WO2019043427A1

WO2019043427A1 - Fast self dispersible dosage forms of deferasirox

Info

Publication number: WO2019043427A1
Application number: PCT/IB2017/001201
Authority: WO
Inventors: Asaad SHAHIN
Original assignee: Jordan Sweden Medical And Sterilization Company
Priority date: 2017-09-01
Filing date: 2017-09-01
Publication date: 2019-03-07
Also published as: EP3675832A1

Abstract

The present invention relates to a pharmaceutical composition comprising a poorly water soluble active pharmaceutical ingredient (API) (such as the iron chelator deferasirox) or a pharmaceutically acceptable salt thereof, and at least two pharmaceutically acceptable excipients. The present invention further relates to a method for the preparation thereof and an use thereof for treatment and/or methods of treatment administering the pharmaceutical composition, wherein the treatment is for treating iron overload in transfusion dependent anemias (transfusion hemosiderosis), in particular thalassemia major, thalassemia intermediate, and in sickle cell disease, to reduce iron-related morbidity and mortality, in patients 2 years and older.

Description

FAST SELF DISPERSIBLE DOSAGE FORMS OF DEFERASIROX:

Pharmaceutical Formulations for Oral administration and Method of Preparing the Same

FIELD OF THE INVENTION

The present invention relates to novel formulations as well as to a new granulation method for poorly water soluble active pharmaceutical ingredients such as the iron chelator deferasirox and the use thereof in the treatment of iron overload in transfusion dependent anemias.

BACKGROUND OF THE INVENTION

Deferasirox has the chemical name 4-[3,5-bis(2-hydroxyphenyl)-[l,2,4]triazol-l- yl]benzoic acid, and has the followin chemical structure:

Deferasirox is an orally active iron chelator, currently marketed under the trade name EXJADE* for the treatment of iron overload in transfusion dependent anemia's (transfusion hemosiderosis), in patients 2 years and older. EXJADE^® is also indicated for the treatment of chronic iron overload in patients 10 years of age and older with non-transfusion-dependent thalassemia syndromes, such as thalassemia major, and thalassemia intermediate, and in sickle cell disease in order to reduce iron-related morbidity and mortality.

Major and intermediate clinical thalassemia are hereditary disorders characterized by defective production of haemoglobin, which leads to decreased production and increased destruction of red blood cells.

Sickle-cell disease (SCD), or sickle-cell anaemia (SCA) or sometimes drepanocytosis, is a hereditary blood disorder, characterized by an abnormality in the oxygen-carrying haemoglobin molecule in red blood cells. This leads to a propensity for the cells to assume an abnormal, rigid, sickle-like shape under certain circumstances. Sickle-cell disease is associated with a number of acute and chronic health problems, such as severe infections, attacks of severe pain ("sickle-cell crisis"), and stroke, and there is an increased risk of death. Further, haemochromatosis, the most common form of iron overload disease, is an inherited disorder that causes the body to absorb and store too much iron. The extra iron builds up in organs and damages them. Without treatment, the disease can cause these organs to fail.

Patients with sickle cell disease or thalassemia, who receive significant numbers of blood transfusions and patients with haematochromatosis, require therapy to remove iron from the body, called chelation therapy.

Deferasirox is a once daily oral iron chelator, which is prescribed in the form of a dispersible tablet, i.e., a tablet which needs to be dispersed in an aqueous medium prior to administration.

The delivery of active agents to their respective targets is often limited; in many instances this limitation may be attributed to the chemical nature of the agent. For example, oral delivery is generally ineffective with active agents that are poorly water-soluble.

The solubility of deferasirox, an iron chelating drug, in water is for example less than 1 mg/ml at 25°C.

Water-insoluble or slightly water soluble drugs (poorly water soluble drugs) are only slowly dissolved from a solid formulation. The drug dissolution step is therefore the rate- limiting step in the drug's absorbency which, in turn, has a direct effect on the drug's concentration in the blood stream, and therefore its potency or effectiveness. It is therefore important to increase the dissolution rate of water-insoluble or slightly water soluble drugs (i.e. drugs that are poorly soluble in water or an aqueous medium), in order to improve their solubility and bioavailability.

In particular where the drug substance is poorly water soluble, the reliance on a formulation which enables good dispersion into gastrointestinal fluids is more profound. In addition, in dosage forms containing a high dose of the active drug substance (above about 25% by weight of the formulation) the dependence on the particular components of the formulation increases. This is mainly due to the limited amount of inactive ingredients present in the formulation (which is limited by the increased size of an oral dosage form).

Several methods have been employed in an effort to alleviate the problems associated with poor solubility of such active drug substances. 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.

Another commonly used method is to dilute the active ingredient with large amounts of excipients. However, this approach is problematic when formulating dosage forms with high doses of active ingredients, due to the limit in size of the dosage forms.

Other known methods include for example, the use of surfactants and inclusion complexation. These techniques may have limited use. For example, as discussed above, in instances where the active drug substance is required to be present in the formulation in a high amount it may be difficult to include suitable and sufficient amounts of surfactants in order to obtain acceptable dissolution and bioavailability.

Complexation and solid dispersion techniques have also been used to achieve acceptable dissolution of active drug substances. However, these techniques may be technically difficult and may increase the size of the oral dosage form. Moreover, when using microsphere encapsulation, the formation of the microspheres requires however the use of volatile organic acids, such as acetic acid and formic acid. Such method results in the release of acidic gases which would require special precautions when carried out on an industrial scale.

Therefore, one of the main challenges in the development of formulations with a high load of poorly soluble active drug substances is to develop a formulation that increases drug solubility while also eliminating the tendency of the drug substance to agglomerate, thereby increasing its bioavailability.

The International Patent Application Publication WO 99/33467 describes an oral preparation for poorly water soluble drug substance, such as itraconazole, having improved bioavailability through the formation of solid dispersions having excellent solubility and increased dissolution rates. These are reported as being prepared by co-dissolving itraconazole and a pH-dependent hydrophilic polymer followed by spray-drying the mixture. The solid dispersions so obtained are then prepared for oral administration. The main drawback of this method is the number of steps involved, making it less advantageous to large-scale operations.

Further, WO 97/44014 describes a solid dispersion of a poorly water soluble drug substance, such as itraconazole, in a water-soluble polymer which is prepared by subjecting a mixture of itraconazole and a water-soluble polymer to a melt- extrusion process at a temperature ranging from 120 °C to 300 °C. Since there exists a possibility that the water- soluble polymer will decompose if it remains in contact too long with the heating element, the melt-extrusion process has to be carefully monitored.

A further complication is presented in cases where the active drug substance is not only poorly water soluble but is also particularly unpalatable and somewhat unstable. Considering that palatability, solubility and "mouth feel" are among the most important characteristics to be considered in providing dispersible or disintegrating oral solid dosage forms, it may be difficult, if not almost impossible, to produce in such instances a solid formulation that fulfills both of requirements of palatability and bioavailability.

