WO2024218790A1

WO2024218790A1 - A pharmaceutical composition of ubrogepant and their process for the preparation of solid dosage form for treating migraine

Info

Publication number: WO2024218790A1
Application number: PCT/IN2024/050399
Authority: WO
Inventors: Nithiyanandam RAVI KUMAR; Praveen Kumar GADAPA; Uday Kumar GOTTAPU
Original assignee: Msn Laboratories Private Limited, R&D Center
Priority date: 2023-04-15
Filing date: 2024-04-15
Publication date: 2024-10-24

Abstract

The present invention relates to solid pharmaceutical composition comprising amorphous form of ubrogepant and process for preparation thereof, which is simple, economic, cost-effective, and industrially amenable to scale up. Further, the said invention is used for the acute treatment of migraine with or without aura in adults.

Description

A pharmaceutical composition of ubrogepant and their process for the preparation of solid dosage form for treating migraine

Related applications:

This application claims the benefit of priority of our Indian patent application numbers 202341027776 filed on Apr 15, 2023 which is incorporated herein by reference.

Field of the Invention:

Background of the Invention:

Migraine is a primary headache disorder characterized by recurrent headaches that are moderate to severe, accompanied by various associated symptoms. The typical headache of migraine is throbbing, unilateral, and aggravated by motion, but bilateral and/or nonthrobbing headache is also commonly reported. Typical migraine-associated symptoms include nausea, vomiting, photophobia, and phonophobia, but a range of other neurological symptoms may occur, with various degrees of cognitive impairment often present. Migraine attacks typically last between 4 to 72 hours in adults. About one-third of individuals with migraine experience transient neurological symptoms before and/or during a migraine attack, referred to as migraine aura. Generally accepted diagnostic criteria for migraine are presented in the International Classification of Headache Disorders (ICHD).

Many products are FDA-approved for the acute treatment of migraine in adults. These products include a number of different triptans, dihydroergotamine, nonsteroidal antiinflammatory drugs (NSAIDs) used alone or in combination with a triptan, and a 5-HT1F agonist, lasmiditan, which was recently approved. In addition, there are many over-the- counter medications that are labeled for the acute treatment of migraine. Recently, three monoclonal antibodies targeting the CGRP (Calcitonin Gene-Related Peptide) system have been approved for the preventive treatment of both chronic and episodic migraine; erenumab (Aimovig) targeting the CGRP receptor, and fremanezumab (Ajovy) and galcanezumab (Emgality) targeting the CGRP peptide.

CGRP (Calcitonin Gene-Related Peptide) is a naturally occurring 37-amino acid peptide that is generated by tissue-specific alternate processing of calcitonin messenger RNA and is widely distributed in the central and peripheral nervous system. Calcitonin gene- related peptide (CGRP) is a potent vasodilatory neurotransmitter believed to play a key role in migraine pathophysiology. The initial human clinical validation of the CGRP target was provided by Boehringer Ingelheim in 2003 with the report that an IV formulation comprising olcegepant was efficacious in the acute treatment of migraine. There are some oral therapies are available in market with CGPR antagonist activity, such are like ubrogepant, rimegepant and atogepant. Some drug candidates are still under development in this CGPR category are Telcagepant and olcegepant.

Ubrogepant is a small molecule targeting CGRP, the chemical name of ubrogepant is (3'S)-N-((3S,5S,6R)-6-methyl-2-oxo-5- phenyl- 1- (2,2,2-trifluoroethyl) piperidin-3-yl)-2'- oxo- l',2',5,7-tetrahydrospiro [cyclopenta [b] pyridine-6,3'-pyrrolo [2,3-b]pyridine]-3- carboxamide and has the following structure:

Ubrogepant (CAS No: 1374248-77-7)

According to FDA reviews, the molecular formula for ubrogepant is C29H26F3N5O3 and molecular weight is 549.6 g/mol. Ubrogepant drug substance is a free base and is a white to off-white powder. It is freely soluble in ethanol, methanol, acetone, and acetonitrile; and is practically insoluble in water. Ubrogepant is hygroscopic and has several known polymorphs and solvates and it is a BCS IV (low solubility/low permeability) drug substance.

