EA042135B1 - DEFERIPRONE DELAYED RELEASE TABLET AND METHOD FOR ITS MANUFACTURE - Google Patents

Description

Certain aspects of the present invention relate to a delayed-release tablet containing deferiprone for oral administration to a human subject, where administration of the delayed-release tablet twice daily is bioequivalent at steady state to the same daily dose of the immediate-release tablet containing deferiprone administered three times a day. times a day.

In another aspect, the present invention relates to a tablet for oral administration of an active pharmaceutical ingredient (in particular, deferiprone) to a human subject, where the tablet contains (a) a core containing the active pharmaceutical ingredient in a therapeutically effective amount and an enteric polymer; and (b) enteric coating, where the tablet is scored so that it can be administered as a whole tablet or half a tablet, and where, if the tablet is administered as one or more half tablets, half the tablet is bioequivalent to the whole, for example, in a single dose study doses on an empty stomach after a meal or both.

In another aspect, the invention relates to a tablet for oral administration of an active pharmaceutical ingredient, comprising (a) a core containing the active pharmaceutical ingredient in a therapeutically effective amount and an enteric polymer; and (b) an enteric coating, wherein the tablet is scored on the surface to facilitate breaking into tablet halves, where both the whole and half of the tablets have a delayed release dissolution profile.

In another aspect, the invention relates to a tablet for oral administration comprising (a) a core containing deferiprone in a therapeutically effective amount and an enteric polymer; and (b) an enteric coating containing an enteric polymer, wherein the tablet is suitable for twice daily administration.

In another aspect, the invention relates to a tablet containing deferiprone for oral administration twice a day to a human subject, where a single dose of the tablet provides an average ratio of AUC ^ / Cmax from 3.5 to 6.0 hours both on an empty stomach and after a meal .

In another aspect, the invention relates to a tablet for oral administration comprising (a) a core containing 1000 or 600 mg of deferiprone, an enteric polymer, a pH adjusting agent, a glidant and a lubricant; and (b) an enteric coating containing a plasticizer, a diluent, an anti-adherent agent, and an enteric polymer, wherein the tablet, which is a whole tablet, has a score to facilitate breaking the tablet into tablet halves.

In another aspect, the invention relates to a method of treating a subject with iron overload or a neurodegenerative disease (e.g., Huntington's disease or amyotrophic lateral

- 1 042135 sclerosis) comprising oral administration to a subject in need thereof of a deferiprone tablet (eg a delayed release tablet) described herein.

In certain aspects, the invention relates to a method of treating Huntington's disease in a subject in need thereof, comprising administering to the subject a composition containing deferiprone.

In certain aspects, the invention relates to a method of treating amyotrophic lateral sclerosis (ALS) in a subject in need thereof, comprising administering to the subject a composition containing deferiprone. Some embodiments relate to methods for reducing or slowing the progression of disability associated with ALS. In some embodiments, the subject is additionally administered riluzole.

In certain aspects, the invention relates to a method of treating a human subject with iron overload comprising orally administering 3000 mg/day of deferiprone to the subject in need thereof, wherein the subject is administered deferiprone twice daily.

In certain aspects, the invention provides a method of treating a human subject with iron overload comprising orally administering 1200 mg/day of deferiprone to the subject in need thereof, wherein the subject is administered deferiprone twice daily.

Brief description of the figures

In FIG. 1 shows the dissolution of whole and half delayed release (DR) tablets in 0.1N. HCl, reflecting dissolution in gastric acid.

In FIG. 2 shows the dissolution of whole and half DR tablets at pH 6.8, reflecting dissolution in the jejunum and ileum.

In FIG. 3 shows the dissolution of whole and half DR tablets at pH 4.5, reflecting dissolution in the duodenum.

In FIG. 4 shows mean serum concentration profiles of deferiprone DR tablets and immediate release (IR) tablets.

Description of the invention

I. Definitions.

As used herein, the singular forms are to be understood as referring to one or more of any component described or listed. For example, 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 related listed items, and the absence of combinations when interpreted alternatively (or).

When an approximate term is used in conjunction with a numeric value or range, it modifies that value or range by extending the boundaries above and below the specified numeric values. The term approximate is used herein to change a numerical value above and below a specified value by a 10 percent deviation, up or down (above or below), i.e. ±10% unless otherwise specified (e.g. ±30, ±20, ±5, ±1%, etc.).

Wherever aspects are described herein using the wording comprising, similar aspects described in terms of consisting of and/or consisting essentially of are also contemplated. To the extent that the term includes or comprising is used in the description or claims, it is intended to be included in the same manner as the term containing, as long as that term is interpreted when used as a transitional word in the claims.

Deferiprone as used herein refers to deferiprone or a pharmaceutically acceptable salt thereof.

The term pharmaceutically acceptable salt of a given compound refers to salts that retain the biological efficacy and properties of the given compound and that are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include, for example, inorganic acid salts and organic acid salts. Deferiprone salts may include pharmaceutically acceptable salts, especially salts with bases, such as salts of the corresponding alkali or alkaline earth metals, such as sodium, potassium or magnesium salts, pharmaceutically acceptable transition metal salts, such as zinc salts, or salts of organic amines, such as cyclic amines. , such as mono-, di- or tri-lower alkylamines, such as hydroxy-lower alkylamines, for example mono-, di- or trihydroxy-lower alkylamines, hydroxy-lower alkyl-lower alkylamines or polyhydroxy-lower alkylamines. Cyclic amines are, for example, morpholine, thiomorpholine, piperidine or pyrrolidine. Suitable mono-lower alkylamines are, for example, ethyl- and tert-butylamine, di-lower alkylamines are, for example, diethyl- and diisopropylamine, and tri-lower-alkylamines are, for example, trimethyl- and triethylamine. Suitable hydroxy-lower alkylamines are, for example, mono-, di- and triethanolamine; hydroxy-lower alkyl-lower alkylamines are, for example, N,N-dimethylαmino- and N,N-diethylaminoethanol; a suitable polyhydroxy lower alkylamine is, for example, glucosamine.

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The term core or tablet core as used herein includes the active ingredient, eg deferiprone, and one or more excipients compressed into an uncoated tablet. The core may be coated with various coatings, including enteric coating.

Delayed release or DR as used herein refers to protecting the active ingredient, e.g. deferiprone, from rapid release at an acidic pH, e.g., in the stomach at least in the fasted state, while allowing the active ingredient to be released at a faster rate at a higher pH, for example, in the intestines. In some embodiments, DR should be understood to mean that when tested in USP device 2 at 75 rpm, the dissolution rate will be less than 20% in 1 hour in 0.1N. HCl and the dissolution rate will be significantly higher (e.g. more than 30%, for example more than 40%, within 1 hour) in phosphate buffer pH 6.8 than the dissolution rate in 0.1N. HCl.

Disintegrant, as used herein, refers to an excipient that is insoluble in water but swells when wet, causing the tablet to disintegrate.

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

Enteric coating or enteric coating, as used herein, refers to a coating containing an enteric polymer. The enteric coating may serve to prevent or delay the dissolution or disintegration of the tablets in the intragastric environment.

An enteric-coated tablet means a tablet having a core containing an active ingredient that is enteric-coated.

Enteric polymer, as used herein, means a polymer that is relatively insoluble at the acidic pH of the stomach on an empty stomach (e.g., about pH 1 to about pH 4), but soluble at a higher pH (e.g., about pH 4.5 to about pH 8), which corresponds to the pH in or after the small intestine, especially in the duodenum or ileum.

Fasting, as used herein, refers to fasting for a certain period of time after a meal (usually at least a few hours, such as 4 or 6 hours, after a meal).

Post-meal, as used herein, refers to administration during a meal or shortly after a meal (eg, within about 1 hour).

Gastric upset refers to discomfort of the gastrointestinal (GI) tract, such as one or more pain, cramps, bloating, nausea, indigestion, heartburn, and gas.

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

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

A scored tablet, as used herein, refers to a tablet on which one or more lines, also referred to as a break line, are applied to facilitate breakage of the tablet, for example to allow half of the tablet to be inserted. In some embodiments, the tablet may be divisible by two, three, four, or more break lines.