Much research has been devoted to designing techniques and approaches to mask the bitter taste of drug in dosage forms. Simple approaches include adding chemical mediating, flavoring or sweetening ingredients to the composition, which thereby mask the bitterness of the drug. Alternative approaches include microencapsulating unpleasant taste active agent in a coating of ethyl cellulose or a mixture of ethyl cellulose and hydroxypropyl cellulose or other cellulose derivatives to provide chewable taste-masked products. However, such products, suffer from the disadvantage that the polymer coating may release the active agent in an inconsistent fashion and may not provide immediate release, or suffer the same shortcomings of the formulations described above. In addition, the processes used for taste masking frequently involve multiple steps which are technically complicated and difficult to reproduce, besides being economically disadvantageous. In view of the above described limitations in providing a formulation for poorly water soluble drug substances such as deferasirox, WO2004035026 describes a dispersible tablet of deferasirox or its pharmaceutically acceptable salt which are present in an amount of 5% to 40% by weight of the tablet with conventional pharmaceutical excipients.

Further, WO2005097062 also describes a dispersible tablet of deferasirox or its pharmaceutically acceptable salt, wherein the active drug substance is present in an amount of 42% to 65% by weight of the tablet which also includes conventional pharmaceutical excipients. According to the applicants of WO2005097062, the dispersible tablet described therein allows an oral dosage form having a drug load of lOOOmg.

Likewise, WO07045445 describes a dispersible tablet of deferasirox or its

pharmaceutically acceptable salt, wherein the active drug substance is present in an amount of 42% to 65% by weight of the tablet which also includes conventional pharmaceutical excipients. WO07045445 asserts that the dispersible tablet of high drug load can be manufactured by granulating the active without adding excipients other than binder and surfactant.

The solid formulations described in WO2004035026, WO2005097062, and WO07045445 suffer from the following drawbacks; a) the solid dosage form/tablet is of large tablet size, b) the taste of the dispersion from the formulation is not palatable, c) dispersability of the solid dosage form/tablet is slow which may result in non-compliance by the patient, d) the formulation has decreased stability in dispersed form (this is problematic especially if the suspension is not taken immediately so that sedimentation can occur), and e) the solid dosage forms/tablets contain a large quantity of lactose which can cause intolerance symptoms (such as bloating, diarrhea, and gas).

Hence, there is a need for formulations and methods of their preparation that effectively increase the bioavailability following administration of a poorly water soluble drug substance such as deferasirox. In particular, the need still exists for a palatable dosage form, especially for children and older people to achieve a better balance between improving its taste masking properties and improving dissolution. Additionally, there remains a need for a method for the preparation of an orally effective deferasirox formulation that minimizes manufacturing costs, that requires a minimal number of steps and that is amenable to large scale preparations.

The present invention provides such improved solid dosage form/tablet wherein the poorly soluble drug substance is formulated with a suitable acid/base couple. Optionally, the formulation further comprises one or more water soluble polymers optionally in combination with water insoluble polymers.

SUMMARY OF THE INVENTION

The present invention provides a novel orally fast self dispersible formulation of a poorly water soluble active pharmaceutical ingredient and a method for preparing such orally fast self dispersible which overcomes many of the limitations of prior formulations discussed above. The poorly water soluble active pharmaceutical ingredient may be deferasirox. The formulation of the present invention exhibits improved bioavailability, improved solubility, improved palatability and has an improved dissolution profile. The present invention also relates to a novel method for preparing an orally fast self dispersible, effective deferasirox formulation that minimizes manufacturing costs requires a minimal number of steps and that is amenable to large scale preparations.

According to one aspect of the present invention, there is provided a taste masked, fast, self dispersible oral formulation comprising an iron chelator, such as deferasirox, and an acid/base couple. The taste masked, fast self dispersible oral formulation can be in the form of a tablet or a powder. The acid/base couple herein can be an effervescent couple.

According to a second aspect of the present invention there is provided an oral pharmaceutical formulation comprising a poorly water soluble active pharmaceutical ingredient wherein the active ingredient is granulated with one or more water soluble polymers or combination of one or more water soluble and water insoluble polymers.

According to a third aspect of the invention there is provided an oral pharmaceutical formulation comprising a poorly soluble active pharmaceutical ingredient, such as the iron chelator deferasirox and an effervescent couple, wherein the poorly water soluble active pharmaceutical ingredient may be granulated with one or more water soluble polymers or combination of water soluble and water insoluble polymers prior to mixing with an effervescent couple. In the formulation of the present invention the effervescent couple is preferably an acid/base couple.

According to a fourth aspect of the invention, there is provided an oral dosage form which is an immediate release fast self dispersible /orally dissolving pharmaceutical

formulation.

According to a fifth aspect of the invention, there is provided an oral dosage form for use in children and other patients who have difficulty swallowing conventional solid dosage forms.

According to a sixth aspect of the invention there is provided a fast self dispersible formulation that provides a uniform suspension even in the absence of stirring. No stirring is required to provide a uniform suspension of the poorly water soluble active ingredient from the formulation of the present invention. This allows for an accurate medication which can be administered to the patient.

According to a seventh aspect of the invention there is provided a palatable oral formulation that provides immediate release of the poorly water soluble active pharmaceutical ingredient in the gastro-intestinal tract (61 tract).

According to an eight aspect of the invention there is provided a formulation having flexibility of dosage titration, especially for children and geriatric patients.

According to a ninth aspect of the invention there is provided a formulation for a poorly water soluble active pharmaceutical ingredient, such as deferasirox, which provides an improved balance between taste masking and dissolution properties compared to prior known formulations.

According to a tenth aspect of the invention there is provided a fast self dispersible formulation, preferable in tablet dosage form, of a poorly water soluble active pharmaceutical ingredient, such as deferasirox, with reduced or no foam generation during dispersion in an aqueous medium.

According to an eleventh aspect of the invention there is provided a fast self dispersible formulation, preferable in tablet dosage form, of a poorly water soluble active pharmaceutical ingredient, such as deferasirox, that can be dispersed in a carbonated beverage without much (with reduced) or no foam generation, contributing to the palatability, acceptability, and therefore patient compliance with a dosage regime for such poorly water soluble active pharmaceutical ingredient.

According to a twelfth aspect of the invention there is provided an orally fast self dispersible solid dosage form, preferably in the form of a tablet dosage form, which can be administered as dispersed in an aqueous medium, as an orally dissolving dosage form, as a chewable tablet, or as a solid dosage form (a tablet dosage form) to be swallowed as a whole by the patient.

According to a thirteenth aspect of the invention there is provided an orally fast self dispersible solid dosage form of a poorly water soluble active pharmaceutical ingredient, such as the iron chelator deferasirox, with a reduced lactose content so as to reduce the lactose intolerance symptoms that may be experienced, such as for example bloating, diarrhea, and/or gas). The solid dosage form of the present invention suitably comprises less than 30 weight %, more suitably comprises 5 to 25 wt %, even more suitably comprises about 10 to about 20 wt% lactose.