Ubrogepant was first approved in United States on Dec 23, 2019 as an immediate release oral tablet dosage form of 50 mg and lOOmg dose for the acute treatment of migraine with or without aura in adults. The inactive ingredients include in UBRELVY are colloidal silicon dioxide, croscarmellose sodium, mannitol, microcrystalline cellulose, polyvinyl pyrrolidone vinyl acetate copolymer, sodium chloride, sodium stearyl fumarate, and vitamin E polyethylene glycol succinate.

US patent no. US8912210B2 discloses ubrogepant freebase and its pharmaceutically acceptable salts thereof.

US patent no. US9833448B2 discloses method of treating migraine by administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising ubrogepant.

US patent no. US9850246B2 discloses crystalline form of ubrogepant monohydrate.

US patent no. US10117836B2 discloses a tablet comprising an extrudate comprising water soluble polymer matrix, dispersing agent and ubrogepant further comprising disintegrating system and other pharmaceutically acceptable excipients, wherein the polymer matrix in said extrudate is a water soluble polyvinylpyrrolidone/vinyl acetate (PVP-VA) copolymer, wherein said dispersing agent is vitamin E-tocopherol polyethylene glycol succinate (TPGS), wherein said disintegration system comprises powdered sodium chloride and croscarmellose sodium, further comprising mannitol; colloidal silica; microcrystalline cellulose; and sodium stearyl fumarate.

Literature suggests that formulating low soluble compounds like ubrogepant into suitable solid oral dosage forms like tablets is challenging because the formulation development requires solid dispersion via Hot Melt Extrusion (HME). While employing HME technique, ubrogepant tend to thermally degrade when attempts are made to incorporate them into a matrix comprising certain commercially available cellulosic polymers. In addition to the matrix polymer, the extrudate prepared by HME technique also requires dispersing agent such as TPGS to reduce the thermal energy required to drive ubrogepant into solution in the matrix polymer and promote formation of the dispersion with lower degradation of ubrogepant.

As a consequence, there is an imperious necessity in the field of pharmaceutical industry to develop robust, stable, more economical, less hazardous, reproducible pharmaceutical formulations of ubrogepant in combination with a suitable pharmaceutical excipients by careful selection of pharmaceutically acceptable carriers / excipients in order to provide bioavailability to the active substance, stability over shelf life, and bioequivalence with the originator product.

In order to solve the above problem, the inventors of the present invention have conducted a series of experiments and surprisingly developed a simple, economic, cost- effective, industrially amenable to scale up and advantageous solid pharmaceutical composition comprising ubrogepant which exhibits a dissolution profile, stability and bioavailability that is at least comparable to that of UBRELVY® formulations without the need of solid dispersion or hot-melt extrusion (HME).

Summary of the Invention:

The present invention relates to pharmaceutical composition comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients. Furthe, the present invention also provides process for the preparation of said pharmaceutical composition.

First embodiment of the present invention is to provide a pharmaceutical composition comprising ubrogepant as an active ingredient and one or more pharmaceutical acceptable excipients, wherein said pharmaceutical composition is free from solid dispersion or solid solution.

Second embodiment of the present invention is to provide a pharmaceutical composition comprising ubrogepant as an active ingredient and one or more pharmaceutical acceptable excipients, wherein said pharmaceutical composition is free from dispersing agent and / or a matrix polymer.

Third embodiment of the present invention is to provide a pharmaceutical composition comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients.

First aspect of third embodiment of the present invention is to provide a pharmaceutical composition comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients wherein said excipients are those which improve the solubility / dissolution and permeability / absorption of the said pharmaceutical composition.

Fourth embodiment of the present invention is to provide a pharmaceutical composition comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients wherein said pharmaceutically acceptable carriers / excipients include one or more binder and / or surfactant.

First aspect of the fourth embodiment of the present invention is to provide a pharmaceutical composition comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients include one or more binder and / or surfactants. Wherein binder is present in an amount of about 1% w/w to about 10% w/w and surfactant is present in an amount of about 0.01% w/w to about 15% w/w. Preferably binder is present from about 2% w/w to about 8% w/w and surfactant is present from about 0.1% w/w to about 10% w/w.

Second aspect of the fourth embodiment of the present invention is to provide a pharmaceutical composition comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients wherein said pharmaceutically acceptable carriers / excipients include but not limited to one or more fillers, diluents, disintegrants, binders, surfactants, glidants, lubricants etc...

