Modified release pharmaceutical formulations containing deferiprone

Abstract

The present invention relates to pharmaceutical compositions for oral administration comprising deferiprone. In particular, the present invention relates to delayed release tablets suitable for either twice-daily or once-daily administration. The present invention also relates to methods for their preparation and use.

Description

[Technical field]

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

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

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

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

[0005] The introduction of deferiprone in current therapy represents an important advance in the treatment of liver iron concentration (LIC) and cardiac iron overload. In particular, Maggio A et al. Blood Cells Mol Dis. 2002, 28(2):196-198) and Galanello R et al. Haematologica. 2006, 91(9):1241-1243 suggested that deferiprone monotherapy appears to be superior to deferoxamine monotherapy in improving myocardial iron deposition and cardiac function.

[0006] Regarding safety, the most frequent adverse event was gastrointestinal discomfort due to gastrointestinal irritation. Such discomfort may lead patients to refrain from taking the drug, leading to a worsening of symptoms. Other adverse events observed were musculoskeletal disorders (arthralgia), elevated alanine aminotransferase (ALT), agranulocytosis and neutropenia.

[0007] Agranulocytosis appears to be an idiosyncratic reaction, occurring more frequently during the first year of treatment. The incidence of neutropenia and agranulocytosis is stable and appears to be unrelated to dose (Hider RC et al N Engl J Med. 2018;379:2140-2150).

[0008] Deferiprone has a long half-life of 2-3 hours but has an unpleasant bitter taste.

[0009] The drug is commonly sold under the trade name Ferriprox® in immediate release (IR) 500 mg and 1000 mg tablets, and a 100 mg / ml liquid formulation.

[0010] Given its pharmacological and ADME profile, deferiprone has also recently been marketed as a 1000 mg delayed release (DR) tablet for oral administration to improve patient compliance.

[0011] The tablets are suitable for twice-daily administration and are bioequivalent at steady state to the same daily dose in immediate release form administered three times daily.

[0012] The tablets are also imprinted with a score line to facilitate patient division of the tablet into two approximately equal halves for dosing flexibility.

[0013] The composition of the DR tablet is described in WO 2019 / 082128 and includes (a) a core comprising an active pharmaceutical ingredient and a release-controlling enteric polymer having a pH-dependent solubility, and (b) an enteric coating.

[0014] Upon oral administration, the enteric coating results in negligible dissolution in the stomach, and subsequent dissolution of the physiologically active substance is facilitated at slightly acidic to slightly alkaline pH (e.g., pH 4.5-8) corresponding to dissolution in the small intestine, particularly the duodenum to ileum.

[0015] In the case of commercial deferiprone products, hydroxypropyl methylcellulose acetate succinate (HPMC-AS) is used as an enteric polymer in the tablet core to provide sustained release.

[0016] However, HPMC-AS has a pH-dependent solubility.

[0017] This can result in a release that is influenced by the external environment that the unit must encounter while moving along the area in which the release of the active ingredient occurs, this area being characterized by physiological fluids with different pH and therefore difficult to predict due to the effects of random microenvironmental fluctuations in pH.

[0018] It would therefore be advantageous to provide a tablet suitable for twice-daily oral administration that has improved properties in terms of reproducibility of the predicted release profile.

[0019] It would be further advantageous for patient compliance to provide a tablet having the above properties but with an extended release, and preferably suitable for once daily oral administration.

[0020] The present invention provides a solution to the problem.

[0021] US Patent Application No. 2006 / 18935 generally discloses formulations containing glyceryl esters of fatty acids as modified release agents, but does not disclose the application of deferiprone. Summary of the Invention

[0022] In a first aspect, the present invention relates to the use of glyceryl esters of long chain fatty acids as modified release agents for the manufacture of a pharmaceutical formulation comprising deferiprone as an active ingredient, suitable for twice-daily or once-daily oral administration.

[0023] The release characteristics depend on the amount of modified release agent.

[0024] Preferably, the modified release agent is a mixture of glyceryl esters of behenic acid known as Compritol®.

[0025] In a second aspect, the present invention provides a modified release enteric coated pharmaceutical formulation for twice-daily oral administration, wherein the tablet core comprises: a) deferiprone in an amount of 85-95%, b) glyceryl esters of long chain fatty acids as modified release agent in an amount of 1.0-2.0%, c) a lubricant and / or glidant in an amount of 1.0-2.0%, and d) other suitable pharma- ceutical acceptable excipients in an amount of 1.0-13%, calculated by weight relative to the total weight of the formulation.

[0026] In a third aspect, the present invention provides a modified release enteric coated pharmaceutical formulation for once-daily oral administration, wherein the tablet core comprises, calculated by weight relative to the total weight of the formulation, a) deferiprone in an amount of 80-88%, b) glyceryl esters of long chain fatty acids as modified release agent in an amount of 8.0-20.0%, c) a lubricant and / or glidant in an amount of 0-2%, and d) optionally other suitable pharma- ceutically acceptable excipients in an amount of 0-5%.

[0027] Other suitable pharma- ceutically acceptable excipients may belong to the classes of pH adjusters and bulking agents.

