Modified-release pharmaceutical formulations containing 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 minitablets suitable for twice-daily oral administration for the treatment of diseases that cause iron overload, such as thalassemia, sickle cell anemia, hemochromatosis, and myelodysplasia, or for the prevention and / or treatment of diseases caused by iron overload. The present invention also relates to a method for producing the formulation.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to pharmaceutical formulations containing the iron chelator deferiprone.

[0002] In particular, the present invention relates to modified release formulations in the form of minitablets suitable for twice-daily oral administration for the treatment of diseases that cause 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 technology]

[0003] Background of the Invention 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 in the treatment of generalized iron overload, particularly conditions resulting from frequent blood transfusions, including, for example, thalassemia and sickle cell disease.

[0005] The introduction of deferiprone into current treatment represents an important advancement because it reduces liver iron concentrations (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 may be superior to deferoxamine monotherapy in improving myocardial siderosis and cardiac function.

[0007] Regarding safety, the most frequent adverse event was gastrointestinal disturbance due to gastrointestinal irritation.

[0008] Such discomfort may lead patients to stop taking the drug and worsen their condition. Other observed adverse events are musculoskeletal disorders (arthralgia), elevated alanine aminotransferase (ALT), agranulocytosis, and neutropenia.

[0009] Agranulocytosis is considered an idiosyncratic reaction and is more frequent during the first year of treatment.

[0010] Events of neutropenia and agranulocytosis were stable and appeared to be dose-unrelated (Hider RC et al N Engl J Med. 2018;379:2140-2150).

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

[0012] The drug is commonly sold under the trade name Ferriprox (登録商標) It is marketed under the trade name of Pharmacy No. 10014449 as immediate release (IR) 500 mg and 1000 mg tablets and a 100 mg / ml liquid formulation.

[0013] In view of its pharmacological and ADME profile and to improve patient compliance, deferiprone has also recently been marketed as a 1000 mg delayed-release (DR) tablet for oral administration.

[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 embossed with a score line to facilitate patient division of the tablet into two approximately equal pieces for dosing flexibility.

[0016] The composition of the DR tablet is disclosed in WO2019 / 0822128 and includes (a) a core comprising an active pharmaceutical ingredient and a release-controlling enteric polymer and (b) an enteric coating.

[0017] After oral administration, the enteric coating results in minimal dissolution in the stomach, thereby facilitating subsequent dissolution of the active substance in physiologically weakly acidic to weakly alkaline conditions (e.g., pH 4.5 to 8) that correspond to dissolution in the duodenum to ileum.

[0018] To provide sustained release, the commercial deferiprone product uses hydroxypropyl methylcellulose acetate succinate (HPMC-AS) as the enteric polymer in the tablet core.

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

[0020] This means that release of the active ingredient can be affected by the external environment the unit encounters during movement through regions characterized by physiological fluids with different pHs, making the release less predictable and therefore subject to random microenvironmental fluctuations in pH.

[0021] Furthermore, enteric-coated tablets are difficult to break in two without compromising the delayed-release properties, because the interfacial surfaces of the broken tablet are no longer protected by the enteric coating.

[0022] If the unprotected core rapidly disintegrates and / or dissolves, the dissolution of the broken tablet in gastric acid will be faster than the intact tablet, and thus, some protection against gastric irritation will be lost and the broken tablet will no longer deliver drug at the same rate as the intact tablet. Summary of the Invention [Problem to be solved by the invention]

[0023] It would therefore be advantageous to provide a pharmaceutical formulation containing deferiprone that is suitable for twice-daily oral administration without the potential drawbacks mentioned above and that allows for greater dosing flexibility.