A tablet, as used herein, refers to a solid oral pharmaceutical dosage form. In some embodiments, the tablet is a compressed tablet.

A whole tablet means a full tablet, i.e. not broken or in pieces.

Terms such as cure or therapy or treat or ameliorate or alleviate or alleviate may refer to both 1) therapeutic measures that treat, arrest, lessen symptoms, reverse and/or halt the progression of a diagnosed condition or disorder, as well as and 2) prophylactic or preventive measures that prevent, reduce the spread, reduce the risk and/or slow the development of the target condition or disorder. Thus, those in need of treatment include those who already have the disorder; prone to developing disorders; and those in whom the disorder must be prevented. Beneficial or desirable clinical outcomes include, but are not limited to, relief of symptoms, reduction in disease severity, stabilization (i.e., not worsening) of the disease state, delay or retardation of disease progression, improvement or temporary alleviation of the disease state, and remission (partial or complete) both detectable and undetectable. Treatment may also mean an increase in survival compared to expected survival if no treatment is given. Those in need of treatment include those who already have the disease or disorder, as well as those who are prone to developing the disease or disorder, or those in whom the disease or disorder needs to be prevented or reduced in frequency.

By subject, individual, or patient is meant any human subject for whom a diagnosis, prognosis, treatment, or therapy is desired.

By therapeutically effective dose or amount or effective amount is meant an amount of an active pharmaceutical ingredient, such as deferiprone, which, when administered, produces a positive therapeutic response in relation to the treatment or reduction of the risk of a disease in the subject to be treated.

It is understood that the Deferiprone IR Tablets used herein as a reference or reference product are FDA-approved IR Ferriprox® (500 mg) tablets sold in the United States. For example, the reference or reference product herein may be an IR Ferriprox® tablet with (1) a core containing deferiprone 500 mg, microcrystalline cellulose, colloidal nitrogen dioxide, and magnesium stearate; and (2) a coating containing hydroxypropyl methylcellulose, polyethylene glycol and titanium dioxide. II. Pills.

In certain aspects, the application relates to a delayed release tablet containing deferiprone in its core. Delayed release, eg provided by an enteric coating, serves to delay the dissolution of the active ingredient, eg deferiprone, from the tablet core. In some embodiments, delayed release is desirable either for a drug that causes gastric irritation when released in a fasted stomach and/or for a drug that is acid labile and therefore will be degraded when released in a fasted stomach.

Some pharmaceutical tablets for oral administration are enteric-coated to provide delayed release. Some other pharmaceutical tablets for oral administration are debossed with a break line to make it easy for the patient to split the tablets into two approximately equal portions to allow the administration of half tablets, for example, for flexible dosing. However, it is difficult to combine both functions into one tablet, ie. get a tablet that is enteric-coated but can be split into two parts without destroying the delayed release function. This is because the surface on the surface of the broken tablet is no longer protected by the enteric coating. This leads to at least the following problems:

(1) if the unprotected core disintegrates and/or dissolves rapidly, the dissolution of the broken tablet in gastric acid will be faster than the intact tablet, so that protection against gastric irritation will be lost;

(2) alternatively, if the unprotected tablet core disintegrates and/or dissolves slowly enough to prevent gastric irritation, even without enteric coating protection, then dissolution and intestinal absorption may also be relatively slow, causing a decrease in absorption and/or peak levels in serum; and (3) the divided tablet no longer delivers the drug at the same rate and possibly to the same extent as the whole tablet.

These problems can result in half tablets not being bioequivalent to whole tablets. For example, Iranian Patent Application 90-07-27-71996 describes a formulation of deferiprone that is enteric coated. It discloses protection against gastric upset by using a methacrylic acid copolymer for enteric coating of a deferiprone tablet, the coating being approximately 7.4% of the total tablet weight (800 mg core tablet containing 500 mg deferiprone). The enteric-coated tablet formulation described in Iranian Patent Application 90-07-27-71996 loses the benefit of the enteric coating when the tablets are split or halved. The EC tablet from Iranian patent application 90-07-27-71996 (Avicenna Lab) included a tablet core of 500 mg deferiprone, 290 mg microcrystalline cellulose, 1 mg colloidal silicon dioxide and 9 mg magnesium stearate (800 mg total core weight); and a coating of 34.68 mg methacrylic acid copolymer, 15.56 mg talc, 3.61 mg PEG 6000, 4.38 mg titanium dioxide, 4.93 mg hypromellose, 6 cm Poaz and 0.82 mg sodium bicarbonate (total weight coverage 63.98 mg). The weight of the coating is approximately 7.4% of the total weight of the EC tablet. In certain embodiments, the tablets of the present application are different from the EU tablets of Iranian patent application 90-07-2771996. For example, in some embodiments, the DR tablets described herein do not include 290 mg microcrystalline cellulose, 1 mg colloidal silicon dioxide, and/or 9 mg magnesium stearate (800 mg total core weight); and in some embodiments, the coating of the DR tablets described herein does not include 34.68 mg of methacrylic acid copolymer,

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15.56 mg talc, 3.61 mg PEG 6000, 4.38 mg titanium dioxide, 4.93 mg hypromellose, 6 cm Poaz, and/or

0.82 mg sodium bicarbonate (total coating weight 63.98 mg). In addition, in some embodiments, the coating weight of the DR tablets described herein is not approximately

7.4% of the total weight of the EC tablet.

In certain aspects, the present invention relates to a composition, such as a tablet, containing deferiprone for oral administration to a human subject. In one embodiment, the composition is an oral tablet containing (a) a core containing deferiprone; and (b) an enteric coating.

Preferably, the tablet is designed to release deferiprone in the post-gastric portions of the gastrointestinal (GI) tract. In some embodiments, the tablet does not substantially disintegrate in the stomach, or at least in the stomach on an empty stomach, i. the tablet practically does not dissolve until the tablet reaches the intestines. In some embodiments, at least 75%, at least 80%, at least 85%, at least 95%, at least 99, or 100% of the tablet disintegrates in the intestine.

In some embodiments, the tablet is administered as a whole tablet. In some embodiments, the implementation of the tablet has a risk for the introduction of approximately half the dose of the whole tablet. In some embodiments, the tablet is administered as half a tablet. In some embodiments, the tablet is administered as one or more whole tablets in combination with one or more tablet halves.

In certain aspects, the tablet of the present invention is formulated to have relatively little (e.g., less than 20%), if any, dissolution in the stomach on an empty stomach, but will dissolve more rapidly in the intestines and thus may be referred to as a delayed release formulation. . In some embodiments, the tablet of the present invention provides the same dissolution rate for half and whole tablets, regardless of the pH of the dissolution medium. In some aspects, the tablet of the present invention encompasses the features of an enteric-coated tablet without the drawbacks such that the tablets can be halved to allow fine adjustment of the dose to administer whole tablets, half tablets, or any combination thereof. Halves of the tablets according to the invention resist dissolution in an acidic environment (0.1 N. HCl), representing the contents of the stomach on an empty stomach, as well as whole tablets; and at higher pH, representing the contents of the small intestine, also exhibit a dissolution rate similar to whole tablets.

In some embodiments, the enteric coating is about 1-20%, 1-15%, 1-10%, about 1-9%, about 1-8%, about 1-7%, about 1-6%, about 1-5% , about 1-4%, about 1-3%, about 1-2%, about 0.5-5%, or about 0.5-2% of the total tablet weight. In some embodiments, coverage is less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2.5%, less than 2.4%, less than 2.3%, less than 2.2%, less than 2.1% or less than 2% of the total weight of the tablet; and/or the coating is more than 1% of the total weight of the tablet. In some embodiments, the coverage is about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1 .7%, approximately 1.8%, approximately 1.9%, approximately 2.0%, approximately 2.1%, approximately 2.2%, approximately 2.3%, approximately 2.4%, approximately 2.5 %, about 2.6%, about 2.7%, about 2.8%, about 2.9%, or about 3.0%, or a range between any two of the previous values, such as 1.0-1.8, 1 .0-2.0, 1.0-2.4, 1.2-1.7, 1.5-2.0, 2.0-2.5, 2.2-2.7 or 2.5 -3.0% of the total weight of the tablet. In some embodiments, the implementation of the coating is approximately 1.5% of the total weight of the tablet. In other embodiments, the coating is approximately 2.5% of the total weight of the tablet.

