WO2023198641A1 - Modified release pharmaceutical formulations comprising deferiprone - Google Patents

Abstract

The invention is directed to pharmaceutical compositions for oral administration comprising deferiprone. In particular, the invention is also directed to delayed release tablets suitable either for twice daily administration or once daily administration. The invention is also directed to methods of making and using the same.

Description

MODIFIED RELEASE PHARMACEUTICAL FORMULATIONS COMPRISING DEFERIPRONE

FIELD OF INVENTION

The invention relates to pharmaceutical formulations comprising the iron chelator deferiprone.

In particular the invention is directed to modified release formulations suitable for twice-a- day or once-a-day oral administration for the treatment of iron overload which occurs in patients suffering for example from thalassemia, sickle cell disease, hemochromatosis, and myelodysplasia.

BACKGROUND OF THE INVENTION

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

It is used in the treatment of generalized iron overload, particularly in conditions where frequent blood transfusions lead to iron overload including, e.g., thalassemia and Sickle Cell Disease (SCD).

The introduction of deferiprone in the current therapy has represented an important advancement as it 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 seems to be superior to deferoxamine monotherapy in improving myocardial siderosis and cardiac function.

With regards to safety, the most frequent adverse events are gastrointestinal disorders due to gastrointestinal irritation. Such discomfort could cause patients to refrain from taking the medication, leading to a worsening of their condition. Other observed adverse events are musculoskeletal disorders (arthralgia), Alanine Aminotransferase (ALT) increase, agranulocytosis and neutropenia.

Agranulocytosis seems to be an idiosyncratic response and it is more frequent in the first year of treatment. The incidence of neutropenia and agranulocytosis is stable and seems to be not related with dose (Hider RC et al N Engl J Med. 2018;379:2140-2150).

Deferiprone is endowed with a long half-life of 2-3 hour), but with an unpleasant bitter taste.

Said drug is sold as Immediate Release (IR) 500 mg and 1000 mg tablets, as well as a 100 mg/ml liquid formulation, generally, under the trade name Ferriprox®. In view of its pharmacological and ADME profile, and in order to improve the compliances of the patients, recently, deferiprone has also been launched commercially as 1000 mg Delayed Release (DR) tablets for oral administration.

Said tablets are suitable for a twice daily administration being bioequivalent in the steady state to the same daily dose of an immediate release tablet administered three times daily.

Said tablets are also debossed with a score line, to make it easy for the patient to break the tablets into two approximately equal parts for dosing flexibility.

The composition of the DR tablets has been disclosed in WO 2019/082128, and it comprises: (a) a core comprising the active pharmaceutical ingredient and a releasing controlling enteric polymer, and (b) an enteric coating.

Upon oral administration, the enteric coating makes the dissolution in the stomach negligible, and hence subsequent dissolution of the physiologically active substance at weakly acidic to weakly alkaline pH (e.g., pH 4.5 to 8), which corresponds to dissolution in the small intestine and, especially in the duodenum to ileum, is facilitated.

To sustain the release, in the case of the marketed deferiprone product, as enteric polymer in the tablet core, hydroxypropyl methylcellulose acetate succinate (HPMC-AS), is used.

However, HPMC-AS has a pH-dependent solubility.

This could lead to a release influenced by the external environment that the unit must face during the transit along the regions in which the release of the active principle takes place, that are characterized by physiological fluids having different pH's, and hence less predictable being at the mercy of random microenvironmental variation of the pH.

Therefore, it would be advantageous to provide a tablet suitable for twice a day oral administration, with improved properties in terms of reproducibility of the expected release profiles.

It would even be more advantageous, for the compliance of the patient, to provide tablets having the above properties but with an even more prolonged release, possibly suitable for once- day oral administration.

The solution is provided by the present invention.

US 2006/18935 generically discloses formulations comprising glyceryl esters /tatty acids as modifying release agent, but it is silent about the application to deferiprone.

SUMMARY OF THE INVENTION

In a first aspect, the invention is directed to the use of glyceryl esters of long fatty acids, as modifying release agent for the preparation of a pharmaceutical formulation comprising deferiprone as active ingredient, suitable for twice-a-day or once-a-day oral administration. The characteristics of the release depends on the amount of the modifying release agent.

Preferably the modifying release agent is a mixture of glyceryl esters of behenic acid known as Compritol®.

In a second aspect, the invention provides a modified release enteric coated pharmaceutical formulation for twice-a-day oral administration, wherein the core of the tablet comprises: a) deferiprone in an amount comprised between 85 to 95%, b) glyceryl esters of long fatty acids as modifying release agent in an amount comprised between 1.0 and 2.0%, c) a lubricant and/or glidant in an amount from 1.0 to 2.0%, and d) other suitable pharmaceutically acceptable excipients in an amount comprised between from 1.0 to 13%, all the amounts calculated by weight on the total weight of the formulation.

In a third aspect, the invention provides a modified release enteric coated pharmaceutical formulation for once-a-day oral administration, wherein the core of the tablet comprises: a) deferiprone in an amount comprised between 80 to 88%, b) glyceryl esters of long fatty acids as modifying release agent in an amount comprised between 8.0 and 20.0%, c) a lubricant and/or glidant in an amount from 0 to 2%, and d) optionally other suitable pharmaceutically acceptable excipients in an amount comprised between from 0 to 5%, all the amounts calculated by weight on the total weight of the formulation.

