WO2018208242A1

WO2018208242A1 - Formulation of deferasirox tablet for oral suspension composition with better processability

Info

Publication number: WO2018208242A1
Application number: PCT/TR2017/050180
Authority: WO
Inventors: Hatice Öncel; Yilmaz Çapan; Onur PINARBAŞLI; Sibel AKANSEL; Nagehan SARRAÇOĞLU
Original assignee: İlko Ilaç Sanayi Ve Ticaret Anonim Şirketi
Priority date: 2017-05-10
Filing date: 2017-05-10
Publication date: 2018-11-15

Abstract

The invention relates to oral pharmaceutical composition comprising deferasirox or pharmaceutically acceptable salts, and at least one pharmaceutically acceptable excipient suitable for the preparation of tablets for oral suspension, wherein weight ratio of binder to disintegrant is about 1:10 – 1:11 in order to produce deferasiroxinner phase having particle size distribution (D90)between 300 µm - 400 µm. The invention also relates to process for preparing said oral pharmaceutical compositions and its uses thereof. Also, the pharmaceutical formulation according to the invention is bioequivalent to the FDA approved product, Exjade® tablet for oral suspension according to a bioavailability study conducted in humans.

Description

FORMULATION OF DEFERASIROX TABLET FOR ORAL SUSPENSION

COMPOSITION WITH BETTER PROCESSABILITY

DESCRIPTION

Technical field:

The invention relates to formulation of oral pharmaceutical composition comprising deferasirox or pharmaceutically acceptable salts, and at least one pharmaceutically acceptable excipient suitable for the preparation of tablets for oral suspension with allowing for better processability comparable to the innovator product. The invention also relates to process for preparing said oral pharmaceutical compositions and its uses thereof.

Prior Art:

Deferasirox is an orally active iron chelating agent with a molecular formula of C₂i H₁₅N₃0₄.lts chemical name is 4-[3,5-Bis-(2-hydroxyphenyl)-[1 ,2,4]-triazol-1 -yl] benzoic acid and the structural formula is represented below (Formula I). The synthesis of deferasirox is described in, for example, the international patent application WO 97/49395.

Formula (I)

Deferasirox is a white to slightly yellow powder and is a non-chiral compound. At the physiological pH of the intestine, the solubility is about 40 mg/L.lt is an orally active chelator that is highly selective for iron (III). Its main use is to reduce chronic iron overload in patients who are receiving long-term blood transfusions for conditions such as beta-thalassemia and other chronic anemias. Chronic iron overload is a result of regularblood transfusions used in the treatment of several conditions including β- thalassemia,sickle cell disease and myelodysplasia syndromes. The harmful effects of chronic iron overload can lead to damage of the liver, heart and endocrine glands,

l resulting in organ compromise and death. Deferasirox is a tridentate iron chelator, meaning that two molecules are required to form a stable complex with each iron (Fe³⁺) ion. It promotes excretion of iron, primarily in the faeces. Deferasirox has very low affinity for zinc and copper and does not cause constant low serum levels of these metals.

The active molecule deferasirox is highly lipophilic and 99% protein-bound. Also it was generally well tolerated across a wide range of toxicology studies, and no toxicities prohibitive for use in humans were identified. The key chelation properties of deferasirox are listed as (Cappellini M. (2007)):

• High and specific affinity for Fe³⁺ (approximately 14 and 21 times greater than its affinity for copper [Cu²⁺] and zinc [Zn²⁺], respectively [Steinhauser et al 2004])

• Oral bioavailability

• Highly efficient and efficacious

• Effective at multiple doses; allowing flexible regimens

• Long half-life (8-16 hours); allowing once-daily dosing

· Generally well tolerated

Deferasirox is commercially available as tablets for oral suspension under the trade name of Exjade® (Novartis). Exjade® is supplied as a tablet for oral suspension containing 125 mg, 250 mg and 500 mg of deferasirox per tablet. This tablet is dispersed in a glass of water or any other suitable drink (100-200 ml_), and this resulting suspension is then administered to the patient.

The pharmaceutical tablet for oral suspension (dispersible tablet)allows an oral dosage form with a high drug loading and which is convenient to administer to, for example children and elderly.

The mechanism of action for deferasiroxis described as iron chelation therapy with a chelating drug binds with free or labile iron in the blood and organs, which allows for removal of excess iron from the body.

