EP3554480A2 - Forme posologique orale pharmaceutique solide à libération de principe actif prolongée comprenant du mirabegron - Google Patents

Forme posologique orale pharmaceutique solide à libération de principe actif prolongée comprenant du mirabegron

Info

Publication number
EP3554480A2
EP3554480A2 EP17829162.1A EP17829162A EP3554480A2 EP 3554480 A2 EP3554480 A2 EP 3554480A2 EP 17829162 A EP17829162 A EP 17829162A EP 3554480 A2 EP3554480 A2 EP 3554480A2
Authority
EP
European Patent Office
Prior art keywords
dosage form
active ingredient
form according
mixture
hydrogel
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.)
Withdrawn
Application number
EP17829162.1A
Other languages
German (de)
English (en)
Inventor
Jessica Schönborn
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.)
Stada Arzneimittel AG
Original Assignee
Stada Arzneimittel AG
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 Stada Arzneimittel AG filed Critical Stada Arzneimittel AG
Publication of EP3554480A2 publication Critical patent/EP3554480A2/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K9/2027—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
    • 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
    • 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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

Definitions

  • the present invention relates to a sustained-release solid pharmaceutical oral dosage form comprising mirabegron or a pharmaceutically acceptable salt thereof as the active ingredient, wherein the active ingredient is contained in a sustained release matrix.
  • Mirabegron is the International Nonproprietary Name (INN) for 2- (2-amino-l, 3-thiazol-4-yl) -N- [4- (2- ⁇ [(2R) -2-hydroxy] 2-phenylethyl] amino] ethyl) phenyl] acetamide and has the following structural formula:
  • Mirabegron is used for the symptomatic treatment of imperative urgency, increased urinary frequency and / or urge incontinence that can occur in adults with overactive bladder.
  • Mirabegron is originally disclosed in WO 99/20607 A1, processes for their preparation are described for example in CN 103304511 A, CN 103387500 A and WO 2015/044965 A1.
  • Mirabegron is a potent beta-3 adrenoceptor agonist. In model experiments, it was found that the drug causes a relaxation of the smooth urinary bladder muscles and thus has a harnblasenentspannende effect. Mirabegron increases the mean voiding volume per micturition and reduces the frequency of bladder contractions that do not lead to bladder emptying.
  • Mirabegron is on the market under the trade name Betmiga *. These are prolonged-release tablets with a dosage of 25 mg or 50 mg Mirabegron. The retarding effect is achieved in said tablets essentially by means of a mixture of polyethylene oxide and hydroxypropyl cellulose, for the stabilization of which butylhydroxytoluene is used as antioxidant.
  • the matrix comprises a hydrogel forming agent selected from the group consisting of a mixture of at least two mutually different hydroxypropylmethylcelluloses, alginate, alginic acid, on poly (meth) acrylate-based polymer and from Carrageenan, wherein the dosage form is an in vitro release rate of the active ingredient, measured using the rotating basket apparatus according to Eur. Ph.
  • the formulation of the present invention can be prepared using the specified hydrogel generators in the matrix by dry methods - that is, without the use of solvents - again reducing the cost of manufacture.
  • Solid prolonged release pharmaceutical pharmaceutical oral dosage forms are known in the art, such as Example in the European Pharmacopoeia, 8th edition, base work 2014, 8.0 / 0478 "tablets", p 1203-1207, where under the heading “tablets with modified drug release”, inter alia, tablets with prolonged release of active ingredient (sustained-release tablets) is mentioned ,
  • Hydrogels, hydrogel formers and corresponding matrix formulations are also known in the art (see “The Tablet”, Handbook of Development, Manufacture and Quality Assurance, A. Bauer-Brandl et al., Editio Cantor Verlag, 3rd Edition, 2012 (ISBN 978- 3-87193-407-0)).