Fifth embodiment of the present invention is to provide a pharmaceutical composition comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients comprising: ubrogepant from about 8 % w/w to about 13 % w/w filler from about 10 % w/w to about 90 % w/w optionally disintegrating system from about 1 % w/w to about 40 % w/w disintegrant from about 1 % w/w to about 20 % w/w binder from about 1 % w/w to about 10 % w/w surfactant from about 0.01 % w/w to about 15 % w/w glidant from about 0.01 % w/w to about 5 % w/w lubricant from about 0.01 % w/w to about 5 % w/w

First aspect of fifth embodiment of the present invention is to provide a pharmaceutical composition comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients comprising: ubrogepant from about 8 % w/w to about 13 % w/w filler from about 20 % w/w to about 85 % w/w optionally disintegrating system from about 2 % w/w to about 25 % w/w disintegrant from about 8 % w/w to about 13 % w/w binder from about 2 % w/w to about 8 % w/w surfactant from about 0.1 % w/w to about 10 % w/w glidant from about 0.1 % w/w to about 2 % w/w lubricant from about 0.1 % w/w to about 2.5 % w/w

Second aspect of fifth embodiment of the present invention is to provide a pharmaceutical composition comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients comprising: ubrogepant from about 8 % w/w to about 13 % w/w filler from about 20 % w/w to about 85 % w/w disintegrating system from about 2 % w/w to about 25 % w/w disintegrant from about 5 % w/w to about 15 % w/w binder from about 2 % w/w to about 8 % w/w surfactant from about 0.1 % w/w to about 10 % w/w glidant from about 0.1 % w/w to about 2 % w/w lubricant from about 0.1 % w/w to about 2.5 % w/w

Sixth embodiment of the present invention is to provide a process for preparing a pharmaceutical composition comprising amorphous form of ubrogepant wherein said process for the preparation of pharmaceutical composition comprises granulation technique.

First aspect of the sixth embodiment of the present invention wherein, said granulation technique preferably comprises wet granulation.

Seventh embodiment of the present invention relates to a process for the preparation of solid dosage form comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients. First aspect of the seventh embodiment of the present invention relates to a process of preparing solid dosage form comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients comprising the following steps:

1. sifting & blending ubrogepant, microcrystalline cellulose, mannitol, optionally sodium chloride and optionally croscarmellose sodium.

2. sifting & blending suitable binders and surfactants in suitable solvent to prepare binder solution

3. granulating the blend obtained in step (1) by using binder solution of obtained in step (2);

4. further processing the granules obtained form step (3) for the preparation of tablet.

Eighth embodiment of the present invention discloses pharmaceutical formulations comprising amorphous ubrogepant for use as medicament for the treatment of migraine with or without aura in adults.

The present invention may be embodied in other specific form without departing its spirit or essential characteristics. The described embodiments are to be considered in all respect only as illustrative and not restrictive. 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 pharmaceutical compositions that comprise amorphous form of ubrogepant wherein said invention is used for the acute treatment of migraine with or without aura in adults. Further the invention relates to the process for the preparation of said pharmaceutical composition.

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 CGRP (Calcitonin Gene-Related Peptide) receptor antagonist or a pharmaceutically acceptable salt thereof, preferably ubrogepant.

As used herein, the term “composition or pharmaceutical composition or formulation” refers to solid dosage forms, such as but not limited to tablet, capsule, granules, pellets, films, implants, suppositories etc.. Preferably, the pharmaceutical composition is an oral dosage form, more preferably tablet dosage form.

As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably herein. These terms refer 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, not with standing that the patient may still be afflicted with the underlying disorder. For prophylactic benefit, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. The compositions may be administered to a subject to prevent progression of physiological symptoms or to prevent progression of the underlying disorder.

As used herein, the term "therapeutically effective amount" of a compound as used herein means an amount sufficient to cure, alleviate 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 carriers” 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.