WO 2004/035026 (Novartis) discloses dispersible tablets comprising deferasirox as active ingredient in an amount of from 5 to 40% in weight by weight of the total tablet and at least one disintegrant in a total amount of 10% to 35% in weight based on the total weight of the tablet. WO 2005/097062 (Novartis) discloses a dispersible tablet of deferasirox wherein the active ingredient is present in an amount of from 42% to 65% by weight based on total weight of the tablet.

WO 2007/045445 (Novartis) discloses a dispersible tablet of deferasirox or a pharmaceutically acceptable salt thereof present in an amount of from 42% to 65% by weight based on total weight of the tablet and at least one pharmaceutically acceptable excipient suitable for the preparation of dispersible tablets and to process for making said dispersible tablet.

WO 2009/067557 (Teva) discloses a method for producing a pharmaceutical composition containing a poorly water soluble active pharmaceutical deferasirox or a pharmaceutically acceptable salt thereof, comprising co-milling in a dry process with at least two pharmaceutically acceptable excipients to obtain a co-milled composition.

WO 2009/106824 (Cipla) describes effervescent tablets containing deferasirox wherein the active ingredient, or combination of the active ingredient and each adjuvant, is coated with water soluble polymer or combination of water soluble and a water insoluble polymer.

WO 2010/035282 (Matrix) discloses an oral pharmaceutical composition in the form of a dispersible tablet comprising deferasirox or pharmaceutically acceptable salts thereof, wherein said deferasirox has a mean particle size less than about 100 μηι and is present in an amount at least 66% by weight based on total weight of said tablet.

Deferasirox is highly water insoluble and is highly lipidsoluble, and is also observed to possess good permeability. According to the Biopharmaceutics Classification System (BCS), it has been classified as a Class II drug, implying that it is a poorly soluble, and a highly permeable drug. Though deferasirox is highly water insoluble, whatever limited solubility it has, that too exhibits high pHdependent solubility. Though it is practically insoluble in lower pH, even at a pH of 6.8, it still remains insoluble, until the buffer strength is altered to get optimal dissolution profile.

Deferasirox being practically insoluble in aqueous media exhibits a generally poor dissolution profile and hence consequently poor bioavailability. Several strategies and formulations have been employed to overcome these limitations of solubility and poor bioavailability.

The bioavailability (the percentage of the drug absorbed compared to its initial dosage) is limited by insolubility. Dissolution rate is a direct function of total surface area for a dispersed phase.This relationship between particle size and bioavailability is well known in the pharmaceutical industry and across a range of pharmaceutical products. WO 98/35681 (Novartis) illustrates the effect of reducing the particle size of a drug with poor aqueous solubility. The formulations disclosed therein comprise micronised oxcarbazepine particles with a median particle size of between 2 - 12 microns (μηι). Such particle size enhances the dissolution rate and consequently the bioavailability. The problem with micronised particles of such a small size is that the particles can agglomerate into larger particles, thereby reducing the solubility and consequently the bioavailability of the drug. Also micronising to a small particle size can also lead to stability and/or discolouration problems. Additionally, micronisation to such a small particle size requires greater energy input, more time and greater controls on the micronisation process to achieve the required range whilst reducing the amount of rejected material.

Since deferasirox is practically insoluble in water, it gives difficulties in formulation of dosage forms to variable dissolution rates. Low solubility and low bioavailability of deferasirox require the use of small particle size active substance which makes the process difficult as given in prior art. In addition, the fact that the dose of the active substance is also high makes the process even more difficult. Several methods have been employed in an effort to alleviate the problems associated with the poor solubility of such active ingredients. For example, particle size reduction is often the method of choice. By reducing particle size, the effective surface area increases, thus allowing a greater dissolution rate. However, known shortcomings of particle size reduction are an increase in the tendency to agglomerate and an increase in static charge, reducing the tendency of the particles to flow and also leading to poor wetting properties.

Therefore, in this invention one of the main challenges in the development of formulations with small particle size deferasirox having difficulties on process is to develop a formulation that eliminates the tendency of the deferasirox to agglomerate and adhesion to the punch of the tabletting machine.

Description of the Invention:

The objective of the present invention is to provide a pharmaceutical tablets for oral suspension composition comprising of poorly water soluble active pharmaceutical ingredient deferasirox or its pharmaceutically acceptable salts with fast dispersion which will pass swiftly through a 710 μηι diameter mesh size sieve (dispersion quality), which is capable of dispersing in water within 3 minutes, preferably within 2 minutes and most preferably within 1 minute, having a pleasant taste and the absence of perceptible granules in the mouth. The present invention provides a simple and easy process of manufacturing of such a composition, in other words formulate deferasirox dispersible tablets for oral suspension with allowing better production steps.

