EP3518904A1 - Pharmaceutical composition comprising deferasirox - Google Patents

Pharmaceutical composition comprising deferasirox

Info

Publication number
EP3518904A1
EP3518904A1 EP17769011.2A EP17769011A EP3518904A1 EP 3518904 A1 EP3518904 A1 EP 3518904A1 EP 17769011 A EP17769011 A EP 17769011A EP 3518904 A1 EP3518904 A1 EP 3518904A1
Authority
EP
European Patent Office
Prior art keywords
tablet
deferasirox
present
amount
film
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.)
Pending
Application number
EP17769011.2A
Other languages
German (de)
French (fr)
Inventor
Sara FRADERA GELABERT
Marta VIVANCOS MARTINEZ
Lisardo ÁLVAREZ FERNÁNDEZ
Jose VELADA CALZADA
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.)
Synthon BV
Original Assignee
Synthon BV
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 Synthon BV filed Critical Synthon BV
Publication of EP3518904A1 publication Critical patent/EP3518904A1/en
Pending 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/04—Chelating agents

Definitions

  • Deferasirox is a BCS class II product, demonstrating high permeability and low solubility.
  • the active ingredient is practically insoluble in water and in acid medium, the solubility increasing with pH.
  • Exjade ® is supplied in Europe and US as dispersible tablets for suspension in three different strengths: 125, 250 and 500 mg.
  • the tablet is dispersed in a glass of water or any other suitable drink and the resulting suspension is then administered to the patient.
  • the dispersible tablets have to be taken on an empty stomach at least 30 minutes before a meal.
  • Exjade ® was developed as dispersible tablets with 29.4% drug load. More recently, film-coated oral tablets were developed in the strengths 90, 180 and 360 mg.
  • the film-coated oral tablets contain 55% by weight of deferasirox based on the total weight of the tablet.
  • the tablets do not contain sodium lauryl sulfate as surfactant, but instead poloxamer.
  • the film-coated oral tablets do not contain lactose.
  • WO2004035026 discloses dispersible tablets of deferasirox wherein the active ingredient is present in an amount of from 5 to 40% by weight based on the total weight of the tablet.
  • the application covers the composition of the marketed Exjade ® dispersible tablet for suspension.
  • WO2005097062 discloses dispersible tablets of deferasirox wherein deferasirox is present in an amount of from 42 to 65% by weight based on the total weight of the tablet.
  • WO2007045445 discloses dispersible tablets of deferasirox wherein the active ingredient is present in an amount of from 42 to 65% by weight based on the total weight of the tablet and the tablet further comprises at least one pharmaceutically acceptable excipient suitable for preparing dispersible tablets.
  • WO2009067557 provides a process for preparing formulations of deferasirox with a sufficiently high dissolution rate and good bioavailability, wherein said process comprises co- milling deferasirox in the absence of any solvent with at least two pharmaceutically acceptable excipients.
  • WO2010035282 discloses oral pharmaceutical compositions in the form of dispersible tablets comprising deferasirox wherein the active ingredient has a mean particle size less than about 100 ⁇ and is present in an amount greater than 66% by weight based on the total weight of the tablet.
  • WO2012042224 discloses compositions comprising nanosized deferasirox having improved surface area and solubility.
  • WO2014136079 discloses oral formulations in the form of film-coated oral tablets comprising deferasirox present in an amount of from 45 to 60% by weight based on the total weight of the tablet. This application discloses the composition of the Exjade ® /Jadenu ® film- coated oral tablet.
  • the present invention provides a film-coated swallowable tablet comprising deferasirox in an amount of at least 60% by weight based on the total weight of the tablet and poloxamer, wherein the weight ratio of deferasirox to poloxamer is at least 1:0.002.
  • Said tablet may be used as medicament in the treatment of chronic iron overload.
  • Figure 1 shows the dissolution profiles of the core and coated tablets in accordance with the present invention and the Jadenu ® film-coated oral tablets.
  • the recently developed film-coated oral tablets of Exjade ® /Jadenu ® comprising deferasirox show some significant improvements over the original marketed dispersible tablets for suspension of Exjade ® .
  • a major advantage for patients is that the film-coated oral tablets can be swallowed as such instead of dispersing them first in a suitable drink as the dispersible tablets for suspension require.
  • the film-coated oral tablets do not exhibit the food effect as observed for the dispersible tablets for suspension and the film- coated oral tablets do not give rise to gastrointestinal irritation as observed with the dispersible tablets for suspension.