According to a fourteenth aspect of the invention there is provided an orally fast self dispersible solid dosage form of a poorly water soluble active pharmaceutical ingredient, such as the iron chelator deferasirox, with a reduced weight of the formulation. Particularly, a tablet dosage form of the present invention comprising 125 mg, 250 mg, 500 mg, and 1000 mg of the poorly water soluble active pharmaceutical ingredient suitably has a total weight of the solid dosage form in the range from about 200 to about 400 mg, from about 400 mg to about 750 mg, from about 600 mg to about 1500 mg, from about 1200 mg to about 3000 mg respectively. More suitable, such dosage forms of the present invention have a total weight of about 304 mg, about 609 mg, about 1219 mg, and about 2438 mg respectively. Suitably, the dosage forms of the present invention comprise the poorly water soluble active pharmaceutical ingredient in an amount of about 20 wt% to about 85 wt%, more suitably from about 30 wt% to about 65 wt%, even more suitably about 40 wt% to about 45 wt , even more suitably about 41 wt%, wherein the weight percent is in relation to the total weight of the dosage form of the present invention.

According to a fifteenth aspect of the invention there is provided an orally fast self dispersible solid dosage form of a poorly water soluble active pharmaceutical ingredient, such as an iron chelator, more preferably deferasirox, wherein the formulation is such that not less than 75 wt%, preferably not less than 80 wt%, of the active pharmaceutical ingredient dissolves within 30 minutes of administration.

According to a sixteenth aspect of the invention there is provided a orally fast self dispersible solid dosage form of a poorly water soluble active pharmaceutical ingredient comprising deferasirox and a pH independent hydrophilic polymer. The composition may further comprise non-active excipients such as a filler and/or binder, a disintegrating agent and a lubricant.

According to a seventeenth aspect of the invention there is provided an orally fast self dispersible solid dosage form of a poorly water soluble active pharmaceutical ingredient, such as an iron chelator preferably deferasirox, for use in treating iron overload in transfusion dependent anemia's (transfusion haemosiderosis), in patients 2 years and older for treating chronic iron overload in patients 10 years of age and older with non-transfusion-dependent thalassemia syndromes, such as thalassemia major, and thalassemia intermediate, and in sickle cell disease.

According to an eighteenth aspect of the invention there is provided a method of treatment comprising administering to a patient in need thereof an effective amount of a formulation of the present invention of an orally fast self dispersible solid dosage form of a poorly water soluble active pharmaceutical comprising an iron chelator such as deferasirox, wherein the treatment is of iron overload in transfusion dependent anemia's (transfusion hemosiderosis), in patients 2 years and older or of chronic iron overload in patients 10 years of age and older with non-transfusion-dependent thalassemia syndromes, such as thalassemia major, and thalassemia intermediate, and sickle cell disease.

According to a nineteenth aspect of the invention there is provided an orally fast self dispersible solid dosage form of a poorly water soluble active pharmaceutical ingredient such as deferasirox having excellent mechanical strength sufficient to be processed in high speed tableting machines.

According to a twentieth aspect of the invention there is provided a method of producing an orally fast self dispersible solid dosage form of a poorly water soluble active pharmaceutical ingredient such as deferasirox, wherein the method of manufacture is a simple and relative easy production method.

According to a twenty first aspect of the invention there is provided a process for manufacturing a taste masked orally fast dispersible solid dosage form of a poorly water soluble active pharmaceutical ingredient such as deferasirox comprising combining in solid dosage form the poorly water soluble active pharmaceutical ingredient and an acid/base couple.

According to a twenty second aspect of the invention there is provided a process for manufacturing a taste masked fast self dispersible / orally dissolving pharmaceutical formulation comprising a poorly water soluble active pharmaceutical ingredient such as deferasirox, wherein the poorly water soluble active ingredient, preferably an iron chelator such as deferasirox, is granulated with one or more water soluble polymers or a combination of one or more water soluble and water insoluble polymers and compressing the blend into tablets.

According to a twenty third aspect of the invention, there is provided a method for preparing an oral, fast self dispersible formulation comprising an iron chelator such as deferasirox, the method comprising the steps of producing granules by co-granulating the iron chelator (defersirox) and a pH-independent hydrophilic polymer in a solvent system; forming a powder by combining a first set of excipients in a mixer; forming a granulation by combining the deferasirox and the pH- independent hydrophilic polymer with the powder composed of the first set of excipients; and finally adding a second set of excipients to the granulation. Brief description of the Drawings:

Fig. 1 shows a comparative dissolution profile between a 500 mg formulation according to the present invention Fl and the commercial formulation for Deferasirox (Exjade^®) at pH 6.8.

Fig. 2 shows a comparative dissolution profile between a 500 mg formulation according to the present invention F2 and commercial formulation for Deferasirox (Exjade^®) at pH 6.8.

Detailed description of the Invention:

Oral dosage forms provide the most popular route of administration for most medications despite having some disadvantages like slow absorption and a resulting prolonged onset of action. This can be overcome by administrating the drug in liquid form but, many active pharmaceutical ingredients (APIs) have a limited level of stability in liquid form.

Accordingly, solid dosage forms in the form of fast self dispersible dosage forms as provided by the present invention may provide an alternative to conventional dosage forms.

As discussed hereinbefore, there is a continuing need for palatable and taste masked dosage forms for poorly water soluble active pharmaceutical ingredients, such as Deferasirox. Such dosage forms may have flexibility in dosage titrations, especially for children and geriatric patients while achieving a better balance between taste masking and dissolution. The solid dosage form of the present invention overcomes one or more of the above stated problems and/or goals. Moreover, the pharmaceutical composition of the present invention can be administered orally in different presentations, such as for example an orally ingested tablet which rapidly dissolves in the gastrointestinal tract or in the form of a solution prepared immediately prior to oral administration from a fast dissolving pharmaceutical composition.

Unexpectedly, the use of an acid/base couple in the formulation of the present invention results in a solid dosage form with improved dissolution characteristics, while at the same time providing excellent taste masking properties. Optionally, the poorly water soluble active pharmaceutical ingredient can be granulated with a water soluble polymer or a combination of water insoluble and water soluble polymers. More specifically, the use of an acid/base couple in a pharmaceutical composition of the present invention unexpectedly provides a fast self dispersible/orally disintegrating solid dosage form, for example in the form of a tablet or chewable tablet, with enhanced taste. Therefore, the present invention provides a

pharmaceutical composition comprising a poorly water soluble active pharmaceutical ingredient with improved palatability and bioavailability.

As such, the pharmaceutical compositions described herein overcomes many limitations of previously known pharmaceutical formulations comprising poorly water soluble active pharmaceutical ingredients such as Deferasirox. The compositions described herein provide a solid dosage formulation, such as for example an oral dosage form, for use in children and other patients who have difficulty swallowing conventional solid dosage forms of such poorly water soluble active pharmaceutical ingredients. Further, herein is provided a fast self dispersible dosage form, preferably in the form of a tablet dosage form, which does not require stirring before use. The use of such pharmaceutical composition allows for preparing a uniform suspension prior to administering the active pharmaceutical ingredient, and provides improvements in accurately administering such medication to the patient. In addition, the pharmaceutical compositions described herein provide a palatable oral formulation that provides immediate release of the active ingredient in the stomach.

