FIELD OF THE INVENTION:

The present invention relates to a pharmaceutical composition comprising ubrogepant or pharmaceutically acceptable salts thereof and selfadministration injection device comprising composition of ubrogepant for parenteral administration.

BACKGROUND OF THE INVENTION:

Migraine is a primary headache disorder characterized by recurrent headaches that are moderate to severe, accompanied by various associated symptoms. It is a common neurological disorder that greatly affects quality of life and increases work disruption. The cause of migraine is uncertain but may be the result of vascular and/or neurological dysfunction. It is often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. Migraine attacks can last for hours to days, and the pain can be so severe that it interferes with daily activities.

There are many therapies approved by different regulatory agencies for acute migraine such as triptans, dihydroergotamines (DHE), lasmiditan, and certain non-steroidal anti-inflammatory drugs (NSAIDs), which can be used alone or in combination with a triptan and CGRP antagonists like Ubrogepant, Rimegepant, Atogepant. Triptans and DHE are contraindicated in patients with cardiovascular (CV) disease and NSAIDS have labelling that warns patients of the risk of CV events with the use of these products. Lasmiditan includes a restriction on driving for 8 hours following a dose, and does not allow for a second dose within 24 hours. In addition, there are several over-the-counter drugs marketed for migraine. Ubrogepant is an oral, calcitonin gene-related peptide (CGRP) receptor antagonist. It is marketed as immediate release 50mg and 100mg oral tablet under the tradename UBRELVY by Allergan and is indicated for the acute treatment of migraine with or without aura in adults. CGRP and its receptors are expressed in regions of the nervous system associated with migraine pathophysiology. CGRP levels in the cranial circulation are increased during a migraine attack and CGRP itself has been shown to trigger migraine-like headache. UBRELVY is not indicated for the preventive treatment of migraine. The most common adverse reactions (at least 2% and greater than placebo) of UBRELVY were nausea and somnolence.

The US patents 8,754,096, 8,912,210, 9,499,545 and 9,833,448 claims the compound ubrogepant or salts thereof and method of treating migraine by administering composition along with carriers. The said patents generically disclose that Ubrogepant may be administered by parenteral route (e.g., intramuscular, intraperitoneal, intravenous, Intracerebroventricular, intracisternal injection or infusion, subcutaneous injection, or implant) along with oral, inhalation, nasal, vaginal, rectal, sublingual, buccal or topical routes of administration.

The US patent 10,1 17,836 claims fast disintegration tablet composition comprising ubrogepant along with polymer matrix disintegration system for oral administration.

The US patent publications 20190374520 and 20210379029 teaches method of prophylactically treating migraine by orally administering CGRP- antagonist such as atogepant, ubrogepant, rimegepant or salts thereof. It generically discloses the CGRP-antagonist can be administered orally, sublingually, transdermally, subcutaneous, intravenous, or intramuscular routes. The PCT publication WO2015038736A2 discloses alcohol-free, low volume oral liquid composition comprising Ubrogepant along with polyethylene glycol 400, propylene glycol, Vitamin E-TPGS, PVP, sucralose and water for treating migraine headache.

The US patent publication 20220031849 is related to aqueous liquid comprising polymeric nanoparticles for the targeted delivery of hydrophobic modulators of endosomal GPCRs is Ubrogepant from the long list and their use in the treatment of migraine. US’849 is specific to intrathecal injection composition of aprepitant.

The PCT publication W02020077038A1 discloses prodrugs of CGRP antagonists, composition, and treatment of migraine. It is generically teaches that CGRP antagonist can be formulated as different dosage forms including injectable formulation for parenteral (IM, IV, SC etc) administration as one of the routes of administration from the list.

The current treatment options for migraine are inadequate and restricted due to their side effects. However, many patients still do not respond adequately to these therapies.

One of the most important requirements in migraine patients is rapid onset of relief. The existing medications for migraine administered by oral routes and non-oral routes such as transdermal or nasal, which are limited due to slow absorption that can delay relief by an hour or more. Oral medications have the additional disadvantage that they are ineffective in the patients when the migraine is associated with vomiting. Few migraine medications such as sumatriptan are available as injection and administered subcutaneously as prefilled auto injector but the use of triptans is limited in certain patients due to their side effects. The migraine patients need more frequent visits to hospitals and emergency rooms than non-migraine patients for the acute treatment of migraine pain. The frequent visit of migraine patients to emergency rooms requires dependability on another person to drive them, more cost, long wait time in hospital to see the doctor and noisy environment that can worsen the symptoms. Further the follow-up care is essential to patients with frequent migraine headaches in order to prevent repeat emergency room visits.

Ubrogepant is commercially available as tablet by oral route; which is limited due to certain disadvantages in migraine treatment and requirement of quick onset of action in migraine patient.

None of the art teaches or suggest the injectable composition comprising Ubrogepant. Further, the art is silent on self-administration injection device injectable composition comprising Ubrogepant for treatment of migraine.

Accordingly, there is an unmet medical need in the art to develop effective drug delivery system for the treatment of migraine, that may provide enhanced patient benefits compared to existing therapies. Hence the present invention provides pharmaceutical composition comprising ubrogepant or salts thereof for parenteral administration. It also provides administration by self-administration injection device comprising liquid injectable composition of ubrogepant for parenteral administration. The present invention self-administration injection device of Ubrogepant is easy to use, may improves outcomes and quality of life in the treatment of migraine. Furthermore, the administration of ubrogepant injectable composition by self-administration device of present invention provides fast onset of action, easy self-administration, improved patient compliance, reduced anxiety, and dosage accuracy. SUMMARY OF THE INVENTION:

The present invention relates to a pharmaceutical composition comprising ubrogepant or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipient.

The present invention relates to a pharmaceutical composition comprising ubrogepant or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipient; wherein the said composition is administered by parenteral route such as subcutaneous and/or intramuscular injection.

The present invention relates to a pharmaceutical composition comprising ubrogepant or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipient; wherein said dose ranges from about 0.1 mg to about 150mg/ dose.

