelating agent, anti-oxidant, preservative, bulking agent, surfactant / detergent and pH adjusting agents and any other pharmaceutical excipients for improving stability.

Second aspect of fifth embodiment of the present invention is to provide a stable dosage forms comprising parenteral dosage forms like and not limited to i.v. lyophilized powder formulation, or i.v. injectable solution formulation of selexipag or pharmaceutically acceptable salts, solvates, hydrates thereof, wherein, said solubility and stability improving excipients are one or more selected from a buffering agent, bulking agent, detergent and pH adjusting agent.

Sixth embodiment of the present invention is to provide a stable dosage forms comprising parenteral dosage forms like and not limited to i.v. lyophilized powder formulation, or i.v. injectable solution formulation of selexipag or pharmaceutically acceptable salts, solvates, hydrates thereof, wherein, the diluent or solvent in injectable solution or lyophilized powder formulation is aqueous or alcoholic.

First aspect of sixth embodiment of the present invention is to provide a stable dosage forms comprising parenteral dosage forms like and not limited to i.v. lyophilized powder formulation, or i.v. injectable solution formulation of selexipag or pharmaceutically acceptable salts, solvates, hydrates thereof, wherein, the diluent or solvent in injectable solution or lyophilized powder formulation is aqueous solution, preferably water, sterile water, pyrogen free water, WFI and saline, further more preferably WFI and saline.

Seventh embodiment of the present invention is to provide a stable dosage forms comprising parenteral dosage forms like and not limited to i.v. lyophilized powder formulation, or i.v. injectable solution formulation of selexipag or pharmaceutically acceptable salts, solvates, hydrates thereof, and one or more pharmaceutical acceptable excipients which is buffered to a pH of about 4.0 to about 10.0 to further increase the solubility and stability of the said pharmaceutical composition.

First aspect of seventh embodiment of the present invention is to provide a stable dosage forms comprising parenteral dosage forms like and not limited to i.v. lyophilized powder formulation, or i.v. injectable solution formulation of selexipag or pharmaceutically acceptable salts, solvates, hydrates thereof, and one or more pharmaceutical acceptable excipients which is buffered to a pH of about 6.0 to about 8.0 to further increase the solubility and stability of the said pharmaceutical composition.

Second aspect of seventh embodiment of the present invention is to provide a stable dosage forms comprising parenteral dosage forms like and not limited to i.v. lyophilized powder formulation, or i.v. injectable solution formulation of selexipag or pharmaceutically acceptable salts, solvates, hydrates thereof, and one or more pharmaceutical acceptable excipients which is buffered to a pH of about 7.5 ± 0.2 to further increase the solubility and stability of the said pharmaceutical composition.

Eight embodiment of the present invention is to provide a stable dosage forms comprising parenteral dosage forms like and not limited to i.v. lyophilized powder formulation, or i.v. injectable solution formulation of selexipag comprising: selexipag from about 0.001 w/v % to about 0.1 w/v %; bulking agent from about 1 w/v % to 10 w/v %; detergent / surfactant from about 0.1 w/v % to 0.8 w/v %; buffering agent form about 0.05 w/v % to 0.5 w/v% and water; where the pH of the composition is from about 6.0 to about 8.0

First aspect of eight embodiment of the present invention is to provide a stable dosage forms comprising parenteral dosage forms like and not limited to i.v. lyophilized powder formulation, or i.v. injectable solution formulation of selexipag comprising: selexipag from about 0.036 w/v % to about 0.09 w/v %; bulking agent from about 3.6 w/v % to 9 w/v %; detergent / surfactant from about 0.216 w/v % to 0.54 w/v %; buffering agent form about 0.1 w/v % to 0.25 w/v% and water; where the pH of the composition is from about 6.0 to about 8.0

Ninth embodiment of the present invention relates to a process for the preparation of stable dosage forms comprising parenteral dosage forms like and not limited to i.v. lyophilized powder formulation, or i.v. injectable solution formulation of selexipag or pharmaceutically acceptable salts, solvates, hydrates thereof, and one or more pharmaceutical acceptable excipients.