Moreover, use of the pharmaceutical composition of the present invention allows the pharmaceutical formulation having flexibility in dosage titration, especially for children and geriatric patients, and achieves a better balance between taste masking and dissolution when compared to known formulations of poorly water soluble active pharmaceutical ingredients. The fast self dispersible solid dosage form described herein can be dispersed without foam generation during dispersion. This fast self dispersible dosage form can be dispersed in a carbonated beverage without much foam generation, contributing to the palatability, acceptability, and hence patient compliance with the dosing regimen of the poorly water soluble active ingredient such as deferasirox.

The present invention therefore relates to a novel, orally fast self dispersible, effective deferasirox formulation characterized by improved bioavailability, improved solubility, improved palatability and displaying an improved dissolution profile. In addition, the present invention provides a method of preparing such formulation, which method is a simple method and is more economical.

For the avoidance of doubt, it is hereby stated that the information described earlier in this specification under the heading "Background" is relevant to the invention and is to be read as part of the disclosure of the invention.

Suitably, unless stated otherwise, where reference is made to a parameter (e.g. pH, pKa, etc.) or state of a material (e.g. liquid, gas, etc.) which may depend on pressure and/or temperature, suitably in the absence of further clarification such a reference refers to said parameter at standard ambient temperature and pressure (SATP). SATP is a temperature of 298.15 K (25 °C, 77 °F) and an absolute pressure of 100 kPa (14.504 psi, 0.987 atm).

As described herein the terms "practically insoluble" or "insoluble" as well as the term "poorly water soluble" are to be understood as defined in the United States Pharmacopoeia for "practically insoluble" and "insoluble", i.e. a "very slightly soluble" compound requiring from 1000 to 10,000 parts of water for 1 part of solute.

In the present invention the term "self dispersible" refers to the active pharmaceutical ingredient (especially the iron chelator, particularly deferasirox) being released from the formulation in an aqueous environment which does not require any manipulation to result in a homogeneous dispersion of the active pharmaceutical ingredient from the formulation.

Particularly, the dispersion of the active pharmaceutical ingredient from the formulation does not require stirring.

The term "orally dissolving" as used in the present invention refers to the formulation being in an oral dosage form which can be dissolved within the gastro-intestinal tract in an immediate manner. A fast self dispersible/ orally dissolving formulation therefore relates to a pharmaceutical formulation which may be dissolved in water, liquid, or other beverage, or in the mouth prior to ingestion into the gastro-intestinal tract, in an immediate and fast self release manner.

In the present invention the term "fast" when combined with the term "fast dispersible" or "fast self dispersible" refers to a dispersion or dissolution rate of the active pharmaceutical ingredient from the solid dosage form that is greater than 60%, suitably greater than 70%, by weight of the total amount of the active pharmaceutical ingredient is being released from the solid dosage in 5 minutes, and/or greater than 80% by weight of the total amount of the active pharmaceutical ingredient is being released from the solid dosage form within 30 min, suitably within 20 minutes, more suitably within 15 min, more suitably within 10 min.

Herein, amounts stipulated for components and ingredients, whether specified in terms of "parts", ppm (parts per million), percentages (%, e.g. wt%), or ratios, are intended to be by weight, unless stated otherwise.

Where the quantity or concentration of a particular component of a given composition is specified as a weight percentage (wt% or %w/w), said weight percentage refers to the percentage of said component by weight relative to the total weight of the composition as a whole. It will be understood by those skilled in the art that the sum of weight percentages of all components of a composition (whether or not specified) will total 100 wt%. However, where not all components are listed (e.g. where compositions are said to "comprise" one or more particular components), the weight percentage balance may optionally be made up to 100 wt% by unspecified ingredients (e.g. a diluent, such as water, or other non-essential but suitable additives).

Where a composition is said to comprise a plurality of stipulated ingredients (optionally in stipulated amounts of concentrations), said composition may optionally include additional ingredients other than those stipulated. However, in certain embodiments, a composition said to comprise a plurality of stipulated ingredients may in fact consist essentially of or consist of all the stipulated ingredients.

Herein, where a composition is said to "consists essentially of" a particular component, said composition suitably comprises at least 85 wt% of said component, suitably at least 90 wt% thereof, suitably at least 95 wt% thereof, most suitably at least 99 wt% thereof. Suitably, a composition said to "consist essentially of" a particular component consists of said component save for one or more trace impurities.

When used herein the active pharmaceutical ingredient may be present in any suitable pharmaceutically acceptable form, including but not limited to any pharmaceutically acceptable salt forms, hydrates or solvates of the active pharmaceutical ingredient. Most suitable the active pharmaceutical ingredient in the composition of the present invention is Deferasirox, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

Deferasirox, in its free base form has the following molecular formula C21H15 3O4 and a molecular weight of 373.362 g/mol. For the purposes of various molar calculations (e.g. for molar ratios between deferasirox and another component of the solid dosage form of the present invention, the molecular weight of deferasirox may be taken to be 373,36 g/mol. This is not intended to be in any way limiting regarding the nature of any deferasirox (or salt therof) covered by the scope of the present invention, nor the amount of hydration or salvation, either of which may effect the actual molecular weight. The molecular weight of any suitable pharmaceutically acceptable salt, hydrate or solvated form of Deferasirox can be easily calculated by adding the molecular weight of the addition salt, hydrate or solvate to the molecular weight of Deferasirox. However, where the particular deferasirox does have a different molecular weight, the abovementioned reference molecular weight should be suitably used for the purposes of assessing whether or not such form of deferasirox falls within the scope of any molar definitions stipulated within this specification. So the number of moles in a known weight of said deferasirox should be calculated, just for the purposes of this invention, using the above reference molecular weight.

Herein, references to any given component of a composition, unless stated otherwise, suitably includes alternative forms of said component or includes said component where it is formed from alternative forms, such as any salt, free base, free acid, solvate, or complex thereof. As such, reference to a composition comprising a given compound includes any equivalent compositions comprising said component in an alternative form, or any equivalent composition formed by the incorporation of an alternative form of such compound. However, unless stated otherwise, any amounts stipulated in respect of the given component (especially when given in terms of weight or weight concentration/proportion) will suitably relate to the amount of the stipulated form of said component, not the amount of any alternative form thereof (e.g. salt). A conversion factor will need to be applied to establish the equivalent amount of said component in any alternative form, such as salt, free base, free acid, solvate, or complex thereof - this may be calculated by the skilled person, simply by reference to relevant molecular weights of the relevant species.

As used herein the term "solvent system" refers to the solvent media used for the granulation process in preparing the dosage form of the present invention. Such solvent system can be purified water, ethanol, isopropyl alcohol, mixture of water and isopropyl alcohol, or mixture of ethanol and water.

Herein, the terms "pharmaceutical composition", "pharmaceutical formulation" or "solid dosage form" refer to a formulation of a pharmaceutical active, suitably a poorly water soluble active pharmaceutical ingredient, which renders the biological activity of the active ingredient therapeutically effective, but which does not include other ingredients which are obviously toxic to a subject to which the formulation are intended to be administered.

The solid dosage form of the present invention, preferably in the form of a tablet dosage form, can be administered as: a fast self dispersible; a fast self orally dispersible, a chewable tablet, and/or a conventional swallowable tablet. More suitably, the oral pharmaceutical formulation of the present invention may be in the form of mouth dissolving tablets; dispersible tablets; effervescent tablets; chewable tablets; a powder (in sachets), or a capsule. More suitably, the oral dosage form according to the present invention is in the form of fast self dispersible tablets/Orally disintegrating tablet and chewable tablet.

