Modified release pharmaceutical formulations containing deferiprone

Abstract

The present invention relates to a pharmaceutical composition for oral administration in the form of a coated tablet that exhibits delayed release properties when administered as a whole or half tablet. In particular, the present invention relates to a delayed release tablet containing deferiprone, which is suitable for oral administration twice daily. The present invention also relates to a method for producing and using said tablet.

Description

[Technical field]

[0001] The present invention relates to pharmaceutical formulations containing the chelating agent deferiprone.

[0002] In particular, the present invention relates to modified release formulations suitable for twice daily oral administration for the treatment of iron overload occurring, for example, in patients with thalassemia, sickle cell disease, iron overload and myelodysplasia. [Background technology]

[0003] Deferiprone, also known as 3-hydroxy-1,2-dimethylpyridin-4-one, is a bidentate ligand that binds iron in a 3:1 molar ratio.

[0004] It is used to treat systemic iron overload, particularly conditions where frequent blood transfusions lead to iron overload, including thalassemia and sickle cell disease (SCD).

[0005] The introduction of deferiprone in modern therapy represents an important advance in the treatment of liver iron concentration (LIC) and cardiac iron overload.

[0006] In particular, Maggio A et al. Blood Cells Mol Dis. 2002, 28(2):196-198) and Galanello R et al. Haematologica. 2006, 91(9):1241-1243 suggested that deferiprone monotherapy appears to be superior to deferoxamine monotherapy in improving myocardial iron deposition and cardiac function.

[0007] Regarding safety, the most frequent adverse event was gastrointestinal discomfort due to gastrointestinal irritation. Such discomfort may lead patients to refrain from taking the drug, leading to a worsening of symptoms. Other adverse events observed were musculoskeletal disorders (arthralgia), elevated alanine aminotransferase (ALT), agranulocytosis and neutropenia.

[0008] Agranulocytosis appears to be an idiosyncratic reaction, occurring more frequently during the first year of treatment. The incidence of neutropenia and agranulocytosis is stable and appears to be unrelated to dose (Hider RC et al N Engl J Med. 2018;379:2140-2150).

[0009] Deferiprone has a long half-life of 2-3 hours but has an unpleasant bitter taste.

[0010] The drug is commonly sold under the trade name Ferriprox® in immediate release (IR) 500 mg and 1000 mg tablets, and a 100 mg / ml liquid formulation.

[0011] Given its pharmacological and ADME profile, deferiprone has also recently been marketed as a 1000 mg delayed release (DR) tablet for oral administration to improve patient compliance.

[0012] The tablets are suitable for twice-daily administration and are bioequivalent at steady state to the same daily dose in immediate release form administered three times daily.

[0013] Commercially available tablets are also stamped with a score line to make it easier for patients to split the tablet into two roughly equal halves for dosing flexibility.

[0014] The composition of the DR tablet is described in WO 2019 / 082128 and includes (a) a core comprising an active pharmaceutical ingredient and an enteric polymer having a pH-dependent solubility, and (b) an enteric coating.

[0015] Indeed, due to the potential irritation and damage to the gastric mucosa and its relatively high solubility in an acidic environment, oral pharmaceutical dosage forms containing deferiprone must be provided with an enteric coating (e.g. a polymer film with solubility at pH>5) to avoid or at least reduce the release of the active ingredient during its stay in the stomach and to avoid reaching plasma concentrations that would cause systemic adverse reactions.

[0016] In the case of commercial deferiprone products, hydroxypropyl methylcellulose acetate succinate (HPMC-AS) is used as an enteric polymer in the tablet core to provide sustained release.

[0017] However, HPMC-AS has a pH-dependent solubility.

[0018] This can result in a release that is influenced by the external environment that the unit must encounter while moving along the area in which the release of the active ingredient occurs, this area being characterized by physiological fluids with different pH and therefore difficult to predict due to the effects of random microenvironmental fluctuations in pH.

[0019] It would therefore be advantageous to provide a tablet suitable for twice-daily oral administration that has improved properties in terms of reproducibility of the predicted release profile.

[0020] Some prior art documents disclose deferiprone formulations that contain, among others, hydroxypropylmethylcellulose polymer as excipient (Aguilar-De-Levya A et al Pharm Dev Tech 2014, 19,728-734; Kaul D et al J Drug Dev Ind Pharm 1992, 18, 1023-1035; US Patent Application No. 2006 / 122273; China Patent Application No. 106983746).However, they do not describe the task of improving the reproducibility of release profile.

[0021] The present invention provides a technical solution. Summary of the Invention

[0022] The present invention provides a pharmaceutical formulation in the form of a modified release enteric coated tablet suitable for oral administration twice daily, said tablet core comprising, calculated by weight relative to the total weight of the formulation, a) deferiprone in an amount of 85.0-95.0%, b) as modified release agent, a hydroxypropyl methylcellulose polymer having a viscosity of 100 cP, alone or in combination with a hydroxypropyl methylcellulose polymer having a viscosity of 4000 cP, in an amount of 4.0-10.0%, c) a lubricant and / or glidant in an amount of 0.2-2.0%, and d) 0-5% of other suitable pharmacologic acceptable excipients.

