WO2025242589A1

WO2025242589A1 - Pharmaceutical dosage forms for deferiprone and deferasirox combined therapy

Info

Publication number: WO2025242589A1
Application number: PCT/EP2025/063656
Authority: WO
Inventors: Marisa PERTILE; Roberta LUZZI
Original assignee: Chiesi Farmaceutici SpA
Current assignee: Chiesi Farmaceutici SpA
Priority date: 2024-05-21
Filing date: 2025-05-19
Publication date: 2025-11-27
Anticipated expiration: 2026-11-21

Abstract

The invention relates to a pharmaceutical dosage form filled with formulations for once-a-day oral administration of deferiprone and deferasirox. Both formulations are in form of coated pellets or coated minitablets. The invention is directed to the claimed pharmaceutical dosage form for use in the treatment of diseases which cause an overload of iron.

Description

PHARMACEUTICAL DOSAGE FORMS FOR DEFERIPRONE AND DEFERASIROX

COMBINED THERAPY

FIELD OF THE INVENTION

The invention relates to a pharmaceutical dosage form for once-a-day oral administration of deferiprone and deferasirox.

BACKGROUND OF THE INVENTION

Deferiprone and deferasirox are well-known iron chelator drugs indicated for the treatment of diseases characterized by iron accumulation.

Deferasirox is marketed as Exjade™ and is formulated in different pharmaceutical forms for the oral administration once daily.

Due to the poor solubility of the active ingredient, a high dose is required to achieve the desired therapeutic effect, which may result in unwanted side effects, such as gastrointestinal (GI) irritation and kidney toxicity.

Deferiprone, marketed as Ferriprox® in form of tablets, also requires high doses, i.e. 500- 1000 mg. Furthermore, due to its shorter plasmatic half-life, it is currently orally administered twice-a-day or three times-a-day.

In the prior art, oral combination of deferiprone and deferasirox was used to increase the efficacy of iron chelation therapy in patients who do not adequately respond to monotherapy or in those with severe iron overload, particularly in sensitive tissues such as the heart. Further, monotherapy may not be suitable for patients who are underdosed due to adverse drug reactions that prevent optimal dosing of one or both active ingredients, or in those with poor treatment adherence.

The extemporaneous oral combination of said active ingredients was found to be safe, efficacious, and a feasible option in patients with suboptimal response to monotherapy (Totadri S et al Pediatr Blood Cancer. 2015 Sep;62(9): 1592-6).

In Clin Pract. 2017 Jan 12;7(1 ): 912, Karami H et al reported that the combination improves some iron and cardiac parameters in beta-thalassemic patients. Deferasirox was utilized with doses in the ordinary ranges, while for deferiprone, a lower dose was administered in four patients out of six (mean about 54 mg/kg/day and hence about 30% lower than the ordinary dose, i.e. 75 mg/kg/day).

Other authors suggested an improvement for some patients in both cardiac and liver iron concentrations (DivakarJose RR et al Indian J Pediatr. 2021, 88, 330-335; Hammond J et al J Pediatr Hematol Oncol. 2019, 41, e47-e50; Gomber S et al Indian Pediatr. 2016,53, 207-210; Elalfy MS et al Eur J Haematol. 2015, 95, 411-420; Karami H et al Clin Pract. 2017 Jan 12;7(1):912).

The major efficacy of the combined therapy may allow administering lower doses of both active ingredients, and hence improving both safety and compliance of the patients.

Therefore, it would be advantageous to provide a ready-to-use combination therapy of deferiprone and deferasirox formulations for once-a-day administration.

On the other hand, the development of an extended-release formulation for once-a-day continuous administration is not recommended for deferiprone for safety reasons.

Therefore, in developing a formulation of deferiprone for once-daily administration, pulsatile release is necessary to avoid its potential toxicity, observed in animals undergoing continuous infusion for periods longer than 24 hours.

Furthermore, the two formulations of deferiprone and deferasirox shall be provided in pharmaceutical forms compatible for a simultaneous administration.

WO 2014/072673 discloses a fixed combination of deferiprone with deferasirox, but it is silent about the problems associated with drugs having a different plasmatic half-life.

The problem is solved by the pharmaceutical dosage form of the present invention.

SUMMARY OF THE INVENTION

In a first aspect, the invention is directed to a pharmaceutical dosage form for once-a-day oral administration comprising: i) a pharmaceutical formulation for the delivery of deferasirox or a pharmaceutically acceptable salt thereof; and ii) a pharmaceutical formulation for pulsatile release capable of delivering deferiprone or a pharmaceutically acceptable salt thereof after a programmed time period.

Advantageously, both formulations are in form of coated pellets or coated minitablets. Preferably the pharmaceutical dosage form is a capsule or a sachet.

In a second aspect, the invention is directed to a process for filling the pharmaceutical dosage form with the pellets or the minitablets according to the invention.

In a third aspect, the invention is directed to the claimed pharmaceutical dosage form for use in the treatment of diseases which cause an overload of iron, or in the prevention and/or treatment of diseases which are caused by an overload of iron. Preferably, the disease is a severe form of iron overload.

In a fourth aspect, the invention is directed to the claimed pharmaceutical dosage form in the manufacture of a medicament for the treatment of diseases which cause an overload of iron, or for the prevention and/or treatment of diseases which are caused by an overload of iron.

In a fifth aspect, the invention refers to a method for the treatment of diseases which cause an overload of iron, or for the prevention and/or treatment of diseases which are caused by an overload of iron in a patient in need thereof, said method comprising orally administering the claimed pharmaceutical dosage form.

In a sixth aspect, the invention is directed to a method for reducing gastric distress or the risk of gastric distress in a patient in need thereof, comprising orally administering to the patient the claimed dosage form.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 - Alternative plasma concentration versus time profile simulated with the validated PBPK model (solid line); desired in-silico generated profiles (squares line).

Figure 2 - Release profiles of deferiprone from minitablets obtained according to the invention; a) CO, C3, C6; b) C9, Cl l, C17.

Figure 3 - Relationship between lag time and thickness of the outer layer.

