Modified release pharmaceutical formulations comprising deferiprone

Abstract

The present invention relates to a pharmaceutical composition for oral administration comprising deferiprone. In particular, the present invention relates to a modified release formulation in the form of a tablet suitable for twice daily oral administration for use in the treatment of diseases causing overload of iron, such as thalassemia, sickle cell anemia, hemopigmentation and spinal cord dysplasia, or for the prevention and / or treatment of diseases caused by overload of iron. The invention also relates to a method for preparing said formulation.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical preparation comprising the iron chelator deferiprone.

[0002] Specifically, the present invention relates to a modified release preparation in the form of minitablets suitable for oral administration twice a day for the treatment of diseases causing iron overload, such as thalassemia, sickle cell anemia, hemochromatosis and myelodysplasia, or for the prevention and / or treatment of diseases caused by iron overload. Background Art

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

[0004] It is used for the treatment of generalized iron overload, particularly conditions in which iron overload is caused by frequent blood transfusions, including, for example, thalassemia and sickle cell disease.

[0005] The introduction of deferiprone into current therapies has represented an important advance since it reduces 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) have shown that deferiprone monotherapy may be superior to desferrioxamine monotherapy in improving myocardial iron deposition and cardiac function.

[0007] In terms of safety, the most frequent adverse events are gastrointestinal disorders due to gastrointestinal irritation.

[0008] Such discomfort may cause patients to refuse to take the drug, leading to the worsening of their condition. Other observed adverse events are musculoskeletal disorders (arthralgia), elevated alanine aminotransferase (ALT), agranulocytosis and neutropenia.

[0009] Agranulocytosis appears to be an atopic reaction and it is more frequent in the first year of treatment.

[0010] The incidence of neutropenia and agranulocytosis is stable and does not appear to be dose-dependent (Hider RC et al., N Engl J Med. 2018; 379:2140-2150).

[0011] Deferiprone has a half-life of 2-3 hours and also has an unpleasant bitter taste.

[0012] The drug is available as immediate release (IR) 500 mg and 1000 mg tablets and a 100 mg / ml liquid formulation, usually under the trade name for sale.

[0013] Recently, deferiprone has also been commercially available as 1000 mg delayed release (DR) tablets for oral administration, given its pharmacological and ADME properties and to improve patient compliance.

[0014] The tablets are suitable for twice-daily administration and are bioequivalent at steady state to immediate release tablets administered three times daily at the same daily dose.

[0015] The DR tablets are also scored to enable patients to easily break the tablets into two approximately equal parts to ensure dosing flexibility.

[0016] The composition of the DR tablets has been disclosed in WO 2019 / 0822128 and comprises: (a) a core containing the active pharmaceutical ingredient and a release controlling enteric polymer, and (b) an enteric coating.

[0017] After oral administration, the enteric coating renders dissolution in the stomach negligible and thus promotes subsequent dissolution of the active substance at physiological weakly acidic to weakly basic pH (e.g., pH 4.5 to 8), which corresponds to dissolution in the duodenum to the ileum.

[0018] In the case of marketed deferiprone products, hypromellose acetate succinate (HPMC-AS) is used as the enteric polymer in the tablet core to maintain release.

[0019] However, HPMC-AS has pH-dependent solubility.

[0020] This can lead to release that is influenced by the external environment that the unit has to face during transit in the region where release of the active ingredient occurs, which is characterized by physiological fluids with different pHs, and thus renders the release less predictable under the domination of random microenvironmental changes in pH.

[0021] In addition, enteric-coated tablets are difficult to break into two parts without compromising the delayed release characteristics. This is because the surface at the interface of the broken tablet is no longer protected by the enteric coating.

[0022] If the unprotected core disintegrates and / or dissolves rapidly, the broken tablets may dissolve faster in gastric acid than the intact tablets, thus partially losing the protection against gastric irritation and the broken tablets will no longer deliver the drug at the same rate as the intact tablets.

[0023] Accordingly, it is advantageous to provide a pharmaceutical preparation containing deferiprone suitable for twice-daily oral administration, which has great flexibility in dosing but without the aforementioned possible drawbacks.