  • removing lactose from the film- coated oral tablet formulation and replacing the surfactant sodium lauryl sulfate with poloxamer are accountable for the advantages of the film-coated oral tablet over the dispersible tablet for suspension.
  • the film-coated oral Exjade ® /Jadenu ® tablets contain 55% by weight of deferasirox based on the total weight of the tablet. It would be advantageous to increase the drug load of the film-coated oral tablets further resulting in smaller tablets and thereby reducing the pill burden for patients.
  • deferasirox being a low soluble compound with only moderate flowability properties, it is not self-evident to increase the drug load of deferasirox in the film-coated oral tablet even further above 55% by weight based on the total weight of the tablet.
  • a film-coated swallowable tablet comprising deferasirox in an amount of at least 60% by weight based on the total weight of the tablet and poloxamer, wherein the weight ratio of deferasirox to poloxamer is at least 1:0.002 is bioequivalent to the film-coated oral Exjade ® /Jadenu ® tablet, but significantly smaller in size.
  • the tablet is prepared by a robust and cost effective process.
  • the weight ratio of deferasirox to poloxamer in the film-coated swallowable tablet comprising deferasirox in amount of at least 60% by weight based on the total weight of the tablet ranges from 1:002 to 1:008. More preferably, the weight ratio of deferasirox to poloxamer in the tablet ranges from 1:003 to 1:005.
  • deferasirox is present in the film-coated swallowable tablet in an amount of
  • deferasirox is present in an amount of 64 to 67% by weight based on the total weight of the tablet.
  • the poloxamer is present in the film-coated swallowable tablet in an amount of 0.15 to 0.50% by weight based on the total weight of the tablet. More preferably, the poloxamer is present in an amount of 0.20 to 0.35% by weight based on the total weight of the tablet.
  • the wettability of the deferasirox particles is optimal resulting in tablets displaying a dissolution profile that is similar to the profile of the film-coated oral Exjade ® /Jadenu ® tablets.
  • the poloxamer prevents the occurrence of gastrointestinal irritation.
  • Poloxamers are synthetic block copolymers of hydrophilic poly(oxyethylene) and hydrophobic poly(oxypropylene). Properties such as viscosity, HLB and physical state are dependent on the relative chain lengths of the hydrophilic and hydrophobic blocks.
  • Poloxamers are supplied commercially as Pluronic ® , Kolliphor ® , Lutrol ® and Synperonic ® .
  • Poloxamer 188 commercially available as Pluronic ® F-68, Kolliphor ® P 188, Lutrol ® F-68 or Synperonic ® F68, is a particularly preferred non-ionic surfactant to be used in accordance with the present invention.
  • the film-coated swallowable tablet in accordance with the present invention comprising deferasirox and a poloxamer further comprises one or more pharmaceutically acceptable excipients.
  • the excipients to be used in accordance with the present invention are well-known and are those excipients which are conventionally used by the person skilled in the art.
  • the pharmaceutically acceptable excipients are chosen from one or more binders, diluents, disintegrants, glidants or lubricants.
  • the diluent to be used in accordance with the present invention may be any diluent known to a person of ordinary skill in the art.
  • the diluent to be used in accordance with the present invention is an inorganic diluent, polysaccharide, mono- or disaccharide or sugar alcohol.
  • Microcrystalline cellulose is a particularly preferred diluent.
  • the binder to be used in accordance with the present invention may be any binder known to a person of ordinary skill in the art. Suitable binders are selected from the group consisting of celluloses, starch, polyethylene glycol (PEG), sodium carboxymethylcellulose and polyvinyl pyrrolidone (PVP). PVP is a particularly preferred binder.
  • the amount of binder in the film-coated swallowable tablet is between 1.3 and 2.7% by weight based on the total weight of the tablet.
  • the amount of binder in the tablet is between 1.8 and 2.4% by weight based on the total weight of the tablet.
  • the disintegrant to be used in accordance with the present invention may be any disintegrant known to a person of ordinary skill in the art. Suitable disintegrants to be used in accordance with the present invention are selected from the group consisting of
  • PVPP polyvinylpolypyrrolidone
  • the disintegrant is present in an amount of 6.0 to 9.0% by weight based on the total weight of the tablet.
  • the disintegrant is present both intragranularly and extragranularly.
  • the amount of disintegrant present in the intragranular phase is between 5.0 and 6.5% by weight based on the total weight of the tablet.
  • the glidant to be used in accordance with the present invention may be any glidant known to a person of ordinary skill in the art. Colloidal silicon dioxide is a particularly preferred glidant.
  • the amount of glidant in the tablet is between 0.2 and 1% by weight based on the total weight of the tablet. Preferably, the amount is between 0.4 and 0.6% by weight based on the total weight of the tablet.