DEFINITIONS

As used herein, the indefinite articles "a" or "an" should be understood to refer to "one or more" of any recited or enumerated component. For example, "a tablet" refers to one or more tablets.

Also as used herein, "and/or" refers to and encompasses all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative ("or").

When the term "about" is used in conjunction with a numerical value or range, it modifies that value or range by extending the boundaries above and below the numerical values set forth. The term "about" is used herein to modify a numerical value above and below the stated value by a variance of 10 percent, up or down (higher or lower), i.e., ± 10%, unless a different variance is indicated (e.g., ± 30%, ± 20%, ± 5%, ± 1%, etc.).

Wherever aspects are described herein with the language "comprising," otherwise analogous aspects described in terms of "consisting of" and/or "consisting essentially of" are also provided. To the extent that the term "includes" or "including" is used in the specification or the claims, it is intended to be inclusive in a manner similar to the term "comprising" as that term is interpreted when employed as a transitional word in a claim.

As used herein, the term "active ingredient" or "active pharmaceutical ingredient" (API) or “drug” are used as synonymous and mean any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals.

The terms "iron overload" or "overload of iron" are used interchangeably herein and refer to medical conditions where the body contains or stores too much (or "excess") iron. An example is transfusional iron overload, where the excess iron is introduced by one or more blood transfusions.

The term “coated small units” refers to pharmaceutical forms comprising an active ingredient, and one or more excipients having a diameter of few millimeters coated with at least one layer.

The term “minitablets” commonly refers to compressed tablets with smaller size than typical tablets. Although there are currently no regulatory guidelines defining minitablets (sometimes referred to as microtablets), the term has been used to describe tablets with diameters between 0.3 to three millimeters.

The term “pellets” refers to pharmaceutical forms formed by the agglomeration of fine powdered excipient and an active ingredients together that leads to the formation of small free flowing spherical or semi spherical particles.

In the present context, the term "hydrophilic" describes a molecule or portion of a molecule which is typically electrically polarized and capable of forming hydrogen bonds with water molecules, enabling it dissolve more readily in water than in oil or other "nonpolar" solvents.

Conversely, the term "hydrophobic" denotes a compound tending to be electrically neutral and non-polar, and thus preferring other neutral and nonpolar solvents or molecular environments.

For “pulsatile drug release” it is meant the repeated succession of drug pulses at variable time intervals. In other words, it refers to the release of a portion of the total payload in a burst followed by periods of little/no release in a defined temporal pattern.

For “with channeling properties” it is intended an excipient with swelling properties in water capable of favoring liquid inflow by generating molecular -to-micron size channel/pores in the film of a film-forming insoluble polymer. “Lag time” in pharmacokinetics (PK) corresponds to the finite time taken for a drug to appear in systemic circulation following extravascular administration. Lag time is a reflection of the processes associated with the absorption phase such as drug dissolution and/or release from the delivery system and drug migration to the absorbing surface.

For “pH dependent solubility” it is meant a substance having different solubilities at different pHs. These pH-dependent solubility differences lead to pH-dependent dissolution profiles.

The expression “insoluble or poorly water soluble” refers to a substance having a solubility in water as defined in the European Pharmacopoeia Ed. 4^th, 2003, page 2891.

In the present context, the terms "controlled release", “prolonged release”, "modified release" and “delayed release” are collectively indicated as “DR” and are intended to be terms covering some types of release of deferiprone from a composition of the invention that is appropriate to obtain a specific therapeutic or prophylactic response after administration to a subject.

"Superdisintegrant agent" as used herein refers to an excipient that is insoluble in water but swells when wetted to cause a tablet to disintegrate.

"Dissolution" as used herein refers to the process by which a solute forms a solution in a solvent.

"Enteric coat" or "enteric coating" as used herein refers to a coating comprising an enteric polymer. An enteric coating can serve to prevent or delay a tablet's dissolution or disintegration in a gastric environment.

"Enteric coated tablet" means a tablet having a core comprising an active ingredient, which is coated with an enteric coating.

"Enteric polymer" as used herein is understood to mean a polymer that is relatively insoluble at the acidic pH of the fasted stomach (e.g., from about pH 1 to about pH 4), but soluble at higher pH (e.g., from about pH 4.5 to about pH 8), which corresponds to the pH in the small intestine or thereafter, particularly in the duodenum or ileum.

The term “plasticizer” means an additive that increase the elasticity of coatings based on film-forming material.

The term “filler” means a pharmacologically-inert pharmaceutically acceptable excipient used to make a drug product easier to handle.

The terms “diluents” and “bulking agents” are used as synonymous.

With the term “therapeutic equivalence” is meant a drug product having the same clinical effect and safety profile of a reference product when administered to patients. With the term “PK bioequivalence" it is meant the absence of a significant difference between the bioavailability, i.e. the extent of absorption and peak concentration, of two pharmaceutical drug products (e.g. a test product and a reference product) over the course of a period of time, at the same dose and under the same conditions.

The determination of whether or not a test product is PK bioequivalent to a reference product is determined by performing a study, referred to as a bioequivalence or comparative bioavailability study, in a group of subjects, usually about 18-36 subjects or more, under controlled conditions.

The PK study can be done in a "crossover" design, which means that the study is done in 2 or more phases, usually at least a week apart, depending in part on the half-life of the drug. In the first phase, half the subjects are randomly assigned to ingest the test product first and the other half ingest the reference product first. In the second phase, each subject ingests the alternate product.

In each phase, blood samples are drawn from each subject, on a predetermined schedule after ingestion of the test product. The blood samples are then analyzed to determine serum concentrations of the drug at each time point. For example, drugs are bioequivalent if they enter circulation at the same rate when given in similar doses under similar conditions.

Parameters often used in bioequivalence studies are tmax, Cmax, Cmin, AUCo-infinity and AUCo-t.

In the present context "tmax" denotes the time to reach the maximal plasma concentration (Cmax) after administration; “AUCo-infinity” denotes the area under the plasma concentration versus time curve from time 0 to infinity; “AUCo-t” denotes the area under the plasma concentration versus time curve from time 0 to time t; “W50” denotes the time where the plasma concentration is 50% or more of C_ma_X; “W75” denotes the time where the plasma concentration is 75% or more of C_ma_X; and “MRT” denotes mean residence time for the active ingredient.