The formulation of the present invention therefore can be administered via multiple routes of administration to a patient in need of treatment with such poorly water soluble active pharmaceutical ingredient as described herein. This is can be advantageous to patients who are traveling or who are in locations where water is not easily available. For such patients the present invention provides an alternative and as such provides for a better patient compliance with recommended pharmaceutical therapies. Hence, orally disintegrating formulations are becoming an increasingly important tool in the area of improving patient compliance. This is particularly true when compared to conventional solid dosage forms for oral administration such as capsules and tablets, which are the most commonly used.

In particular, the present invention provides an orally fast self dispersible dosage formulation, for example in a tablet formulation, of a poorly water soluble active

pharmaceutical ingredient such as for example deferasirox which solid dosage form has good mechanical strength enough to be processed in high speed tableting machines.

In one embodiment, the pharmaceutical composition, for example in the form of a tablet, is dispersed or dissolved in a suitable solvent such as water just before administration. Such dispersed or dissolved active pharmaceutical ingredient is to be ingested immediately. In this embodiment, the pharmaceutical composition is quickly broken apart by internal action of the disintegrant in water. In the invention described herein this is achieved by an acid/ base couple.

The amount of the poorly water soluble active ingredient in the pharmaceutical composition of the present invention is suitably in the range of about 10 wt to about 80 weight %, more suitably from about 10 wt% to about 60 wt%, more suitably from about 10 wt% to about 50 wt%, more suitably from about 10 wt% to about 45 wt%, more suitably from about 10 wt% to about 42 wt%, more suitably from about 20 wt% to about 42 wt%, more suitably from about 30 wt% to about 42 wt%, more suitably from about 40 wt% to about 42 wt . In a specific embodiment of the present invention the amount of poorly water soluble active ingredient is about 41 wt%.

Considering that in the pharmaceutical composition of the present invention the amount of pharmaceutical active ingredients may be present in a relative high percentage, the resulting size of the pharmaceutical composition of the present invention can be much smaller than for other known solid pharmaceutical compositions comprising a poorly water soluble active ingredient such as deferasirox. Therefore, as described above, one of the advantageous of the present invention is that the pharmaceutical composition described herein provides a composition comprising a poorly water soluble active ingredient, e.g. deferasirox, that can be more easily swallowed compared to previously known compositions comprising such poorly water soluble composition.

The acid/base couple in the formulation of the present invention suitably comprises a relative weak acid and a relative weak base. Suitably, the acid/base couple is an effervescent couple. The effervescent couple of the present invention suitable comprises an acid and a carbonate, such as for example a carbonate or bicarbonate. Suitably the acid is a weak acid. Suitably the acid is a weak acid with a pKa ranges from 2 to 7.5, more suitable a pKa from 3 to 7. Suitably such range is from 4 to 6.5. Suitably the acid used in the acid/base couple/effervescent couple of the present invention include citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, phosphoric acid, and succinic acids, or a mixture thereof. Suitable acid salts may include sodium, dihydrogen phosphate, disodium dihydrogen pyrophosphate, acid citrate salts and sodium acid sulfite or mixtures thereof. Most suitably the acid is citric acid. Suitably, the carbonate is present in the formulation of the present invention as an alkali metal or earth alkali metal carbonate. Suitable carbonates for use in the effervescent couple of the present invention include for example sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, magnesium carbonate and sodium sesquicarbonate, sodium glycine carbonate, L-lysine carbonate, arginine carbonate and amorphous calcium carbonate or mixtures thereof. Most suitably, the alkali metal carbonate used in the acid/base

couple/effervescent couple is sodium bicarbonate.

In a most suitable embodiment the acid/base couple or effervescent couple for use in the pharmaceutical composition of the present invention comprises citric acid and sodium bicarbonate.

The interaction between acid with alkali metal carbonates or bicarbonates in the presence of water releases C0₂ gas. Without being bound by theory, the liberation of C0₂ gas enhances both the dissolution of API in water as well as provides a taste masking effect. The advantages provided by the use of an acid/ base couple as a disintegrant in pharmaceutical compositions as provided in the present invention and described herein to prepare a fast self dispersible pharmaceutical composition as a solid oral dosage form includes an opportunity for the formulator to improve taste and provide a composition with a more gentle action on a patient's stomach.

The acid/base couple/effervescent couple suitably is present in the pharmaceutical composition of the present invention in an amount from about 7 wt% to about 50 wt%, suitable from about 10 wt% to about 40 wt%, more suitably from about 20 wt% to about 35 wt%, more suitably from about 25 wt% to about 35 wt%, or suitably about 30 wt%. Suitably, the pharmaceutical composition of the present invention includes an acid, of the acid/base couple, in an amount from about 4 wt% to about 20 wt%, suitably from about 5 wt% to about 15 wt%, more suitably from about 7 wt% to about 12 wt%, suitably the pharmaceutical composition of the present invention includes about 10 wt% of the acid, from the acid/base couple. Suitably, the pharmaceutical composition of the present invention includes from about 5 wt% to about 30 wt%, suitably from about 5 wt% to about 25 wt%, suitably from about 10 wt% to about 25 wt%, suitable from about 10 wt% to about 20 wt% of the carbonate in the acid/base couple or effervescent couple. Suitably the pharmaceutical composition of the present invention includes about 20 wt% of the carbonate in the acid/base couple or effervescent couple. The ratio of acid to base or acid to carbonate in the effervescent couple may suitably in the range from about 1:3 to about 1:1, more suitably in the range from about 1.5:3 to about 1.5:2, more suitably from about 2:3 to about 1:2.

In the pharmaceutical composition of the present invention the molar ratio of the active pharmaceutical ingredient, the poorly water soluble active ingredient such as deferasirox, to the acid/base couple or effervescent couple is suitably in the range from about 3:1 to about 3:7, suitably from about 3:2 to about 1:2, more suitably from about 1:1 to about 3:5, more suitably about 3:4.

The taste masking properties of the pharmaceutical composition described herein comprising an acid/base pair may be further enhanced when the composition further comprises a water soluble polymer or a combination of a water soluble and water insoluble polymer.

In a preferred embodiment of the present invention, the fast self dispersible oral formulation comprises an iron chelator, such as deferasirox and an acid/base pair granulated with one or more water soluble polymers or a combination of water soluble and insoluble polymers.

The water soluble polymers that may be used, according to the present invention, are suitably pH-independent water soluble polymers. Suitably such water soluble polymers include hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinyl pyrrolidone (PVP), guar gum, xanthan gum, gum arabic, tragacantha, hydroxyethyl cellulose, poloxamer, povidone and polyethylene glycol (PEG). More suitably, the pH-independent water soluble polymer is povidone. The amount of the water soluble polymer is preferably in the range of about 0.1 wt% to about 5 wt% by weight of the formulation. More suitably, the water soluble polymers is present in the pharmaceutical composition of the present invention from about 0.5 wt to about 5 wt , more suitably from about 1 wt% to about 4 wt%, more suitably about 2.5 wt%.