Other suitable pharmaceutically acceptable excipients may belong to the classes of pH adjusting agents, and bulking agents.

Therefore, in a fourth aspect the invention provides a process for the preparation of a coated deferiprone tablet as described above, which process comprises the following steps:

(i) mixing deferiprone with the modifying release agent and the pharmaceutically acceptable excipients, if present, to form a mixture;

(ii) wet-granulating the mixture obtained in step (i) in a high shear granulator followed by drying and screening to produce a granulate;

(iii) optionally mixing the granulate obtained in step (ii) with the lubricant and/or glidant excipient to form a mixture;

(iv) compressing the mixture obtained in step (iii) to form a tablet; and

(v) coating the tablet.

In an alternative embodiment, the process comprises the steps of:

(i) mixing deferiprone with the modifying release agent and the pharmaceutically acceptable excipients, if present, to form a mixture;

(ii) optionally adding the lubricant and/or glidant excipient by further mixing; (iii) directly compressing the mixture obtained in step (ii) to form a tablet; and

(iv) coating the tablet.

In a fifth aspect, the invention is directed to the claimed pharmaceutical composition for use for the treatment of diseases which cause an overload of iron, or for the prevention and/or treatment of diseases which are caused by an overload of iron.

In a sixth aspect, the invention is directed to the claimed pharmaceutical composition in the manufacture of a medicament for the treatment of diseases which cause an overload of iron, or for the prevention and/or treatment of diseases which are caused by an overload of iron.

In a seventh aspect, the invention refers to a method for the treatment of diseases which cause an overload of iron, or for the prevention and/or treatment of diseases which are caused by an overload of iron thereof in a patient in a need thereof, said method comprising orally administering the claimed pharmaceutical composition.

In an eight aspect, the invention is directed to a method for reducing gastric distress or the risk of gastric distress in a patient in need of deferiprone treatment, comprising orally administering to the patient a modified release enteric coated pharmaceutical formulation, wherein the core of the tablet comprises: a) deferiprone in an amount comprised between 80 to 88%, b) glyceryl esters of long fatty acids as modifying release agent in an amount comprised between 8.0 and 20.0%, c) a lubricant and/or glidant in an amount from 0 to 2%, and d)optionally other suitable pharmaceutically acceptable excipients in an amount comprised between from 0 to 5%, all the amounts calculated by weight on the total weight of the formulation and whereby the formulation is suitable for once-a-day oral administration.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: Dissolution tests of glyceryl esters of behenic acid (e.g., Compritol®) formulations carried out in 900 ml of pH 6.8 medium, basket (apparatus 1) having rotational speed of 100 rpm. The line with a triangular indicator is referred to as the commercial product.

Figure 2: Dissolution tests of glyceryl esters of behenic acid (e.g., Compritol® ) formulations carried out in 900 ml of pH 4.5 medium, paddle (apparatus 2) having rotational speed of 50 rpm. The line with a triangular indicator is referred to as the commercial product.

Figure 3: Dissolution tests of the coated tablets comprising glyceryl esters of behenic acid (e.g., Compritol® ) 1.5% carried out in 900 ml of pH 1.2 medium (120 min) and then pH 6.8 medium, basket (apparatus 1) having rotational speed of 100 rpm.

Figure 4: Dissolution tests of the half-coated tablets comprising glyceryl esters of behenic acid (e.g., Compritol® ) 1.5% in 900 ml of pH 1.2 medium (120 min) and then pH 6.8 medium, basket (apparatus 1) having rotational speed of 100 rpm. The line with a triangular indicator is referred to as the commercial product.

Figure 5: Dissolution test of uncoated tablets comprising 10% Compritol® vs uncoated tablets comprising 10% Precirol® 5 ATO in 900 ml of pH 6.8 medium, USP apparatus II, with a rotational speed of 50 rpm.

DEFINITIONS

As used herein, the indefinite articles "a" or "an" should be understood to refer to "one or more" of any recited or enumerated component. For example, "a tablet" refers to one or more tablets.

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 the lack of combinations when interpreted in the alternative ("or").

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

Wherever aspects are described herein with the language "comprising," otherwise analogous aspects described in terms of "consisting of and/or "consisting essentially of are also provided. To the extent that the term "includes" or "including" is used in the specification or the claims, it is intended to be inclusive in a manner similar to the term "comprising" as that term is interpreted when employed as a transitional word in a claim.

As used herein, the term "active ingredient" or "active pharmaceutical ingredient" (API) or “drug” are used as synonymous and mean any component that is intended to furnish 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 body of man or other animals.

The terms "iron overload" or "overload of iron" are used interchangeably herein and refer to medical conditions where the body contains or stores too much (or "excess") iron. An example is transfusional iron overload, where the excess iron is introduced by one or more blood transfusions.