"Fasted state" as used herein refers to abstinence from food for a defined period of time after a meal (typically, at least several hours, e.g., 4 or 6 hours, after a meal).

“Fed state" as used herein refers to administration with a meal or soon after a meal (e.g. within about 1 hour).

The term “chemical stable” refers to stability of the active agent in the formulation, wherein changes in the drug assay values and/or impurities content are equal to or lesser than 5%, preferably lesser than 3%, during storage at 25 °C and 60% relative humidity (RH), or 40 °C and/or 75% RH, for at least 1 month. The term “in vitro-in vivo” correlation (IVIVC) refers to an in vitro dissolution test that is predictive of the in vivo performance of the drug product.

"Gastric distress" as used herein refers to discomfort of the gastrointestinal (GI) tract, e.g. one or more of pain, cramping, bloating, nausea, indigestion, heartburn and gas.

"Percent" or "%" as used herein refers to weight percentage (w/w) unless otherwise specified.

Terms such as "treating" or "treatment" or "to treat" or "ameliorating" or "alleviating" or "to alleviate" can refer to both 1) therapeutic measures that cure, slow down, lessen symptoms of, reverse and/or halt progression of a diagnosed pathologic condition or disorder, and 2) prophylactic or preventative measures that prevent, reduce the incidence of, reduce the risk of, and/or slow the development of a targeted pathologic condition or disorder. Thus, those in need of treatment include those who already have the disorder; those prone to developing the disorder; and those in whom the disorder is to be prevented. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those who already have the condition or disorder as well as those prone to developing the condition or disorder or those in which the condition or disorder is to be prevented or incidence reduced.

By "subject" or "individual" or "patient" any human subject is meant for whom diagnosis, prognosis, treatment or therapy is desired.

By "therapeutically effective dose or amount" or "effective amount" an amount of active pharmaceutical ingredient, e.g., deferiprone, is intended that when administered brings about a positive therapeutic response with respect to treatment or reduces the risk of a disease in a subject to be treated.

It will be understood that the deferiprone DR tablets used as the "reference" or "Reference Product" herein are the immediate release 1000 mg Ferriprox® tablets for three- times-a-day administration and the 1000 mg delayed release Ferriprox® tablets as approved by FDA and sold in the United States.

In the context of the present description, the term “synergistic” means the capacity of a combination to give rise to an effect superior than would be expected by the capacity of each component. DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a pharmaceutical dosage form for once-a-day oral administration comprising: i) a pharmaceutical formulation for the delivery of deferasirox or a pharmaceutically acceptable salt thereof; and ii) a pharmaceutical formulation for pulsatile release capable of delivering deferiprone or a pharmaceutically acceptable salt thereof after a programmed time period.

Advantageously, both formulations are in form of coated pellets or coated minitablets.

The pharmaceutical dosage form of the invention provides a significant advantage in terms of compliance of the patients seeking for a combined therapy for the treatment of iron overload. In particular, it allows administering both formulations simultaneously as well as reducing the number of administrations of the deferiprone formulation.

Furthermore, by the combined administration of both drugs it may be possible to achieve a significant reduction of the doses of one or both active ingredients, up to about 30%.

This allows an advantage in terms of safety of the therapy, for example in avoiding gastric side effects.

It also permits a better compliance of the patients, in particular elderly and pediatric subjects, due to the reduced number of formulation units to be ingested.

Without being limited by the theory, it is hypothesized that a synergistic reduction of the doses of one or both active ingredients may also be achieved due to the shuttling properties of deferiprone.

In fact, deferiprone, being able of penetrating across the cellular membranes, could extract the iron inside the cells, making it available for the chelation by both the active ingredients.

Advantageously, the formulation in form of coated pellets or coated minitablets for the delivery of deferasirox is prepared according to the teaching of WO 2014/136079.

More advantageously, the formulation comprising deferasirox is constituted by coated units comprising deferasirox, or a pharmaceutically acceptable salt thereof, as active ingredient in an amount comprised between 45 % and 60 %, and further comprises:

(i) at least one filler in an amount comprised between 10 % and 40 % ;

(ii) at least one disintegrant in an amount comprised between 1 % and 10 %;

(iii) at least one binder in an amount comprised between 1 % and 5 %;

(iv) at least one surfactant in an amount comprised between 0.0 % and 2 %; (v) at least one glidant in an amount comprised between 0.0 % and 1 %;

(vi) at least one lubricant in an amount comprised between 0.0 % and 2%; and

(vii) a coating; wherein all the percentages are calculated by weight on the total weight of the pellets formulation.

Suitable fillers according to the invention include but are not limited to microcrystalline cellulose, including but not limited to Avicel® PH 102 and PH 101.

Suitable fillers may be selected from the group consisting of microcrystalline cellulose, lactose, sucrose, magnesium stearate, glucose, plant cellulose and calcium carbonate.

Suitable disintegrants according to the invention include but are not restricted to maize starch, CarboxyMethylcellulose Calcium (CMC-Ca), CarboxyMethylcellulose Sodium (CMC-Na), microcrystalline cellulose, cross-linked polyvinylpyrrolidone (PVP), e.g. as known and commercially available under the trade names Crospovidone®, Polyplasdone®, available commercially from the ISP company, or Kollidon® XL, alginic acid, sodium alginate and guar gum. In a preferred embodiment, cross-linked PVP, e.g. Crospovidone®, is used.

Suitable binders include but are not restricted to: starches, e.g. potato, wheat or corn starch; microcrystalline cellulose, e.g. products such as Avicel®, Filtrak®, Heweten® or Pharmacel®; hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, e.g. hydroxypropylmethyl cellulose-Type 2910 USP, hypromellose and polyvinylpyrrolidone, e.g. Povidone® K30 from BASF. In a preferred embodiment, polyvinylpyrrolidone is used, most preferably PVP K30™.