The water insoluble polymers that may be used, according to the present invention, include acrylic copolymers e.g. Eudragit E100 or any Eudragit form or grade; polyvinylacetate, for example, Kollicoat SR 30D, cellulose derivatives such as ethyl cellulose, cellulose acetate, carboxypolymethylene, hydrxpropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose, hydroxyethylcellulose, or methylcellulose.

Additional pharmaceutical excepients that may be present in the pharmaceutical formulations of the present invention comprise one or more pharmaceutical excepients known to the person skilled in the art which include, but are not limited to, diluents, binders, sweeteners, flavors, fillers, disintegrants, surfactants, glidants, lubricants, preservatives, stabilizers.

Suitable diluents that may be used, according to the present invention, comprise cellulose-microcrystalline, cellulose powdered, lactose, mannitol, sorbitol, pregelatinized starch, and equivalents thereof, dextrose, calcium phosphate, malitol, or their mixtures. The amount of the diluents is preferably in the range of about 10 wt% to about 60 wt% by weight of the formulation, more suitably from about 10 wt% to about 50 wt , more suitably from about 10 wt% to about 20 wt%.

Suitable binders that may be used, according to the present invention, comprise cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone (e.g. PVP K30), and cellulose derivatives and equivalents thereof, or mixtures thereof. Suitably, the solid oral dosage formulation according to the present invention includes polyvinylpyrrolidone (e.g. PVP K30) as a binder. Suitably, the amount of binders in the solid dosage form of the present invention is in the range is from about 0.5 wt% to about 5.0 wt% of the formulation, more suitably from about 1.0 wt% to 5 wt% and even more suitably from about 1.5 wt% to about 2.5 wt% of the formulation.

Suitable surfactants that may be used, for example, are a nonionic surfactant, an anionic surfactant, a cationic surfactant, an amphoteric surfactant, or a mixture thereof. Suitably, the solid oral dosage formulation according to the present invention includes Sodium lauryl Sulphate as a surfactant. Suitably the amount of surfactant in the solid dosage form of the present invention is in the range from about 0.1 wt% to about 2.0 wt of the formulation, more suitably from about 0.2 wt% to 1.5 wt% and even more suitably from about 0.3 wt% to about 0.5 wt% of the formulation.

Suitable sweeteners that may be used, according to the present invention, comprise saccharides such as, dextrose, glucose, maltose, dextrins, D-tagatose, trehalose, dried invert sugar, fructose, levulose, galactose, and the like, alone or in combination. Other examples of sweeteners comprise sucralose, sodium saccharin; aspartame; sugarless sweeteners including polyhydric alcohols such as sorbitol, mannitol, xylitol, glycerol, hydrogenated starch

hydrolysates, maltitol, isomaltitol, erythritol, lactitol and the like, alone or in combination. Suitably the amount of sweeteners in the solid dosage form of the present invention is in the range is from about 0.02 wt% to about 0.5 wt% of the formulation, more suitably from about 0.05 wt% to 0.3 wt% and even more suitably from about 0.1 wt% to about 0.15 wt% of the formulation.

Suitable lubricants/glidants that may be used, according to the present invention, comprise stearic acid, esters and its derivatives like magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate; talc; hydrogenated vegetable oil; sucrose esters of fatty acid; microcrystall^'ine wax; colloidal silicon dioxide or mixtures thereof. The amount of the lubricant/glidant is preferably in the range of about 0.1 wt% to about 4 wt% by weight of the formulation. Suitably, the amount of glidant (e.g. Colloidal silicon dioxide) in the

pharmaceutical composition of the present invention is from about 0.1wt% to about 2.0 wt% of the formulation, more suitably from about 0.2 wt% to about 1.5 wt% and more suitably from about 0.3 wt% to about 0.6 wt% by weight of the formulation. Suitably, the range of Lubricant( e.g. Sodium stearyl fumerate) is from about 0.1 wt% to about 2.0 wt% of the formulation, more suitably from about 0.2 wt% to about 1.5 wt% and more suitably from about 0.3 wt% to about 0.9 wt% by weight of the formulation.

In addition to the acid/base couple or effervescent couple, other non-effervescent disintegrants can be present in the pharmaceutical composition of the present invention Such, suitable disintegrants in addition to the effervescent couple that may be used, according to the present invention, alginic acid, carboxymethylcellulose, hydroxypropyl cellulose (low- substituted), microcrystalline cellulose, powdered cellulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone, magnesium aluminum silicate, methylcellulose, povidone, sodium alginate, disodium disulfite, EDTA and disodium phosphate. More suitably, such non-effervescent disintegrant can be crospovidone. Suitably, the amount of non- effervescent disintegrant in the pharmaceutical composition of the present invention is from about 1.5 wt% to about 15 wt% of the formulation, more suitably from about 5 wt% to about 10 wt% and more suitably about 7 wt% by weight of the formulation.

In the pharmaceutical composition of the present invention the non-effervescent disintegrant may be present both intra-granularly and extra-granularly when processed in a wet granulation method. When the non-efervescent disintegrant is used processed both intra- and extra-gran ularly, the ratio of extra-granularly to intra-granularly is suitably from about 4 : 2 to 2: 4, more suitable about 2:1, more suitably about 1.8 : 1 ratio.

In one specific an embodiment the solid dosage form of the present invention may have the following composition :

a) about 10 to 41.5% by weight of deferasirox;

b) about 1 to 5% by weight of povidone;

c) about 5 to 30% by weight of Lactose Spray Dried;

d) about 0.1 to 1.5% by weight of sodium lauryl sulphate;

e) about 1.5 to 15% by weight of crospovidone;

f) about 5 to 15% by weight of citric acid;

g) about 5 to 25% by weight of sodium bicarbonate;

h) about 0.1 to 1.5 % by weight of colloidal silicon dioxide; and

i) about 0.2 to 2.5 % by weight of sodium stearyl fumerate.

j) about 0.02 to 0.5 % by weight of sucralose.

In a more specific embodiment of the present invention, the fast self dispersible, effective deferasirox formulation has the following composition:

a) about 41% by weight of deferasirox;

b) about 2.5% by weight of povidone;

c) about 17% by weight of Lactose Spray Dried;

d) about 0.5 % by weight of sodium lauryl sulphate;

e) about 7% by weight of crospovidone;

f) about 10% by weight of citric acid;

g) about 20% by weight of sodium bicarbonate;

h) about 0.6 % by weight of colloidal silicon dioxide;

i) about 0. % by weight of sodium stearyl fumerate; and

j) about 0.1 % by weight of sucralose.

Such fast dispersible pharmaceutical formulation as described in the present invention has a dispersion or dissolution rate of the active pharmaceutical ingredient from the solid dosage form that is greater than 60%, suitably greater than 70%, by weight of the total amount of the active pharmaceutical ingredient is being released from the solid dosage in 5 minutes, and/or greater than 80% by weight of the total amount of the active pharmaceutical ingredient is being released from the solid dosage form within 30 min, suitably within 20 minutes, more suitably within 15 min, more suitably within 10 min.

The fast self dispersible oral pharmaceutical formulations according to the present invention can be manufactured by various techniques or processes known to the person skilled in the art including direct compression, dry or wet granulation, fluidized bed granulation, melt extrusion, spray drying and solution evaporation, preferably the manufacturing process involves conventional wet granulation technique.