[0024] The present invention provides this technical solution. SUMMARY OF THE INVENTION

[0025] In a first aspect, the present invention provides a modified-release enteric-coated pharmaceutical preparation in the form of tablets for twice-daily oral administration, wherein the core of the tablets contains an amount of deferiprone as the active ingredient between 74% and 87%, an amount of glycerol ester of long-chain fatty acid as the modified-release agent between 10% and 20%, an amount of lubricant and / or glidant between 1% and 6%, and an amount of an optional further excipient between 0% and 2%, all amounts being calculated by weight based on the total weight of the uncoated preparation, wherein the enteric coating contains a mixture of methacrylic acid-ethyl acrylate copolymer (1:1), a plasticizer.

[0026] In a second aspect, the present invention provides a method for preparing the coated deferiprone tablets as described above, the method comprising the following steps:

[0027] (i) Mixing deferiprone with the modified-release agent and, if present, the optional excipient to form a mixture;

[0028] (ii) Tableting the mixture of step (i) to obtain a compact;

[0029] (iii) Crushing the compact through a granulator with a suitable screen size to obtain granules;

[0030] (iv) Mixing the granules obtained in step (iii) with the lubricant / glidant excipient to form a final mixture;

[0031] (v) Compressing the final mixture obtained in step (iv) to form tablets; and

[0032] (vi) Coating and drying the tablets.

[0033] In a third aspect, the present invention relates to a container filled with the tablets of the present invention.

[0034] In a fourth aspect, the present invention relates to the claimed pharmaceutical composition for treating diseases causing iron overload, or for preventing and / or treating diseases caused by iron overload.

[0035] In a fifth aspect, the present invention relates to the claimed pharmaceutical composition for preparing a medicament for treating diseases causing iron overload, or for preventing and / or treating diseases caused by iron overload.

[0036] In a sixth aspect, the present invention relates to a method for treating a disease causing iron overload or for preventing and / or treating a disease caused by iron overload in a patient in need thereof, the method comprising orally administering the claimed pharmaceutical composition. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 - The dissolution profiles of deferiprone itself and deferiprone from uncoated tablets containing different controlled release agents.

[0038] Figure 2 - The dissolution profiles of deferiprone from a reference commercial product and enteric-coated tablets.

[0039] DEFINITIONS

[0040] As used herein, the indefinite article "a" or "an" shall be understood to mean "one or more / one or more kinds of" any of the recited or listed components. For example, "a tablet" means one or more tablets.

[0041] Also as used herein, "and / or" means and encompasses all possible combinations of one or more of the related listed items, and when interpreted in the alternative way ("or"), means the absence of the combination.

[0042] When the term "about" is used with a numerical value or range, it adjusts the value or range by extending the boundaries above and below the numerical value. The term "about" is used herein to adjust a numerical value above and below the stated value by a variation of up to or down (higher or lower) 10%, i.e., ±10%, unless a different variation is specified (e.g., ±30%, ±20%, ±5%, ±1%, etc.).

[0043] Any aspect described herein in the language "comprising / including" also provides other similar aspects described in terms of "consisting of" and / or "consisting essentially of". In the case where the term "includes" or "including" is used in the specification or claims, it is intended to be inclusive in a manner similar to the term "comprising", as it is interpreted when used as a transitional word in a claim.

[0044] As used herein, the terms "active ingredient" or "active pharmaceutical ingredient" (API) or "drug" are used synonymously and mean any component intended to provide pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of a disease, or to affect the structure or any function of the body of a human or other animal.

[0045] The terms "iron overload" or "overload of iron" are used interchangeably herein and refer to a medical condition in which the body contains or stores too much (or "excessive") iron. An example is transfusional iron overload, in which excessive iron is introduced by one or more blood transfusions.

[0046] The term "minitablet" generally refers to a compressed tablet having a smaller size than a typical tablet. Although there are currently no regulatory guidelines defining minitablets (sometimes referred to as microtablets), the term has been used to describe tablets having a diameter between one and four millimeters.

[0047] The term "glyceride of long-chain fatty acid" means a substance in which one, two, or three alcohol groups of the glycerol moiety are esterified with long-chain saturated fatty acids C 14 -C 22 to form monoglycerides, diglycerides, triglycerides, or mixtures thereof.

[0048] In the context of this document, the term "hydrophilic" describes a molecule or portion of a molecule that is typically electrically polarized and capable of forming hydrogen bonds with water molecules, such that it is more soluble in water than in oil or other "nonpolar" solvents.

[0049] Conversely, the term "hydrophobic" denotes a compound that tends to be electrically neutral and nonpolar and thus prefers other neutral and nonpolar solvents or molecular environments.