III. Core.

The present invention relates to a composition, eg a delayed release tablet, comprising a core containing an active pharmaceutical ingredient, eg deferiprone or a pharmaceutically acceptable salt thereof.

In some embodiments, the tablet core contains about 100 mg to about 1500 mg, about 250 mg to about 1250 mg, or about 900 mg to about 1100 mg of deferiprone. In some embodiments, the tablet contains about 100 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 750 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, or about 1500 mg of deferiprone. In some embodiments, the tablet contains approximately 1000 mg of deferiprone.

In some embodiments, the active pharmaceutical ingredient, eg deferipron, is approximately 75-95% (eg 80-95 or 85-95%) of the total weight of the core. In some embodiments, the active pharmaceutical ingredient, such as deferiprone, is about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94% % or approximately 95% of the total mass of the kernel.

In some embodiments, the tablet core of one DR tablet for single, double, or triple daily dosing is at least about 200 mg, at least about 300 mg, at least about 400 mg, at least about 500 mg, or at least about 600 mg deferiprone. In some embodiments, the tablet core of one DR tablet for single, double or triple daily dosing is at least about 600 mg of deferiprone. In some embodiments, the tablet core of one DR tablet for single, double or triple daily dosing is at least about 500 mg of deferiprone. In some embodiments, the tablet core contains from about 200 mg to about 1500 mg, from about 300 mg to about 900 mg, from about 300 mg to about 700 mg, from about 500 mg to about 700 mg, from about 500 to 1500 mg, about 500 mg to 750 mg, about 900 mg to about 1100 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 750 mg, about 800 mg, about 1000 mg, about 1200 mg, about 1250 mg or approximately 1500 mg deferiprone. In some embodiments, tablet cores containing 600 or 1000 mg of deferiprone are preferred.

In some embodiments, the tablet core of one DR tablet for single, double, or triple daily dosing is at least about 200 mg, at least about 300 mg, or at least about 400 mg of deferiprone. In some embodiments, the tablet core of one DR tablet for single, double, or triple daily dosing is about 200 mg to about 500 mg, about 200 mg to about 400 mg, about 200 mg, about 300 mg, about 400 mg, or about 500 mg of deferiprone . In some embodiments, the tablet core of one twice daily DR tablet comprises at least about 500 mg of deferiprone. In some embodiments, the tablet core contains from about 200 mg to about 1500 mg, about 300 mg to about 900 mg, about 300 mg to about 600 mg, about 300 mg to about 500 mg, about 500 to 1500 mg, about 500 to 750 mg, about 900 mg to about 1100 mg, about 600 mg, about 750 mg, about 800 mg, about 1000 mg, about 1200 mg, about 1250 mg or about 1500 mg of deferiprone.

In some embodiments, the tablet core contains an enteric polymer as an excipient. Prior to the present application, when an enteric-coated tablet was broken, eg, in half along the break line, the surface at the boundary of the break line, eg, the two halves, was no longer protected by the enteric coating. In some embodiments, the inclusion of an enteric polymer in the core helps maintain a relatively low dissolution rate of 0.1N. HCl for a divided tablet, such as half a tablet, thus limiting dissolution in the stomach on an empty stomach while still allowing rapid dissolution at intestinal pH.

In some embodiments, the enteric polymer is from about 1 to 20, 1-15, 1-10, or 1-5% by weight of the core. In some embodiments, the enteric polymer is about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5% , about 5.5%, about 6%, about 6.5%, or about 7% by weight of the core, or a range between any two of the previous values, e.g., about 2-2.5, 2.5-3, 3-3 .5, 3.5-4, 4-4.5 or 4.5-5% by weight of the core. In some embodiments, the enteric polymer makes up about 2.5% by weight of the core. In some embodiments, the enteric polymer makes up approximately 4.5% by weight of the core.

In some embodiments, the enteric core polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), succinate acetate (i.e., HPMCAS), HPMC phthalate, polyvinyl acetate phthalate, methacrylic acid copolymers, a derivative thereof, and combinations thereof. In some embodiments, the enteric core polymer is HPMCAS.

In some embodiments, the tablet core of the tablet, e.g., the delayed release tablet described herein, comprises from about 900 mg to about 1100 mg of deferiprone and from about 10 mg to about 80 mg, from about 20 mg to about 80 mg, from about 20 mg to about 60 mg, about 20 mg to about 50 mg, about 20 mg to about 40 mg, about 25 mg to about 35 mg of an enteric polymer such as HPMCAS. In some embodiments, the tablet core of the tablet, e.g., the delayed release tablet described herein, comprises from about 500 mg to about 750 mg of deferiprone and from about 10 mg to about 80 mg, from about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 50 mg, about 20 mg to about 40 mg, about 25 mg to about 35 mg of an enteric polymer such as HPMCAS. In some embodiments, the tablet core of the tablet, e.g., the delayed release tablet described herein, comprises from about 400 mg to about 800 mg of deferiprone (e.g., about 600 mg) and from about 10 mg to about 80 mg, from about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 50 mg, about 20 mg to about 40 mg, or about 25 mg to about 35 mg of an enteric polymer such as HPMCAS.

In some embodiments, the tablet core of the tablet, e.g., the delayed release tablet described herein, comprises from about 200 mg to about 500 mg of deferiprone and from about 10 mg to about 80 mg, from about 20 mg to about 80 mg, from about 20 mg to about 60 mg, about 20 mg to about 50 mg, about 20 mg to about 40 mg, about 25 mg to about 35 mg of an enteric polymer such as HPMCAS.

In some embodiments, the tablet core of the tablet, eg, the delayed release tablet described herein, comprises about 1000 mg of deferiprone and about 30 mg of an enteric polymer, eg, HPMCAS. In particular, the tablet core of the tablet comprises 1000 mg of deferiprone and 28.5 mg of HPMCAS.

In some embodiments, the tablet core of the tablet, eg, the delayed release tablet described herein, comprises about 600 mg of deferiprone and about 30 mg of an enteric polymer, eg, HPMCAS. In particular, the tablet core of the tablet comprises 600 mg of deferiprone and 29.5 mg of HPMCAS.

In some embodiments, the tablet core of the tablet, eg the delayed release tablet described herein, comprises about 400 mg of deferiprone and about 20 to about 30 mg of an enteric polymer, eg HPMCAS. In some embodiments, the tablet core of the tablet, such as the delayed release tablet described herein, comprises about 600 mg of deferiprone and about 20 mg to about 30 mg of an enteric polymer, such as HPMCAS.

In some embodiments, the implementation of the core contains one or more basic excipients. In some embodiments, the main excipient is 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, the sodium or potassium salts of carbonate, bicarbonate, acetate, and citrate. In some embodiments, the primary excipient is magnesium oxide, meglumine, or a combination thereof. In some embodiments, the main excipient is magnesium oxide.

In some embodiments, the base excipient is about 1-10%, about 1-5%, about 1-4%, about 2-8%, about 2-6%, about 2-5%, about 2-4%, about 3-5%, approximately 3-4% or approximately 4-5% of the total mass of the kernel. In some embodiments, the tablet core of the tablet, eg, the delayed release tablet described herein, comprises magnesium oxide in an amount of about 3%, about 4%, or about 5% of the total weight of the core. In some embodiments, the implementation of the main excipient is approximately 4.5% of the total weight of the core. In some embodiments, the implementation of the main excipient is approximately 3.7% of the total weight of the core.

In some embodiments, the tablet core of the tablet, such as the delayed release tablet described herein, comprises about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 , 80, 90, or 100 mg of base excipient, or a range between any two of the previous values, such as about 5-100, 5-80, 10-60, 40-60, or 20-30 mg of base excipient.

In some embodiments, the tablet core of the tablet, eg, the delayed release tablet described herein, comprises about 1000 mg of deferiprone and about 50 mg of a base excipient, eg, magnesium oxide. In some embodiments, the tablet core of the tablet, eg, the delayed release tablet described herein, comprises about 600 mg of deferiprone and about 25 mg of a base excipient, eg, magnesium oxide. In some embodiments, the tablet core of the tablet, eg, the delayed release tablet described herein, comprises about 400 mg of deferiprone and about 10 to about 20 mg of a base excipient, eg, magnesium oxide.