Suitable surfactants according to the invention include but are not restricted to: betain, quaternary ammonium salts, polysorbates, sorbitan esters, poloxamers and sodium lauryl sulfate (SLS). Preferably, the surfactant is selected from sodium lauryl sulfate and a poloxamer. A poloxamer is a polyoxyethylene-polyoxypropylene block copolymer. In a more preferred embodiment, the surfactant is a poloxamer, preferably Pluronic™ F68 grade. Pluronic F68™ grade is also indicated as PEO76PPO29PEO76, wherein PEO stands for (poly (ethylene oxide) and PPO is polypropylene oxide). Pluronic F68™ is a poloxamer in flake (F) solid form having an approximate molecular weight of 8400.

Suitable glidants include but are not restricted to: silica, colloidal silica, e.g. colloidal silica anhydrous, e.g. Aerosil® 200, magnesium trisilicate, powdered cellulose, starch and talc. Preferably, colloidal silica is used. Suitable lubricants include but are not restricted to: Mg-, Al- or Ca-stearate, PEG 4000 - 8000, talc, sodium benzoate, glyceryl mono fatty acid, e.g. having a molecular weight of from 200 to 800 Daltons, e.g. glyceryl monostearate (e.g. Danisco, UK), glyceryl dibehenate (e.g. Compritol AT0888™, Gattefosse France), glyceryl palmito-stearic ester (e.g. Precirol™, Gattefosse France), polyoxyethylene glycol (PEG, BASF), hydrogenated cotton seed oil (Lubitrab™, Edward Mendell Co Inc), castor seed oil (Cutina™ HR, Henkel). In a preferred embodiment, magnesium stearate is used.

The formulation in both forms is provided with a full enteric coating. The enteric coating comprises Eudragit™ which is a synthetic copolymer derived from esters of acrylic and methacrylic acid (Acryl-EZE™). Eudragit™ was applied to a deferasirox tablet core at level of 5-15% by weight gain. An addition of sub-coating, such as Opadry™ 03K19229, enhanced the effectiveness of enteric coating. Full enteric protection is achieved after greater than 5% by weight gain.

The presence of the coating minimizes local GI irritation.

According to a preferred embodiment, the formulation has the composition reported in the following Table 1.

Table 1

In another aspect of the present invention, it is provided a process for the preparation of the deferasirox formulation, in form of coated pellets, comprising the steps of:

(i) mixing deferasirox or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient;

(ii) wet-granulating the mixture obtained in step (i) in a high shear granulator;

(iii) extruding and spheronizing the wet granulates obtained in step (ii);

(iv) drying the extruded and spheronized pellets obtained in step (iii); and

(v) coating the pellets. Accordingly, the manufacture of deferasirox coated pellets using a fluidized process technique or other pelletization techniques includes but is not limited to the following considerations: a) pre-wetting: water is evenly distributed to the dry blend of the drug and the other excipients in a high shear granulator. b) pelletization: the pre-wetted blend was pelletized by mechanical and gravitational forces acting on the blend while being processed. Moisture (water) was constantly applied. Once the pellets reached the desired particle size range, a small percentage of the dry blend was incorporated on the pellets to stop growth and smooth the pellet surface. c) drying: the drying of the pellets was performed in a fluid-bed processor; the pellets were dried to moisture content below 3% by weight.

The invention also provides a process for the preparation of the deferasirox formulation in form of coated minitablets, said process comprising the following steps:

(i) mixing the active ingredient with pharmaceutical excipients to form a mixture;

(ii) compressing the mixture obtained in step (i) to form the minitablets; and

(iii) coating the minitablets;

(iv) optionally, the mixture of step i) is wet granulated in order to obtain granules suitable to be tableted.

Apparatus and conditions for compaction and granulation are known to the skilled person in the art. Therefore, the operating parameters shall be adjusted according to their knowledge.

In view of the advantages linked to the administration in combination with deferiprone, a suitable unit dose of deferasirox, expressed as free acid form, ranges from 80 to 300 mg, preferably from 100 to 200 mg, being in particular a 90, 100, 180 and 200 mg unit dosage.

However, the dose of deferasirox administered to a patient will depend on numerous factors such as sex, age weight of patient, and the severity of symptoms.

The formulation for pulsatile release of deferiprone or a pharmaceutically acceptable salt thereof is disclosed in the pending application n. EP23175449.0.

Desired pulsatile profiles were simulated in silico (see Figure 1).

Therefore the invention relates to a pharmaceutical formulation providing a pulsatile release profile, said form comprising coated small units, wherein each unit in turn comprises deferiprone as active ingredient, a filler agent, a lubricant and/or a glidant and it is coated with an inner layer and, optionally, an outer layer, whereby one part of the coated small units releases part of the active ingredient in a time comprised between 10 minutes and 8 hours, while the remaining part of the coated small units releases the remaining part of the active ingredient, preferably in a time comprised between 6 hours and 24 hours.

Preferably, at least the coated small units releasing fraction of the active ingredient in a time comprised between 10 minutes and 8 hours are covered with the outer layer.

More preferably, at least the part of the small units releasing the active ingredients in a time comprised between 6 hours and 24 hours are coated with the outer layer.

For example, one part of the coated small units could release part of the active ingredient in a time comprised between 30 minutes and 6 hours, while the remaining part of the coated small units could release the remaining part of the active ingredient in a time comprised between 8 hours and 24 hours.

The first part of the release pulse could occur in one to three peaks, preferably one or two peaks, while the second part of the release pulse typically gives rise to one peak only.

Advantageously, the part of the coated small units releasing deferiprone in a time comprised between 10 minutes and 8 hours could be comprised between 20 and 80%, preferably between 30 and 70% by weight. In certain embodiments it could be comprised between 40 and 60% by weight.

Analogously, the fraction of deferiprone released in a time comprised between 10 minutes and 8 hours could be comprised between 20 and 80%, preferably between 30 and 70% by weight. In certain embodiments it could be comprised between 40 and 60% by weight.

Advantageously, the in vivo lag time, if present, is equal to or less than one hour, preferably between 2 and 50 minutes, more preferably 30-45 minutes.