[0050] In the context of this document, the term "amphiphilic" describes a molecule having a polar water-soluble group attached to a water-insoluble hydrocarbon chain. Thus, one end of the molecule is hydrophilic (polar) and the other end is hydrophobic (nonpolar).

[0051] "pH-dependent solubility" means a substance that has different solubilities at different pHs. These pH-dependent solubility differences result in pH-dependent dissolution profiles.

[0052] The expression "insoluble or poorly water-soluble" refers to a substance having a solubility in water as defined in the European Pharmacopoeia, 4th Edition, 2003, page 2891.

[0053] As used herein, a "core" or "tablet core" contains an active ingredient, such as deferiprone, and one or more excipients, which are compressed into an uncoated tablet. The core can be coated with various coatings, including enteric coatings.

[0054] In the context of this text, the terms "controlled release", "sustained release", "modified release", and "delayed release" are intended as equivalent terms encompassing some types of release of deferiprone from the compositions of the invention, which compositions are suitable for obtaining a specific therapeutic or prophylactic response after administration to a subject. The terms refer to protecting the active ingredient, such as deferiprone, from rapid release at acidic pH, such as in the stomach, while enabling the active ingredient to be released at a higher rate at a higher pH, such as in the intestine. In some aspects, DR will be understood to mean that when tested in USP Apparatus 2 at 75 rpm, the dissolution in 0.1 N HCl in 1 hour will be about 20 ± 5%, and the dissolution rate in phosphate buffer with pH 6.8 will be significantly higher (e.g., more than 30% in 1 hour, such as more than 40%) than the dissolution rate in 0.1 N HCl.

[0055] Alternatively, when tested in USP Apparatus 1 at 100 rpm, the dissolution in 0.1 N HCl in 2 hours will be less than 10%, and the dissolution rate in phosphate buffer with pH 6.8 will be significantly higher (e.g., more than 40% in 1 hour) than the dissolution rate in 0.1 N HCl.

[0056] As used herein, "disintegrant" refers to an excipient that is insoluble in water but swells when wetted to cause tablet disintegration.

[0057] As used herein, "dissolution" refers to the process by which a solute forms a solution in a solvent.

[0058] As used herein, "enteric coat" or "enteric coating" refers to a coating containing an enteric polymer. The enteric coating can be used to prevent or delay the dissolution or disintegration of a tablet in the gastric environment.

[0059] "Enteric-coated tablet" means a tablet having a core containing an active ingredient coated with an enteric coating.

[0060] As used herein, "enteric polymer" is understood to mean a polymer that is relatively insoluble at the acidic pH of the fasting stomach (e.g., about pH 1 to about pH 4), but soluble at a higher pH (e.g., about pH 4.5 to about pH 8), which higher pH corresponds to the pH in the small intestine or beyond, particularly in the duodenum or ileum.

[0061] The term "plasticizer" means an additive that increases the elasticity of a coating based on a film-forming material.

[0062] The terms "filler", "diluent", and "bulking agent" are used synonymously.

[0063] The term "bioequivalence" means that there are no significant differences in bioavailability (i.e., extent of absorption and peak concentration) between two drug products (e.g., test product and reference product) at the same dose and under the same conditions over a period of time.

[0064] The determination of whether a test product is bioequivalent to a reference product is made by conducting a study in a group of subjects (usually about 18 - 36 subjects or more) under controlled conditions, which is called a bioequivalence or comparative bioavailability study.

[0065] The study can be conducted in a "cross - over" design, which means that the study is conducted in more than 2 phases, usually separated by at least one week, which depends in part on the half - life of the drug. In the first phase, half of the subjects are randomly assigned to take the test product first, and the other half take the reference product first. In the second phase, each subject takes the replacement product.

[0066] In each phase, after administration of the test product, blood samples are drawn from each subject according to a pre - determined schedule. 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, if when administered at a similar dose under similar conditions, the drugs enter the circulation at the same rate, they are bioequivalent. The parameters commonly used in bioequivalence studies are t max 、C max 、C min 、AUC 0-infinity 、AUC 0-t 。

[0067] In the context of this article, "t max " represents the time to reach the maximum plasma concentration (C max ) after administration; "AUC 0-infinity " represents the area under the plasma concentration - time curve from time 0 to infinity; "AUC 0-t " represents the area under the plasma concentration - time curve from time 0 to time t; "W50" represents the time during which the plasma concentration is more than 50% of C max ; "W75" represents the time during which the plasma concentration is more than 75% of C max ; and "MRT" represents the mean residence time of tacrolimus.