With the term “glyceryl esters of long fatty acids” is meant a substance wherein one two, or three alcoholic groups of the glycerol moiety are esterified with long chain saturated fatty acids C14-C22, and mono-, di-, triglycerides are formed or any mixture thereof. In the present context, the term "hydrophilic" describes a molecule or portion of a molecule which is typically electrically polarized and capable of forming hydrogen bonds with water molecules, enabling it dissolve more readily in water than in oil or other "non-polar" solvents.

Conversely, the term "hydrophobic" denotes a compound tending to be electrically neutral and non-polar, and thus preferring other neutral and nonpolar solvents or molecular environments.

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

For “pH dependent solubility” it is meant a substance having different solubilities at different pHs. These pH-dependent solubility differences lead to pH-dependent dissolution profiles.

The expression “insoluble or poorly water soluble” refers to a substance having a solubility in water as defined in the European Pharmacopoeia Ed. 4^th, 2003, page 2891.

"Core" or "tablet core" as used herein comprises an active ingredient, e.g., deferiprone, and one or more excipients compressed into an uncoated tablet. The core can be coated with various coatings, including an enteric coating.

In the present context, the terms "controlled release", “prolonged release”, "modified release" and “delayed release” are intended to be equivalent terms covering any type of release of deferiprone from a composition of the invention that is appropriate to obtain a specific therapeutic or prophylactic response after administration to a subject". The terms refer to protecting an 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 intestines. In some aspects, DR will be understood to mean that, when tested in USP apparatus 2 at 75 rpm, the extent of dissolution will be around 20 ± 5% at 1 hour in 0.1N HC1, and the rate of dissolution will be substantially higher (e.g., over 30%, e.g. over 40%, in 1 hour) in phosphate buffer with pH 6.8 than the rate of dissolution in 0. 1 N HC1.

"Disintegrant" as used herein refers to an excipient that is insoluble in water, but swells when wetted to cause a tablet to disintegrate.

"Dissolution" as used herein refers to the process by which a solute forms a solution in a solvent.

"Enteric coat" or "enteric coating" as used herein refers to a coating comprising an enteric polymer. An enteric coating can serve to prevent or delay a tablet's dissolution or disintegration in a gastric environment.

"Enteric coated tablet" means a tablet having a core comprising an active ingredient, which is coated with an enteric coating. "Enteric polymer" as used herein is understood to mean a polymer that is relatively insoluble at the acidic pH of the fasted stomach (e.g., about pH 1 to about pH 4), but soluble at higher pH (e.g., about pH 4.5 to about pH 8), which corresponds to the pH in the small intestine or thereafter, particularly in the duodenum or ileum.

The terms “fillers”, “diluents” and “bulking agents” are used as synonymous.

With the term “bioequivalence" it is meant the absence of a significant difference between the bioavailability, i.e., the extent of absorption and peak concentration, between two pharmaceutical drug products (e.g., a test product and a reference product) over the course of a period of time, at the same dose and under the same conditions,

The determination of whether or not a test product is bioequivalent to a reference product is determined by performing a study, referred to as a bioequivalence or comparative bioavailability study, in a group of subjects, usually about 18-36 subjects or more, under controlled conditions.

The study can be done in a "crossover" design, which means that the study is done in 2 or more phases, usually at least a week apart, depending in part on the half-life of the drug. In the first phase, half the subjects are randomly assigned to ingest the test product first and the other half ingest the reference product first. In the second phase, each subject ingests the alternate product.

In each phase, blood samples are drawn from each subject, on a predetermined schedule after ingestion of the test product. The blood samples are then analyzed to determine serum concentrations of the drug (test product, e.g., deferiprone) at each time point. For example, drugs are bioequivalent if they enter circulation at the same rate when given in similar doses under similar conditions. Parameters often used in bioequivalence studies are tmax, Cmax, Cmin, AUCo- inf inity , AUC 0-t .

In the present context "tmax" denotes the time to reach the maximal plasma concentration (Cmax) after administration; AUCo-infmity denotes the area under the plasma concentration versus time curve from time 0 to infinity; AUCo-t denotes the area under the plasma concentration versus time curve from time 0 to time t; W50 denotes the time where the plasma concentration is 50% or more of Cmax; W75 denotes the time where the plasma concentration is 75% or more of Cmax; and MRT denotes mean residence time for tacrolimus.

"Fasted state" as used herein refers to abstinence from food for a defined period of time after a meal (typically, at least several hours, e.g., 4 or 6 hours, after a meal).

“Fed state" as used herein refers to administration with a meal or soon after a meal (e.g., within about 1 hour).

The term “chemical stable” refers to stability of the active agent in the formulation, wherein changes in the drug assay values and/or impurities content are equal to or lesser than 5%, preferably lesser than 3%, during storage at 25°C and 60% relative humidity (RH), or 40°C and/or 75% RH, for at least 1 month.

The term “vitro-in vivo correlation (IVIVC) refers to an in vitro dissolution test that is predictive of the in vivo performance of the drug product.

"Gastric distress" as used herein refers to discomfort of the gastrointestinal (GI) tract, e.g., one or more of pain, cramping, bloating, nausea, indigestion, heartburn, and gas.