First aspect of the ninth embodiment of the present invention relates to a process of preparing a stable dosage forms comprising parenteral dosage forms like and not limited to i.v. lyophilized powder formulation, or i.v. injectable solution formulation comprising the following steps: a) preparing an aqueous solution of active ingredient(s), suitable bulking agent(s), suitable detergent (s), suitable buffering agent (s) and suitable pH adjusting agent(s) and dissolving then simultaneously and/ or sequentially in WFI and b) freeze-drying said aqueous pharmaceutical composition of step a) to form a cake using a method comprising the steps of:

(i) freezing the aqueous pharmaceutical composition of step a) at a first temperature for a period sufficient to transform the liquid formulation into solid state (especially for a period of at least about 1 hour), wherein said first temperature is in the range of about -55° C. to -25° C. (especially about -45° C.);

(ii) annealing the frozen composition of step b) (i) at a second temperature (notably for a period of at least about 1 hour, especially at least about 2 hours); wherein said second temperature is in the range of about -20° C. to -1° C. (notably about -10° C. to -2° C.; especially about -3° C );

(iii) subjecting the frozen composition of step b) (ii) to a vacuum (notably a vacuum of about 0.1 to 1.5 mbar, especially about 0.2 to 1.2 mbar, in particular 0.5±0.1 mbar) at a third temperature wherein said third temperature is in the range of about -55° C. to -25° C. (especially about -45° C ); and

(iv) drying the composition from step b) (iii) in said vacuum at a fourth temperature (notably for a period of at least about 2 hours, especially of at least about 5 hours, in particular between about 5 to 15 hours, about 5 to 19 hours, preferably between about 5 to 22 hours or between 5 to 15 hours) wherein said fourth temperature is in the range of about 20° C. to 40° C.; notably in the range of about 25° C. to 35° C.; especially about 35° C.

(v) optionally, the composition may be hold at a closing temperature of about 20° C. to 35° C., preferably 20° C.

Tenth embodiment of the present invention comprising: a lyophilized composition comprising 1800 pg of selexipag, a buffering agent, wherein selexipag and buffer present in a ratio of 1 : 2.5, wherein the lyophilized composition is formulated such that reconstitution with 5 - 10 mL of water will yield a solution having a pH of 6 to 8, and wherein the lyophilized composition further comprises a degradation product resulting from hydrolysis of selexipag at a value no greater than 0.8%, 0.7%, 0.6%, 0.5%, 0.4% 0.3%, 0.2% or 0.1%. wt./wt based upon the total weight of selexipag.

Eleventh embodiment of the present invention is to provide a stable dosage forms comprising parenteral dosage forms like and not limited to i.v. lyophilized powder formulation, or i.v. injectable solution formulation of selexipag or pharmaceutically acceptable salts, solvates, hydrates thereof, wherein lyophilized composition comprises water content at a value no greater than 2%, 1% or 0.5 % based upon the total weight of composition

Twelfth embodiment of the present invention is to provide a stable dosage forms comprising parenteral dosage forms like and not limited to i.v. lyophilized powder formulation and/or i.v. injectable solution formulation, wherein said pharmaceutical composition is in a container, preferably in a vial or in a syringe or in an ampule; more preferably in a vial.

Thirteenth embodiment of the present invention relates to a method for the preparation of a reconstituted pharmaceutical composition; said method comprising step of reconstituting the lyophilized cake composition by adding at least one suitable diluent to said cake composition.

First aspect of thirteenth embodiment of the present invention, said suitable diluents to reconstitute said pharmaceutical composition include but not limited to water for injection (WFI), sterile water for injection (SWFI) and saline.

Fourteenth embodiment of the present invention discloses methods to access stable pharmaceutical formulations of selexipag for use as medicament for the treatment of pulmonary arterial hypertension (PAH) to delay disease progression and reduce the risk of hospitalization for PAH.

The present invention may be embodied in other specific form with out departing its spirit or essential characteristics. The described embodiments are to be considered in all respect only as illustrative and not restrictive. The scope of invention is, therefore, indicated by the appended claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within the scope.