[0028] Therefore, in a fourth aspect, the present invention provides a method for the preparation of the coated deferiprone tablets as described above, comprising the steps of: (i) mixing deferiprone with a modified release agent, and, if present, other pharma- ceutically acceptable excipients, to form a mixture; (ii) wet granulating the mixture obtained in step (i) in a high shear granulator, drying and sieving to produce granules; (iii) optionally blending the granules obtained in step (ii) with a lubricant and / or glidant, excipient to form a blend; (iv) compressing the mixture obtained in step (ii) to form a tablet; and (v) Coating tablets The present invention provides a method comprising:

[0029] In another embodiment, the method comprises the steps of: (i) mixing deferiprone with a modified release agent, and, if present, other pharma- ceutically acceptable excipients, to form a mixture; (ii) Optionally, add lubricants and / or glidants, excipients and further mix; (iii) directly compressing the mixture obtained in step (ii) to form a tablet; and (iv) Coating tablets The present invention provides a method comprising:

[0030] In a fifth aspect, the present invention relates to a pharmaceutical composition as claimed for use in the treatment of a disease causing iron overload or for the prevention and / or treatment of a disease caused by iron overload.

[0031] In a sixth aspect, the present invention relates to a pharmaceutical composition as claimed in the manufacture of a medicament for the prevention and / or treatment of a disease causing or caused by iron overload.

[0032] In a seventh aspect, the present invention refers to a method for treating a disease causing iron overload or for preventing and / or treating a disease caused by iron overload in a subject in need of such treatment, comprising administering a pharmaceutical composition as claimed.

[0033] In an eighth aspect, the present invention provides a method for reducing gastric discomfort or the risk of gastric discomfort in a patient in need of deferiprone treatment comprising orally administering to said patient a modified release enteric coated pharmaceutical formulation, wherein the tablet core comprises, calculated on the total weight of the formulation, a) deferiprone in an amount of 80-88%, b) glyceryl esters of long chain fatty acids as modified release agent in an amount of 8.0-20.0%, c) a lubricant and / or glidant in an amount of 0-2%, and d) optionally other suitable pharma- ceutically acceptable excipients in an amount of 0-5%, whereby the formulation is suitable for once daily oral administration. [Brief description of the drawings]

[0034] [Figure 1] Dissolution test of glyceryl ester of behenic acid (eg, Compritol®) formulations carried out in a vessel (apparatus 1) with 900 ml of medium at pH 6.8 and a stirring speed of 100 rpm. The line with the triangle symbol represents the commercial product. [Diagram 2] Dissolution test of glyceryl ester of behenic acid (eg Compritol®) formulations carried out in 900 ml of pH 4.5 medium, impeller (apparatus 2) with stirring speed of 50 rpm. The line with triangle symbols represents the commercial product. [Diagram 3] Figure 1 shows dissolution testing of coated tablets containing 1.5% glyceryl ester of behenic acid (e.g., Compritol®) in 900 ml of pH 1.2 medium (120 min) and then in pH 6.8 medium in a vessel (apparatus 1) with agitation speed of 100 rpm. [Figure 4] Dissolution test of semi-coated tablets containing glyceryl ester of behenic acid (e.g. Compritol® 1.5%) carried out in 900 ml of medium at pH 1.2 (120 min) and then in medium at pH 6.8 in a vessel (apparatus 1) with a stirring speed of 100 rpm. The line with the triangle symbol represents the commercial product. [Diagram 5]Dissolution testing of uncoated tablets containing 10% Compritol® versus 10% Precirol® 5 ATO using USP Apparatus 2 with agitation speed of 50 rpm in 900 ml of pH 6.8 medium. The line with triangle symbols represents the commercial product.

[0035] definition As used herein, the indefinite article "a" or "an" should be understood to refer to "one or more" of any cited or listed component. For example, "a tablet" refers to one or more tablets.

[0036] Also, as used herein, "and / or" refers to and includes any and all possible combinations of one or more of the associated listed items, or when interpreted in the alternative ("or"), no combination is present.

[0037] When the term "about" is used in conjunction with a numerical value or a range, it modifies that numerical value or range by extending the boundaries above and below the numerical values ​​set forth. Unless a different variability is indicated (e.g., ±30%, ±20%, ±5%, ±1%, etc.), the term "about" is used to modify a numerical value by 10 percent above or below (higher or lower) the set forth value, i.e., a variability of ±10%.

[0038] Whenever an embodiment is described herein using the word "comprising," analogous embodiments described with the terms "consisting of" and / or "consisting essentially of" are also provided. To the extent that the terms "include" or "including" are used in the specification or claims, the terms are intended to be inclusive in the same manner as the term "comprising" is interpreted when used as a transitional term in the claims.

[0039] As used herein, the terms "active ingredient" or "active pharmaceutical ingredient" (API) or "drug" are used synonymously and mean any component that is intended to provide pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect the structure or any function of the human or other animal body.

[0040] The terms "iron overload" or "iron overload" are used interchangeably herein and refer to the body containing too much (or "excess") iron, including transfusional iron overload, in which excess iron is introduced through one or more blood transfusions.

[0041] The term "glyceryl ester of a long-chain fatty acid" refers to a glyceryl ester in which one, two or three alcohol groups of the glycerol moiety are selected from the group consisting of long-chain saturated fatty acids C 14 -C 22 and esterified to form mono-, di-, or triglycerides or mixtures thereof.

[0042] As used herein, the term "hydrophilic" means that a molecule or portion of a molecule is typically electrically polarizable and can form hydrogen bonds with water molecules, allowing it to dissolve more readily in water than in oil or other "non-polar" solvents.

[0043] In contrast, the term "hydrophobic" refers to a compound that tends to be electrically neutral and non-polar, and therefore prefers other neutral and non-polar solvents or molecular environments.

[0044] As used herein, 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).

[0045] By "pH-dependent solubility," it is meant that a substance has different solubilities at different pHs. These pH-dependent solubility differences result in a pH-dependent dissolution profile.

[0046] The expression "insoluble or poorly soluble in water" is defined in the European Pharmacopoeia Ed. th , 2003, page 2891.