  • the lubricant to be used in accordance with the present invention may be any lubricant known to a person of ordinary skill in the art.
  • Magnesium stearate is a particularly preferred lubricant. It is present in an amount of 0.5 to 2% by weight based on the total weight of the tablet. Most preferably, the amount of magnesium stearate in the film-coated swallowable tablet is between 1.3 and 1.6% by weight based on the total weight of the tablet.
  • the amount of binder in the swallowable tablet is between 1.3 and 2.7% by weight, the amount of disintegrant is between 6.0 and 9.0% by weight, the amount of glidant is between 0.2 and 1% by weight and the amount of lubricant is between 0.5 and 2% by weight, all based on the total weight of the tablet.
  • the film-coated swallowable tablet comprises between 1.8 and 2.4% by weight of PVP, between 6.0 and 9.0% by weight of PVPP, between 0.4 and 0.6% by weight of colloidal silicon dioxide and between 1.3 and 1.6% by weight of magnesium stearate, all based on the total weight of the tablet.
  • the total amount of intragranular components is preferably between 90 and 95% by weight of the total weight of the tablet.
  • the tablets are further coated by a film-coat.
  • the coating serves generally for cosmetic purposes.
  • the coating material typically has no influence on the release rate, except of an inherent short initial delay in dissolution due to the time necessary to dissolve the coat.
  • the coating may be selected from amongst one or more of those suitable coating materials known in the art. Coating may be performed by applying one or more film forming polymers, with or without other pharmaceutically inert excipients, as a solution/suspension. Coating is done 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 of the current invention is coated with Opadry ® II, comprising hydroxypropylmethyl cellulose, lactose and triacetin.
  • the particle size of the active pharmaceutical ingredient in the film-coated swallowable tablet of the present invention is not particularly limited. However, it is preferred that the deferasirox in the tablet of the present invention has a D90 particle size equal to or less than 100 ⁇ . More preferably, the D90 particle size of deferasirox is equal to or less than 30 ⁇ . Most preferably, the D90 particle size of deferasirox in the film-coated swallowable tablet is equal to or less than 15 ⁇ . A particularly preferred D90 particle size of deferasirox in the film-coated swallowable tablet in accordance with the present invention is between 4 and 10 ⁇ .
  • the present invention further provides a process to prepare a film-coated swallowable tablet comprising deferasirox in an amount of at least 60% by weight based on the total weight of the tablet and poloxamer, wherein the weight ratio of deferasirox to poloxamer is at least 1:0.002 comprising granulation.
  • the granulation process applied is a standard wet granulation technique, using equipment and methods well-known in the art.
  • the granulation process to prepare the film-coated swallowable tablet consists of two steps.
  • the aim of the first step is not to obtain granules, but to distribute the surfactant homogeneously over the active pharmaceutical ingredient (API) thereby lowering the interfacial tension between the hydrophobic and poorly soluble API particles.
  • the disintegrant and part of the binder are included in this step as well.
  • the aim of the second step is to obtain the final granules by adding the remaining intragranular excipients, viz. diluent and the second part of the binder.
  • the amount of granulation liquid used is between 30 and 45% based on the total intragranular weight.
  • the appearance, disintegration time and dissolution of the granules are optimal, resulting in tablets displaying a dissolution profile that is similar to the profile of the film-coated oral Exjade ® /Jadenu ® tablets.
  • the amount of granulation liquid applied is below 30%, a relatively high amount of fines is obtained affecting the physical properties of the granules.
  • the amount of granulation liquid is between 33 and 42% based on the total intragranular weight. More preferably, the amount of granulation liquid is between 35 and 40% based on the total intragranular weight.
  • the granulation liquid to be used in accordance with the present invention may be any granulation liquid known to a person of ordinary skill in the art.
  • a particularly preferred granulation liquid is water.
  • the tablet composition of the present invention displays dissolution behavior typical for immediate-release formulations.
  • the film-coated swallowable tablet in accordance with the present invention exhibits a dissolution rate of at least 80% in 20 minutes and at least 90% in 30 minutes when tested in 900 ml phosphate buffer pH 6.8 (+ 0.5% Tween ® 20) in a USP apparatus II with vessels at 75 rpm (FDA dissolution method) or peak vessels at 50 rpm.
  • the film-coated swallowable tablets of the present invention are preferably packed in blister pack material.