[0023] Other suitable pharma- ceutically acceptable excipients may belong to the classes of pH adjusters and bulking agents.

[0024] Therefore, in a second aspect, the present invention provides a method for the preparation of the coated deferiprone tablets as described above, comprising the steps of: (i) mixing deferiprone with a modified release agent, and, if present, other pharma- ceutically acceptable excipients, to form a mixture; (ii) wet granulating the mixture obtained in step (i) in a high shear granulator, drying and sieving to produce granules; (iii) blending the granules obtained in step (ii) with a lubricant and / or glidant, excipient to form a blend; (iv) compressing the mixture obtained in step (ii) to form a tablet; and (v) Coating tablets The present invention provides a method comprising:

[0025] In another embodiment, the method comprises the steps of: (i) mixing deferiprone with a modified release agent, and, if present, other pharma- ceutically acceptable excipients, to form a mixture; (ii) adding lubricants and / or glidants, excipients and further mixing; (iii) directly compressing the mixture obtained in step (ii) to form a tablet; and (iv) Coating tablets The present invention provides a method comprising:

[0026] In a third aspect, the present invention relates to a pharmaceutical composition as claimed for use in the treatment of a disease causing iron overload or for the prevention and / or treatment of a disease caused by iron overload.

[0027] In a fourth aspect, the present invention relates to a pharmaceutical composition as claimed in the manufacture of a medicament for the prevention and / or treatment of a disease causing or caused by iron overload.

[0028] In a fifth aspect, the present invention refers to a method for treating a disease causing iron overload or for preventing and / or treating a disease caused by iron overload in a subject in need of such treatment, comprising administering a pharmaceutical composition as claimed. [Brief description of the drawings]

[0029] [Figure 1] Dissolution tests of HPMC formulations carried out in a vessel (apparatus 1) with 900 ml of pH 6.8 medium and agitation speed of 100 rpm. The line with triangle symbols represents the commercial product. [Diagram 2] Dissolution test of HPMC formulations carried out in 900 ml of pH 4.5 medium, impeller (apparatus 2) with stirring speed of 50 rpm. The line with triangle symbols represents the commercial product. [Diagram 3] Dissolution test of HPMC formulations carried out in 900 ml of pH 1.2 medium (120 min), followed by pH 6.8 medium, vessel (apparatus 1) with stirring speed of 100 rpm. The line with triangle symbols indicates the commercial product. [Figure 4] Dissolution test of HPMC formulations carried out in 900 ml of pH 1.2 medium (120 min), followed by pH 6.8 medium, vessel (apparatus 1) with stirring speed of 100 rpm. The line with triangle symbols indicates the commercial product. [Diagram 5]Dissolution test of HPMC formulations carried out in 900 ml of pH 1.2 medium (120 min), followed by pH 6.8 medium, vessel (apparatus 1) with stirring speed of 100 rpm. The line with triangle symbols indicates the commercial product. [Figure 6] Dissolution testing of semi-coated tablets in 900 ml of medium pH 1.2 (120 min), then medium pH 6.8, vessel (apparatus 1) with stirring speed of 100 rpm. The line with triangle symbols indicates the commercial product.

[0030] definition As used herein, the indefinite article "a" or "an" should be understood to refer to "one or more" of any cited or listed component. For example, "a tablet" refers to one or more tablets.

[0031] Also, as used herein, "and / or" refers to and includes any and all possible combinations of one or more of the associated listed items, or when interpreted in the alternative ("or"), no combination is present.

[0032] When the term "about" is used in conjunction with a numerical value or a range, it modifies that numerical value or range by extending the boundaries above and below the numerical values ​​set forth. Unless a different variability is indicated (e.g., ±30%, ±20%, ±5%, ±1%, etc.), the term "about" is used to modify a numerical value by 10 percent above or below (higher or lower) the set forth value, i.e., a variability of ±10%.

[0033] Whenever an embodiment is described herein using the word "comprising," analogous embodiments described with the terms "consisting of" and / or "consisting essentially of" are also provided. To the extent that the terms "include" or "including" are used in the specification or claims, the terms are intended to be inclusive in the same manner as the term "comprising" is interpreted when used as a transitional term in the claims.

[0034] As used herein, the terms "active ingredient" or "active pharmaceutical ingredient" (API) or "drug" are used synonymously and mean any component that is intended to provide 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 human or other animal body.

[0035] The terms "iron overload" or "iron overload" are used interchangeably herein and refer to the body containing too much (or "excess") iron, including transfusional iron overload, in which excess iron is introduced through one or more blood transfusions.

[0036] As used herein, the term "hydrophilic" means that something is "water-loving", i.e., a hydrophilic molecule or portion of a molecule is typically electrically polarizable and can form hydrogen bonds with water molecules, allowing it to dissolve more readily in water than in oil or other "non-polar" solvents.

[0037] In contrast, the term "hydrophobic" refers to a compound that tends to be electrically neutral and non-polar, and therefore prefers other neutral and non-polar solvents or molecular environments.

[0038] By "pH-dependent solubility," it is meant that a substance has different solubilities at different pHs. These pH-dependent solubility differences result in a pH-dependent dissolution profile.