The present invention further provides a process to manufacture the fast self dispersible oral pharmaceutical formulation, which method comprises the steps of: (1) Granulating a poorly water soluble active pharmaceutical ingredient with one or more water soluble polymers or a combination of one or more water soluble and water insoluble polymers to form an aggregate granules containing the active ingredient or ingredients,

(2) Drying the wet granules using tray oven drier or fluid bed drying method,

(3) Optionally sifting and sizing of the granules,

(4) Mixing the sized granules obtained in step (3) with the acid/base couple or effervescent couple and one or more pharmaceutical excipients forming the final mix, and

(5) Finally compressing the mixture formed in step (4) to form tablets or which may alternatively be filled into capsules or sachets.

As such steps 1 to 3 of the method described above provide a granular composition comprising the poorly water soluble active pharmaceutical ingredient. The remaining process steps comprise mixing the granular composition with extra granular components in the process of preparing a solid dosage form.

In the process of the present invention the non-effervescent disintegrant may be processed both intra-granularly and extra-gran ularly. When the non-efervescent disintegrant is used processed both intra- and extra-granularly, the ratio of extra-granularly to intra-granularly is suitably from about 4 : 2 to 2: 4, more suitable about 2:1, more suitably about 1.8 : 1 ratio.

Alternatively, the process does not include steps 1 to 3 described above and the pharmaceutical composition of the present invention is prepared by mixing the active pharmaceutical ingredient, the acid/base couple or effervescent couple together with one or more additional excipients and compressing the mixture in the form of tablets.

The invention also provides a method for treating a medical condition by administering the high-dose composition of at least one of the above embodiments to a patient in need thereof. Examples of the medical conditions that may be treated include treatment of iron overload in transfusion dependent anemias (transfusion hemosiderosis), in particular thalassemia major, thalassemia intermediate and in sickle cell disease to reduce iron-related morbidity and mortality, in patients 2 years and older.

The thus described pharmaceutical composition of the present invention, comprising a poorly water soluble active pharmaceutical ingredient and an acid/base couple or effervescent couple has various advantages over previously known compositions. In addition to having improved dissolution, the solid dosage forms of the present invention can include a higher percentage of active ingredient. In addition to having improved dissolution, the solid dosage forms of the present invention can include a lower percentage of inactive ingredients

(excipients). As a result the pharmaceutical composition of the present invention can be formulated into a smaller dosage form which, as an oral dosage form, is more easily swallowed. In addition to being more easily swallowed and having improved dissolution characteristics, the fast dispersible pharmaceutical composition of the present invention, further provides improved taste masking properties. Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The disclosures of the references referred to in this patent application are incorporated herein by reference. The invention is further defined by reference to the following examples describing in detail the compositions and process of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES

Example 1

Deferasirox tablet (Table 1)

Production Method

The Deferasirox fast self dispersible tablet was prepared by producing a premix of items 1, 4, 5, and 6, from table 1. This mixture was granulated with aqueous solution of items 2 and 3 from table 1. Subsequently, the granulate was dried at a temperature of about 70° C. until the moisture content in the granulate was less than 2 wt %. The granulate was mixed with the remaining extra-granular components from table 1. This mixture was mixed well and compressed into tablets.

More specifically, in a first step povidone and sodium lauryl sulphate were dissolved in purified water (q.s). Subsequently, deferasirox was suspended in the above liquid mixture (used as granulating mixture). Crospovidone (intra-granular), lactose monohydrate Spray dried (intra granular), and sucralose powder were passed through a 1.00 mm sieve. This powder mixture of crospovidone, lactose monohydrate and sucralose was granulated using the above granulating mixture including deferasirox. The granules were spread in stainless steel trays (granule bed thickness 2.0 cm) and dried in an oven at 60°C, to an LOD 1.0-2%. The dried granules were sifted using a 0.6 mm sieve. The retained granules were milled using a 1 mm screen. The sifted and milled granules were transferred to a blender. Lactose monohydrate Pray dried (extra- granular), crospovidone, citric acid anhydrous, aerosol, and sodium carbonate were passed through a 1.00 mm sieve and transferred to the blender. The materials in the blender were mixed for 5 minutes. Sodium stearyl fumerate was passed through a 0.6 mm sieve and added to the blender. The resulting mixture was mixed for 5 minutes. The resulting final mixture was compressed with a rotary table machine at the following weights: Deferasirox 500 mg:

theoretical weight 1219 mg, a round flat beveled, 18 mm punch was used. For tablets with Deferasirox 1000 mg: theoretical weight 2438 mg, a round flat beveled, 24 mm punch was used. For tablets with Deferasirox 250 mg: theoretical weight 609 mg, a round flat beveled, 13 mm punch was used.

Example 2

Deferasirox granules that can be filled into sachet (Table 2)

The Deferasirox fast self dispersible powder was prepared by producing a premix of items 1, 4, 5, and 6, from table 2. This mixture was granulated with aqueous solution of items 2 and 3 from table 2. Subsequently, the granulate was dried at a temperature of about 70° C. until the moisture content in the granulate was less than 2 wt %. The granulate was mixed with the remaining extra-granular components from table 2. This mixture was mixed well and filled into sachets.

Example 3:

Unit dose Formula (Table 3)

Production Method

The Deferasirox fast self dispersible tablet was prepared by producing a premix of items 1, 4, 5, and 6, from table 3. This mixture was granulated with aqueous solution of items 2 and 3 from table 3. Subsequently, the granulate was dried at a temperature of about 70° C. until the moisture content in the granulate was less than 2 wt %. The granulate was mixed with the remaining extra-granular components from table 3. This mixture was mixed well and compressed into tablets. Example 4:

Comparative dissolution Profile (Table 4)

The dissolution profile study for the inventor formula in comparison with the innovator product is conducted according to the USFDA Dissolution methods Database, which recommend using apparatus II (Paddle) at 50 rpm and (Phosphate buffer pH 6.8 with 0.5% Tween 20) as a dissolution medium for 10, 20, 30 and 45 minutes.

TABLE 4

The results for formulation Fl are represented graphically in Figure 1. The results for formulation F2 are represented graphically in Figure 2.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A pharmaceutical composition comprising a poorly water soluble active pharmaceutical ingredient and an acid/base couple.

2. The pharmaceutical composition according to claim 1, wherein the acid/base couple is an effervescent couple selected comprising a weak acid and a carbonate.

3. The pharmaceutical composition according to claim 2 wherein the weak acid is selected from the group consisting of citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acids, and phosphoric acid and acid anhydrides and salts thereof, and wherein the carbonate is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, magnesium carbonate and sodium sesquicarbonate, sodium glycine carbonate, L-lysine carbonate, arginine carbonate, amorphous calcium carbonate and mixtures thereof.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the acid/base couple is citric acid and sodium bicarbonate.

5. The pharmaceutical composition according to any one of the preceding claims, wherein the relative amount of the acid/base couple in the pharmaceutical composition is from about 7 weight percent to about 50 weight percent.

