FIELD OF INVENTION

The invention relates to the pharmaceutical field. More specifically, it relates to dispersible pharmaceutical compositions comprising deferasirox and one or more pharmaceutically acceptable excipients.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ARTS
Deferasirox is an iron chelating agent and is indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients, 2 years of age and older. Deferasirox is designated chemically as 4-[3, 5-Bis (2-hydroxyphenyl)-1H-1, 2, 4-triazol-lyl]-benzoic acid. Its molecular formula is C21H15N3O4 and its molecular weight is 373.4. In the U.S., Deferasirox is marketed by Novartis under the brand name Exjade as a dispersible tablet containing either 125mg, 250mg and 500mg of deferasirox and the following inactive ingredients: lactose monohydrate (NF), crospovidone (NF), povidone (K30) (NF), sodium lauryl sulphate (NF), microcrystalline cellulose (NF), silicon dioxide (NF), and magnesium stearate (NF). Exjade® tablet should be completely dispersed by stirring in water, orange juice, or apple juice until a fine suspension is obtained and then swallowed. U.S. Patent Application No. 2008/0311194 discloses a dispersible tablet comprising (a) deferasirox in an amount of from 42% to 65% by weight based on the total weight of the tablet and (b) at least one pharmaceutically acceptable excipient, wherein said pharmaceutically acceptable excipients are: (i) at least one filler in a total amount of about 35 to 45% by weight based on the total weight of the tablet, (ii) at least one disintegrant in a total amount of about 2% to 8% by weight based on the total weight of the tablet (iii) at least one binder in a total amount of about 1% to 5% by weight based on the total weight of the tablet, (iv) at least one surfactant in a total amount of about 0.01% to 1% by weight based on the total weight of the tablet, (v) at least one glidant in a total amount of about 0.1% to 5% by weight based on the total weight of the tablet and (vi) at least one lubricant present in a total amount of about 0.45 to 0.85% by weight based on the total weight of the tablet.

According to said patent application, appropriate surfactants may be selected from a group comprising sodium laurylsulfate, quaternary ammonium salts, polysorbates, sorbitan esters and/or poloxamer. Preferably, the surfactant is sodium laurylsulfate. The dispersible tablets were prepared by wet-granulation process using granulation liquid comprising one or more surfactant and/or one or more binder using a high-shear granulator. The patent application discloses that the inventors have encountered difficulties in the production of dispersible tablets comprising deferasirox which may be due to the low density of the active ingredient, and to its electrostatic characteristics which may lead to a poor flowability and to its sticking tendency and also discloses that in general, wet-granulation may be used to improve flowability and sticking tendency, however, wet-granulation process is not preferred when the pharmaceutical composition is to be a dispersible tablet as wet-granulation process increases the cohesion of the active ingredient particles and increases the disintegration time of the final tablet. U.S. Patent Application No. 2009/0142395 discloses a process of preparing a high-load tablet or dispersible tablet of deferasirox with a sufficiently high dissolution rate and good bioavailability, wherein the process comprises co-milling in a dry or wet process, deferasirox with at least two pharmaceutically acceptable excipients to obtain a co-milled composition; (A) wherein the pharmaceutically acceptable excipients are selected from a group comprising of: (i) a surfactant and a sugar or sugar derivative, (ii) a surfactant and a disintegrant, and (iii) a combination thereof, and (B) wherein co-milling is performed using a jet-mill.

