WO2018202224A1 - Film-coated tablets of deferasirox - Google Patents

Film-coated tablets of deferasirox Download PDF

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Publication number
WO2018202224A1
WO2018202224A1 PCT/CZ2018/000017 CZ2018000017W WO2018202224A1 WO 2018202224 A1 WO2018202224 A1 WO 2018202224A1 CZ 2018000017 W CZ2018000017 W CZ 2018000017W WO 2018202224 A1 WO2018202224 A1 WO 2018202224A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
composition according
weight
poloxamer
deferasirox
Prior art date
Application number
PCT/CZ2018/000017
Other languages
English (en)
French (fr)
Inventor
Michaela GAJDOSOVA
Jaroslava SVOBODOVA
Daniel PECEK
Original Assignee
Zentiva, K.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 Zentiva, K.S. filed Critical Zentiva, K.S.
Priority to EP18726029.4A priority Critical patent/EP3618814A1/en
Publication of WO2018202224A1 publication Critical patent/WO2018202224A1/en

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
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the technical solution relates to a novel pharmaceutical composition with the active ingredient Deferasirox and to a method for producing the same.
  • Deferasirox with the systematic name 4-[(3Z,5E)-3,5-bis(6-oxo-l-cyclohexa-2,4- dienylidene)-l,2,4-triazolidin-l-yl] benzoic acid, exhibits a chelating effect on iron ions, which makes it useful for the treatment of chronic iron overload of the organism due to frequent blood transfusions.
  • a pharmaceutical composition of Deferasirox was first described in patent application W09749395. This is an application that introduces new diphenyltriazol compounds, which form chelates with iron and represent a suitable agent for patients whose organism is overloaded by iron.
  • the molecule of deferasirox, inter alia, is first described therein.
  • Example B on page 32 describes a coated tablet containing 400 mg of the active ingredient, which forms about 68% of the total composition. Lactose and corn starch are used as fillers, the tablet is coated with HPMC.
  • Patent application WO2005097062 discloses a new composition with a dispersible tablet.
  • the tablet according to this application should disintegrate in 5 minutes at the most, preferably in 2 minutes.
  • the application describes two particular compositions with 1000 mg of deferasirox, which represents 50% of the entire tablet.
  • Silicified microcrystalline cellulose Prosolv (SMCC) and spray-dried lactose are used as the filler.
  • the tablet also comprises sodium lauryl sulfate as a surfactant. Tablets of this type turned out to exhibit problems with irritation of the stomach wall.
  • Significant disorders of the alimentary track related to the use of Deferasirox in this formulation have also been described (see WO 201413079).
  • Patent application WO2014136079 which describes a novel composition of Deferasirox in the form of coating tablets, a drug for oral administration is claimed, comprising Deferasirox in an amount of 45 to 60% by weight, which is characterized by reduced releasing in the acidic environment of the stomach and quick releasing near or at the neutral pH value.
  • This concept was to solve the irritating effects occurring during the use of Deferasirox in the composition described in the previous paragraph.
  • the technical solution of this composition was not easy.
  • One of the possible solutions was enterosolvent coating.
  • enterosolvent coating In its use, it was a problem to achieve very quick release of the active ingredient during the passage to the intestinal tract. When quick-solving coating is used, the releasing of the API as such is prevented by the acidic pH where the API is nearly insoluble.
  • composition of the film-coated tablets of the reference drugs Jadenu (US market) and Exjade (EC market) coated tablets (FCT - film-coated tablets) is proportional for all the available strengths of 360, 180 or 90 mg, as well as the composition of the soluble tablets Exjade (DT) of the strengths of 500, 250 or 125 mg.
  • the composition of Jadenu comprises Poloxamer 188 (trade name PluronicTM F68 or Kolliphor ® PI 88, chemical name of a copolymer consisting of blocks of polyoxyethylene and polyoxypropylene), but it does not comprise sodium lauryl sulfate or lactose.
  • the preparations Jadenu and Exjade FCT achieved the same therapeutic effect at a lower quantity of the API as compared to the preparation Exjade (DT).