6. The pharmaceutical composition according to claim 5, wherein the acid is present in about 4 weight percent to about 20 weight percent and the carbonate is present from about 5 weight percent to about 30 weight percent.

7. The pharmaceutical composition according to any one of claims 1-6, wherein the poorly water soluble active pharmaceutical ingredient, the acid/base couple and a non-effervescent disintegrant have been granulated into the pharmaceutical composition.

8. The pharmaceutical composition according to claim 7, wherein the non-effervescent disintegrant is present extra-granularly and intra-granularly in a 4:2 to 2:4 ratio.

9. The pharmaceutical composition according to claim 7 or 8, wherein the non-effervescent disintegrant is selected from the group consisting of alginic acid, carboxymethylcellulose, hydroxypropyl cellulose (low-substituted), microcrystalline cellulose, powdered cellulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone, magnesium aluminum silicate, methylcellulose, povidone, sodium alginate, disodium disulfite, and EDTA and disodium phosphate.

10. The pharmaceutical composition according to any one of claims 7 to 9, wherein the non- effervescent disintegrant is crospovidone.

11. The pharmaceutical composition according to any one of the preceding claims, further comprising a pH-independent hydrophilic polymer.

12. The pharmaceutical composition according to claim, wherein the pH-independent polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinyl pyrrolidone (PVP), guar gum, xanthan gum, gum arabic, tragacantha, hydroxyethyl cellulose, poloxamer, povidone and polyethylene glycol (PEG).

13. The pharmaceutical composition according to any one of claims 11-12, wherein the pH- independent polymer is povidone.

14. The pharmaceutical composition according to any one of claims 11-13, wherein the pH- independent polymer is present in an amount from about 0.5 % by weight percent to about 5^Λ weight percent.

15. The pharmaceutical composition according to any one of the preceding claims, wherein the poorly water soluble active pharmaceutical ingredient is an iron chelator.

16. The pharmaceutical composition according to any one of the preceding claims, wherein the poorly water soluble active pharmaceutical ingredient is deferasirox.

17. The pharmaceutical composition according to any one of the preceding claims, wherein the amount of poorly water soluble active pharmaceutical ingredient is from about 10 weight percent to about 45 weight percent.

18. The pharmaceutical composition according to claim 17, wherein the amount of poorly water soluble active pharmaceutical ingredient is about 41 weight percent.

19. The pharmaceutical composition according to any one of the preceding claims, wherein the poorly water soluble active ingredients is present in a unit dosage strength selected from the group consisting of 125, 250, 500, or 1000, milligrams and the final tablet, sachet or capsule weight range is: between 200 to 400 mg for a 125 mg unit dosage strength; between 400 to 750 mg for a 250 mg unit dosage strength; between 600 to 1500 for a 500 mg unit dosage strength; and between 1200 to 3000 mg for a 1000 mg strength.

20. The pharmaceutical composition according to claim any one of the preceding claims, wherein the pharmaceutical composition is in the form of an oral dosage form.

21. The pharmaceutical composition according to claim 20, wherein the oral dosage form is a tablet or a chewable tablet.

22. The pharmaceutical composition according to claim 21, wherein the tablet is an effervescent tablet.

23. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition is a fast self dispersible dosage form.

24. The pharmaceutical composition according to any one of the preceding claims further comprising a filler or binder, a disintegrating agent, a sweetener and a lubricant.

25. The pharmaceutical composition according to claim 24, wherein the filler or binder are selected from the group consisting of acacia, alginic acid, carboxymethyl celiulose, dextrin, dibasic calcium phosphate, ethyl cellulose, glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, gelatin, guar gum, Lactose Spray Dried, magnesium aluminum silicate, microcrystalline cellulose, polyethylene oxide, polymethacrylates, povodone, sodium alginate and starch.

26. The pharmaceutical composition according to claim 24 or 25, wherein the filler and the binder are spray dried lactose and povidone.

27. The pharmaceutical composition according to any one of claims 24-26, wherein the lubricant is selected from the group consisting of calcium stearate, canola oil, glyceryl palmitostearate, lutein, lycopene, magnesium oxide, magnesium aluminum silicate, magnesium carbonate, magnesium oxide, magnesium silicate, magnesium stearate, magnesium trisilicate, maltitol, maltol, maltose, mannitol, mineral oil, poloxamer, polyethylene glycol, polyvinyl alcohol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.

28. The pharmaceutical composition according to any one of claims 24-27, wherein the lubricant is sodium stearyl fumerate.

29. The pharmaceutical composition according to any one of claims 24-28, wherein the surfactant is sodium lauryl sulphate.

30. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition is an oral fast- self dispersible formulation comprising:

a) about 10 to 41.5% by weight of deferasirox;

b) about 1 to 5% by weight of povidone;

c) about 5 to 30% by weight of Lactose Spray Dried;

d) about 0.1 to 1.5% by weight of sodium lauryl sulphate;

e) about 1.5 to 15% by weight of crospovidone;

f) about 5 to 15% by weight of citric acid;

g) about 5 to 25% by weight of sodium bicarbonate;

h) about 0.1 to 1.5 % by weight of colloidal silicon dioxide;

i) about 0.2 to 2.5 % by weight of sodium stearyl fumerate; and

j) about 0.02 to 0.5 % by weight of sucralose.

31. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition is an oral fast- self dispersible formulation comprising:

a) about 41% by weight of deferasirox;

b) about 2.5% by weight of povidone;

c) about 17% by weight of Lactose Spray Dried;

d) about 0.5 % by weight of sodium lauryl sulphate;

e) about 7% by weight of crospovidone;

f) about 10% by weight of citric acid;

g) about 20% by weight of sodium bicarbonate;

h) about 0.6 % by weight of colloidal silicon dioxide;

i) about 0. % by weight of sodium stearyl fumerate; and

j) about 0.1 % by weight of sucralose.

32. A method of treatment comprising administering to a person in need thereof a

therapeutically effective amount of the pharmaceutical composition according to any one of the preceding claims.

33. The method according to claim 32, wherein the treatment is of iron overload in transfusion dependent anemias (transfusion haemosiderosis), thalassemia major, thalassemia intermediate and in sickle cell disease in patients 2 years and older.

34. A method for preparing a pharmaceutical composition comprising:

(a) granulating a poorly water soluble active pharmaceutical ingredient with one or more water soluble polymers to form aggregate granules containing the active ingredient,

(b) drying the wet granules,

(c) combining the dried granules with a second set of excipients including an

effervescent acid/base couple forming a mixture, and

(d) blending the mixture obtained in step (c) and compressing the blended mixture, forming tablets, or filling the blended mixture into capsules or sachets.

35. The method according to claim 34, wherein the pharmaceutical composition is an orally fast self dispersible formulation.

36. The method according to claim 35, wherein the orally fast self dispersible comprises defirasirox.

37. The method as defined in claims 34 to 36, wherein said one or more water soluble polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinyl pyrrolidone (PVP), guar gum, xanthan gum, gum arabic, tragacantha, hydroxyethyl cellulose, poloxamer, povidone and polyethylene glycol (PEG).

38. The method as defined in claim 34, wherein the granulating in step (a) is carried in a solvent system of purified water or mixture of ethanol and water.