In some embodiments, the tablet core does not contain a disintegrant.

In some embodiments, the tablet core is coated with an enteric coating as described herein. In some embodiments, the implementation of the core contains the same or different enteric polymer than the enteric polymer in the coating.

In some embodiments, the core is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least at least 97%, at least 98% or at least 99% of the total weight of the tablet.

In some embodiments, other excipients included in the tablet core are selected from fillers, binders (e.g. to increase tablet hardness), lubricants such as magnesium stearate (e.g. to prevent sticking to the tool during compression into tablets), glidants , such as colloidal silicon dioxide (for example, to improve fluidity during tabletting), and combinations thereof.

In some embodiments, the implementation of the core contains a glidant, such as, for example, colloidal silicon dioxide. In some embodiments, the glidant is approximately 1%, 0.5%, 0.45%, 0.4%, 0.35%, 0.3%, 0.25%, 0.2%, 0.1% by weight of the nucleus, or a range between any two previous values, for example approximately 0.2-0.5, 0.2-0.4, 0.2-0.3, 0.3-0.5, 0.3-0.4 or 0.4-0 .5% by weight of the core. In some embodiments, the implementation of the core contains approximately 0.45% by weight of glidant (for example, colloidal silicon dioxide). In some embodiments, the implementation of the core contains approximately 0.3% by weight of glidant (for example, colloidal silicon dioxide).

In some embodiments, the tablet core of the tablet, eg, the delayed release tablet described herein, comprises about 1000 mg of deferiprone and about 5 mg of a glidant, eg, colloidal silicon dioxide. In some embodiments, the tablet core of the tablet, eg, the delayed release tablet described herein, comprises about 600 mg of deferiprone and about 2 mg of glidant, eg, colloidal silicon dioxide. In some embodiments, the tablet core of the tablet, eg, the delayed release tablet described herein, comprises about 400 mg of deferiprone and about 1 mg to about 2 mg of a glidant, eg, colloidal silicon dioxide.

In some embodiments, the implementation of the core contains a lubricant, such as, for example, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate or talc. In some embodiment, the core contains magnesium stearate as a lubricant.

In some embodiments, the lubricant 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, or 2% by weight of the kernel, or a range between any two of the previous values, such as 0.5-1, 0.5-2, 0.6-2, 0, 7-2, 1-1.5, 1.2-1.7 or 1.5-2% by weight of the core. In some embodiments, the implementation of the core contains approximately 0.6% by weight of a lubricant (for example, magnesium stearate). In some embodiments, the implementation of the core contains approximately 1.5% by weight of a lubricant (for example, magnesium stearate).

In some embodiments, the tablet core of the tablet, such as the delayed release tablet described herein, comprises about 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 21, 22, 23, 24, or 25 mg of lubricant, or a range between any two of the previous values, such as approximately 2-25, 2-10, 2-8, 2-6, 7-20, 10-20 or 15-20 mg of lubricant.

In some embodiments, the tablet core of the tablet, eg, the delayed release tablet described herein, comprises about 1000 mg of deferiprone and about 17 mg of a lubricant, eg, magnesium stearate. In some embodiments, the tablet core of the tablet, eg, the delayed release tablet described herein, comprises about 600 mg of deferiprone and about 4 mg of a lubricant, eg, magnesium stearate. In some embodiments, the tablet core of the tablet, such as the delayed release tablet described herein, comprises about 400 mg of deferiprone and about 1 mg to about 4 mg of a lubricant, such as magnesium stearate.

In some embodiments, the core contains HPMC acetate succinate, magnesium oxide, colloidal silicon dioxide, magnesium stearate, and approximately 1000 mg of deferiprone.

In some embodiments, the core contains HPMC acetate succinate, magnesium oxide, colloidal silicon dioxide, magnesium stearate, and approximately 600 mg of deferiprone.

In some embodiments, the core contains HPMC acetate succinate, magnesium oxide, colloidal silicon dioxide, magnesium stearate, and approximately 400 mg of deferiprone.

IV. Enteric coating.

In some aspects of the present invention, the composition, such as a tablet, may contain

- 8 042135 enteric coating. Such a coating may serve to reduce gastric irritation.

The enteric coating may delay the dissolution of the core core until the tablet reaches the intestine. The present invention relates to a composition, eg a delayed release tablet, containing a core containing an active pharmaceutical ingredient, eg deferiprone or a pharmaceutically acceptable salt thereof, and an enteric coating.

Suitable enteric polymers for enteric coating include, for example, hydroxypropyl methylcellulose acetate succinate (also called hypromellose acetate succinate or HPMCAS), HPMC phthalate (also called hypromellose phthalate), polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, shellac, zein, methacrylic acid copolymers (eg methacrylic acid copolymer type C, dispersion 30%) their derivatives and combinations thereof.

In some embodiments, the preferred enteric polymers in the enteric coating are HPMC acetate succinate and methacrylic acid copolymers, eg type C methacrylic acid copolymer 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 previous values, for example 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 coating polymer (eg, methacrylic acid copolymer) is approximately 0.8% by weight of the tablet. In some embodiments, the enteric coating polymer (eg, methacrylic acid copolymer) is approximately 1.4% by weight of the tablet (eg, methacrylic acid copolymer).

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

In some embodiments, a tablet, such as a delayed release DR tablet described herein, includes about 1000 mg of deferiprone and about 9 mg of an enteric polymer in a coating, such as a methacrylic acid copolymer (out of about 31 mg of dispersion). In some embodiments, the tablet core of the tablet, e.g., the delayed release tablet described herein, comprises about 600 mg of deferiprone and about 9 mg of an enteric coating polymer, e.g., methacrylic acid copolymer (out of about 31 mg of dispersion). In some embodiments, the tablet core of the tablet, e.g., the delayed release tablet described herein, comprises about 400 mg of deferiprone and about 9 mg of an enteric coating polymer, e.g., methacrylic acid copolymer (out of about 31 mg of dispersion).

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

In some embodiments, the enteric coating plasticizer is diethyl phthalate, citric acid esters (eg, triethyl citrate), polyethylene glycol, glycerin, acetylated glycerides, acetylated citric acid esters, dibutyl sebacate, castor oil, or any combination thereof.

In some embodiments, the enteric coating contains about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 mg or 5 mg of plasticizer or a range between any two of the previous values, for example approximately 0.5-5, 0.7-2 or 0.8-1, 2 mg plasticizer.

In some embodiments, the enteric coating contains a diluent (eg, lactose, sucrose, fructose, mannitol, and the like, or combinations thereof). In some embodiments, the enteric coating contains talc in the form of a lubricant or anti-stick agent.

Certain aspects of the application relate to a composition (eg, delayed release tablet) containing a core containing 1000 mg of deferiprone, an enteric polymer, a pH adjusting agent, a glidant, and a lubricant; and the coating contains a plasticizer, a diluent, an anti-tack agent, and an enteric polymer. In some embodiments, the core contains 1000 mg deferiprone, HPMCAS-LF, magnesium oxide, colloidal silicon dioxide, magnesium stearate; and the coating contains triethyl citrate, sucrose, talc and a methacrylic acid copolymer dispersion. In a further embodiment, the composition core (e.g., delayed release tablet) contains 1000 mg deferiprone, 28 mg HPMCAS-LF, 50 mg oxide

- 9 042135 magnesium, 4.8 mg (2.6+2.2 mg) colloidal silicon dioxide, 17.2 mg magnesium stearate; and the coating contains 1.03 mg of triethyl citrate, 3.09 mg of sucrose, 3.09 mg of talc, and 31 mg of a methacrylic acid copolymer dispersion.