Detailed Description of the Invention:

The present invention relates to stable dosage forms comprising parenteral dosage forms like and not limited to i.v. lyophilized powder formulation or i.v. injectable solution formulation of selexipag, for the treatment of pulmonary arterial hypertension (PAH) to delay disease progression and reduce the risk of hospitalization for PAH.

One of the requirements for an acceptable pharmaceutical formulation especially liquid formulation is that it must be sterile and stable, so as not to exhibit substantial decomposition of the active ingredient during the time between manufacture of the composition and usage by the patient. Therefore, stability is considered as one of the most important requirements of pharmaceutical product quality. Only stable preparations would promise precise delivery of the drug to the patients.

Parenteral preparations are defined as solutions, suspensions, emulsions for injection or infusion, powders for injection or infusion, gels for injection and implants. They are sterile preparations intended to be administrated directly into the systemic circulation in humans or animals. In addition to being sterile, parenteral preparations must be pyrogen-free. Sterility can be achieved by different processes of sterilization like and not limited to filtration that should be appropriate to the formulations.

Parenterals are usually supplied in single dose or multiple dose glass or plastic containers. The various routes of administration of parenteral preparations are intradermal (intra cutaneous) injections, hypodermis (subcutaneous) injections, intramuscular injections, intravenous injections, intra-arterial injections, intra cardiac injections, intrathecal injections, intracisternal injections, peridural injections, intrarticular injections and intracerebral injections.

Lyophilization or freeze drying is a process in which water is removed from a product after it is frozen and placed under a vacuum, allowing the ice to change directly from solid to vapor without passing through a liquid phase. The process consists of three separate, unique, and interdependent processes; freezing, primary drying (sublimation), and secondary drying (desorption). The advantages of Lyophilization include, ease of processing a liquid, which simplifies aseptic handling, enhanced stability of a dry powder, removal of water without excessive heating of the product, enhanced product stability in a dry state and rapid and easy dissolution of reconstituted product.

This disclosure is not limited to the particular systems, devices and methods described, as these may vary. The terminology used in the description is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope.

The term “active ingredient”, “drug”, “biologically active molecule”, “biologically active moiety” or “biologically active agent”, when used herein means any substance which can affect any physical or biochemical properties of a biological organism, including but not limited to viruses, bacteria, fungi, plants, animals, and humans. In particular, as used herein, Active ingredient include any substance intended for diagnosis, cure mitigation, treatment, or prevention of disease in humans or other animals, or to otherwise enhance physical or mental well-being of humans or animals or to have direct effect in restoring, correcting or modifying physiological functions in human beings. As used herein includes an selective IP receptor agonist or a pharmaceutically acceptable salt thereof, preferably, a Selexipag.

As used herein, the term “composition or pharmaceutical composition or formulation” refers to liquid dosage forms, such as but not limited to, solution, drops, emulsion, suspension, powder for injection. Preferably, the pharmaceutical composition is a liquid injectable and/or lyophilized composition.

As used herein, "stability" is referred as to both the physical and chemical stability.

As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably herein. These terms refers to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient. As used herein, the term "therapeutically effective amount" of a compound means an amount sufficient to cure, alleviates or partially arrest the clinical manifestations of a given disease and its complications. An amount adequate to accomplish this is defined as "therapeutically effective amount". Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician.

As used herein “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” or “pharmaceutically acceptable inactive ingredient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions of the invention is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

When used herein the term “about” will compensate for variability allowed for in the pharmaceutical industry and inherent in pharmaceutical products, such as differences in product strength due to manufacturing variation and time-induced product degradation. In one embodiment the term allows for any variation which in the practice of pharmaceuticals would allow the product being evaluated to be considered pharmaceutically equivalent or bioequivalent to the recited strength. In another embodiment the term allows for any variation within ±10% of value.

The invention can be defined based on several principal embodiments which can be combined in any manner physically and mathematically possible to create additional principal embodiments.