[0047] As used herein, a "core" or "tablet core" comprises an active ingredient, e.g., deferiprone, and one or more excipients compressed into an uncoated tablet. The core may be coated with a variety of coatings, including enteric coatings.

[0048] In this specification, the terms "controlled release", "sustained release", "modified release" and "delayed release" are intended to be equivalent terms that include any type of deferiprone release from the composition of the present invention that is suitable for obtaining a specific therapeutic or prophylactic response after administration to a subject. The terms refer to protecting the active ingredient, e.g., deferiprone, from rapid release at acidic pH, e.g., in the stomach, while allowing the active ingredient to be released at high pH, ​​e.g., in the digestive tract. In some embodiments, DR is understood to mean that when tested in USP apparatus 2 at 75 rpm, the dissolution degree is about 20±5% in 1 hour in 0.1N HC1, and the dissolution rate is substantially higher (e.g., more than 30%, e.g., more than 40% in 1 hour) in phosphate buffer at pH 6.8 than in 0.1N HC1.

[0049] "Disintegrant" refers to an excipient 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. An enteric coating can serve to prevent or delay dissolution or disintegration of a tablet in the gastric environment.

[0052] "Enteric coated tablet" means a tablet having a core containing the active ingredient surrounded by an enteric coating.

[0053] As used herein, "enteric polymer" is understood to mean a polymer that is relatively poorly soluble at the acidic pH of the fasting stomach (e.g., from about pH 1 to about pH 4), but is soluble at a higher pH (e.g., from about pH 1 to about pH 4) corresponding to the pH of the small intestine or beyond, in particular the duodenum or ileum.

[0054] The terms "filler," "diluent," and "bulking agent" are used synonymously.

[0055] The term "bioequivalence" means the absence of significant differences in bioavailability, i.e., degree of absorption and peak concentrations, between two medicinal products (e.g., test and reference products) at the same doses and under the same conditions over a period of time.

[0056] The determination of whether a test product is bioequivalent to a reference product is determined by conducting studies called bioequivalence or bioavailability studies under controlled conditions in a group of subjects, usually about 18-36 or more.

[0057] The study may be conducted in a "crossover" design, meaning that the study is conducted in two or more phases, usually at least one week apart, depending in part on the half-life of the drug. In the first phase, half of the subjects are randomly assigned to receive the test product first, and the other half of the subjects to receive the reference product first. In the second phase, each subject receives the other product.

[0058] At each stage, blood samples are taken from each subject on a predetermined schedule after ingestion of the test product. The blood samples are then analyzed to determine the serum concentration of the drug (test product, e.g., deferiprone) at each time point. For example, drugs are bioequivalent if they enter the circulation at the same rate when administered at similar doses and under similar conditions. A parameter commonly used in bioequivalence studies is the t max , C max , C min , AUC 0-∞ , AUC 0-t It is.

[0059] In the context of this specification, "t max " is the maximum plasma concentration (C max ) and AUC 0-∞ is the area under the plasma concentration versus time curve from 0 to ∞; AUC 0-t indicates the area under the plasma concentration versus time curve from time 0 to t; W50 indicates the area under the plasma concentration versus time curve from time 0 to t; max W75 is the time when the plasma concentration is greater than or equal to C max indicates the time when the concentration was greater than 75% of the time; MRT indicates the residence time for tacrolimus.

[0060] As used herein, "fasted state" refers to not having eaten for a period of time following a meal (typically at least several hours, e.g., 4 or 6 hours, after eating).

[0061] As used herein, "satisfied state" refers to administration with a meal or shortly after (eg, within about an hour) a meal.

[0062] The term "chemically stable" refers to the stability of the active agent in a formulation in which the change in drug assay value and / or impurity content is less than 5%, preferably less than 3%, during a storage period of at least one month at 25° C. and 60% relative humidity (RH), or at 40° C. and 75% RH.

[0063] The term "vitro-in vivo correlation (IVIVC)" refers to an in vitro dissolution test that predicts the in vivo disposition of an in vivo drug product.

[0064] As used herein, "gastric discomfort" refers to discomfort in the gastrointestinal (GI) tract, such as one or more of the following: pain, cramping, bloating, nausea, indigestion, heartburn, and gas.

[0065] As used herein, "half tablet" refers to one of two portions of a tablet obtained by splitting a tablet into two portions of equal or approximately equal weight. In some embodiments, a half tablet is about 40% to about 60% of the weight of the whole tablet from which it is derived. In some embodiments, the approximately equal weight of each half tablet is about 45% to about 55% of the weight of the whole tablet.

[0066] As used herein, "percent" or "%" refers to percent by weight (w / w) unless otherwise specified.

[0067] As used herein, a "scored tablet" refers to a tablet that has one or more lines, also called "scores," impressed into it to facilitate tablet division, e.g., to allow administration of half tablets. In some embodiments, the tablet may have two, three, four, or more score lines.

[0068] As used herein, "tablet" refers to a solid oral pharmaceutical dosage form. In some embodiments, the tablet is a compressed tablet.

[0069] "Whole tablet" means a complete tablet, i.e., not broken or divided into portions.

[0070] Terms such as "treat" or "treatment" or "to treat" or "ameliorate" or "alleviate" or "to alleviate" can refer to both 1) therapeutic measures that cure, delay, reduce, reverse and / or halt the progression of a diagnosed pathological condition or disorder, and 2) prophylactic or preventative measures that prevent, reduce the incidence, reduce the risk, and / or delay the onset of the targeted pathological condition or disorder. Thus, patients in need of treatment include those already with the disorder, those susceptible to developing the disorder, and those in need of preventing the disorder. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, reduction in the extent of the disease, stabilization of the extent of the disease (i.e., not worsening), delay or slowing of the progression of the disease, improvement or alleviation of the disease state, and remission (partial or complete), whether detectable or undetectable. "Treatment" can also mean extending survival compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to developing the condition or disorder or those in whom the onset of the condition or disorder is to be prevented or reduced.