Certain aspects of the application relate to a composition (eg, a delayed release tablet) containing a core containing 600 mg of deferiprone, an enteric polymer, a pH adjusting agent, a glidant, and a lubricant; and the coating contains a plasticizer, a diluent, an anti-tack agent, and an enteric polymer. In some embodiments, the implementation of the core contains 600 mg of deferiprone, HPMCAS-LF, magnesium oxide, colloidal silicon dioxide and magnesium stearate; and the coating contains triethyl citrate, sucrose, talc and a methacrylic acid copolymer dispersion. In an additional embodiment, the core contains 600 mg deferiprone, 29.5 mg HPMCAS-LF, 24.5 mg magnesium oxide, 2 mg (1+1 mg) colloidal silicon dioxide, and 4 mg magnesium stearate; and the coating contains 1.03 mg triethyl citrate, 3.09 mg sucrose, 3.09 mg talc, and 31 mg methacrylic acid copolymer dispersion.

In some embodiments, the core contains 600 mg deferiprone, hypromellose acetate succinate AS-LF, light magnesium oxide, colloidal silicon dioxide, and magnesium stearate; and the coating contains triethyl citrate, sucrose, talc, a methacrylic acid copolymer dispersion, and titanium dioxide. In a further embodiment, the core contains 600 mg deferiprone, 29.5 mg hypromellose acetate succinate AS-LF, 24.5 mg light magnesium oxide, 2 mg (1+1 mg) colloidal silicon dioxide, and 4 mg magnesium stearate; and the coating contains 1.032 mg triethyl citrate, 3.09 mg sucrose, 2.09 mg talc, 30.96 mg methacrylic acid copolymer dispersion, and 8.5 mg titanium dioxide.

In some embodiments, the enteric coating is about 1-20%, 1-15%, 1-10%, about 1-9%, about 1-8%, about 1-7%, about 1-6%, about 1-5% , about 1-4%, about 1-3%, about 1-2%, about 0.5-5% or about 0.5-2% of the total tablet weight. In some embodiments, the coating is less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, or less than 2% of the total weight of the tablet. In some embodiments, the enteric coating is from 0.5 to 5% of the total weight of the tablet. In some embodiments, the enteric coating is from 0.5 to 3% of the total weight of the tablet. In some embodiments, the enteric coating makes up 0.5 to 2% of the total weight of the tablet. In some embodiments, the enteric coating makes up 0.5 to 1.5% of the total weight of the tablet. In some embodiments, the coverage is about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5% or about 6% of the total weight of the tablet.

In some embodiments, the implementation of the coating is approximately 1.5% of the total weight of the tablet. In some embodiments, the implementation of the coating is approximately 2.5% of the total weight of the tablet.

In some embodiments, the tablet, eg, the delayed release tablet described herein, includes about 1000 mg of deferiprone and about 1.5% enteric coating by weight of the tablet. In some embodiments, the tablet, eg, the delayed release tablet described herein, includes about 600 mg of deferiprone and about 2.5% enteric coating by weight of the tablet.

Another aspect of the invention relates to a method for the delayed release of deferiprone in a human subject, comprising administering a tablet of the present invention to the subject, wherein the tablet comprises a core and an enteric coating as described herein, and is administered as a whole tablet, half tablet, or combinations thereof.

Another aspect of the invention relates to a method for reducing gastric distress in a human subject in need of treatment with deferiprone, comprising administering a tablet of the invention to the subject, wherein the tablet comprises a core and an enteric coating as described herein, and the tablet is administered as a whole tablet, a tablet half, or both. combinations.

V. Dosing.

The present invention provides dosing regimens useful for the use of pharmaceutical compositions, such as delayed release tablets, as described herein. In some embodiments, the deferiprone composition of the present invention is administered to a subject in need thereof one, two, or three times daily. In particular, a composition of the invention containing deferiprone is administered to a subject in need thereof twice a day.

In some embodiments, the subject in need thereof is suffering from iron overload (eg, transfusional iron overload, such as in subjects suffering from thalassemia, myelodysplasia, or sickle cell disease). In some embodiments, the subject in need thereof is suffering from a neurodegenerative disease (e.g., Parkinson's disease,

- 10 042135 amyotrophic lateral sclerosis (ALS), Huntington's disease, Friedreich's ataxia, pantothenatkinase-associated neurodegeneration (PKAN) or brain iron storage neurodegeneration (NBIA)).

In some embodiments, the subject in need thereof is suffering from iron overload, ie. 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 transfusional iron overload and has a cardiac T2* MPT of 20 ms or less (eg, 10 ms).

In some embodiments, the implementation of the pharmaceutical composition is intended for oral delivery, such as tablets according to the present invention.

In some aspects, the deferiprone DR composition (particularly tablet compositions) of the invention is administered twice a day. Deferiprone IR tablets are inconvenient for patients as they require a three times daily dose (TID dosing). Patients generally prefer a twice daily (BID) or once daily regimen. One of the reasons why TID dosing is required is that the half-life of deferiprone is only about 2 hours. After swallowing a deferiprone IR tablet, the deferiprone content is rapidly absorbed from the upper gastrointestinal tract, appearing in the blood within 5-10 minutes after oral administration. Peak serum concentrations occur approximately 1 hour after a single dose in healthy subjects and patients on an empty stomach and up to 2 hours after a single dose after a meal. Because the half-life is short, serum concentrations decline to levels below therapeutically effective levels long before the next dose if dosing is less frequent than TID.

Another problem associated with IR deferiprone is acute gastric upset, which may persist for several days or longer. This is a limiting side effect for a significant number of patients, such as patients who stop taking the medication in the first few days as a result of gastric upset and thus forfeit the benefits of deferiprone.

Sustained release (ER) dosage forms have been developed to allow the administration of some drugs twice a day or once a day. Such dosage forms are designed to gradually release the active drug over an extended period of time, typically about 5 to 10 hours for a twice-daily dosage form and about 8 to 20 hours for a dosage form intended for oral administration. taking once a day. This can generally only be done for drugs that are absorbed through the ileum and duodenum so that the extent of absorption is not impaired by gradual release as the dosage form passes through the intestines.

A problem with ER formulations is related to the maximum (or peak) serum concentration (C _max ). By increasing the absorption period, for example using a sustained release formulation, the C _max will be much lower than with an IR tablet. This can be a problem in achieving the desired effects of some drugs, such as iron chelators, where both C _max and area under the serum concentration versus time (AUC) plot can affect efficacy.

Some aspects of the present invention relate to a deferiprone twice-daily (BID) dosing tablet that is bioequivalent at steady state to an IR TID dosing tablet using the same total daily dose. In some embodiments, the BID is bioequivalent at steady state where, after at least three days of dosing, the average ratio of AUC (over 24 hours) and average ratio of C _max for BID dosing tablets relative to TID IR tablets is in the range of 80- 125%. The twice-daily dosing tablets thus provide the subject with the same chelation benefit as the IR tablets, but with some of the benefits of twice-daily dosing. In addition to the convenience of BID dosing, this regimen improves patient compliance, such as those who choose not to bring their daily dose to school or work and thus lose the benefit of a full daily dose of deferiprone.

In certain aspects, the disclosed formulations are used to target specific serum concentration-time profiles and achieve the improved properties disclosed herein.

Some aspects of the invention relate to overcoming the problems associated with TID dosing, without compromising the benefits of achieving Cmax, by providing a twice daily tablet that provides both of the following, compared to a TID IR tablet having a similar total daily dose. :

i) a degree of absorption similar to IR tablets and thus a similar mean serum concentration; and ii) a similar peak serum concentration but with peaks occurring twice a day

- 11 042135 instead of three times a day.

Some aspects of the invention relate to overcoming the problems associated with dosing

TID, without compromising the benefits of achieving C _max by providing a twice daily tablet that provides both of the following, compared to an IR tablet administered by TID having a similar total daily dose:

i) equivalent extent of absorption as IR tablets, and thus a similar mean serum concentration; and ii) an equivalent peak serum concentration, but with peaks occurring twice a day instead of three times a day.

Another aspect of the present invention is to provide a tablet dosage form containing deferiprone for twice daily administration that exhibits a delayed onset of release and also increases the duration of release, but does not affect the terminal half-life, thus achieving peak and trough values in serum. This benefit extends to both whole and half tablets, as the dissolution rate of half tablets is similar to that of whole tablets at all relevant pH values, such that half tablets are bioequivalent to whole tablets in single dose bioequivalence studies in both fasted and postprandial states.