  • the in vitro release rate of the dosage form according to the invention is determined using the rotary basket apparatus (apparatus 1) and the corresponding execution instructions according to Eur.Ph. (European Pharmacopoeia, 8th edition, 7th supplement, 2.9.3 "drug release from solid dosage forms", pp 7367-7375) at 100 U / min in 900 ml of phosphate buffer (34.03 g of potassium dihydrogen phosphate with 112 ml 1.0 M NaOH and make up with demineralized water to 5000 ml) with a pH of 6.8 at 37 ° C.
  • the amount of active substance released is preferably determined by means of UV detection at a wavelength of 250 nm.
  • the dosage form according to the invention may contain mirabegron not only in the form of the free base but also in the form of a pharmaceutically acceptable salt thereof.
  • Mirabegron's pharmaceutically acceptable salts include, for example, Mirabegron acid addition salts which can be prepared by reacting mirabegron with inorganic or organic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, lactic, citric, tartaric, succinic, maleic or fumaric acids.
  • inorganic or organic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, lactic, citric, tartaric, succinic, maleic or fumaric acids.
  • the HPMC grades preferably have a (dynamic) viscosity in a range from 6 to 100,000 mPa * s, more preferably a viscosity in a range from 100 to 100,000 mPa ⁇ s, more preferably a viscosity in a range from 100 to 10,000 mPa * s and more preferably a viscosity in a range of 100 to 4000 mPa * s.
  • the viscosity is according to the invention preferably according to Eur.Ph. (European Pharmacopoeia, 8th edition, 6th supplement, 8.6 / 0348 "Hypromellose", S. 7595-7597).
  • the alginate is a sodium alginate or a calcium alginate, it also being possible for the alginate to be present in admixture with at least one hydroxypropylmethylcellulose.
  • Alginic acid (also algin) is formed by brown algae and some bacteria (eg Azotobacter). In the algae, it represents the structural element of the cell walls. It is suitable as a hydrogel former in both treated and untreated form.
  • Carrageenan are long-chain carbohydrates found in red algae cells.
  • the carbohydrates are linear anionic hydrocolloids, which can be differentiated according to their chemical structure.
  • the poly (meth) acrylate-based polymer is a copolymer of Ethyl acrylate and methyl methacrylate or a terpolymer of ethyl acrylate, methyl methacrylate and a methacrylic acid ester, in particular the copolymer Polyethylacrylatmethylmethacrylat having an ethyl acrylate / methyl methacrylate ratio of 2: 1, for example Eudragit * NE 30 D.
  • the matrix is free of polyethylene oxide, wherein it is even more preferred if the entire dosage form is free of polyethylene oxide.
  • polyethylene oxide synonymous with polyethylene glycol - residues may be present that are suspected to be hazardous to health.
  • polyethylene oxide is sensitive to oxidation, which can lead to an adverse change in the release profile of the dosage form over time.
  • the matrix is free of antioxidants, preferably the entire dosage form.
  • Antioxidants are to be understood as meaning chemical compounds which slow down or prevent the oxidation of chemical substances, for example polyethylene oxide. The renunciation of antioxidants increases the drug compatibility and thus the patient's acceptance. Examples of antioxidants to be excluded are especially butylhydroxytoluene and tocopherols.
  • the weight ratio of active ingredient to the hydrogel former is in a range from 50: 1 to 1:50, more preferably in a range from 20: 1 to 1:20 and particularly preferably in one Range from 10: 1 to 1:10. This ensures a sufficiently delayed release of the active ingredient.
  • the weight ratio of active ingredient to the hydrogel forming agent is in a range from 1: 1 to 1:50, more preferably in a range from 1: 2 to 1:20 and particularly preferably in a range of 1: 3 to 1:10. This also ensures a sufficiently delayed release of the active ingredient.
  • the content of the dosage form of Mirabegron based on the free base is 1 to 100 mg, more preferably 25 mg to 50 mg and even more preferably 25 mg or 50 mg.
  • the extended-release matrix consists of at least 10% by weight of the hydrogel former, more preferably at least 20% by weight, more preferably at least 30% by weight more preferably at least 50% by weight and even more preferably at least 70% by weight.
  • the dosage form is free from pharmaceutical excipients which react basicly in water.