  • the blister pack material to be used in accordance with the present invention may be any blister pack material known to a person of ordinary skill in the art. Suitable blister pack materials to be used in accordance with the present invention are selected from the group of PVC/Alu, PVDC/PVC/Alu and Alu/Alu. A particularly preferred blister pack material to be used in accordance with the present invention is PVDC/PVC/Alu.
  • the film-coated swallowable tablet of the present invention exhibits excellent long term stability. Moreover, the pharmaceutical composition of the present invention is very suitable for production on commercial scale making use of equipment and techniques commonly used in industry.
  • the film-coated swallowable tablet in accordance with the present invention may be used as a medicament.
  • the tablet typically may be used in the treatment of chronic iron overload.
  • the following examples are intended to illustrate the scope of the present invention but not to limit it thereto.
  • Example 1 Pharmaceutical composition comprising 65 wt% deferasirox and 0.25 wt% poloxamer 188
  • the tablets comprising 65 wt deferasirox and 0.25 wt poloxamer 188 have the composition as given in table 1.
  • Poloxamer 188 and half of the total amount of povidone K30 were dissolved in water. Deferasirox and crospovidone were mixed in a high shear mixer. The solution containing the poloxamer and povidone K30 was added. A granulation (first step) was carried out.
  • Microcrystalline cellulose was added and the mixture was mixed in the high shear mixer.
  • the other half of the total amount of povidone K30 was dissolved in water and the resulting aqueous solution was added to the high shear mixer and a granulation (second step) was carried out.
  • the wet granules were sieved and dried in a fluid bed at 60-80°C.
  • the granules were sieved and transferred into an appropriate bin blender.
  • Microcrystalline cellulose, crospovidone and colloidal silicon dioxide were sieved, added to the blender and the mixture was mixed. Magnesium stearate was sieved and mixed with the blend in the bin blender.
  • the homogeneous blend was compressed under controlled humidity on a tablet press.
  • the tablets were coated with Opadry ® II.
  • the tablets were packed in blisters.
  • the tablets obtained exhibit a dissolution rate of at least 80% in 20 minutes and at least 90% in 30 minutes when tested in 900 ml phosphate buffer pH 6.8 (+ 0.5% Tween ® 20) in a USP apparatus II with vessels at 75 rpm or peak vessels at 50 rpm.
  • the dissolution profiles of the tablets are similar to the profiles of the film-coated oral Exjade ® /Jadenu ® tablets.
  • Figure 1 shows the dissolution profiles of the core and coated tablets prepared following the process as described in this example and the Jadenu ® film-coated oral tablets.
  • the tablets obtained are bioequivalent to the film-coated oral Exjade ® /Jadenu ® tablets.

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Abstract

The present invention relates to a film-coated swallowable tablet comprising deferasirox in an amount of at least 60% by weight based on the total weight of the tablet and poloxamer, wherein the weight ratio of deferasirox to poloxamer is at least 1:0.002. The invention further relates to the use of said tablet as medicament in the treatment of chronic iron overload.

Description

PHARMACEUTICAL COMPOSITION COMPRISING DEFERASIROX BACKGROUND OF THE PRESENT INVENTION
Deferasirox, chemically [4-[(3Z,5E)-3,5-bis(6-oxo-l-cyclohexa-2,4-dienylidene)- 1,2,4- triazolidin-l-yl]benzoic acid of formula (I),
(I)
is an orally active iron chelator for the treatment of chronic iron overload due to blood transfusion. The compound has been first disclosed in W09749395. Deferasirox is a BCS class II product, demonstrating high permeability and low solubility. The active ingredient is practically insoluble in water and in acid medium, the solubility increasing with pH.
Deferasirox is marketed by Novartis under the brand names Exjade® and Jadenu®. Exjade® is supplied in Europe and US as dispersible tablets for suspension in three different strengths: 125, 250 and 500 mg. The tablet is dispersed in a glass of water or any other suitable drink and the resulting suspension is then administered to the patient. The dispersible tablets have to be taken on an empty stomach at least 30 minutes before a meal. To meet the high dose requirement and reduce pill burden, Exjade® was developed as dispersible tablets with 29.4% drug load. More recently, film-coated oral tablets were developed in the strengths 90, 180 and 360 mg. These tablets are in Europe on the market under the brand name Exjade® and in the US under the name Jadenu®. The advantage of these film-coated oral tablets over the dispersible tablets for suspension is that these tablets do not require the step of dispersing, but can be swallowed as such and that they demonstrate a higher bioavailability. Moreover, the film-coated oral tablets do not exhibit the food effect and do not give rise to
gastrointestinal irritation, unlike the dispersible tablets for suspension. The film-coated oral tablets contain 55% by weight of deferasirox based on the total weight of the tablet. The tablets do not contain sodium lauryl sulfate as surfactant, but instead poloxamer. In addition, the film-coated oral tablets do not contain lactose.
