CN119300809A - Modified release pharmaceutical preparations containing deferiprone - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for oral administration comprising deferiprone. In particular, the present invention also relates to a delayed release tablet suitable for twice daily administration or once daily administration. The present invention also relates to methods of preparing and using such tablets.

Description

Modified release pharmaceutical preparations containing deferiprone

Field of the Invention

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

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

Background of the Invention

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

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

The introduction of deferiprone in current therapy has represented an important advance because it reduces 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 showed that deferiprone monotherapy appears to be superior to deferoxamine monotherapy in improving myocardial iron deposition and cardiac function.

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

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

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

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

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

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

The tablet is also scored with a score line to allow the patient to easily divide the tablet into two approximately equal parts for flexibility of dosing.

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

After oral administration, the enteric coating renders dissolution in the stomach negligible and thus promotes subsequent dissolution of the physiologically active substance at a weakly acidic to weakly alkaline pH (e.g., pH 4.5 to 8), which corresponds to dissolution in the small intestine, and particularly in the duodenum to ileum.

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

However, HPMC-AS has pH-dependent solubility.

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

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

Even more advantageous for patient compliance would be to provide a tablet having the above properties but with an even more prolonged release, perhaps suitable for once-daily oral administration.

The present invention provides the technical solution.

US2006/18935 generally discloses formulations comprising glycerides of fatty acids as modified release agents, but it does not mention the use of deferiprone.

SUMMARY OF THE INVENTION

In a first aspect, the present invention relates to the use of glycerides of long-chain fatty acids as a modified release agent for the preparation of a pharmaceutical formulation comprising deferiprone as an active ingredient suitable for oral administration twice daily or once daily.

The characteristics of the release depend on the amount of the modified release agent.

Preferably, the modified release agent is a mixture of glycerides of behenic acid, known as

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

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

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

Therefore, in a fourth aspect the present invention provides a method for preparing a coated deferiprone tablet as described above, the method comprising the steps of:

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

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

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

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

(v) Coating the tablets.

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

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

(ii) optionally adding lubricant and/or glidant excipients by further mixing;

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

(iv) coating the tablets.

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

In a sixth aspect, the present invention relates to a pharmaceutical composition as claimed, which is used for the preparation of a medicament for treating a disease causing iron overload, or for preventing and/or treating a disease caused by iron overload.

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

In an eighth aspect, the present invention relates to a method for reducing gastric discomfort or the risk of gastric discomfort 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 between 80 and 88%, b) glycerides of long chain fatty acids as a modified release agent in an amount between 8.0 and 20.0%, c) a lubricant and/or a glidant in an amount between 0 and 2%, and d) optionally other suitable pharmaceutically acceptable excipients in an amount between 0 and 5%, all amounts being calculated by weight based on the total weight of the formulation, and whereby the formulation is suitable for once daily oral administration.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: Glycerides of behenic acid (e.g., ) Dissolution test of the preparation. The line with the triangle mark is referred to as the commercial product.

Figure 2: Glycerides of behenic acid (e.g., ) Dissolution test of the preparation. The line with the triangle mark is referred to as the commercial product.

Figure 3: Hydrolysis of glycerides containing 1.5% behenic acid (e.g., ) of coated tablets.

Figure 4: In a basket with a rotation speed of 100 rpm (device 1), glycerides containing 1.5% behenic acid (e.g., The line with the triangle mark is referred to as the commercial product.

Figure 5: In 900 ml of pH 6.8 medium containing 10% The uncoated tablets contain 10% Dissolution test of uncoated tablets of 5ATO.

definition

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

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

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

Any aspects described herein using the language "comprising" also provide similar aspects described using the terminology "consisting of" and/or "consisting essentially of. Where the term "includes" or "including" is used in the specification or claims, it is intended to be inclusive, in a manner similar to the term "comprising" as interpreted when that term is used as a transitional word in a claim.

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

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

The term "glycerides of long-chain fatty acids" refers to substances in which one, two or three alcohol groups of the glycerol moiety are esterified with long-chain saturated fatty acids _C14 - _C22 and form mono-, di-, tri-glycerides, or any mixtures thereof.