Advantageously, the coated small unit comprises deferiprone in an amount comprised between 75 % and 90 %, a filler in an amount comprised between 10% and 24%, a lubricant and/or glidant in an amount of 0.5 to 1.0%, all the amounts calculated by weight based on the total weight of the uncoated unit, and it is coated with an inner layer and optionally an outer layer, wherein the inner layer comprises a swellable hydrophilic polymer and a plasticizer, and the outer layer, when present, comprises a film-forming insoluble polymer and an agent with channeling properties.

Within the scope of the present invention, deferiprone is in any physical form (crystals, amorphous powder, any possible polymorphs, any possible solvate). Included are also pharmaceutically acceptable salts and/or solvates thereof. Preferably, deferiprone is used as a base in its anhydrous form. It has been found that the coated small units according to the invention show satisfactory technological characteristics and release performance meeting the desired pulsatile behaviour.

In a preferred embodiment, the small units coated with the inner layer are further coated with the outer layer.

In fact, without being limited by the theory, it is expected that when present, the outer layer would act synergistically with the inner layer to slow down the penetration of water. Therefore, the two layers together constitute a very efficient controlling mechanism responsible for the delay of the release of the drug in the bowel.

In particular, the delay is mainly correlated to the thickness of the outer layer.

As it can be appreciated from Figure 2-a, CO and C3 coated small units displays an in vitro release profile potentially providing the first release pulse occurring in one or two peaks of the simulated in vivo profile, while C9, Cl l and C17 small units provide the delayed release involved/necessary to in the second (or third) peak of the simulated profile, while C6 small units have a release profile that could match either the first part or the delayed part of the simulated in vivo profile.

It will be appreciated that the formulation according to the invention could surprisingly deliver the complete dosage of the drug to achieve the desired pulsatile release of the drug over the course of about 24 hours with a single oral administration.

It is also contemplated that the dosage form of the invention would turn out to be therapeutically bioequivalent to the immediate release reference Ferriprox® tablets for three- times-a-day administration and/or to the reference Ferriprox® delayed-release tablets for twice-a-day administration. Advantageously, the coated small units are in form of minitablets or pellets, preferably minitablets.

The filler shall be selected form the group of diluents and superdisintegrant agents or mixture thereof. Diluents may also be indicated as bulking agents.

Preferably, the filler is a mixture of a diluent and a superdisintegrant agent in any suitable ratio.

Advantageously, the diluent may be selected from the group consisting of calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrans, dextrins, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose and alpha-lactose monohydrate. Preferably, the diluent is microcrystalline cellulose of different varieties. For instance, microcrystalline cellulose known as Avicel® PH 101 marketed by DuPont Inc (Wilmington, USA) may be used.

When the small units are in form of pellets, microcrystalline cellulose marketed as Vivapur 101 by JSR Pharma GmbH (Rosemberg, Germany), may be used, a variety especially suitable for wet granulation.

The superdisintegrant agent is selected from the group consisting of carboxymethylcellulose (CMC) and its crosslinked sodium salt known as croscarmellose sodium, crospovidone (also known as cross-linked PVP) and sodium starch glycolate.

All said superdisintegrant agents are commercially available.

For example, sodium starch glycolate is sold as Explotab® CLV by JSR Pharma (Rosemberg, Germany).

More advantageously, the filler is a mixture of a diluent, preferably microcrystalline cellulose, and a superdisintegrant agent in a ratio between 85: 15 and 75 :25 w/w, preferably 80:20 w/w.

Preferably, the superdisintegrant agent is in turn a mixture of crospovidone and sodium starch glycolate in a ratio comprised between 50:50 and 30:70, preferably 35:65 by weight.

In one embodiment, when the small units are in form of pellets, a mixture of microcrystalline cellulose and carboxymethylcellulose marketed as Avicel® CL 611 by DuPont Inc (Wilmington, USA) may be used.

The composition of the small unit of the invention also comprises a lubricant to prevent sticking to the tooling during compression into tablets, and/or a glidant to improve flow in the tableting process, or combinations thereof.

Advantageously, the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate and any combination thereof.

Advantageously, the glidant is selected from the group consisting of colloidal silicon dioxide, starch and talc, preferably colloidal silicon dioxide (also known as colloidal silica), or any combination thereof.

In a preferred embodiment, the small unit comprises a mixture of colloidal silicon dioxide and magnesium stearate in a ratio of 10:90 to 20:80 w/w, preferably 15:85 by weight.

All the aforementioned excipients are commercially available.

To achieve the programmed release of the active ingredient in the gut, the small unit is suitably coated with swell able/erodible coating layers.

Advantageously, they are coated with an inner layer comprising a swellable hydrophilic polymer, such as a hydrophilic derivative of cellulose, for example hydroxyethyl cellulose or hydropropylmethyl cellulose.

More advantageously, the inner layer comprises a hydroxypropylmethyl cellulose and a plasticizer, and optionally a glidant, such as talc, in any suitable ratio by weight.

The presence of the talc reduces the sticking of the layer.

The hydroxypropylmethyl cellulose polymer (HPMC) of different molecular weights is commercially available as Methocel®, for example from DuPont (Delaware, USA). Preferably, a HPMC of low viscosity is used as it allows a more rapid and efficient coating process in an aqueous medium and it is endowed with lesser gelling properties than HPMC of higher viscosity which could slow down the diffusion and hence the release of the active ingredient.

For example, Methocel® E50 may be used, a highly substituted HPMC which is reported to give a low viscosity (about 50 cP at a 2% addition in water at 20 °C).

Advantageously, the plasticizer is selected from the group comprising, but not limited to, diethyl phthalate, citrate esters, such as triethyl citrate (TEC), polyethylene glycol, glycerol, acetylated glycerides, acetylated citrate esters, dibutyl sebacate, castor oil, or any combination thereof, preferably polyethylene glycol.

Polyethylene glycol (PEG) of different molecular weights is available from Sigma Aldrich Inc (St. Louis, USA). Preferably PEG 400 is used as plasticizer as it is reported to be endowed with better plasticizing properties.

According to a preferred embodiment, the inner layer is constituted of HPMC and PEG 400 in a ratio comprised between 95:5 and 80:20 w/w, more preferably 90: 10 by weight.