Present invention relates to pharmaceutical tablets for oral suspension composition of 500 mg of deferasirox which is bioequivalent to 500 mg of reference drug of deferasiroxtabletsfor oral suspension (Exjade®) respectively under fasting condition.

In one embodiment of the invention, there is provided a process of producing pharmaceutical dispersible tablet composition comprising;

(a) forming an innerphase comprising (i) mixing deferasiroxtogether withpharmaceutically acceptable excipients,(ii) wetgranulatingthe mixture obtained in (i);

(b) forming an outer phase comprising (iii) adding further pharmaceuticallyacceptable excipients to the inner phase obtained in (ii) and mixing;

(c) forming the dispersible tablet by (iv) compressing themixture obtained in step (iii).

"Reference drug" means a deferasirox product as described in U.S. Federal Food and Drug Administration's New Drug Application No. 021368 approved on Nov 21 , 2003 as provided in the U.S. Federal Food and Drug Administration's Orange Book, Approved Drug Products with Therapeutic Equivalence Evaluations.

By "inner phase" is meant the granulate phase (steps (i) and (ii)) including the active ingredient deferasirox and one or more the pharmaceutically acceptable excipients.

By "outer phase" is meant one or more pharmaceutically acceptable excipients added to the inner phase (granulates) (step(iii)).

According to another aspect of the present invention there is provided a pharmaceutical tablets for oral suspension composition comprising;

a) Deferasirox or a pharmaceutically acceptable salt thereof and

b) at least one pharmaceutically acceptable excipient suitable for the preparation of tablets for oral suspension wherein weight ratio of binder to disintegrant is about 1 :10— 1 :1 1 in order to produce deferasiroxinner phase having D₉₀particle size between 300 μηι to 400 μηι, especially disintegrant ratio is 37.90% (w/w) in unit dose. The term "Deferasirox" is used in broad sense to include not only "Deferasirox" per se but also their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable esters, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable complexes etc.

In a preferred embodiment of the invention, the present invention provides tablets for oral suspension wherein deferasirox is in the free acid form.

Further aspect of the invention provides for pharmaceutical compositions of deferasirox wherein the in vitro dissolution release profile matches with the commercially available Exjade® and also it is bioequivalent with Exjade®.

The dispersible tablets of the invention are useful for the treatment of iron overload in transfusion dependent anemias, in particular thalassemia major, thalassemia intermediate and sickle cell disease and in the treatment of hemochromatosis.

Deferasirox is, for example, low density material, with its electrostatic characteristics. These properties may lead to a poor flowability and to its sticking tendency. These properties make it difficult to formulate an effective amount of dispersible tablet with uniformity of weight, hardness, disintegrating time and other desirable tablet properties.

Solid oral dosage forms have superior properties of ensuring uniformity of dosage, more robust, less microbial issued compared to liquid dosage forms. In this invention dispersible tablet is studied. Dispersible tablets as defined in Ph. Eur. are uncoated or filmcoated tablets intended to be dispersed in water before administration giving a homogeneous dispersion. Typically a dispersible tablet is dispersed in about 100-200 mL of water or any other suitable drink and the resulting dispersion is administered to the patient. Dispersible tablets are required to disintegrate within 3 minutes in water according to European Pharmacopeia.

A major requirement of a desirable oral form is that it must be palatable, since an unpalatable formulation greatly increases the risk of a patient neglecting to take a medication. Palatability and "mouth feel" are among the most important characteristics to be considered in providing fast dissolving or disintegrating solid dosage forms, or matrix, for a drug. Unfortunately, many drugs have a bitter or otherwise unpalatable taste, or an unacceptable mouth feel, which make such drugs unsuitable for administration as fast dissolving or fast disintegrating dosage forms. The particle size of the active ingredient(s) may be of primary significance in determining the rate and extent of dissolution, the bioavailability, and the uniformity of a drug product, especially for substances of low solubility in aqueous media.

Particle size can be determined, for example, by laser light scattering using a particle size analyzer, such as the proprietary Mastersizer™ apparatus in a dry/wet dispersion system available from Malvern Instruments Ltd. (Malvern Mastersizer-2000, single narrow mode). Laser diffraction enables to measure particle size distributions by measuring the angular variation by scattering light intensity as a laser beam passes through a dispersed particulate sample. Large particles scatter light at small angles relative to the laser beam and small particles scatter light at large angles. The angular scattering intensity data is then analyzed to calculate the size of the particles responsible for creating the scattering pattern, using the Mie theory of light scattering. The particle size is reported as a volume equivalent sphere diameter.