[0071] By "subject," "individual," or "patient" is meant any human subject in need of diagnosis, prognosis, treatment, or therapy.

[0072] By "therapeutically effective dose or amount" or "effective amount" is intended an amount of an active pharmaceutical ingredient, e.g., deferiprone, that when administered results in a positive therapeutic response towards treating or reducing the risk of a disease in the subject being treated.

[0073] Deferiprone DR tablets, used herein as the "reference" or "reference product," are Ferriprox® tablets (1000 mg) approved by the FDA and marketed in the United States.

[0074] 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 a modified release of the active ingredient.

[0075] The active ingredient in the formulation of the present invention is deferiprone.However, any physical form of deferiprone (crystal, amorphous powder, any possible polymorph, any possible solvate) is included within the scope of the present invention.Its pharmaceutically acceptable salts and / or solvates are also included.Preferably, deferiprone is used as a base in anhydrous form.

[0076] In a first aspect, the present invention relates to glyceryl esters of long chain fatty acids as modified release agents to provide for the preparation of pharmaceutical formulations containing deferiprone as an active ingredient, suitable for twice-daily or once-daily oral administration.

[0077] Indeed, by using Compritol® 888 as an exemplary excipient, it has been discovered that a formulation containing deferiprone suitable for twice-daily oral administration can be converted into a formulation suitable for once-daily administration by changing the amount of the modified release agent by a relatively small amount.

[0078] Advantageously, the glyceryl ester of a long chain fatty acid is selected from the group consisting of glyceryl palmitate stearate, glyceryl monostearate and glyceryl dibehenate.

[0079] Glyceryl dibehenate, also known as Compritol® 888 ATO, is a water-insoluble mixture of glyceryl behenate esters, commercially available from Gattefosse SAS (Saint-Priest Cedex, France). Specifically, it is a mixture of mono-, di- and triglycerides, with a high content of diesters (40-60% by weight).

[0080] Glyceryl palmitate stearate is also known as Precirol® 5 ATO and is also commercially available from Gattefosse SAS (Saint-Priest Cedex, France).

[0081] Glyceryl monostearate is a monoglyceride commercially available from Sigma Aldrich GmbH (Germany).

[0082] In a preferred embodiment, Compritol® 888 ATO is used.

[0083] Deferiprone causes gastric irritation when released on an empty stomach and may degrade somewhat by acid hydrolysis.

[0084] Thus, for example, the pharmaceutical preparation may be in the form of a gastro-resistant capsule, an enteric-coated capsule or an enteric-coated tablet, preferably in the form of an enteric-coated tablet.

[0085] Advantageously, the tablets of the invention are provided with an enteric coating which serves both to delay the dissolution of deferiprone and to avoid dissolution in the stomach, especially in fasting patients.

[0086] Due to the coating, tablets according to the invention are formulated to have negligible dissolution in the empty stomach but more rapid dissolution in the intestine.

[0087] Thus, in a particular embodiment, the present invention relates to a modified release enteric coated pharmaceutical formulation for twice-daily oral administration, wherein the tablet core comprises deferiprone in an amount of 85-95%, glyceryl esters of long chain fatty acids as modified release agents in an amount of 1.0-2.0%, preferably 1.5%, a lubricant and / or glidant in an amount of 0-2.0%, and other suitable pharma- ceutical acceptable excipients in an amount of 0-13.0%, calculated by weight relative to the total weight of the formulation.

[0088] In this case, the ratio of glyceryl ester of long-chain fatty acid or mixture thereof to deferiprone is preferably 1:99 to 2:98.

[0089] In another particular embodiment, the present invention relates to a modified release enteric coated pharmaceutical formulation for once-daily oral administration, wherein the tablet core comprises deferiprone in an amount of 80-88%; glyceryl esters of long chain fatty acids as modified release agents in an amount of 8.0-20.0%; a lubricant and / or glidant in an amount of 0-2.0%; and optionally other suitable pharma- ceutically acceptable excipients in an amount of 0-5.0%, calculated by weight relative to the total weight of the formulation.

[0090] Preferably, the amount of glyceryl ester of a long chain fatty acid is from 10 to 15% by weight.

[0091] The ratio of glyceryl ester of long chain fatty acid or mixture thereof to deferiprone is preferably 10:90 to 80:20.

[0092] Suitable enteric polymers for enteric coating include, for example, hydroxypropylmethylcellulose acetate succinate (also referred to as hypromellose acetate succinate or HPMCAS), HPMC phthalate (also referred to as hypromellose phthalate), polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, shellac, zein, methacrylic acid copolymers (e.g., Type C methacrylic acid copolymer dispersion 30%), derivatives thereof, and any combination thereof.

[0093] In some embodiments, the preferred enteric polymer in the enteric coating is HPMC acetate succinate and a methacrylic acid copolymer, for example, Type C methacrylic acid copolymer in an aqueous dispersion.