According to another preferred embodiment, the inner layer is constituted of HPMC, PEG 400 and talc in a ratio of 89: 10: 1.0 by weight.

Advantageously, the thickness of the inner layer is comprised between 25 and 250 micron corresponding to a weight increase comprised between 6 and 60% by weight.

The outer layer, when present, comprises a film-forming insoluble polymer and an agent with channeling properties in a suitable ratio by weight.

More advantageously, said agent with channeling properties is a superdisintegrant agent, such as of croscarmellose sodium, crospovidone, and sodium starch glycolate, preferably starch sodium glycolate.

Suitable film-forming insoluble polymers available on the market are: a blend of polyvinyl acetate and povidone in the ratio 8:2 sold under the trademark of Kollidon SR; methacrylate derivatives, such as Eudragit™ RS and Eudragit™ RL, and cellulose derivatives, such as ethylcellulose.

In a preferred embodiment of the invention, the superdisintegrant is sodium starch glycolate and the film-forming insoluble polymer is ethylcellulose.

Advantageously, the ratio between the superdisintegrant agent and the film-forming insoluble polymer is comprised between 95:5 and 80:20 w/w, preferably 90: 10 by weight.

As reported above, sodium starch glycolate is marketed as Explotab® CLV by JSR Pharma GmbH (Rosemberg, Germany).

Ethylcellulose (EC) is marketed as aqueous dispersion with the name of Surelease® by Colorcon Inc (PA, USA).

According to a preferred embodiment, the pharmaceutical dosage form may contain coated small units in form of minitablets having the composition reported in Table 2.

Table 2

As mentioned above, thickness of the layers is of paramount importance to determine the release profile.

Therefore said thickness was determined according to different methods, i.e. weight gain after coating (%), coating layer thickness (pm), coating amount per unit area (mg/cm²), while the latter one being considered the most reliable and convenient one as it would be independently of the weight of the nuclei.

Detailed procedures are reported in the paragraph about the general experimental details and methods. Advantageously, the coating thickness of the inner layer shall be comprised between about 10 and 300 micron, preferably comprised between about 25 and 280 micron, more preferably comprised between 200 and 260 micron, the latter interval corresponding to a coating amount per unit area of about 20-25 mg/cm².

The coating thickness of the outer layer shall be comprised between 0 and about 60 micron, corresponding to a coating amount per unit area of 0 to 10 mg/cm².

More advantageously, to make coated small units suitable for the first phase of the release, the coating outer layer may be present or not, and when present thickness may be comprised between about 15 and 50 micron. Depending on the number of peaks that are needed, part of the coated small units may be administered without any outer layer, while part with thickness values of 20-22 micron, 30-35 micron and 45-50 micron.

Said thickness values corresponds to an increment in weight of 4 to 11%.

When expressed as coating amount per unit area, said thickness values may be comprised between about 2 and 6 mg/cm². Suitable values may be 2.2-2.3 mg/cm², 3.4-3.6 mg/cm², and 5.3-5.4 mg/cm².

Advantageously, to make the coated small units suitable for the second phase of the release, the coating outer layer shall be present and its thickness comprised between about 45 and 60 micron.

Said thickness values correspond to an increment in weight of 10 to 18%, preferably of 12 to 16.5%.

When expressed as coating amount per unit area, said thickness values will be comprised between 4.5 and 10 mg/cm², preferably between 5 and 6 mg/cm² .

The release profile of the minitablets of the invention has been determined according to the dissolution medium and conditions reported in the paragraph about the general experimental details and methods (Release test).

According to the desired pulsatile profile, and in particular if two or three peaks are desired, the skilled person in the art could mix in suitable amounts different types of minitablets having selected thickness of the outer layer.

The invention also provides a process for the preparation of the coated small units as described above in form of minitablets, said process comprising the following steps:

(i) mixing the active ingredient with the filler agent, and with the lubricant/glidant excipient to form a mixture;

(ii) compressing the mixture obtained in step (i) to form the minitablets;

(iii) coating the minitablets with the inner layer, and (iv) optionally, coating the minitablets of step iii) with a further outer layer to obtain double coated minitablets, and

(v) drying the coated minitablets.

Optionally, the mixture of step i) is wet granulated in order to obtain granules suitable to be tableted.

Apparatus and conditions for compaction and granulation are known to the skilled person in the art. Therefore, the operating parameters shall be adjusted according to its knowledge.

For example, typical process parameters are reported in Table 5 of Example 2.

In an alternative embodiment, when the small coated units are in form of pellets, the invention provides a process for the preparation of the coated pellets, said process comprising the following steps: i) mixing the active ingredient with the filler agent, and with the lubricant/glidant excipient to form a mixture; ii) wetting the mixture of step i) with a suitable liquid binder; iii) extruding the wet mixture of step ii) through a die with holes to form cylindrical extrudates; iv) spheronizing the extrudates of step iii) to obtain wet pellets; v) drying the obtained wet pellets: vi) coating the pellets with the inner layer; vii) optionally coating the pellets of step vi) with a further outer layer, and viii) drying the coated pellets.

Apparatus and conditions for manufacturing pellets are known to the skilled person in the art.

Therefore, the operating parameters shall be adjusted according to its knowledge.

Typically, the minitablets have a diameter of 2.0-3.0 mm, preferably 2.5-2.7 mm, and a height of 2.3-3.2 mm, preferably 2.5-3.0 mm.

Apparatus and conditions for drying the coated formulations are known in the art.

In view of the advantages linked to the administration in combination with deferiprone, a suitable unit dose of deferiprone, expressed as free form, ranges from 200 to 1000 mg, preferably from 250 to 500 mg.

However, the dose of deferiprone administered to a patient will depend on numerous factors such as sex, age, weight of patient, and the severity of symptoms. The claimed dosage forms are useful for the treatment of diseases which cause an overload of iron, or for the prevention and/or treatment of diseases which are caused by an overload of iron.

In some embodiments, the subject in need thereof suffers from iron overload, in particular severe iron overload, due to transfusional iron overload, or due to diseases such as thalassemia, myelodysplasia, or sickle cell disease.