Presently useful compositions may include one or more other components in amounts effective to facilitate the usefulness and effectiveness of the present methods and/or the presently useful compositions. Examples of such other components include, without limitation, one or more selected from a buffering agent, chelating agent, anti-oxidant, preservative, bulking agent, surfactant / detergent and pH adjusting agents and any other pharmaceutical excipients for improving stability.

As used herein the term “bulking agent” refers to a substance or component that is chemically compatible with the active pharmaceutical ingredient and with further excipients of a composition, and that adds mass to a lyophilized composition. Some suitable bulking agents for pharmaceutical compositions according to the present invention is for example but not limited to mannitol, trehalose, L-proline, glycine and polyvinylpyrrolidone. Further, more preferable bulking agent typically used in the present invention is glycine.

As used herein the term “detergent/emulsifyer/surfactant” refers to a substance or component that is “Polysorbate 20” may be defined as (non-ionic) detergent. Detergents, especially commercially available detergent products, are usually not pure compounds but may be rather complex mixtures of compounds containing one primary major detergent component. Polysorbate 20 for example is a polysorbate-type nonionic detergent formed by the ethoxylation of sorbitan before the addition of lauric acid. The ethoxylation process leaves the molecule with 20 repeat units of polyethylene glycol; in practice these are distributed across 4 different chains leading to a commercial product containing a range of chemical species. Polysorbate 20 may contain variable amounts of said primary major detergent component, and residual amounts of further components such as for example residual polyethyleneglycols (which may stem from the chemical production process). The above-mentioned variation in the chemical species and the residual further components possibly comprised in the commercial product are encompassed in the scope of term “polysorbate 20” as used herein.

Buffer solutions particularly maintain the solution / injection dosage forms at a particular ion concentration and pH, some suitable buffer components, for example, and without limitation include citric acid, sodium citrate, sodium tartrate, sodium acetate trihydrate, sodium carbonate, sodium bicarbonate, phosphoric acid, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, Glacial acetic acid, dipotassium hydrogenphosphate, trisodium phosphate, tripotassium phosphate, 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 may be employed to maintain a suitable pH in the present invention. Preferable buffer solutions used in the present invention are acetate buffer such as sodium acetate trihydrate, glacial acetic acid and bicarbonate buffer such as sodium bicarbonate.

Ninth embodiment of the present invention relates to a process for the preparation of stable dosage forms comprising parenteral dosage forms like and not limited to i.v. lyophilized powder formulation, or i.v. injectable solution formulation of selexipag or pharmaceutically acceptable salts, solvates, hydrates thereof, and one or more pharmaceutical acceptable excipients.

First aspect of the ninth embodiment of the present invention relates to a process of preparing a stable dosage forms comprising parenteral dosage forms like and not limited to i.v. lyophilized powder formulation, or i.v. injectable solution formulation comprising the following steps: a) preparing an aqueous pharmaceutical composition by shifting active ingredient(s), suitable bulking agent(s), suitable detergent (s), suitable buffering agent (s) and suitable pH adjusting agent(s) and dissolving simultaneously and/ or sequentially in WFI.; and b) freeze-drying said aqueous pharmaceutical composition of step a) to form a cake using a method comprising the steps of:

(i) freezing the aqueous pharmaceutical composition of step a) at a first temperature for a period sufficient to transform the liquid formulation into solid state (especially for a period of at least about 1 hour), wherein said first temperature is in the range of about -55° C. to -25° C. (especially about -45° C.);

(ii) annealing the frozen composition of step b) (i) at a second temperature (notably for a period of at least about 1 hour, especially at least about 2 hours); wherein said second temperature is in the range of about -20° C. to -1° C. (notably about -10° C. to -2° C.; especially about -3° C );

(iii) subjecting the frozen composition of step b) (ii) to a vacuum (notably a vacuum of about 0.1 to 1.5 mbar, especially about 0.2 to 1.2 mbar, in particular 0.5±0.1 mbar) at a third temperature wherein said third temperature is in the range of about -55° C. to -25° C. (especially about -45° C ); and

(iv) drying the composition from step b) (iii) in said vacuum at a fourth temperature (notably for a period of at least about 2 hours, especially of at least about 5 hours, in particular between about 5 to 15 hours, about 5 to 19 hours, preferably between about 5 to 22 hours or between 5 to 15 hours) wherein said fourth temperature is in the range of about 20° C. to 40° C.; notably in the range of about 25° C. to 35° C.; especially about 35° C.

