WO2025242589A1 - Formes posologiques pharmaceutiques pour thérapie combinée de défériprone et de déférasirox - Google Patents

Formes posologiques pharmaceutiques pour thérapie combinée de défériprone et de déférasirox

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Publication number
WO2025242589A1
WO2025242589A1 PCT/EP2025/063656 EP2025063656W WO2025242589A1 WO 2025242589 A1 WO2025242589 A1 WO 2025242589A1 EP 2025063656 W EP2025063656 W EP 2025063656W WO 2025242589 A1 WO2025242589 A1 WO 2025242589A1
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WIPO (PCT)
Prior art keywords
dosage form
pharmaceutical dosage
form according
coated
comprised
Prior art date
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Pending
Application number
PCT/EP2025/063656
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English (en)
Inventor
Marisa PERTILE
Roberta LUZZI
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Chiesi Farmaceutici SpA
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Chiesi Farmaceutici SpA
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Publication of WO2025242589A1 publication Critical patent/WO2025242589A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the invention relates to a pharmaceutical dosage form for once-a-day oral administration of deferiprone and deferasirox.
  • Deferiprone and deferasirox are well-known iron chelator drugs indicated for the treatment of diseases characterized by iron accumulation.
  • Deferasirox is marketed as ExjadeTM and is formulated in different pharmaceutical forms for the oral administration once daily.
  • GI gastrointestinal
  • 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.
  • 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.
  • 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 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.
  • both formulations are in form of coated pellets or coated minitablets.
  • the pharmaceutical dosage form is a capsule or a sachet.
  • the invention is directed to a process for filling the pharmaceutical dosage form with the pellets or the minitablets according to the invention.
  • 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.
  • the disease is a severe form of iron overload.
  • 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.
  • 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.
  • 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.
  • 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.
  • a tablet refers to one or more tablets.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • hydrophobic denotes a compound tending to be electrically neutral and non-polar, and thus preferring other neutral and nonpolar solvents or molecular environments.
  • 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.
  • 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.
  • 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.
  • 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.
  • controlled release 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 refers to an excipient that is insoluble in water but swells when wetted to cause a tablet to disintegrate.
  • Dissolution 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.
  • plasticizer means an additive that increase the elasticity of coatings based on film-forming material.
  • filler means a pharmacologically-inert pharmaceutically acceptable excipient used to make a drug product easier to handle.
  • a drug product having the same clinical effect and safety profile of a reference product when administered to patients.
  • 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.
  • 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.
  • first phase half the subjects are randomly assigned to ingest the test product first and the other half ingest the reference product first.
  • each subject ingests the alternate product.
  • 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.
  • drugs are bioequivalent if they enter circulation at the same rate when given in similar doses under similar conditions.
  • 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 m a X
  • W75 denotes the time where the plasma concentration is 75% or more of C m a X
  • 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 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.
  • 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.
  • 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.
  • subject or “individual” or “patient” any human subject is meant for whom diagnosis, prognosis, treatment or therapy is desired.
  • terapéuticaally 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • both drugs it may be possible to achieve a significant reduction of the doses of one or both active ingredients, up to about 30%.
  • 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.
  • 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:
  • 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.
  • 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 K30TM.
  • 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).
  • the surfactant is selected from sodium lauryl sulfate and a poloxamer.
  • a poloxamer is a polyoxyethylene-polyoxypropylene block copolymer.
  • the surfactant is a poloxamer, preferably PluronicTM F68 grade.
  • Pluronic F68TM grade is also indicated as PEO76PPO29PEO76, wherein PEO stands for (poly (ethylene oxide) and PPO is polypropylene oxide).
  • Pluronic F68TM 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.
  • glyceryl palmito-stearic ester e.g. PrecirolTM, Gattefosse France
  • polyoxyethylene glycol PEG, BASF
  • hydrogenated cotton seed oil LubitrabTM, Edward Mendell Co Inc
  • castor seed oil CutinaTM HR, Henkel
  • magnesium stearate is used.
  • the formulation in both forms is provided with a full enteric coating.
  • the enteric coating comprises EudragitTM which is a synthetic copolymer derived from esters of acrylic and methacrylic acid (Acryl-EZETM). EudragitTM was applied to a deferasirox tablet core at level of 5-15% by weight gain. An addition of sub-coating, such as OpadryTM 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.
  • the formulation has the composition reported in the following Table 1.
  • step (ii) wet-granulating the mixture obtained in step (i) in a high shear granulator
  • step (iii) extruding and spheronizing the wet granulates obtained in step (ii);
  • step (iv) drying the extruded and spheronized pellets obtained in step (iii);
  • 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:
  • step (ii) compressing the mixture obtained in step (i) to form the minitablets
  • step i) optionally, the mixture of step i) is wet granulated in order to obtain granules suitable to be tableted.