The results presented herein also demonstrate that, at steady state, the delayed release tablets of the present invention, when administered with BID, were able to achieve the same maximum peak concentrations (C _max ) as the Ferriprox® IR tablets when the IR tablets were given three times a day. , and the total amount absorbed (AUC) was the same for both products over 24 hours. Thus, one obtains certain benefits from taking twice a day and in some cases less gastrointestinal disturbances without sacrificing efficacy.

Bioequivalence refers to the absence of a significant difference between bioavailability, i.e. the rate of absorption, and peak concentration, between two pharmaceutical products (e.g., a test product and a reference product) over a period of time at the same dose and under the same conditions.

Determining whether a test product is bioequivalent to a reference drug is determined by conducting a study, called a bioequivalence or comparative bioavailability study, in a group of subjects, typically about 18-36 subjects or more, under controlled conditions.

The study can be performed in a crossover study, which means that the study is carried out in 2 or more stages, usually at least a week apart, depending in part on the half-life of the drug. In the first stage, half of the subjects are randomly assigned to take the test drug first and the other half to take the reference drug first. In the second stage, each subject receives an alternative drug.

At each stage, blood samples were collected from each subject on a predetermined schedule after administration of the test drug. The blood samples are then analyzed to determine the serum concentration of the drug (test drug, eg deferiprone) at each time point. The results for each subject, for both test product and reference product, are then compiled to determine the following parameters:

AUC is defined as the area under the serum concentration versus time curve during a selected time period after ingestion, eg 24 hours;

AUCT or AUCT is defined as the area under the serum concentration curve versus time from ingestion to the time of last sampling;

AUCI or AUQ - defined as the area under the curve of serum concentration versus time from the time of ingestion to infinity, which is estimated using AUCT and the rate of terminal elimination;

Cmax - defined as peak serum concentration;

AUC ratio - defined as the ratio of AUC from test drug to AUC from reference drug, calculated for each subject;

ratio C _max - is defined as the ratio of C _max from the test drug to C _max from the reference drug, also calculated for each subject;

mean AUC ratio - defined as the antilogarithm of the mean of the logarithms of the AUC ratios for all subjects;

mean Cmax ratio - is defined as the antilogarithm of the average of the logarithms of the Cmax ratios for all subjects.

Equivalent absorption is defined as the average ratio of AUC between 80% and 125% calculated for the test drug compared to the reference drug in a study typically conducted on 18 or more subjects.

The equivalent peak concentration is defined as the average ratio of C _max from 80 to 125%,

- 12 042135 calculated for the test drug compared to the reference drug, in a study usually conducted on 18 or more subjects.

Both an equivalent absorption rate and an equivalent peak concentration must be achieved to be considered bioequivalent.

For any bioavailability parameter, the true mean ratio of the parameter measured in the test preparation to the value measured in the reference preparation is defined as the average ratio that can be found in a study with an infinite number of subjects. Since no study can be done on an infinite number of subjects, the average ratio determined in any study is only an estimate of the true average ratio. As the number of subjects in a study increases, mean ratio results tend to become a better estimate of the true mean ratio. Unless otherwise stated herein, a reference to a drug having a particular parameter relationship to a reference drug will be understood to be the mean value determined in a study of at least 18 subjects.

Bioequivalence studies may be conducted as single dose studies, either on an empty stomach or after a meal. In a fasting study, drugs are taken orally without food and usually at least a few hours before or after a meal. If the study is carried out in a state after a meal, the drugs are taken during a meal or shortly after a meal. In some embodiments, bioequivalence studies may be conducted with a single dose of the drug or at steady state. In a single dose study, each subject receives only one dose of the drug taken by mouth at each stage, although this dose may include more than 1 tablet depending on the study dose size. In a steady state study, subjects are dosed according to a dosing regimen (e.g., two or three times a day) of at least several doses until steady state is reached, and then blood samples are taken over a predetermined period, usually within one day . To evaluate modified release formulations, whether delayed release or sustained release, a study is often performed in the presence of food and after several doses to reach a steady state (to mimic the effects of constant dosing).

Administration of a tablet to a patient who has recently taken a meal may alter the rate and extent of absorption, and if the drug is to be taken with food, it is important to characterize the rate and extent of absorption of a delayed release tablet with food compared to an IR tablet with food.

Bioequivalence studies can also be conducted as multi-dose studies conducted over at least several days of dosing to determine if two products are bioequivalent at steady state after several days of dosing. Steady state, as used herein, is reached when the rate of drug administration is equal to the rate of drug elimination, as determined by the absence of a further increase in drug concentrations in the subject after repeated doses. Bioequivalence at steady state is to be understood as meaning that after at least three days of administration of the test preparation, the mean AUC (over 24 hours) and mean _Cmax ratios are between 80% and 125% of those of the reference drug.

In some embodiments, the present invention provides a composition, e.g., a delayed release tablet, for dosing twice a day, which is bioequivalent at steady state to the same daily dose of an IR tablet taken three times a day, for example, as shown in the examples below.

Certain aspects of the invention relate to a tablet for oral administration comprising deferiprone, for which administration twice a day provides an equivalent degree of absorption, at least in a study at steady state, compared with the same total daily dose administered three times a day, as IR tablets.

Certain aspects of the invention relate to an oral tablet comprising deferiprone, for which administration twice a day provides an equivalent peak serum concentration, at least in a study at steady state, compared to the same total daily dose administered three times a day like IR tablets.

Certain aspects of the invention relate to a BID oral tablet containing deferiprone, for which the characteristics of the equivalent degree of absorption and/or absorption rate, as indicated above, correspond not only to whole tablets, but also to halves of the tablet, so that halves of the tablets can be dosed. In some embodiments, tablets are preferably debossed with a break line to facilitate breaking into tablet halves.

For example, if a whole tablet contains approximately 1000 mg of deferiprone, so that half of the tablet contains approximately 500 mg of deferiprone, then a dose of approximately 1500 mg can be taken as one whole tablet plus one half tablet and a total daily dose of 3000 mg can be achieved by administration of BID .

- 13 042135

In some embodiments, in order to achieve the desired absorption characteristics, the tablets of the invention are formulated to exhibit the desired dissolution rates as shown by in vitro dissolution tests. References to dissolution tests in this document are to be understood as testing in USP device 2 at 75 rpm, in 900 ml of medium, i.e. 0.1 N hydrochloric acid (HCl), 0.5 M phosphate buffer at pH 4.5 and 0.5 M phosphate buffer at pH 6.8, unless otherwise noted. The claimed dissolution result is the average result of 6 or more tablets.

Certain aspects of the invention relate to a half tablet or a whole tablet for oral administration to a human subject, comprising a core containing deferiprone, for which the dissolution at 60 minutes at pH 4.5 is from about 55% to about 90%, from about 60% to about 90% or from about 65% to about 85%.

Certain aspects of the invention relate to a half tablet or a whole tablet for oral administration to a human subject, comprising a core containing deferiprone, for which the dissolution at 60 minutes at pH 6.8 is from about 55% to about 90%, from about 60% to about 90% or from about 65% to about 85%.

In some aspects, approximately 100% deferiprone is released within approximately 90 minutes as measured by the USP Apparatus Type II paddle method at 75 rpm in 900 ml at pH 6.8 or 4.5. In some aspects, approximately 50% of deferiprone is released within approximately 30 minutes as measured by the USP Apparatus Type II paddle method at 75 rpm in 900 ml at pH 6.8 or 4.5.

In addition, some aspects of the invention relate to a half tablet or a whole tablet for oral administration to a human subject containing a core containing deferiprone, for which dissolution within 60 minutes in 0.1 N. HCl is less than 20% or less than 10%.

In some embodiments, a single dose of a tablet of the present invention provides an average AUCn/C _max ratio of 3.5 hours to 6 hours in a fasted state when the tablet is administered to a human subject.

