WO2016120299A1 - Formulations de dronédarone à délitement buccal - Google Patents

Formulations de dronédarone à délitement buccal Download PDF

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Publication number
WO2016120299A1
WO2016120299A1 PCT/EP2016/051640 EP2016051640W WO2016120299A1 WO 2016120299 A1 WO2016120299 A1 WO 2016120299A1 EP 2016051640 W EP2016051640 W EP 2016051640W WO 2016120299 A1 WO2016120299 A1 WO 2016120299A1
Authority
WO
WIPO (PCT)
Prior art keywords
dronedarone
weight
orally disintegrating
sodium
pharmaceutical formulation
Prior art date
Application number
PCT/EP2016/051640
Other languages
English (en)
Inventor
Ali TÜRKYILMAZ
Gülay Yelken
Melike Eceoglu
Original Assignee
Sanovel Ilac Sanayi Ve Ticaret A.S.
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 Sanovel Ilac Sanayi Ve Ticaret A.S. filed Critical Sanovel Ilac Sanayi Ve Ticaret A.S.
Publication of WO2016120299A1 publication Critical patent/WO2016120299A1/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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone

Definitions

  • the present invention relates to an orally disintegrating pharmaceutical formulation comprising dronedarone or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
  • the background of the invention is a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
  • Dronedarone is a noniodinated benzofuran derivative with antiarrhythmic properties.
  • Dronedarone is an amiodarone analog that differs structurally from amiodarone in that the iodine moiety was removed and a methane sulfonyl group was added. These modifications reduce thyroid and other adverse effects and makes dronedarone less lipophilic, with a shorter half-life.
  • the chemical name of dronedarone is N-[2-butyl-3-[4- [3-(dibutylamino)propoxy]benzoyl]-1 -benzofuran-5-yl]methanesulfonamide and has the structure shown in the following formula I.
  • Dronedarone hydrochloride (shown in formula II) is an antiarrhythmic drug indicated to reduce the risk of hospitalization for atrial fibrillation (AF) in patients in sinus rhythm with a history of paroxysmal or persistent AF. It was approved by the FDA on 2009 and marketed under the brandname MULTAQTM. Recommended dose is one tablet of 400 mg twice a day with morning and evening meals.
  • dronedarone and pharmaceutically acceptable salts thereof are described in EP 0 471 609 B1 .
  • US 7 323 493 B1 discloses tablet formulations of dronedarone HCI.
  • ODTs are solid dosage forms containing active ingredients which disintegrate rapidly through buccal mucosa. It is desirable in the treatment of a number of diseases including pediatric and geriatric treatments. They are also advantageous for administrations of medicaments to patients who are traveling or have little access to water or patients who have difficulties swallowing other dosage forms.
  • dronedarone is used mostly for elderly patients with atrial fibrillation with high risk, there is a need in the art for orally disintegrating tablet of dronedarone.
  • it is not easy to develop orally disintegrating formulations for all active agents because of several different reasons and requirements such as disintegration, stability, compressibility and taste masking.
  • Dosage form must disintegrate in the oral cavity with the existence of saliva in a short period of time. So those compositions should have a porous structure. However, these porous characteristic tend to be very sensitive to humidity and may be lead to stability problems.
  • the orally disintegrating tablet formulation of dronedarone needs to be adapted in particular by a careful excipient selection give a suitable porous structure with suitable disintegrating time and high stability.
  • the present invention relates to an orally disintegrating pharmaceutical formulation comprising dronedarone or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
  • dronedarone or a pharmaceutically acceptable salt used in this present invention is dronedarone hydrochloride.
  • dronedarone hydrochloride (HCI) is present in an amount of between 5 to 90 %, preferably between 20 to 75 % and more preferably it is 40 to 75 % by weight of total formulation.
  • dronedarone hydrochloride present in an amount of between 50 to 1000 mg, preferably 200 to 800 mg and more preferably it is 400 to 800 mg.
  • the orally disintegrating formulation comprising dronedarone HCI
  • desired disintegration time is achieved.
  • the orally disintegrating formulation of dronedarone HCI is disintegrated in less than 1 min.
  • the orally disintegrating formulation of this present invention comprises one or more pharmaceutically acceptable excipient selected from the group comprising super disintegrants, taste masking agents, diluents, lubricants, binders, glidants, sweeteners, flavouring agents, acidifying agents and alkalizing agents.
  • the term "super-disintegrant” is defined as the pharmaceutical ingredient that provides improved compressibility, stability as well as achieves disintegration substantially faster than the conventional disintegrants.
  • the term “super-disintegrant” is selected from the group comprising crospovidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose (L-HPC), povidone, alginic acid and alginates, cross-linked alginic acid, croscarmellose sodium, sodium carboxymethyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, docusate sodium, soy polysaccharide, guar gum, gellan gum, xanthan gum, magnesium alumina silica, polyacrylin potasium, poloxamer, sodium dodecyl sulphate, sodium lauryl sulphate, calcium silicate, sodium glycine carbonate and ion exchange resins.