The present invention relates to a pharmaceutical composition comprising ubrogepant or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipient; wherein said dose volume ranges from about 0.05 to about 5 mL.

The present invention relates to a pharmaceutical composition comprising ubrogepant or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipient; wherein one or more pharmaceutically acceptable excipient comprises solvent and solubilizing agent is polyethylene glycol 200 to 600, cyclodextrins; solvents may include alcohol, polyethylene glycol, pharmaceutically acceptable oils such as vitamin E, castor oil, MCT and N,N-dimethylacetamide or combinations thereof. The present invention relates to a pharmaceutical composition comprising ubrogepant or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipient; wherein one or more pharmaceutically acceptable excipient comprises of vehicle for delivery as propylene glycol, polyethylene glycol (200 to 3000), alcohol, pharmaceutically acceptable oils such as vitamin E, castor oil, MCT or combinations thereof.

The present invention relates to a pharmaceutical composition comprising ubrogepant or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipient; wherein one or more pharmaceutically acceptable excipient comprises antioxidant is butylated hydroxytoluene; antioxidants can also include vitamin E and other commonly used antioxidants.

The present invention relates to a pharmaceutical composition comprising ubrogepant or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipient; wherein one or more pharmaceutically acceptable excipient comprises non-ionic surfactants such as sorbitan fatty acid esters, polysorbates, poloxamer and the like.

The present invention relates to a pharmaceutical composition comprising ubrogepant or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipient; where the composition is anhydrous; water content in such composition is < 5%.

The present invention relates to a pharmaceutical composition comprising ubrogepant or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipient; wherein, the composition remains stable from initial to 36 months; 0- 3months, 4-6 months, 7-12 months, 12- 18months, 19-24months; 24- 36 months. The present invention relates to a self-administration injection device, comprising: drug reservoir of liquid injectable composition comprising,

(i) ubrogepant or pharmaceutically acceptable salts thereof and

(ii) one or more pharmaceutically acceptable excipient.

The present invention relates to a self-administration injection device, comprising: drug reservoir of liquid injectable composition comprising,

(i) ubrogepant or pharmaceutically acceptable salts thereof and

(ii) one or more pharmaceutically acceptable excipient; wherein the said injection device is single dose auto-injector and/or prefilled syringe for subcutaneous administration.

The present invention relates to self-administration injection device provided as kit comprising: container comprising liquid injectable composition of ubrogepant and instructions for use.

The present invention provides ubrogepant liquid injectable composition and self-administration injection device comprising ubrogepant liquid injectable composition for treating migraine and/or ubrogepant sensitive diseases or disorders in mammals.

DETAILED DESCRIPTION:

The present invention relates to a pharmaceutical composition comprising ubrogepant or pharmaceutically acceptable salts thereof and selfadministration injection device comprising liquid injectable composition of ubrogepant for parenteral administration.

As used herein, the words or terms set forth below have the following definitions: The term "active pharmaceutical ingredient" or "drug" or “API” refers to a substance that has a physiological effect when ingested or otherwise introduced into the body, in particular or a chemical substance used in the treatment, cure, prevention, or diagnosis of disease or used to otherwise enhance physical or mental well- being. The "active pharmaceutical ingredient" or "drug" or “API” is Ubrogepant or its derivative or its metabolite or optical isomer, diastereomer, enantiomer, tautomer, or physiologically acceptable salt and solvates thereof.

The term “pharmaceutically acceptable” means approved by a regulatory agency or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in mammals, and more particularly in humans.

The term "pharmaceutically-acceptable salts" or “salts thereof” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts, solvate, hydrate, esters and the like thereof. Pharmaceutically-acceptable salt forms of compounds provided herein are synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.

As used herein, the term "composition" or "formulation" or "preparation" or “finished product” is intended to encompass a combination including active ingredients with or without pharmaceutically acceptable excipients, as well as any product which results, directly or indirectly, from combination, complexation, or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions involving one or more of the ingredients. The term "formulation" or "dosage form" or "composition" refers to finished pharmaceutical products that are suitable for administration, including, but not limited to, injections, liquid dosage form, etc., liquid dosage form including but not limited to solution, suspension, nano suspension, emulsion, nano emulsion and the like.

The term “injection device” as used herein refer to a device intended for the injection of a medicament to the body and includes devices configured for various delivery methods, such as intradermal, subcutaneous, intramuscular, intravenous, intraperitoneal, intrathecal, epidural, intracardiac, intraarticular, intracavernous, and intravitreal, which may include via a cannula, catheter or similar device. The term includes devices such as auto-injector, prefilled syringe, injection pen device, for subcutaneous and/ or intramuscular administration.

The term "self-administration injection devices" as used herein includes administration of the preparation or composition or formulation by a person himself or caregiver and/or without the intervention of another person. Self- administrable devices may include auto injector, single dose auto injector, single dose reusable auto injector, dual chamber cartridge with autoinjector, auto injector with prefilled syringe, injection pen, prefilled syringe and the like. The term “caregiver” or “caretaker” as used herein includes healthcare professional such as doctors, nurses or non-healthcare professionals such as family member, friends, relatives who assists in administration of injection to the patient.

The term "parenteral” as used herein the compositions are administered by injection, infusion, or implantation into the human body. They may be directly administered or diluted before administration.

The term "parenteral administration" as used herein is intramuscular, intraperitoneal, intra-abdominal, subcutaneous, intravenous, intraarterial, intradermal, intravitreal, intracerebral, intrathecal and epidural administration. In some embodiments, administration is subcutaneous or intramuscular.

"Carrier" or "vehicle" or "solvent" or “diluent” as used herein refers to pharmacologically inert materials that provide a more or less fluid matrix, suitable for parenteral drug administration. Carriers, vehicles or diluent useful herein include any such materials known in the art, which are nontoxic and do not interact with other components of a pharmaceutical formulation or drug delivery system in a deleterious manner. Further, they also can be used Interchangeably with other excipients.

