Patent Application
20230390254
This application claims priority from an Indian Patent Application IN 202241031816 filed on Jun. 3, 2022.
The present invention relates to a stable solid oral pharmaceutical compositions of Ubrogepant and pharmaceutically acceptable excipients and a process for preparation thereof.
Ubrogepant is a Calcitonin Gene-related Peptide (CGRP) receptor antagonist. The chemical name is (3′S)—N-((3 S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2trifluoroethyl)piperidin-3-yl)-2′-oxo-1′,2′,5,7 tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3b]pyridine]-3-carboxamide and has the following structural formula:
The molecular formula is C29H26F3N5O3 and molecular weight is 549.6. Ubrogepant is a white to off-white powder. It is freely soluble in ethanol, methanol, acetone, and acetonitrile; and is insoluble in water. It has been found to be a BCS Class IV compound, which has low solubility and low permeability and difficult to formulate into a solid dosage form for e.g., tablets with desired dissolution and/or bioavailability profiles.
Ubrogepant is commercially available in US market under the brand name UBRELVY® in 50 mg and 100 mg tablets and marketed by Allergan. Ubrogepant is indicated for the acute treatment of migraine with or without aura in adults. The inactive ingredients include colloidal silicon dioxide, croscarmellose sodium, mannitol, microcrystalline cellulose, polyvinyl pyrrolidone vinyl acetate copolymer, sodium chloride, sodium stearyl fumarate and vitamin E polyethylene glycol succinate.
U.S. Pat. No. 8,754,096 discloses Ubrogepant compound.
U.S. Pat. No. 10,117,836 (US′836) discloses that Ubrogepant has poor aqueous solubility and describes compositions comprising an extrudate or solid solution of Ubrogepant in a water-soluble polymer matrix which further comprises a disintegration system allowing a tablet made therefrom to rapidly disintegrate in the environment in which the Ubrogepant is to be released.
The US'836 describes that poorly-soluble Class II compounds are frequently dispersed in many different polymers for the improvement of water solubility. However, in case of Ubrogepant it tends to thermally degrade when attempts are made to incorporate it into a matrix comprising hydroxypropyl methylcellulose acetate succinate (HPMCAS), because it led to the formation of excessive degradation products in the dispersion produced through Hot Melt Extrusion process (HME). In some experiments, use of a cellulosic polymer as the dispersion matrix for preparing dispersions of Ubrogepant by HME resulted in up to 25 times the amount of API degradation that subjecting the API alone to the same thermal excursion generated.
However, inventors of US '836 invented that dispersions or extrudates prepared by HME technique using Ubrogepant, PVP-VA (polyvinylpyrrolidone/vinylacetate) in a polymer matrix of vitamin E in the form of its polyethylene glycol succinate (d-alpha-tocopheryl polyethyleneglycol succinate, or TPGS) with polyethylene glycol 1000; with a disintegration system comprising of croscarmellose sodium and powdered sodium chloride.
Due to at least one of the below reasons, there are greater challenges to design an Ubrogepant oral solid dosage forms, for e.g., tablets with conventionally known pharmaceutically acceptable excipients and/or simple processes:
Thus, there is an unmet need to design a desired Ubrogepant oral solid dosage form, like tablets and a simple economical process for producing Ubrogepant tablets having acceptable results of tablet disintegration, tablet dissolution, chemical stability & bioavailability.
In one aspect, the present invention provides a stable immediate release tablet comprising of Ubrogepant and a water insoluble polymer selected from the group consisting of hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, wherein the tablet is prepared by hot melt extrusion process.
In yet another aspect, the present invention provides a stable immediate release tablet comprising of Ubrogepant, a water-soluble polymer, a dispersing agent, a disintegration system and other pharmaceutically acceptable excipients, wherein the composition is devoid of solid dispersions or solid solutions or extrudates comprising of Ubrogepant.
In another aspect, the present invention provides use of an immediate release tablet of Ubrogepant for the acute treatment of migraine with or without aura in adults.
The present invention relates to a stable immediate release tablet comprising of Ubrogepant, a water insoluble or water soluble polymer and pharmaceutically acceptable excipients and a process for preparation thereof.
The tablet composition of the present invention further comprises, a dispersing agent, a disintegration system, a plasticizer and one or more other pharmaceutically acceptable excipients.
The term “Ubrogepant” as used herein includes “Ubrogepant” per se or its derivatives, solvates, hydrates, enantiomers, isomers, polymorphs, thereof.
According to the present disclosure, Ubrogepant is present in an amount from about 0.5% to about 50% by weight based on the total weight of the composition, preferably Ubrogepant is present in an amount from about 1% to about 20% by weight based on the total weight of the composition.
Examples of water-insoluble polymer include but not limited to hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. Water-insoluble polymer is present according to the present invention in an amount from about 1% to about 50% by weight based on the total weight of the composition, preferably, the amount of water-insoluble polymer is from about 2.5% to about 25% by weight based on the total weight of the composition.
Examples of water-soluble polymer include but not limited to polyvinylpyrrolidone-vinyl acetate (PVP-VA) copolymer (copovidone), hydroxypropyl methylcellulose, polyethylene glycol, hydroxypropyl cellulose, carboxymethyl cellulose. Water-soluble polymer is present according to the present invention in an amount from about 1% to about 50% by weight based on the total weight of the composition.
Examples of “dispersing agent” include but not limited to tocopherol-polyethylene-glycolsuccinate (vitamin E TPGS or TPGS), poloxamer, macrogolglycerol hydroxystearate 40, polyoxyethylene castor oils, polyoxyethylene hydrogenated castor oils or combination thereof.