According to said patent application in a preferred embodiment, deferasirox is co-milled in a dry process with a surfactant, preferably sodium lauryl sulfate in an amount of less than about 1.75% by weight, and a sugar or sugar derivative or surfactant, wherein the formulation has a dissolution profile such that at least about 60% is dissolved in 60 min. PCT Application No. 2012/003987 discloses an oral dosage form containing deferasirox, binder, disintegrant and optionally wicking agent prepared by using melt granulation process, wherein the introduction of the dosage form into water leads to a suspension, wherein the suspended particles have an average particle size (D50) from 20 urn to 120 urn.
PCT Application No. 2012/042224 discloses a pharmaceutical composition comprising nanosized deferasirox having improved surface area and solubility, wherein the process comprises the steps of: (i) docusate sodium, HPMC, sodium lauryl sulphate and sucrose were solubilized in water under stirring conditions, (ii) deferasirox was dispersed in the solution obtained in step (i), (3) dispersion obtained in step (ii) was homogenized and then nanomilled, (iv) nanomilled drug slurry was adsorbed by spraying on lactose monohydrate, microcrystalline cellulose and crospovidone mixture in a fluidized bed granulator, (v) granules obtained were sized and lubricated, (vi) lubricated granules were finally compressed into tablets.

Thus, from the above mentioned prior art, it is clear that it is very difficult to prepare deferasirox dispersible tablet using conventional high-shear granulator due to low density of the deferasirox itself, and its electrostatic characteristics which may lead to a poor flowability and to its sticking tendency. Hence there is an un-met need to prepare said tablets comprising deferasirox, using a suitable pharmaceutical process/ equipment in a way that would avoid the problems encountered by the person skilled in the art, during the development of said tablets viz, poor flowability, stickiness and hardness issues. The present inventors surprisingly found that the deferasirox dispersible tablet prepared by using Cremophor® RH 40 and employing the top-spray fluid bed granulation process, does not have sticking tendency and the tablet thus prepared after compression has comparable physical characteristics of the tablet, in terms of hardness, disintegration time etc. Further, said tablet exhibit in-vitro dissolution profile and in-vivo pharmacokinetic parameters comparable with that the marketed Exjade® tablets.

SUMMARY AND OBJECTIVES OF THE INVENTION

The invention relates to dispersible pharmaceutical compositions comprising deferasirox and one or more pharmaceutically acceptable excipients. More specifically, it relates to dispersible tablet comprising deferasirox, Cremophor® RH 40 and one or more pharmaceutically acceptable excipients, wherein the tablet is prepared by top-spray fluid bed granulation process. One of the objectives of the invention is to prepare pharmaceutical compositions comprising deferasirox, Cremophor® RH 40 and one or more pharmaceutically acceptable excipients. Another objective of the invention is to prepare dispersible tablet comprising deferasirox, Cremophor® RH 40 and one or more pharmaceutically acceptable excipients, wherein the tablet is prepared by top-spray fluid bed granulation process. Yet another objective of the invention is to prepare dispersible tablet comprising deferasirox, Cremophor® RH 40 and one or more pharmaceutically acceptable excipients, having comparable in-vitro dissolution profile and in-vivo pharmacokinetic parameters with that of the marketed Exjade® tablets, where in the tablet is prepared by top-spray fluid bed granulation process.

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

The invention relates to dispersible tablet comprising deferasirox, Cremophor® RH 40 and one or more pharmaceutically acceptable excipients, wherein the tablet is prepared by top-spray fluid bed granulation process. More specifically the invention relates to - A pharmaceutical composition comprising deferasirox, polyoxyl 40 hydrogenated castor oil (Cremophor® RH 40) and one or more pharmaceutically acceptable excipients, wherein the composition is prepared using top-spray fluid-bed granulation process. A dispersible tablet comprising deferasirox, polyoxyl 40 hydrogenated castor oil (Cremophor® RH 40) and one or more pharmaceutically acceptable excipients, wherein the tablet is prepared using top-spray fluid-bed granulation process. A top-spray fluid-bed granulation process for preparing dispersible tablet comprising deferasirox, polyoxyl 40 hydrogenated castor oil (Cremophor® RH 40) and one or more pharmaceutically acceptable excipients, wherein the process comprises the following steps:

i. Dissolve povidone, polyoxyl 40 hydrogenated castor oil (Cremophor® RH 40) in water to get a solution;

ii. Add deferasirox to the solution of step (i) to get granulating fluid;

iii. Mix the intra-granular excipients in a fluid-bed processor;

iv. Spray the granulating fluid of step (ii) onto the intra-granular excipients of step (iii) to get granules;

v. Blend the granules from step (iv) with extra-granular excipients to get a blend;

vi. Compress the blend of step (v) to get said dispersible tablet. Cremophor® RH 40 is a nonionic emulsifying agent. The main constituent of Cremophor RH 40 is glycerol polyethylene glycol oxystearate, which together with fatty acid glycerol polyglycol esters, forms the hydrophobic part of the product. The hydrophilic part consists of polyethylene glycols and glycerol ethoxylate.