(v) optionally, the composition may be hold at a closing temperature of about 20° C. to 35° C., preferably 20° C.

Second aspect of the ninth embodiment of the present invention relates to a process of preparing a stable dosage forms comprising parenteral dosage forms like and not limited to i.v. lyophilized powder formulation, or i.v. injectable solution formulation comprising the following steps:

1) preparing an aqueous pharmaceutical composition by shifting selexipag, glycine, polysorbate 20, sodium acetate trihydrate and suitable pH adjusting agent(s) and dissolving simultaneously and/ or sequentially in WFI. ; and

2) freeze-drying said aqueous pharmaceutical composition of step 1) to form a cake using a method comprising the steps of:

(a) freezing the aqueous pharmaceutical composition of step 1) at a first temperature for a period sufficient to transform the liquid formulation into solid state (especially for a period of at least about 1 hour), wherein said first temperature is in the range of about -55° C. to -25° C. (especially about -45° C.);

(b) annealing the frozen composition of step 2) (a) at a second temperature (notably for a period of at least about 1 hour, especially at least about 2 hours); wherein said second temperature is in the range of about -20° C. to -1° C. (notably about -10° C. to -2° C.; especially about -3° C );

(c) subjecting the frozen composition of step 2) (b) to a vacuum (notably a vacuum of about 0.1 to 1.5 mbar, especially about 0.2 to 1.2 mbar, in particular 0.5±0.1 mbar) at a third temperature wherein said third temperature is in the range of about -55° C. to -25° C. (especially about -45° C ); and

(d) drying the composition from step 2) (c) in said vacuum at a fourth temperature (notably for a period of at least about 2 hours, especially of at least about 5 hours, in particular between about 5 to 15 hours, about 5 to 19 hours, preferably between about 5 to 22 hours or between 5 to 15 hours) wherein said fourth temperature is in the range of about 20° C. to 40° C.; notably in the range of about 25° C. to 35° C.; especially about 35° C.

(e) optionally, the composition may be hold at a closing temperature of about 20° C. to 35° C., preferably 20° C.

Tenth embodiment of the present invention comprising: a lyophilized composition comprising 1800 pg of selexipag, a buffering agent, wherein selexipag and buffer present in a ratio of 1 : 2.5, wherein the lyophilized composition is formulated such that reconstitution with 5 - 10 mL of water will yield a solution having a pH of 6 to 8, and wherein the lyophilized composition further comprises a degradation product resulting from hydrolysis of selexipag at a value no greater than 0.8%, 0.7%, 0.6%, 0.5%, 0.4% 0.3%, 0.2% or 0.1%. wt/wt based upon the total weight of selexipag.

Eleventh embodiment of the present invention is to provide a stable dosage forms comprising parenteral dosage forms like and not limited to i.v. lyophilized powder formulation, or i.v. injectable solution formulation of selexipag or pharmaceutically acceptable salts, solvates, hydrates thereof, wherein lyophilized composition comprises water molecules at a value no greater than 2%, 1% or 0.5 % based upon the total weight of composition

Twelfth embodiment of the present invention is to provide a stable dosage forms comprising parenteral dosage forms like and not limited to i.v. lyophilized powder formulation, or i.v. injectable solution formulation, wherein said pharmaceutical composition is in a container, preferably in a vial or in a syringe or in an ampule; more preferably in a vial.

Thirteenth embodiment of the present invention relates to a method for the preparation of a reconstituted pharmaceutical composition; said method comprising step of reconstituting the lyophilized cake composition by adding at least one suitable diluent to said cake composition.