[0039] The expression "insoluble or poorly soluble in water" is defined in the European Pharmacopoeia Ed. th , 2003, page 2891.

[0040] As used herein, a "core" or "tablet core" comprises an active ingredient, e.g., deferiprone, and one or more excipients compressed into an uncoated tablet. The core may be coated with a variety of coatings, including enteric coatings.

[0041] In this specification, the terms "controlled release", "sustained release", "modified release" and "delayed release" are intended to be equivalent terms that include any type of deferiprone release from the composition of the present invention that is suitable for obtaining a specific therapeutic or prophylactic response after administration to a subject. The terms refer to protecting the active ingredient, e.g., deferiprone, from rapid release at acidic pH, e.g., in the stomach, while allowing the active ingredient to be released at high pH, ​​e.g., in the digestive tract. In some embodiments, DR is understood to mean that when tested in USP apparatus 2 at 75 rpm, the dissolution degree is about 20±5% in 1 hour in 0.1N HC1, and the dissolution rate is substantially higher (e.g., more than 30%, e.g., more than 40% in 1 hour) in phosphate buffer at pH 6.8 than in 0.1N HC1.

[0042] "Disintegrant" refers to an excipient that is insoluble in water but swells when wet, causing the tablet to disintegrate.

[0043] As used herein, "dissolution" refers to the process by which a solute forms a solution in a solvent.

[0044] As used herein, "enteric coat" or "enteric coating" refers to a coating that includes an enteric polymer. An enteric coating can serve to prevent or delay dissolution or disintegration of a tablet in the gastric environment.

[0045] By "burst effect" it is meant an initial rapid release before the release rate reaches a stable profile, which occurs immediately following a change in pH in the release medium.

[0046] "Enteric coated tablet" means a tablet having a core containing the active ingredient surrounded by an enteric coating.

[0047] As used herein, "enteric polymer" is understood to mean a polymer that is relatively poorly soluble at the acidic pH of the fasting stomach (e.g., from about pH 1 to about pH 4), but is soluble at a higher pH (e.g., from about pH 1 to about pH 4) corresponding to the pH of the small intestine or beyond, in particular the duodenum or ileum.

[0048] The terms "filler," "diluent," and "bulking agent" are used synonymously.

[0049] The term "bioequivalence" means the absence of significant differences in bioavailability, i.e., degree of absorption and peak concentrations, between two medicinal products (e.g., test and reference products) at the same doses and under the same conditions over a period of time.

[0050] The determination of whether a test product is bioequivalent to a reference product is determined by conducting studies called bioequivalence or bioavailability studies under controlled conditions in a group of subjects, usually about 18-36 or more.

[0051] The study may be conducted in a "crossover" design, meaning that the study is conducted in two or more phases, usually at least one week apart, depending in part on the half-life of the drug. In the first phase, half of the subjects are randomly assigned to receive the test product first, and the other half of the subjects to receive the reference product first. In the second phase, each subject receives the other product.

[0052] At each stage, blood samples are taken from each subject on a predetermined schedule after ingestion of the test product. The blood samples are then analyzed to determine the serum concentration of the drug (test product, e.g., deferiprone) at each time point. For example, drugs are bioequivalent if they enter the circulation at the same rate when administered at similar doses and under similar conditions. A parameter commonly used in bioequivalence studies is the t max , C max , C min , AUC 0-∞ , AUC 0-t It is.

[0053] In the context of this specification, "t max " is the maximum plasma concentration (C max ) is the time it takes to reach the target; AUC 0-∞ is the area under the plasma concentration versus time curve from 0 to ∞; AUC 0-t indicates the area under the plasma concentration versus time curve from time 0 to t; W50 indicates the area under the plasma concentration versus time curve from time 0 to t; max W75 is the time when the plasma concentration is greater than or equal to C max indicates the time when the concentration was greater than 75% of the time; MRT indicates the residence time for tacrolimus.

[0054] As used herein, "fasted state" refers to not having eaten for a period of time following a meal (typically at least several hours, e.g., 4 or 6 hours, after eating).

[0055] As used herein, "satisfied state" refers to administration with a meal or shortly after (eg, within about an hour) a meal.

[0056] The term "chemically stable" refers to the stability of the active agent in a formulation in which the change in drug assay value and / or impurity content is less than 5%, preferably less than 3%, during a storage period of at least one month at 25° C. and 60% relative humidity (RH), or at 40° C. and 75% RH.

[0057] The term "vitro-in vivo correlation (IVIVC)" refers to an in vitro dissolution test that predicts the in vivo disposition of an in vivo drug product.

[0058] As used herein, "gastric discomfort" refers to discomfort in the gastrointestinal (GI) tract, such as one or more of the following: pain, cramping, bloating, nausea, indigestion, heartburn, and gas.

[0059] As used herein, "half tablet" refers to one of two portions of a tablet obtained by splitting a tablet into two portions of equal or approximately equal weight. In some embodiments, a half tablet is about 40% to about 60% of the weight of the entire tablet from which it is derived. In some embodiments, the approximately equal weight of each half tablet is about 45% to about 55% of the weight of the entire tablet.