The present inventors surprisingly found that deferasirox dispersible tablet prepared using Cremophor® RH 40 and employing the top-spray fluid bed granulation process, does not have sticking tendency and the tablet thus prepared after compression has comparable physical characteristics of the tablet, in terms of hardness, disintegration time etc, and further said tablet exhibit in-vitro dissolution profile and in-vivo pharmacokinetic parameters comparable with that the marketed Exjade® tablets. According to the invention, deferasirox may be present in the amorphous or crystalline form. As used herein, the term "deferasirox " is intended to include the active agent itself, as well as its pharmaceutically acceptable salts or derivatives thereof. According to the invention, the process for preparing dispersible tablet comprising deferasirox, Cremophor® RH 40 and one or more pharmaceutically acceptable excipients involves top-spray fluid bed granulation process, wherein the granulating fluid comprises a binder, a surfactant and deferasirox and is prepared by:

(i) dissolving binder and surfactant in water to get a solution; and

(ii) adding deferasirox to the solution obtained in step (i) and mixing both to get uniform granulating fluid. Fluid-bed processor (FBP) is commonly used in the pharmaceutical industries for wet granulation process, as a one-step, enclosed operation, because several ingredients can be mixed, granulated, and dried in the same equipment.

The technique reduces material handling and shortens process times compared with conventional high-shear granulation process. The granulation in fluid bed processor may be carried out either by top-spray, bottom-spray or tangential-spray of the granulating solution. According to an embodiment of the invention, granulation is carried out in fluid bed processor as a top-spray method. The fluid-bed top-spray granulation method produces highly dispersible granules with a characteristic porous structure and lower bulk densities that enhances wettability during tablet disintegration compared with granules prepared by conventional high-shear granulation process. In an embodiment, the dispersible tablet of deferasirox is prepared in a fluid-bed top-spray granulation processor having optimum processing parameters for granulation. According to the invention, Glatt® FBE5 and Glatt® GPCG -1.1 fluid-bed processors is used for experimental and scale-up process. Following are the critical process parameters involved in fluid-bed top-spray granulation process. The dispersible tablet of the invention may be prepared by using one or more pharmaceutically acceptable excipient(s), which may be selected from a group comprising diluents, binder, surfactant, disintegrants/super-disintegrants, glidants, and/ or lubricants.

Suitable diluents according to the invention include, but are not limited to mannitol, xylitol, sorbitol, lactose, sucrose, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, calcium phosphate dibasic anhydrous, calcium phosphate dibasic dihydrate, calcium phosphate tribasic, starch, calcium trisilicate, magnesium trisilicate, cellulose acetate, dextrose, or combinations thereof. Suitable binders according to the invention include, but are not limited to povidone, copovidone, pregelatinized starch, polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), starch, hydroxyethyl cellulose (HEC), ethyl cellulose (EC), chitosan, guar gum, methyl cellulose (MC), carbomer, acacia, sodium alginate, calcium alginate or combinations thereof. Suitable disintegrants according to the invention include, but are not limited to starch, microcrystalline cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, polacrilin potassium or combinations thereof. Suitable super-disintegrants according to the invention include, but are not limited to crospovidone, croscarmellose sodium, and sodium starch glycolate, low-substituted hydroxypropyl cellulose (L-HPC), pregelatinised starch or combinations thereof. Suitable glidants and lubricants according to the invention include, but are not limited to, colloidal silicon dioxide, talc, magnesium stearate, sodium stearyl fumarate, calcium stearate or combinations thereof.

