Modulated release pharmaceutical formulations comprising deferiprone

Abstract

The present invention relates to a pharmaceutical composition for oral administration in the form of a coated tablet, which exhibits delayed release properties when administered as a whole or half tablet. In particular, the present invention relates to a delayed release tablet comprising deferiprone, said tablet being suitable for oral administration twice a day. The invention also relates to methods of making and using such tablets.

Description

Field of the Invention

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

[0002] In particular, the present invention relates to modified release formulations suitable for twice daily oral administration for the treatment of iron overload that occurs in patients suffering from, for example, thalassemia, sickle cell disease, hemochromatosis and myelodysplasia. Background of the Invention

[0004] Deferiprone, also known as 3-hydroxy-1,2-dimethylpyridin-4-one, is a bidentate ligand that binds iron in a 3:1 molar ratio.

[0005] It is used to treat generalized iron overload, particularly conditions where frequent blood transfusions lead to iron overload, including, for example, thalassemia and sickle cell disease (SCD).

[0006] The introduction of deferiprone in current therapy has represented an important advance as it reduces hepatic iron concentration (LIC) and cardiac iron overload.

[0007] 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 showed that deferiprone monotherapy appeared to be superior to deferoxamine monotherapy in improving myocardial iron deposition and cardiac function.

[0008] In terms of safety, the most common adverse events were gastrointestinal disturbances due to gastrointestinal irritation. Such discomfort may cause patients to refuse to take the medication, which may lead to a worsening of their condition. Other adverse events observed were musculoskeletal disorders (arthralgia), increased alanine aminotransferase (ALT), agranulocytosis, and neutropenia.

[0009] Agranulocytosis appears to be an idiopathic reaction and it is more frequent in the first year of treatment. The incidence of neutropenia and agranulocytosis is stable and does not appear to be dose-related (Hider RC et al. N Engl J Med. 2018; 379: 2140-2150).

[0010] Deferiprone has a long half-life of 2-3 hours but has an unpleasant bitter taste.

[0011] The drug is available as immediate release (IR) 500 mg and 1000 mg tablets and a 100 mg / ml liquid formulation, commonly under the trade name Sale.

[0012] Considering its pharmacological and ADME properties, and in order to improve patient compliance, deferiprone has also recently been commercially launched as a 1000 mg delayed-release (DR) tablet for oral administration.

[0013] 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.

[0014] Commercial tablets are also scored with a score line to allow the patient to easily divide the tablet into two approximately equal portions for dosing flexibility.

[0015] The composition of the DR tablet has been disclosed in WO 2019 / 082128, and it comprises: (a) a core comprising an active pharmaceutical ingredient and an enteric polymer having pH-dependent solubility, and (b) an enteric coating.

[0016] In fact, oral pharmaceutical dosage forms containing deferiprone, due to its potential irritation and damage to the gastric mucosa, and its relatively high solubility in an acidic environment, should be provided with an enteric coating (e.g. a polymer film with solubility at pH>5) in order to avoid or at least reduce the release of the active ingredient during the residence of the unit in the stomach, avoiding the reaching of plasma concentrations that could cause systemic adverse reactions.

[0017] In the case of the marketed deferiprone product, hydroxypropylmethylcellulose acetate succinate (HPMC-AS) is used as the enteric polymer in the tablet core for sustained release.

[0018] However, HPMC-AS has pH-dependent solubility.

[0019] This may result in a release that is influenced by the external environment, and therefore less predictable, subject to random microenvironmental variations in pH, which the unit must face during transport along the area where the release of the active ingredient occurs, characterized by physiological fluids with different pH.

[0020] It would therefore be advantageous to provide tablets suitable for twice-daily oral administration having improved properties with respect to the reproducibility of the expected release profile.

[0021] Some documents of the prior art disclose deferiprone formulations containing hydroxypropylmethylcellulose as an 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 2006 / 122273; CN 106983746). However, they do not mention the problem of improving the reproducibility of the release curve.

[0022] The present invention provides the technical solution. SUMMARY OF THE INVENTION

[0024] The present invention provides a pharmaceutical formulation in the form of a modified release enteric coated tablet suitable for oral administration twice daily, wherein the core of the tablet comprises: a) deferiprone in an amount between 85.0 and 95.0%, b) hydroxypropylmethylcellulose polymer having a viscosity of 100 cP alone or in mixture with hydroxypropylmethylcellulose polymer having a viscosity of 4000 cP as a modified release agent in an amount between 4.0 and 10.0%, c) a lubricant and / or a glidant in an amount between 0.2 and 2.0%, and d) other suitable pharmaceutically acceptable excipients in an amount between 0 and 5%, all amounts being calculated by weight based on the total weight of the formulation.