[0068] As used herein, the "fasting state" refers to abstaining from food for a defined period of time after a meal (typically, at least several hours after a meal, e.g., 4 or 6 hours).

[0069] As used herein, the "fed state" refers to administration with a meal or shortly after a meal (e.g., within about 1 hour).

[0070] The term "chemically stable" refers to the stability of the active agent in the formulation, where the change in the drug assay value and / or impurity content is equal to or less than 5%, preferably less than 3%, during storage at 25 °C and 60% relative humidity (RH) or 40 °C and / or 75% RH for at least 1 month.

[0071] The term "in vivo-in vitro" correlation (IVIVC) refers to an in vitro dissolution test that predicts the in vivo performance of a drug product.

[0072] As used herein, "stomach upset" refers to discomfort in the gastrointestinal (GI) tract, such as one or more of pain, cramps, flatulence, nausea, indigestion, heartburn, and bloating.

[0073] As used herein, "tablet" refers to a solid oral dosage form of a drug.

[0074] As used herein, "half tablet" means one of the two parts of a tablet obtained by dividing the tablet into two parts of equal or approximately equal weight.

[0075] As used herein, "percentage" or "%" refers to weight percentage (w / w), unless otherwise specified.

[0076] As used herein, "scored tablet" refers to a tablet that is scored with one or more lines (also referred to as "score lines") to facilitate splitting of the tablet, such as to enable administration of a half tablet.

[0077] "Whole tablet" refers to an intact tablet, i.e., one that is not broken or divided into parts.

[0078] 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, attenuate the symptoms of a diagnosed pathological condition or disorder, reverse and / or stop the progression of a diagnosed pathological condition or disorder, and 2) prophylactic or protective measures that prevent, reduce the incidence of, reduce the risk of, and / or slow the development of a targeted pathological condition or disorder. Thus, subjects in need of treatment include those who already have a disorder; those who are predisposed to having a disorder; and those in whom a disorder is to be prevented. Beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms, attenuation of disease severity, stabilization (i.e., non-worsening) of disease state, delay or slowing of disease progression, improvement or mitigation of disease state, and remission (whether partial or complete), whether detectable or not. "Treatment" can also mean an extended survival period compared to the expected survival period if treatment is not received. Subjects in need of treatment include those who already have a condition or disorder and those who are predisposed to having a condition or disorder or in whom a condition or disorder is to be prevented or the incidence is to be reduced.

[0079] "Subject" or "individual" or "patient" means any human subject in need of diagnosis, prognosis, treatment, or therapy.

[0080] "Therapeutically effective dose or amount" or "effective amount" is intended to mean the amount of an active pharmaceutical ingredient, such as deferiprone, which when administered to a subject to be treated produces a positive therapeutic response therapeutically or reduces the risk of disease.

[0081] It will be understood that the deferiprone DR tablets used herein as "reference" or "reference product" are those approved by the FDA and sold in the United States tablets (1000 mg). Detailed Description

[0082] The present invention relates to pharmaceutical formulations for the prevention and / or treatment of diseases caused by iron overload, and particularly to compositions that provide a modified release of the active ingredient.

[0083] The active ingredient in the formulations of the present invention is deferiprone.

[0084] However, within the scope of the present invention is deferiprone in any physical form (crystalline, amorphous powder, any possible polymorph, any possible solvate). Also included are its pharmaceutically acceptable salts and / or solvates. Preferably, deferiprone is used as the base in its anhydrous form.

[0085] In a first aspect, the present invention relates to a modified-release enteric-coated pharmaceutical formulation in the form of tablets for twice-daily oral administration, wherein the core of the tablets comprises an amount between 74% and 87% of deferiprone as the active ingredient, an amount between 10 and 20% of glycerides of long-chain fatty acids as the modified-release agent, an amount of 3 to 6% of lubricant and / or glidant, and an amount of 0 to 2% of an optional further excipient, all amounts being calculated by weight based on the total weight of the uncoated formulation, wherein the enteric coating comprises a mixture of methacrylic acid-ethyl acrylate copolymer (1:1), a plasticizer, and an emulsifier.

[0086] It has been found that within statistically significant limits, the formulations of the present invention are able to provide in vitro dissolution profiles similar to those of commercial deferiprone DR tablets. This is shown in Figure 2 .

[0087] Since it has been established that for tablets, deferiprone modified-release formulations exhibit good IVIV correlation (WO 2019 / 082128), it is expected that the in vitro release profiles will reflect the in vivo behavior, and thus it is expected that the formulations of the present invention will show the same bioavailability at steady state, making them suitable for twice-daily oral administration.