Suitable surfactants according to the invention include, but are not limited to only polyoxyl hydrogenated castor oil, however polyoxyl hydrogenated castor oil (Cremophor® RH) is the preferred one. Polyoxyl hydrogenated castor oil is a nonionic surfactant, which is used as emulsifying and solubilising agents in cosmetics and in pharmaceutical formulations. Examples of polyoxyl hydrogenated castor oil commonly used as surfactants are polyoxyl 30 hydrogenated castor oil (Cremophor® RH 30), polyoxyl 60 hydrogenated castor oil (Cremophor® RH 60) and polyoxyl 40 hydrogenated castor oil (Cremophor® RH 40), preferably according to the invention polyoxyl 40 hydrogenated castor oil (Cremophor® RH 40) is used as a surfactant. According to an embodiment of the invention, polyoxyl 40 hydrogenated castor oil (Cremophor® RH 40) is present in an amount of 0.1% to 10.0%, preferably in an amount of 0.1% to 5% by weight based on the total weight of composition or tablet. According to an embodiment, the process for preparing dispersible tablet comprising deferasirox, Cremophor® RH 40 and one or more pharmaceutically acceptable excipients comprises the steps of:

(i) Sifting suitable intragranular diluents and glidants through suitable size sieve and mixing well to get uniform blend;

(ii) Placing the blend obtained in the step (i) in fluidized bed processor and fluidizing the blend using dry air;

(iii) Dissolving Cremophor® RH 40 and a binder in water to get a solution;

(iv) Adding deferasirox to the solution obtained in step (iii) and mixing to get granulating fluid;

(v) Spraying the granulating fluid of step (iv) using an atomizer at top-spray position onto the fluidized powder blend of dry blend, to get wet granules;

(vi) Continuing fluidization to dry the wet granules until loss on drying of about 3% w/w (at 105°C for 10 minutes) is achieved;

(vii) Blending the dried granules obtained in step (vi) with extragranular excipients.

(viii) Compressing the blend obtained in step (vii) into tablets. Various processing parameters of fluid bed processor as set or optimized in the process for the preparation of deferasirox dispersible tablet are provided below:
Granulation in FBP

Drying of granules:

Prelubrication & Lubrication:

Further, it has been found that the dispersible tablet of deferasirox prepared according to the invention is bioequivalent to the commercially available Exjade ®. The following examples illustrate specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner. Comparative Examples 1 & 2 (Granulation using Rapid Mixer Granulator with Cremophor® RH 40) Unit Compositions:

Brief Manufacturing Process:

(i) Sift Deferasirox, lactose, microcrystalline cellulose and colloidal silicon dioxide through suitable size sieve and mixing well to get uniform blend;

(ii) Dissolve povidone K30 and Cremophor® RH 40 in water to get a solution;

(iii) Granulate the blend of step (i) with the solution obtained in step (ii) by using rapid mixer granulator;

(iv) Dry the wet granules obtained in step (iii) using suitable drying process and optionally sifting through suitable size sieve;

(v) Blend the granules obtained in step (iv) with extra granular lactose monohydrate, microcrystalline cellulose, crospovidone, colloidal silicon dioxide and silicon dioxide to get uniform blend;

(vi) Lubricate the blend obtained in step (v) with magnesium stearate;

(vii) Compress the blend obtained in step (vii) into tablets.