"Half tablet" as used herein means either of the two parts of a tablet obtained by splitting the tablet into two parts of equal or approximately equal weight. In some embodiments, a half tablet is from about 40% to about 60% by weight of the whole tablet from which the half was derived. In some aspects, the approximately equal weight of each half tablet is about 45-55% of the total weight of the whole tablet.

"Percent" or "%" as used herein refers to weight percentage (w/w) unless otherwise specified.

"Scored tablet" as used herein refers to a tablet that is debossed with one or more lines, also known as a "score line", to facilitate splitting the tablet, e.g., to enable administration of a half tablet. In some aspects, the tablet can be scored with two, three, four, or more score lines.

"Tablet" as used herein refers a solid oral pharmaceutical dosage form. In some aspects, the tablet is a compressed tablet.

"Whole tablet" means a complete tablet, i.e., not broken or split into parts.

Terms such as "treating" or "treatment" or "to treat" or "ameliorating" or "alleviating" or "to alleviate" can refer to both 1) therapeutic measures that cure, slow down, lessen symptoms of, reverse, and/or halt progression of a diagnosed pathologic 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 pathologic condition or disorder. Thus, those in need of treatment include those who already have the disorder; those prone to developing the disorder; and those in whom the disorder is to be prevented. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those who already have the condition or disorder as well as those prone to developing the condition or disorder or those in which the condition or disorder is to be prevented or incidence reduced. By "subject" or "individual" or "patient," is meant any human subject, for whom diagnosis, prognosis, treatment, or therapy is desired.

By "therapeutically effective dose or amount" or "effective amount" is intended an amount of active pharmaceutical ingredient, e.g., deferiprone, that when administered brings about a positive therapeutic response with respect to treatment of or reducing the risk of a disease in a subject to be treated.

It will be understood that the deferiprone DR tablets used as the "reference" or "reference product" herein are Ferriprox® tablets (1000 mg) as approved by FDA and sold in the United States.

DETAILED DESCRIPTION OF THE INVENTION

The present invention concerns pharmaceutical formulations for the prevention and/or treatment of diseases which are caused by an overload of iron, especially compositions providing modified release of the active ingredient.

The active ingredient in the inventive formulations is deferiprone. However, within the scope of the present invention is deferiprone in any physical form (crystals, amorphous powder, any possible polymorphs, any possible solvate. Included are also pharmaceutically acceptable salts and/or solvates thereof. Preferably, deferiprone is used as a base in its anhydrous form.

In a first aspect, the invention is directed to the use of glyceryl esters of long fatty acids, as modifying release agent to provide, for the preparation of a pharmaceutical formulation comprising deferiprone as active ingredient, suitable for twice-a-day or once-a-day oral administration.

In fact, by using Compritol® 888 ATO as exemplary excipient, it has been found that relatively small variation of the amount of said modifying release agent may transform a formulation comprising deferiprone suitable for twice-a-day oral administration in a formulation suitable for once-a-day administration.

Advantageously, the glyceryl esters of long fatty acids are selected from the group consisting of glyceryl palmitostearate, glyceryl monostearate and glyceryl dibehenate.

Glyceryl dibehenate, also known as Compritol® 888 ATO is a water-insoluble mixture of glyceryl esters of behenic acid commercially available from Gattefosse SAS, Saint-Priest Cedex, France. In particular is a mixture of mono-, di- and triglycerides, the di-ester being the predominant (40-60% by weight).

Glyceryl palmitostearate is also known as Precirol® 5 ATO and is commercially available from Gattefosse SAS, Saint-Priest Cedex, France as well. Glyceryl monostearate is a monoglyceride commercially available from Sigma Aldrich GmbH (Germany).

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

Deferiprone may cause gastric irritation if released in the fasted stomach, and some degradation by acidic hydrolysis.

Therefore, pharmaceutical formulations could be, for instance, in form of gastro-resistant capsules, enteric coated capsules, or enteric coated tablets, preferably in form of enteric coated tablets.

Advantageously, the tablets of the invention will be provided by an enteric coating, which serves both to delay dissolution of deferiprone and to avoid dissolution in the stomach, in particular in fasted patient.

Due to the coating, the tablets as per the invention are formulated to have a neglectable dissolution in the fasted stomach but will more rapidly dissolve in the intestines.

Accordingly, in a particular aspect, the present invention is directed to a modified release enteric coated pharmaceutical formulation for twice-a-day oral administration, wherein the core of the tablets comprises deferiprone in an amount comprised between 85 to 95%, glyceryl esters of long fatty acids as modifying release agent in an amount comprised between 1.0 and 2.0%, preferably 1.5%, a lubricant and/or glidant in an amount from 0 to 2.0% other suitable pharmaceutically acceptable excipients in an amount comprised between from 0 to 13.0%, all the amounts calculated by weight on the total weight of the formulation.

In this case, the ratio between glyceryl esters of long fatty acids or mixture thereof and deferiprone is preferably comprised between 1 :99 and 2:98.

In another particular embodiment, the invention is directed to a modified release enteric coated pharmaceutical formulation for once-a-day oral administration, wherein the core of the tablets comprises deferiprone in an amount comprised between 80 to 88%, glyceryl esters of long fatty acids as modifying release agent in an amount comprised between 8.0 and 20.0%, a lubricant and/or glidant in an amount from 0 to 2.0% optionally other suitable pharmaceutically acceptable excipients in an amount comprised between from 0 to 5.0%, all the amounts calculated by weight on the total weight of the formulation.

