EP3675832A1 - Formes posologiques à auto-dispersion rapide de déférasirox - Google Patents

Formes posologiques à auto-dispersion rapide de déférasirox

Info

Publication number
EP3675832A1
EP3675832A1 EP17795049.0A EP17795049A EP3675832A1 EP 3675832 A1 EP3675832 A1 EP 3675832A1 EP 17795049 A EP17795049 A EP 17795049A EP 3675832 A1 EP3675832 A1 EP 3675832A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
composition according
weight
acid
water soluble
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP17795049.0A
Other languages
German (de)
English (en)
Inventor
Asaad SHAHIN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jordan Sweden Medical And Sterilization Co
Original Assignee
Jordan Sweden Medical And Sterilization Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jordan Sweden Medical And Sterilization Co filed Critical Jordan Sweden Medical And Sterilization Co
Publication of EP3675832A1 publication Critical patent/EP3675832A1/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Definitions

  • 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.
  • 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 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.
  • 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.
  • chelation therapy 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 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 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.
  • particle size reduction is often the method of choice. By reducing particle size, the effective surface area increases, thus allowing a greater dissolution rate.
  • 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.
  • 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.
  • 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 poorly water soluble drug substance such as itraconazole
  • 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.
  • 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.
  • the processes used for taste masking frequently involve multiple steps which are technically complicated and difficult to reproduce, besides being economically disadvantageous.
  • 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.
  • 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.
  • WO07045445 describes a dispersible tablet of deferasirox or its
  • 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).
  • the present invention provides such improved solid dosage form/tablet wherein the poorly soluble drug substance is formulated with a suitable acid/base couple.
  • the formulation further comprises one or more water soluble polymers optionally in combination with water insoluble polymers.
  • 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.
  • 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.
  • 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.
  • 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.
  • the effervescent couple is preferably an acid/base couple.
  • an oral dosage form which is an immediate release fast self dispersible /orally dissolving pharmaceutical
  • an oral dosage form for use in children and other patients who have difficulty swallowing conventional solid dosage forms.
  • 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.
  • a palatable oral formulation that provides immediate release of the poorly water soluble active pharmaceutical ingredient in the gastro-intestinal tract (61 tract).
  • a formulation having flexibility of dosage titration, especially for children and geriatric patients.
  • 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.
  • 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.
  • 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.
  • a poorly water soluble active pharmaceutical ingredient such as deferasirox
  • 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.
  • 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.
  • an orally fast self dispersible solid dosage form of a poorly water soluble active pharmaceutical ingredient such as the iron chelator deferasirox
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a poorly water soluble active pharmaceutical ingredient such as an iron chelator preferably deferasirox
  • 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.
  • transfusion dependent anemia's transfusion hemosiderosis
  • non-transfusion-dependent thalassemia syndromes such as thalassemia major, and thalassemia intermediate, and sickle cell disease.
  • 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.
  • 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.
  • 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.
  • a poorly water soluble active pharmaceutical ingredient such as deferasirox
  • the poorly water soluble active ingredient preferably an iron chelator such as deferasirox
  • 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.
  • an iron chelator such as deferasirox
  • 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.
  • 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.
  • APIs active pharmaceutical ingredients
  • 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.
  • the solid dosage form of the present invention overcomes one or more of the above stated problems and/or goals.
  • 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.
  • 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.
  • 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.
  • 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
  • composition comprising a poorly water soluble active pharmaceutical ingredient with improved palatability and bioavailability.
  • 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.
  • 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.
  • the pharmaceutical compositions described herein provide a palatable oral formulation that provides immediate release of the active ingredient in the stomach.
  • 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.
  • the present invention provides a method of preparing such formulation, which method is a simple method and is more economical.
  • a parameter e.g. pH, pKa, etc.
  • state of a material e.g. liquid, gas, etc.
  • SATP standard ambient temperature and pressure
  • 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.
  • the dispersion of the active pharmaceutical ingredient from the formulation does not require stirring.
  • orally dissolving 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.
  • 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.
  • 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).
  • a diluent such as water, or other non-essential but suitable additives
  • 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.
  • a composition said to comprise a plurality of stipulated ingredients may in fact consist essentially of or consist of all the stipulated ingredients.
  • composition 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.
  • a composition said to "consist essentially of” a particular component consists of said component save for one or more trace impurities.
  • 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.
  • 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.
  • 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.
  • references to any given component of a composition 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.
  • 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.
  • 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.
  • solvent system refers to the solvent media used for the granulation process in preparing the dosage form of the present invention.
  • solvent system can be purified water, ethanol, isopropyl alcohol, mixture of water and isopropyl alcohol, or mixture of ethanol and water.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 .
  • the amount of poorly water soluble active ingredient is about 41 wt%.
  • 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.
  • 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.
  • the acid is a weak acid.
  • 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.
  • 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.
  • the acid is citric acid.
  • 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.
  • the alkali metal carbonate used in the acid/base includes 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.
  • couple/effervescent couple is sodium bicarbonate.
  • the acid/base couple or effervescent couple for use in the pharmaceutical composition of the present invention comprises citric acid and sodium bicarbonate.
  • 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%.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • the solid oral dosage formulation according to the present invention includes polyvinylpyrrolidone (e.g. PVP K30) as a binder.
  • 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.
  • the solid oral dosage formulation according to the present invention includes Sodium lauryl Sulphate as a surfactant.
  • 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
  • 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.
  • the amount of glidant e.g. Colloidal silicon dioxide
  • 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.
  • 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.
  • non-effervescent disintegrants can be present in the pharmaceutical composition of the present invention
  • 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.
  • 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.
  • the non-effervescent disintegrant may be present both intra-granularly and extra-granularly when processed in a wet granulation method.
  • 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.
  • the fast self dispersible, effective deferasirox formulation has the following composition:
  • 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,
  • step (3) 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
  • step (4) Finally compressing the mixture formed in step (4) to form tablets or which may alternatively be filled into capsules or sachets.
  • 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.
  • the non-effervescent disintegrant may be processed both intra-granularly 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.
  • 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.
  • 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.
  • 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.
  • the solid dosage forms of the present invention can include a higher percentage of active ingredient.
  • the solid dosage forms of the present invention can include a lower percentage of inactive ingredients
  • 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.
  • the fast dispersible pharmaceutical composition of the present invention further provides improved taste masking properties.
  • 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.
  • 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:
  • 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.
  • 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.
  • 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.

