WO2023228027A1 - Composition de tablette de mirabegron - Google Patents

Composition de tablette de mirabegron Download PDF

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Publication number
WO2023228027A1
WO2023228027A1 PCT/IB2023/055155 IB2023055155W WO2023228027A1 WO 2023228027 A1 WO2023228027 A1 WO 2023228027A1 IB 2023055155 W IB2023055155 W IB 2023055155W WO 2023228027 A1 WO2023228027 A1 WO 2023228027A1
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WO
WIPO (PCT)
Prior art keywords
controlled release
pharmaceutical composition
mirabegron
release pharmaceutical
pharmaceutically acceptable
Prior art date
Application number
PCT/IB2023/055155
Other languages
English (en)
Inventor
Sathyanarayana Vemula
Namdev Kashid
Saswat Abhishek Padhi
Original Assignee
V-Ensure Pharma Technologies Private Limited
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 V-Ensure Pharma Technologies Private Limited filed Critical V-Ensure Pharma Technologies Private Limited
Publication of WO2023228027A1 publication Critical patent/WO2023228027A1/fr

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Classifications

    • 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles

Definitions

  • the present invention relates to a controlled release pharmaceutical composition of Mirabegron or pharmaceutically acceptable salt(s) thereof.
  • Mirabegron is a potent and selective agonist of the human beta-3 adrenergic receptor. Mirabegron is used as urinary antispasmodics and it is chemically known as 2-(2- aminothiazol-4-yl)-N-[4-(2- ⁇ [(2R)-2-hydroxy-2 phenylethyl] amino ⁇ ethyl)phenyl] acetamide.
  • the structural formula of mirabegron is as follows:
  • Mirabegron is also used as a therapeutic agent for overactive bladder, such as overactive bladder accompanied by prostatic hyperplasia, or overactive bladder accompanied by urinary urgency, urinary incontinence, and urinary frequency as reported in PCT application number W004041276 (assigned to Yamanouchi Pharmaceutical Co., Ltd., referred to herein as WO’276).
  • EP2298752B1 (assigned to M/s Astellas Pharma Inc, referred to herein as EP’752) claims a crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2- phenylethyl) amino] ethyl] -acetanilide having a moisture-holding amount of not more than 0.2 % over the entire range of relative humidity from 5 % to 95 % and having main peaks at around 5.32, 8.08, 15.28, 17.88, 19.04, 20.20, 23.16 and 24.34 in the terms of 20(°) in the powder X-ray diffraction.
  • European Patent Number EP1559427B1 (assigned to M/s Astellas Pharma Inc, referred to herein as EP’427) teaches use of Mirabegron in the treatment of overactive bladder.
  • US10,842,780 (assigned to M/s Astellas Pharma Inc, referred to herein as US’780) teaches modified release compositions of Mirabegron with hydrogel forming polymer and an additive wherein the hydrogel-forming polymer is at least one compound selected from the group consisting of polyethylene oxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose sodium, hydroxyethyl cellulose, and a carboxyvinyl polymer, wherein the additive is at least one selected from the group consisting of polyethylene glycol, polyvinylpyrrolidone, D-mannitol, D-sorbitol, xylitol, lactose, sucrose, anhydrous maltose, D-fructose, dextran, glucose, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, polyoxyethylene sorbitan higher fatty acid ester, sodium chloride, magnesium chloride, citric acid,
  • a tablet composition comprising mirabegron or pharmaceutically acceptable salt(s) with less toxic and pharmacologically inactive excipients.
  • the amino group is present in mirabegron, especially secondary amines. Under acidic reactions there may be formation of nitrosamine in presence of secondary amines which is present in the mirabegron. Nitrosamines are carcinogenic which are not safe for patients.
  • FDA United States Food and Drug Administration
  • EMA European Medicines Agency
  • mirabegron contains N-Nitroso Mirabegron impurity which may be formed during synthesis of mirabegron or manufacturing of pharmaceutical composition of mirabegron.
  • the N-Nitroso Mirabegron impurity which is having chemical structure as follows:
  • the object of the present invention is to provide a controlled release pharmaceutical composition of Mirabegron or pharmaceutically acceptable salt(s).
  • a controlled release pharmaceutical composition for oral administration comprising a therapeutically effective amount of mirabegron or a pharmaceutically acceptable salt thereof, as an active ingredient, a hydrogel-forming polymer, as release controlling polymer, a colloidal agent, as a diluent and a pharmaceutically acceptable polymer of average molecular weight of less than 100,000, as a binder, wherein said active ingredient is released from said composition 30% or less after 2 hours, as measured in accordance with United States Pharmacopoeia in 900 m of a USP buffer having a pH of 6.8 at a basket rotation speed of 100 rpm.
  • a controlled release pharmaceutical composition of mirabegron or pharmaceutically acceptable salt thereof comprising a. hydrogel forming polymer is in the range of 5 to 50% by weight with respect to the total weight of the composition; b. colloidal agent is in the range of 15 to 65% by weight with respect to the total weight of the composition; c. pharmaceutically acceptable polymer of average molecular weight of less than 100,000 is in the range of 5 to 50% by weight with respect to the total weight of the composition; and d. further comprises at least one pharmaceutically acceptable excipient selected from lubricants, antioxidants and glidants;
  • composition releases 30% or less mirabegron after 2 hours, as measured in accordance with United States Pharmacopoeia in 900 mb of a USP buffer having a pH of 6.8 at a basket rotation speed of 100 rpm.