As used herein, “dispersing agent” can reduce the thermal energy required to drive drug compound into solution in the matrix polymer and promote formation of the dispersion with even low degradation losses in the drug compound dispersed in the matrix at higher temperatures used in some of the solid dispersion techniques like HME. Preferred dispersing agents are vitamin E in the form of its polyethylene glycol succinate (d-alpha-tocopheryl polyethyleneglycol succinate, or TPGS, herein). An example of a commercially available TPGS suitable in solid dispersions are any that provide esterified d-alpha-tocopheryl succinate with polyethylene glycol 1000, for example, but not limited to, Vitamin E d-TPGS NF.

As used herein, “disintegration system” is a combination of a conventional disintegrant and a rapidly dissolving salt.

As used herein “solvent” is a substance that is capable of dissolving other substances to form a homogenous solution. In the pharmaceutical industry, solvents are used for various purposes, such as dissolving active pharmaceutical ingredients (APIs), excipients, and other ingredients to create liquid and solid formulations such as syrups, suspensions, and solid dosage forms. Commonly used solvents in the pharmaceutical industry include water, propylene glycol, glycerin, ethanol, dimethyl sulfoxide (DMSO), and various oils and fats, depending on the specific requirements of the formulation and the intended route of administration. The selection of solvents in the pharmaceutical industry is carefully evaluated to ensure their safety, efficacy, and compatibility with the intended application. Preferably water or ethanol.

When used here in 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 the recited value.

Pharmaceutical excipients are substances other than the pharmacologically active drug or prodrug which are included in the manufacturing process or are contained in a finished pharmaceutical product dosage form. In addition to transporting the active drug to the site in the body where the drug is intended to exert its action, excipients play an important part in the manufacturing process. They may also be important for keeping the drug from being released too early in the assimilation process in places where it could damage tender tissue and create gastric irritation or stomach upset. Some helps the drug to disintegrate into particles small enough to reach the blood stream more quickly and still others protect the product's stability so it will be at maximum effectiveness at time of use. In addition, some excipients are used to aid the identification of a drug product.

The pharmaceutical composition according to the invention typically comprises at least one diluent. Suitable diluents include monosaccharides and oligosaccharides such as glucose, fructose, saccharose, lactose (anhydrous and monohydrate), raffinose, trehalose and dextrates, sugar alcohols such as mannitol, sorbitol, maltitol, xylitol and lactitol, compressible sugar, microcrystalline cellulose, magnesium aluminium metasilicate, pregelatinized starch, corn/ maize starch, powdered cellulose, silicified microcrystalline cellulose, silicon dioxide, crospovidone, croscarmellose sodium, calcium hydrogen phosphate, calcium carbonate, calcium lactate and mixtures thereof. The preferred diluent is at least one selected from silicified microcrystalline cellulose, microcrystalline cellulose, and mannitol.

The binder is used in a pharmaceutical composition to improve the flow properties of powder and to improve compatibility. The binders are selected from but are not limited to cellulose derivatives such as hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose sodium, microcrystalline cellulose, gelatin, starch paste, pregelatinized starch, povidone or polyvinylpyrrolidone and sucrose. The preferred binder is at least on selected from starch and povidone.

Surfactants are compounds that lower the surface tension (or interfacial tension) between two liquids or between a liquid and a solid. The surfactant used in the present invention may be amphoteric, non-ionic, cationic or anionic. Examples include, but are not limited to, sodium lauryl sulfate, sodium dioctylsulfosuccinate (DOSS), lecithin, cetrimide, polysorbate, poloxamer, spans, polyoxyethylene resin oil, polyoxyethylene fatty acid glycerides, and mixtures thereof. The most preferred surfactant is at least one selected form polysorbate, sodium lauryl sulphate and poloxamer.

Disintegrating agents suitable for use in the present formulations include which facilitate the break up of a tablet when it is placed in aqueous environment. Disintegrants once in contact with water or gastric juice, swell, hydrate, change in volume or form to produce a disruptive force that opposes the efficiency of the binder/s causing the compressed table to break apart. The disintegrants are selected from maize starch, potato starch, carboxymethylstarche, sodium starch glycolate, crospovidones, sodium carboxymethylcelluloses, croscarmellose sodium, sodium alginate, microcrystalline cellulose, methacrylic acid copolymer, potassium polacrilin. The most preferred disintegrant in a present pharmaceutical composition are at least one selected from crospovidone and croscarmellose sodium.