[0024] The present invention provides a solution. [Means for solving the problem]

[0025] Summary of the Invention In a first aspect, the present invention provides a modified release enteric coated pharmaceutical formulation in the form of minitablets for twice-daily oral administration, wherein the minitablet core comprises deferiprone as the active ingredient in an amount ranging from 74% to 87%, a long fatty acid glyceryl ester as a release modifier in an amount ranging from 10% to 20%, a lubricant and / or glidant in an amount ranging from 1 to 6% and optionally other additives in an amount of 0 to 2%, all amounts calculated by weight relative to the total weight of the uncoated formulation, and wherein the enteric coating comprises 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, comprising the steps of: (i) combining deferiprone with a release-modifying agent and optional additives, if present, to form a mixture; (ii) compressing the mixture of step i) into tablets to obtain compacts; (iii) Breaking the small pieces through a suitable screen size maker to obtain granules; (iv) blending the granules obtained in step (iii) with a lubricant / glidant additive to form a final blend; (v) compressing the final blend from step (iv) to form minitablets; and (vi) Coating the mini-tablets and drying them A method is provided, comprising the steps of:

[0027] In a third aspect, the present invention relates to a container filled with the minitablets of the present invention.

[0028] In a fourth aspect, the present invention relates to the claimed pharmaceutical composition for use in the treatment of a disease causing iron overload or in the prevention and / or treatment of a disease caused by iron overload.

[0029] In a fifth aspect, the present invention relates to the pharmaceutical composition of the present invention in the manufacture of a medicament for the treatment of a disease causing iron overload or for the prevention and / or treatment of a disease caused by iron overload.

[0030] In a sixth aspect, the present invention relates to a method for the treatment of a disease causing iron overload or for the prevention and / or treatment of a disease caused by iron overload in a patient in need thereof, comprising orally administering the pharmaceutical composition of the present application. [Brief explanation of the drawings]

[0031] [Figure 1] Dissolution profiles of deferiprone from uncoated minitablets neat and containing various release modifiers.

[0032] [Figure 2] Dissolution profiles of deferiprone from control commercial product and enteric coated minitablets. DETAILED DESCRIPTION OF THE INVENTION

[0033] definition As used herein, the terms "a," "an," and "the" are to be understood as referring to "one or more" of any described or listed ingredients. For example, "a tablet" refers to one or more tablets.

[0034] Also, as used herein, "and / or" refers to and includes all possible combinations of one or more of the associated listed items, and the absence of any combinations when there is an intervening alternative ("or").

[0035] When the term "about" is used in conjunction with a numerical value or range, it modifies that value or range by extending the boundaries above and below the numerical values ​​set forth. The term "about" herein modifies the stated value by 10 percent above or below (higher or lower), i.e., ±10%, unless a different variability (e.g., ±30%, ±20%, ±5%, ±1%, etc.) is indicated.

[0036] When embodiments are described herein using the term "comprising," otherwise similar embodiments are also provided that are described in terms of "consisting of" and / or "consisting essentially of." To the extent that the terms "including" or "including" are used in this specification and claims, they are intended to be inclusive, just as the term "comprising" is interpreted when that term is used as a transitional phrase in the claims.

[0037] As used herein, the terms "active ingredient" or "active pharmaceutical ingredient" (API) or "drug" are used interchangeably and mean any component 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.

[0038] The terms "iron overload" or "iron overload" are used interchangeably herein to refer to a medical condition in which the body contains or stores too much (or "excess") iron. An example is transfusional iron overload, in which excess iron is introduced by one or more blood transfusions.

[0039] The term "minitablets" generally refers to compressed tablets that are smaller in size than a typical tablet. While there are currently no regulatory guidelines defining minitablets (which are sometimes called microtablets), the term is used to refer to tablets that are 1 to 4 millimeters in diameter.

[0040] The term "glyceryl ester of long fatty acids" refers to glyceryl esters of fatty acids in which one, two or three alcohol groups of the glycerol moiety are long-chain saturated fatty acids C 14 -C 22 esterified with glycerol to form mono-, di-, tri-glycerides or mixtures thereof.

[0041] In the context of this specification, the term "hydrophilic" refers to a molecule or portion of a molecule that is typically electrically polarizable and can form hydrogen bonds with water molecules, thereby dissolving more readily in water than in oil or other "non-polar" solvents.

[0042] Conversely, 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.

[0043] In the present context, the term "amphiphilic" refers to a molecule that has a polar, water-soluble group attached to a water-insoluble hydrocarbon chain, such that one end of the molecule is hydrophilic (polar) and the other end is hydrophobic (non-polar).

[0044] By "pH-dependent solubility" is meant a substance that has different solubilities at different pHs. These pH-dependent solubilities result in a pH-dependent dissolution profile.