In some embodiments, the subject in need thereof may suffer from a neurodegenerative disease (e.g. Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, Friedreich's Ataxia, Pantothenate Kinase Associated Neurodegeneration (PKAN), or neurodegeneration with brain iron accumulation (NBIA).

In some embodiments, the subject in need thereof suffers from iron overload that is transfusional iron overload.

In certain aspects, the subject suffers from transfusional iron overload and whose prior chelation therapy is inadequate. In certain aspects, the subject suffers from transfusional iron overload and has a cardiac MRI T2* of 20 ms or less (e.g. 10 ms).

Typically, the pharmaceutical dosage forms may be capsules or sachets.

The pharmaceutical dosage form shall be filled with the same type of formulations, i.e coated pellets for both active ingredients or coated minitablets for both active ingredients.

The invention is also directed to a process for filling the pharmaceutical dosage form with the disclosed formulations.

Apparatus and parameters for filling capsules or sachets are known in the art.

The following examples illustrate the invention without limiting its scope.

General Experimental details and methods

Characterization of the formulations

Units were characterized for weight (m), height (h) and diameter (d).

Weight gain was calculated according to the formula: 100 where m_COated and m_uncoated are the mean weight values of n = 100 units.

Thickness of both the coating layers was calculated according to the formula: thickness 1000 where h_COated and huncoated and dcoated and duncoated are the mean height and diameter values of n = 20 units.

Coating mass per unit area was calculated according to the formula:

Coating where uncoated 2 duncoated

Release test

Release tests were performed by an adapted three-position disintegration testing apparatus. This was selected to overcome the possible adhesion of the hydrated HPMC coating to the vessels of a paddle dissolution apparatus. Each unit was inserted into a basketrack assembly so that only one of the 6 available tubes was filled. During the test, every basket-rack assembly moved at a rate of 31 cycles/min in a separate vessel containing 800 ml of water t = 37±0.5 °C. Fluid samples were withdrawn automatically at predetermined time points and deferiprone or the tracer (acetaminophen) was quantified spectrophotometrically (Lambda 25, Perkin Elmer, Italy).

Example 1 - Deferasirox pellets formulation

It is prepared according to the method reported in WO 2014/136079.

A composition is reported in Table 3.

Table 3

A deferasirox formulation with the same composition in form of minitablets may be prepared according to methods reported in the art.

Example 2 - Preparation and characterization of the deferiprone coated minitablets according to the invention

Minitablet cores were double coated to provide a first inner HPMC layer of 250 pm thickness and an outer layer consisting of an insoluble polymer and generally containing Explotab® CLV (EXP) as film pore former. In an initial stage of this evaluation, Eudragit™ NE was selected as the coating polymer for the outer layer, then ethylcellulose (EC) was preferred.

However, the amount in which Eudragit™ NE could be applied was poorly drivable within the coating operations in use, thus a meaningful differentiation of the performances of the various coated units could not be achieved.

For the production of the minitablets containing Explotab® CLV in the outer layer, PVP concentration of the binder solution as well as the concentration of Methocel® E50 in the coating formulation were adjusted to improve the outcome of spraying.

The composition of the minitablets before drying is reported in Table 4, while the process parameters and their characterization are reported in Tables 5 and 6, respectively.

Table 4 - Composition of the minitablets of the invention after drying

Table 5 - Process parameters

Table 6 - Characterization of the minitablets of the invention

*mean ± sd n = 20

^#mean n = 100

The described minitablets show satisfactory technological characteristics and release performance meeting the expected pulsatile behaviour.

The outer film thickness brings a fundamental value to the mechanism of release control. Indeed, the delay performance is directly correlated to this parameter. As it can be appreciated from Figures 2, CO, C3 and C6 minitablets displayed in vitro lag phases potentially suitable for determining in vivo the pursued, distinct release pulses, while C9, Cl 1 and C17 minitablets would be expected to exhibit a delayed release matching the scope of their use in deferiprone oral therapy. From Figure 3, it may be appreciated how the lag time of the minitablets depend on the thickness of the outer layer.

Example 3 - Preparation of the deferiprone uncoated pellets according to the invention Small units in form of pellets with compositions reported in Table 8 were prepared by extrusion/spheronization.

Table 8 - Composition of the uncoated pellets.

Deferiprone and excipients were mixed in a planetary mixer and water was added to the powders. The mixture was pushed into the extruder with a screen size of 1000 pm. Experimental conditions of the extrusion and spheronization phases are reported in Tables 9 and 10, respectively. The wet units were dried in static oven at 40 °C overnight.

Table 9 - Extrusion experimental conditions.

Table 10 - Spheronization experimental conditions. It is expected that the pellets, when coated as reported in Example 2, would show the same release profile of the coated minitablets.

Claims

1. A pharmaceutical dosage form for once-a-day oral administration comprising: i) a pharmaceutical formulation for the delivery of deferasirox or a pharmaceutically acceptable salt thereof; and ii) a pharmaceutical formulation for pulsatile release able of delivering deferiprone or a pharmaceutically acceptable salt thereof after a programmed time period.

2. The pharmaceutical dosage form according to claim 1, wherein both pharmaceutical formulations are in form of coated small units, selected from coated pellets and coated mini tablets.

3. The pharmaceutical dosage form according to claim 2, wherein deferasirox is present in the coated pellet formulation in an amount between 45 % and 60 % by weight based on the total weight of the formulation.

4. The pharmaceutical dosage form according to claim 3 wherein the coated pellet formulation comprising deferasirox further comprises:

(i) at least one filler in a total amount comprised between 10% and 40 %;

(ii) at least one disintegrant in a total amount comprised between 1 % to 10 %;

(iii) at least one binder in a total amount comprised between 1 % and 5 %;

(iv) at least one surfactant in a total amount comprised between 0.0 % and 2 %;

(v) at least one glidant in a total amount comprised between 0.0 % to 1 %;

(vi) at least one lubricant in a total amount comprised between 0.0 % and 2 %; and

(vii) a coating, wherein all percentages are expressed by weight based on the total weight of the formulation.

5. The pharmaceutical dosage form according to claim 4, wherein the surfactant is selected from betain, quaternary ammonium salts, polysorbates, sorbitan esters, poloxamers and sodium lauryl sulfate, preferably selected between sodium lauryl sulfate and a poloxamer.