  • a suitable unit dose of deferasirox ranges from 80 to 300 mg, preferably from 100 to 200 mg, being in particular a 90, 100, 180 and 200 mg unit dosage.
  • 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.
  • Desired pulsatile profiles were simulated in silico (see Figure 1).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the in vivo lag time is equal to or less than one hour, preferably between 2 and 50 minutes, more preferably 30-45 minutes.
  • 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.
  • 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.
  • the small units coated with the inner layer are further coated with the outer layer.
  • 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.
  • the delay is mainly correlated to the thickness of the outer layer.
  • 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
  • C9, Cl l and C17 small units provide the delayed release involved/necessary to in the second (or third) peak of the simulated profile
  • C6 small units have a release profile that could match either the first part or the delayed part of the simulated in vivo profile.
  • 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.
  • 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.
  • 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.
  • the filler is a mixture of a diluent and a superdisintegrant agent in any suitable ratio.
  • 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.
  • 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.
  • 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.
  • CMC carboxymethylcellulose
  • crospovidone also known as cross-linked PVP
  • sodium starch glycolate sodium starch glycolate
  • sodium starch glycolate is sold as Explotab® CLV by JSR Pharma (Rosemberg, Germany).
  • 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.
  • 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.
  • the small units 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.
  • 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.
  • the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate and any combination thereof.
  • 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.
  • 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.
  • the small unit is suitably coated with swell able/erodible coating layers.
  • swellable hydrophilic polymer such as a hydrophilic derivative of cellulose, for example hydroxyethyl cellulose or hydropropylmethyl cellulose.
  • 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.
  • HPMC hydroxypropylmethyl cellulose polymer
  • Methocel® for example from DuPont (Delaware, USA).
  • 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.
  • 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).
  • 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.
  • citrate esters such as triethyl citrate (TEC)
  • TEC triethyl citrate
  • polyethylene glycol glycerol
  • acetylated glycerides acetylated citrate esters
  • dibutyl sebacate castor oil
  • castor oil or any combination thereof, preferably polyethylene glycol.
  • PEG Polyethylene glycol
  • 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.
  • the inner layer is constituted of HPMC, PEG 400 and talc in a ratio of 89: 10: 1.0 by weight.
  • 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.
  • 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 EudragitTM RS and EudragitTM RL, and cellulose derivatives, such as ethylcellulose.
  • the superdisintegrant is sodium starch glycolate and the film-forming insoluble polymer is ethylcellulose.
  • 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.
  • sodium starch glycolate is marketed as Explotab® CLV by JSR Pharma GmbH (Rosemberg, Germany).
  • Ethylcellulose is marketed as aqueous dispersion with the name of Surelease® by Colorcon Inc (PA, USA).
  • the pharmaceutical dosage form may contain coated small units in form of minitablets having the composition reported in Table 2.
  • thickness of the layers is of paramount importance to determine the release profile.
  • said thickness was determined according to different methods, i.e. weight gain after coating (%), coating layer thickness (pm), coating amount per unit area (mg/cm 2 ), while the latter one being considered the most reliable and convenient one as it would be independently of the weight of the nuclei.
  • 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/cm 2 .
  • 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/cm 2 .
  • the coating outer layer may be present or not, and when present thickness may be comprised between about 15 and 50 micron.
  • 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%.
  • said thickness values When expressed as coating amount per unit area, said thickness values may be comprised between about 2 and 6 mg/cm 2 . Suitable values may be 2.2-2.3 mg/cm 2 , 3.4-3.6 mg/cm 2 , and 5.3-5.4 mg/cm 2 .
  • 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%.
  • said thickness values When expressed as coating amount per unit area, said thickness values will be comprised between 4.5 and 10 mg/cm 2 , preferably between 5 and 6 mg/cm 2 .
  • 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).
  • 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:
  • step (ii) compressing the mixture obtained in step (i) to form the minitablets
  • step 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
  • the mixture of step i) is wet granulated in order to obtain granules suitable to be tableted.
  • the invention when the small coated units are in form of pellets, 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.
  • 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.
  • a suitable unit dose of deferiprone ranges from 200 to 1000 mg, preferably from 250 to 500 mg.
  • 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.
  • 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.
  • 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).
  • 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).
  • 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).
  • the subject in need thereof suffers from iron overload that is transfusional iron overload.
  • 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).
  • 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.
  • Coating mass per unit area was calculated according to the formula:
  • a deferasirox formulation with the same composition in form of minitablets may be prepared according to methods reported in the art.
  • 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.
  • EXP Explotab® CLV
  • EudragitTM NE was selected as the coating polymer for the outer layer, then ethylcellulose (EC) was preferred.
  • 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.
  • 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.