[0025] Other suitable pharmaceutically acceptable excipients may fall into the category of pH adjusters and bulking agents.

[0026] Therefore, in a second aspect the present invention provides a process for preparing a coated deferiprone tablet as described above, the process comprising the steps of:

[0027] (i) mixing deferiprone with a modified release agent and other pharmaceutically acceptable excipients (if present) to form a mixture;

[0028] (ii) wet granulating the mixture obtained in step (i) in a high shear granulator, followed by drying and sieving to produce granules;

[0029] (iii) mixing the granules obtained in step (ii) with a lubricant and / or a glidant excipient to form a mixture;

[0030] (iv) compressing the mixture obtained in step (iii) to form tablets; and

[0031] (v) Coating the tablets.

[0032] In an alternative aspect, the method comprises the steps of:

[0033] (i) mixing deferiprone with a modified release agent and other pharmaceutically acceptable excipients (if present) to form a mixture;

[0034] (ii) adding lubricant and / or glidant excipients and further mixing;

[0035] (iii) directly compressing the mixture obtained in step (ii) to form tablets; and

[0036] (iv) coating the tablets.

[0037] In a third aspect, the present invention relates to the claimed pharmaceutical composition for use in the treatment of diseases leading to iron overload, or for use in the prevention and / or treatment of diseases caused by iron overload.

[0038] In a fourth aspect, the present invention relates to a pharmaceutical composition as claimed for use in the preparation of a medicament for the treatment of a disease resulting in iron overload, or for the prevention and / or treatment of a disease resulting from iron overload.

[0039] In a fifth aspect, the present invention relates to a method for treating a disease causing iron overload in a patient in need thereof, or a method for preventing and / or treating a disease caused by iron overload in a patient in need thereof, said method comprising orally administering the claimed pharmaceutical composition.

[0040] BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 - Dissolution test of HPMC formulations carried out in 900 ml of pH 6.8 medium in a basket with a rotation speed of 100 rpm (device 1). The lines with triangle signs are referred to as commercial products.

[0042] Figure 2 - Dissolution test of HPMC formulations carried out in 900 ml of pH 4.5 medium in a paddle with a rotation speed of 50 rpm (device 2). The lines with the triangle sign are referred to as commercial products.

[0043] Figure 3 - Dissolution tests of HPMC formulations carried out in 900 ml of pH 1.2 medium (120 min) and then pH 6.8 medium in a basket with a rotation speed of 100 rpm (device 1). The lines with triangle signs are referred to as commercial products.

[0044] Figure 4 - Dissolution tests of HPMC formulations carried out in 900 ml of pH 1.2 medium (120 min) and then pH 6.8 medium in a basket with a rotation speed of 100 rpm (device 1). The lines with triangle signs are referred to as commercial products.

[0045] Figure 5 - Dissolution tests of HPMC formulations carried out in 900 ml of pH 1.2 medium (120 min) and then pH 6.8 medium in a basket with a rotation speed of 100 rpm (device 1). The lines with triangle signs are referred to as commercial products.

[0046] Figure 6- Dissolution test of half-coated tablets in 900 ml of pH 1.2 medium (120 min) and then pH 6.8 medium in a basket with a rotation speed of 100 rpm (device 1). The line with the triangle mark is referred to as the commercial product.

[0047] definition

[0048] As used herein, the indefinite article "a" or "an" is to be understood to refer to "one or more" of any stated or listed components. For example, "a tablet" means one or more tablets.

[0049] Also as used herein, "and / or" refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as when interpreted in the alternative fashion ("or"), refers to the lack of a combination.

[0050] When the term "about" is used with a numerical value or range, it modifies the value or range by extending the boundaries above and below the numerical value. The term "about" is used herein to modulate a numerical value above and below the numerical value by a variation of 10% up or down (higher or lower), i.e., ±10%, unless a different variation is specified (e.g., ±30%, ±20%, ±5%, ±1%, etc.).

[0051] Any aspects described herein using the language "comprising" also provide similar aspects described using the terminology "consisting of" and / or "consisting essentially of. 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 interpreted when that term is used as a transitional word in a claim.

[0052] As used herein, the terms "active ingredient" or "active pharmaceutical ingredient" (API) or "drug" are used as synonyms and refer to 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.

[0053] The terms "iron overload" or "iron overload" are used interchangeably herein and 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 the excess iron is introduced through one or more blood transfusions.

[0054] In the present context, the term "hydrophilic" describes a substance that "likes water", i.e., a hydrophilic molecule or portion of a molecule is one that is generally electrically polarized and is able to form hydrogen bonds with water molecules, making it more soluble in water than in oil or other "non-polar" solvents.