6. The pharmaceutical dosage form according to claim 5, wherein the poloxamer has an approximate molecular weight of 8400.

7. The pharmaceutical dosage form according to any one of claims 3 to 6, wherein the coating agent is a synthetic copolymer derived from esters of acrylic and methacrylic acid.

8. The pharmaceutical dosage form according to any one of claims 3 to 7 wherein deferasirox is present in its free acid form.

9. The pharmaceutical dosage form according to claim 8 wherein the unit dose of deferasirox ranges from 80 to 300 mg.

10. The pharmaceutical dosage form according to claim 1 or 2, wherein the deferiprone formulation is constituted by coated small units, wherein each unit in turn comprises deferiprone or a pharmaceutically acceptable salt as active ingredient in an amount comprised between 75 % and 90 % by weight based on the total weight of the uncoated unit.

11. The pharmaceutical dosage form according to claim 10, wherein the deferiprone formulation further comprises a filler, a lubricant and/or a glidant and it is coated with an inner layer, whereby one part of the coated small units releases a fraction of the active ingredient in a time comprised between 10 minutes and 8 hours, while the remaining part of the coated small units releases the remaining part of the active ingredient in a time comprised between 6 hours and 24 hours.

12. The pharmaceutical dosage form according to claim 10 or 11, wherein each coated small unit of the deferiprone formulation comprises a filler in an amount comprised between 10 % and 24 %, and a lubricant and/or glidant in an amount of 0.5 to 1.0 %, all the amounts calculated by weight on the total weight of the uncoated unit; wherein the inner layer comprises a swellable hydrophilic polymer and a plasticizer, and wherein each coated small unit optionally comprises an outer layer, which, when present, comprises a film-forming insoluble polymer and an agent with channeling properties.

13. The pharmaceutical dosage form according to claim 11 or 12, wherein the filler is a mixture of a diluent and a superdisintegrant agent in any suitable ratio.

14. The pharmaceutical dosage form according to claim 13, wherein the ratio between the diluent and the superdisintegrant agent is comprised between 85: 15 and 75:25 w/w.

15. The pharmaceutical dosage form according to claim 14, wherein the ratio is 80:20 w/w.

16. The pharmaceutical dosage form according to any one of claims 13 to 15, wherein the diluent is selected from the group consisting of calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrans, dextrins, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose and alpha-lactose monohydrate.

17. The pharmaceutical dosage form according to claim 16, wherein the diluent is microcrystalline cellulose.

18. The pharmaceutical dosage form according to any one of claims 13 to 17, wherein the superdisintegrant agent is selected from the group consisting of croscarmellose sodium, crospovidone and sodium starch glycolate.

19. The pharmaceutical dosage form according to claim 18, wherein the superdisintegrant agent is a mixture of crospovidone and sodium starch glycolate in a ratio comprised between 50:50 and 30:70 w/w.

20. The pharmaceutical dosage form according to claim 19, wherein the ratio is 35:65 by weight.

21. The pharmaceutical dosage form according to any one of claims 11 to 20, wherein the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate and any combination thereof.

22. The pharmaceutical dosage form according to any one of claims 11 to 21 , wherein the glidant is selected from the group consisting of colloidal silicon dioxide, starch and talc, preferably colloidal silicon dioxide, or any combination thereof.

23. The pharmaceutical dosage form according to any one of claims 10 to 22, wherein the small unit comprises a mixture of colloidal silicon dioxide and magnesium stearate in a ratio of 10:90 to 20:80 w/w.

24. The pharmaceutical dosage form according to claim 23, wherein the ratio is 15:85 by weight.

25. The pharmaceutical dosage form according to any one of claims 11 to 24, wherein the inner layer of the coating comprises a swellable hydrophilic polymer, such as hydroxyethyl cellulose or hydropropylmethyl cellulose.

26. The pharmaceutical dosage form according to claim 25, wherein the inner layer comprises a hydroxypropylmethyl cellulose and a plasticizer, and optionally a glidant.

27. The pharmaceutical dosage form according to claim 26, wherein the plasticizer is selected from the group consisting of diethyl phthalate, citrate esters, such as triethyl citrate, polyethylene glycol, glycerol, acetylated glycerides, acetylated citrate esters, dibutyl sebacate, castor oil and any combination thereof.

28. The pharmaceutical dosage form according to claim 27, wherein the plasticizer is polyethylene glycol 400 (PEG 400).

29. The pharmaceutical dosage form according to any one of claims 26 to 28, wherein the ratio between hydroxypropyl methylcellulose and PEG 400 is comprised between 95:5 and 80:20 w/w.

30. The pharmaceutical dosage form according to claim 29, wherein the ratio is 90: 10 by weight.

31. The pharmaceutical dosage form according to any one of claims 12 to 30, wherein the outer layer of the coating comprises a film-forming insoluble polymer and a superdisintegrant agent.

32. The pharmaceutical dosage form according to claim 31, wherein the superdisintegrant agent is sodium starch glycolate and the film-forming insoluble polymer is ethylcellulose.

33. The pharmaceutical dosage form according to claim 31 or 32, wherein the ratio between the superdisintegrant agent and the film-forming insoluble polymer is comprised between 95:5 and 80:20 w/w.

34. The pharmaceutical dosage form according to claim 33, wherein the ratio is 90: 10 by weight.

35. The pharmaceutical dosage form according to any one of claims 10 to 34, wherein the unit dose of deferiprone ranges from 200 to 1000 mg.

36. The pharmaceutical dosage form according to any one of the preceding claims in form of capsules or sachets.

37. The pharmaceutical dosage form according to any one of the preceding claims for use in the treatment of diseases which cause an overload of iron, or for the prevention and/or treatment of diseases which are caused by an overload of iron.

38. The pharmaceutical dosage form for use according to claim 37, wherein the disease is thalassemia or sickle cell anemia.

39. The pharmaceutical dosage form for use according to claim 37, wherein said iron overload is transfusional iron overload.

40. The pharmaceutical dosage form for use according to claim 39, wherein the disease is severe iron overload.