  • a controlled release pharmaceutical composition comprising a therapeutically effective amount of mirabegron or a pharmaceutically acceptable salt thereof comprises less than 250 ppm of nitrosamine related impurities.
  • nitrosamine impurities of a controlled release pharmaceutical composition comprising a therapeutically effective amount of mirabegron or a pharmaceutically acceptable salt thereof is N-Nitroso Mirabegron.
  • a controlled release pharmaceutical composition for oral administration comprising a therapeutically effective amount of mirabegron or a pharmaceutically acceptable salt thereof, as an active ingredient, a hydrogel-forming polymer, as release controlling polymer, a colloidal agent, as a diluent and a pharmaceutically acceptable polymer of average molecular weight of less than 100,000, as a binder, wherein said active ingredient is released from said composition 30% or less after 2 hours, as measured in accordance with United States Pharmacopoeia in 900 mU of a USP buffer having a pH of 6.8 at a basket rotation speed of 100 rpm.
  • a controlled release pharmaceutical composition of mirabegron or pharmaceutically acceptable salt thereof comprising a. hydrogel forming polymer is in the range of 5 to 50% by weight with respect to the total weight of the composition; b. colloidal agent is in the range of 15 to 65% by weight with respect to the total weight of the composition; c. pharmaceutically acceptable polymer of average molecular weight of less than 100,000 is in the range of 5 to 50% by weight with respect to the total weight of the composition; and d. at least one pharmaceutically acceptable excipient selected from lubricants, antioxidants and glidants;
  • composition releases 30% or less mirabegron after 2 hours, as measured in accordance with United States Pharmacopoeia in 900 mb of a USP buffer having a pH of 6.8 at a basket rotation speed of 100 rpm.
  • controlled release pharmaceutical compositions comprising Mirabegron or pharmaceutically acceptable salt(s) wherein 30% or less mirabegron is released after 2 hours may be developed using pharmacologically inactive excipients such as colloidal agents. Colloidal agents enable penetration of water into the pharmaceutical composition.
  • the particle size of Mirabegron or pharmaceutically acceptable salt thereof used in the present invention may have particle size D(90) : NMT 35 microns, D(50): NMT 20 microns, D(10) : NMT 10 microns.
  • the said controlled release pharmaceutical composition is in the form of tablets, minitablets, pellets, capsules, granules or spheroids.
  • the controlled release pharmaceutical composition of mirabegron of the present invention comprises hydrogel forming polymer is selected from polyethylene oxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose sodium, hydroxyethyl cellulose and a carboxyvinyl polymer, or mixtures thereof.
  • the controlled release pharmaceutical composition of mirabegron comprises hydrogel forming polymer is polyethylene oxide with the average molecular weight approximately 2,000,000.
  • the hydrogel forming polymer is in the range of 5 to 50%; preferably 10 to 40% and most preferred being 10 to 30% by weight with respect to the total weight of the composition.
  • the controlled release pharmaceutical composition of mirabegron of the present invention comprises colloidal agent selected from starch, pregelatinized starch, starch derivatives and gelatin, or mixtures thereof. Colloidal agents enable penetration of water into the pharmaceutical composition due to the fine particle size.
  • the colloidal agent is in the range of 15 to 65%; preferably 20 to 60% and most preferred being 20 to 50% by weight with respect to the total weight of the composition.
  • the controlled release pharmaceutical composition of mirabegron of the present invention comprises pharmaceutically acceptable polymer of average molecular weight of less than 100,000 selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose and methylcellulose, or mixtures thereof.
  • the pharmaceutically acceptable polymer of average molecular weight of less than 100,000 is in the range of 5 to 50%; preferably 10 to 45% and most preferred being 10 to 40% by weight with respect to the total weight of the composition.
  • a controlled release pharmaceutical composition of mirabegron or pharmaceutically acceptable salt thereof comprising a. hydrogel forming polymer preferably in the range of 10 to 40% weight by total weight of the composition; b. colloidal agent preferably in the range of 20 to 60% weight by total weight of the composition; c. pharmaceutically acceptable polymer of average molecular weight of less than 100,000 preferably in the range of 10 to 45% weight by total weight of the composition; and d.
  • the tablet composition of the present invention is less than 30% or less mirabegron after 2 hours, preferably less than 20%.
  • the total weight of the tablet composition of the present invention is typically in the range of 100 to 400 mg and preferably 200 to 300 mg.
  • the tablet composition of the present invention may comprise pharmaceutical excipient(s) selected from lubricants, antioxidants and glidants.
  • the lubricants used in the present invention may be selected from stearic acid, calcium stearate, sodium stearyl fumarate, mixtures thereof.
  • the lubricants may be in the range of 0.2 to 2% by weight with respect to the total weight of the tablet composition.
  • the antioxidants used in the present invention may be selected from butylated hydroxytoluene (BHT), butylhydroxyanisol (BHA), ascorbic acid, sodium ascorbate, sodium bisulfite, sodium pyrosulfite.
  • BHT butylated hydroxytoluene
  • BHA butylhydroxyanisol
  • ascorbic acid sodium ascorbate
  • sodium bisulfite sodium pyrosulfite
  • the antioxidants may be in the range of 0.01 to 1.00% by weight with respect to the total weight of the tablet composition.