A common approach to define the distribution width is to cite three values on the x-axis as D₁₀, D₅₀ and D₉₀. The D₅₀, named as median, has been defined as the diameter where 50 percent of the distribution lies below this value. Similarly, D₉₀ has been defined as 90 percent of the distribution lies below, and 10 percent of the population lies below the D₁₀.

According to the invention, there are provided pharmaceutical compositions of deferasirox in the form of dispersible tablet, wherein the active ingredient has D₉₀ of about 20 μηι or less. More preferably, in some embodiments, there are provided pharmaceutical compositions of deferasirox wherein the active ingredient has a Dgoparticle size diameter of about less than 10 μηι.

Particle size distribution results of deferasirox used in the present invention is given below (determined by Malvern Mastersizer-2000, single narrow mode, dry dispersion system). d(0.5): 3.2 μηι d(0.9): 7^m

The desired particle size range material is obtained directly from a synthesis process or alternatively any known particle size reduction processes can be used, such as but not limited to sifting, milling, micronization, fluid energy milling, ball milling and the like.

According to the invention, pharmaceutical compositions comprising deferasirox may be in the form of encapsulated free flowing powders or granules; compressed solid dosage forms such as tablets, including chewable or dispersible or mouth dissolving, as well as the conventional tablets; pellets or beads or spheres or cores filled into sachets or capsules; syrups, suspensions or dispersions; elixirs, lyophilized powders and the like. But pharmaceutical compositions of deferasirox in the form of tabletsfor oral suspension are the most preferred according to patient compliance.

One or more pharmaceutically acceptable excipients used according to the invention includes without any limitations, those that are conventionally used, for the dispersible tablets e.g. fillers/diluents, disintegrants, binders, surfactants, glidants, lubricants, and optionally outer coating ingredients.

Suitable fillers/diluents according to the invention may include, but are not limited to lactose, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, sugar alcohols, dextrates, dextrin, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, starch, pregelatinized starch, and the like. Suitable disintegrants according to the invention may include, but are not limited to cross- linked polypyrollidone commercially available as Crospovidone™ &Polyplasdone™, sodium starch glycolate, maize starch, salts of carboxy methyl cellulose, microcrystalline cellulose, alginic acid, sodium alginate, guar gum, low-substituted hydroxypropyl cellulose and the like. Preferably, lactose monohydrate is used.

Suitable disintegrants according to the invention include but are not restricted to maize starch, CMC-Ca, CMC-Na, microcrystalline cellulose, cross-linked PVP, e.g. as known and commercially available under the trade names Crospovidone®, Polyplasdone®, or Kollidon® XL, alginic acid, sodium alginate and guar gum. Preferably, crospovidone and microcrystalline cellulose are used. In addition, microcrystalline cellulose imparts an almost creamy mouth feel, which helps to offset the negative impact of its swellability.

Suitable binders according to the invention may include, but are not limited to starchese.g. potato, wheat or corn starch; microcrystalline cellulosee.g. products such as Avicel®, Filtrak®, Heweten® or Pharmacel®;hydroxypropyl cellulosee.g. hydroxypropylmethyl cellulose-Type 2910 USP; hydroxyethyl cellulose, hypromellose, polyvinylpyrrolidonee.g. Povidone® K30; gelatin, and the like. Preferably polyvinylpyrrolidoneis used.

Suitable surfactants according to the invention may include, but are not limited to sodium lauryl sulfate, quaternary ammonium salts, polysorbates, sorbitan esters, poloxamer, betaines, higher fatty alcohols such as cetyl alcohol and oleyl alcohol and the like. Preferably sodium lauryl sulfate is used.

As glidants, one or more of the following may be used: silica; colloidal silica, e.g. colloidal silica anhydrous, e.g. Aerosil® 200, magnesium trisilicate, powdered cellulose, starch and talc. Preferably, colloidal silicon dioxide is used.

As lubricants one or more of the following may be used Mg, Al or Castearate, PEG 4000 - 8000, talc,sodium benzoate, glyceryl mono fatty acid, e.g. having a molecular weight of from 200 to 800 Daltons, e.g. glycerylmonostearate, glyceryl dibehenate, glyceryl palmitostearicester, polyoxyethylene glycol, hydrogenated cotton seed oil, castor seed oil. Preferably, magnesium stearate is used.