[0088] It can also be seen therefrom that the formulations of the present invention will be bioequivalent at steady state to immediate-release tablets for three-times-daily administration, and the mean ratio of the AUC (within 24 hours) of the tablets of the present invention relative to the immediate-release (IR) tablets and the mean ratio of C max will be within 80% to 125%.

[0089] In other words, it is reasonable that at steady state, the modified-release tablets of the present invention, when administered twice-daily, will be able to achieve a maximum peak concentration (Cmax) similar to that of the IR tablets of when the IR tablets are administered three-times-daily, and the total amount of absorption (AUC) of the two products over a 24-hour period will be similar.

[0090] On the other hand, the formulations of the present invention will overcome the problems associated with half-tablet administration, namely partial destruction of the enteric coating.

[0091] In fact, it will be possible to administer the desired dose by simply calculating the number of tablets required, which in turn will maintain the integrity of the entire coating, thus ensuring greater dosing flexibility.

[0092] In addition, the formulations of the present invention have the advantage of having a composition based on excipients with non-pH-dependent solubility, and thus they do not directly interfere with the release of deferiprone at different pH values in the gastrointestinal tract. This will demonstrate an undeniable improvement in the reproducibility of the expected release profiles.

[0093] Advantageously, the glyceride of long-chain fatty acid is selected from the group consisting of glyceryl palmitostearate, glyceryl monostearate, and glyceryl behenate.

[0094] Glyceryl behenate, also known as 888ATO, is a water-insoluble mixture of glycerides of behenic acid and is commercially available from Gattefossé SAS, Saint-Priest Cedex, France. In particular, it is a mixture of monoglycerides, diglycerides, and triglycerides, with the diglyceride being the major form (40 - 60% by weight).

[0095] Glyceryl palmitostearate is also known as 5ATO and is also commercially available from Gattefossé SAS, Saint-Priest Cedex, France.

[0096] Glyceryl monostearate is a monoglyceride and is commercially available from Sigma Aldrich GmbH (Germany).

[0097] In a preferred embodiment, 888ATO or 5ATO is used.

[0098] In fact, as can be understood from Figure 1 it can be seen that 888ATO or 5ATO produce similar dissolution profiles.

[0099] In an even more preferred embodiment of the present invention, 888ATO is used.

[0100] The amount of the glyceride of long-chain fatty acid should be between 10 and 20%, preferably 10 to 15%, more preferably 10%, based on the total amount of the formulation.

[0101] In fact, it has been found that, contrary to what is reported in co-pending application EP22167557.2 (where an amount of about 10% of is considered suitable for once-daily administration, while lower amounts are suitable for twice-daily administration), in the case of the tablets of the present invention, higher amounts are required to provide dissolution suitable for twice-daily administration.

[0102] Without being bound by theory, this may be because tablets with the same mass have a larger surface area than standard tablets.

[0103] Deferiprone may cause gastric irritation if released in the fasting stomach and some degradation due to acid hydrolysis.

[0104] Thus, the coating should be able to cause negligible dissolution in the stomach.

[0105] This is achieved by using an enteric coating comprising a copolymer of methacrylic acid and ethyl acrylate (1:1).

[0106] The copolymer of methacrylic acid and ethyl acrylate (1:1) is known as L30-D55 and is commercially available from Evonik Operations GmbH, Essen, Germany.

[0107] In addition to the enteric polymer, the enteric coating may also contain other excipients such as plasticizers, lubricants or anti-adhesion agents, opacifiers, colorants, diluents or any combination thereof.

[0108] Advantageously, the enteric coating plasticizer is diethyl phthalate, a citrate such as triethyl citrate (TEC), polyethylene glycol, glycerol, acetylated glycerides, acetylated citrates, dibutyl sebacate, castor oil or any combination thereof, preferably triethyl citrate.

[0109] The enteric coating may additionally contain an emulsifier and a co-emulsifier or a mixture thereof. Advantageously, the emulsifier may be selected from the group consisting of, but not limited to: sorbitan monolaurate, polysorbate 20 (known as Tween )), polysorbate 80 (known as Tween ), preferably polysorbate 80, while the co-emulsifier may be selected from cetyl alcohol, cetearyl alcohol, sucrose stearate and glycerol monostearate, preferably glycerol monostearate (GMS).