  • the tablets may be optionally coated by a film-coat.
  • the coating agents may be selected from water soluble or water insoluble polymers.
  • the water soluble polymers used in the coating according to the present invention may be selected from hydroxypropylethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxybutyl cellulose, modified starch, polyvinyl alcohol, xanthan gum, or polyethylene oxide, polyvinylpyrrolidone (PVP), carboxyvinyl polymer, poloxamer, methylcellulose, carboxymethyl cellulose, polyvinyl alcohol, carrageenans, xanthan gum, and mixtures of one or more thereof.
  • PVP polyvinylpyrrolidone
  • the water insoluble polymers used in the coating according to the present invention may be selected from acrylic acid polymers, polymethacrylates or methacrylic acid copolymers, ethylcellulose, cellulose acetate, hydroxypropylcellulose succinate, hydroxypropylmethylcellulose succinate, alginate, acacia, chitosan, carmellose sodium, carmellose calcium, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, polyvinyl acetate phthalate, cellulose acetate trimellitate, shellac and derivatives and mixtures thereof.
  • Coating is done by using any conventional coating technique known in the art, such as spray coating in a conventional coating pan or fluidized bed processor or dip coating.
  • the pharmaceutical composition for e.g. Tablet composition according to the present invention is packaged in primary packaging material e.g. blisters, bottles.
  • the tablet composition of the present invention is preferably packaged in PVC/PE/PVDC blisters (triplex) or Alu-Alu blisters or HDPE bottles.
  • the pharmaceutical composition of the present invention releases 30% or less of mirabegron after 2 hours.
  • the test method is in accordance with United States Pharmacopoeia in 900 mb of a USP buffer having a pH of 6.8 at a basket rotation speed of 100 rpm.
  • the process for the preparation of controlled release pharmaceutical composition of Mirabegron or pharmaceutically acceptable salts may be selected from wet granulation, dry granulation, direct compression, slugging, tabletting, coating, capsule filling, sachet filling and the like.
  • a process for the preparation of a controlled release pharmaceutical composition for oral administration comprising a therapeutically effective amount of mirabegron or a pharmaceutically acceptable salt thereof, as an active ingredient, a hydrogel-forming polymer, as release controlling polymer, a colloidal agent, as a diluent and a pharmaceutically acceptable polymer of average molecular weight of less than 100,000, as a binder, wherein said active ingredient is released from said composition 30% or less after 2 hours, as measured in accordance with United States Pharmacopoeia in 900 mb of a USP buffer having a pH of 6.8 at a basket rotation speed of 100 rpm, wherein said process comprises the following steps: a.
  • mirabegron contains secondary amines. Under acidic reactions there may be formation of nitrosamine in presence of secondary amines which is present in the mirabegron. The formation of nitrosamines is also possible when secondary or tertiary amines react with nitrous acid. The nitrosamines impurities are carcinogenic in nature. Exposure to Nitrosamines, even in small amounts, poses a significant risk to patients. The presence of nitrosamines could form in a finished drug product over the drug product’s shelf life.
  • ND MA N-nitrosodimethylamine
  • WHO World Health Organization
  • IARC International Agency for Research on Cancer
  • nitrosamine impurities of which NDMA and NMBA impurities having 96 ng/day limit and NDEA, NIPEA, NMPA, NDIPA, having 26.5 ng/day limits. These nitrosamine impurities can be detected by using analytical method like LCMS.
  • a controlled release pharmaceutical composition comprising a therapeutically effective amount of mirabegron or a pharmaceutically acceptable salt thereof comprises less than 250 ppm of nitrosamine related impurities.
  • the nitrosamine impurities of a controlled release pharmaceutical composition comprising a therapeutically effective amount of mirabegron or a pharmaceutically acceptable salt thereof is N-Nitroso Mirabegron. Further, the detection of N-Nitroso Mirabegron impurity is analysed by using Liquid Chromatography Mass Spectroscopy (LCMS) method.
  • LCMS Liquid Chromatography Mass Spectroscopy
  • Fig. 1 depicts the In-vitro dissolution profile comparison of Myrbetriq with Comparative Examples of Mirabegron Composition of the present invention as exemplified in Example 3.
  • Example 1 Comparative examples of mirabegron compositions as shown in Table 1
  • the comparative examples of controlled release pharmaceutical composition of Mirabegron as mentioned in the Table 1 are prepared by sifting intragranular part.
  • Granulating fluid prepared by using suitable solvent as given in Table 1 respectively.
  • Dissolution Media 900 mb of pH 6.8 phosphate buffer (USP)
  • the dissolution rate of comparative examples of controlled release pharmaceutical composition of Mirabegron after 2 hours is less than 30%.
  • Table 3 Provides the dissolution release profiles for Exla, Exlb & Exlc (Fig.1 .)
  • Example 4 Detection of N-Nitroso Mirabegron impurity by using Liquid Chromatography Mass Spectroscopy (LCMS) method. N-Nitroso Mirabegron impurity was analysed by using LCMS and the results are furnished below.
  • LCMS Liquid Chromatography Mass Spectroscopy
  • the above comparative examples are subjected for accelerated stability studies and it was observed that the N-Nitroso mirabegron impurities are stable and not increased during stability.
  • the amount of the corresponding N-Nitroso mirabegron impurity formed in the present invention is significantly reduced to an acceptable level over the shelf-life of the product.