  • Basic-reacting auxiliaries are auxiliaries which react basicly when combined with demineralized water at 20 ° C., ie the water after the combination has a pH of greater than 7.
  • the dosage form comprises a filler, a binder, a disintegrant, a lubricant and / or a
  • the dosage form is a tablet which is optionally provided with a film coating.
  • tablets have a relatively high level of patient acceptance.
  • Tablets are single-dose solid dosage forms that can be prepared using a pressing pressure from powders, granules, or powder / granule mixtures on tablet presses.
  • a tablet is typically the unit dose that is easiest to handle for patients and, moreover, relatively inexpensive.
  • the tablet is directly compressed.
  • the powder containing the tablet components is pressed into a tablet without further pretreatment.
  • the advantage of a directly compressed tablet is that it is relatively easy to manufacture and therefore inexpensive.
  • the tablet is produced by means of a granule containing the active substance. By this measure, a mechanically relatively stable tablet can be obtained. In this case, it is particularly preferred if the active ingredient is present together with the hydrogel former in the granules.
  • the present invention further relates to a process for the preparation of the dosage form according to the invention, comprising the steps of
  • step (b) processing the mixture of step (a) into the dosage form, the process being carried out in the absence of the use of a solvent.
  • the feature according to which the method according to the invention for producing the dosage form according to the invention is carried out without the use of solvents is to be understood such that the agent provided and the hydrogel former provided are not brought into contact with a liquid at any time during production of the dosage form.
  • this refers only to the intentional targeted use of liquids / solvents and not to any residual moisture that adheres to the active ingredient, the hydrogel or any pharmaceutical excipients.
  • Such processes are also referred to in the art as dry processes.
  • the inventive method has the advantage that the resulting dosage form is characterized by both a relatively high morphological stability of the active substance contained therein as well as by a relatively high chemical stability of the same.
  • the method comprises the steps
  • step (c) directly compressing the mixture from step (b) to obtain a tablet core.
  • This preferred embodiment of the method according to the invention leads to a dosage form according to the invention which is particularly cost-effective.
  • the method comprises the steps
  • step (c) dry granulating the mixture of step (b) to obtain a dry granulate
  • step (d) pressing the dry granules from step (c) to obtain a tablet core.
  • the tablet cores obtained are provided in a conventional manner with a film coating.
  • the present invention further relates to a second solid prolonged release solid pharmaceutical oral dosage form comprising mirabegron or a pharmaceutically acceptable salt thereof as active ingredient, wherein the active ingredient is contained in a sustained release matrix comprising a mixture of polyvinyl acetate and polyvinylpyrrolidone, wherein the dosage form an in vitro release rate of the active ingredient, measured using the rotary basket apparatus according to Eur. Ph. (according to the above-mentioned specification) at 100 rpm in 900 ml of phosphate buffer with a pH of 6.8 at a temperature of 37 ° C, from 20% to 40% in 3 h, from 44% to 64% in 5 h and of more than 80% in 8.5 h.
  • This second dosage form according to the invention also solves the problem mentioned in the introduction.
  • the mixture contains 50% by weight to 90% by weight of polyvinyl acetate and 10% by weight to 50% by weight of polyvinylpyrrolidone.
  • a mixture particularly preferred according to the invention is commercially available under the name Kollidon * SR, which consists of 80% by weight of polyvinyl acetate, 19% by weight of polyvinylpyrrolidone, about 0.8% by weight of sodium lauryl sulfate and about 0.2% by weight of silicon dioxide where the latter two are stabilizing agents.