In accordance with innovator product, the dispersible tablets may be prepared by granulation, preferably wet-granulation, followed by compression methods, preferably under spray lubrication. However, in this present invention the formulation achieves the process without any spray lubrication while compression due to physical properties of prepared deferasiroxinner phase.

In the pharmaceutical industry,granulationrefers to the act orprocessin which primary powder particles are made to adhere to form larger, multiparticle entities called granules. It is theprocessof collecting particles together by creating bonds between them.

The powders are wetted with a granulating liquid like water, isopropyl alcohol or acetone or dichloromethane and other hydro-alcoholic solvents such as isopropyl alcohol-water mixture. Binders may be included in the granulating liquid. The moist mass is granulated, e.g., by forcing through a screen of suitable mesh size, dried, and, if desired, the particles further reduced in size. Granulates obtained are then compressed in conventional manner, using lubricants, glidants, etc., as required.

In general, wet-granulation may be used to improve flowability and sticking tendency, however, in prior art wet-granulation process is not preferred when the pharmaceutical composition is to be a dispersible tablet due to increasing the cohesion of the active ingredient particles and increasing the disintegration time of the final tablet which is not in accordance with patient compliance or the European Pharmacopoeia which requests a disintegration time of 3 minutes or less for a dispersible tablet. Present inventors have now surprisingly found that stickiness problem may be resolved with using wet granulation process by formulation using weight ratio of binder to disintegrant about 1 :10 - 1 :1 1 in order to produce deferasiroxinner phase having particle size between 300 μηι to 400 μηι. ^specially disintegrantratio is 37.90% (w/w) in unit dose without increasing the disintegration time, e.g. below acceptable values, e.g. below 3 minutes.

Tablet binders are used in the formulation of solid oral dosage forms to hold the active pharmaceutical ingredient and inactive ingredients together in a cohesive mix. Normally, disintegrants are used to cause a tablet to disintegrate quickly and thus to release the active agent from the tablet in a short time. They are usually employed in a concentration of 15 %, in exceptional cases up to 20 %. [Die Tablette, W. A. Ritschel, A. BauerBrandl]. It has now surprisingly been found that deferasirox can advantageously be formulated in a tablet that disintegrates very quickly if the proportion of binder to disintegrant ratio is 1 :10-1 :1 1 . This ratio has a positive effect on the deposition of the particles and the distribution of the particles in water, so that a stable suspension can be obtained even after storage.

Dispersible tablets according to the invention are dispersible tablets containing 125 mg, 250 mg or 500 mg of deferasirox free acid form as active ingredient.

In one aspect the present invention provides a process comprising:

(i) mixingdeferasirox and pharmaceutically acceptable excipients, e.g. one or more fillers, and oneor more disintegrants in a high shear mixer;

(ii) adding a solution of one or more surfactant and one or more binder, subjecting the mixture to wet granulating, e.g. in a high shear mixer;drying using, e.g. in a fluidized bed dryer, thenmilling and;

(iii) adding pharmaceutically acceptable excipients, e.g. sieved excipients, such as one or more fillers, disintegrant, one or more glidant/lubricant, and mixing, e.g. in a free fall mixer;

(iv) tabletting the mixture obtained in step (iii) by compression, e.g. in a conventional tablet press, preferably a rotarymachine.

In the present invention, the disintegration time is not more than 3minutes;preferably less than 2 minutes; most preferably the disintegration time is less than 1 minutes as measured using a disintegration time apparatus.

By "disintegration time" is meant the time that needs the dispersible tablet to disintegrate in water at room temperature in a disintegration time device.

The dispersible tablet of the present invention is dispersible in an aqueous phase, preferably water. By "fineness of dispersion" is specified as smooth dispersion which passes through a sieve screen with a nominal mesh aperture of 710 μηι. Two tablets are placed in 100 ml of purified water, which is stirred until complete dispersion. The dispersion obtained is homogeneous and passes through a screen with a nominal mesh size of 710 μηι. The fineness of dispersion is measured according to the method described in the European Pharmacopoeia, 6^thEdition, 2010, Chapter 7, relating to the definition of dispersible tablets.

The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.

Example 1

Deferasirox tablets have dose proportionality between 500 mg, 250 mg and 125 mg. All doses are prepared with the following unit formula.

DEFERASIROX TABLETS % amount in unit

FOR SUSPENSION dose (%w/w)

Deferasirox 29.40

Lactose monohydrate 28.00

Crospovidone 23.00

Microcrystalline cellulose 14.90

Colloidal silicon dioxide 0.20

Polyvinyl pyrrolidone 3.50

Sodium Lauryl Sulphate 0.50

Magnesium Stearate 0.50

Water q.s.