[0055] In contrast, the term "hydrophobic" refers to compounds that tend to be electrically neutral and non-polar, and therefore prefer other neutral and non-polar solvents or molecular environments.

[0056] "pH-dependent solubility" refers to substances that have different solubility at different pH. These pH-dependent solubility differences result in pH-dependent dissolution profiles.

[0057] The expression "insoluble or poorly soluble in water" refers to a substance having a solubility in water as defined in European Pharmacopoeia 4th edition, 2003, page 2891.

[0058] As used herein, the "core" or "tablet core" comprises the 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.

[0059] In this context, the terms "controlled release", "extended release", "modulated release" and "delayed release" are intended as equivalent terms covering any type of release of deferiprone from the composition of the present invention, which is suitable for obtaining a specific therapeutic or preventive response after administration to a subject. The term refers to protecting the active ingredient (e.g., deferiprone) from rapid release at acidic pH (e.g., in the stomach) while enabling the active ingredient to be released at a higher rate at a higher pH (e.g., in the intestine). In some aspects, DR should be understood to mean that when tested at 75 rpm in USP apparatus 2, the dissolution rate in 0.1N HCl at 1 hour will be around 20±5%, and the dissolution rate in phosphate buffer with pH 6.8 will be much higher (at 1 hour, for example, more than 30%, for example, more than 40%) than the dissolution rate in 0.1N HCl.

[0060] As used herein, "disintegrant" refers to an excipient that is insoluble in water but swells when wetted to cause disintegration of the tablet.

[0061] As used herein, "dissolution" refers to the process by which a solute forms a solution in a solvent.

[0062] As used herein, "enteric coat" or "enteric coating" refers to a coating comprising an enteric polymer. Enteric coatings can be used to prevent or delay dissolution or disintegration of a tablet in the gastric environment.

[0063] The "burst effect" refers to the initial rapid release before the release rate reaches a steady-state curve, which occurs immediately upon a change in pH in the release medium.

[0064] "Enteric-coated tablet" refers to a tablet having a core comprising the active ingredient, which is coated with an enteric coating.

[0065] As used herein, "enteric polymer" is understood to refer 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 a higher pH (e.g., about pH 4.5 to about pH 8), which corresponds to the pH in or beyond the small intestine, particularly in the duodenum or ileum.

[0066] The terms "filler," "diluent," and "bulking agent" are used synonymously.

[0067] The term "bioequivalence" means the absence of significant differences in bioavailability (ie, extent of absorption and peak concentration) between two drug products (eg, test and reference products) at the same dose and under the same conditions over a period of time.

[0068] The determination of whether a test product is bioequivalent to a reference product is made by conducting studies under controlled conditions in a small group of subjects (usually about 18-36 subjects or more), called bioequivalence or comparative bioavailability studies.

[0069] The study can be conducted using a "crossover" design, which means that the study is conducted in 2 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 take the test product first, and the other half to take the reference product first. In the second phase, each subject takes the alternate product.

[0070] At each stage, blood samples are drawn from each subject on a predetermined schedule after taking 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, if the drugs enter the circulation at the same rate when given at similar doses under similar conditions, they are bioequivalent. The parameters commonly used in bioequivalence studies are t max , C max , C min , AUC 0-infinity , AUC 0-t .

[0071] In this context, “t max" indicates the maximum plasma concentration (C max ) time; AUC 0-infinity AUC represents the area under the plasma concentration-time curve from time 0 to infinity; 0-t represents the area under the plasma concentration-time curve from time 0 to time t; W50 represents the plasma concentration C max 50% or more of the time; W75 means that the plasma concentration is C max 75% or more of the time; and MRT means the mean residence time of tacrolimus.

[0072] As used herein, "fasted state" refers to fasting after a meal for a defined period of time (generally, at least several hours, eg, 4 or 6 hours, after a meal).

[0073] As used herein, "fed state" refers to administration with a meal or shortly after a meal (eg, within about 1 hour).

[0074] The term "chemically stable" refers to the stability of the active agent in a formulation wherein the drug assay and / or impurity levels vary by 5% or less, preferably less than 3%, during storage for at least 1 month at 25°C and 60% relative humidity (RH) or 40°C and 75% RH.

[0075] 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.

[0076] As used herein, "stomach upset" refers to an uncomfortable sensation in the gastrointestinal (GI) tract, for example, one or more of pain, cramping, bloating, nausea, indigestion, heartburn, and flatulence.

[0077] As used herein, "half tablet" refers to one of the two parts of a tablet obtained by dividing a tablet into two parts of equal or approximately equal weight. In some embodiments, a half tablet is about 40% to about 60% by weight of the whole tablet from which the half is derived. In some aspects, the approximately equal weight of each half tablet is about 45-55% of the total weight of the whole tablet.