[0060] As used herein, "percent" or "%" refers to percent by weight (w / w) unless otherwise specified.

[0061] As used herein, a "scored tablet" refers to a tablet that has one or more lines, also called "scores," impressed into it to facilitate tablet division, e.g., to allow administration of half tablets. In some embodiments, the tablet may have two, three, four, or more score lines.

[0062] As used herein, "tablet" refers to a solid oral pharmaceutical dosage form. In some embodiments, the tablet is a compressed tablet.

[0063] "Whole tablet" means a complete tablet, i.e., not broken or divided into portions.

[0064] In the present context, viscosity is expressed in centipoise (1 cP = 0.01 P), which is more commonly used than poise itself. The analogous unit in the International System of Units is the Pascal second (Pa s). 1 cP corresponds to 1 mPa s.

[0065] Terms such as "treat" or "treatment" or "to treat" or "ameliorate" or "alleviate" or "to alleviate" can refer to both 1) therapeutic measures that cure, delay, reduce, reverse and / or halt the progression of a diagnosed pathological condition or disorder, and 2) prophylactic or preventative measures that prevent, reduce the incidence, reduce the risk, and / or delay the onset of the targeted pathological condition or disorder. Thus, patients in need of treatment include those already with the disorder, those susceptible to developing the disorder, and those in need of preventing the disorder. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, reduction in the extent of the disease, stabilization of the extent of the disease (i.e., not worsening), delay or slowing of the progression of the disease, improvement or alleviation of the disease state, and remission (partial or complete), whether detectable or undetectable. "Treatment" can also mean extending survival compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to developing the condition or disorder or those in whom the onset of the condition or disorder is to be prevented or reduced.

[0066] By "subject," "individual," or "patient" is meant any human subject in need of diagnosis, prognosis, treatment, or therapy.

[0067] By "therapeutically effective dose or amount" or "effective amount" is intended an amount of an active pharmaceutical ingredient, e.g., deferiprone, that when administered results in a positive therapeutic response towards treating or reducing the risk of a disease in the subject being treated.

[0068] Deferiprone DR tablets, used herein as the "reference" or "reference product," are Ferriprox® tablets (1000 mg) approved by the FDA and marketed in the United States.

[0069] Detailed Description of the Invention The present invention relates to pharmaceutical formulations for the prevention and / or treatment of diseases caused by excess iron, in particular compositions providing modified release of the active ingredient.

[0070] The active ingredient in the formulation of the present invention is deferiprone.However, any physical form of deferiprone (crystal, amorphous powder, any possible polymorph, any possible solvate) is included within the scope of the present invention.Its pharmaceutically acceptable salts and / or solvates are also included.Preferably, deferiprone is used as a base in anhydrous form.

[0071] According to a first embodiment, the present invention relates to a pharmaceutical formulation in the form of a modified release enteric coated tablet suitable for twice daily oral administration, the tablet core comprising, calculated by weight relative to the total weight of the formulation, a) deferiprone in an amount of 85.0-95.0%, b) as modified release agent a hydroxypropyl methylcellulose polymer having a viscosity of 100 cP, alone or in a mixture with a hydroxypropyl methylcellulose polymer having a viscosity of 4000 cP, in an amount of 4.0-10.0%, c) a lubricant and / or glidant in an amount of 0.2-2.0%, and d) other suitable pharma- ceutical acceptable excipients in an amount of 0-5%.

[0072] It was found that, within statistical significance, the use of hydrophilic polymers as modified release agents resulted in in vitro release similar to that of commercial Deferiprone DR.

[0073] In particular, the tablet core of the pharmaceutical dosage form of the present invention has the advantage of having a composition based on excipients that have non-pH dependent solubility and therefore do not directly impede the release of deferiprone at the various pH values ​​of the gastrointestinal tract.

[0074] This demonstrates a compelling improvement in terms of the reproducibility of the expected release profile.

[0075] Further surprising advantages associated with the use of these polymers will become apparent from the following description.

[0076] Advantageously, the low substituted thickener hydroxypropyl methylcellulose polymer (HPMC) Methocel® K100LV provides a viscosity of about 100 cP at 2% in water at 20° C.

[0077] The polymers may be used in combination with hydroxypropyl methylcellulose polymer (HPMC) Methocel® K4M, a medium molecular weight HPMC thickener, which gives a viscosity of about 4,000 cP at 2% in water at 20° C.

[0078] They are both commercially available from DuPont (Delaware, USA) or Colorcon Inc (California, USA).

[0079] Advantageously, the modified release agent is present in an amount of from 4.0 to 10.0%, preferably from 7 to 8% by weight.

[0080] In a preferred embodiment, Methocel® K100LV may be used alone in an amount of 7.5%, and in another preferred embodiment, a mixture of 5 wt% Methocel® K100LV and Methocel® K4M may be used, preferably with the two polymers in amounts of 2% and 3.0 wt%, respectively (40:60 w / w ratio).

[0081] Deferiprone causes gastric irritation when released on an empty stomach and may degrade somewhat by acid hydrolysis.