[0094] In some embodiments, the enteric polymer in the coating is about 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.5%, 3%, 3.5%, or 4% by weight of the tablet, or any two or more of the foregoing values. The range is between 0.5-1%, 0.5-2%, 0.5-3%, 0.5-4%, 0.6-1%, 0.6-2%, 0.6-3%, 0.6-4%, 0.7-1%, 0.7-2%, 0.7-3%, 0.7-4%, 1-1.5%, 1.1-1.7%, 1-2%, 1.5-2%, 1-3%, 1-3.5% or 1-4% based on the weight of the tablet. In some embodiments, the enteric polymer (e.g., methacrylic acid copolymer) in the coating agent is about 0.8% based on the weight of the tablet. In some embodiments, the enteric polymer (e.g., methacrylic acid copolymer) in the coating agent is about 1.4% based on the weight of the tablet.

[0095] In some embodiments, the enteric coating comprises about 5 mg, 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg or about 30 mg of enteric polymer, or a range between two of the aforementioned values, e.g., about 5-20 mg, about 7-20 mg, about 7-30 mg, about 8-15 mg or about 8-10 mg of enteric polymer.

[0096] In some embodiments, the enteric coating contains other excipients in addition to the enteric polymer, including, for example, a plasticizer, a lubricant, or an anti-adherent such as talc, an opacifier, a colorant, a diluent, or any combination thereof.

[0097] In some embodiments, the enteric coating plasticizer is diethyl phthalate, citrate esters such as triethyl citrate, polyethylene glycol, glycerol, acetylated glycerides, citrate esters, dibutyl sebacate, castor oil, or any combination thereof.

[0098] In some embodiments, the enteric coating comprises about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg or about 5 mg of plasticizer, or a range between two of the aforementioned values, e.g., about 0.5-5 mg, 0.7-2 mg or 0.8-1.2 mg of plasticizer.

[0099] In some embodiments, the enteric coating may further comprise a diluent, such as lactose, sucrose, fructose, mannitol, or the like, or a combination thereof, In some embodiments, the enteric coating comprises talc as a lubricant or anti-adherent.

[0100] In some embodiments, the enteric coating comprises triethyl citrate, talc, titanium dioxide, and a methacrylic acid copolymer dispersion.

[0101] In a preferred embodiment, the enteric coating comprises a methacrylic acid copolymer dispersion, preferably an ethacrylic acid-ethyl acrylate copolymer (1:1) dispersion in water and propylene glycol. Ethacrylic acid-ethyl acrylate copolymer (1:1) is known as Eudragit® L30-D55 and is available from Evonik Operations GmbH (Essen, Germany).

[0102] In another preferred embodiment, the enteric coating comprises a methacrylic acid-methacrylate copolymer (1:1) in an alcoholic solution, preferably at a concentration of 5-15% w / w, more preferably 10% w / w, with triethyl citrate as a plasticizer, preferably at 2-5% w / w, more preferably 3% w / w relative to the polymer.

[0103] Methacrylic acid-methacrylate copolymer (1:1) is known as Eudragit® L100 (dissolution pH around 6.8) and is commercially available, for example, from Sigma-Aldrich (Missouri, USA).

[0104] The coating should be carried out according to methods known to those skilled in the art. In some embodiments, the core may include one or more pharma- ceutically acceptable excipients, such as a bulking agent and / or a basic excipient.

[0105] Advantageously, when present, a filler is used to increase the hardness of the tablet and may be selected from the group consisting of calcium carbonate, calcium hydrogen phosphate, calcium dihydrogen phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextran, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, α-lactose monohydrate.

[0106] Advantageously, the basic excipient may be selected from 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 carbonates, bicarbonates, acetates, and succinates. In certain embodiments, the basic excipient is magnesium oxide, meglumine, or a combination thereof. In some embodiments, the basic excipient is magnesium oxide.

[0107] Tablets may also contain a lubricant to prevent tooling jamming during compression into tablets, and / or a glidant to improve flow in the tabletting process, or a combination thereof.

[0108] 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, and is included in an amount of 0.1-1.0%.

[0109] Preferably, the lubricant is magnesium stearate.

[0110] 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.

[0111] In a preferred embodiment, the tablet core comprises a mixture of magnesium stearate and colloidal silicon dioxide.

[0112] In an exemplary embodiment of the tablet core, the coating formulation comprises: a) deferiprone in an amount of 90.9% by weight; glyceryl behenate in an amount of 1.5% by weight; and a pH adjuster in an amount of 0.5% by weight. b) a bulking agent in an amount of 6.9% by weight; and c) A mixture of lubricants and glidants in an amount of 0.2% by weight Includes.

[0113] In another exemplary embodiment, the core of the coating formulation comprises: a) deferiprone in an amount of 90.7% by weight; b) glyceryl behenate in an amount of 9.1% by weight; c) A mixture of lubricants and glidants in an amount of 0.2% by weight Includes.

[0114] In certain embodiments, the core of the coating formulation may consist solely of deferiprone and glyceryl behenate.

[0115] For example, the core of the coating formulation may comprise: a) deferiprone in an amount of 98.0-99.0% by weight; and b) glyceryl behenate in an amount of 1.0 to 2.0% by weight It may consist of:

[0116] Alternatively, the core of the coating formulation comprises: a) deferiprone in an amount of 80-90% by weight; and b) glyceryl behenate in an amount of 10 to 20% by weight It may consist of:

[0117] In fact, it has been found that glyceryl behenate can act as a lubricant due to its squeezeable properties, so that a lubricant may not be necessary to improve tabletting.

[0118] Furthermore, by using a highly hydrophobic excipient that is insensitive to pH changes, such as glyceryl behenate, the formulation reduces the influence of the external environment that the unit faces while moving along the region where the release of the active ingredient occurs, characterized by physiological fluids with different pH, making the formulation less dependent on random microenvironmental changes in pH and more predictable.

[0119] This may be particularly beneficial during transit through the stomach of a fed subject, where random microenvironmental fluctuations in pH occur more frequently.