WO2004035026 discloses dispersible tablets of deferasirox wherein the active ingredient is present in an amount of from 5 to 40% by weight based on the total weight of the tablet. The application covers the composition of the marketed Exjade® dispersible tablet for suspension.
WO2005097062 discloses dispersible tablets of deferasirox wherein deferasirox is present in an amount of from 42 to 65% by weight based on the total weight of the tablet.
WO2007045445 discloses dispersible tablets of deferasirox wherein the active ingredient is present in an amount of from 42 to 65% by weight based on the total weight of the tablet and the tablet further comprises at least one pharmaceutically acceptable excipient suitable for preparing dispersible tablets.
WO2009067557 provides a process for preparing formulations of deferasirox with a sufficiently high dissolution rate and good bioavailability, wherein said process comprises co- milling deferasirox in the absence of any solvent with at least two pharmaceutically acceptable excipients.
WO2010035282 discloses oral pharmaceutical compositions in the form of dispersible tablets comprising deferasirox wherein the active ingredient has a mean particle size less than about 100 μιη and is present in an amount greater than 66% by weight based on the total weight of the tablet. WO2012042224 discloses compositions comprising nanosized deferasirox having improved surface area and solubility.
WO2014136079 discloses oral formulations in the form of film-coated oral tablets comprising deferasirox present in an amount of from 45 to 60% by weight based on the total weight of the tablet. This application discloses the composition of the Exjade®/Jadenu® film- coated oral tablet.
In view of the prior art cited above, there is still a need for alternative film-coated swallowable tablets comprising deferasirox, which are bioequivalent to the Exjade®/Jadenu® tablets, cost effective, simple to prepare and suitable for use on commercial scale. It would be advantageous if these tablets would contain an even higher load of deferasirox when compared to the Exjade®/Jadenu® film-coated tablets, resulting in smaller tablets and thereby reducing the pill burden for patients.
BRIEF DESCRIPTION OF THE PRESENT INVENTION
The present invention provides a film-coated swallowable tablet comprising deferasirox in an amount of at least 60% by weight based on the total weight of the tablet and poloxamer, wherein the weight ratio of deferasirox to poloxamer is at least 1:0.002.
It also provides a process to prepare said tablet comprising the step of wet granulation.
Said tablet may be used as medicament in the treatment of chronic iron overload.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows the dissolution profiles of the core and coated tablets in accordance with the present invention and the Jadenu® film-coated oral tablets. DETAILED DESCRIPTION OF THE PRESENT INVENTION
The recently developed film-coated oral tablets of Exjade®/Jadenu® comprising deferasirox show some significant improvements over the original marketed dispersible tablets for suspension of Exjade®. A major advantage for patients is that the film-coated oral tablets can be swallowed as such instead of dispersing them first in a suitable drink as the dispersible tablets for suspension require. Moreover, the film-coated oral tablets do not exhibit the food effect as observed for the dispersible tablets for suspension and the film- coated oral tablets do not give rise to gastrointestinal irritation as observed with the dispersible tablets for suspension. According to Novartis, removing lactose from the film- coated oral tablet formulation and replacing the surfactant sodium lauryl sulfate with poloxamer are accountable for the advantages of the film-coated oral tablet over the dispersible tablet for suspension. The film-coated oral Exjade®/Jadenu® tablets contain 55% by weight of deferasirox based on the total weight of the tablet. It would be advantageous to increase the drug load of the film-coated oral tablets further resulting in smaller tablets and thereby reducing the pill burden for patients.
Because of the characteristics of deferasirox, being a low soluble compound with only moderate flowability properties, it is not self-evident to increase the drug load of deferasirox in the film-coated oral tablet even further above 55% by weight based on the total weight of the tablet.
It was surprisingly found by the present inventors that a film-coated swallowable tablet comprising deferasirox in an amount of at least 60% by weight based on the total weight of the tablet and poloxamer, wherein the weight ratio of deferasirox to poloxamer is at least 1:0.002 is bioequivalent to the film-coated oral Exjade®/Jadenu® tablet, but significantly smaller in size. The tablet is prepared by a robust and cost effective process. Preferably, the weight ratio of deferasirox to poloxamer in the film-coated swallowable tablet comprising deferasirox in amount of at least 60% by weight based on the total weight of the tablet, ranges from 1:002 to 1:008. More preferably, the weight ratio of deferasirox to poloxamer in the tablet ranges from 1:003 to 1:005.