  • the ratio of dronedarone to super disintegrant is also affects the compressibility.
  • the certain ratio of dronedarone to super disintegrants is in the range of between 1 and 30 (w/w), preferably 1 and 15 (w/w) and more preferably 2 and 10 (w/w).
  • Suitable taste-masking agents may include but not limited to PVA (polyvinyl alcohol) based coating, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat IR), butyl methacrylate and methyl methacrylate (Eudragit E 100) (Poly(butyl methacrylate-co-(2- demethylaminoeethyl)methacrylate-co-methyl methacrylate)) , ethylcellulose dispersions (Surelease), Kerry-HPC, polyethylene glycol, polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA) and all kinds of OpadryTM, as well as pigments, dyes, titanium dioxide, iron oxide, talc or polymethylmetacrylate copolymers (Eudragit).
  • PVA polyvinyl alcohol
  • Kollicoat IR polyvinyl alcohol-polyethylene glycol copolymers
  • Suitable diluents are selected from the group comprising mannitol, xylitol, microcrystalline cellulose (MCC), lactose, corn starch dibasic calcium phosphate, xylitol, spray-dried lactose, sorbitol, sucrose, trehalose, isomalt, LudiFlash® (mannitol, crospovidon and polivinyl acetate), starch, calcium phosphate anhydrate, calcium phosphate dihydrate, calcium phosphate trihydrate, tribasic calcium phosphate, calcium carbonate, calcium sulfate, dicalcium sulfate, sodium chloride, carboxymethyl cellulose calcium, powdered cellulose, cellulose acetate, pregelatinized starch, lactose monohydrate, sodium carbonate, sodium bicarbonate, isomalt, heavy magnesium carbonate, maltodextrine, mixture of sucrose - maltodextrine, dextrose, lactitol, calcium carbonate,
  • Suitable lubricants are selected from the group comprising sodium stearyl fumarate, magnesium stearate, sodium lauryl sulphate, zinc stearate, calcium stearate, mineral oil, talc, polyethylene glycol, glyceryl monostearate, glyceryl palmitostearate, magnesium lauryl sulphate, fumaric acid, zinc stearate, stearic acid, hydrogenated natural oils, silica, paraffin and mixtures thereof.
  • Suitable binders are selected from the group comprising polyvinylpyrrolidone (PVP) (Kollidon) (povidone K30), carnauba wax, hydroxypropyl methyl cellulose (HPMC), pullulan, polymethacrylate, glyceryl behenate, hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), methyl cellulose (MC), hydroxyethyl cellulose, sodium carboxymethyl cellulose (Na CMC), carboxymethyl cellulose calcium, ethyl cellulose and other cellulose derivatives, polymetacrylates, polyethylene oxide, polyvinyl alcohol, polycarbophil, polyvinyl acetate and their copolymers, gelatin, starch, xanthan gum, guar gum, alginate, carrageen, kollagen, agar, pectin, hyaluronic acid, carbomer, chitosan, cellulose acetate phthalate, hydroxypropyl starch, hydroxy
  • Suitable glidants are selected from the group comprising colloidal anhydrose silica, colloidal silicon dioxide (Aerosil), talc, aluminum silicate, powdered cellulose, calcium phosphate tribasic, hydrophobic colloidal silica, magnesium oxide, magnesium trisilicate, magnesium silicate and mixtures thereof.
  • Suitable sweeteners may include but not limited to sucralose, erythritol, thaumatin, mogroside, inuline, acesulfame-K, aspartame, saccharin or its sodium and calcium salts, sodium cyclamate, sucrose, fructose, glucose, sorbitol, menthol, peppermint, cinnamon, chocolate, vanillin and fruit essences such as cherry, orange, strawberry, grape or mixtures thereof.
  • Suitable flavouring agents may include but not limited menthol, peppermint, cinnamon, chocolate, vanillin and fruit essences such as cherry, orange, strawberry, grape etc. and mixtures thereof.
  • Suitable acidifying agents may include but not limited to citric acid, fumaric acid, adipic acid, acetic acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, sulfuric acid, tartaric acid and mixtures thereof.
  • Suitable alkalizing agents may include but not limited to sodium bicarbonate, sodium glycine carbonate, ammonia solution, ammonium carbonate, diethanolamine, diisopropanolamine, potassium hydroxide, sodium carbonate, sodium borate, sodium hydroxide, trolamine and mixtures thereof.
  • orally disintegrating formulations comprising dronedarone HCI has been designed made up of the following:
  • flavouring agent - 0.10 5.00 % by weight of flavouring agent
  • PVP polyvinylpyrrolidone
  • colloidal anhydrose silica 0.10 - 1 .00
  • flavouring agent 0.10 - 5.00 The production of the formulation is carried out as follows: Dronedarone HCI, mannitol and 50% of crospovidone are taken into granulator and mixed. Granulation is achieved in suitable amount of water and PVP mixture and granules are dried in fluid bed dryer or oven. Dried granules are sieved and sucralose, colloidal anhydrose silica, 50% of crospovidone and flavouring agent are mixed. Sodium stearyl fumarate is added to mixture then mixed. Then, the mixture is pressed into tablets.
  • the production of the formulation is carried out as follows: Dronedarone HCI, sucralose, sodium starch glycolate, xylitol, colloidal anhydrose silica and flavouring agent are mixed. Then, sodium stearyl fumarate is added and mixed. The mixture is pressed into tablets.
  • colloidal anhydrose silica 0.10 - 1 .00
  • flavouring agent 0.10 - 5.00 The production of the formulation is carried out as follows: Dronedarone HCI, mannitol, xylitol, L-HPC and sucralose are mixed. Then, colloidal anhydrose silica and flavouring agent are added and mixed. Then, sodyum stearyl fumarate is added and mixed. The mixture is pressed into tablets.