Preferably, the amount of glyceryl esters of long fatty acids is comprised between 10 and 15% by weight.

The ratio between glyceryl esters of long fatty acids or mixture thereof and deferiprone is preferably comprised between 10:90 and 80:20. Suitable enteric polymers for the enteric coating include, e.g., hydroxypropyl methylcellulose 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., methacrylic acid copolymer Type C Dispersion 30%), derivatives thereof, and any combination thereof.

In some embodiments, the preferred enteric polymers in the enteric coating are HPMC acetate succinate and methacrylic acid copolymers, e.g., methacrylic acid copolymer type C, in aqueous dispersion.

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 preceding values, e.g., 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%, by weight of the tablet. In some embodiments, the enteric polymer in the coating (e.g., methacrylic acid copolymer) is about 0.8% by weight of tablet. In some embodiments, the enteric polymer in the coating (e.g., methacrylic acid copolymer) is about 1.4% by weight of the tablet (e.g., methacrylic acid copolymer).

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

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

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

In some embodiments, the enteric coating comprises about 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, or 5 mg of a plasticizer, or a range between any two of the preceding values, e.g. about 0.5-5 mg, 0.7-2 mg, or 0.8-1.2 mg of a plasticizer. In some embodiments, the enteric coating may further comprise a diluent (e.g., lactose, sucrose, fructose, mannitol, and the like, or combinations thereof). In some embodiments, the enteric coating comprises talc as the lubricant or anti-tack agent.

In some embodiments the enteric coating comprised triethyl citrate, talc, titanium dioxide, and a methacrylic acid copolymer dispersion.

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

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

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).

The coating shall be performed according to methods known to the skilled person. In some embodiments, the core may comprise one or more pharmaceutically acceptable excipients such as bulking agents and/or basic excipient.

Advantageously, the bulking agent that when present is utilizes to increase tablet hardness, could be selected from the group consisting of calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrans, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, alpha-lactose monohydrate.

Advantageously the basic excipient could be selected from the group consisting of meglumine, metal oxides, metal hydroxides, basic salts of weak acids, and a combination 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 carbonate, bicarbonate, acetate, and citrate. In certain embodiments, the basic excipient is magnesium oxide, meglumine or a combination thereof. In some embodiments, the basic excipient is magnesium oxide.

The tablets shall also comprise a lubricant to prevent sticking to the tooling during compression into tablets), and/or a glidant to improve flow in the tableting process), or combinations thereof. Advantageously, the lubricant is selected from the group consisting of, but not limited to, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, or combination thereof in amount comprised between 0.1 and 1.0% by weight.

Preferably the lubricant is magnesium stearate.

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 combination thereof.

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

As an exemplary embodiment of the core of said coated formulations comprises: a) deferiprone in an amount of 90.9% by weight; glyceryl behenate in an amount of 1.5% by weight; a pH adjusting agent in an amount of 0.5% by weight; b) a bulking agent in an amount of 6.9% by weight; c) a mixture of a lubricant and glidant in an amount of 0.2% by weight.

In another exemplary embodiment, the core of the coated 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 a lubricant and glidant in an amount of 0.2% by weight.

In a particular embodiment, the core of coated formulations may only consist of deferiprone and glyceryl behenate.

For example, it could be made of: a) deferiprone in an amount comprised between 98.0 and 99.0% by weight; and b) glyceryl behenate in an amount comprised between 1.0 and 2.0% by weight

Otherwise, it could be made of: a) deferiprone in an amount comprised between 80 and 90% by weight; and b) glyceryl behenate in an amount comprised between 10 and 20% by weight.

It has indeed been found that glyceryl behenate, due to its squeezing out properties, may act as a lubricant, so other lubricants to improve tabletting might not be needed.

Furthermore, by using a very hydrophobic excipient such as glyceryl behenate, which is insensitive to pH variation, the formulation would be less influenced by the external environment that the unit must face during the transit along the regions in which the release of the active principle takes place, that are characterized by physiological fluids having different pH's, and hence more predictable not being anymore at the mercy of random microenvironmental variation of the pH.

This is particular would be of benefit during the transit in the stomach of fed subjects, wherein random microenvironmental variation of the pH occur more frequently.

Advantageously, the pharmaceutical tablets of the invention are debossed with a score line, to make it easy for the patient to break the tablets into two approximately equal parts to enable administration of half tablets, allowing a dosing flexibility.

Needless-to-say, it is difficult to combine both features into a single tablet; that is, to produce a tablet that is enteric coated but can be broken into two parts without destroying the delayed release feature. This is because the surface at the interface of a broken tablet is no longer protected by the enteric coating.

If the unprotected core disintegrates and/or dissolves quickly, the dissolution of the broken tablet in the stomach acid will be faster than the whole tablet, so that protection against gastric irritation will be partially lost and the broken tablet no longer delivers the drug at the same rate and possibly of the whole tablet.