Required quantities of deferasirox, lactose monohydrate and crospovidone are mixed for 5 minutes at high shear mixer for producing inner phase. Produced powder mixture is granulated with binder solution, namely polyvinylpyrrolidonesolution to form wet mass. These granules are dried at fluid bed drier and milled. Particle size distribution (D₉₀) of obtained inner phase is measured as between 300 - 400 μΓΠ.ΑίίβΓ that, required amounts of crospovidone, lactose monohydrate and microcrystalline cellulose (formed the outer phase) are mixed with obtained deferasirox granule for 10 minutes. Then colloidal silicon dioxide and magnesium stearate are mixed for 5 minutes. The final blend is compressed into tablets with using suitable tooling.

Disintegrating time: Below 1 minutes (42 seconds)

Fineness of dispersion: Complies with specification of smooth dispersion which passes through a sieve screen with a nominal mesh aperture of 710 μηι.

Example 2

In order to examine the effect of particle size distribution of obtained deferasiroxgranule on drug release and disintegrating time for dispersible tablet, same production method of Example 1 is performed with different binder todisintegrant ratio.

DEFERASIROX TABLETS % amount in unit

FOR SUSPENSION dose (%w/w)

Deferasirox 29.40

Lactose monohydrate 26.50

Crospovidone 23.00

Microcrystalline cellulose 14.90

Colloidal silicon dioxide 0.20

Polyvinyl pyrrolidone 5.00

Sodium Lauryl Sulphate 0.50

Magnesium Stearate 0.50

Water q.s.

Required quantities of deferasirox, lactose monohydrate and crospovidone are mixed for 5 minutes at high shear mixer for producing inner phase. Produced powder mixture is granulated with binder solution, namely polyvinylpyrrolidone solution to form wet mass. These granules are dried at fluid bed drier and milled. Particle size distribution (D₉₀) of obtained inner phase is measured as higher than 500 μηι. After that, required amounts of crospovidone, lactose monohydrate and microcrystalline cellulose (formed the outer phase) are mixed with obtained deferasirox granule for 10 minutes. Then colloidal silicon dioxide and magnesium stearate are mixed for 5 minutes. The final blend is compressed into tablets with using suitable tooling.

Disintegrating time:Higher than 3 minutes

Example 3

In order to examine the effect of particle size distribution of obtained deferasirox granule on drug release and disintegrating time for dispersible tablet, same formulation and production method of Example 1 is performed with different binder to disintegrant ratio.

DEFERASIROX TABLETS % amount in unit

FOR SUSPENSION dose (%w/w)

Deferasirox 29.40

Lactose monohydrate 29.50

Crospovidone 23.00

Microcrystalline cellulose 14.90

Colloidal silicon dioxide 0.20

Polyvinyl pyrrolidone 2.50

Sodium Lauryl Sulphate 0.50

Magnesium Stearate 0.50

Water q.s.

Required quantities of deferasirox, lactose monohydrate and crospovidone are mixed for 5 minutes at high shear mixer for producing inner phase. Produced powder mixture is granulated with binder solution, namely polyvinylpyrrolidone solution to form wet mass. These granules are dried at fluid bed drier and milled. Particle size distribution (D₉₀) of obtained inner phase is measured as below than 200 μηι. After that, required amounts of crospovidone, lactose monohydrate and microcrystalline cellulose (formed the outer phase) are mixed with obtained deferasirox granule for 10 minutes. Then colloidal silicon dioxide and magnesium stearate are mixed for 5 minutes. However, the final blend could not be compressed into tablets because the tablets adhered to the punches. Table 1 : Effect of particle size (D₉₀) of inner phase

Example Dgo of Inner Phase Disintegrating time

300-400μηι Less than 1 min

2 >500μηι More than 3 min

3 <200μηι Not compressed

Example 4.Particle size distribution of suspended product:

In the present invention, the final product composition has a desired disintegration and/or dispersion time with a good mouthfeel by absence of perceptible granules in the mouth. The particle size distribution D₉₀ of suspended product is measured as 180 μηι for test product (Example -1 ) whereas the reference product (Exjade®) particle size distribution D₉₀ is measured as 350 μηι. These results show that the developed product has a good mouthfeel with respect to particle size distribution.