[0078] As used herein, "percent" or "%" refers to percent by weight (w / w), unless otherwise indicated.

[0079] As used herein, a "scored tablet" refers to a tablet having one or more lines (also referred to as "score lines") cut therein to facilitate splitting the tablet, e.g., so that half a tablet can be administered. In some aspects, the tablet can be scored with two, three, four or more score lines.

[0080] As used herein, "tablet" refers to a solid oral pharmaceutical dosage form. In some embodiments, the tablet is a compressed tablet.

[0081] "Intact tablet" refers to a tablet that is intact, ie, not broken or split into parts.

[0082] 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.

[0083] Terms such as "treating" or "treatment" or "to treat" or "ameliorate" or "alleviating" or "to alleviate" may refer to both: 1) therapeutic measures that cure, slow down, alleviate the symptoms of, reverse and / or stop the progression of a diagnosed pathological condition or disorder, and 2) prophylactic or preventative measures that prevent, reduce the incidence of, reduce the risk of, and / or slow the development of a targeted pathological condition or disorder. Thus, persons in need of treatment include persons already suffering from the disorder; persons susceptible to the disorder; and persons in whom the disorder is to be prevented. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, reduction in the extent of the disease, a stable (i.e., non-worsening) disease state, delay or slowing of disease progression, improvement or alleviation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" may also refer to prolonged survival compared to the 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 having the condition or disorder or those in whom the condition or disorder is to be prevented or its incidence is to be reduced.

[0084] "Subject" or "individual" or "patient" refers to any human subject for whom diagnosis, prognosis, treatment or therapy is desired.

[0085] "Therapeutically effective dose or amount" or "effective amount" means the amount of active pharmaceutical ingredient (eg, deferiprone) which, when administered, produces a positive therapeutic response with respect to the treatment or reduction of risk of a disease in the subject being treated.

[0086] It should be understood that the deferiprone DR tablets used herein as the "reference" or "reference product" are those approved by the FDA and sold in the U.S. Tablets (1000 mg). DETAILED DESCRIPTION OF THE INVENTION

[0088] The present invention relates to pharmaceutical preparations for preventing and / or treating diseases caused by an excess of iron, in particular compositions providing a modified release of an active ingredient.

[0089] The active ingredient in the formulation of the present invention is deferiprone. However, within the scope of the present invention is deferiprone in any physical form (crystals, amorphous powder, any possible polymorphs, any possible solvates). Pharmaceutically acceptable salts and / or solvates thereof are also included. Preferably, deferiprone is used as a base in its anhydrous form.

[0090] 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 oral administration twice daily, wherein the core of the tablet comprises: a) deferiprone in an amount between 85.0 and 95.0%, b) hydroxypropylmethylcellulose polymer having a viscosity of 100 cP alone or in mixture with hydroxypropylmethylcellulose polymer having a viscosity of 4000 cP as a modified release agent in an amount between 4.0 and 10.0%, c) a lubricant and / or a glidant in an amount between 0.2 and 2.0%, and d) other suitable pharmaceutically acceptable excipients in an amount between 0 and 5%, all amounts being calculated by weight based on the total weight of the formulation.

[0091] It has been found that using hydrophilic polymers as release modifying agents, an in vitro release similar to that of the commercial deferiprone DR tablets can be obtained within a statistically significant range.

[0092] In particular, the core tablets of the pharmaceutical dosage form object of the present invention have the advantage of being based on a composition of excipients having a pH-independent solubility, and therefore they do not directly interfere with the release of dexamethasone at different pH values ​​in the gastrointestinal tract.

[0093] This demonstrated an undeniable improvement in the reproducibility of the expected release profile.

[0094] Additional surprising advantages associated with the use of these polymers will become apparent from the description that follows.

[0095] Advantageously, hydroxypropyl methylcellulose polymer (HPMC) K100LV is a low substituted thickener that produces a viscosity of approximately 100 cP at 2% addition in water at 20°C.

[0096] The polymer can be combined with hydroxypropyl methylcellulose polymer (HPMC) Used in combination with K4M, K4M is a medium molecular weight hydroxypropyl methylcellulose (HPMC) thickener. Its addition at 2% in water at 20°C will produce a viscosity of about 4,000 cP.

[0097] They are all commercially available from DuPont (Delaware, USA) or from Colorcon Inc (California, USA).

[0098] Advantageously, the modified release agent is present in an amount comprised between 4.0 and 10.0 wt%, preferably between 7 and 8 wt%.

[0099] In a preferred embodiment, 7.5% by weight of K100LV, while in another preferred embodiment, 5% by weight of K100LV and A mixture of K4M, preferably wherein the amounts of the two polymers are 2 wt% and 3.0 wt% respectively (ratio 40:60 w / w).