[0082] Thus, the tablets of the present invention are provided with an enteric coating that serves both to delay dissolution of deferiprone and to avoid dissolution in the stomach, especially in fasting patients, and a diluent such as water, ethanol, propylene glycol or mixtures thereof.

[0083] Due to the coating, tablets according to the invention are formulated to have negligible dissolution in the empty stomach but more rapid dissolution in the intestine.

[0084] Suitable enteric polymers for enteric coating include, for example, hydroxypropylmethylcellulose acetate succinate (also referred to as hypromellose acetate succinate or HPMCAS), HPMC phthalate (also referred to as hypromellose phthalate), polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, shellac, zein, methacrylic acid copolymers (e.g., Type C methacrylic acid copolymer dispersion 30%), derivatives thereof, and any combination thereof.

[0085] In some embodiments, the preferred enteric polymer in the enteric coating is HPMC acetate succinate and a methacrylic acid copolymer, for example, Type C methacrylic acid copolymer in an aqueous dispersion.

[0086] In some embodiments, the enteric polymer in the coating is about 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.5%, 3%, 3.5%, or 4% by weight of the tablet, or any two or more of the foregoing values. In another embodiment, the enteric polymer in the coating agent is about 2.0% or about 3.0% based on the weight of the tablet.

[0087] For tablets according to the invention, it was found that a thicker coating (2-3 wt%) was preferred in order to obtain a similar release profile to the reference product, which has a coating of about 1-4-1.5 wt%.

[0088] In some embodiments, the enteric coating contains other excipients in addition to the enteric polymer, including, for example, a plasticizer, a lubricant, or an anti-adherent such as talc, an opacifier, a colorant, a diluent, or any combination thereof.

[0089] Advantageously, the enteric coating plasticizer is diethyl phthalate, a citrate ester such as triethyl citrate, polyethylene glycol, glycerol, acetylated glycerides, a citrate ester, dibutyl sebacate, castor oil or any combination thereof.

[0090] In other embodiments, the enteric coating may further comprise a diluent, such as lactose, sucrose, fructose, mannitol, or the like, or a combination thereof. In some embodiments, the enteric coating comprises talc as a lubricant or anti-adherent.

[0091] In a preferred embodiment, the enteric coating comprises a methacrylic acid copolymer dispersion, preferably an ethacrylic acid-ethyl acrylate copolymer (1:1) dispersion in water and propylene glycol. Ethacrylic acid-ethyl acrylate copolymer (1:1) is known as Eudragit® L30-D55 and is available from Evonik Operations GmbH (Essen, Germany).

[0092] In another preferred embodiment, the enteric coating comprises a methacrylic acid-methacrylate copolymer (1:1) in an alcoholic solution, preferably at a concentration of 5-15% w / w, more preferably 10% w / w, with triethyl citrate as a plasticizer, preferably at 2-5% w / w, more preferably 3% w / w relative to the polymer.

[0093] Methacrylic acid-methacrylate copolymer (1:1) is known as Eudragit® L100 (dissolution pH around 6.8) and is commercially available, for example, from Sigma-Aldrich (Missouri, USA).

[0094] Coating should be carried out according to methods known to those skilled in the art, typically for 5 to 20 minutes.

[0095] In some embodiments, the core may include one or more pharma- ceutically acceptable excipients, such as a bulking agent and / or a basic excipient.

[0096] Advantageously, when present, a filler is used to increase the hardness of the tablet and may be selected from the group consisting of calcium carbonate, calcium hydrogen phosphate, calcium dihydrogen phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextran, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, α-lactose monohydrate.

[0097] Advantageously, the basic excipient may be selected from metal oxides, metal hydroxides, basic salts of weak acids, and combinations thereof. Metal oxides include, but are not limited to, magnesium oxide, aluminum oxide, and zinc oxide. Metal hydroxides include, but are not limited to, sodium hydroxide, potassium hydroxide, magnesium hydroxide, and calcium hydroxide. Basic salts of weak acids include, but are not limited to, sodium or potassium carbonates, bicarbonates, acetates, and succinates. In certain embodiments, the basic excipient is magnesium oxide, meglumine, or a combination thereof. In some embodiments, the basic excipient is magnesium oxide.

[0098] Tablets may also contain a lubricant to prevent tooling jamming during compression into tablets, and / or a glidant to improve flow in the tabletting process, or a combination thereof.

[0099] Advantageously, the lubricant is selected from the group consisting of, but not limited to, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, or combinations thereof.

[0100] Preferably, the lubricant is magnesium stearate.

[0101] Advantageously, the glidant is selected from the group consisting of, but not limited to, colloidal silicon dioxide, starch and talc, preferably colloidal silicon dioxide or any combination thereof.

[0102] In a preferred embodiment, the tablet core comprises a mixture of magnesium stearate and colloidal silicon dioxide.

[0103] In an exemplary embodiment, the core of the coating formulation comprises: a) deferiprone in an amount of 91% by weight; b) Methocel® K100LV in an amount of 7.5% by weight; and c) A mixture of lubricants and glidants in an amount of 1.5% by weight Includes.