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Abstract

La présente invention concerne une composition pharmaceutique comprenant un principe actif pharmaceutique (API) faiblement hydrosoluble (tel que le chélateur du fer déférasirox) ou un sel pharmaceutiquement acceptable correspondant, et au moins deux excipients pharmaceutiquement acceptables. La présente invention concerne en outre un procédé de préparation de ladite composition et une utilisation de cette dernière pour le traitement et/ou des méthodes de traitement consistant à administrer la composition pharmaceutique, le traitement étant destiné à traiter la surcharge en fer observée dans les anémies liées à des transfusions (hémosidérose transfusionnelle), en particulier la thalassémie majeure et la thalassémie intermédiaire, et dans la drépanocytose, afin de diminuer la morbidité et la mortalité liées au fer, chez les patients âgés d'au moins 2 ans.
EP17795049.0A 2017-09-01 2017-09-01 Formes posologiques à auto-dispersion rapide de déférasirox Pending EP3675832A1 (fr)

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NZ330739A (en) 1996-05-20 1999-06-29 Janssen Pharmaceutica Nv Particulate solid dispersion of itraconazole and a water soluble polymer
BR9814729A (pt) 1997-12-31 2002-01-08 Choongwae Pharma Corp Método e composição de uma preparação oral de itraconazol
GB0223978D0 (en) 2002-10-15 2002-11-20 Novartis Ag Organic compound
GB0408078D0 (en) 2004-04-08 2004-05-12 Novartis Ag Organic compounds
CA2625112A1 (fr) 2005-10-19 2007-04-26 Novartis Ag Comprimes dispersibles contenant du deferasirox
WO2009106824A2 (fr) * 2008-02-25 2009-09-03 Cipla Limited Formulations pharmaceutiques
US20150320677A1 (en) * 2012-08-17 2015-11-12 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Effervescent tablet formulations of dapoxetine and a pde5 inhibitor
WO2014057059A1 (fr) * 2012-10-11 2014-04-17 Sanovel Ilac Sanayi Ve Ticaret A.S. Formulation effervescente de cefdinir
EP2815743A1 (fr) * 2013-06-21 2014-12-24 Sanovel Ilac Sanayi ve Ticaret A.S. Formulations comprenant du ceftibutène
WO2015117987A1 (fr) * 2014-02-05 2015-08-13 Sanovel Ilac Sanayi Ve Ticaret A.S. Formulations effervescentes comprenant de l'ibuprofène et de la n-acétylcystéine
EP2987482A1 (fr) * 2014-08-22 2016-02-24 Santa Farma Ilaç Sanayi A.S. Composition pharmaceutique soluble et dispersible contenant du déférasirox

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