[0045] The expression "insoluble or sparingly water-soluble" refers to a substance having a water solubility as defined in the European Pharmacopoeia, 4th edition, 2003, p. 2891.

[0046] As used herein, a "core" or "tablet core" refers to a tablet that contains 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.

[0047] In the present context, the terms "controlled release," "sustained release," "modified release," and "delayed release" are intended to be equivalent terms covering several types of release of deferiprone from the compositions of the present invention appropriate for achieving a specific therapeutic or prophylactic response after administration to a subject. This term refers to protecting the active ingredient, e.g., deferiprone, from rapid release at acidic pH, for example, in the stomach, while allowing the active ingredient to be released at high pH, ​​for example, in the intestine. In one embodiment, when tested in USP Apparatus 2 at 75 rpm, the degree of dissolution of DR is about 20±5% in 0.1N HCl in 1 hour, and the dissolution rate in pH 6.8 phosphate buffer is significantly higher (e.g., more than 30%, e.g., more than 40% in 1 hour) than the dissolution rate in 0.1N HCl.

[0048] Alternatively, when tested in USP Apparatus 1 at 100 rpm, the extent of dissolution is less than 10% in 0.1 N HCl for 2 hours, and the dissolution rate in pH 6.8 phosphate buffer is significantly higher than the dissolution rate in 0.1 N HCl (e.g., more than 40% in 1 hour).

[0049] As used herein, "disintegrant" refers to an additive that is insoluble in water but swells when wet, causing the tablet to disintegrate.

[0050] As used herein, "dissolution" refers to the process by which a solute forms a solution in a solvent.

[0051] As used herein, "enteric coat" or "enteric coating" refers to a coating that includes an enteric polymer. Enteric coatings can serve to prevent or delay the dissolution or disintegration of a tablet in the gastric environment.

[0052] "Enteric coated tablet" refers to a tablet having a core containing the active ingredient coated with an enteric coating.

[0053] As used herein, "enteric polymer" refers to a polymer that is relatively insoluble at the acidic pH of the fasted stomach (e.g., about pH 1 to about pH 4), but is soluble at higher pHs (e.g., about pH 4.5 to about pH 8) corresponding to the pH of the small intestine or later, particularly the duodenum or ileum.

[0054] The term "plasticizer" means an additive that increases the elasticity of a coating based on a film-forming material.

[0055] The terms "filler," "diluent," and "extender" are used interchangeably.

[0056] The term "bioequivalence" means that there is no difference in bioavailability, i.e., the extent of absorption and peak concentrations, over a period of time between two pharmaceutical products (e.g., test and reference products) at the same dose and under the same conditions.

[0057] The determination of whether a test product is bioequivalent to a reference product is determined by conducting a study called a bioequivalence or comparative bioavailability study under controlled conditions with a subject group, usually about 18 to 36 subjects or more.

[0058] The study may be a "crossover" design, meaning that the study is conducted in two or more phases, usually at least two weeks 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 receive the control product first. In the second phase, each subject receives a different product.

[0059] At each time point, blood samples are drawn from each subject on a scheduled schedule after ingestion of the test article. The blood samples are then analyzed to determine the serum concentration of the drug (test article, e.g., deferiprone) at each time point. For example, drugs are bioequivalent if they enter the circulation at the same rate when given in similar doses under similar conditions. A parameter often used in bioequivalence studies is t max , C max , C min , AUC 0-無限大 , AUC 0-t is.

[0060] In the context of this specification, "t max ” is the maximum plasma concentration after administration (C max ) and "AUC 0-無限大」 means the area under the plasma concentration versus time curve from time 0 to infinity; AUC 0-t " refers to the area under the plasma concentration versus time curve from 0 to t; "W50" refers to the area under the plasma concentration versus time curve from 0 to t; max "W75" means the time when the plasma concentration is greater than or equal to 50% of C max and "MRT" means the mean residence time of tacrolimus.

[0061] As used herein, "fasted state" refers to not eating for a specified period of time after a meal (typically at least several hours, e.g., 4 or 6 hours after a meal).

[0062] As used herein, "full stomach" refers to administration with a meal or shortly after (e.g., within about 1 hour) a meal.