Preferably, deferasirox is present in the film-coated swallowable tablet in an amount of
60 to 70% by weight based on the total weight of the tablet. More preferably, deferasirox is present in an amount of 64 to 67% by weight based on the total weight of the tablet.
Preferably, the poloxamer is present in the film-coated swallowable tablet in an amount of 0.15 to 0.50% by weight based on the total weight of the tablet. More preferably, the poloxamer is present in an amount of 0.20 to 0.35% by weight based on the total weight of the tablet. By using these amounts of poloxamer, the wettability of the deferasirox particles is optimal resulting in tablets displaying a dissolution profile that is similar to the profile of the film-coated oral Exjade®/Jadenu® tablets. The poloxamer prevents the occurrence of gastrointestinal irritation.
Poloxamers are synthetic block copolymers of hydrophilic poly(oxyethylene) and hydrophobic poly(oxypropylene). Properties such as viscosity, HLB and physical state are dependent on the relative chain lengths of the hydrophilic and hydrophobic blocks.
Poloxamers are supplied commercially as Pluronic®, Kolliphor®, Lutrol® and Synperonic®. Poloxamer 188, commercially available as Pluronic® F-68, Kolliphor® P 188, Lutrol® F-68 or Synperonic® F68, is a particularly preferred non-ionic surfactant to be used in accordance with the present invention.
The film-coated swallowable tablet in accordance with the present invention comprising deferasirox and a poloxamer further comprises one or more pharmaceutically acceptable excipients. The excipients to be used in accordance with the present invention are well-known and are those excipients which are conventionally used by the person skilled in the art. The pharmaceutically acceptable excipients are chosen from one or more binders, diluents, disintegrants, glidants or lubricants.
The diluent to be used in accordance with the present invention may be any diluent known to a person of ordinary skill in the art. Preferably, the diluent to be used in accordance with the present invention is an inorganic diluent, polysaccharide, mono- or disaccharide or sugar alcohol. Microcrystalline cellulose is a particularly preferred diluent.
The binder to be used in accordance with the present invention may be any binder known to a person of ordinary skill in the art. Suitable binders are selected from the group consisting of celluloses, starch, polyethylene glycol (PEG), sodium carboxymethylcellulose and polyvinyl pyrrolidone (PVP). PVP is a particularly preferred binder. The amount of binder in the film-coated swallowable tablet is between 1.3 and 2.7% by weight based on the total weight of the tablet. Preferably, the amount of binder in the tablet is between 1.8 and 2.4% by weight based on the total weight of the tablet. By using these amounts of binder, the final blend flowability is optimal.
The disintegrant to be used in accordance with the present invention may be any disintegrant known to a person of ordinary skill in the art. Suitable disintegrants to be used in accordance with the present invention are selected from the group consisting of
croscarmellose sodium, sodium starch glycolate or polyvinylpolypyrrolidone (PVPP). PVPP is a particularly preferred disintegrant. The disintegrant is present in an amount of 6.0 to 9.0% by weight based on the total weight of the tablet. Preferably, the disintegrant is present both intragranularly and extragranularly. Most preferably, the amount of disintegrant present in the intragranular phase is between 5.0 and 6.5% by weight based on the total weight of the tablet.
The glidant to be used in accordance with the present invention may be any glidant known to a person of ordinary skill in the art. Colloidal silicon dioxide is a particularly preferred glidant. The amount of glidant in the tablet is between 0.2 and 1% by weight based on the total weight of the tablet. Preferably, the amount is between 0.4 and 0.6% by weight based on the total weight of the tablet.
The lubricant to be used in accordance with the present invention may be any lubricant known to a person of ordinary skill in the art. Magnesium stearate is a particularly preferred lubricant. It is present in an amount of 0.5 to 2% by weight based on the total weight of the tablet. Most preferably, the amount of magnesium stearate in the film-coated swallowable tablet is between 1.3 and 1.6% by weight based on the total weight of the tablet.
In order to mimic the dissolution profile of the film-coated oral Exjade®/Jadenu® tablets, the amount of binder in the swallowable tablet is between 1.3 and 2.7% by weight, the amount of disintegrant is between 6.0 and 9.0% by weight, the amount of glidant is between 0.2 and 1% by weight and the amount of lubricant is between 0.5 and 2% by weight, all based on the total weight of the tablet. Most preferably, the film-coated swallowable tablet comprises between 1.8 and 2.4% by weight of PVP, between 6.0 and 9.0% by weight of PVPP, between 0.4 and 0.6% by weight of colloidal silicon dioxide and between 1.3 and 1.6% by weight of magnesium stearate, all based on the total weight of the tablet.