Plasticizers are capable of softening polymers to make them more flexible and lower the processing temperature and thereby decrease the glass transition temperature (Tg) and melt viscosity of the polymer. Examples of “plasticizer” include but not limited to polyethylene glycol 3350, triethyl citrate, or combination thereof.
The term “disintegration system” is a combination of a conventional disintegrant and a rapidly dissolving salt which provides beneficial anti-gellation effects when placed into an environment in which the dosage form within which the disintegration system is incorporated is placed into an environment in which the dosage form disintegrates. For use in a formulation of the present invention, the disintegration system comprises a conventional disintegrant, for example, croscarmellose sodium or crospovidone and sodium chloride. In some embodiments it is preferred for the disintegration system to comprise powdered sodium chloride and croscarmellose sodium, and more preferably in a 1:1 weight ratio. In some embodiments it is preferred for the disintegration system to comprise from about 10% to about 25% by weight based on the total weight of the composition.
The term “pharmaceutically acceptable excipient”, means a pharmacologically inactive component such as a diluent or filler, binder, glidant, lubricant, coloring agent or the like.
Examples of diluent include, but are not limited to microcrystalline cellulose, sodium alginate, silicified microcrystalline cellulose, microfine cellulose, mannitol, maltitol, lactose, anhydrous lactose, lactose monohydrate, spray dried lactose, maltodextrin, isomalt, dicalcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, sucrose, dextrose, magnesium carbonate and mixtures thereof.
Examples of lubricants include, but are not limited to stearic acid, zinc stearate, sodium stearyl fumarate, magnesium stearate, sucrose stearate, aluminum stearate, adipic acid, carnauba wax, glycerol ester of fatty acid, calcium stearate, glycerol tribehenate, glyceryl behenate, polyethylene glycol and mixtures thereof.
Examples of glidant include, but are not limited to talc, colloidal silicon dioxide, calcium silicate, magnesium silicate, magnesium trisilicate, fumed silica, bentonite, magnesium carbonate, glyceryl monostearate, glyceryl palmitostearate, light anhydrous silicic acid, crystalline cellulose, calcium phosphate tribasic and a combination thereof.
Examples of disintegrating agents include, but are not limited to crospovidone, sodium starch glycolate, croscarmellose sodium, carboxymethyl cellulose sodium, polacrilin potassium and mixtures thereof.
In one embodiment, the present invention provides a stable immediate release tablet comprising:
In another embodiment, the present invention provides a stable immediate release tablet comprising:
In one embodiment, the present invention relates to a stable immediate release tablet comprising of:
In a particular embodiment, the present invention relates to a stable immediate release tablet comprising of:
In one embodiment, the present invention relates to a process of making stable immediate release tablet comprising of the following steps:
The stable immediate release tablet comprising Ubrogepant according to present invention disintegrates within 15 minutes or preferably between about 1 to 5 minutes.
In yet another embodiment, the present invention provides an immediate release pharmaceutical composition comprising of Ubrogepant, a water-soluble polymer, a dispersing agent, a disintegration system and other pharmaceutically acceptable excipients, wherein the composition is devoid of solid dispersions or solid solutions or extrudates comprising of Ubrogepant. The water-soluble polymer is a polyvinylpyrollidone-vinyl acetate copolymer (PVP-VA), the dispersing agent comprising of tocopherol-polyethylene-glycolsuccinate (TPGS) and the disintegration systems is, for example, croscarmellose sodium (crosslinked sodium carboxymethylcellulose polymer) or crospovidone or combination of croscarmellose sodium/crospovidone and powdered sodium chloride.
In one embodiment, the present invention relates to a stable immediate release tablet comprising of:
In a particular embodiment, the present invention relates to a stable immediate release tablet comprising of:
In another embodiment, a process of making stable immediate release tablet comprising of the following steps:
In yet another embodiments of the present invention it provides use of a stable immediate release tablet in the manufacture of a medicament for treating migraine with or without aura in adults.
The following examples serve to illustrate the embodiments of the present invention. However, they do not intend to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.
The tablet composition comprising Ubrogepant as per the present invention was prepared according to the formula and process of example 2 and the tablets were tested for in-vitro disintegration in a standard disintegration testing apparatus using aqueous HCl (pH 1.8) as a disintegration medium at 37° C. The results of test are mentioned in Table-1 below:
The release profile of the tablet composition comprising Ubrogepant as per the present invention was evaluated through in-vitro dissolution studies. The composition was prepared according to the formula and process of example 2 and stored at accelerated stability conditions (40° C./75% RH for 1.5 month). The initial samples and stability samples were subjected to an in vitro dissolution study in 900 ml of pH 1.8 Simulated Gastric Fluid (Without enzymes) at a temperature of 37±0.5° C. using a USP apparatus-2 (paddle) with peak vessel at a rotation of about 75 rpm in and results are given in Table-2 below. The composition comprising Ubrogepant according to present invention provides comparative dissolution with commercially marketed Ubrogepant tablets (UBRELVY®) at initial and stability condition.
The stability of the tablet composition comprising Ubrogepant as per the present invention was evaluated through accelerated stability studies. The compositions were prepared according to the formula and process of example 2, and the compositions were subjected to stability study at various temperature and humidity conditions. The compositions were found to be stable at accelerated conditions (40° C./75% RH). Table-3 represents the study result data.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202241031816 | Jun 2022 | IN | national |