[0100] Deferiprone may cause gastric irritation if released in the fasting stomach, and some degradation by acid hydrolysis.

[0101] Thus, the tablets of the present invention will be provided with an enteric coating and a diluent such as water, ethanol, propylene glycol or a mixture thereof, the enteric coating being used to delay the dissolution of deferiprone and avoid dissolution in the stomach, particularly in fasting patients.

[0102] Due to the coating, the tablets according to the invention are formulated to have negligible dissolution in the fasting stomach, but will dissolve more rapidly in the intestine.

[0103] Suitable enteric polymers for enteric coatings include, for example, hydroxypropyl methylcellulose acetate succinate (also known as hydroxypropyl methylcellulose acetate succinate or HPMCAS), HPMC phthalate (also known as hypromellose phthalate), polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, shellac, zein, methacrylic acid copolymers (e.g., methacrylic acid copolymer type C dispersion 30%), derivatives thereof, and any combination thereof.

[0104] In some embodiments, a preferred enteric polymer in the enteric coating is HPMC acetate succinate and methacrylic acid copolymer, for example, methacrylic acid copolymer type C, in aqueous dispersion.

[0105] 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 a range between any two of the foregoing values, for example. For example, 0.5-1% by weight, 0.5-2% by weight, 0.5-3% by weight, 0.5-4% by weight, 0.6-1% by weight, 0.6-2% by weight, 0.6-3% by weight, 0.6-4% by weight, 0.7-1% by weight, 0.7-2% by weight, 0.7-3% by weight, 0.7-4% by weight, 1-1.5% by weight, 1.1-1.7% by weight, 1-2% by weight, 1.5-2% by weight, 1-3% by weight, 1-3.5% by weight, or 1-4% by weight of the tablet. In other embodiments, the enteric polymer in the coating is about 2.0% by weight or about 3.0% by weight of the tablet.

[0106] It has been found that for tablets of the invention, a thicker coating (2-3 wt%) would be preferred to obtain a release profile similar to the reference product, which had a coating of about 1.4-1.5 wt%.

[0107] In some embodiments, the enteric coating comprises other excipients in addition to the enteric polymer, including, for example, plasticizers, lubricants or anti-adherents such as talc, opacifiers, colorants, diluents, or any combination thereof.

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

[0109] In other embodiments, the enteric coating may further comprise a diluent, such as lactose, sucrose, fructose, mannitol, etc., or a combination thereof. In some embodiments, the enteric coating comprises talc as a lubricant or anti-adherent.

[0110] 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 L30-D55 and is commercially available from Evonik Operations GmbH, Essen Germany.

[0111] In an alternative preferred embodiment, the enteric coating comprises methacrylic acid-methacrylic acid ester copolymer (1:1) in alcoholic solution, preferably in a concentration of 5-15% w / w, more preferably in a concentration of 10% w / w, with triethyl citrate as a plasticizer, preferably in a concentration of 2-5% w / w, more preferably in a concentration of 3% w / w relative to the polymer.

[0112] Methacrylic acid-methacrylate copolymer (1:1) is called L100 (dissolution pH around 6.8), and is commercially available, for example, from Sigma-Aldrich (Missouri, USA).

[0113] Coating should be carried out according to methods known to the skilled person and usually lasts for a period of 15 to 20 minutes.

[0114] In some embodiments, the core may comprise one or more pharmaceutically acceptable excipients such as bulking agents and / or alkaline excipients.

[0115] Advantageously, the bulking agent 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, alpha-lactose monohydrate.

[0116] Advantageously, the alkaline excipient may be selected from the group consisting of 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 salts of carbonates, bicarbonates, acetates, and citrates. In certain embodiments, the alkaline excipient is magnesium oxide, meglumine, or a combination thereof. In some embodiments, the alkaline excipient is magnesium oxide.

[0117] Tablets should also contain a lubricant to prevent sticking to process equipment during compression into tablets, and / or a glidant to improve flow during tableting, or a combination thereof.

[0118] 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.

[0119] Preferably, the lubricant is magnesium stearate.

[0120] 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.

[0121] In a preferred embodiment, the core of the tablet comprises a mixture of magnesium stearate and colloidal silicon dioxide.

[0122] As an exemplary embodiment, the core of the coating formulation comprises:

[0123] a) deferiprone in an amount of 91% by weight;

[0124] b) 7.5% by weight K100LV; and

[0125] c) A mixture of lubricants and glidants in an amount of 1.5% by weight.

[0126] In another exemplary embodiment, the core of the coating formulation comprises:

[0127] a) Deferiprone in an amount of 93% by weight:

[0128] b) 2.0 wt% K100LV;

[0129] c) 3.0% by weight K4M;

[0130] d) A mixture of a lubricant and a glidant in an amount of 2.0% by weight.