Glidant in the context of the present invention is taken to mean an ingredient which enhances product flow by reducing inter-particulate friction. The glidant is selected from colloidal silicon dioxide, aluminum silicate, magnesium silicate, calcium stearate, fumed silica, talc, powdered cellulose, starch and tribasic calcium phosphate. The most preferred glidant are talc and colloidal silicon dioxide.

Lubricants are used in the tablet formulation to reduce the friction during the compression stages and to prevent the sticking of the tablet to the punch faces. Lubricant is selected from stearic acid (calcium stearate and magnesium stearate), vegetable oils(corn oil), mineral oils, polyethylene glycol, inorganic salts (such as sodium chloride), organic salts (sodium benzoate, sodium acetate), and polyvinyl alcohols, fumarate like sodium stearyl fumarate. The most preferred lubricant is selected from magnesium stearate and sodium stearyl fumarate.

Coating is a process by which an essentially dry, outer layer of coating material is applied to the surface of a dosage form in order to confer specific benefits over uncoated variety. Coating may be carried out by using coating agents such as Opadry Yellow, Opadry Black, Opadry Red and Opadry White.

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.

Third aspect of fifth embodiment of the present invention is to provide a pharmaceutical composition comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients, wherein, ubrogepant is about 8 % w/w based on total weight percent of composition, microcrystalline cellulose is about 34.5 % w/w, mannitol is about 30 % w/w, croscarmellose sodium is about 15% w/w, povidone is about 5 % w/w, sodium lauryl sulphate is about 6 % w/w, colloidal silicon dioxide is about 0.5 % w/w and sodium stearyl fumarate is about 1 % w/w.

Fourth aspect of fifth embodiment of the present invention is to provide a pharmaceutical composition comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients, wherein, ubrogepant is about 10% w/w based on total weight percent of composition, microcrystalline cellulose is about 30.5 % w/w, mannitol is about 30 % w/w, croscarmellose sodium is about 15% w/w, povidone is about 5 % w/w, sodium lauryl sulphate is about 8 % w/w, colloidal silicon dioxide is about 1 % w/w and sodium stearyl fumarate is about 0.5 % w/w.

Fifth aspect of fifth embodiment of the present invention is to provide a pharmaceutical composition comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients, wherein, ubrogepant is about 13% w/w based on total weight percent of composition, microcrystalline cellulose is about 32.5 % w/w, mannitol is about 28 % w/w, croscarmellose sodium is about 15% w/w, povidone is about 5 % w/w, sodium lauryl sulphate is about 5 % w/w, colloidal silicon dioxide is about 0.5 % w/w and sodium stearyl fumarate is about 1 % w/w.

Sixth aspect of fifth embodiment of the present invention is to provide a pharmaceutical composition comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients, wherein, ubrogepant is about 8 % w/w based on total weight percent of composition, microcrystalline cellulose is about 15 % w/w, mannitol is about 30.5 % w/w, sodium chloride is about 15 % w/w, croscarmellose sodium is about 15% w/w, povidone is about 10 % w/w, sodium lauryl sulphate is about 5 % w/w, colloidal silicon dioxide is about 0.5 % w/w and sodium stearyl fumarate is about 1 % w/w.

Seventh aspect of fifth embodiment of the present invention is to provide a pharmaceutical composition comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients, wherein, ubrogepant is about 10% w/w based on total weight percent of composition, microcrystalline cellulose is about 20 % w/w, mannitol is about 23.5 % w/w, sodium chloride is about 15 % w/w, croscarmellose sodium is about 20% w/w, povidone is about 5 % w/w, sodium lauryl sulphate is about 5 % w/w, colloidal silicon dioxide is about 0.5 % w/w and sodium stearyl fumarate is about 1 % w/w.

Eighth aspect of fifth embodiment of the present invention is to provide a pharmaceutical composition comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients, wherein, ubrogepant is about 13% w/w based on total weight percent of composition, microcrystalline cellulose is about 15 % w/w, mannitol is about 25.5 % w/w, sodium chloride is about 15 % w/w, croscarmellose sodium is about 20% w/w, povidone is about 5 % w/w, sodium lauryl sulphate is about 5 % w/w, colloidal silicon dioxide is about 1 % w/w and sodium stearyl fumarate is about 0.5 % w/w.