[0120] Advantageously, the pharmaceutical tablets of the present invention are imprinted with a score line to facilitate the patient in dividing the tablet into approximately equal halves, allowing for dosage flexibility.

[0121] Obviously, it is difficult to combine both features in a single tablet; i.e., to produce a tablet that is enteric coated but can be split into two parts without losing its delayed release properties, since the interface of the split tablet would no longer be protected by the enteric coating.

[0122] If the unprotected core rapidly disintegrates and / or dissolves, the dissolution of the split tablet in gastric acid will be faster than a whole tablet, resulting in some loss of protection against gastric irritation and the split tablet may not be delivered at the same rate as a whole tablet.

[0123] On the other hand, as long as the dissolution is good at about 20% or less at acidic pH, it is considered acceptable.

[0124] As an added advantage, as shown in FIG. 4, although the release at low pH is a little faster than that observed for the commercial tablets, the half tablets of the present invention do not show the undesirable burst effect when a change in pH occurs, but rather show a smooth release of the active ingredient in the first phase of dissolution.

[0125] Indeed, it is well known that transient high concentrations of deferiprone, and thus elevated plasma levels, can be associated with transient elevations in liver enzymes and other side effects (Cohen ER et al Br J Haematology, 2000, 108, 305-312).

[0126] Thus, the tablets may be administered whole or, alternatively, may be divided to provide for administration of approximately half the dose of the whole tablet.

[0127] Advantageously, the tablets of the invention containing a small amount of matrix have the properties of enteric coated tablets suitable for twice daily administration without the drawbacks thereof, allowing the tablets to be split in half and the dosage fine-tuned to administer whole tablets, half tablets or any combination thereof. The half tablets of the invention, like the whole tablets, are substantially resistant to dissolution in an acidic medium (0.1N HC1) representative of the contents of the fasting stomach, and at higher pH representative of the contents of the small intestine, show a similar dissolution rate as the whole tablets, but without the undesirable burst effect of the commercial reference product.

[0128] In another embodiment, the tablets of the present invention containing higher amounts of matrix have the properties of enteric coated tablets suitable for once-daily administration.

[0129] According to the conditions given in Example 2, the release profile of the tablet of the present invention was determined in various dissolution media with different pH.

[0130] For Ferriprox® tablets, WO 2019 / 082128 reported that deferiprone modified release formulations showed good IVIV correlation, so the in vitro release profile is considered to reflect the in vivo behavior.

[0131] In particular, tablets containing small amounts of glyceryl behenate, i.e., 1.0-2.0%, produce dissolution profiles at pH 6.8 that are very similar, within statistical significance, to the dissolution profile of FDA-approved, U.S.-marketed Ferriprox®, and therefore are considered to have similar bioavailability at steady state, making them suitable for twice-daily oral dosing.

[0132] The formulation demonstrated steady-state bioequivalence to immediate release Ferriprox® tablets for three times daily administration and demonstrated mean ratios of AUC(24 hours) and C for the tablets of the present invention relative to immediate release (IR) tablets. max It is considered that the average ratio may be 80% to 125%.

[0133] In other words, at steady state, the modified release tablets of the present invention containing a small amount of glyceryl behenate, when administered twice daily, have a similar maximum plasma concentration (C) as the IR tablets of Ferriprox® when the IR tablets are given three times daily. max ) and the total absorption (AUC) was similar for both over 24 hours.

[0134] In contrast, tablets containing higher amounts of glyceryl behenate, ie, 8.0-15%, provide a slower dissolution profile that may be suitable for once-daily oral administration.

[0135] This may improve patient compliance and adherence to the treatment regimen, increase safety, and reduce gastrointestinal discomfort without compromising efficacy.

[0136] Typically, as a result of dissolution testing, at pH 4.5 or pH 6.8, formulations of the invention for once daily administration release less than 20% w / w of the active ingredient within 1.0 hour, less than 40% w / w within 3 hours, and less than 50% w / w within 6 hours.

[0137] The present invention also provides a method for preparing the above coated deferiprone tablets, comprising the steps of: i) mixing the modified release agent, and, if present, the pharma- ceutically acceptable excipients, with deferiprone to form a mixture; ii) Wet granulating the mixture obtained in step (i) in a high shear granulator, drying and sieving to obtain granules; iii) optionally blending the granules obtained in step (ii) with a lubricant and / or glidant, excipients to form a blend; iv) compressing the mixture obtained in step (iii) to form tablets; and v) Coating tablets.

[0138] In another embodiment, the method comprises the steps of: i) mixing the modified release agent, and, if present, the pharma- ceutically acceptable excipients, with deferiprone to form a mixture; ii) optionally adding lubricants and / or glidants, excipients and further mixing; iii) directly compressing the mixture obtained in step (ii) to form tablets; and iv) Coating the tablets.

[0139] Equipment and conditions for direct compression and / or compression during granulation are known to those skilled in the art.

[0140] Tablets can be manufactured in any suitable weight, but preferably the weight of each unit ranges from 800 to 1500 mg, preferably 1000 mg to 1200 mg.

[0141] For the avoidance of doubt, for these and other pharma- ceutically acceptable excipients and methods described herein, reference is made to the extensive literature on the subject, in particular Handbook of Pharmaceutical Excipients, Third Edition, edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, USA and Pharmaceutical Press, London; and Lexikon der Hilfsstoffe fi.ir Pharmazie, Kosmetik and angrenzende Gebiete edited by HP Fiedler, 4th Edition, Editor Cantar, Aulendorf, and previous editions.