[0131] Advantageously, the tablets of the present invention are scored with a score line to allow the patient to easily divide the tablet into two approximately equal parts so that half the tablet can be administered, allowing for dosing flexibility.

[0132] Needless to say, when the tablet is broken, its surface at the interface is no longer protected by the enteric coating, and some dissolution in gastric acid can be observed.

[0133] On the other hand, as long as the dissolution rate at acidic pH is around 20%, or even better below this value, this is considered acceptable.

[0134] As an additional advantage, Figure 6 As reported in , although the release at low pH is slightly higher than observed for the commercial tablets, the half-tablets of the invention do not show any undesirable burst effect when a pH shift occurs and exhibit a smoother release of the active ingredient during the first phase of dissolution.

[0135] In fact, it is well known that transiently higher concentrations and thus transiently higher plasma levels of deferiprone can be associated with transient elevations of liver enzymes and other side effects (Cohen ER et al. Br J Haematology, 2000, 108, 305-312).

[0136] Advantageously, the tablets of the present disclosure include the attributes of enteric coated tablets without their drawbacks, and thus the tablets can be split in half to enable fine-tuning of the dosage to administer the whole tablet, half tablet, or any combination thereof. The half tablets of the present disclosure are substantially resistant to dissolution in an acidic medium (0.1N HCl) representative of fasting stomach contents, as is the whole tablet; and, at a higher pH representative of the contents of the small intestine, also exhibit similar dissolution rates to the whole tablet, but without the undesirable burst effect of the reference product on the market.

[0137] The release profiles of the tablets of the invention have been determined according to the conditions reported in Examples 2 and 3 in different dissolution media with varying pH.

[0138] As reported in WO 2019 / 082128, for Tablets, modified release formulations of deferiprone showed good IVIV correlation, therefore it was expected that the in vitro release profile would reflect the in vivo behavior.

[0139] The tablets according to the present invention produce the same pH as that approved by the FDA and sold in the United States at pH 6.8. The dissolution profiles of the tablets are similar and therefore they are expected to show the same bioavailability at steady state, making them suitable for twice daily oral administration.

[0140] It is expected that the formulation will be comparable to the immediate release three times daily administration in the steady state. The tablets are bioequivalent and the mean ratio of AUC (over 24 hours) and the mean ratio of Cmax of the tablets of the present invention relative to the immediate release (IR) tablets will be within 80% to 125%.

[0141] In other words, at steady state, the modified release tablets of the present invention when administered twice daily will be able to achieve the same results as when the IR tablets are administered three times daily. The same maximum peak concentration (C max ), and the total amount absorbed (AUC) of both products was the same over a 24-hour period.

[0142] The present invention also provides a method for preparing the coated deferiprone tablet as described above, the method comprising:

[0143] i) mixing deferiprone with a modified release agent and a pharmaceutically acceptable excipient (if present) to form a mixture;

[0144] ii) wet granulating the mixture obtained in step (i) in a high shear granulator, followed by drying and sieving to produce granules;

[0145] iii) mixing the granules obtained in step (ii) with a lubricant and / or a glidant excipient to form a mixture;

[0146] iv) compressing the mixture obtained in step (iii) to form tablets;

[0147] v) Coating the tablets.

[0148] In an alternative embodiment, the method comprises the following steps:

[0149] i) mixing deferiprone with a modified release agent and a pharmaceutically acceptable excipient (if present) to form a mixture;

[0150] ii) adding lubricant and / or glidant excipients and further mixing;

[0151] iii) directly compressing the mixture obtained in step (ii) to form tablets; and

[0152] iv) coating the tablets.

[0153] Apparatus and conditions for direct compression and / or compression after granulation are known to those skilled in the art.

[0154] The tablets may be prepared in any suitable weight but preferably the weight of each individual unit will be in the range 800 to 1500 mg, preferably in the range 1000 mg to 1200 mg.

[0155] For the avoidance of doubt, reference is made to the extensive literature on the subject of these and other pharmaceutically acceptable excipients and procedures mentioned herein, in particular to Handbook of Pharmaceutical Excipients, 3rd edition, Arthur H. Kibbe, ed., American Pharmaceutical Association, Washington, U.S.A. and Pharmaceutical Press, London; and Lexikon der Hilfsstoffe fi.ir Pharmazie, Kosmetik und angrenzende Gebiete, HP Fiedler, ed., 4th edition, ed. Cantar, Aulendorf and earlier editions.

[0156] The present invention provides dosing regimens that can be used for therapeutic uses of the pharmaceutical formulations described herein.

[0157] Typically, the oral daily dose of deferiprone may range from 75 mg / kg to 100 mg / kg.