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

As a further advantage, as reported in Figure 4, although the release is a little bit higher at low pH than the commercial tablets was observed, the half tablets of the invention, when a change of the pH occurs, do not show any undesired burst effect, and exhibit a smoother release of the active ingredient in the first phase of the dissolution.

In fact, it is well known that transient higher concentrations and hence plasma levels of deferiprone, could be associated with transient increase of liver enzymes and other side effects (Cohen ER et al Br J Haematology, 2000, 108, 305-312).

Accordingly, the tablet could be administered as a whole tablet, otherwise the tablet could be scored for administration of about half the dosage of the whole tablet.

Advantageously, a tablet of the present disclosure comprising a low amount of the matrix embraces the attributes of an enteric coated tablet suitable for twice-a-day administration, without its deficiencies, so that tablets can be halved, to enable fine tuning of the dosing to administer whole tablets, half tablets, or any combination thereof. Half tablets of the disclosure substantially resist dissolution in acidic media (0.1 N HC1), representing the fasted stomach contents, as do whole tablets; and, at a higher pH, representing the contents of the small intestine, also exhibit a rate of dissolution similar to whole tablets, but without the undesired burst effect of the reference product on the market.

In another aspects, a tablet of the present disclosure comprising a higher amount of the matrix embraces the attributes of an enteric coated tablet suitable for once-a-day administration.

The release profile of the tablets of the invention has been determined in different dissolution media varying the pH according to the conditions reported in Example 2.

Since it has been reported in WO 2019/082128 that for Ferriprox® tablets, that deferiprone modified release formulations exhibit a good IVIV correlation, it is contemplated that the in vitro release profile will reflect the in vivo behaviour.

In particular, the tablets containing a small amount of glyceryl behenate, i.e 1.0-2.0% give rise to a dissolution profile at pH 6.8 very similar to that of Ferriprox® tablets as approved by FDA and sold in the United States, within the limits of the statstica significance, so it is contemplated that they will show the same bioavailability at the steady state, making it suitable for a twice a day oral administration.

It is contemplated that said formulation would turn out to be bioequivalent in the steady state, to the immediate release Ferriprox® tablets for three times a day administration, the mean ratio of AUC (over 24 hours) and the mean ratio of Cmax for the tablets of the invention relative to the immediate release (IR) tablets would be within 80% to 125%.

In other words, in the steady state, the modified release tablets of the present invention comprising a lower amount of glyceryl behenate when administered twice-a-day would be able to achieve the same maximum peak concentrations (Cmax) as IR tablets of Ferriprox®, when the IR tablets were given three times a day, and the total amount absorbed (AUC) was the same for both products over a 24-hour period.

In contrast, the tablets containing a higher amount of glyceryl behenate, i.e 8.0-15% give rise to a slower dissolution profile that could make them suitable for a once -a-day oral administration.

This would improve the compliance of the patients and their therapeutic regimen adherence to the, as well as the safety, causing less gastrointestinal distress, without a compromise on efficacy.

Typically, as a result of the dissolution test, a pH 4.5 or a pH 6.8 the formulation of the invention for once-a-day administration releases less than 20% w/w of the active ingredient within 1.0 hours, less than 40% w/w within 3 hours, less than 50% within 6 hours.

The invention also provides a process for the preparation of a coated deferiprone tablet as described above, which process comprises: i) mixing deferiprone with the modifying release agent and the pharmaceutically acceptable excipients, if present, to form a mxture; ii) wet-granulating the mixture obtained in step (i) in a high shear granulator followed by drying and screening to produce a granulate; iii) optionally mixing the granulate obtained in step (ii) with the lubricant and/or glidant excipient to form a mixture; iv) compressing the mixture obtained in step (iii) to form a tablet; and v) coating the tablet.

In an alternative embodiment, the process comprises the following steps: i) mixing deferiprone with the modifying release agent and the pharmaceutically acceptable excipients, if present, to form a mixture; ii) optionally adding the lubricant and/or glidant excipient and further mixing; iii) directly compressing the mixture obtained in step (iii) to form a tablet; and iv) coating the tablet.

Apparatus and conditions for direct compression and/or compression upon granulation are known to the skilled person in the art.

The tablets could be prepared in any suitable weight, but preferably the weight of each single unit would be in the range of 800 to 1500 mg, preferably of 1000 mg to 1200 mg.

For avoidance of doubts, reference is made to the extensive literature on the subject for these and other pharmaceutically acceptable excipients and procedures mentioned herein, see 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 H.P. Fiedler, 4th Edition, Editor Cantar, Aulendorf and earlier editions.

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

Typically, the oral daily dose of deferiprone could range from 75 mg/kg to 100 mg/kg.

In some embodiments, the deferiprone composition of the present invention is administered to a subject in need thereof twice daily, while in other embodiments is administered once daily.

The unit dose of deferiprone the tablets shall be comprised between 500 and 1500 mg, preferably between 600 and 1000 mg, depending on the frequency of administration. The claimed formulations are useful for the treatment of diseases which cause an overload of iron, or for the prevention and/or treatment of diseases which are caused by an overload of iron In some embodiments, the subject in need thereof suffers from iron overload due to transfusional iron overload, or due diseases such as thalassemia, myelodysplasia, sickle cell disease, or hemochromatosis.