Comparative Examples 3 & 4 (Granulation using top-spray Fluid-Bed Granulator without Cremophor® RH 40, but with sodium lauryl sulfate and Span® 20 as surfactants)

Unit Compositions:

Brief Manufacturing Process:

(i) Sift lactose, microcrystalline cellulose and colloidal silicon dioxide through suitable size sieve and mixing well to get uniform blend;

(ii) Dissolve povidone K30 and sodium lauryl sulphate or Span® 20 in water to get a solution;

(iii) Add deferasirox to the solution obtained in step (ii) and mix well to get granulating fluid;

(iv) Granulate the blend obtained in step (i) with granulating fluid obtained in step (iii) by using top-spray fluid bed granulation process;

(v) Dry the wet granules obtained in step (iv) using suitable drying process and optionally sifting through suitable size sieve;

(vi) Blend the granules obtained in step (v) with extragranular lactose monohydrate, microcrystalline cellulose, crospovidone, colloidal silicon dioxide to get uniform blend;

(vii) Lubricate the blend obtained in step (vi) with magnesium stearate; (viii) Compress the blend obtained in step (vii) into tablets. Inventive Examples 5,6 & (Granulation using top-spray Fluid-Bed Granulator with Cremophor® RH 40)
Unit Compositions:

Brief Manufacturing Process:

(i) Sift lactose, microcrystalline cellulose and colloidal silicon dioxide through suitable size sieve and mixing well to get uniform blend;

(ii) Dissolve povidone K30 and Cremophor® RH 40 in water to get a solution;

(iii) Add deferasirox to the solution obtained in step (ii) and mix well to get granulating fluid;

(iv) Granulate the blend obtained in step (i) with granulating fluid obtained in step (iii) by using top-spray fluid bed granulation process;

(v) Dry the wet granules obtained in step (iv) using suitable drying process and optionally sifting through suitable size sieve;

(vi) Blend the granules obtained in step (v) with extragranular lactose monohydrate, microcrystalline cellulose, crospovidone, colloidal silicon dioxide and silicon dioxide to get uniform blend;

(vii) Lubricate the blend obtained in step (vi) with magnesium stearate;

(viii) Compress the blend obtained in step (vii) into tablets.
Inventive Examples 8,9 & 10 (Granulation using top-spray Fluid-Bed Granulator with Cremophor® RH 40) Unit Compositions:

Brief Manufacturing Process:

(i) Sift lactose, microcrystalline cellulose and colloidal silicon dioxide (extragranular) through a suitable sifter and mixing well to get uniform blend;

(ii) Dissolve Cremophor® RH 40 in lukewarm purified water to get clear solution;

(iii) Dissolve Povidone K-30 in purified water to get the clear solution; (iv) Mix solution from step (ii) and step (iii) using mechanical stirrer;

(v) Add deferasirox to the solution obtained in step (iv) and mix well to get uniform dispersion;

(vi) Load material of step (i) in Fluid bed processor (FBP) and granulate with step

(v) dispersion to get the desired granules;

(vii) Dry the wet granules obtained in step (vi) using suitable drying process and optionally sift through suitable size sieve;

(viii) Blend the granules obtained in step (vii) with extragranular lactose monohydrate, microcrystalline cellulose, crospovidone, colloidal silicon dioxide and silicon dioxide to get uniform blend;

(ix) Lubricate the blend obtained in step (viii) with magnesium stearate;

(x) Compress the blend obtained in step (vii) into tablets. Physical Observations and Disintegration Test: As discussed previously, tablets prepared according to the invention (Inventive Examples 5, 6 and 7) and as per the prior arts (Comparative Examples 1, 2, 3 and 4) were evaluated for physical evaluation to assess stickiness and sticking tendency and further they were also subjected to physical testing such as hardness and disintegration test and the results are compiled in Table 1.

Table 1 Deferasirox dispersible tablets according to Example 5, 6 and 7 containing Cremophor® RH 40 and prepared by using top-spray fluid bed granulation process showed no stickiness on the surface of the tablets, whereas surfaces of the tablets prepared according to the comparative Example 1 and 2 containing Cremophor® RH 40 and prepared by using rapid mixer granulator were sticky in nature and also the surface of tablets prepared according to comparative Example 3 and 4 containing sodium lauryl sulphate and Span® 20 respectively and prepared by using top-spray granulation process were also sticky in nature. The marketed (8) Exjade tablet has disintegration time of about 68 seconds and hardness of 8.8 to 10.5 kP. This implies that the selection of Cremophor® RH 40 and the top spray granulation process is critical in having a quality product meeting the required physical characteristics.