[0158] In some embodiments, the deferiprone compositions of the invention are administered to a subject in need thereof twice daily.

[0159] The unit dose of deferiprone tablets should be comprised between 500 and 1200 mg, preferably between 600 and 1000 mg, depending on the frequency of administration.

[0160] The claimed preparations can be used for treating diseases which lead to iron overload, or for preventing and / or treating diseases which are caused by iron overload.

[0161] In some embodiments, the subject in need thereof has iron overload caused by transfusional iron overload or iron overload caused by a disease such as thalassemia, myelodysplasia, sickle cell disease, or hemochromatosis.

[0162] In some embodiments, the subject in need thereof suffers from a neurodegenerative disease (e.g., Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, Friedreich's ataxia, pantothenate kinase-associated neurodegeneration (PKAN), or neurodegeneration with brain iron deposition (NBIA).

[0163] In some embodiments, the subject in need thereof suffers from iron overload as transfusional iron overload. In certain aspects, the subject suffers from transfusional iron overload and their previous chelation therapy was inadequate.

[0164] In certain aspects, the subject has transfusional iron overload and has a cardiac MRI T2* of 20 ms or less (eg, 10 ms).

[0165] The present invention is illustrated in detail by the following examples. Example

[0166] Example 1 - Preparation of tablets.

[0167] Tablets were prepared by direct compression using a rotary tablet press (Officine Meccaniche Ronchi, AM8S) equipped with an oblong die measuring 22 mm x 10 mm. The compression force was set at 25 kN to give a tablet with a compressive strength of approximately 70 N.

[0168] The hydrophilic matrix consists of 1000 mg of active substance and different percentages of HPMC polymer ( K100LV, K4M, Colorcon, USA).

[0169] Table 1. Formulation of oblong tablets formulated with hydrophilic swellable excipients

[0170]

[0171]

[0172] Example 2 - Dissolution Test

[0173] The maximum absorption spectra of the active substances are obtained in various liquids in which the release tests are to be carried out by means of a spectrophotometer.

[0174] The composition of the dissolution medium is reported below.

[0175] pH 1.2: for 1 L, 3.73 g KCl, 7.07 ml HCl 1N (deionized water to volume);

[0176] pH 4.5: for 1 L, 6.80 g KH2PO4 (deionized water to volume);

[0177] pH 6.8: For 1 L, 6.80 g KH2PO4, 0.90 g NaOH (deionized water to volume).

[0178] For each of the release media, a calibration curve was established at both the wavelength of 276 nm where the peak of absorbance was recorded and at 243 nm where a decrease in absorbance was observed, so as not to exceed the instrument maximum absorbance value.

[0179] Release tests of commercial products were performed in pH 4.5 phosphate neutralization and in pH variation mode (HCl 0.1 N for the first 120 minutes and phosphate buffer pH 6.8 for the remainder of the test) at a wavelength of 276 nm. Sampling, dilution and manual reading were performed at high absorbance values ​​(released over 30%).

[0180] Release tests were performed in a dissolution testing paddle apparatus (USP type 2) with a rotation speed of 50 rpm and a basket apparatus (USP type 1) with a rotation speed of 100 rpm. Tests were always performed at 37°C in 900 mL of dissolution medium.

[0181] For the experimental formulations, the active ingredient was quantified by spectrophotometry at a wavelength of 243 nm.

[0182] Results for uncoated tablets at pH 6.8 and 4.5 are reported in Figure 1 and 2 middle.

[0183] It can be seen that including K100LV 7,5% or Tablets of a mixture of K100LV 2% and K4M 3% showed a release profile more similar to the reference product.

[0184] Example 3 - Enteric Coating

[0185] Based on the results with the uncoated tablets, tablets were formulated as follows:

[0186] - K100LV 7.5%

[0187] - K100LV 2% and K4M 3%

[0188] Selected to be coated with an enteric film.

[0189] The tablets were then coated with different acrylic polymers that had a dissolution pH around 6 and were formulated in the following aqueous dispersions:

[0190] - L30-D55 aqueous dispersion 60% w / w (containing 25% solids)

[0191] - Deionized water 38% w / w

[0192] - Propylene glycol 2% w / w

[0193] The process parameters are as follows:

[0194] -Nozzle: 0.8mm

[0195] - Atomization pressure: 0,8 bar

[0196] -Control pressure: 2 bar

[0197] -Embossing pressure: 0,5 bar

[0198] -Peristaltic pump: 2rpm

[0199] - Air temperature: 57℃

[0200] The coating process lasted for 20 minutes and samples were collected every 5 minutes to test different coating amounts by dissolution testing. The analysis was performed under the same conditions as the previous test.

[0201] The results are reported in Figure 3 and 4 middle.