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 accumulation (NBIA).

In some embodiments, the subject in need thereof suffers from iron overload that is transfusional iron overload. In certain aspects, the subject suffers from transfusional iron overload and whose prior chelation therapy is inadequate. In certain aspects, the subject suffers from transfusion iron overload and has a cardiac MRI T2* of 20 ms or less (e.g., 10 ms).

The invention is also directed to a method for reducing gastric distress or the risk of gastric distress in a patient in need of deferiprone treatment, comprising orally administering to the patient a modified release enteric coated pharmaceutical formulation, wherein the core of the tablet comprises deferiprone in an amount comprised between 85 to 88%, glyceryl esters of long fatty acids or mixture thereof as modified release agent in an amount comprised between 8.0 and 20.0%, a lubricant and/or glidant in an amount from 0 to 2% optionally other suitable pharmaceutically acceptable excipients in an amount comprised between from 0 to 5%, all the amounts calculated by weight on the total weight of the formulation., wherein the formulation is suitable for once daily dosing.

Because the administration of a modified release tablet suitable for once-a-day oral administration is less frequent, it is believed that the gastric distress of the patient is reduced as compared to orally administering an immediate release formulation and/or a twice-a-day formulation, with an advantage for the comfort of the patient.

The invention is illustrated in detail by the following examples.

EXAMPLES

Example 1 - Preparation of the tablets.

Tablets were prepared by direct compression using a rotary tablet press (Officine Meccaniche Ronchi, AM8S) equipped with oblong punches having dimensions of 22 mm X 10 mm. Compression force was set at 25 kN in order to have tablets with a crushing strength of about 70 N. The composition of tablets containing 1000 mg of active and Compritol® 888 ATO (Gattefosse SAS) in different percentages is reported in Table 1.

Table 1. Formulations of oblong tablets formulated with inert excipient Compritol 888 ATO

The release profiles acquired in different dissolution media

Example 2 - Dissolution test

The spectrum of maximum absorption of the active was acquired in the various fluids in which the release tests will be conducted by means of a spectrophotometer.

Compositions of dissolution media are reported below. pH 1.2: for 1 L, 3.73 g KCI, 7.07 ml HCI IN (deionized water up to volume) pH 4.5: for 1 L, 6.80 g of KH2PO4 (deionized water up to volume) pH 6.8: for 1 L, 6.80 g KH2PO4, 0.90 g of NaOH {deionized water up to volume)

Calibration curves were built for each of the release media both at the wavelength of 276 nm at which a peak of absorbance was recorded, and at 243nm, in which reduced absorption was observed, in order not to exceed the instrument maximum absorbance value.

The release test of the commercial product was analyzed at the wavelength of 276 nm both in pH 4.5 phosphate, and with the pH change mode (HCI 0.1 N for the first 120 minutes and phosphate buffer pH 6.8 for the remainder of the test). At high values of absorbance (over 30% of the release) sampling, dilutions and manual readings was performed.

Release tests were carried out in a dissolution test paddle apparatus (USP type 2) with a rotation speed of 50 rpm and basket apparatus (USP type 1) with a rotation speed of 100 rpm. The tests were always conducted in 900 mL of dissolution medium at 37 °C.

For the experimental formulations, the active ingredient was quantified by spectrophotometry at a wavelength of 24 3nm.

The release profiles acquired in different dissolution media at pH 6.8 and 4.5 are reported in Figures 1 and 2.

As it can be appreciated, using different % of Compritol® 888 ATO as a matrix different release profiles are obtained. In particular, with an amount of 1.5% by weight, a formulation could be prepared having a release profile similar to the reference product, and hence suitable for twice a day administration.

On the contrary, using an amount of 10% by weight, the dissolution dramatically slows down and an in vitro profile potentially suitable for once-a-day administration is obtained.

Example 3 - Gastroresistant coating

Tablets comprising Compritol® 888 ATO 1.5% were coated with an acrylic polymer having a dissolution pH around 6 and formulated in aqueous dispersion:

Eudragit® L30-D55 aqueous dispersion 60% w/w (containing 25% solids)

Deionized water 38% w/w

Propylene glycol 2% w/w

Process parameters were the followings:

Nozzle: 0.8 mm

Atomization pressure: 0,8 bar

Control pressure: 2 bar

Pattern pressure: 0,5 bar

Peristaltic pump: 2 rpm

Air temperature: 57 °C

Coating process lasted for 20 minutes and samples were subjected to dissolution test.

Said tests have been conducted at 37 ° in Apparatus 1 (basket) with a rotational speed of 100 rpm in the following dissolution media: pH 1.2 (for 1 L, 3.73 g KC1, 7.07 mL HC1 IN and deionized water up to volume) for the first 120 minutes pH 6.8 (for 1 L, 6.80 g KH2PO4, 0.90 g of NaOH and deionized water up to volume) for the rest of the dissolution time.

The results for the whole tablets were reported in Figures 3 and 4, respectively.