[0104] In another exemplary embodiment, the core of the coating formulation comprises: a) deferiprone in an amount of 93% by weight; b) Methocel® K100LV in an amount of 2.0% by weight; c) Methocel® K4M in an amount of 3.0% by weight; d) A mixture of lubricants and glidants in an amount of 2.0% by weight. Includes.

[0105] Advantageously, the pharmaceutical tablets of the present invention are imprinted with a score line to facilitate the patient in dividing the tablet into approximately equal halves, allowing for dosage flexibility.

[0106] Needless to say, when the tablet is broken, its inner surface is not protected by the enteric coating and can be observed to dissolve to some extent in gastric acid.

[0107] On the other hand, as long as the dissolution is good at about 20% or less at acidic pH, it is considered acceptable.

[0108] As an added advantage, as shown in FIG. 6, although the release is a little faster at low pH than observed for the commercial tablets, the half tablets of the present invention do not show the undesirable burst effect when a change in pH occurs, but rather show a smooth release of the active ingredient in the first phase of dissolution.

[0109] Indeed, it is well known that transient high concentrations of deferiprone, and thus elevated plasma levels, can be associated with transient elevations in liver enzymes and other side effects (Cohen ER et al Br J Haematology, 2000, 108, 305-312).

[0110] Advantageously, the tablet of the present invention has the properties of enteric coated tablets without their drawbacks, allowing fine adjustment of the dosage by breaking the tablet in half to administer whole tablets, half tablets or any combination thereof. The half tablets of the present invention, like the whole tablets, are substantially resistant to dissolution in acidic medium (0.1N HC1) representative of the contents of the fasting stomach, and at higher pH representative of the contents of the small intestine, show a similar dissolution rate as the whole tablets, but without the undesirable burst effect of the commercial reference product.

[0111] According to the conditions given in Examples 2 and 3, the release profiles of the tablets of the present invention were determined in various dissolution media with different pH.

[0112] For Ferriprox® tablets, WO 2019 / 082128 reported that deferiprone modified release formulations showed good IVIV correlation, so the in vitro release profile is considered to reflect the in vivo behavior.

[0113] Because the tablets according to the invention have a dissolution profile at pH 6.8 similar to that of Ferriprox®, which is FDA approved and marketed in the United States, it is contemplated that they will exhibit similar bioavailability at steady state, making them suitable for twice-daily oral administration.

[0114] The formulation demonstrated steady-state bioequivalence to immediate release Ferriprox® tablets for three times daily administration and demonstrated mean ratios of AUC(24 hours) and C for the tablets of the present invention relative to immediate release (IR) tablets. max It is considered that the average ratio may be 80% to 125%.

[0115] In other words, at steady state, the modified release tablets of the present invention, when administered twice daily, have a similar maximum plasma concentration (C) as the IR tablets of Ferriprox®, when the IR tablets are given three times daily. max ) and the total absorption (AUC) was similar for both over 24 hours.

[0116] The present invention also provides a method for preparing the above coated deferiprone tablets, comprising the steps of: i) mixing the modified release agent, and, if present, the pharma- ceutically acceptable excipients, with deferiprone to form a mixture; ii) Wet granulating the mixture obtained in step (i) in a high shear granulator, drying and sieving to obtain granules; iii) blending the granules obtained in step (ii) with a lubricant and / or glidant, excipients to form a blend; iv) compressing the mixture obtained in step (iii) to form tablets; and v) Coating tablets.

[0117] In another embodiment, the method comprises the steps of: i) mixing the modified release agent, and, if present, the pharma- ceutically acceptable excipients, with deferiprone to form a mixture; ii) adding lubricants and / or glidants, excipients and further mixing; iii) directly compressing the mixture obtained in step (ii) to form tablets; and iv) Coating the tablets.

[0118] Equipment and conditions for direct compression and / or compression during granulation are known to those skilled in the art.

[0119] Tablets can be manufactured in any suitable weight, but preferably the weight of each unit ranges from 800 to 1500 mg, preferably 1000 mg to 1200 mg.

[0120] For the avoidance of doubt, for these and other pharma- ceutically acceptable excipients and methods described herein, reference is made to the extensive literature on the subject, in particular Handbook of Pharmaceutical Excipients, Third Edition, edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, USA and Pharmaceutical Press, London; and Lexikon der Hilfsstoffe fi.ir Pharmazie, Kosmetik and angrenzende Gebiete edited by HP Fiedler, 4th Edition, Editor Cantar, Aulendorf, and previous editions.

[0121] The present invention provides dosing regimens useful for therapeutic use of the pharmaceutical formulations described herein.

[0122] Typically, the oral daily dose of deferiprone can range from 75 mg / kg to 100 mg / kg.

[0123] In some embodiments, the deferiprone compositions of the invention are administered to a subject in need of treatment twice daily.

[0124] A unit dose of deferiprone tablets should contain 500-1200 mg, preferably 600-1000 mg, depending on the frequency of administration.

[0125] The formulations of the present invention are useful for the prevention and / or treatment of iron overload or diseases caused by iron overload.

[0126] In some embodiments, the subject in need of treatment has iron overload due to transfusional iron overload or due to a disease such as thalassemia, myelodysplasia, sickle cell disease or iron overload.