The term “Ubrogepant sensitive diseases or disorders” includes but not limited to migraine, acute migraine, chronic migraine, episodic migraine, basilar type migraine, migraine with brainstem aura, migraine with headache, migraine without headache (silent migraine), migraine with or without aura, classical migraines, common migraines, migraine attacks, abdominal migraine, ophthalmoplegic migraine, retinal migraine (ocular migraine), vestibular migraine, hemiplegic migraine, status migrainosus, transformed migraine, cyclic migraines, menstrual migraine, headache, cluster headache, chronic headache, and tension headache.

The term “treating migraine” or “treatment of migraine” as used herein refers to acute treatment of migraine, acute treatment of migraine with or without aura, preventive treatment of migraine, preventive treatment of episodic migraine.

The term “amount” as used herein refers to quantity or to concentration as appropriate to the context.

The term “about” or “approximately” means within 10% of a given value or range or within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. Alternatively, the term “about” means within an acceptable standard error of the mean.

The term “comprising” or "comprises” is inclusive or open-ended i.e. comprising what is specified in the present invention, but not excluding other or additional aspects, unrecited elements or method steps.

The term "optional" or "optionally" means that the subsequently described element, component or circumstance may or may not be present, so that the description includes instances where the element, component, or circumstance is included and instances where it is not.

The term "stability" or "stable" as used herein includes both physical and chemical stability. Stability parameters include but not limited to potency, stable pH value and other physico-chemical parameters.

The term “sterilization” means that the subsequently described process that removes, kills, or deactivates all forms of life (particularly microorganisms such as fungi, bacteria, spores, and unicellular eukaryotic organisms) and other biological agents such as prions present in or on a specific surface, object, or fluid. Sterilization can be achieved through various means, including heat (moist- Autoclaving, dry heat sterilization, flaming, incineration, tyndallisation, glass bead sterilization), chemicals (ethylene oxide (ETO), nitrogen dioxide, ozone, glutaraldehyde and formaldehyde, hydrogen peroxide, peracetic acid), irradiation ultraviolet light, X- rays, gamma- rays, ionizing radiation, non- ionizing radiation, high pressure, and filtration (membrane filters). Sterilization is distinct from disinfection, sanitization, and pasteurization, in that those methods reduce rather than eliminate all forms of life and biological agents present. After sterilization, an object is referred to as being sterile or aseptic.

Migraine is a common episodic disorder, the hallmark of which is a disabling headache generally associated with nausea and/or light and sound sensitivity. There are two treatments approaches like preventive treatment and abortive (symptomatic) therapy. The pharmacologic approach to migraine is directed mainly by the severity of the attacks, the presence of associated nausea and vomiting, the treatment setting (outpatient or medical care facility), and patient-specific factors. There are several treatment options such as use of simple analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen to triptans, antiemetics, calcitonin gene-related peptide (CGRP) antagonists, lasmiditan, and dihydroergotamine. Patients who present with migraine in emergency settings generally have unusually severe attacks, and in many cases their customary acute migraine treatment has failed to provide relief. The current treatment options are inadequate for patients who present to the hospital emergency department with severe migraine, particularly if the migraine is accompanied by severe nausea or vomiting. Hence present invention provides solution to the prior art problems of acute treatment of migraine by providing injectable composition comprising Ubrogepant which is administered by self-administration injection device such as auto injector, prefilled syringe, injection pen and/or similar devices. The present invention self-administration injection device provides fast onset of action in acute treatment of migraine and easy administration, better patient compliance.

In one embodiment of present invention provides a pharmaceutical composition, comprising:

(i) ubrogepant or pharmaceutically acceptable salts thereof and

(ii) one or more pharmaceutically acceptable excipient. In one embodiment of present invention provides a pharmaceutical composition, comprising:

(i) ubrogepant or pharmaceutically acceptable salts thereof and

(ii) one or more pharmaceutically acceptable excipient. wherein the said composition is administered by parenteral route.

In one embodiment of the present invention, the pharmaceutical composition comprises Ubrogepant or a pharmaceutically acceptable salt thereof in the dosage range between from about 0.1 mg/dose to about 150 mg/dose, about 0.1 mg/dose to about 120 mg/dose, about 0.2mg/dose to about 100 mg/dose, about 0.5mg/dose to about 80 mg/dose, about 1 mg/dose to about 50 mg/dose.

In one embodiment of the present invention, the pharmaceutical composition comprises Ubrogepant or a pharmaceutically acceptable salt thereof in the dose volume range between from about 0.05mL to about 5 mL, 0.05mL to about 4 mL, about 0.05mL to about 3 mL, about 0.05mL to about 2 mL, about 0.05mL to about 1 mL.

The pharmaceutical composition of present invention further comprises one or more pharmaceutically acceptable excipients such as tonicity adjusting agent, buffering agent, vehicle, carrier, pH modifiers, antioxidants, preservatives, chelating agents, bulking agents and lyoprotectants, diluents, surfactant, stabilizers, solvents and co-solvents, solubilizing, wetting, suspending, emulsifying or thickening agents, bulking agents and the like or mixtures thereof. The choice of excipients depends on the desired characteristics of the compositions and on the nature of other pharmacologically active compounds in the formulation. Suitable excipients are known to those skilled in the art (see Handbook of Pharmaceutical Excipients, edited by Rowe et al). The pharmaceutical preparation, wherein, tonicity adjusting agent include but not limited to mannitol, sucrose, maltose, dextrose, trehalose, glycerin, sodium chloride, potassium chloride or mixtures thereof. Tonicity adjusting agents decrease the haemolysis of blood cells and reduce pain and irritation at the injection site.