In the present context, the term "hydrophilic" describes a molecule or part of a molecule which is generally electrically polarized and is able to form hydrogen bonds with water molecules, making it more soluble in water than in oil or other "non-polar" solvents.

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

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 end is hydrophobic (non-polar).

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

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

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

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

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

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

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

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

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

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

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

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

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

At each stage, after taking the test product, blood samples are drawn from each subject on a predetermined schedule. The blood samples are then analyzed to determine the serum concentration of the drug (test product, e.g., deferiprone) at each time point. For example, if the drugs enter the circulation at the same rate when given at similar doses under similar conditions, they are bioequivalent. The parameters commonly used in bioequivalence studies are t _max , C _max , C _min , AUC _0-infinity , AUC _0-t .

In the present context, " _tmax " means the time to maximum plasma concentration ( _Cmax ) after administration; AUC0 _-infinity means the area under the plasma concentration-time curve from time 0 to infinity; _AUC0-t means the area under the plasma concentration-time curve from time 0 to time t; W50 means the time at which the plasma concentration is 50% or more of _Cmax ; W75 means the time at which the plasma concentration is 75% or more of _Cmax ; and MRT means the mean residence time of tacrolimus.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

DETAILED DESCRIPTION OF THE INVENTION

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

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

In a first aspect, the present invention relates to the use of glycerides of long-chain fatty acids, provided as a modified release agent, for the preparation of a pharmaceutical formulation comprising deferiprone as an active ingredient, said formulation being suitable for oral administration twice daily or once daily.

In fact, by using 888ATO is used as an exemplary excipient, and it has been found that relatively small changes in the amount of the modified release agent can convert a formulation containing deferiprone suitable for twice-daily oral administration into a formulation suitable for once-daily administration.

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

Glyceryl Disodium Behenate, also known as 888 ATO, a water-insoluble mixture of glycerides of behenic acid, is commercially available from Gattefossé SAS, Saint-Priest Cedex, France. Specifically, it is a mixture of mono-, di- and tri-glycerides, with the diester being the major one (40-60 wt %).

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

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

In a preferred embodiment, using 888ATO.

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

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

Advantageously, the tablets of the invention will be provided with an enteric coating which serves to delay dissolution of deferiprone and avoid dissolution in the stomach, particularly in fasting patients.

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

Thus, in a particular aspect, the present invention relates to a modified release enteric coated pharmaceutical formulation for twice daily oral administration, wherein the core of the tablet comprises deferiprone in an amount between 85 and 95%, glycerides of long chain fatty acids as a modified release agent in an amount between 1.0 and 2.0%, preferably 1.5%, lubricants and/or glidants in an amount between 0 and 2.0%, other suitable pharmaceutically acceptable excipients in an amount between 0 and 13.0%, all amounts being calculated by weight based on the total weight of the formulation.

In this case, the ratio between the glycerides of long-chain fatty acids or mixtures thereof and deferiprone is preferably between 1:99 and 2:98.

In another specific embodiment, the present invention is directed to a modified release enteric coated pharmaceutical formulation for once-daily oral administration, wherein the core of the tablet comprises deferiprone in an amount between 80 and 88%, glycerides of long chain fatty acids as a modified release agent in an amount between 8.0 and 20.0%, a lubricant and/or a glidant in an amount between 0 and 2.0%, optionally other suitable pharmaceutically acceptable excipients in an amount between 0 and 5.0%, all amounts being calculated by weight based on the total weight of the formulation.

Preferably, the amount of glycerides of long-chain fatty acids is between 10% and 15% by weight.

The ratio between the glycerides of long chain fatty acids or mixtures thereof and deferiprone is preferably between 10:90 and 80:20.