[0127] In some embodiments, the subject in need of treatment has a neurodegenerative disease (e.g., Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, Friedreich's ataxia, pantothenate kinase-associated neurodegeneration (PKAN), or brain iron deposition neurodegeneration (NBIA).

[0128] In some embodiments, the subject in need of treatment has an iron overload condition that is transfusional iron overload. In certain embodiments, the subject has transfusional iron overload and previous chelation therapy is inadequate.

[0129] In certain embodiments, the subject has transfusion iron overload and has a cardiac MRI T2* of 20 ms or less (eg, 10 ms).

[0130] The present invention will now be described in more detail with reference to the following examples. EXAMPLES

[0131] Example 1 - Preparation of tablets Tablets were produced by direct compression using a rotary tablet press (Officine Meccaniche Ronchi, AM8S) equipped with rectangular punches with dimensions of 22 mm x 10 mm. The compression force was set at 25 kN so that the crushing strength of the tablets was approximately 70 N.

[0132] The hydrophilic matrix consists of a mixture containing 1000 mg of active ingredient and different proportions of hypromellose polymer (HPMC) of two viscosity grades (Methocel® K100LV, Methocel® K4M, Colorcon, USA). [Table 1]

[0133] Example 2 - Dissolution Test A spectrophotometer was used to obtain the maximum absorption spectra of the active ingredient in the various liquids in which the release tests were carried out.

[0134] The composition of the dissolution medium is shown below. pH 1.2: 3.73 g KCl, 7.07 ml HCl 1N for 1 L (add deionized water to volume); pH 4.5: 6.80g KH2PO4 per 1L (add deionized water to volume); pH 6.8: 6.80 g KH2PO4, 0.90 g NaOH per liter (add deionized water to volume).

[0135] Calibration curves were prepared for each release medium at both wavelengths, 276 nm, where the absorbance peak was recorded, and 243 nm, where the decrease in absorbance was observed, so as not to exceed the maximum absorbance value of the instrument.

[0136] The release studies of the commercial products were analyzed at a wavelength of 276 nm using both pH 4.5 phosphate and pH change methods (0.1 N HCl for the first 120 min, pH 6.8 phosphate buffer for the remainder of the study). Sampling, dilution and manual readings were performed at high absorbance values ​​(>30% of release).

[0137] The release studies were performed in a dissolution paddle apparatus (USP type 2) with a rotation speed of 50 rpm and in a basket apparatus (USP type 1) with a rotation speed of 100 rpm. The studies were always performed in 900 mL of dissolution medium at 37° C.

[0138] For the test formulations, the active ingredient was quantified spectrophotometrically at 243 nm.

[0139] The results for uncoated tablets at pH 6.8 and 4.5 are shown in Figures 1 and 2.

[0140] It can be seen that tablets containing 7.5% Methocel® K100LV or a mixture of 2% Methocel® K100LV and 3% K4M show a release profile more similar to the reference product.

[0141] Example 3 - Gastro-resistant coating From the results of the non-coated tablets, -Methocel® K100LV 7.5% -Methocel® K100LV 2% and K4M 3% We chose to coat the co-formulated tablets with a gastroresistant film.

[0142] The tablets were then coated with various acrylic acid polymers having a dissolution pH of about 6 and formulated in aqueous dispersions: - Eudragit® L30-D55 aqueous dispersion 60% w / w (containing 25% solids) -Deionized water 38%w / w -Propylene glycol 2%w / w

[0143] The process parameters are as follows: -Nozzle: 0.8mm - Spray pressure: 0.8 bar - Control pressure: 2 bar - Pattern pressure: 0.5 bar -Peristaltic pump: 2 rpm -Air temperature: 57°C.

[0144] To test the different coating amounts by dissolution testing, the coating process was continued for 20 minutes and samples were collected every 5 minutes. The analysis was carried out under the same conditions as before.

[0145] The results are shown in Figures 3 and 4.

[0146] The K100LV 7.5% tablets were more difficult to coat during the first minute. In fact, the coating process continued for 5 minutes longer for this formulation than for the K100LV 2% K4M 3% tablets; both ultimately reached 2% weight.

[0147] As an alternative coating method, Eudragit® L100 (dissolution pH approximately 6.8) was applied in an alcoholic solution (10% w / w) containing triethyl citrate (3% w / w with respect to the polymer).

[0148] The coating process was carried out in a small coating pan (opening diameter 10 cm) and the process parameters were as follows: -Nozzle: 0.8mm - Spray pressure: 0.5 bar - Control pressure: 0.6 bar - Pattern pressure: 2 bar -Peristaltic pump: 2 rpm -Air temperature: 50℃.

[0149] The process was stopped when the tablets reached a weight gain (wg) of 3%.

[0150] Dissolution tests were carried out at 37° C. in apparatus 1 (basket) with a rotation speed of 100 rpm in the following dissolution media: - pH 1.2 for the first 120 minutes (for 1 L, 3.73 g KCl, 7.07 mL HCl 1N and deionized water to volume); - Remaining dissolution time, pH 4.5: (for 1 L, 6.80 g KH2PO4, 0.90 g NaOH and deionized water to volume).