  • the weight ratio of active ingredient to the mixture is in a range from 1: 1 to 1:50, more preferably in a range from 1: 2 to 1:20 and particularly preferably in a range from 1: 3 to 1:10. This also ensures a sufficiently delayed release of the active ingredient.
  • the content of the dosage form of Mirabegron with respect to the free base is 1 to 100 mg, more preferably 25 mg to 50 mg and even more preferably 25 mg or 50 mg.
  • the extended-release matrix consists of at least 10% by weight of the mixture, more preferably at least 20% by weight, more preferably at least 30% by weight, even more preferably at least 50% by weight and even more preferably at least 70% by weight.
  • the second administration form according to the invention can be produced by the method according to the invention for the production of the first-mentioned administration form.
  • the preparation of the tablets was carried out by first mixing the alginic acid as a hydrogel-forming agent and mirabegron as an active ingredient to obtain a mixture. This mixture was compressed by means of a roller compactor and then ground and sieved. The granules thus obtained were mixed with silica as a flow regulator and stearic acid as a lubricant, and the resulting mixture was compressed into tablet cores.
  • the tablet cores thus obtained were film-coated with a commercially available water-based film coating containing hypromellose and T1O2.
  • the film-coated tablets have an in vitro release rate of the active ingredient of 20% to 40% in 3 hours, 44% to 64% in 5 hours and more than 80% in 8.5 hours.
  • the film-coated tablets have an in vitro release rate of the active ingredient of 20% to 40% in 3 hours, 44% to 64% in 5 hours and more than 80% in 8.5 hours.
  • the film-coated tablets have an in vitro release rate of the active ingredient of 20% to 40% in 3 hours, 44% to 64% in 5 hours and more than 80% in 8.5 hours.
  • Embodiment 4
  • Tablets were prepared by first mixing alginic acid as a hydrogel former, mirabegron as an active ingredient, silica as a flow control agent, and stearic acid as a lubricant to obtain a mixture. This mixture was compressed by means of a conventional tablet press into tablet cores. The tablet cores thus obtained were film-coated with a commercially available water-based film coating containing hypromellose and TiO 2.
  • the film-coated tablets have an in vitro release rate of the active ingredient of 20% to 40% in 3 hours, 44% to 64% in 5 hours and more than 80% in 8.5 hours.
  • Embodiment 5
  • the film-coated tablets have an in vitro release rate of the active ingredient of 20% to 40% in 3 hours, 44% to 64% in 5 hours and more than 80% in 8.5 hours.
  • the film-coated tablets have an in vitro release rate of the active ingredient of 20% to 40% in 3 hours, 44% to 64% in 5 hours and more than 80% in 8.5 hours.
  • Tablets were prepared by first mixing the hypromelloses as hydrogel formers, mirabegron as active ingredients, microcrystalline cellulose as fillers, silica flow control agents and stearic acid lubricants to give a mixture. This mixture was compressed by means of a conventional tablet press into tablet cores. The tablet cores thus obtained were film-coated with a commercially available water-based film coating containing hypromellose and TIO 2 .
  • the film-coated tablets have an in vitro release rate of the active ingredient of 20% to 40% in 3 hours, 44% to 64% in 5 hours and more than 80% in 8.5 hours.
  • the tablets were produced by first mixing the hypromelloses as hydrogel formers, mirabegron as the active ingredient, microcrystalline cellulose as fillers, to obtain a mixture. This mixture was compressed by means of a roller compactor and then ground and sieved. The granules thus obtained were mixed with silica as a flow regulator and stearic acid as a lubricant, and the resulting mixture was compressed into tablet cores.
  • the tablet cores thus obtained were film-coated with a commercial water-based film coating containing hypromellose and TiOa.
  • the film-coated tablets have an in vitro release rate of the active ingredient of 20% to 40% in 3 hours, 44% to 64% in 5 hours and more than 80% in 8.5 hours.
  • the film-coated tablets have an in vitro release rate of the active ingredient of 20% to 40% in 3 hours, 44% to 64% in 5 hours and more than 80% in 8.5 hours.