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Abstract

L'invention concerne une forme posologique pharmaceutique remplie de formulations pour une administration par voie orale une fois par jour de défériprone et de déférasirox. Les deux formulations se présentent sous la forme de pastilles enrobées ou de minicomprimés enrobés. L'invention concerne la forme posologique pharmaceutique revendiquée destinée à être utilisée dans le traitement de maladies qui provoquent une surcharge de fer.
PCT/EP2025/063656 2024-05-21 2025-05-19 Formes posologiques pharmaceutiques pour thérapie combinée de défériprone et de déférasirox Pending WO2025242589A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014072673A1 (fr) 2012-11-12 2014-05-15 Cipla Limited Composition pharmaceutique à dose fixe à base de déférasirox et de déféripone
WO2014136079A1 (fr) 2013-03-08 2014-09-12 Novartis Ag Formulations orales de déférasirox

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014072673A1 (fr) 2012-11-12 2014-05-15 Cipla Limited Composition pharmaceutique à dose fixe à base de déférasirox et de déféripone
WO2014136079A1 (fr) 2013-03-08 2014-09-12 Novartis Ag Formulations orales de déférasirox

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
"European Pharmacopoeia", 2003, pages: 2891
ANONYMOUS: "Ferriprox : EPAR - Product Information", 13 December 2022 (2022-12-13), XP093297706, Retrieved from the Internet <URL:https://www.ema.europa.eu/en/documents/product-information/ferriprox-epar-product-information_en.pdf> [retrieved on 20250721] *
DIVAKARJOSE RR ET AL., INDIAN J PEDIATR, vol. 88, 2021, pages 330 - 335
ELALFY MS ET AL., EUR J HAEMATOL, vol. 95, 2015, pages 411 - 420
GOMBER S ET AL., INDIAN PEDIATR, vol. 53, 2016, pages 207 - 210
HAMMOND J ET AL., J PEDIATR HEMATOL ONCOL, vol. 41, 2019, pages 47 - 50
KARAMI H ET AL., CLIN PRACT, vol. 7, no. 1, 12 January 2017 (2017-01-12), pages 912
KARAMI H ET AL., CLIN PRACT., vol. 7, no. 1, 12 January 2017 (2017-01-12), pages 912
TOTADRI S ET AL., PEDIATR BLOOD CANCER, vol. 62, no. 9, September 2015 (2015-09-01), pages 1592 - 6

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