[0151] The results are shown in Figure 5.

[0152] It can be seen that for the K100LV 7.5% tablets a release very similar to the reference product was observed.

[0153] The release profile of half tablets according to the invention coated with Eudragit® L30-D55 against half tablets of a reference product was also studied.

[0154] Dissolution tests were carried out at 37° C. in apparatus 1 (basket) with a rotation speed of 100 rpm in the following dissolution media: - pH 1.2 for the first 120 minutes (for 1 L, 3.73 g KCl, 7.07 mL HCl 1N and deionized water to volume); - Remaining dissolution time, pH 4.5: (for 1 L, 6.80 g KH2PO4, 0.90 g NaOH and deionized water to volume).

[0155] The results are shown in Figure 6.

[0156] As can be seen from the figure, the release of active ingredient at low pH is a little higher than that of the commercial tablet, but the half tablet of the present invention does not show a burst effect when a pH change occurs, and shows a smoother release of active ingredient in the first stage of dissolution.

Claims

1. 1. A pharmaceutical formulation in the form of a modified release enteric coated tablet suitable for oral administration twice daily, the core of said tablet comprising, calculated on the total weight of said formulation, a) deferiprone in an amount of 85.0-95.0%, b) a hydroxypropyl methylcellulose polymer having a viscosity of 100 cP, alone or in a mixture with a hydroxypropyl methylcellulose polymer having a viscosity of 4000 cP, as modified release agent, in an amount of 4.0-10.0%, c) a lubricant and / or glidant in an amount of 0.2-2.0%, and d) other suitable pharma- ceutical acceptable excipients in an amount of 0-5%,

2. 2. The pharmaceutical formulation of claim 1, wherein the modified release agent comprises a hydroxypropyl methylcellulose polymer having a viscosity of 100 cP in an amount of 7.5% by weight.

3. 2. The pharmaceutical formulation of claim 1, wherein the modified release agent comprises a hydroxypropyl methylcellulose polymer having a viscosity of 100 cP in an amount of 5% by weight, alone or in admixture with a hydroxypropyl methylcellulose polymer having a viscosity of 4000 cP.

4. 4. The pharmaceutical formulation according to claim 3, wherein the ratio of the two polymers is 40:60 w / w.

5. The pharmaceutical formulation of any one of claims 1 to 4, wherein the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, talc, and combinations thereof.

6. 6. The pharmaceutical formulation of claim 5, wherein the lubricant is magnesium stearate.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the glidant is selected from the group consisting of colloidal silicon dioxide, starch and talc, and combinations thereof.

8. 8. The pharmaceutical composition of claim 7, wherein the glidant is colloidal silicon dioxide.

9. A pharmaceutical formulation according to any one of claims 1 to 8, wherein other suitable pharma- ceutically acceptable excipients are selected from the classes of pH adjusters and bulking agents.

10. The pharmaceutical formulation according to any one of claims 1 to 9, wherein the enteric coating comprises an enteric polymer, a diluent and optionally a plasticizer.

11. 11. The pharmaceutical formulation of claim 10, wherein the enteric coating comprises an ethacrylic acid-ethyl acrylate copolymer (1:1) dispersion in water and propylene glycol.

12. 11. The pharmaceutical formulation of claim 10, wherein the enteric coating comprises a methacrylic acid-methacrylate copolymer (1:1) in an alcoholic solution containing triethyl citrate.

13. A pharmaceutical formulation according to any one of claims 1 to 12, wherein the tablet core comprises 500 to 1500 mg of deferiprone.

14. 14. The pharmaceutical formulation of claim 13, wherein the tablet core contains 1000 mg of deferiprone.

15. A pharmaceutical formulation according to any one of claims 1 to 14, suitable for twice daily administration.

16. A method for producing a pharmaceutical formulation according to any one of claims 1 to 15, said method comprising the steps of: (i) mixing deferiprone with the modified release agent, and, if present, other pharma- ceutically acceptable excipients, to form a mixture; (ii) The mixture obtained in step (i) is wet granulated in a high shear granulator, dried and sieved to produce granules. (iii) mixing the mixture obtained in step (ii) with a lubricant and / or glidant, excipients to form a mixture; compressing the mixture obtained in step (iii) to form a tablet; and (iv) Coating tablets A method comprising:

17. A method for producing a pharmaceutical formulation according to any one of claims 1 to 15, said method comprising the steps of: (i) mixing deferiprone with the modified release agent, and, if present, other pharma- ceutically acceptable excipients, to form a mixture; (ii) adding lubricants and / or glidants, excipients and further mixing; (iii) directly compressing the mixture obtained in step (ii) to form a tablet; and (iv) Coating tablets A method comprising:

18. A pharmaceutical composition according to any one of claims 1 to 15 for the prevention and / or treatment of iron overload or diseases caused by iron overload.

19. 19. The pharmaceutical composition for use according to claim 18, wherein the disease is thalassemia or sickle cell disease.

20. 19. The pharmaceutical composition for use according to claim 18, wherein the iron overload is transfusional iron overload.

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