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

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

In some embodiments, the enteric polymer in the coating is about 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.5%, 3%, 3.5%, or 4% by weight of the tablet, or a range between any two of the foregoing values, for example. For example, 0.5-1% by weight, 0.5-2% by weight, 0.5-3% by weight, 0.5-4% by weight, 0.6-1% by weight, 0.6-2% by weight, 0.6-3% by weight, 0.6-4% by weight, 0.7-1% by weight, 0.7-2% by weight, 0.7-3% by weight, 0.7-4% by weight, 1-1.5% by weight, 1.1-1.7% by weight, 1-2% by weight, 1.5-2% by weight, 1-3% by weight, 1-3.5% by weight, or 1-4% by weight of the tablet. In some embodiments, the enteric polymer (e.g., methacrylic acid copolymer) in the coating is about 0.8% by weight of the tablet. In some embodiments, the enteric polymer (e.g., methacrylic acid copolymer) in the coating 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 foregoing values, for example, 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 other excipients in addition to the enteric polymer, including, for example, plasticizers, lubricants or anti-adherents such as talc, opacifiers, colorants, diluents, or any combination thereof.

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

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 plasticizer, or a range between any two of the foregoing values, for example, about 0.5-5 mg, 0.7-2 mg, or 0.8-1.2 mg of plasticizer.

In some embodiments, the enteric coating may further include a diluent (eg, lactose, sucrose, fructose, mannitol, etc., or a combination thereof). In some embodiments, the enteric coating includes talc as a lubricant or anti-adherent.

In some embodiments, the enteric coating comprises 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. Ethacrylic acid-ethyl acrylate copolymer (1:1) is known as L30-D55 and is commercially available from Evonik Operations GmbH, Essen Germany.

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

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

The coating should 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 alkaline excipients.

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

Advantageously, the alkaline excipient may be selected from the group consisting of meglumine, metal oxides, metal hydroxides, basic salts of weak acids, and combinations thereof. Metal oxides include, but are not limited to, magnesium oxide, aluminum oxide, and zinc oxide. Metal hydroxides include, but are not limited to, sodium hydroxide, potassium hydroxide, magnesium hydroxide, and calcium hydroxide. Basic salts of weak acids include, but are not limited to, sodium or potassium salts of carbonates, bicarbonates, acetates, and citrates. In certain embodiments, the alkaline excipient is magnesium oxide, meglumine, or a combination thereof. In some embodiments, the alkaline excipient is magnesium oxide.

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

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 in an amount between 0.1 wt % and 1.0 wt %.

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 a combination thereof.

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

As an exemplary embodiment of the core of the coating preparation, it comprises:

a) 90.9% by weight of deferiprone; 1.5% by weight of behenic acid glyceryl; and 0.5% by weight of a pH adjuster;

b) an extender in an amount of 6.9% by weight;

c) A mixture of a lubricant and a glidant in an amount of 0.2% by weight.

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 a lubricant and a glidant in an amount of 0.2% by weight.

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

For example, it can be made from:

a) deferiprone in an amount between 98.0 wt % and 99.0 wt %; and

b) Glyceryl behenate in an amount between 1.0% and 2.0% by weight.

Alternatively, it can be made from:

a) deferiprone in an amount between 80% and 90% by weight; and

b) Glyceryl behenate in an amount between 10% and 20% by weight.

In fact it has been found that due to the extrusion properties of glyceryl behenate it can act as a lubricant so that no other lubricants may be needed to improve tableting.

Furthermore, by using a very hydrophobic excipient such as glyceryl behenate which is insensitive to pH variations, the formulation will be less affected by the external environment and will therefore be more predictable, no longer subject to random microenvironmental variations in pH which the unit must face during transport along the area where the release of the active ingredient occurs, characterized by physiological fluids with different pH.

This would be particularly beneficial during transit in the stomach of fed subjects, where random microenvironmental changes in pH occur more frequently.

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

Needless to say, it is difficult to combine both functions into a single tablet; i.e., it is difficult to produce an enteric-coated tablet that can be divided into two parts without destroying the delayed-release function. This is because the surface at the interface of the ruptured tablet is no longer protected by the enteric coating.