[0063] The term "chemical stability" refers to the stability of the active agent in a formulation where the drug assay value and / or impurity content changes by no more than 5%, preferably less than 3%, during storage for at least one month at 25°C and 60% relative humidity (RH) or 40°C and / or 75% RH.

[0064] The term "in vitro-in vivo" correlation (IVIVC) refers to an in vitro dissolution test that is predictive of a pharmaceutical product's in vivo performance.

[0065] As used herein, "gastric discomfort" refers to discomfort in the gastrointestinal (GI) tract, such as one or more of pain, cramping, bloating, nausea, indigestion, heartburn, and gas.

[0066] As used herein, "tablet" refers to a solid oral pharmaceutical dosage form.

[0067] As used herein, "half tablet" means either of two portions of a tablet obtained by dividing the tablet into two halves of equal or approximately equal weight.

[0068] As used herein, "percent" or "%" refers to weight percentage (w / w) unless otherwise specified.

[0069] As used herein, a "scored tablet" refers to a tablet that has one or more lines, also known as "scores," embossed into it to allow the tablet to be easily broken, e.g., to allow for the administration of half tablets.

[0070] "Intact tablet" means a whole tablet, i.e., a tablet that has not been broken or divided into portions.

[0071] Terms such as "treat" or "treatment" or "to treat" or "ameliorate" or "alleviate" can refer to both 1) therapeutic measures that cure, slow, reduce, reverse the progression and / or halt the symptoms of a diagnosed pathological condition or disorder, and 2) prophylactic or preventative measures that prevent, reduce the occurrence, reduce the risk and / or delay the onset of the target pathological condition or disorder. Thus, subjects in need of treatment include those already with the disorder; those predisposed 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, whether detectable or undetectable, reduction in the extent of the disease, stabilization of the disease state (i.e., not worsening), delay or slowing of disease progression, improvement or palliation and remission (whether partial or complete) of the disease state. "Treatment" can also mean prolonging survival compared to life expectancy without treatment. Those in need of treatment include those already with the condition or disorder as well as those predisposed to developing the condition or disorder or those in whom the condition or disorder is to be prevented or reduced in frequency.

[0072] "Subject" or "individual" or "patient" means any human subject for whom diagnosis, prognosis, treatment or therapy is desired.

[0073] By "therapeutically effective dose or amount" or "effective amount" is intended the amount of active pharmaceutical ingredient, e.g., deferiprone, that when administered, results in a positive therapeutic response with respect to treating or reducing the risk of disease in the treated subject.

[0074] Deferiprone DR tablets, as used herein as the "control" or "comparator," are the FDA-approved and commercially available Ferriprox tablets in the United States. (登録商標) It is understood that it is a tablet (1000 mg).

[0075] Detailed Description of the Invention The present invention relates to pharmaceutical formulations for the prevention and / or treatment of diseases caused by iron overload, in particular compositions providing modified release of the active ingredient.

[0076] The active ingredient in the formulation of the present invention is deferiprone.

[0077] However, all physical forms of deferiprone (crystals, amorphous powder, all possible polymorphs, all possible solvates) are within the scope of the present invention, including pharmaceutically acceptable salts and / or solvates thereof. Preferably, deferiprone is used as a base in anhydrous form.

[0078] In a first aspect, the present invention relates to a modified release enteric coated pharmaceutical formulation in the form of minitablets for twice-daily oral administration, wherein the minitablet core comprises deferiprone as the active ingredient in an amount ranging from 74% to 87%, a long fatty acid glyceryl ester as a release modifier in an amount ranging from 10% to 20%, a lubricant and / or glidant in an amount ranging from 3 to 6% and optionally other additives in an amount of 0 to 2%, all amounts calculated by weight relative to the total weight of the uncoated formulation, and wherein the enteric coating comprises a mixture of methacrylic acid-ethyl acrylate copolymer (1:1), a plasticizer and an emulsifier.

[0079] It was found that, within the limits of statistical significance, the formulation of the present invention was able to provide an in vitro dissolution profile similar to that of the commercially available deferiprone DR tablets, which is shown in FIG.