Examples of buffering agent include but not limited to acetate, sodium acetate, acetic acid, glacial acetic acid, ammonium acetate, citrate, citric acid, sodium citrate, disodium citrate, trisodium citrate, tartrate, sodium titrate, tartaric acid, phosphate, phosphoric acid, monobasic potassium phosphate, dibasic potassium phosphate, monobasic sodium phosphate, sodium biphosphate, sodium dihydrogen phosphate, or sodium dihydrogen orthophosphate, dibasic sodium phosphate, sodium phosphate, disodium hydrogen phosphate, tribasic sodium phosphate, benzoate, benzene sulfonic acid, benzoate sodium/acid, lactate, gluconate, bicarbonate, organic amines, tromethamine/ triethanolamine (tris), ammonium sulfate, ammonium hydroxide, arginine, aspartic acid, sodium bicarbonate, boric acid, sodium borate, sodium carbonate, diethanolamine, glucono delta lactone, glycine/glycine HCI, histidine/histidine HCI, hydrochloric acid, hydrobromic acid, lysine, maleic acid, meglumine, methanesulfonic acid, monoethanolamine, sodium hydroxide, succinate sodium/disodium, sulfuric acid and its salts, hydrates, solvates, or any mixtures thereof. In some embodiments, the pH of a pharmaceutical composition is controlled.

Examples of vehicle or carriers include but not limited to water for injection, hydroalcoholic solvents like, propylene glycol, polyethylene glycol, ethanol, glycerol, oils, triglycerides and mixtures thereof.

Examples of antioxidants include but not limited to monothioglycerol, thioglycerol, cystein/ cysteinate hydrochloride, thioglycolic acid, thiourea, sodium metabisulfite, metabisulfite potassium, acetone sodium bisulfite, sulfite sodium, bisulfite sodium, ascorbic acid, sodium formaldehyde sulfoxylate, sodium bisulfate, butylated hydroxy toluene (BHT), butylated hydroxy anisole (BHA), argon, ascorbyl palmitate, phenylmercuric nitrate, thiomersal, benzalkonium chloride, benzethonium chloride, phenol, cresol or chlorobutanol, dithionite sodium (sodium hydrosulfite, sodium sulfoxylate), gentisic acid, gentisic acid ethanolamine, glutamate monosodium, glutathione, formaldehyde sulfoxylate sodium, methionine, nitrogen, propyl gallate, tocopherol alpha, alpha tocopherol hydrogen succinate, thioglycolate sodium, and the like or any mixtures thereof.

Examples of preservatives include but not limited to benzyl alcohol, m- cresol, phenol, methyl parabens, propylparaben, butylparaben, chlorobutanol, thiomersal, phenylmercuric salts, or mixtures thereof. The sterile solution of the present invention comprises preservative in amounts sufficient to maintain sterility of the solution in the injection device, throughout the shelf life of the product, which may be exposed to repeated multiple injections. This is because it is possible that the antimicrobial preservative concentration in a given preparation may decrease during the product's shelf life.

Examples of chelating agents include but not limited to ethylene diamine tetraacetic acid (EDTA) and acceptable salts thereof, citric acid, sodium citrate, ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) and acceptable salts thereof, and 8-Amino-2-[(2-amino-5- methylphenoxy) methyl]-6-methoxyquinoline-N,N,N',N'-tetraacetic acid, tetrapotassium salt (QUIN-2) and acceptable salts thereof and the like or mixtures thereof.

Examples of stabilizers include but not limited to polyols, amino acids, surfactants, poloxamer and its co-polymers; polyols include but not limited to propylene glycol, polyethylene glycol, polypropylene glycol and the like or mixtures thereof; amino acids include but not limited to aspartic acid, glutamic acid, glycine, arginine, lysine, L-histidine and the like or mixtures thereof; surfactants include but not limited to polysorbate-20, polysorbate- 80, and the like or mixtures thereof.

Examples of surfactants include but not limited to polyoxyethylene sorbitan monooleate (tween 80), sorbitan monooleate polyoxyethylene sorbitan monolaurate (tween 20), polyoxyethylene polyoxypropylene copolymers (pluronics), Pluronic F-68, Lecithin, Polysorbate 20, Polysorbate 80, Sorbitan trioleate (span 85), Span 20, poloxamer, Vitamin E-TPGS and the like or mixtures thereof.

Examples of emulsifier include but not limited to polysorbate 80, polyoxyalkylene alkylene ethers, polyalkylene oxide ethers of alkyl alcohols, polyalkylene oxide ethers of alkylphenols, lecithin, soy lecithin, diacetyl tartaric acid ester of monoglyceride, mustard, sodium stearoyl lactylate, sodium phosphates and the like or mixtures thereof.

Examples of solvents and co-solvents include but not limited to propylene glycol, glycerin, ethanol, polyethylene glycols (PEG 200, PEG 300, PEG 400, PEG 600, PEG 3350, PEG 4000, PEG with any suitable molecular weight), 1 ,3-butylene glycol, 1 ,3-butanediol, sorbitol, dimethylacetamide and cremophor, benzyl benzoate, castor oil, cottonseed oil, N,N dimethylacetamide, N-([3-hydroxyethyl)-lactamide, ethanol/ethanol dehydrated, glycerine (glycerol), n-methyl-2- pyrrolidone, sulfoxides, peanut oil, poppyseed oil, safflower oil, sesame oil, soybean oil, vegetable oil, triglycerides, medium chain triglycerides, isopropyl myristate, oleic acid esters of glycerine, ethyl oleate, dioxolanes, ethyl lactate, ethyl a- hydroxypropionate, ethyl carbonate, diethyl carbonate, a polyoxyethylene sorbitan fatty acid ester such as polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80 and the like or mixtures thereof. The solvents may be aqueous and/ or non-aqueous.