If the unprotected core disintegrates and/or dissolves rapidly, the fractured tablet will dissolve faster in gastric acid than the whole tablet, so protection from gastric irritation will be partially lost and the fractured tablet will no longer deliver drug at the same rate and potential as the whole tablet.

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

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

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

Thus, the tablet may be administered as a whole tablet, or the tablet may be scored to administer a dose of about half of the whole tablet.

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

In another aspect, tablets of the present disclosure comprising a greater amount of matrix include attributes of an enteric coated tablet suitable for once-daily administration.

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

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

In particular, tablets containing a small amount of behenyl glyceryl (i.e., 1.0-2.0%) produced similar results at pH 6.8 to those approved by the FDA and sold in the United States. The dissolution profiles of the tablets were very similar to those of the AG-100 tablets, within statistically significant limits, and therefore they were expected to show the same bioavailability at steady state, making them suitable for twice-daily oral administration.

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

In other words, at steady state, the modified release tablet of the present invention comprising a smaller amount of glyceryl behenate when administered twice daily will be able to achieve the same results as when the IR tablet is administered three times daily. The IR tablets of TRIZOL® and TRIZOL® had the same maximum peak concentration (C _max ) and the total amount absorbed (AUC) over a 24-hour period was the same for both products.

In contrast, tablets containing larger amounts of glyceryl behenate (ie, 8.0-15%) produced slower dissolution profiles, which may make them suitable for once-daily oral administration.

This will improve patient compliance and their adherence to treatment regimens, as well as safety, leading to less gastrointestinal upset, without compromising efficacy.

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

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

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

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

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

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

and

v) Coating the tablets.

In an alternative embodiment, the method comprises the following steps:

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

ii) optionally adding lubricant and/or glidant excipients and further mixing;

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

iv) coating the tablets.

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

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

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

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

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

In some embodiments, the deferiprone compositions of the invention are administered to a subject in need thereof twice daily, while in other embodiments they are administered once daily.

The unit dose of deferiprone tablets should be comprised between 500 and 1500 mg, preferably between 600 and 1000 mg, depending on the frequency of administration.

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

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

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

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

The present invention also relates to a method for reducing gastric discomfort or the risk of gastric discomfort 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 between 85 and 88%, glycerides of long chain fatty acids or mixtures thereof as a modified release agent in an amount between 8.0 and 20.0%, a lubricant and/or a glidant in an amount between 0 and 2%, optionally other suitable pharmaceutically acceptable excipients in an amount between 0 and 5%, all amounts being calculated by weight based on the total weight of the formulation, wherein the formulation is suitable for once daily administration.

Because modified release tablets suitable for once-daily oral administration are administered less frequently, it is believed that patients experience less gastric upset and benefit in terms of patient comfort compared to oral administration of immediate release formulations and/or twice-daily formulations.

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

Example

Example 1 Preparation of tablets.

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

Contains 1000 mg of active substance and various percentages of The composition of the tablets of 888 ATO (Gattefossé SAS) is reported in Table 1.

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

Release profiles were obtained in different dissolution media.

Example 2 - Dissolution Test

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

The composition of the dissolution medium is reported below.

pH 1.2: For 1L, 3.73g KCI, 7.07ml HCl 1N (deionized water to volume)

_pH 4.5: For 1L, 6.80g _KH2PO4 (deionized water to volume)

pH 6.8: For 1L, 6.80g KH ₂ PO ₄ , 0.90g NaOH (deionized water to volume)

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

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

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

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

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

As can be appreciated, using different percentages of 888ATO was used as the matrix to obtain different release profiles.

In particular, with an amount of 1.5 wt. %, a formulation can be prepared that has a release profile similar to the reference product and is therefore suitable for twice daily administration.

In contrast, using an amount of 10 wt%, dissolution was significantly slowed down and an in vitro profile was obtained that might be suitable for once-daily administration.