[0110] Advantageously, the components of the enteric coating are present in the following percentages: 90-95% enteric polymer, 1.0-3.0% plasticizer, 2.0-4.0% emulsifier or a mixture thereof with a co-emulsifier.

[0111] In a preferred embodiment, the enteric coating comprises a copolymer of methacrylic acid and ethyl acrylate (1:1), triethyl citrate, polysorbate 80 and glycerol monostearate.

[0112] The coating should be carried out according to methods known to those skilled in the art.

[0113] The tablets of the present invention may also contain a lubricant to prevent sticking to the tool during tabletting, and / or a glidant to improve flow during the tabletting process, or a combination thereof, in an amount of 1.0 to 6.0%, preferably 3.0 to 5.0% by weight based on the weight of the uncoated formulation.

[0114] Advantageously, the lubricant is selected from the group consisting of, but not limited to: magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate or a combination thereof.

[0115] Advantageously, the glidant is selected from the group consisting of, but not limited to: colloidal silica, starch, and talc, preferably colloidal silica, or a combination thereof.

[0116] In a preferred embodiment, the core of the tabletlet contains 5% talc and 0.5% magnesium stearate.

[0117] In some embodiments, the core of the tabletlet may contain one or more pharmaceutically acceptable excipients such as diluents.

[0118] Advantageously, diluents that are utilized to increase tablet hardness when present may be selected from the group consisting of: calcium carbonate, calcium hydrogen phosphate, calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextran, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, α-lactose monohydrate.

[0119] In certain embodiments, the tabletlet may further contain basic excipients selected from the group consisting of: meglumine, 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, the sodium or potassium salts of carbonate, bicarbonate, acetate, and citrate. In certain embodiments, the basic excipient is magnesium oxide, meglumine, or a combination thereof. In some embodiments, the basic excipient is magnesium oxide.

[0120] However, it is preferred that the tabletlets of the present invention do not contain basic excipients.

[0121] As a preferred embodiment, the core of the coated tabletlet of the present invention contains:

[0122] i) deferiprone in an amount of 84.5% by weight; glyceryl behenate in an amount of 10% by weight;

[0123] ii) talc in an amount of 5.0% by weight;

[0124] iii) magnesium stearate in an amount of 0.5% by weight.

[0125] Preferably, the coating has the following composition:

[0126]

[0127] Those skilled in the art should appropriately adjust the thickness of the coating so that the dissolution profile of the tabletlet is similar to that of the reference preparation.

[0128] Typically, the thickness of the coating is 20 - 40 microns.

[0129] The thickness corresponds to an increase of 10 to 20%, preferably 12 to 18%, of the weight. Additionally, the thickness expressed as the value of the amount of polymer per unit surface can be between 4 and 10 mg / cm 2 2.

[0130] The release profiles of the tablets of the invention have been determined in different dissolution media with varying pH according to the conditions reported in Example 1.

[0131] Typically, as a result of the dissolution test, no significant release is observed at pH 1.2, while after the change, in the formulation of the invention at pH 6.8, less than 50% w / v of the active ingredient is released within 1.0 hour, equal to or less than 85% w / v of the active ingredient is released within 3 hours, and equal to or less than 95% w / v of the active ingredient is released within 4 hours.

[0132] The invention also provides a method for preparing the coated deferiprone tablets as described above, the method comprising:

[0133] i) mixing deferiprone with a controlled release agent and, if present, an optional excipient to form a mixture;

[0134] ii) tabletting the mixture of step i) to obtain a green compact; crushing the green compact through a granulator with a suitable screen size to obtain granules;

[0135] iii) mixing the granules obtained in step (iii) with a lubricant / glidant excipient to form a final mixture;

[0136] iv) compressing the final mixture obtained in step (iv) to form tablets; and

[0137] v) coating and drying the tablets.

[0138] The devices and conditions for granulation, green compaction and compression are known to those skilled in the art. Therefore, the operating parameters should be adjusted according to their knowledge.

[0139] For example, typical parameters are reported in Table 3 of Example 1.

[0140] Typically, the tablets have a diameter of 2.5 - 3.0 mm, preferably 2.6 - 2.7 mm and a height of 2.2 - 2.3 mm.

[0141] The devices and conditions for drying the coated tablets are known in the art.

[0142] The present disclosure provides dosing regimens for the therapeutic use of the pharmaceutical formulations described herein.

[0143] Typically, the oral daily dose of deferiprone can range from 75 mg / kg to 100 mg / kg.