[0080] Ferriprox (登録商標) For tablets, it has been established that deferiprone modified release formulations show good IVIV correlation (WO2019 / 082128), so the in vitro release profile is intended to reflect in vivo behavior and therefore the formulations of the present invention are intended to show the same bioavailability at steady state, thereby making them suitable for twice-daily oral administration.

[0081] The formulation of the present invention is a three-times-daily immediate-release Ferriprox (登録商標) The mean ratios of AUC (over 24 hours) and C for the tablets of the present invention to the immediate release (IR) tablets were found to be bioequivalent at steady state to the tablets.max The average ratio is in the range of 80% to 125%.

[0082] In other words, at steady state, the modified-release tablets of the present invention provide Ferriprox® when administered twice daily and three times daily. (登録商標) The maximum peak concentration (C max ) can be achieved and the total amount absorbed (AUC) over a 24-hour period is similar for both products.

[0083] On the other hand, the formulation of the present invention overcomes the problem associated with half-tablet administration, namely partial disruption of the enteric coating.

[0084] In fact, it is possible to administer the desired dose by simply counting the number of minitablets required, which helps to keep the coating intact and ensures high dosing flexibility.

[0085] Furthermore, the formulations of the present invention have the advantage of having a composition based on additives that have a non-pH dependent solubility and therefore do not directly interfere with the release of deferiprone at different pH values ​​of the gastrointestinal tract, which supports a clear improvement in terms of reproducibility of the predicted release profile.

[0086] Advantageously, the glyceryl esters of long fatty acids are selected from the group consisting of glycerol palmitate stearate, glyceryl monostearate and glyceryl dibehenate.

[0087] Glyceryl dibehenate is Compritol (登録商標) Also known as 888 ATO, it is a water-insoluble mixture of glyceryl esters of behenic acid, commercially available from Gattefosse SAS, Saint-Priest Cedex, France. Specifically, it is a mixture of mono-, di-, and triglycerides, with the di-ester being the predominant form (40-60% by weight).

[0088] Glycerin Palmitate Stearate is Precirol (登録商標)5 Also known as ATO, also commercially available from Gattefosse SAS, Saint-Priest Cedex, France.

[0089] Glyceryl monostearate is a monoglyceride commercially available from Sigma Aldrich GmbH (Germany).

[0090] In a preferred embodiment, Compritol (登録商標) 888 ATO or Precirol (登録商標) 5 Use ATO.

[0091] In fact, as is clear from Figure 1, Compritol (登録商標) 888 ATO or Precirol (登録商標) 5 ATO produces a similar dissolution profile.

[0092] In an even more preferred embodiment of the present invention, Compritol (登録商標) Use 888 ATO.

[0093] The amount of glyceryl esters of long fatty acids constitutes 10-20%, preferably 10-15%, more preferably 10%, based on the total amount of the formulation.

[0094] In fact, about 10% of Compritol (登録商標) Contrary to what is stated in co-pending application EP22167557.2, where an amount of 0.1% is suitable for once-daily administration, while a lower amount is suitable for twice-daily administration, in the minitablets of the present invention a higher amount is suitable in order to provide a dissolution suitable for twice-daily administration.

[0095] Without being bound by theory, this may be because the surface area of ​​minitablets is larger than that of standard tablets of equal mass.

[0096] Deferiprone is released in the stomach during fasting and, if partially degraded by acid hydrolysis, can cause gastric irritation.

[0097] Therefore, the coating must be capable of causing negligible dissolution in the stomach.

[0098] This is achieved through the use of an enteric coating comprising methacrylic acid-ethyl acrylate copolymer (1:1).

[0099] Methacrylic acid-ethyl acrylate copolymer (1:1) is known as Eudragit® L30-D55 and is commercially available from Evonik Operations GmbH, Essen Germany.

[0100] In addition to the enteric polymer, the enteric coating may contain other additives such as a plasticizer, a lubricant or anti-adherent agent, an opacifier, a colorant, a diluent, or any combination thereof.

[0101] Advantageously, the enteric coating plasticizer is diethyl phthalate, a citrate ester such as triethyl citrate (TEC), polyethylene glycol, glycerol, acetylated glycerides, acetylated citrate esters, dibutyl sebacate, castor oil or any combination thereof, preferably triethyl citrate.