Dissolution Profiles:

Comparative dissolution tests were conducted based on the general dissolution test method. The progress of dissolution is monitored for 45 minutes. Dissolution testing measures the portion (%) of Deferasiroxthat has been released from tablets and has dissolved in the dissolution medium. Dissolution test was performed with USP-II, pH 6.8 phosphate buffer with 0.5% Tween™ 20, 50 rpm and 900 mL (FDA test). The above exemplified compositions comprising deferasirox were tested in vitro for drug release and they were compared with the commercially available Exjade®tablet for suspension. Obtaining results are shown in table2 and dissolution profiles are shown in Figure 1 & 2.

Table 2: Comparative drug release (%) of deferasirox

(Medium: pH 6.8 phosphate buffer with 0.5% w/v Tween™ 20. Apparatus: USP type II (Paddle). Volume: 900 ml_. Rotation Speed: 50 rpm.)

Cumulative percentage drug release (%)

Deferasirox 500 Deferasirox 500

Sampling time Exjade® 500 mg

mg Tablet for oral mg Tablet for oral (minutes) Tablet for oral

suspension - suspension - suspension

Example 1 Example 2

10 79 76 43

20 85 83 54

30 86 84 61

45 88 86 67

Stability Studies:

The stability of a drug substance is an important factor in the manufacture of safe and effective pharmaceutical products. Stability issues can be caused by environmental factors such as humidity, temperature and the like.The physical and chemical stability may be tested in conventional manner, e.g. the dispersible tablets may be tested as such by measurement of dissolution, friability, disintegration time, assay for deferasirox, degradation products, and appearance.

In the development of deferasirox tablets for oral suspension dosage form, stability was assessed under three different storage conditions (25°C ± 2°C, 30°C ± 2°C and 40°C ± 2°C) in temperature-programmable control cabinets. A temperature of 25°C ± 2°C/ 60 ± 5% RH (Relative Humidity) represents ambient temperature and carries out up to 24 months; 30°C ± 2°C/ /65 ± 5% RH represents intermediate temperature and carries out up to 12 months; 40°C ± 2°C/ 75 % ± 5 % RH represents extreme conditions and carries out up to 6 months.

The physical and chemical stability may be tested in conventional manner, e.g. the dispersible tablets may be tested assuch by measurement of dissolution, friability, disintegration time, assay for deferasirox, degradation products, appearance, e.g. after storage at 25°C ± 2°C, 30°C ± 2°C and 40°C ± 2°C conditions. The dispersible tablets of the invention are stable at three different conditions, in conventional packaging, e.g. sealed PVC/PE/PVDC/Alu blister.

Bioequivalence study

As per USFDA guideline titled "Bioavailability and Bioequivalence Studies for Orally Administered Drug Products— General Considerations" Bioequivalence is defined as: "the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study." The following pharmacokinetic parameters were estimated by noncompartmental methods using actual elapsed time from dosing:

Cmax (Mg/mL) : Maximum observed plasma concentration, obtained directly from the observed concentration versus time data.

T_max (h) : Time to maximum plasma concentration, obtained directly from the observed concentration versus time data.

AUCo-∞ (Mg /ml_*h) : Area under the curve from time zero extrapolated to infinity, calculated by linear up/log down trapezoidal summation and extrapolated to infinity by addition of the last quantifiable concentration divided by the elimination rate constant

AUC_0-Tiast (Mg/mL*h) : Area under the curve from time zero to time of last measurable concentration, calculated by linear up/log down trapezoidal summation.

The in-vivo studies were conducted in 35 healthy volunteers to assess the bioequivalence of the tablet composition of test preparation (Example -1 , Deferasirox 500 mg Tablet for Oral Suspension-Batch No: 1508219001 ) against reference preparation (Exjade® 500 mg Tablets for Oral Suspension, manufactured and distributed by Novartis Pharma GmbH, Germany- Batch No: S0174B)as using an open- label, single dose, 2-period crossover, randomized design in healthy subjects under fasting conditions.

Evaluation of the pharmacokinetic profiles and the relative bioavailability of deferasirox was performed from the test preparation (Example -1 , Deferasirox500 mg Tablet for Oral Suspension) in comparison with the reference preparation (Exjade® 500 mg Tablets for Oral Suspension) so that to demonstrate the bioequivalence of the test product with the reference product under fasting conditions. The pharmacokinetic parameters and statistical results are given at the following tables (Table 3& Table 4). Also, the mean plasma concentration versus time profile of deferasirox is presented in Figure 1 .