Examples of solubilizing agents include but not limited to Cyclodextrins, modified cyclodextrins, such as hydroxypropyl-[3-cyclodextrin and sulfobutylether- [3 -cyclodextrin, phospholipids, phosphatidylcholine, soybean phosphatidylcholine, hydrogenated soybean phosphatidylcholine (HSPC), dimyristoyl phosphatidylcholine (DMPC), distearoyl phosphatidylcholine (DSPC), 1 ,2 dioleoyl-sn-glycero-3-phosphocholine (DOPC), distearoyl phosphoethanolamine (DSPE), L- alphadimyristoylphosphatidylglycerol (DMPG), 1 ,2-dipalmitoyl-snglycero-3- phosho-rac-(1 -glycerol), poloxamer or pluronic, polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, glycerin, N-methyl-2- pyrrolidone, dimethylacetamide, dimethylsulfoxide, Cremophor EL, Cremophor RH 40, Cremophor RH 60, d-a-tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol HS 15, sorbitan monooleate, poloxamer 407, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44/14, Softigen 767, mono- and di-fatty acid esters of PEG 300, 400, or 1750, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, medium-chain triglycerides and medium-chain triglycerides of coconut oil and palm seed oil, beeswax, d-a- tocopherol, oleic acid, medium-chain mono- and diglycerides, phospholipids (hydrogenated soy phosphatidylcholine, distearoylphosphatidylglycerol, l-a- dimyristoylphosphatidylcholine, l-a-dimyristoylphosphatidylglycerol) and the like or mixtures thereof.

Examples of bulking agents and lyoprotectants include but not limited to sucrose, lactose, trehalose, mannitol, sorbitol, glucose, raffinose, glycine, histidine, polyethylene glycol (PEG), PVP (K40), and the like or mixtures thereof. The present invention composition may further comprise biodegradable, biocompatible, injectable polymers include but not limited to lactide copolymers, PLGA, polyvinyl alcohol, block copolymer of PLA-PEG, polycyanoacrylate, polyanhydrides, cellulose, alginate, collagen, modified HSA, albumin, starches, dextrans, hyaluronic acid and its derivatives, hydroxyapatite.

In one embodiment the composition is in the form of solution, wherein water content of the solution is < 10%; for example < 8%, < 6%, <5%, <4%, <3%, <2%, or <1 %.

In one embodiment the composition is in the form of non - aqueous solution, wherein water content is < 5%; for example <4%, <3%, <2%, or <1%.

Solubility studies were carried out with various solvents, to check the solubility of Ubrogepant. The details are summarized in table 01 :

Table 01 : Solubility study of Ubrogepant #SBECD: Sulfobutylether beta cyclodextrin; MCT: medium chain triglycerides; DMSO: Dimethylsulfoxide; NA- Not Applicable; Acidic pH: Water + HCi; Basic pH: Water + NaOH.

The compositions of the present invention comprise cyclodextrins (CD) or derivatives thereof. In some embodiments cyclodextrin is alpha cyclodextrin (a-CD/ Alfadex), beta cyclodextrin (|3-CD/ Betadex), gamma cyclodextrin (y- CD), Sulfobutyl-ether [3-cyclodextrin (SBE-[3-CD), hydroxypropyl beta cyclodextrin (HP-[3-CD/ Hydroxypropyl-betadex), randomly methylated [3- cyclodextrin (RM-[3-CD) and the like. Cyclodextrins are cyclic oligosaccharides made up of a number of dextrose units of (a-1 ,4)-linked a- D glucopyranose. Cyclodextrins are used as complexing agents to increase the aqueous solubility of active substances poorly soluble in water, in order to increase their bioavailability and to improve stability.

In another embodiment of present invention provides a pharmaceutical composition comprising: a) Ubrogepant, b) cyclodextrin and c) optionally one or more excipients.

In another embodiment of present invention provides a pharmaceutical composition comprising: a) Ubrogepant, b) cyclodextrin and c) one or more excipients.

The composition of the present invention may be in the form of a powdered/ lyophilized pharmaceutical composition comprising: a) Ubrogepant, b) cyclodextrin and c) optionally one or more excipients.

The pharmaceutical composition of the present invention may be in the form of solution comprising: a) Ubrogepant, b) cyclodextrin and c) optionally one or more excipients, wherein the said composition is in the form of ready to use solution, ready to administer or premix, can be administered directly to the patient or after dilution with diluent or vehicle.

In another embodiment of the present invention provides a process for preparation of pharmaceutical composition comprising: a) ubrogepant, b) cyclodextrin, c) optionally one or more excipients.

In another embodiment of the present invention of pharmaceutical composition comprising Ubrogepant, cyclodextrin, sodium metabisulphite and sufficient water or alcohol is added to form solution.

In another embodiment of the present invention of pharmaceutical composition comprising Ubrogepant, cyclodextrin, sodium metabisulphite and sufficient water or alcohol is added to form suspension.

In another embodiment of the present invention provides a process for producing ubrogepant with solubilizer which comprises a) dissolving ubrogepant in a solvent, b) mixing the resulting solution with an aqueous solution of the solubilizer and, c) optionally, removing the solvent and water. In another embodiment of the present invention provides a process for producing ubrogepant with a cyclodextrin which comprises a) dissolving ubrogepant in a solvent, b) mixing the resulting solution with an aqueous solution of the cyclodextrin and, c) optionally, removing the solvent and water.

The pharmaceutical compositions of the present invention also comprise one or more solvents include, but not limited to dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methylpyrrolidone, a polyoxyethylene sorbitan fatty acid ester, dimethylisosorbide, ethanol, propylene glycol, glycerine, polyethylene alcohol, propylene glycol esters, polyethylene glycols and the like.

In another embodiment of present invention provides a pharmaceutical composition comprising: a) Ubrogepant, b) one or more solvents and c) optionally one or more excipients.

In another embodiment of present invention provides a pharmaceutical composition comprising: a) Ubrogepant, b) one or more solvents and c) one or more excipients.

In another embodiment of present invention provides a pharmaceutical composition comprising: a) Ubrogepant, b) propylene glycol and c) optionally one or more excipients.

In another embodiment of the present invention of pharmaceutical composition comprising Ubrogepant and polyethylene glycol to form solution.

In another embodiment of the present invention of pharmaceutical composition comprising Ubrogepant, butylated hydroxytoluene and polyethylene glycol to form solution.

In another embodiment of the present invention of pharmaceutical composition comprising Ubrogepant, butylated hydroxytoluene and polyethylene glycol, MCT, polysorbate, water and/or any other excipients to form emulsion.

In another embodiment of the present invention of pharmaceutical composition comprising Ubrogepant, butylated hydroxytoluene, water and polyethylene glycol to form suspension.

In another embodiment of present invention provides a pharmaceutical composition comprising: a) Ubrogepant, b) polyethylene alcohol and c) optionally one or more excipients.

In another embodiment of present invention provides a pharmaceutical composition comprising: a) Ubrogepant, b) N-methylpyrrolidone and c) optionally one or more excipients. In another embodiment of present invention provides a pharmaceutical composition comprising: a) Ubrogepant, b) polyoxyethylene sorbitan fatty acid ester and c) optionally one or more excipients.

In one embodiment of present invention provides a pharmaceutical composition comprising: a) Ubrogepant, b) medium chain triglycerides (MCT) and c) optionally one or more excipients.

In another embodiment of the present invention of pharmaceutical composition comprising Ubrogepant, MCT, butylated hydroxytoluene, polysorbate 80 and water to form suspension.

In another embodiment of the present invention of pharmaceutical composition comprising Ubrogepant, MCT, butylated hydroxytoluene, polysorbate 80 and water to form emulsion.

In another embodiment of the present invention of pharmaceutical composition comprising Ubrogepant, castor oil, butylated hydroxytoluene, polysorbate 80 and water to form suspension.

In another embodiment of the present invention of pharmaceutical composition comprising Ubrogepant, castor oil, butylated hydroxytoluene, polysorbate 80 and water to form emulsion.

In another embodiment of the present invention of pharmaceutical composition comprising Ubrogepant, tocopherol, polyethylene glycol butylated hydroxytoluene and alcohol to form solution. In another embodiment of the present invention of pharmaceutical composition comprising Ubrogepant, polyethylene glycol, butylated hydroxytoluene, alcohol, water and/or suspending agents to form suspension.

In another embodiment of the present invention of pharmaceutical composition comprising Ubrogepant, tocopherol, polyethylene glycol polysorbate (or any other emulsifiers), butylated hydroxytoluene and alcohol water to form emulsion.

In another embodiment of the present invention of pharmaceutical composition comprising Ubrogepant, D-a-tocopheryl polyethylene glycol succinate, sodium metabisulphite and water to form suspension.

In another embodiment of the present invention of pharmaceutical composition comprising Ubrogepant, D-a-tocopheryl polyethylene glycol succinate, sodium metabisulphite and water to form emulsion.

As these composition are parenteral preparation, hence sterility is important, in one embodiment of present invention provides a pharmaceutical composition can be sterilized by different sterilization technique such as including but not limited to heat (moist- Autoclaving, dry heat sterilization, flaming, incineration, tyndallisation, glass bead sterilization), chemicals (ethylene oxide (ETO), nitrogen dioxide, ozone, glutaraldehyde and formaldehyde, hydrogen peroxide, peracetic acid), irradiation (ultraviolet light, X- rays, gamma- rays, ionizing radiation, nonionizing radiation), high pressure, and filtration (membrane filters)

In one embodiment of present invention provides a pharmaceutical composition can be sterilized by autoclaving. In one embodiment of present invention provides a pharmaceutical composition can be sterilized by filtration membrane filters.

In one embodiment of present invention provides a pharmaceutical composition can be sterilized by chemical ethylene oxide (ETO).

In one embodiment of present invention provides a pharmaceutical composition can be sterilized by irradiation gamma- rays.

In another embodiment of present invention provides a pharmaceutical composition can be administered by different parenteral routes such as but not limited to intradermal, subcutaneous, intramuscular, intravenous, intraperitoneal, intrathecal, epidural, intracardiac, intraarticular, intracavernous, and intravitreal.

In another embodiment of present invention provides a pharmaceutical composition can be administered by subcutaneous and/or intramuscular injection.

In one embodiment, the present invention compositions may be in the form of injectable dosage forms includes but not limited to suspension, solution, emulsion, nanosuspension, nano-emulsion, co-crystals, concentrated solutions for injections, ready to use or premix, ready to be dissolved in and/or diluted with a pharmaceutically acceptable vehicle/diluent, dry products ready to be dissolved in and/or diluted with a pharmaceutically acceptable vehicle, injectable microspheres, injectable microparticles, nanoparticles, lyophilized powder for injection and the like.

In one embodiment, the present invention compositions may be in the form of aqueous and/or non aqueous injectable dosage forms.

T1 In one embodiment, the present invention compositions comprise a solid (e.g., a powder) or a liquid solution that is diluted with a liquid carrier or diluent prior to administration to a subject.

In one embodiment, the present invention compositions may be in the form of lyophilized composition for reconstitution with one or more pharmaceutically acceptable diluents to provide a solution suitable for administration.

In another embodiment, the present invention provides lyophilized compositions comprising ubrogepant can be reconstituted by adding the pharmaceutically acceptable diluent(s) to the lyophilized ubrogepant formulation to provide the desired concentration for direct administration or further dilution for parenteral administration.

In one embodiment, the present invention provides pharmaceutical composition comprising ubrogepant nanoparticles and one or more pharmaceutical excipients, suitable for parenteral administration by any suitable acceptable injectable dosage form.

In one embodiment, the present invention provides pharmaceutical composition comprising Ubrogepant microparticles and one or more pharmaceutical excipients, suitable for parenteral administration by any suitable acceptable injectable dosage form.

In one embodiment, the present invention provides pharmaceutical composition comprising Ubrogepant, the average particle size of the Ubrogepant may be less than 50 microns, less than 45 microns, less than 40 microns, less than 35 microns, less than 30 microns, less than 25 microns, less than 20 microns, less than 15 microns, less than 10 microns, less than 9 microns, less than 8 microns, less than 7 microns, less than 6 microns, less than 5 microns, less than 4.5 microns, less than 4 microns, less than 3.5 microns, less than 3 microns, less than 2.5 microns, less than 2 microns, less than 1 .5 microns, less than 1 microns, less than 0.5 microns or any value less than 10 microns.

In one embodiment, the present invention provides pharmaceutical emulsion composition comprising Ubrogepant, wherein the average globule size of active pharmaceutical ingredient that have D90 from about 1 pm to about 5 pm; Dso from about 1 pm to about 3 pm; D10 from about 1 pm to about 2 pm.

In one embodiment, the present invention provides pharmaceutical nano emulsion composition comprising Ubrogepant, wherein the average globule size of active pharmaceutical ingredient that have D90 is from about 10 nm to about 10OOnm; D50 is from about 10 nm to about 500nm; D10 is from about 10 nm to about 100nm.

In one embodiment, the present invention provides pharmaceutical suspension composition comprising Ubrogepant, wherein the average particle size of active pharmaceutical ingredient that have Dgo from about 1 pm to about 5 pm; Dsofrom about 1 pm to about 3 pm; D10 from about 1 pm to about 2 pm.

In one embodiment, the present invention provides pharmaceutical nano nano suspension composition comprising Ubrogepant, wherein the average particle size of active pharmaceutical ingredient that have D90 is from about 10 nm to about 1000nm; Dso is from about 10 nm to about 500nm; D10 is from about 10 nm to about 100nm.

In one embodiment, the present invention provides methods or process for preparation of injectable composition comprising ubrogepant or salts thereof and one or more pharmaceutically acceptable excipients. In one embodiment, the present invention injectable composition is prepared by the methods known in the art that maintains sterility, avoid the introduction of contaminants and microbial growth.

In one embodiment, the process of injectable composition is prepared by the following steps: i. mix solubilizing agent and antioxidant under stirring with applied heat. Cool the mixture to room temperature. ii. add Ubrogepant to above mixture under stirring till completely dissolved. iii. then make up the volume to 100% using vehicle. Sterilised the composition.

In another embodiment, the process of injectable composition is prepared by the following steps: i. mix the suitable grades of polyethylene glycol and butylated hydroxytoluene under stirring with applied heat. Cool the mixture to room temperature. ii. add Ubrogepant to above mixture under stirring till completely dissolved. iii. then make up the volume to 100% using suitable grades of polyethylene glycol. Fill in the suitable container/primary packaging and proceed with sterilization by autoclave.

In another embodiment, the process of injectable composition is prepared by the following steps: i. mix the suitable grades of polyethylene glycol and butylated hydroxytoluene under stirring with applied heat. Cool the mixture to room temperature. ii. add Ubrogepant to above mixture under stirring till completely dissolved. iii. then make up the volume to 100% using suitable grades of polyethylene glycol. Then, proceed with sterilisation by filtration.

In one embodiment, the present invention compositions disclosed herein can be dispensed by suitable device such as autoinjector devices, prefilled syringes, injection pen, ampoules, vials, a glass vial, a plastic vial and/ or similar devices.

In some embodiments, the present invention compositions disclosed herein can be dispensed by pre-filled syringe, auto-injector device, pre-filled syringe fully assembled into an auto-injector device, injection pen and the like.

In one embodiment of present invention provides a self-administration injection device, comprising: drug reservoir of liquid injectable composition comprises, (i) ubrogepant or pharmaceutically acceptable salts thereof and (ii) one or more pharmaceutically acceptable excipient.

In another embodiment of present invention provides a self-administration injection device disclosed herein can be autoinjector, injection pen, prefilled syringe, pre-filled syringe fully assembled into an auto-injector device and the like.

Auto-injectors have become very popular and have experienced widespread use due to a variety of advantages that they have over typical manual syringe injectors. Essentially, an auto-injector is an automatic injection system which is designed to subcutaneously deliver a specific dosage of a liquid medicament into an individual. In one embodiment of present invention provides the self- administration injection device is auto injector.

In another embodiment of present invention provides the self- administration injection device is auto injector for single dose.

In one embodiment of present invention provides the self- administration injection device is prefilled syringe.

In another embodiment of present invention provides the self- administration injection device is prefilled syringe for single dose.

In one embodiment of present invention provides the self- administration injection device is injection pen.

In another embodiment of present invention provides the self- administration injection device is injection pen for single dose or multiple dose.

In some embodiments, the compositions disclosed herein can be dispensed in disposable, single-use auto-injector containing ubrogepant in a pre-filled syringe (PFS) fully assembled for ready use.

In one embodiment of present invention provides an auto-injector device in various dimensions, designs and components of device assembly.

In another embodiment, an auto-injector device can be customised in different design and configured for different fill volumes for individual dosing requirements.

Another embodiment of present invention an auto-injector device includes housing, a cartridge disposed in housing, drug reservoir, plunger, needle and other associated device assembly parts. Another embodiment of present invention, an auto-injector device further includes an actuation assembly and said device is digitally configured.

Another embodiment, an auto-injector device in a self-contained, reusable, preset and prefilled cartridge device configured to present a dosing choice to an end-user and to deliver a dose associated with the choice made by the end-user. As such, the auto-injector is configured to be capable of delivering a single dose chosen from a plurality of different doses of a pharmaceutical composition or medicament. In one aspect, the auto-injector is configured to be capable of delivering a single dose chosen from two different doses of a pharmaceutical composition or medicament. In other words, the device is capable of delivering different preset doses. The prefilled device may be a single chamber; wherein single chamber may comprise of the ready to use preparation or multi chamber.

Another embodiment of present invention provides self- administration injection device an auto-injector device may be configured to allow for delivering of one or optionally two, three, four or multiple doses.

Another embodiment of present invention provides self- administration injection device an auto-injector device may be configured to allow for delivering single or optionally multiple doses.

The sterile solution filled cartridge should be loaded into the reusable autoinjector device and ensure proper closure of the device to make ready for dosing. Before initiating next dose ensure the rigid needle shield should be removed or ejected from auto injector device. After removing the needle shield the recorded dose is administered immediately.

The auto-injector is thereby configured to administer to a patient a pharmaceutical composition stored in a medicament reservoir disposed within it. The medicament reservoir cooperates with the dose selection component so that only the volume of pharmaceutical composition, at a given concentration corresponding to the selected dose is administered to the patient using the device. In one other embodiment, the medicament reservoir is a suitable device such as cartridge or refillable cartridge and the like thereof, incorporated into the auto-injector housing, either permanent or removable. The auto-injector is configured with the assembly for selection of the dose, either the higher dose or lower, yet already preset dose, is made by some form of manipulation of the injector such as by use of a button, slide, dial, shaking, audible/visible selection, or other input mechanism on the single use, auto-injector. The injection device is calibrated so that only the amount of medicament that corresponds to the end-user dosage selection is dispensed from the reservoir and administered to the patient.

The auto injector shall contain at least an auto penetration mechanism and an autoinjection mechanism and also contains an auto return mechanism.

Auto injector device of present invention further comprises feedback mechanism provided to the user can be any form of sensory feedback, such as for example visual feedback, auditory feedback, tactile feedback or related mechanism.

Another embodiment of present invention, an auto-injector device is digitally configured with smart device or smart phone. The smart digital device assembly may display to the user a current status of the injection device to display, for example, information to assist a user with injection technique. The smart device may display on a display screen a scaled force profile to allow a user to monitor progress of an injection event, dose scale, set dose to be injected, dose left in cartridge or like. The calculation of the scaling prior to user display may be performed on the smart device. The smart device may indicate an end of injection event detected by the machine learning algorithm implemented by the processor.

In one embodiment of the present invention, provides a kit comprising:

(a) a container comprising pharmaceutical composition described herein;

(b) instructions for use in accordance with any of the methods described herein.

Generally, these instructions comprise a description of administration of the pharmaceutical composition to treat, ameliorate or prevent ubrogepant sensitive diseases or disorders, according to any of the methods described herein. The kit may, for example, comprise a description of selecting an individual suitable for treatment based on identifying whether that individual has headache or whether the individual is at risk of having headache. The instructions are typically provided in the form of a package insert, or label, in accordance with the requirements of the regulatory having authority over the jurisdiction where the pharmaceutical composition is to be provided to patients.

In one embodiment of the present invention, provides a kit comprising:

(a) a container comprising liquid injectable composition of ubrogepant;

(b) instructions for use in accordance with any of the methods described herein

In another embodiment of the present invention, provides a kit comprising: cartridge filled with liquid injectable composition of Ubrogepant which is assembled in self-administration injection device and instructions for use.

In another embodiment of the present invention, provides a kit comprising: cartridge filled with liquid injectable composition of Ubrogepant which is assembled in auto injector device and instructions for use. In one embodiment of present invention, provides a method of treating migraine in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of Ubrogepant, or a pharmaceutically acceptable salt thereof.

In one embodiment of present invention, provides a method of treating migraine in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of Ubrogepant, or a pharmaceutically acceptable salt thereof along with one or more pharmaceutically acceptable excipients.

In one embodiment of present invention, provides a method of treating migraine in a patient in need thereof, comprising a pharmaceutical composition of Ubrogepant delivered in self administration injection device for parenteral administration.

In one embodiment of present invention, provides acute treatment of migraine in a patient in need thereof, comprising a pharmaceutical composition of Ubrogepant delivered in self administration injection device for parenteral administration.

In another embodiment of present invention, provides a method of treating migraine in a patient in need thereof, comprising a pharmaceutical composition of Ubrogepant delivered in self administration injection device such as auto injector, prefilled syringe, injection pen for subcutaneous and/or intramuscular administration.

In another embodiment of present invention, provides a method of treating migraine in a patient in need thereof, comprising a pharmaceutical composition of Ubrogepant delivered in auto injector device for subcutaneous administration. In one embodiment of the present invention, provides the method of treating one or more symptoms of acute migraine attack, the method comprising administration of ubrogepant, or a pharmaceutically acceptable salt thereof, in an amount sufficient to treat one or more symptoms of an acute migraine attack by self-administration injection device.

In one embodiment of the present invention, provides the method of treating one or more symptoms of acute migraine attack, the method comprising administration of liquid injectable composition of ubrogepant or salt thereof in an amount sufficient to treat one or more symptoms of an acute migraine attack by self-administration injection device.

To further illustrate the invention, the following examples are provided. It is to be understood that these examples are provided for illustrative purposes and are not to be construed as limiting the scope of the present invention in any manner whatsoever.

Considering the above solubility details (Table 01 ) the below formulations were formulated:

Examples:

Table:02 Compositions with Ubrogepant.

Table:03 Compositions with Ubrogepant.

Considering the above solubility details the below formulations were formulated and considered for further studies:

Table:04 Ubrogepant Formulation-1 (UF1)

Table: 05 Ubrogepant Formulation-2 (UF2) Table:06 Ubrogepant Formulation-3 (UF3)

Manufacturing Process:

1. Mix above polyethylene glycol grades (200 or 300 or 400) and Butylated hydroxytoluene under stirring with applied heat. Stir until completely solubilized and cool the mixture to room temperature.

2. Add Ubrogepant to above mixture under stirring till completely dissolved.

3. Then make up the volume to 100% using polyethylene glycol grades (200 or 300 or 400). Stir for uniformity.

4. Filter the composition and fill into vials for sterilization.

Table:07. Sterilization details- Autoclaving.

From the above sterilization study details, it can be inferred that there is no change in physical and chemical assay parameters. Hence, the composition seem to be stable. Table:08. Stability data of Ubrogepant Formulation.

From the above stability study details, by considering the 60°C , 40°C, 25°C and 5°C temperature condition and time points, it can be inferred that there is no change in physical and chemical parameters. Hence the composition seems to be stable.