[0102] The enteric coating may further comprise an emulsifier and a co-emulsifier or a mixture thereof. Advantageously, the emulsifier is sorbitan monolaurate, polysorbate 20 (Tween 20), (登録商標) Polysorbate 80 (also known as Tween 80) (登録商標) The co-emulsifier may be selected from the group consisting of, but not limited to, cetyl alcohol, cetearyl alcohol, sucrose stearate and glyceryl monostearate, preferably glyceryl monostearate (GMS).

[0103] Advantageously, the ingredients 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 mixture with co-emulsifier.

[0104] In a preferred embodiment, the enteric coating comprises methacrylic acid-ethyl acrylate copolymer (1:1), triethyl citrate, polysorbate 80, and glyceryl monostearate.

[0105] The coating is carried out by methods known to those skilled in the art.

[0106] The minitablets of the present invention may also contain a lubricant to prevent sticking to the die during compression into tablets and / or a glidant to improve flow during the tableting process, or a combination thereof, in an amount of 1.0 to 6.0%, preferably 3.0 to 5.0% by weight, calculated on the weight of the uncoated formulation.

[0107] 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.

[0108] 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 combinations thereof.

[0109] In a preferred embodiment, the minitablet core contains 5% talc and 0.5% magnesium stearate.

[0110] In certain embodiments, the minitablet core may include one or more pharmaceutically acceptable excipients, such as a filler.

[0111] Advantageously, when present, the filler utilized to increase the hardness of the tablet may be selected from the group consisting of calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextran, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, alpha-lactose monohydrate.

[0112] In certain embodiments, the minitablets may also contain a basic additive 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, sodium or potassium carbonate, bicarbonate, acetate, and citrate. In some embodiments, the basic additive is magnesium oxide, meglumine, or a combination thereof. In some embodiments, the basic additive is magnesium oxide.

[0113] Preferably, however, the minitablets of the present invention do not contain basic additives.

[0114] Preferred embodiments of the coated minitablet cores of the present invention include: i) deferiprone in an amount of 84.5% by weight; glyceryl behenate in an amount of 10% by weight; ii) talc in an amount of 5.0% by weight; iii) magnesium stearate in an amount of 0.5% by weight Includes:

[0115] Preferably, the coating has the following composition: [Table 1]

[0116] One skilled in the art will appropriately adjust the coating thickness to make the dissolution profile of the minitablets similar to the control formulation.

[0117] Typically, the coating thickness is 20 to 40 microns.

[0118] The thickness is in increments of 10-20% by weight, preferably 12-18%, otherwise the thickness expressed as a value of the amount of polymer per surface unit is in the range of 4-10 mg / cm. 2 The range may be:

[0119] The release profile of the tablets of the present invention is determined in different dissolution media at different pH according to the conditions described in Example 1.

[0120] Typically, dissolution tests show that no significant release is observed at pH 1.2, while upon shifting to pH 6.8, the formulations of the present invention release less than 50% w / v of the active ingredient within 1.0 hour, 85% w / v or less within 3 hours, and 95% w / v or less within 4 hours.

[0121] The present invention also provides a method for producing the coated deferiprone minitablets described above, comprising the steps of: i) combining deferiprone with the release modifier and optional additives, if present, to form a mixture; ii) compressing the mixture of step i) to obtain small particles; breaking the small particles through a tableting machine with an appropriate screen size to obtain granules; iii) blending the granules obtained in step (iii) with a lubricant / glidant additive to form a final blend; iv) compressing the final blend from step (iv) to form minitablets; and v) Coating and drying the minitablets Also provided is a method comprising the steps of:

[0122] The equipment and conditions for compaction and compression after granulation are known to those skilled in the art, and therefore the operating parameters are adjusted accordingly.

[0123] For example, typical parameters are shown in Table 3 of Example 1.

[0124] Typically, minitablets have a diameter of 2.5 to 3.0 mm, preferably 2.6 to 2.7 mm, and a height of 2.2 to 2.3 mm.

[0125] Equipment and conditions for drying coated minitablets are known in the art.

[0126] The present invention provides dosing regimens useful for therapeutic use of the pharmaceutical formulations described herein.

[0127] Typically, the oral daily dose of deferiprone can range from 75 mg / kg to 100 mg / kg.