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

Abstract

Une composition pharmaceutique à libération contrôlée pour administration orale comprenant une quantité thérapeutiquement efficace de mirabegron ou d'un sel pharmaceutiquement acceptable de celui-ci, en tant que principe actif, un polymère de formation d'hydrogel, en tant que polymère de contrôle de libération, un agent colloïdal, en tant que diluant et un polymère pharmaceutiquement acceptable de poids moléculaire moyen inférieur à 100 000, en tant que liant, ledit ingrédient actif étant libéré de ladite composition à 30 % ou moins après 2 heures, tel que mesuré conformément à United States Pharmacopoeia dans 900 mL d'un tampon USP ayant un pH de 6,8 à une vitesse de rotation de panier de 100 tr/min. Ladite composition comprend une impureté N-Nitroso Mirabegron inférieure à 250 ppm.
PCT/IB2023/055155 2022-05-23 2023-05-19 Composition de tablette de mirabegron WO2023228027A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202221029548 2022-05-23
IN202221029548 2022-05-23

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019077644A (ja) * 2017-10-25 2019-05-23 富士フイルム株式会社 医薬組成物及び医薬組成物の製造方法
US20200206197A1 (en) * 2017-07-14 2020-07-02 Daewoong Pharmaceutical Co., Ltd. Pharmaceutical preparation and preparation method therefor
WO2021069944A1 (fr) * 2019-10-09 2021-04-15 Alvogen Korea Co., Ltd. Composition pharmaceutique comprenant du mirabégron et son procédé de fabrication
WO2021259396A2 (fr) * 2021-08-20 2021-12-30 威智医药有限公司 Impureté de nitrosamine, composition pharmaceutique de varénicline pouvant réduire la génération d'impuretés de nitrosamine et préparation et utilisation associées
CN115721625A (zh) * 2021-08-27 2023-03-03 山东威智中科药业有限公司 一种包含米拉贝隆的药物组合物及其制备与应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200206197A1 (en) * 2017-07-14 2020-07-02 Daewoong Pharmaceutical Co., Ltd. Pharmaceutical preparation and preparation method therefor
JP2019077644A (ja) * 2017-10-25 2019-05-23 富士フイルム株式会社 医薬組成物及び医薬組成物の製造方法
WO2021069944A1 (fr) * 2019-10-09 2021-04-15 Alvogen Korea Co., Ltd. Composition pharmaceutique comprenant du mirabégron et son procédé de fabrication
WO2021259396A2 (fr) * 2021-08-20 2021-12-30 威智医药有限公司 Impureté de nitrosamine, composition pharmaceutique de varénicline pouvant réduire la génération d'impuretés de nitrosamine et préparation et utilisation associées
CN115721625A (zh) * 2021-08-27 2023-03-03 山东威智中科药业有限公司 一种包含米拉贝隆的药物组合物及其制备与应用

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