In some embodiments, a single dose of a tablet of the present invention provides an average AUCn/C _max ratio of 3.5 to 6 hours postprandial when the tablet is administered to a human subject. In some embodiments, the tablet contains 1000 mg of deferiprone. In some embodiments, the tablet contains 600 mg of deferiprone. In some embodiments, the average C _max is between 2.670 and 13.232 μg/ml when the tablet is administered to a human subject. In some embodiments, the median T _max is 1.33 to 4.00 hours when the tablet is administered to a human subject. In some embodiments, the median T _max is 2.00 to 8.00 hours when the tablet is administered to a human subject. In some embodiments, the median T _max is 1.33 to 6.03 hours when the tablet is administered to a human subject. In some embodiments, the AUC _I /C _max ratio is between 2.858 and 6.596 hours when the tablet is administered to a human subject. In some embodiments, the AUC _I /C _max ratio is between 3.225 and 8.506 hours when the tablet is administered to a human subject.

In some embodiments, the dosage is for the treatment of a subject suffering from iron overload (eg, transfusional iron overload, eg, in subjects suffering from thalassemia, myelodysplasia, or sickle cell disease). Certain aspects of the invention relate to dosing regimens useful for methods of treating iron overload as described herein. In some embodiments of methods for treating iron overload, the total amount of deferiprone administered per day is from about 1 mg/kg/day to about 200 mg/kg/day, from about 1 mg/kg/day to about 150 mg/kg/day , from about 20 mg/kg/day to about 150 mg/kg/day, from about 50 mg/kg/day to about 125 mg/kg/day, or from about 50 mg/kg/day to about 100 mg/kg/day day. In some embodiments, the implementation of the introduction is carried out once, twice or three times a day. In some embodiments, the dosage for the treatment of iron overload is from about 1 mg/kg to about 150 mg/kg, from about 20 mg/kg to about 150 mg/kg, 25 mg/kg to about 125 mg/kg, from about 50 mg/kg to approximately 100 mg/kg twice daily (BID).

In some embodiments, the dosage is for the treatment of a subject suffering from a neurodegenerative disease, such as Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, Friedreich's ataxia, pantothenate kinase-associated neurodegeneration (PKAN), or brain iron storage neurodegeneration (NBIA). In some embodiments, a deferiprone composition of the invention (IR or DR composition) is administered once, twice, or three times daily to a subject suffering from a neurodegenerative disease, e.g., Parkinson's disease, ALS, Huntington's disease, Friedreich's ataxia, pantothenate kinase-associated neurodegeneration (PKAN), or neurodegeneration with brain iron accumulation (NBIA). In some embodiments, the subject is suffering from ALS. In some embodiments, the subject is suffering from Huntington's disease. In some embodiments, the subject suffers

- 14 042135 Parkinson's disease.

Certain aspects of the invention relate to dosing regimens useful for the methods of treating neurodegenerative disease described herein. In some embodiments of methods for treating a neurodegenerative disease, the total amount of deferiprone administered per day is from about 1 mg/kg/day to about 200 mg/kg/day, from about 1 mg/kg/day to about 150 mg/kg/day, from about 1 mg/kg/day to about 100 mg/kg/day, from about 1 mg/kg/day to about 50 mg/kg/day, from about 1 mg/kg/day to about 40 mg/kg/day, about 1 mg/kg/day to about 30 mg/kg/day, about 1 mg/kg/day to about 20 mg/kg/day, about 1 mg/kg/day to about 15 mg/kg/day , from about 1 mg/kg/day to about 10 mg/kg/day, or from about 1 mg/kg/day to about 5 mg/kg/day. In some embodiments, the implementation of the introduction is carried out once, twice or three times a day. In some embodiments, the dosage for treating a neurodegenerative disease is about 1 mg/kg to about 100 mg/kg, about 1 mg/kg to about 50 mg/kg, 1 mg/kg to about 40 mg/kg, about 1 mg/kg up to about 25 mg/kg or about 1 mg/kg to about 20 mg/kg twice a day (BID).

In some embodiments of the methods, the amount of deferiprone in the composition (e.g., tablet) is from about 100 mg to about 1500 mg, from about 200 mg to about 1500 mg, from about 400 mg to about 1500 mg, from about 600 mg to about 1500 mg , from about 800 mg to about 1500 mg, from about 1200 mg to about 1500 mg, from about 200 mg to about 1200 mg, from about 400 mg to about 1200 mg, from about 600 mg to about 1200 mg, from about 800 mg up to about 1200 mg, from about 200 mg to about 1000 mg, from about 400 mg to about 1000 mg, from about 600 mg to about 1000 mg, from about 800 mg to about 1000 mg, from about 200 mg to about 800 mg, from about 400 mg to about 800 mg, from about 600 mg to about 800 mg, from and about 200 mg to about 600 mg, about 400 mg to about 600 mg, or about 200 mg to about 400 mg. In some embodiments of the methods, the amount of deferiprone in the composition (e.g., tablet) is about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 800 mg, about 1000 mg, about 1100 mg , about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, or any range thereof. In particular, the amount of deferiprone in a composition (eg tablet) is 600 or 1000 mg of deferiprone. In some embodiments, the amount of deferiprone per tablet is 1000 mg of deferiprone. In some embodiments, the amount of deferiprone per tablet is 600 mg of deferiprone.

In some embodiments of the methods, the total daily dose of deferiprone is from about 100 mg/day to about 3000 mg/day, from about 200 mg/day to about 3000 mg/day, from about 400 mg/day to about 2400 mg/day, from about 600 mg/day to about 2400 mg/day, from about 800 mg/day to about 2400 mg/day, from about 1200 mg/day to about 2400 mg/day, from about

1600 mg/day to about 2400 mg/day, from about 1800 mg/day to about

2400 mg/day, from about 2000 mg/day to about 2400 mg/day, from about

400 mg/day to about 2000 mg/day, from about 600 mg/day to about

2000 mg/day, about 800 mg/day to about 2000 mg/day, about 1200 mg/day to about 2000 mg/day, about 1600 mg/day to about

2000 mg/day, from about 1800 mg/day to about 2000 mg/day, from about

400 mg/day to about 1800 mg/day, from about 600 mg/day to about

1800 mg/day, from about 800 mg/day to about 1800 mg/day, from about 1200 mg/day to about 1800 mg/day, from about 1600 mg/day to about 1800 mg/day, from about 400 mg/day up to about 1600 mg/day, from about 600 mg/day to about 1600 mg/day, from about 800 mg/day to about 1600 mg/day, from about 1200 mg/day to about 1600 mg/day, from about 400 mg /day to about 1200 mg/day, from about 600 mg/day to about 1200 mg/day, from about 800 mg/day to about 1200 mg/day, from about 400 mg/day to about 800 mg/day, from about 600 mg/day to about 800 mg/day, or from about 400 mg/day to about 600 mg/day. In some embodiments of the methods, the total daily dose of deferiprone is about 200 mg/day, about 400 mg/day, about 600 mg/day, about 800 mg/day, about 1000 mg/day, about 1200 mg/day, about 1400 mg/day. day, approximately 1600 mg/day, approximately 1800 mg/day, approximately 2000 mg/day, approximately 2200 mg/day, approximately 2400 mg/day, approximately 2600 mg/day, approximately 2800 mg/day, approximately

- 15 042135

3000 mg/day or any range.

In some embodiments of the methods, the composition (eg, tablet) is administered once, twice, or three times a day. In some embodiments, the composition (e.g., tablet) contains about 100 mg, about 200 mg, about 400 mg, about 600 mg, about 800 mg, about 1000 mg, about 1200 mg, about 1600 mg, about 1800 mg, about 2000 mg , approximately 2200 mg, or approximately 2400 mg of deferiprone and is administered once, twice or three times a day. In some embodiments, the implementation of the composition (eg, tablet) contains approximately 600 mg of deferiprone and is administered once or twice a day.

In some embodiments, the composition (eg, tablet) contains about 100, 200, 300, or 400 mg of deferiprone and is administered once, twice, or three times a day. In some embodiments, the composition (eg, tablet) contains approximately 400 mg of deferiprone and is administered once, twice, or three times a day. In some embodiments, the composition (eg, tablet) contains approximately 500 mg of deferiprone and is administered once, twice, or three times a day. In some embodiments, the composition (eg, tablet) contains approximately 1000 mg of deferiprone and is administered once, twice, or three times a day.

Such embodiments described herein may be used to prevent or reduce the risk of gastric distress and/or to treat iron overload in a subject (e.g., suffering from thalassemia, myelodysplasia, or sickle cell disease) or a neurodegenerative disease (e.g., amyotrophic lateral sclerosis). ).