[0144] The solid unit dose of deferiprone is typically 1000 mg, but depending on the number of tablets, different doses can be administered according to the patient's gender, age, and weight.

[0145] The claimed formulation can be used to treat diseases causing iron overload or for the prevention and / or treatment of diseases caused by iron overload.

[0146] In some embodiments, the subject in need has iron overload caused by transfusional iron overload or iron overload caused by diseases such as thalassemia, myelodysplasia, or sickle cell disease.

[0147] In some embodiments, the subject in need may have 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).

[0148] In some embodiments, the subject in need has iron overload as transfusional iron overload.

[0149] In certain aspects, the subject has transfusional iron overload and their previous chelation therapy has been inadequate. In certain aspects, the subject has transfusional iron overload and has a cardiac MRI T2* of less than 20 ms (e.g., 10 ms).

[0150] The present invention also relates to a container filled with the disclosed tablets.

[0151] For example, typical containers are capsules or sachets.

[0152] The present invention is illustrated in detail by the following examples.

[0153] Examples

[0154] Example 1 - Preparation and Related Characterization of Uncoated Tablets

[0155] Tablets containing deferiprone were prepared by tabletting dry granules obtained by the compression block method.

[0156] Dry granulation。A mixture having the composition reported in Table 1 except for magnesium stearate was tabletted into cylindrical compacts in a rotary tablet press (Officine Meccaniche Ronchi, AM8S) equipped with a flat punch of 11 mm diameter. The compacting force (Fa) was set to give tablets a compressive strength of about 40 N. The compacts were comminuted in an oscillating granulator (Erweka, wet granulator FGS) with a screen size of 1000 μm. The excipients were evaluated according to their usual application in pharmaceutical formulations: Compritol 888ATO and Precirol ATO were used as controlled release materials; Vivapur, PEG 8000, Emcompress were used as diluents / fillers; talc was used as an anti-adherent; magnesium stearate was used as a lubricant during tabletting.

[0157] Table 1. Formulation and properties of uncoated small tablets.

[0158]

[0159] * Mean ± standard deviation (sd) n = 20

[0160] Tabletting. 0.5% magnesium stearate was added to the granules and tabletted into small tablets by means of the same tablet press equipped with a concave punch (diameter 2.5 mm, radius of curvature 2.5 mm). The pressing force was set to 1 kN. The small tablets prepared had a mass of approximately 12 mg, a height of 2.2 mm and a friability of <1% (Table 1).

[0161] Friability was determined according to the method reported in the 10th edition of the European Pharmacopoeia.

[0162] Dissolution test (uncoated small tablets). The dissolution test was carried out in apparatus 2, in 900 ml of pH 6.8 medium, at a paddle speed of 50 rpm. The test was repeated three times for a small tablet sample mass corresponding to 1000 mg of deferiprone. Figure 1 The dissolution curves of formulations A - F together with the dissolution curve of the unformulated drug are shown.

[0163] As can be understood, due to and the lipophilic nature of, the formulations containing them showed similar dissolution curves.

[0164] Formulation B (10% w / w 888ATO) was selected for coating with an enteric - type film.

[0165] Example 2 - Preparation and related characterization of coated small tablets

[0166] The coating is carried out in a fluidized bed apparatus equipped with a Wurster insert (Mini-Glatt, Glatt GmbH, D). The coating suspension (composition in Table 2) is applied under the experimental conditions reported in Table 3.

[0167] The resulting coated tablets are dried.

[0168] Table 2. Composition of enteric-coated preparations.

[0169]

[0170] Table 3. Coating process parameters.

[0171]

[0172] To prepare units with different coating levels, samples are collected after 27 minutes (batch 1) and 41 minutes (batch 2) during the process, which correspond to weight increases of 11.92% and 17.89% respectively, calculated according to the following formula:

[0173]

[0174] A digital micrometer (Absolute, Mitutoyo, J, n = 20) is used to characterize the height and diameter of the units; the thickness of the coating layer is calculated using the following formula:

[0175]

[0176] Table 4. Properties of enteric-coated tablets

[0177]

[0178] Dissolution test of coated small tablets

[0179] According to "Delayed-release solid dosage forms, method B" of the European Pharmacopoeia, 10th edition, the test is carried out in apparatus 2 at 37 °C and a paddle speed of 50 rpm.

[0180] The maximum absorption spectra of the active substance are obtained in various fluids, and the release tests are carried out in these fluids using a spectrophotometer.