[0142] The present invention provides dosing regimens useful for 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] In some embodiments, the deferiprone compositions of the present invention are administered to a subject in need of treatment twice daily, and in other embodiments, once daily.

[0145] A unit dose of deferiprone tablets should contain 500-1500 mg, preferably 600-1000 mg, depending on the frequency of administration.

[0146] The formulations of the present invention are useful for the prevention and / or treatment of iron overload or diseases caused by iron overload.

[0147] In some embodiments, the subject in need of treatment has iron overload due to transfusional iron overload or due to a disease such as thalassemia, myelodysplasia, sickle cell disease or iron overload.

[0148] In some embodiments, the subject in need of treatment has a neurodegenerative disease (e.g., Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, Friedreich's ataxia, pantothenate kinase-associated neurodegeneration (PKAN), or brain iron deposition neurodegeneration (NBIA).

[0149] In some embodiments, the subject in need of treatment has iron overload, which is transfusional iron overload.In certain embodiments, the subject has transfusional iron overload and previous chelation therapy is insufficient.In certain embodiments, the subject has transfusional iron overload and has cardiac MRI T2* of 20ms or less (e.g., 10ms).

[0150] The present invention also relates to a method for reducing gastric discomfort or the risk of gastric discomfort comprising orally administering to a patient in need of deferiprone treatment a modified release enteric coated pharmaceutical formulation, wherein the tablet core comprises deferiprone in an amount of 85-88%, glyceryl esters of long chain fatty acids or mixtures thereof as modified release agents in an amount of 8.0-20.0%, a lubricant and / or glidant in an amount of 0-2%, and optionally other suitable pharma- ceutical acceptable excipients in an amount of 0-5%, calculated by weight relative to the total weight of the formulation, wherein said formulation is suitable for once-daily administration.

[0151] The less frequent administration of modified release tablets suitable for oral administration once daily may also be beneficial to patient comfort by causing less gastric discomfort to the patient compared to oral administration of immediate release and / or twice daily formulations.

[0152] The present invention will now be described in more detail with reference to the following examples. EXAMPLES

[0153] Example 1 - Preparation of tablets. Tablets were produced by direct compression using a rotary tablet press (Officine Meccaniche Ronchi, AM8S) equipped with rectangular punches with dimensions of 22 mm x 10 mm. The compression force was set at 25 kN so that the crushing strength of the tablets was approximately 70 N.

[0154] Tablet compositions containing 1000 mg of active ingredient and Compritol® 888 ATO (Gattefosse SAS) in various proportions are shown in Table 1. [Table 1]

[0155] Release profiles were obtained in various dissolution media.

[0156] Example 2 - Dissolution Test A spectrophotometer was used to obtain the maximum absorption spectra of the active ingredient in the various liquids in which the release tests were carried out.

[0157] The composition of the dissolution medium is shown below. pH 1.2: 3.73 g KCl, 7.07 ml HCl 1N for 1 L (add deionized water to volume); pH 4.5: 6.80g KH2PO4 per 1L (add deionized water to volume); pH 6.8: 6.80 g KH2PO4, 0.90 g NaOH per liter (add deionized water to volume).

[0158] Calibration curves were prepared for each release medium at both wavelengths, 276 nm, where the absorbance peak was recorded, and 243 nm, where the decrease in absorbance was observed, so as not to exceed the maximum absorbance value of the instrument.

[0159] The release studies of the commercial products were analyzed at a wavelength of 276 nm using both pH 4.5 phosphate and pH change methods (0.1 N HCl for the first 120 min, pH 6.8 phosphate buffer for the remainder of the study). Sampling, dilution and manual readings were performed at high absorbance values ​​(>30% of release).

[0160] The release studies were performed in a dissolution paddle apparatus (USP type 2) with a rotation speed of 50 rpm and in a basket apparatus (USP type 1) with a rotation speed of 100 rpm. The studies were always performed in 900 mL of dissolution medium at 37° C.

[0161] For the test formulations, the active ingredient was quantified spectrophotometrically at 243 nm.

[0162] The release profiles obtained in different dissolution media at pH 6.8 and 4.5 are shown in Figures 1 and 2.

[0163] As can be seen, using different percentages of Compritol® 888 ATO as the matrix results in different release profiles.

[0164] In particular, an amount of 1.5% by weight can be used to produce a formulation with a similar profile to the reference product, and thus suitable for twice-daily administration.

[0165] In contrast, using an amount of 10% by weight dramatically slows dissolution, potentially resulting in an in vitro profile suitable for once-daily dosing.

[0166] Example 3 - Gastro-resistant coating Tablets containing Compritol® 888 ATO 1.5% were coated with various acrylic acid polymers having a dissolution pH of about 6 and formulated in aqueous dispersions: - Eudragit® L30-D55 aqueous dispersion 60% w / w (containing 25% solids) -Deionized water 38%w / w -Propylene glycol 2%w / w

[0167] The process parameters are as follows: -Nozzle: 0.8mm - Spray pressure: 0.8 bar - Control pressure: 2 bar - Pattern pressure: 0.5 bar -Peristaltic pump: 2 rpm -Air temperature: 57°C.

[0168] The coating process was continued for 20 minutes and the samples were subjected to dissolution testing.

[0169] The test was carried out at 37° C. in apparatus 1 (basket) with a rotation speed of 100 rpm in the following dissolution media: - pH 1.2 for the first 120 minutes (for 1 L, 3.73 g KCl, 7.07 mL HCl 1N and deionized water to volume); - Remaining dissolution time, pH 4.5: (for 1 L, 6.80 g KH2PO4, 0.90 g NaOH and deionized water to volume).