[0128] The solid unit dose of deferiprone is typically 1000 mg, but depending on the number of minitablets, different doses may be administered depending on the patient's sex, age, and weight.

[0129] The formulations of the present invention are useful for treating diseases that cause iron overload or for preventing and / or treating diseases caused by iron overload.

[0130] In certain embodiments, the subject in need of treatment has iron overload due to transfusion iron overload or a disease such as thalassemia, myelodysplasia, or sickle cell disease.

[0131] In certain embodiments, the subject in need of treatment 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 associated with brain iron accumulation (NBIA).

[0132] In certain embodiments, the subject in need of treatment has iron overload, which is transfusional iron overload.

[0133] In some embodiments, the subject has transfusion iron overload and prior chelation therapy is inadequate. In some embodiments, the subject has transfusion iron overload and a cardiac MRI T2* of 20 ms or less (e.g., 10 ms).

[0134] The present invention also provides a container filled with the disclosed minitablets.

[0135] For example, a typical container is a capsule or a sachet.

[0136] The present invention will now be described in more detail by the following examples. [Example]

[0137] Example 1 - Preparation of uncoated minitablets and related characterization Minitablets containing deferiprone were prepared by compression of the dry granules obtained by slugging.

[0138] dry granulation The mixtures of the compositions shown in Table 1, except for magnesium stearate, were compressed into cylindrical compacts using a rotary tablet press (Officine Meccaniche Ronchi, AM8S) equipped with 11 mm diameter flat punches. The compression force (Fa) was set so that the tablets had a crushing strength of approximately 40 N. The compacts were broken in an oscillating granulator (Erweka, Wet granulator FGS) with a screen size of 1000 μm. The proposed excipients were evaluated according to their typical application in pharmaceutical formulations: Compritol 888 ATO and Precirol ATO as release-controlling agents; Vivapur, PEG 8000, Emcompress as diluents / fillers; talc as an anti-adherent; and magnesium stearate was used as a lubricant in tableting.

[0139] [Table 2] *Mean ± sd n=20

[0140] Tablet compression. The granules were added with 0.5% magnesium stearate and compacted into minitablets by means of the same press equipped with a concave punch (diameter 2.5 mm, radius of curvature 2.5 mm). The compression force was set at 1 kN. The minitablets produced had a mass of approximately 12 mg, a height of 2.2 mm, and a friability of <1% (Table 1).

[0141] Friability Ph Eur 10 th The determination was performed according to the method described in Ed.

[0142] Dissolution test (uncoated minitablets). Dissolution tests were performed in Apparatus 2 in 900 ml of pH 6.8 medium at a paddle rotation speed of 50 rpm. Minitablet sample masses corresponding to 1000 mg of deferiprone were tested in triplicate. The dissolution profiles of Formulations A-F, along with the unformulated drug, are shown in Figure 1.

[0143] As can be seen, Compritol (登録商標) and Precirol (登録商標) Formulations containing show similar dissolution profiles due to their lipophilic nature.

[0144] Formulation B (Compritol (登録商標) 888 ATO 10% w / w) was selected for coating with a gastroresistant film.

[0145] Example 2 - Preparation of coated minitablets and related characterization Coating was carried out in a fluidized bed apparatus equipped with a Wurster insert (Mini-Glatt, Glatt GmbH, D). The coating suspension (composition in Table 2) was applied under the experimental conditions described in Table 3.

[0146] The resulting coated minitablets were dried.

[0147] [Table 3]

[0148] [Table 4]

[0149] To produce units with various coating levels, samples were collected after 27 minutes (batch 1) and 41 minutes (batch 2) during the process, corresponding to a weight gain of 11.92 and 17.89%, respectively, calculated by the following formula:

number

[0150] The height and diameter were characterized using a digital micrometer (Absolute, Mitutoyo, J, n=20); the thickness of the coating layer was calculated using the following formula:

number

[0151] [Table 5]

[0152] Dissolution test of coated minitablets The test was carried out in Apparatus 2 at 37°C, with a paddle rotation speed of 50 rpm, according to Ph.Eur. 10 th The results were analyzed using the "Delayed Release Solid Dosage Forms, Method B" by Ed.

