EP3618814A1 - Film-coated tablets of deferasirox - Google Patents

Film-coated tablets of deferasirox

Info

Publication number
EP3618814A1
EP3618814A1 EP18726029.4A EP18726029A EP3618814A1 EP 3618814 A1 EP3618814 A1 EP 3618814A1 EP 18726029 A EP18726029 A EP 18726029A EP 3618814 A1 EP3618814 A1 EP 3618814A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
composition according
weight
poloxamer
deferasirox
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Withdrawn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
EP18726029.4A
Other languages
German (de)
French (fr)
Inventor
Michaela GAJDOSOVA
Jaroslava SVOBODOVA
Daniel PECEK
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.)
Zentiva KS
Original Assignee
Zentiva KS
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 KS filed Critical Zentiva KS
Publication of EP3618814A1 publication Critical patent/EP3618814A1/en
Withdrawn legal-status Critical Current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
    • A61K9/2031—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)

Abstract

The solution relates to a pharmaceutical composition in the form of a film-coated tablet, characterized in that it comprises the active ingredient Deferasirox of formula (I), or its pharmaceutically acceptable salt, in an amount of 40% by weight or less, preferably 40% by weight, based on the total weight of the tablet core, and at least one pharmaceutically acceptable excipient. Another solution provides a process for producing film-coated tablets, containing Deferasirox as the active ingredient. Deferasirox 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.

Description

Film-coated tablets of Deferasirox
Technical Field
The technical solution relates to a novel pharmaceutical composition with the active ingredient Deferasirox and to a method for producing the same.
Background Art
The compound of formula I,
(I)
known as 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. These first described tablets faced problems concerning releasing of the poorly soluble active ingredient. Moreover, the application did not completely solve problems related to poor tableting properties of this highly concentrated active ingredient. 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. However, the technical solution of this composition was not easy. One of the possible solutions was enterosolvent coating. However, 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.
The 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. Unlike the composition of the preparation Exjade (DT), the composition of Jadenu comprises Poloxamer 188 (trade name Pluronic™ 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).
Disclosure of Invention
The invention provides a film-coated tablet composition with a lower content of the active ingredient Deferasirox, preferentially 20 - 40% by weight.
Through the selection of suitable excipients, excellent dissolution parameters comparable to the reference drugs Jadenu and Exjade can be achieved and at the same time, such a low content of the API in the composition makes it possible, while maintaining the same strength of the preparation, to increase the quantity of excipients, which supports more efficient granulation of the active ingredient to the final drug form. Based on this innovative solution, the release rate of the active ingredient in the stomach and thus excessive irritation of the mucous membrane of the stomach can be reduced. Nevertheless, the administered dose is fully released on transition to the neutral environment of the intestinal liquid.
Detailed description of Invention
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).
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.
Brief description of Drawings
Figure 1 : dissolution data of the compositions of Table 4.
List of analytical methods
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.
Examples
Each of the following pharmaceutical compositions was prepared in accordance with the following production procedure:
- Weighing the active ingredients, weighing the excipients
- Homogenization of the mixture
- Granulation of 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.
- Drying the granulate
- Sieving the granulate Homogenization with the other part of fillers (lactose and/or microcrystalline cellulose), the other part of the disintegrant (crospovidone), colloidal silicon dioxide and magnesium stearate (glidants and lubricants facilitating tabletability)
Tableting the cores
Coating the cores
Packing in the primary and secondary package
Examples of compositions are presented in Table 1.
All the percentages are shown as % by weight. Table 1: Examples for 40% concentration of Deferasirox
or 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
** addition to 100% core weight Table 2: Examples for 40% concentration of Deferasirox with a variable quantity of lactose
polyethylene glycol, sodium lauryl sulfate
** addition to 100% core weight
Table 3: Examples for 55% concentration of Deferasirox
polyethylene glycol, sodium lauryl sulfate
** addition to 100% core weight
Note: the composition in Example 9 is presented as a reference example of the composition of Jadenu and Exjade FCT (Novartis)
As examples of composition 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.
Table 4: Examples of compositions where conformity of the dissolution profiles of the tested prototypes has been proved