  • the invention provides a film-coated tablet composition with a lower content of the active ingredient Deferasirox, preferentially 20 - 40% by weight.
  • the pharmaceutical composition according to the invention comprises a low proportion of the active ingredient Deferasirox, namely 20 - 40% by weight.
  • the pharmaceutical composition according to the invention comprises a surfactant from the group of: poloxamers, polysorbates (polyoxyethylene sorbitans) polyethylene glycol, sodium lauryl sulfate, namely in the quantity of 0.01 - 3.0% by weight, preferentially 0.05 - 1% by weight, related to the total weight of the pharmaceutical composition. All these excipients are commonly used for the preparation of drugs for oral administrations and when used in common concentrations, they do not cause irritation of the alimentary tract. Compared to the original drug Jadenu and Exjade FCT comprising a poloxamer as the surfactant, similar results of the dissolution tests were achieved with the use of the above mentioned surfactants.
  • the pharmaceutical composition in accordance with the invention may comprise microcrystalline cellulose, lactose, mannitol, calcium phosphate, native or modified starches, calcium sulfate or sucrose as a filler.
  • the filler represents roughly a third up to half of the total weight of the tablet, i.e., 30 to 50% by weight.
  • the pharmaceutical composition according to the invention may further comprise additional excipients from the group comprising a filler, e.g. povidone, various kinds of starch (potato, corn or wheat), cellulose-based binders (hydroxyethyl cellulose, hydroxypropyl methoxycellulose or hydroxypropyl cellulose or microcrystalline cellulose).
  • a filler e.g. povidone, various kinds of starch (potato, corn or wheat), cellulose-based binders (hydroxyethyl cellulose, hydroxypropyl methoxycellulose or hydroxypropyl cellulose or microcrystalline cellulose).
  • the pharmaceutical composition according to the invention may further comprise additional excipients from the group of disintegrants such as the sodium or calcium salt of croscarmellose, crospovidone, microcrystalline cellulose or corn starch.
  • the pharmaceutical composition according to the invention may further comprise glidants and lubricants such as colloidal silicon dioxide and magnesium stearate, sodium stearyl fumarate, stearic acid, glyceryl dibehenate, polyethylene glycol or various kinds of oil (castor or cottonseed oil).
  • a tablet according to the invention may comprise 50 - 600 mg of Deferasirox.
  • the preparation method of the pharmaceutical composition according to the invention comprises the steps of: homogenization, granulation, drying, sieving, homogenization, tableting, coating, packing.
  • Figure 1 dissolution data of the compositions of Table 4.
  • the dissolution method used to evaluate conformity of the dissolution profiles of the compositions included in Table 2 was set as follows: 500 ml of a gastrointestinal buffer having pH 2 (170 mmol), which was modified to pH 8 with the use of 9 ml of a 2M solution of sodium hydroxide at minute 30 of dissolution.
  • the active ingredient with the first part of the fillers (microcrystalline cellulose), the first part of the disintegrant (crospovidone), binder (povidone) and one or more surfactants from the group of poloxamers, polysorbates, polyethylene glycol and sodium lauryl sulfate.
  • the fillers microcrystalline cellulose
  • the disintegrant crospovidone
  • binder povidone
  • surfactants from the group of poloxamers, polysorbates, polyethylene glycol and sodium lauryl sulfate.
  • compositions are presented in Table 1.
  • t e sur actant can e poss y se ecte rom t e group o : a po oxamer, po ysor ate, polyethylene glycol, sodium lauryl sulfate
  • Example 9 the composition in Example 9 is presented as a reference example of the composition of Jadenu and Exjade FCT (Novartis)
  • compositions that have a comparable dissolution profile to the drugs Jadenu and Exjade FCT, and hence a proven in-vitro conformity concerning releasing of deferasirox into the dissolution media, the following experimentally verified compositions are presented.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/CZ2018/000017 2017-05-04 2018-05-03 Film-coated tablets of deferasirox WO2018202224A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP18726029.4A EP3618814A1 (en) 2017-05-04 2018-05-03 Film-coated tablets of deferasirox