The total amount of intragranular components is preferably between 90 and 95% by weight of the total weight of the tablet.
The tablets are further coated by a film-coat. The coating serves generally for cosmetic purposes. The coating material typically has no influence on the release rate, except of an inherent short initial delay in dissolution due to the time necessary to dissolve the coat.
The coating may be selected from amongst one or more of those suitable coating materials known in the art. Coating may be performed by applying one or more film forming polymers, with or without other pharmaceutically inert excipients, as a solution/suspension. Coating is done 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. Preferably, the pharmaceutical composition of the current invention is coated with Opadry® II, comprising hydroxypropylmethyl cellulose, lactose and triacetin.
The particle size of the active pharmaceutical ingredient in the film-coated swallowable tablet of the present invention is not particularly limited. However, it is preferred that the deferasirox in the tablet of the present invention has a D90 particle size equal to or less than 100 μιη. More preferably, the D90 particle size of deferasirox is equal to or less than 30 μιη. Most preferably, the D90 particle size of deferasirox in the film-coated swallowable tablet is equal to or less than 15 μιη. A particularly preferred D90 particle size of deferasirox in the film-coated swallowable tablet in accordance with the present invention is between 4 and 10 μιη.
The present invention further provides a process to prepare a film-coated swallowable tablet comprising deferasirox in an amount of at least 60% by weight based on the total weight of the tablet and poloxamer, wherein the weight ratio of deferasirox to poloxamer is at least 1:0.002 comprising granulation. The granulation process applied is a standard wet granulation technique, using equipment and methods well-known in the art. In a preferred embodiment of the present invention, the granulation process to prepare the film-coated swallowable tablet consists of two steps. The aim of the first step is not to obtain granules, but to distribute the surfactant homogeneously over the active pharmaceutical ingredient (API) thereby lowering the interfacial tension between the hydrophobic and poorly soluble API particles. Preferably, the disintegrant and part of the binder are included in this step as well. The aim of the second step is to obtain the final granules by adding the remaining intragranular excipients, viz. diluent and the second part of the binder. The amount of granulation liquid used is between 30 and 45% based on the total intragranular weight.
Within this range, the appearance, disintegration time and dissolution of the granules are optimal, resulting in tablets displaying a dissolution profile that is similar to the profile of the film-coated oral Exjade®/Jadenu® tablets. When the amount of granulation liquid applied is below 30%, a relatively high amount of fines is obtained affecting the physical properties of the granules. Preferably, the amount of granulation liquid is between 33 and 42% based on the total intragranular weight. More preferably, the amount of granulation liquid is between 35 and 40% based on the total intragranular weight. The granulation liquid to be used in accordance with the present invention may be any granulation liquid known to a person of ordinary skill in the art. A particularly preferred granulation liquid is water.
The tablet composition of the present invention displays dissolution behavior typical for immediate-release formulations. The film-coated swallowable tablet in accordance with the present invention exhibits a dissolution rate of at least 80% in 20 minutes and at least 90% in 30 minutes when tested in 900 ml phosphate buffer pH 6.8 (+ 0.5% Tween® 20) in a USP apparatus II with vessels at 75 rpm (FDA dissolution method) or peak vessels at 50 rpm.
The film-coated swallowable tablets of the present invention are preferably packed in blister pack material. The blister pack material to be used in accordance with the present invention may be any blister pack material known to a person of ordinary skill in the art. Suitable blister pack materials to be used in accordance with the present invention are selected from the group of PVC/Alu, PVDC/PVC/Alu and Alu/Alu. A particularly preferred blister pack material to be used in accordance with the present invention is PVDC/PVC/Alu.
The film-coated swallowable tablet of the present invention exhibits excellent long term stability. Moreover, the pharmaceutical composition of the present invention is very suitable for production on commercial scale making use of equipment and techniques commonly used in industry.
The film-coated swallowable tablet in accordance with the present invention may be used as a medicament. The tablet typically may be used in the treatment of chronic iron overload. The following examples are intended to illustrate the scope of the present invention but not to limit it thereto.
EXAMPLES
Example 1: Pharmaceutical composition comprising 65 wt% deferasirox and 0.25 wt% poloxamer 188
The tablets comprising 65 wt deferasirox and 0.25 wt poloxamer 188 have the composition as given in table 1.
Table 1
Poloxamer 188 and half of the total amount of povidone K30 were dissolved in water. Deferasirox and crospovidone were mixed in a high shear mixer. The solution containing the poloxamer and povidone K30 was added. A granulation (first step) was carried out.