Ninth aspect of fifth embodiment of the present invention is to provide a pharmaceutical composition comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients, wherein, ubrogepant is about 8 % w/w based on total weight percent of composition, microcrystalline cellulose is about 38.5 % w/w, mannitol is about 25 % w/w, povidone is about 2 % w/w, polysorbate is about 1 % w/w, croscarmellose sodium is about 12% w/w, colloidal silicon dioxide is about 0.5 % w/w, sodium carbonate is about 8 % w/w and sodium stearyl fumarate is about 1 % w/w.

Tenth aspect of fifth embodiment of the present invention is to provide a pharmaceutical composition comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients, wherein, ubrogepant is about 10% w/w based on total weight percent of composition, microcrystalline cellulose is about 30.5 % w/w, mannitol is about 30 % w/w, povidone is about 6 % w/w, polysorbate is about 2 % w/w, croscarmellose sodium is about 10% w/w, colloidal silicon dioxide is about 0.5 % w/w, sodium carbonate is about 10 % w/w and sodium stearyl fumarate is about 1 % w/w.

Eleventh aspect of fifth embodiment of the present invention is to provide a pharmaceutical composition comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients, wherein, ubrogepant is about 13% w/w based on total weight percent of composition, microcrystalline cellulose is about 36.5 % w/w, mannitol is about 25 % w/w, povidone is about 3 % w/w, polysorbate is about 1 % w/w, croscarmellose sodium is about 12 % w/w, colloidal silicon dioxide is about 0.5 % w/w, sodium carbonate is about 8 % w/w and sodium stearyl fumarate is about 1 % w/w.

Twelfth aspect of fifth embodiment of the present invention is to provide a pharmaceutical composition comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients, wherein, ubrogepant is about 8% w/w based on total weight percent of composition, microcrystalline cellulose is about 39.5 % w/w, mannitol is about 26 % w/w, sodium chloride is about 5 % w/w, croscarmellose sodium is about 5% w/w, povidone is about 4 % w/w, polysorbate is about 1 % w/w, crospovidone is about 10% w/w, colloidal silicon dioxide is about 0.5 % w/w and sodium stearyl fumarate is about 1 % w/w.

Thirteenth aspect of fifth embodiment of the present invention is to provide a pharmaceutical composition comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients, wherein, ubrogepant is about 8% w/w based on total weight percent of composition, microcrystalline cellulose is about 39.5 % w/w, mannitol is about 26 % w/w, sodium chloride is about 5 % w/w, croscarmellose sodium is about 6% w/w, povidone is about 5 % w/w, polysorbate is about 1 % w/w, crospovidone is about 8% w/w, colloidal silicon dioxide is about 0.5 % w/w and sodium stearyl fumarate is about 1 % w/w.

Fourteenth aspect of fifth embodiment of the present invention is to provide a pharmaceutical composition comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients, wherein, ubrogepant is about 10% w/w based on total weight percent of composition, microcrystalline cellulose is about 39.5 % w/w, mannitol is about 26 % w/w, sodium chloride is about 5 % w/w, croscarmellose sodium is about 4% w/w, povidone is about 2 % w/w, polysorbate is about 2 % w/w, crospovidone is about 10% w/w, colloidal silicon dioxide is about 0.5 % w/w and sodium stearyl fumarate is about 1 % w/w.

Fifteenth aspect of fifth embodiment of the present invention is to provide a pharmaceutical composition comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients, wherein, ubrogepant is about 10% w/w based on total weight percent of composition, microcrystalline cellulose is about 38.5 % w/w, mannitol is about 25 % w/w, sodium chloride is about 5 % w/w, croscarmellose sodium is about 5% w/w, povidone is about 4 % w/w, polysorbate is about 1 % w/w, crospovidone is about 10% w/w, colloidal silicon dioxide is about 0.5 % w/w and sodium stearyl fumarate is about 1 % w/w.

Sixteenth aspect of fifth embodiment of the present invention is to provide a pharmaceutical composition comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients, wherein, ubrogepant is about 13% w/w based on total weight percent of composition, microcrystalline cellulose is about 36.5 % w/w, mannitol is about 25 % w/w, sodium chloride is about 5 % w/w, croscarmellose sodium is about 5% w/w, povidone is about 3 % w/w, polysorbate is about 1 % w/w, crospovidone is about 10% w/w, colloidal silicon dioxide is about 0.5 % w/w and sodium stearyl fumarate is about 1 % w/w.