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ2017-255A CZ2017255A3 (cs) 2017-05-04 2017-05-04 Filmem potažené tablety Deferasiroxu
CZPV2017-255 2017-05-04

Publications (1)

Publication Number Publication Date
WO2018202224A1 true WO2018202224A1 (en) 2018-11-08

Family

ID=62217693

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CZ2018/000017 WO2018202224A1 (en) 2017-05-04 2018-05-03 Film-coated tablets of deferasirox

Country Status (3)

Country Link
EP (1) EP3618814A1 (cs)
CZ (1) CZ2017255A3 (cs)
WO (1) WO2018202224A1 (cs)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4052698A1 (en) * 2021-03-05 2022-09-07 Sanovel Ilac Sanayi Ve Ticaret A.S. Film coated tablet comprising deferasirox

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997049395A1 (en) 1996-06-25 1997-12-31 Novartis-Erfindungen Verwaltungsgesellschaft M.B.H. Substituted 3,5-diphenyl-1,2,4-triazoles and their use as pharmaceutical metal chelators
WO2005097062A1 (en) 2004-04-08 2005-10-20 Novartis Ag deferasirox DISPERSIBLE TABLETS
WO2012042224A2 (en) * 2010-10-01 2012-04-05 Cipla Limited Pharmaceutical composition
WO2014013079A1 (en) 2012-07-20 2014-01-23 Matricelab Innove Method for increasing implantation success in assisted fertilization
WO2014072673A1 (en) * 2012-11-12 2014-05-15 Cipla Limited Fixed dose pharmaceutical composition comprising deferasirox and deferipone
WO2014136079A1 (en) 2013-03-08 2014-09-12 Novartis Ag Oral formulations of deferasirox
WO2014181108A1 (en) * 2013-05-10 2014-11-13 Cipla Limited Low dose pharmaceutical composition
WO2016205658A1 (en) * 2015-06-17 2016-12-22 Dispersol Technologies, Llc Improved formulations of deferasirox and methods of making the same
WO2017158559A1 (en) * 2016-03-17 2017-09-21 Lupin Limited Compositions of deferasirox

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997049395A1 (en) 1996-06-25 1997-12-31 Novartis-Erfindungen Verwaltungsgesellschaft M.B.H. Substituted 3,5-diphenyl-1,2,4-triazoles and their use as pharmaceutical metal chelators
WO2005097062A1 (en) 2004-04-08 2005-10-20 Novartis Ag deferasirox DISPERSIBLE TABLETS
WO2012042224A2 (en) * 2010-10-01 2012-04-05 Cipla Limited Pharmaceutical composition
WO2014013079A1 (en) 2012-07-20 2014-01-23 Matricelab Innove Method for increasing implantation success in assisted fertilization
WO2014072673A1 (en) * 2012-11-12 2014-05-15 Cipla Limited Fixed dose pharmaceutical composition comprising deferasirox and deferipone
WO2014136079A1 (en) 2013-03-08 2014-09-12 Novartis Ag Oral formulations of deferasirox
US20150017241A1 (en) * 2013-03-08 2015-01-15 Novartis Ag Oral formulations of deferasirox
WO2014181108A1 (en) * 2013-05-10 2014-11-13 Cipla Limited Low dose pharmaceutical composition
WO2016205658A1 (en) * 2015-06-17 2016-12-22 Dispersol Technologies, Llc Improved formulations of deferasirox and methods of making the same
WO2017158559A1 (en) * 2016-03-17 2017-09-21 Lupin Limited Compositions of deferasirox

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4052698A1 (en) * 2021-03-05 2022-09-07 Sanovel Ilac Sanayi Ve Ticaret A.S. Film coated tablet comprising deferasirox
WO2022186809A1 (en) * 2021-03-05 2022-09-09 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi The film coated tablet comprising deferasirox

Also Published As

Publication number Publication date
CZ2017255A3 (cs) 2018-11-14
EP3618814A1 (en) 2020-03-11

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