Microcrystalline cellulose was added and the mixture was mixed in the high shear mixer. The other half of the total amount of povidone K30 was dissolved in water and the resulting aqueous solution was added to the high shear mixer and a granulation (second step) was carried out. The wet granules were sieved and dried in a fluid bed at 60-80°C. The granules were sieved and transferred into an appropriate bin blender. Microcrystalline cellulose, crospovidone and colloidal silicon dioxide were sieved, added to the blender and the mixture was mixed. Magnesium stearate was sieved and mixed with the blend in the bin blender.
The homogeneous blend was compressed under controlled humidity on a tablet press. The tablets were coated with Opadry® II. The tablets were packed in blisters.
The tablets obtained, exhibit a dissolution rate of at least 80% in 20 minutes and at least 90% in 30 minutes when tested in 900 ml phosphate buffer pH 6.8 (+ 0.5% Tween® 20) in a USP apparatus II with vessels at 75 rpm or peak vessels at 50 rpm. The dissolution profiles of the tablets are similar to the profiles of the film-coated oral Exjade®/Jadenu® tablets. Figure 1 shows the dissolution profiles of the core and coated tablets prepared following the process as described in this example and the Jadenu® film-coated oral tablets.
The tablets obtained are bioequivalent to the film-coated oral Exjade®/Jadenu® tablets.

Claims

1. A film-coated swallowable tablet comprising deferasirox in an amount of at least 60% by weight based on the total weight of the tablet and poloxamer, wherein the weight ratio of deferasirox to poloxamer is at least 1:0.002.
2. The tablet according to claim 1, wherein the weight ratio of deferasirox to poloxamer ranges from 1:0.002 to 1:0.008.
3. The tablet according to claim 1 or 2, wherein deferasirox is present in an amount of 60 to 70% by weight based on the total weight of the tablet.
4. The tablet according to any one of claims 1 to 3, wherein poloxamer is present in an amount of 0.15 to 0.50% by weight based on the total weight of the tablet.
5. The tablet according to any one of claims 1 to 4, further comprising a binder.
6. The tablet according to claim 5, wherein the binder is present in an amount of 1.3 to 2.7% by weight based on the total weight of the tablet.
7. The tablet according to claim 5 or 6, wherein the binder is polyvinylpyrrolidone (PVP).
8. The tablet according to any one of claims 1 to 7, further comprising a disintegrant.
9. The tablet according to claim 8, wherein the disintegrant is present in an amount of 6.0 to 9.0% by weight based on the total weight of the tablet.
10. The tablet according to claim 8 or 9, wherein the disintegrant is
polyvinylpolypyrrolidone (PVPP).
11. The tablet according to any one of claims 1 to 10, wherein deferasirox has a particle size distribution D90 equal to or less than 15 μιη.
12. The tablet according to any one of claims 1 to 11 exhibiting a dissolution rate of at least 80% in 20 minutes and at least 90% in 30 minutes when tested in 900 ml phosphate buffer pH 6.8 (+ 0.5% Tween® 20) in a USP apparatus II with vessels at 75 rpm.
13. A process to prepare the tablet according to any one of claims 1 to 12 comprising the step of wet granulation.
14. The process according to claim 13 wherein the granulation consists of two steps.
15. The tablet according to any one of claims 1 to 14 for use in the treatment of chronic iron overload.
EP17769011.2A 2016-09-30 2017-09-11 Pharmaceutical composition comprising deferasirox Pending EP3518904A1 (en)

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GR1009592B (en) * 2018-07-03 2019-09-11 Φαρματεν Α.Β.Ε.Ε. Pharmaceutical composition comprising an iron chelating agent and method for the preparation thereof
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WO2018007956A1 (en) * 2016-07-05 2018-01-11 Jubilant Generics Limited Immediate release pharmaceutical composition of iron chelating agents

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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
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GB0408078D0 (en) 2004-04-08 2004-05-12 Novartis Ag Organic compounds
BRPI0617715A2 (en) 2005-10-19 2011-08-02 Novartis Ag dispersible tablets comprising deferairox
WO2009067557A1 (en) 2007-11-19 2009-05-28 Teva Pharmaceutical Industries Ltd. Deferasirox pharmaceutical compositions
WO2010035282A1 (en) 2008-09-24 2010-04-01 Matrix Laboratories Limited Pharmaceutical compositions comprising deferasirox
MX2013003522A (en) 2010-10-01 2013-05-22 Cipla Ltd Pharmaceutical composition comprising deferasirox.
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