Seventeenth aspect of fifth embodiment of the present invention is to provide a pharmaceutical composition comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients, wherein, ubrogepant is about 13% w/w based on total weight percent of composition, microcrystalline cellulose is about 38.5 % w/w, mannitol is about 25 % w/w, sodium chloride is about 4 % w/w, croscarmellose sodium is about 4% w/w, povidone is about 3 % w/w, polysorbate is about 1 % w/w, crospovidone is about 10% w/w, colloidal silicon dioxide is about 0.5 % w/w and sodium stearyl fumarate is about 1 % w/w.

Seventh embodiment of the present invention relates to a process for the preparation of solid dosage form comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients.

First aspect of the seventh embodiment of the present invention relates to a process of preparing solid dosage form comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients comprising the following steps:

1. sifting ubrogepant, microcrystalline cellulose, mannitol, optionally sodium chloride and optionally croscarmellose sodium and blending / mixing in a rapid mixture granulator for about 10 minutes by keeping impeller / chopper setting as slow (175 RPM);

2. sifting suitable binders and surfactants in suitable solvent under continuous stirring and continue stirring till clear binder solution obtained.

4. drying the granules obtained from step (3) in rapid drier at an inlet temperature of 35 °C - 45 °C with intermittent raking. Checking the loos on drying by using moisture analyser at 105 °C, continued the drying until desired LOD is reached,

5. milling the dried granules obtained in step (4) through suitable sieve, milled the # 30 sieve retains through 40G screen using Quadro comil at medium speed (3500 RPM).

6. sifting extra granular ingredient croscarmellose sodium, optionally crospovidone, optionally microcrystalline cellulose, optionally sodium carbonate and colloidal silicon dioxide through suitable sieve.

7. blending the granules obtained in step (5) and extra granular ingredients obtained in step (6) in a suitable blender for 10 minutes at 15 RPM.

8. lubricating the granules obtained in step (7) with sodium stearyl fumarate for 5 minutes at 15 RPM in a suitable blender.

9. compressing the lubricated blend obtained in step (8) is into tablets using capsule shape, concave punches and collecting the tablets in double lined poly bag containing HDPE drum.

10. optionally, coating the tablet with film coating solution

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.

5 EXAMPLES

Examples 1-4:

10 Manufacturing process: 1. Ubrogepant, microcrystalline cellulose, mannitol, optionally sodium chloride and optionally croscarmellose sodium were co-sifted through suitable sieve and the sifted material is loaded in rapid mixer granulator and mix well.

2. Binder solution was prepared by dissolving Povidone K-30, Polysorbate 80 (or) sodium lauryl sulfate, optionally sodium chloride in ethanol / water and stirring was continued till the clear solution was obtained.

3. Granulation: granulation of blend obtained in step (1) was done by using binder solution of obtained in step (2);

4. Granules formed in step (3) were dried at suitable temperature to obtain suitable loss on drying (LOD);

5. Dried granules of step (4) were sifted and milled and passed through suitable sieve;

6. Extra granular ingredient croscarmellose sodium, optionally crospovidone, optionally microcrystalline cellulose, optionally sodium carbonate and colloidal silicon dioxide were sifted through suitable sieve.

7. Granules of step (5) and extra granular ingredients of step (6) were mixed and blended in a suitable blender;

8. Sodium stearyl fumarate was added to granules of step (7).

9. The blend of step (8) was compressed using suitable tooling to form uncoated tablets and was film coated.

In vitro dissolution study

Dissolution studies were performed separately in accordance with the dissolution method. The dissolution conditions were 900 ml of simulated gastric fluid SGF (without enzyme), 0.05% HCl/34mM NaCl, pH of 1.8 at 37±0.5°C with USP type II dissolution test apparatus at a speed of 50 & 75 rpm. The sample (10 ml) was withdrawn at regular time intervals (5, 10, 15, 20, 30, 45, 60 and 75 Min.) and replaced the same with fresh dissolution medium. The samples were estimated for amount of drug dissolved by measuring their absorbance. The amount of drug released was calculated and plotted against time in below table. Table 01:

Content of Related substance or Impurity: (% w/w by HPLC):

Stability samples of present invention pharmaceutical composition comprising ubrogepant and a pharmaceutically acceptable carrier were evaluated for related substance or impurities by HPLC. Wherein the said pharmaceutical composition has a Acid impurity, Amine impurity, Any unspecified degradation products of less than about 1.0 % as measured by HPLC are tabulated below.