[0153] The maximum absorption spectra of the active substance were obtained in the different fluids in which the release test was carried out by means of a spectrophotometer.

[0154] The composition of the dissolution medium is shown below.

[0155] pH 1.2: 3.73g KCI, 7.07ml HCl 1N per liter (add deionized water to the specified volume) pH 4.5: 6.80g KH2P04 per 1L (drain with deionized water to the specified volume) pH 6.8: 6.80g KH2P04, 0.90g NaOH per liter (drain to the specified volume with deionized water)

[0156] Calibration curves were recorded for each of the release media at both wavelengths, 276 nm, where the absorbance peak was recorded, and 243 nm, where the decrease in absorbance was observed, in order not to exceed the instrument maximum absorbance value.

[0157] The release test of the commercial product was analyzed at a wavelength of 276 nm in pH change mode (HCl 0.1N for the first 120 minutes and phosphate buffer pH 6.8 for the remainder of the test).

[0158] The dissolution profiles of coated minitablets with different coating levels are shown in Figure 2 along with a commercial control.

[0159] As can be seen from Figure 2, within statistical significance, the formulation of the present invention was able to provide an in vitro dissolution profile similar to the commercially available deferiprone DR tablets (control).

[0160] In particular, up to 240 minutes the two profiles substantially overlap.

Claims

1. A modified release enteric coated pharmaceutical formulation in the form of minitablets for oral administration twice daily, wherein the tablet core comprises deferiprone as an active ingredient in an amount ranging from 74% to 87%, a long fatty acid glyceryl ester as a release modifier in an amount ranging from 10% to 20%, a lubricant and / or glidant in an amount of 1 to 6%, and optionally other additives in an amount of 0 to 2%, all amounts calculated by weight based on the total weight of the uncoated formulation, and wherein the enteric coating comprises a mixture of methacrylic acid-ethyl acrylate copolymer (1:1), a plasticizer, and an emulsifier.

2. 2. The modified release formulation of claim 1, wherein the glyceryl ester of long fatty acids is selected from the group consisting of glyceryl palmitate stearate, glyceryl monostearate, and glyceryl dibehenate.

3. 3. The modified release formulation of claim 1 or 2, wherein the glyceryl ester of a long fatty acid is glyceryl dibehenate.

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

5. 5. The pharmaceutical formulation of claim 4, wherein the lubricant is magnesium stearate.

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

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

8. 8. The pharmaceutical formulation of any of claims 1 to 7, wherein other suitable pharmaceutically acceptable additives, if present, are selected from the class of bulking agents.

9. 9. The pharmaceutical formulation of claim 1, wherein the plasticizer is triethyl citrate.

10. Emulsifiers: sorbitan monolaurate, polysorbate 20 (Tween 20) (登録商標) ) and polysorbate 80 (Tween 80 (登録商標) 2. The pharmaceutical formulation of claim 1, wherein the compound is selected from the group consisting of, but not limited to:

11. 11. The pharmaceutical formulation of claim 10, wherein the emulsifier is polysorbate 80.

12. 12. The pharmaceutical formulation of any of claims 1 to 11, wherein the coating further comprises a co-emulsifier selected from the group consisting of cetyl alcohol, cetearyl alcohol, and sucrose stearate.

13. 13. The pharmaceutical formulation of claim 12, wherein the co-emulsifier is glyceryl monostearate.

14. A method for producing the pharmaceutical formulation of any one of claims 1 to 13, comprising the steps of: (i) combining deferiprone with a release-modifying agent and optional additives, if present, to form a mixture; (ii) compressing the mixture of step i) into tablets to obtain compacts; (iii) Breaking the small pieces through a suitable screen size maker to obtain granules; (iv) blending the granules from step (iii) with a lubricant / glidant additive to form a final blend; (v) compressing the final blend from step (iv) to form minitablets; (vi) coating the minitablets; and (vii) drying the coated minitablets; A method comprising the steps of:

15. 14. The pharmaceutical composition of any one of claims 1 to 13 for use in treating a disease that causes iron overload or for preventing and / or treating a disease caused by iron overload.

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

17. 16. The pharmaceutical composition for use according to claim 15, wherein said iron overload is transfusional iron overload.

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