As it can be appreciated from Figure 3, the release of the coated tablets is neglectable until a change of the pH occurs, then a curve similar to the one reported in Figure is observed for deferiprone, confirming that said profile would be suitable for twice-a-day administration

From Figure 4 concerning the half tablets, it could be observed that, although the release of the active ingredient is a little bit higher at low pH than the commercial tablets, the half tablets of the invention, when a change of the pH occurs, do not show any undesired burst effect, with a smoother release of the active ingredient in the first phase of the dissolution. Example 4 -Release profile of uncoated tablets comprising Percirol® 5 ATO

Tablets were prepared by direct compression using 10% Percirol® 5 ATO as modifying release agent and its dissolution profile was compared to tablets comprising 10% Compritol®.

Said test was conducted at 37 ° in USP Apparatus II with a rotational speed of 50 rpm in a pH 6.8 dissolution medium.

The results are plotted in Figure 5.

As it can be appreciated, the two tablets give rise to an overlappable release profile, indicating that Percirol® 5 ATO would act as Compritol® when used as modifying release agent.

Claims

1. The use of glyceryl esters of long fatty acids, as modifying release agent for the preparation of a pharmaceutical formulation comprising deferiprone as active ingredient, suitable for twice-a-day or once-a-day oral administration.

2. The use according to claim 1, wherein the glyceryl esters of long fatty acids agents are selected from the group consisting of glyceryl palmitostearate, glyceryl monostearate and glyceryl dibehenate.

3. The use according to claim 1 or 2, wherein the glyceryl esters of long fatty acids agent is glyceryl dibehenate.

4. A modified release enteric coated pharmaceutical formulation for twice-a-day oral administration, wherein the core of the tablet comprises: a) deferiprone in an amount comprised between 85 to 95%, b) glyceryl esters of long fatty acids as modifying release agent in an amount comprised between 1.0 and 2.0%, c) a lubricant and/or glidant in an amount from 0 to 2.0%, and d) other suitable pharmaceutically acceptable excipients in an amount comprised between from 0 to 13.0%, all the amounts calculated by weight on the total weight of the formulation.

5. A modified release enteric coated pharmaceutical formulation for once-a-day oral administration, wherein the core of the tablet comprises: a) deferiprone in an amount comprised between 80 to 88%, b) glyceryl esters of long fatty acids as modifying release agent in an amount comprised between 8.0 and 20.0%, c) a lubricant and/or glidant in an amount from 0 to 2.0%, and d) optionally other suitable pharmaceutically acceptable excipients in an amount comprised between from 0 to 5.0%, all the amounts calculated by weight on the total weight of the formulation.

6. The modified release formulation according to claim 4 or 5, wherein the glyceryl esters of long fatty acids agents are selected from the group consisting of glyceryl palmitostearate, glyceryl monostearate and glyceryl dibehenate.

7. The modified release formulation according to claim 6, wherein the glyceryl esters of long fatty acids agent is glyceryl dibehenate. The pharmaceutical formulation according to any one of claims 4 to 7, wherein the lubricant is selected is selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, talc, and a combination thereof. The pharmaceutical formulation according to claim 9, wherein the lubricant is magnesium stearate. The pharmaceutical composition according to any one of claims 4 to 9, wherein the glidant is selected from the group consisting of colloidal silicon dioxide, starch and talc and combination thereof. The pharmaceutical composition according to claim 10, wherein the glidant is colloidal silicon dioxide. The pharmaceutical formulation according to any one of claims 4 to 11, wherein the other suitable pharmaceutically acceptable excipients are selected from the classes of pH adjusting agents, and bulking agents. 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. The pharmaceutical formulation according to claim 13, wherein the enteric coating comprises an ethacrylic acid - ethyl acrylate copolymer (1 :1) dispersion in water and propylene glycol. The pharmaceutical formulation according to claim 13, wherein the enteric coating comprises methacrylic acid- methacrylate copolymer (1 : 1) in an alcoholic solution with tri ethyl citrate. The pharmaceutical formulation according to any one of claims 4 to 15, wherein the core of the tablet comprises from 500 to 1500 mg of deferiprone. The pharmaceutical formulation according to claim 16, wherein the core of the tablet comprises 1000 mg of deferiprone. A process for the preparation of the pharmaceutical formulation according to any one of claims 4 to 17, said process comprising the following steps:

(i) mixing deferiprone with the modifying release agent and the other pharmaceutically acceptable excipients, if present, to form a mixture; (ii) wet-granulating the mixture obtained in step (i) in a high shear granulator followed by drying and screening to produce a granulate;

(iii) optionally mixing the granulate 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 tablet. A process for the preparation of the pharmaceutical formulation according to any one of claims 4 to 17, said process comprising the following steps:

(i) mixing deferiprone with the modifying release agent and the other pharmaceutically acceptable excipients, if present, to form a mixture;

(ii) optionally adding the lubricant and/or glidant excipient and further mixing;

(iii) directly compressing the mixture obtained in step (ii) to form a tablet; and

(iv) coating the tablet. The pharmaceutical composition according to any one of claims 4 to 17, for use for the treatment of diseases which cause an overload of iron, or for the prevention and/or treatment of diseases which are caused by an overload of iron. The pharmaceutical composition for use according to claim 20, wherein the disease is thalassemia or sickle cell anemia. The pharmaceutical composition for us according to claim 20, wherein said iron overload is transfusional iron overload.