Table 3.Pharmacokinetic parameters of deferasirox for composition of the present invention prepared by test preparation (Example -1 , Deferasirox 500 mg Tablet for Oral Suspension; Batch No: 1508219001 ) against reference preparation (Exjade® 500 mg Tablets for Oral Suspension; Batch No: S0174B).

Pharmacokinetic Results of Deferasirox (Fasting Condition)

[Mg/ml*h] [Mg/ml*h] [MQ/ml] [h]

N 35

Test (T)

Batch No: 1 14.70 ± 31 .26 124.96 ± 35.09 1 1 .05 ± 3.21 2.90±0.99

1508219001

Reference (R)

Batch No: 1 14.67 ± 30.62 130.97 ± 37.19 1 1 .06 ± 3.79 2.84±0.75

S0174B Table 4.Statistical Resultsof deferasirox for composition of the present invention prepared by test preparation (Example -1 , Deferasirox 500 mg Tablet for Oral Suspension; Batch No: 1 508219001 ) against reference preparation (Exjade® 500 mg Tablets for Oral Suspension ; Batch No: S0174B).

Statistical Results of Deferasirox (Test vs reference); n=35 Primary pharmacokinetic parameters:

90% confidence interval of

AUCo-tiast

ANOVA (two one-sided t-tests): 93.72 % - 106.99 %

point estimator (ratio) : 1 00.14 % 90% confidence interval of

ANOVA (two one-sided t-tests): 91 .1 6 % - 1 1 0.73 %

point estimator (ratio) : 1 00.47 %

Secondary pharmacokinetic parameters:

90% confidence interval of

AUC_0-∞

ANOVA (two one-sided t-tests): 89.44 % - 102.37 %

point estimator (ratio) : 95.68 % 90% confidence interval of

Non-parametric analysis: -0.50 h - - 0.50 h

Median (difference reference-test): 0.00 h

Figures:

Figure 1. Comparative dissolution profiles of Exjade® 500 mg Tablets for suspension and Test product - Example 1 (n = 6, dissolution medium: phosphate buffer (pH 6.8)).

Figure 2.Comparative dissolution profiles of Exjade® 500 mg Tablets for suspension and Test product - Example 2 (n = 6, dissolution medium: phosphate buffer (pH 6.8)).

Figure 3.Mean deferasirox plasma concentration/time profiles - linear (± SEM) (n = 35)

Claims

I . A tablet for oral suspension composition comprising deferasirox or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient suitable for the preparation of tablets, characterized in that

a) weight ratio of disintegrant(s) is more than 35%, and

b) weight ratio of disintegrant(s) to binder is at least 9 times, and

c) theparticle size distribution (D₉₀) of inner phaseobtained by wet granulationmeasured by laser light scattering methodis between 300 μηι to 400 μηι.

2. A tablet for oral suspension composition according to claim 1 wherein weight ratio of binder to disintegrant is about 1 :10.

3. A tablet for oral suspension composition according to claim 1 wherein weight ratio of binder to disintegrant is about 1 :1 1 .

4. A tablet for oral suspension composition according to claim 1 wherein weight ratio of binder to disintegrant is between 1 :10 to 1 :1 1 .

5. A tablet for oral suspension composition according to claim 1 wherein disintegrant ratio is more than 35% and less than 40% (w/w) in unit dose.

6. A tablet for oral suspension composition according to claim 5 wherein disintegrant ratio is about 38% in unit dose.

7. A tablet for oral suspension composition according to claim 1 wherein the disintegration time of the tablet is of 3 minutes or less.

8. A tablet for oral suspension composition according to claim 1 wherein the disintegration time of the tablet is of 2 minutes or less, more preferably 1 minute or less.

9. A tablet for oral suspension composition according to any of the preceding claims wherein Deferasirox is in the free acid form.

10. A tablet for oral suspension composition according to any of the preceding claims wherein the binder is polyvinylpyrrolidone.

I I . A tablet for oral suspension composition according to any of the preceding claims wherein the disintegrants are crospovidone and microcrystalline cellulose.

12. A tablet for oral suspension composition according to any of the preceding claims, which may be dispersed in water before administration, providing a homogeneous dispersion; wherein said dispersible tablet disintegrates within 3 minutes using water at 15 - 25°C forming a dispersion; wherein the fineness of said dispersion complies with a test comprising placing 2 tablets in 100 ml water and stirring until completely dispersed, whereby a preferably smooth dispersion is produced, which passes through a sieve screen with a nominal mesh aperture of 710 μηι.