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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

La présente invention concerne une forme posologique pharmaceutique orale solide à libération de principe actif prolongée comprenant du Mirabegron ou un sel pharmaceutiquement acceptable de celui-ci comme principe actif, le principe actif étant contenu de façon répartie dans une matrice à libération prolongée. Pour fournir une forme posologique bioéquivalente du type générique, qui peut être produite de façon relativement simple et donc peu coûteuse, il est proposé que la matrice comprenne un agent générateur d'hydrogel choisi dans le groupe constitué par un mélange d'au moins deux Hydroxypropylméthylcelluloses différents, l'alginate, l'acide alginique, le polymère à base de poly(méth)acrylate et le carraghénane. La forme posologique a une vitesse de libération in vitro du principe actif, tel que mesuré à l'aide de l'appareil à panier rotatif selon Eur. Ph. à 100 tours par min dans 900 ml de tampon phosphate de pH 6,8 à une température de 37 °C, de 20 à 40 % en 3h, de 44 à 64 % en 5h et de plus de 80 % en 8,5 h.
EP17829162.1A 2016-12-13 2017-12-12 Forme posologique orale pharmaceutique solide à libération de principe actif prolongée comprenant du mirabegron Withdrawn EP3554480A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP16203722.0A EP3335700A1 (fr) 2016-12-13 2016-12-13 Forme pharmaceutique orale solide à libération prolongée comprenant du mirabegron
PCT/EP2017/082470 WO2018108939A2 (fr) 2016-12-13 2017-12-12 Forme posologique orale pharmaceutique solide à libération de principe actif prolongée comprenant du mirabegron

Publications (1)

Publication Number Publication Date
EP3554480A2 true EP3554480A2 (fr) 2019-10-23

Family

ID=57544342

Family Applications (2)

Application Number Title Priority Date Filing Date
EP16203722.0A Withdrawn EP3335700A1 (fr) 2016-12-13 2016-12-13 Forme pharmaceutique orale solide à libération prolongée comprenant du mirabegron
EP17829162.1A Withdrawn EP3554480A2 (fr) 2016-12-13 2017-12-12 Forme posologique orale pharmaceutique solide à libération de principe actif prolongée comprenant du mirabegron

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP16203722.0A Withdrawn EP3335700A1 (fr) 2016-12-13 2016-12-13 Forme pharmaceutique orale solide à libération prolongée comprenant du mirabegron

Country Status (2)

Country Link
EP (2) EP3335700A1 (fr)
WO (1) WO2018108939A2 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102546923B1 (ko) * 2020-03-03 2023-06-26 동광제약 주식회사 미라베그론을 포함하는 제어 방출 제제

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU9462198A (en) 1997-10-17 1999-05-10 Yamanouchi Pharmaceutical Co., Ltd. Amide derivatives or salts thereof
US9655885B2 (en) * 2011-05-18 2017-05-23 Dr. Reddy's Laboratories Ltd. Amorphous mirabegron and processes for crystal forms of mirabegron
CN103387500A (zh) 2012-05-11 2013-11-13 上海医药工业研究院 一种米拉贝隆及其中间体的制备方法
CN103193730A (zh) 2013-04-17 2013-07-10 苏州永健生物医药有限公司 一种米拉贝隆的合成方法
WO2015044965A1 (fr) 2013-09-30 2015-04-02 Megafine Pharma (P) Ltd. Procédé de préparation du mirabégron et de sa forme alpha cristalline
CN103655503A (zh) * 2013-11-25 2014-03-26 北京润德康医药技术有限公司 一种米拉贝隆缓释片及其制备方法
JP2017078023A (ja) * 2014-02-28 2017-04-27 アステラス製薬株式会社 経口投与用医薬組成物
CN104523635B (zh) * 2014-12-23 2017-05-03 深圳万乐药业有限公司 米拉贝隆缓释药物组合物
CN105769786B (zh) * 2014-12-24 2019-04-26 上海复星星泰医药科技有限公司 一种米拉贝隆缓释片及其制备方法
JP2016188181A (ja) * 2015-03-30 2016-11-04 アステラス製薬株式会社 ミラベグロン含有放出制御錠剤
CN106176650A (zh) * 2016-08-19 2016-12-07 迪沙药业集团有限公司 一种米拉贝隆组合物

Also Published As

Publication number Publication date
EP3335700A1 (fr) 2018-06-20
WO2018108939A3 (fr) 2018-08-16
WO2018108939A2 (fr) 2018-06-21

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