Table 02:

Claims

1. A pharmaceutical composition comprising ubrogepant as an active ingredient and one or more pharmaceutically acceptable excipients, wherein said pharmaceutical composition is free from solid dispersion or solid solution.

2. A pharmaceutical composition comprising ubrogepant as an active ingredient and one or more pharmaceutically acceptable excipients, wherein said pharmaceutical composition is free from dispersing agent and / or a matrix polymer.

3. The pharmaceutical composition according to claim 1 comprising of ubrogepant and one or more pharmaceutically acceptable excipients comprising: ubrogepant from about 8 % w/w to about 13 % w/w filler from about 10 % w/w to about 90 % w/w optionally disintegrating system from about 1 % w/w to about 40 % w/w disintegrant from about 1 % w/w to about 20 % w/w binder from about 1 % w/w to about 10 % w/w surfactant from about 0.01 % w/w to about 15 % w/w glidant from about 0.01 % w/w to about 5 % w/w lubricant from about 0.01 % w/w to about 5 % w/w

4. The pharmaceutical composition according to claim 1 comprising ubrogepant and one or more pharmaceutically acceptable excipients comprising: ubrogepant from about 8 % w/w to about 13 % w/w filler from about 20 % w/w to about 85 % w/w disintegrating system from about 2 % w/w to about 25 % w/w disintegrant from about 5 % w/w to about 15 % w/w binder from about 2 % w/w to about 8 % w/w surfactant from about 0.1 % w/w to about 10 % w/w glidant from about 0.1 % w/w to about 2 % w/w lubricant from about 0.1 % w/w to about 2.5 % w/w.

5. The pharmaceutical composition according to claim 1 wherein ubrogepant is present in amorphous form.

6. The pharmaceutical composition according to claim 1 comprising ubrogepant and one or more pharmaceutically acceptable excipients, wherein, ubrogepant is about 10% w/w based on total weight percent of composition, microcrystalline cellulose is about 38.5 % w/w, mannitol is about 25 % w/w, sodium chloride is about 5 % w/w, croscarmellose sodium is about 5% w/w, povidone is about 4 % w/w, polysorbate is about 1 % w/w, crospovidone is about 10% w/w, colloidal silicon dioxide is about 0.5 % w/w and sodium stearyl fumarate is about 1 % w/w.

7. The pharmaceutical composition according to claim 1 comprising ubrogepant and one or more pharmaceutically acceptable excipients, wherein, ubrogepant is about 8 % w/w based on total weight percent of composition, microcrystalline cellulose is about 34.5 % w/w, mannitol is about 30 % w/w, croscarmellose sodium is about 15% w/w, povidone is about 5 % w/w, sodium lauryl sulphate is about 6 % w/w, colloidal silicon dioxide is about 0.5 % w/w and sodium stearyl fumarate is about 1 % w/w.

8. The pharmaceutical composition according to claim 1 comprising ubrogepant and one or more pharmaceutically acceptable excipients, wherein, ubrogepant is about 13% w/w based on total weight percent of composition, microcrystalline cellulose is about 36.5 % w/w, mannitol is about 25 % w/w, sodium chloride is about 5 % w/w, croscarmellose sodium is about 5% w/w, povidone is about 3 % w/w, polysorbate is about 1 % w/w, crospovidone is about 10% w/w, colloidal silicon dioxide is about 0.5 % w/w and sodium stearyl fumarate is about 1 % w/w.

9. The process according to claim 1 for preparing a pharmaceutical composition comprising ubrogepant wherein said process for the preparation of pharmaceutical composition comprises granulation technique, preferably comprises wet granulation

10. The pharmaceutical formulations according to claim 1 comprising ubrogepant for use as medicament for the treatment of migraine with or without aura in adults.