[0202] The K100LV 7.5% tablets were more difficult to coat in the first few minutes. In fact, the coating process for this formulation lasted 5 minutes longer than the K100LV 2% K4M 3% tablets; both ended up at 2% by weight.

[0203] As an alternative method of coating, a solution of 10% w / w in alcohol with triethyl citrate (3% w / w relative to polymer) was used. L100 (dissolution pH around 6.8).

[0204] The coating process was carried out in a small coating pan (opening diameter 10 cm) and with the following process parameters:

[0205] -Nozzle: 0.8mm

[0206] - Atomization pressure: 0,5 bar

[0207] -Control pressure: 0,6 bar

[0208] -Embossing pressure: 2 bar

[0209] -Peristaltic pump: 2rpm

[0210] - Air temperature: 50℃

[0211] The process was stopped when the tablets reached a 3% weight gain (wg).

[0212] The dissolution tests have been carried out at 37°C in Apparatus 1 (basket) with a rotation speed of 100 rpm in the following dissolution media:

[0213] - 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)

[0214] - pH 6.8 for the remaining dissolution time (for 1 L, 6.80 g KH2PO4, 0.90 g NaOH and deionized water to volume).

[0215] The results are reported in Figure 5 middle.

[0216] It can be seen that for the K100LV 7.5% tablets a very similar release to the reference product was obtained.

[0217] use The release profile of the half tablets according to the invention coated with L30-D55 was also studied relative to the half tablets of the reference product.

[0218] The dissolution tests have been carried out at 37°C in Apparatus 1 (basket) with a rotation speed of 100 rpm in the following dissolution media:

[0219] - 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)

[0220] - pH 6.8 for the remaining dissolution time (for 1 L, 6.80 g KH2PO4, 0.90 g NaOH and deionized water to volume).

[0221] The results are reported in Figure 6 middle.

[0222] As can be observed from the figure, although the release of the active ingredient at low pH is slightly higher than that of the commercial tablet, the half tablet of the present invention does not show any undesirable burst effect when the pH is changed, while the release of the active ingredient in the first stage of dissolution is more stable.

Claims

1. A pharmaceutical formulation in the form of a modified release enteric coated tablet suitable for oral administration twice daily, wherein the core of the tablet comprises: a) deferiprone in an amount between 85.0 and 95.0%, b) hydroxypropylmethylcellulose polymer having a viscosity of 100 cP alone or in mixture with hydroxypropylmethylcellulose polymer having a viscosity of 4000 cP as a modified release agent in an amount between 4.0 and 10.0%, c) a lubricant and / or a glidant in an amount between 0.2 and 2.0%, and d) other suitable pharmaceutically acceptable excipients in an amount between 0 and 5%, all amounts being calculated by weight based on the total weight of the formulation.

2. The pharmaceutical preparation according to claim 1, wherein the modified release agent consists of a hydroxypropylmethylcellulose polymer having a viscosity of 100 cP in an amount of 7.5 wt%.

3. The pharmaceutical preparation according to claim 1, wherein the release-modifying agent consists of the following mixture in an amount of 5% by weight: Hydroxypropyl methylcellulose polymer having a viscosity of 100 cP alone or in mixture with a hydroxypropyl methylcellulose polymer having a viscosity of 4000 cP.

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

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

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

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

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

9. A pharmaceutical formulation according to any one of the preceding claims, wherein the other suitable pharmaceutically acceptable excipients are selected from the class of pH modifiers and bulking agents.

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

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

12. The pharmaceutical formulation according to claim 10, wherein the enteric coating comprises methacrylic acid-methacrylic acid ester copolymer (1:1) in an alcoholic solution with triethyl citrate.

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

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

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

16. A method for preparing a pharmaceutical formulation according to any one of claims 1 to 15, comprising the following steps: (i) mixing deferiprone with the modified release agent and, if present, the other pharmaceutically acceptable excipients to form a mixture; (ii) wet granulating the mixture obtained in step (i) in a high shear granulator, followed by drying and sieving to produce granules; (iii) mixing the granules obtained in step (ii) with the lubricant and / or glidant excipient to form a mixture; compressing the mixture obtained in step (iii) to form a tablet; and (iv) coating the tablets.

17. A method for preparing a pharmaceutical formulation according to any one of claims 1 to 15, comprising the following steps: (i) mixing deferiprone with the modified release agent and, if present, the other pharmaceutically acceptable excipients to form a mixture; (ii) adding the lubricant and / or glidant excipients and further mixing; (iii) directly compressing the mixture obtained in step (ii) to form tablets; and (iv) coating the tablets.

18. The pharmaceutical composition according to any one of claims 1 to 15, for use in treating a disease causing iron overload, or for use in preventing and / or treating a disease caused by iron overload.

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

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

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