Claims

Claims
1. A pharmaceutical composition in the form of a film-coated tablet, characterized in that it comprises Deferasirox or its pharmaceutically acceptable salt, 20 - 40% by weight, preferably 40% by weight, based on the total weight of the tablet core, and at least one pharmaceutically acceptable excipient.
2. The pharmaceutical composition according to claim 1, characterized in that it further comprises
a) at least one filler from the group comprising microcrystalline cellulose and lactose;
b) at least on surfactant from the group comprising a poloxamer, polysorbate, polyethylene glycol and sodium lauryl sulfate;
c) at least one binder from the group of substances comprising povidone, hydroxyethyl cellulose, hydroxypropyl methoxycellulose or hydroxypropyl cellulose;
d) at least one disintegrant from the group of substances comprising crospovidone and the sodium or calcium salt of croscarmellose;
e) and at least one glidant from the group of substances comprising a silicon dioxide-based aerosil, magnesium stearate, calcium stearate or sodium stearyl fumarate.
3. The pharmaceutical composition according to claim 2, characterized in that the filler is microcrystalline cellulose.
4. The pharmaceutical composition according to claims 2 or 3, characterized in that it contains 30 to 50% by weight of the filler.
5. The pharmaceutical composition according to claim 2, characterized in that it contains a poloxamer as the surfactant.
6. The pharmaceutical composition according to claim 5, characterized in that the surfactant is selected from the group comprising poloxamer 188; poloxamer 407 or poloxamer 338.
7. The pharmaceutical composition according to claims 2, 5 or 6, characterized in that it contains 0.05 to 3% by weight of the surfactant.
8. The pharmaceutical composition according to claim 2, characterized in that the binder is povidone.
9. The pharmaceutical composition according to claim 2, characterized in that it is provided with coating, which is a water-soluble polymer.
10. The pharmaceutical composition according to claim 9, characterized in that the coating is hydroxypropyl methylcellulose (HPMC).
11. The pharmaceutical composition according to any one of the preceding claims, characterized in that it comprises Deferasirox in the amount of 40% by weight, based on the total weight of the tablet core, a filler selected from microcrystalline cellulose or lactose or their combinations, a surfactant from the group comprising a poloxamer, polysorbate, polyethylene glycol and sodium lauryl sulfate,
12. The pharmaceutical composition according to claim 11, characterized in that it comprises a surfactant selected from poloxamer 188; poloxamer 388 or poloxamer 407 in an amount of 0.05 to 3% by weight.
13. The pharmaceutical composition according to claims 1 to 10, characterized in that it contains deferasirox in an amount of 50 to 600 mg.
EP18726029.4A 2017-05-04 2018-05-03 Film-coated tablets of deferasirox Withdrawn EP3618814A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ2017-255A CZ2017255A3 (en) 2017-05-04 2017-05-04 Film-coated Deferasirox tablets
PCT/CZ2018/000017 WO2018202224A1 (en) 2017-05-04 2018-05-03 Film-coated tablets of deferasirox

Publications (1)

Publication Number Publication Date
EP3618814A1 true EP3618814A1 (en) 2020-03-11

Family

ID=62217693

Family Applications (1)

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

Country Status (3)

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

Families Citing this family (1)

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

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY129541A (en) 1996-06-25 2007-04-30 Novartis Ag Substituded 3,5-diphenyl-1,2,4-triazoles and their use as pharmaceutical metal chelators
GB0408078D0 (en) 2004-04-08 2004-05-12 Novartis Ag Organic compounds
EP2621471A2 (en) * 2010-10-01 2013-08-07 Cipla Limited Pharmaceutical composition comprising deferasirox
EP2687851A1 (en) 2012-07-20 2014-01-22 Matricelab Innove Method for increasing implantation success in assisted fertilization
AU2013343250A1 (en) * 2012-11-12 2015-04-09 Cipla Limited Fixed dose pharmaceutical composition comprising deferasirox and deferipone
TWI625136B (en) * 2013-03-08 2018-06-01 諾華公司 Oral formulations of deferasirox
MX2015015553A (en) * 2013-05-10 2016-06-17 Cipla Ltd Low dose pharmaceutical composition.
EP3310354A4 (en) * 2015-06-17 2018-12-12 Dispersol Technologies, LLC Improved formulations of deferasirox and methods of making the same
EP3429562A1 (en) * 2016-03-17 2019-01-23 Lupin Limited Compositions of deferasirox

Also Published As

Publication number Publication date
WO2018202224A1 (en) 2018-11-08
CZ2017255A3 (en) 2018-11-14

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