[0170] The results for the whole tablets are shown in Figures 3 and 4, respectively.

[0171] As can be seen from FIG. 3, the release of the coated tablets is negligible until a pH change occurs, after which a curve similar to that shown in the figure is observed for deferiprone, confirming that the profile may be suitable for twice-daily dosing.

[0172] Regarding the half tablets, it can be seen from FIG. 4 that the release of active ingredient at low pH is a little more than that of the commercial tablet, but the half tablets of the present invention do not show a burst effect when pH change occurs, and show a smoother release of active ingredient in the first stage of dissolution.

[0173] Example 4 - Release Profile of Uncoated Tablets Containing Percirol® 5 ATO Tablets were prepared by direct compression using 10% Percirol® 5 ATO as the modified release agent and the dissolution profile was compared to tablets containing 10% Compritol®.

[0174] The test was carried out at 37° C. in a USP type II apparatus with a rotation speed of 50 rpm in a pH 6.8 dissolution medium.

[0175] The results are plotted in FIG.

[0176] As can be seen, the two tablets provide overlapping release profiles indicating that Percirol® 5 ATO can act as Compritol® when used as a modified release agent.

Claims

1. 1. Use of glyceryl esters of long chain fatty acids as modified release agents for the manufacture of pharmaceutical formulations containing deferiprone as an active ingredient, suitable for twice-daily or once-daily oral administration.

2. 2. The use according to claim 1, wherein the glyceryl ester of a long chain fatty acid is selected from the group consisting of glyceryl palmitate stearate, glyceryl monostearate and glyceryl dibehenate.

3. 3. The use according to claim 1 or 2, wherein the glyceryl ester of a long chain fatty acid is glyceryl dibehenate.

4. 1. A modified release enteric coated pharmaceutical formulation for oral administration twice daily, wherein the tablet core comprises: a) deferiprone in an amount of 85-95%; b) glyceryl esters of long chain fatty acids as modified release agents in an amount of 1.0-2.0%; c) a lubricant and / or glidant in an amount of 0-2.0%; and d) other suitable pharmacokinetically acceptable excipients in an amount of 0-13.0%, calculated by weight relative to the total weight of the formulation.

5. 1. A modified release enteric coated pharmaceutical formulation for oral administration twice daily, wherein the tablet core comprises, calculated by weight relative to the total weight of the formulation, a) deferiprone in an amount of 80-88%, b) glyceryl esters of long chain fatty acids as modified release agents in an amount of 8.0-20.0%, c) a lubricant and / or glidant in an amount of 0-2.0%, and d) optionally other suitable pharma- ceutical acceptable excipients in an amount of 0-5.0%.

6. 6. The modified release formulation of claim 4 or 5, wherein the glyceryl ester of a long chain fatty acid is selected from the group consisting of glyceryl palmitate stearate, glyceryl monostearate and glyceryl dibehenate.

7. 7. The modified release formulation of claim 6, wherein the glyceryl ester of a long chain fatty acid is glyceryl dibehenate.

8. The pharmaceutical formulation of any one of claims 4 to 7, wherein the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, talc, and combinations thereof.

9. 10. The pharmaceutical formulation of claim 9, wherein the lubricant is magnesium stearate.

10. The pharmaceutical composition of any one of claims 4 to 9, wherein the glidant is selected from the group consisting of colloidal silicon dioxide, starch and talc, and combinations thereof.

11. 11. The pharmaceutical composition of claim 10, wherein the glidant is colloidal silicon dioxide.

12. A pharmaceutical formulation according to any one of claims 4 to 11, wherein other suitable pharma- ceutically acceptable excipients are selected from the classes of pH adjusters and bulking agents.

13. The pharmaceutical formulation according to any one of claims 4 to 12, wherein the enteric coating comprises an enteric polymer, a diluent and optionally a plasticizer.

14. 14. The pharmaceutical formulation of claim 13, wherein the enteric coating comprises an ethacrylic acid-ethyl acrylate copolymer (1:1) dispersion in water and propylene glycol.

15. 14. The pharmaceutical formulation of claim 13, wherein the enteric coating comprises a methacrylic acid-methacrylate copolymer (1:1) in an alcoholic solution containing triethyl citrate.

16. A pharmaceutical formulation according to any one of claims 4 to 15, wherein the tablet core contains 500 to 1500 mg of deferiprone.

17. 17. The pharmaceutical formulation of claim 16, wherein the tablet core contains 1000 mg of deferiprone.

18. A method for producing a pharmaceutical formulation according to any one of claims 4 to 17, said method comprising the steps of: (i) mixing deferiprone with the modified release agent, and, if present, other pharma- ceutically acceptable excipients, to form a mixture; (ii) The mixture obtained in step (i) is wet granulated in a high shear granulator, dried and sieved to produce granules. (iii) optionally mixing the mixture from step (ii) with a lubricant and / or glidant, excipients to form a mixture; compressing the mixture from step (iii) to form a tablet; and (iv) Coating tablets A method comprising:

19. A method for producing a pharmaceutical formulation according to any one of claims 4 to 17, said method comprising the steps of: (i) mixing deferiprone with the modified release agent, and, if present, other pharma- ceutically acceptable excipients, to form a mixture; (ii) Optionally, add lubricants and / or glidants, excipients and further mix; (iii) directly compressing the mixture obtained in step (ii) to form a tablet; and (iv) Coating tablets A method comprising:

20. A pharmaceutical composition according to any one of claims 4 to 17 for the prevention and / or treatment of iron overload or diseases caused by iron overload.

21. 21. The pharmaceutical composition for use according to claim 20, wherein the disease is thalassemia or sickle cell disease.

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

Images