First aspect of thirteenth embodiment of the present invention, said suitable diluents to reconstitute said pharmaceutical composition include but not limited to water for injection (WFI), sterile water for injection (SWFI) and saline.

Fourteenth embodiment of the present invention discloses methods to access stable pharmaceutical formulations of selexipag for use as medicament for the treatment of pulmonary arterial hypertension (PAH) to delay disease progression and reduce the risk of hospitalization for PAH.

The use of the terms "a," "an" and "the" and similar references in the context of this disclosure (especially in the context of the following) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., such as, preferred, preferably) provided herein, is intended merely to further illustrate the content of the disclosure and does not pose a limitation on the scope of the invention. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present disclosure.

EXAMPLES

Example 1:

Example 2:

Example 3:

Example 4:

Example 5:

Example 6:

Manufacturing process for (Example 1 to 6):

1. Water for Injection was collected in a clean SS vessel and was cooled to 2-25°C, and 2-25 °C was maintained throughout the manufacturing process.

2. weighed quantity of glycine was added to step 1 under continuous stirring and stirring was continued till a clear solution obtained and pH was checked.

3. weighed quantity of Polysorbate 20 was added under continuous stirring to the bulk solution obtained form step 2, and stirring was continued till a clear solution obtained and pH was checked.

4. weighed quantity of glacial acetic acid / sodium acetate trihydrate / sodium bicarbonate was added under continuous stirring to the bulk solution obtained form step 3, and the stirring was continued till a clear solution obtained and pH was checked.

5. weighed quantity of selexipag was added under continuous stirring to the bulk solution obtained form step 4, and the stirring was continued until selexipag gets mixed properly.

6. pH of the bulk solution obtained from Step 5 was adjusted to between 7.0 and 8.0 with Sodium Hydroxide. The selexipag was completely solubilized and clear colorless solution was observed.

7. the volume was made up to 100 mL with WFI and stirred for 10 minutes and pH of the final bulk solution was checked.

8. the bulk solution was filtered through 0.2p PVDF membrane filter.

9. the filtered bulk solution was filled into 10 mL clear tubular European blow back vials with a desired fill volume and half stoppered with Single slotted rubber stoppers and loaded into lyophilizer.

Lyophilization process:

10. Freeze-drying said aqueous pharmaceutical composition of step 9) to form a cake using a method comprising the steps of:

(a) the aqueous pharmaceutical composition of step 9) was freeze at a first temperature for a period sufficient to transform the liquid formulation into solid state (especially for a period of at least about 1 hour), wherein said first temperature is in the range of about -55° C. to -25° C. (especially about -45° C.);

(b) annealing the frozen composition of step 10) (a) at a second temperature (notably for a period of at least about 1 hour, especially at least about 2 hours); wherein said second temperature is in the range of about -20° C. to -1° C. (notably about -10° C. to -2° C.; especially about -3° C.); (c) the frozen composition of step 10) (b) was subjected to a vacuum (notably a vacuum of about 0.1 to 1.5 mbar, especially about 0.2 to 1.2 mbar, in particular 0.5±0.1 mbar) at a third temperature wherein said third temperature is in the range of about -55° C. to -25° C. (especially about -45° C.); and

(d) the composition from step 10) (c) was dried in said vacuum at a fourth temperature (notably for a period of at least about 2 hours, especially of at least about 5 hours, in particular between about 5 to 15 hours, about 5 to 19 hours, preferably between about 5 to 22 hours or between 5 to 15 hours) wherein said fourth temperature is in the range of about 1° C. to 40° C.; notably in the range of about 55° C. to 35° C.; especially about 35° C.

(e) optionally, the composition may be hold at a closing temperature of about 20° C. to 35° C., preferably 20° C.

Stability Data:

The formulations of Example- 1&2 were stored at about 2-8 °C & 25°C temperature and a relative humidity of about 60% after packing into vials with cap. The results of initial & 6 months stability are tabulated below':

The formulation of Example-3 were stored at about 2-8 °C & 25°C temperature and a relative humidity of about 60% after packing into vials with cap. The results of initial & 6 months stability are tabulated below: