[go: up one dir, main page]

WO2024218790A1 - Composition pharmaceutique d'ubrogépant et procédé correspondant pour la préparation d'une forme posologique solide destinée au traitement de la migraine - Google Patents

Composition pharmaceutique d'ubrogépant et procédé correspondant pour la préparation d'une forme posologique solide destinée au traitement de la migraine Download PDF

Info

Publication number
WO2024218790A1
WO2024218790A1 PCT/IN2024/050399 IN2024050399W WO2024218790A1 WO 2024218790 A1 WO2024218790 A1 WO 2024218790A1 IN 2024050399 W IN2024050399 W IN 2024050399W WO 2024218790 A1 WO2024218790 A1 WO 2024218790A1
Authority
WO
WIPO (PCT)
Prior art keywords
ubrogepant
pharmaceutical composition
pharmaceutically acceptable
acceptable excipients
sodium
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/IN2024/050399
Other languages
English (en)
Inventor
Nithiyanandam RAVI KUMAR
Praveen Kumar GADAPA
Uday Kumar GOTTAPU
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
MSN Laboratories Pvt Ltd
Original Assignee
MSN Laboratories Pvt Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by MSN Laboratories Pvt Ltd filed Critical MSN Laboratories Pvt Ltd
Publication of WO2024218790A1 publication Critical patent/WO2024218790A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • 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.
  • 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).
  • CGRP Calcitonin Gene-Related Peptide
  • CGRP Calcitonin Gene-Related Peptide
  • CGRP Calcitonin Gene-Related Peptide
  • CGRP Calcitonin Gene-related peptide
  • 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.
  • 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 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.
  • PVP-VA water soluble polyvinylpyrrolidone/vinyl acetate copolymer
  • said dispersing agent is vitamin E-tocopherol polyethylene glycol succinate (TPGS)
  • said disintegration system comprises powdered sodium chloride and croscarmellose
  • 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.
  • HME Hot Melt Extrusion
  • 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
  • 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).
  • the present invention relates to pharmaceutical composition comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients.
  • 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
  • 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
  • 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
  • a pharmaceutical composition comprising amorphous form of ubrogepant and one or more pharmaceutically acceptable excipients include one or more binder and / or surfactants.
  • 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
  • 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/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.
  • 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:
  • binder solution 1. sifting & blending suitable binders and surfactants in suitable solvent to prepare binder solution
  • 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 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.
  • active ingredient 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.
  • 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.
  • CGRP Calcitonin Gene-Related Peptide
  • a pharmaceutically acceptable salt thereof preferably ubrogepant.
  • 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.
  • the pharmaceutical composition is an oral dosage form, more preferably tablet dosage form.
  • 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.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • 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.
  • 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.
  • 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.
  • “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.
  • 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).
  • TPGS polyethylene glycol succinate
  • 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.
  • disintegration system is a combination of a conventional disintegrant and a rapidly dissolving salt.
  • solvent is a substance that is capable of dissolving other substances to form a homogenous solution.
  • 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.
  • APIs active pharmaceutical ingredients
  • 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.
  • DMSO dimethyl sulfoxide
  • the selection of solvents in the pharmaceutical industry is carefully evaluated to ensure their safety, efficacy, and compatibility with the intended application.
  • 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.
  • 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.
  • the term allows for any variation within ⁇ 10% of the recited value.
  • 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.
  • 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.
  • 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.
  • 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/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
  • Third aspect of fifth embodiment of the present invention is to provide a pharmaceutical composition
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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.
  • 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.
  • 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.
  • step (3) 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,
  • step (4) 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).
  • step (5) 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.
  • step (7) 8. lubricating the granules obtained in step (7) with sodium stearyl fumarate for 5 minutes at 15 RPM in a suitable blender.
  • step (8) 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.
  • 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.
  • 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.
  • step (3) Granules formed in step (3) were dried at suitable temperature to obtain suitable loss on drying (LOD);
  • step (4) Dried granules of step (4) were sifted and milled and passed through suitable sieve;
  • Extra granular ingredient croscarmellose sodium, optionally crospovidone, optionally microcrystalline cellulose, optionally sodium carbonate and colloidal silicon dioxide were sifted through suitable sieve.
  • step (5) Granules of step (5) and extra granular ingredients of step (6) were mixed and blended in a suitable blender;
  • step (8) The blend of step (8) was compressed using suitable tooling to form uncoated tablets and was film coated.
  • 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 Table 01:
  • Stability samples of present invention pharmaceutical composition comprising ubrogepant and a pharmaceutically acceptable carrier were evaluated for related substance or impurities by HPLC.
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une composition pharmaceutique solide comprenant une forme amorphe d'ubrogépant et un procédé de préparation de celle-ci, lequel est simple, économique, rentable et industriellement adapté à une mise à l'échelle. En outre, ladite invention est utilisée pour le traitement aigu de la migraine avec ou sans aura chez les adultes.
PCT/IN2024/050399 2023-04-15 2024-04-15 Composition pharmaceutique d'ubrogépant et procédé correspondant pour la préparation d'une forme posologique solide destinée au traitement de la migraine Pending WO2024218790A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202341027776 2023-04-15
IN202341027776 2023-04-15

Publications (1)

Publication Number Publication Date
WO2024218790A1 true WO2024218790A1 (fr) 2024-10-24

Family

ID=93152350

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2024/050399 Pending WO2024218790A1 (fr) 2023-04-15 2024-04-15 Composition pharmaceutique d'ubrogépant et procédé correspondant pour la préparation d'une forme posologique solide destinée au traitement de la migraine

Country Status (1)

Country Link
WO (1) WO2024218790A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8912210B2 (en) * 2010-11-12 2014-12-16 Merck Sharp & Dohme Corp. Piperidinone carboxamide azaindane CGRP receptor antagonists
US10646481B2 (en) * 2008-08-13 2020-05-12 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10646481B2 (en) * 2008-08-13 2020-05-12 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US8912210B2 (en) * 2010-11-12 2014-12-16 Merck Sharp & Dohme Corp. Piperidinone carboxamide azaindane CGRP receptor antagonists

Similar Documents

Publication Publication Date Title
CA2780428C (fr) Formulations de comprimes de maleate de neratinib
US11925709B2 (en) Tablet formulation for CGRP active compounds
EP2623100B1 (fr) Préparation pour améliorer la solubilité d'un médicament médiocrement soluble
US20100166857A1 (en) Pharmaceutical dosage forms and methods of manufacturing same
CA2715802A1 (fr) Composition pharmaceutique destinee a des medicaments peu solubles
HUE028204T2 (en) Pharmaceutical compositions containing the active ingredient nilotinib or a salt thereof
CA2801020A1 (fr) Preparation pharmaceutique stable contenant du telmisartan et de l'hydrochlorothiazide
EP2701689B1 (fr) Compositions pharmaceutiques de raltégravir, procédés de préparation et utilisation de celles-ci
WO2024218790A1 (fr) Composition pharmaceutique d'ubrogépant et procédé correspondant pour la préparation d'une forme posologique solide destinée au traitement de la migraine
EP2298290A1 (fr) Composition de libération contrôlée comprenant du lévétiracetam
US8512746B2 (en) Extended release pharmaceutical compositions of levetiracetam
US11260055B2 (en) Oral pharmaceutical composition of lurasidone and preparation thereof
EP2438911A1 (fr) Compositions pharmaceutiques comprenant du secrétagogue d'insuline de classe suphonylurée et huile de ricin à base de glycol de polyéthylène
EP3079672B1 (fr) Composition pharmaceutique comprenant un sel pharmaceutiquement acceptable de rasagiline
HK40081563A (en) Tablet formulations of neratinib maleate
HK40081563B (en) Tablet formulations of neratinib maleate
HK1175720A (en) Tablet formulations of neratinib maleate
HK1175720B (en) Tablet formulations of neratinib maleate

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24792288

Country of ref document: EP

Kind code of ref document: A1