[0181] The composition of the dissolution medium is reported as follows.

[0182] pH 1.2: For 1 L, 3.73 g KCl, 7.07 ml HCl 1 N (made up to volume with deionized water) pH 4.5: For 1 L, 6.80 g of KH 2 PO 4Deionized water up to volume

[0183] pH 6.8: For 1 L, 6.80 g KH 2 PO 4 、0.90 g of NaOH (deionized water up to volume)

[0184] For each of the release media, calibration curves are established at both the wavelength of 276 nm at which the peak absorbance is recorded and 243 nm at which a decrease in absorbance is observed, such that the maximum absorbance value of the instrument is not exceeded.

[0185] The release test of the commercial product is analyzed at a wavelength of 276 nm in a pH change mode (0.1 N HCl for the first 120 minutes and pH 6.8 phosphate buffer for the remainder of the test).

[0186] The dissolution curves of the coated tablets at different coating levels and the dissolution curve of the reference commercial product are shown in Figure 2 in.

[0187] As can be understood from Figure 2 Within the statistically significant limits, the formulations of the present invention are capable of providing in vitro dissolution curves similar to those of the commercial deferiprone DR tablets (reference product).

[0188] In particular, up to 240 minutes, the two curves are substantially overlapping.

Claims

1. A modified-release enteric-coated pharmaceutical preparation in the form of small tablets for twice-daily oral administration, wherein the core of the tablet contains an amount of deferiprone as the active ingredient between 74% and 87%, an amount of glycerides of long-chain fatty acids as the modified-release agent between 10% and 20%, an amount of 1 to 6% of a lubricant and / or glidant, and an amount of 0 to 2% of an optional further excipient, all amounts being calculated by weight based on the total weight of the uncoated preparation, wherein the enteric coating comprises a mixture of methacrylic acid-ethyl acrylate copolymer (1:1), a plasticizer, and an emulsifier.

2. The modified-release preparation according to claim 1, wherein the glyceride reagent of the long-chain fatty acid is selected from the group consisting of glyceryl palmitostearate, glyceryl monostearate, and glyceryl behenate.

3. The modified-release preparation according to claim 1 or 2, wherein the glyceride reagent of the long-chain fatty acid is glyceryl behenate.

4. The pharmaceutical preparation according to any one of claims 1 to 3, wherein the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, talc, and combinations thereof.

5. The pharmaceutical preparation according to claim 4, wherein the lubricant is magnesium stearate.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the glidant is selected from the group consisting of colloidal silicon dioxide, starch, talc, and combinations thereof.

7. The pharmaceutical composition according to claim 6, wherein the glidant is talc.

8. The pharmaceutical preparation according to any one of the preceding claims, wherein other suitable pharmaceutically acceptable excipients, if present, are selected from the class of bulking agents.

9. The pharmaceutical preparation according to any one of the preceding claims, wherein the plasticizer is triethyl citrate.

10. The pharmaceutical preparation according to any one of the preceding claims, wherein the emulsifier is selected from the group consisting of, but not limited to: sorbitan monolaurate, polysorbate 20 and polysorbate 80 11. The pharmaceutical preparation according to claim 10, wherein the emulsifier is polysorbate 80.

12. The pharmaceutical preparation according to any one of the preceding claims, wherein the coating further comprises a co-emulsifier selected from the following: cetyl alcohol, cetearyl alcohol, sucrose stearate.

13. The pharmaceutical preparation according to claim 12, wherein the co-emulsifier is glyceryl monostearate.

14. A method for preparing the pharmaceutical preparation according to any one of the preceding claims, the method comprising the following steps: (i) mixing deferiprone with the modified-release agent and, if present, the optional excipient to form a mixture; (ii) tabletting the mixture of step (i) to obtain a compact; (iii) crushing the compact through a granulator with a suitable screen size to obtain granules; (iv) mixing the granules obtained in step (iii) with the lubricant / glidant excipient to form a final mixture; (v) compressing the final mixture obtained in step (iv) to form small tablets; (vi) coating the small tablets, and (vii) drying the coated small tablets.

15. The pharmaceutical composition according to any one of claims 1 to 13, which is used for treating diseases causing iron overload, or for preventing and / or treating diseases caused by iron overload.

16. A pharmaceutical composition for the use according to claim 15, wherein the disease is thalassemia or sickle cell anemia.

17. A pharmaceutical composition for the use according to claim 15, wherein the iron overload is transfusion - related iron overload.

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