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

Abstract

La présente invention concerne une formulation pharmaceutique à délitement buccal, comprenant du dronédarone ou un sel pharmaceutiquement acceptable de celui-ci, et un ou plusieurs excipients pharmaceutiquement acceptables.
PCT/EP2016/051640 2015-01-28 2016-01-27 Formulations de dronédarone à délitement buccal WO2016120299A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR201500925 2015-01-28
TR2015/00925 2015-01-28

Publications (1)

Publication Number Publication Date
WO2016120299A1 true WO2016120299A1 (fr) 2016-08-04

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Family Applications (1)

Application Number Title Priority Date Filing Date
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0471609B1 (fr) 1990-08-06 1996-11-27 Sanofi Dérivés de Benzofuranne, Benzothiophène, Indole ou Indolizine, leur procédé de préparation ainsi que les compositions les contenant
US7323493B1 (en) 1997-06-23 2008-01-29 Sanofi-Aventis Solid pharmaceutical composition containing benzofuran derivatives
CN102078307A (zh) * 2009-12-01 2011-06-01 严洁 一种盐酸决奈达隆固体分散体的药物组合物及其制备方法
WO2011132167A1 (fr) * 2010-04-21 2011-10-27 Sanofi-Aventis Procédé de préparation de compositions pharmaceutiques destinées à une administration orale, comprenant un ou plusieurs principes actifs, et compositions les comprenant
WO2011135581A2 (fr) * 2010-04-28 2011-11-03 Cadila Healthcare Limited Compositions pharmaceutiques de dronédarone
WO2012085284A2 (fr) * 2010-12-24 2012-06-28 Krka, D.D., Novo Mesto Formulations pharmaceutiques à charge médicamenteuse élevée comprenant de la dronédarone et des sels pharmaceutiquement acceptables de celles-ci
WO2013024411A1 (fr) * 2011-08-12 2013-02-21 Lupin Limited Formulation cobroyée de dronédarone

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0471609B1 (fr) 1990-08-06 1996-11-27 Sanofi Dérivés de Benzofuranne, Benzothiophène, Indole ou Indolizine, leur procédé de préparation ainsi que les compositions les contenant
US7323493B1 (en) 1997-06-23 2008-01-29 Sanofi-Aventis Solid pharmaceutical composition containing benzofuran derivatives
CN102078307A (zh) * 2009-12-01 2011-06-01 严洁 一种盐酸决奈达隆固体分散体的药物组合物及其制备方法
WO2011132167A1 (fr) * 2010-04-21 2011-10-27 Sanofi-Aventis Procédé de préparation de compositions pharmaceutiques destinées à une administration orale, comprenant un ou plusieurs principes actifs, et compositions les comprenant
WO2011135581A2 (fr) * 2010-04-28 2011-11-03 Cadila Healthcare Limited Compositions pharmaceutiques de dronédarone
WO2012085284A2 (fr) * 2010-12-24 2012-06-28 Krka, D.D., Novo Mesto Formulations pharmaceutiques à charge médicamenteuse élevée comprenant de la dronédarone et des sels pharmaceutiquement acceptables de celles-ci
WO2013024411A1 (fr) * 2011-08-12 2013-02-21 Lupin Limited Formulation cobroyée de dronédarone

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MOHANACHANDRAN P S ET AL: "Superdisintegrants: An overview", INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES REVIEW AND RESEARCH 2011 GLOBAL RESEARCH ONLINE IND, vol. 6, no. 1, January 2011 (2011-01-01), pages 105 - 109, XP002755784, ISSN: 0976-044X *

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