Comparative Dissolution Data: Deferasirox dispersible tablets prepared according to Example 3, 4, 5, 6, 7 and marketed Exjade® 500mg tablets were subjected to in-vitro dissolution test in 2000ml of pH 6.8 buffer containing 0.5% sodium lauryl sulphate, USP type II dissolution apparatus at 50 rpm and the resultant data is compiled in Table 2.

Table 2 From the above dissolution data, it is found that the deferasirox tablets containing Cremophor® RH 40 and prepared by using top-spray fluid bed granulation process (example 5, 6 & 7) showed comparative in-vitro dissolution profile with that of marketed Exjade® 500mg tablets, whereas the deferasirox tablets containing sodium lauryl sulphate or Span®20 (example 3 and 4) and prepared by using top-spray fluid bed granulation process did not had comparative in-vitro dissolution profile with that of marketed Exjade® 500mg tablets.

Bioequivalence Data: Deferasirox dispersible tablets prepared according to Example 7 (test product) and Exjade® 500mg tablets (reference products) were evaluated for the in-vivo bioequivalence study in healthy human volunteers under fasting condition and the resultant data is compiled in Table 3.

Table 3 Cmax - refers to a maximum plasma concentration obtained. AUC (0 to t) - refers to area under the plasma concentration curve from hour 0 to the last detectable concentration at time t, calculated by the trapezoidal rule. AUC (0 to inf) - refers to area under the concentration-time curve extrapolated to infinity, calculated as the sum of AUCt and the area extrapolated to infinity Thus from the above in-vivo bioequivalence data it is found that the deferasirox tablets containing Cremophor® RH 40 (example 7) and prepared by top-spray fluid bed granulation process showed comparative in-vivo bioequivalence profile with that of marketed Exjade® 500mg tablets.

WE CLAIM:

1. A pharmaceutical composition comprising deferasirox, polyoxyl 40 hydrogenated castor oil (Cremophor® RH 40) and one or more pharmaceutically acceptable excipients, wherein said composition is prepared using top-spray fluid-bed granulation process.

2. A dispersible tablet comprising deferasirox, polyoxyl 40 hydrogenated castor oil (Cremophor® RH 40) and one or more pharmaceutically acceptable excipients, wherein said tablet is prepared using top-spray fluid-bed granulation process.

3. A top-spray fluid-bed granulation process for preparing a dispersible tablet comprising deferasirox, polyoxyl 40 hydrogenated castor oil (Cremophor RH 40) and one or more pharmaceutically acceptable excipients, wherein said process involves the following steps:

i. dissolve povidone, polyoxyl 40 hydrogenated castor oil (Cremophor® RH 40) in water to get a solution;

ii. add deferasirox to the solution of step (i) to get granulating fluid;

iii. mix the intra-granular excipients in a fluid-bed processor;

iv. spray the granulating fluid of step (ii) onto the intra-granular excipients of step (iii) to get granules;

v. blend the granules from step (iv) with extra-granular excipients to get a blend;

vi. compress the blend of step (v) to get said dispersible tablet.

4. The composition or tablet or process according to any of the preceding claim(s), wherein said excipients are selected from a group consisting of
diluent(s), binder(s), disintegrant(s), glidant(s) and/ or lubricant(s).

5. The composition or tablet or process according to any of the preceding claim(s), wherein the polyoxyl 40 hydrogenated castor oil (Cremophor® RH 40) is present in an amount of 0.1% to 5.0% by weight.

6. A dispersible tablet comprising deferasirox, polyoxyl 40 hydrogenated castor oil (Cremophor RH 40) and one or more pharmaceutically acceptable excipients as herein described and exemplified.

7. A dispersible tablet comprising deferasirox having following unit composition: wherein said tablet is prepared by top-spray fluid-bed granulation process.