Example 3 - Enteric Coating

Include 888ATO 1.5% tablets are coated with an acrylic polymer having a dissolution pH of around 6 and formulated in the following aqueous dispersions:

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

- Deionized water 38% w/w

- Propylene glycol 2% w/w

The process parameters are as follows:

-Nozzle: 0.8mm

- Atomization pressure: 0,8 bar

-Control pressure: 2 bar

-Embossing pressure: 0,5 bar

-Peristaltic pump: 2rpm

- Air temperature: 57℃

The coating process lasted for 20 minutes and the samples were subjected to dissolution testing.

The test has been 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)

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

The results for the entire slide are reported in Figures 3 and 4, respectively.

As can be seen in Figure 3, release from the coated tablets was negligible until the pH was changed, and then a profile for deferiprone similar to that reported in the figure was observed, confirming that the profile would be suitable for twice daily administration.

From FIG. 4 regarding the half tablet, it can be observed that, although the release of the active ingredient at low pH is slightly higher than that of the commercial tablet, the half tablet of the present invention does not show any undesirable burst effect when the pH is changed, and the release of the active ingredient in the first stage of dissolution is more stable.

Example 4 - comprising Release profile of 5ATO uncoated tablets

Use 10% Tablets were prepared by direct compression using 5ATO as a modified release agent and their dissolution profiles were compared with those containing 10% tablets for comparison.

The test was performed at 37°C in a USP Apparatus II with a rotation speed of 50 rpm in pH 6.8 dissolution medium.

The results are plotted in Figure 5.

It can be seen that the two tablets produced superimposable release profiles, indicating that 5ATO will act as a controlled release agent

Claims (22)

1. Use of glycerides of long chain fatty acids as modified release agents for the preparation of pharmaceutical formulations comprising deferiprone as active ingredient, suitable for oral administration twice daily or once daily.

2. The use according to claim 1, wherein the glyceride agent of long-chain fatty acids is selected from the group consisting of glyceryl palmitostearate, glyceryl monostearate and glyceryl dibehenate.

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

4. A modified release enteric coated pharmaceutical formulation for oral administration twice daily wherein the core of the tablet comprises a) deferiprone in an amount comprised between 85 and 95%, b) glyceride of long chain fatty acid as a modified release agent in an amount comprised between 1.0 and 2.0%, c) lubricant and/or glidant in an amount comprised between 0 and 2.0%, and d) other suitable pharmaceutically acceptable excipients in an amount comprised between 0 and 13.0%, all amounts being calculated by weight based on the total weight of the formulation.

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

6. The modified release formulation of claim 4 or 5, wherein the glyceride agent of long-chain fatty acids is selected from the group consisting of glyceryl palmitostearate, glyceryl monostearate, and glyceryl dibehenate.

7. The modified release formulation of claim 6, wherein the glyceride agent of long-chain fatty acids is glyceryl dibehenate.

8. The pharmaceutical formulation according to 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. The pharmaceutical formulation of claim 9, wherein the lubricant is magnesium stearate.

10. 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 combinations thereof.

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

12. The pharmaceutical formulation according to any one of claims 4 to 11, wherein the other suitable pharmaceutically acceptable excipients are selected from the class of pH adjusting agents and extenders.

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

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

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

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

18. A process for preparing a pharmaceutical formulation according to any one of claims 4 to 17, the process comprising the steps of:

(i) Mixing deferiprone with the modified release agent and the other pharmaceutically acceptable excipient, if present, to form a mixture;

(ii) Wet granulating the mixture obtained in step (i) in a high shear granulator followed by drying and sieving to produce granules;

(iii) Optionally mixing the granules obtained in step (ii) with the lubricant and/or glidant excipient to form a mixture, compressing the mixture obtained in step (iii) to form a tablet, and

(Iv) The tablets are coated.

19. A process for preparing a pharmaceutical formulation according to any one of claims 4 to 17, the process comprising the steps of:

(i) Mixing deferiprone with the modified release agent and the other pharmaceutically acceptable excipient, 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) The tablets are coated.

20. The pharmaceutical composition according to any one of claims 4 to 17 for use in the treatment of a disease that results in overload of iron, or for use in the prevention and/or treatment of a disease caused by overload of iron.

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

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