VI. Ways to get.

In some embodiments, the pharmaceutical composition is formulated for oral delivery. In some aspects, the present invention relates to the preparation of the delayed release deferiprone tablet described herein.

In some embodiments, a method for preparing a delayed release deferiprone tablet comprises (a) mixing deferiprone and one or more excipients;

(b) compressing mixture (a) into a tablet core; and (c) coating the tablet core with an enteric coating suspension or solution.

The method may further include (d) applying a score to the tablet core.

In some embodiments, the method for coating the core with an enteric coating solution or suspension comprises spray coating. In the case of spray coating, the operation may be carried out according to general coating methods, for example, the tablet core is sprayed with an enteric coating solution or suspension according to, for example, a fluidized bed coating method, a coater coating method, or etc.

In some embodiments, the enteric coating solution or suspension contains an enteric polymer. In some embodiments, the enteric polymer is about 1-50%, about 1-40%, about 5-40%, or about 5-30% of the enteric coating solution or suspension. In some embodiments, the enteric polymer makes up about 20-80%, about 25-75%, or about 30-70% of the enteric coating when the coating is dry. In some embodiments, the enteric polymer makes up approximately 50-60% by weight of the enteric coating when the coating is dry. In some embodiments, the enteric polymer makes up about 55% by weight of the enteric coating when the coating is dry.

In some embodiments, the enteric coating suspension or solution contains a plasticizer such as, for example, diethyl phthalate, citric acid esters (e.g., triethyl citrate), polyethylene glycol, glycerin, acetylated glycerides, glycerol fatty acid ester, cetyl alcohol, stearyl alcohol, acetylated esters of citric acid, dibutyl sebacate, castor oil, or combinations thereof.

In some embodiments, the plasticizer is about 0.1-10%, about 0.1-5%, about 0.5-5%, or about 0.5-2% of the enteric coating suspension or solution. In some embodiments, the plasticizer makes up about 1-10%, or about 4-8% by weight, of the enteric coating when the coating is dry. In some embodiments, the plasticizer makes up about 6% by weight of the enteric coating when the coating is dry.

In some embodiments, the enteric coating suspension or solution contains a lubricant or anti-stick agent (eg, talc).

In some embodiments, the lubricant or anti-stick agent is about 0.5-10%, about 0.5-8%, about 0.5-5%, or about 1-5% of the enteric coating suspension or solution. In some embodiments, the lubricant or anti-tack agent makes up about 1030%, or about 15-25% by weight, of the enteric coating when the coating is dry. In some embodiments, the lubricant or anti-tack agent makes up about 20% by weight of the enteric coating when the coating is dry.

In some embodiments, the enteric coating suspension or solution may further contain a diluent, such as sugar (eg, lactose, sucrose, fructose, mannitol, and mixtures thereof).

In some embodiments, the diluent is about 0.5-10%, about 0.5-8%, about 0.5-5%, or about 1-5% of the enteric coating suspension or solution. In some embodiments, the diluent makes up about 10-30%, or about 15-25% by weight, of the enteric coating when the coating is dry. In some embodiments, the diluent makes up about 20% by weight of the enteric coating when the coating is dry.

In some embodiments, the enteric coating can be applied as a solution or latex suspension in organic solvents or aqueous solvents, or mixtures thereof. Solvents such as water, lower alcohol, lower chlorinated hydrocarbons, ketones or mixtures thereof can be used.

In some embodiments, the solvent makes up about 20-80%, about 30-80%, about 40-80%, or about 50-75% of the enteric coating solution or suspension.

In some embodiments, at least one ionic, non-ionic, or polymeric surfactant may be added as a stabilizing agent to the enteric coating suspension or solution. Suitable examples of the surfactant include diethanolamine, fatty acids, hydroxypropyl methylcellulose, hydroxypropyl cellulose, monoethanolamine, nonoxynol, octoxynol, oleic acid, poloxamers, polyoxyethylene50-stearate, polyhydroxy fatty acids, polyoxyl hydrocarbon esters, polysorbates (e.g. polysorbate 80 and the like). .), but not limited to povidone, fatty acid salts, sodium lauryl sulfate, sorbitan esters, trolamine, and the like.

In some embodiments, the enteric coating suspension or solution contains a plasticizer, diluent, lubricant, or anti-tack agent, and an enteric polymer.

After coating, in some embodiments, an antistatic agent such as talc may also be used.

By coating the tablet core described herein with a coating layer using the methods described herein, the immediate dissolution of the physiologically active substance from the enteric granule at an acidic pH (e.g., pH 1-4) is suppressed, which corresponds to dissolution in the immediate vicinity of the stomach at an early stage. stage after oral administration, and facilitates the subsequent dissolution of the physiologically active substance at a slightly acidic to slightly alkaline pH (eg pH 4.5-8), which corresponds to dissolution in the small intestine and then especially in the duodenum to the ileum. In particular, dissolution can be more strictly controlled at an early stage after administration.

VII. Application methods.

The present invention provides methods for using the pharmaceutical compositions disclosed herein. In some embodiments, the pharmaceutical composition is for oral delivery. Preferably the pharmaceutical composition is a tablet for oral delivery. In some embodiments, the pharmaceutical composition is a tablet (eg, a delayed release tablet as described herein).

For example, the most common adverse event with immediate-release deferiprone tablets (Ferriprox®) is that it causes significant stomach upset. Such discomfort can cause patients to refrain from taking medication, which will worsen their condition. In addition, a GI disorder can impair health-related quality of life and lead to physical, mental, and social distress. Spiegel, Am. J. Gastroenterol. March 2011; 106(3):380-5, incorporated herein by reference in its entirety. In some embodiments, the compositions, eg, delayed release tablets, of the present invention are formulated to reduce gastric upset, a problem that occurs in approximately 15-30% of patients who initiate therapy with deferiprone. In some embodiments, the formulations, such as the delayed release tablets described herein, have low gastric dissolution to minimize gastric distress while achieving fast enough intestinal dissolution to provide the desired intestinal release rate. In some embodiments, the compositions, e.g., the delayed release tablets described herein, have negligible gastric dissolution to minimize gastric distress while achieving similar, but not identical, plasma concentration profiles over time, in vivo. as immediate release deferiprone tablets, with an added delay time of approximately one hour.

Some embodiments of the invention relate to a method of reducing gastric distress in a human subject in need of treatment with deferiprone, comprising administering a tablet (e.g., deferiprone delayed-release scored tablets) described herein (e.g., a whole tablet, half a tablet, or a combination thereof). ).

Some embodiments of the invention relate to a method for the sustained release of deferiprone in a human subject, comprising administering a tablet as described herein (eg, a whole tablet, half a tablet, or a combination thereof). Some embodiments of the invention relate to a method of treating a medical condition in a human subject, for example, where deferiprone is required, comprising administering a tablet (e.g., deferiprone delayed-release scored tablets) described herein (e.g., a whole tablet, half a tablet, or their combinations).

Compositions, such as delayed release tablets, of the present invention may be particularly useful in patients requiring blood transfusions to ensure viability, such as hemoglobinopathies, including thalassemia and sickle cell disease, or in patients who have secondary impairment of their ability to the formation of red blood cells, such as patients with myelodysplasia.

Deferiprone immediate release tablets (Ferriprox®) are currently used to minimize the toxicity of high concentrations of iron in the body, tissues, or cells. Thalassemia is a form of hereditary autosomal recessive blood disorder characterized by abnormal production of hemoglobin. Abnormal hemoglobin results in inadequate oxygen transport and an accelerated rate of red blood cell destruction. People with thalassemia produce less hemoglobin and have fewer circulating red blood cells than normal, leading to moderate to severe anemia. Patients require a lifelong blood transfusion to treat thalassemia, typically every 2 to 4 weeks, and each blood transfusion results in an increase in the amount of iron in the body, equivalent to the amount normally absorbed from food in the intestines for 6 months. Because there is no excretion pathway for iron, this excess will cause iron overload, especially in the liver and other more sensitive tissues, with endocrine disruption and iron-induced cardiovascular disease as a result.

Iron overload occurs in patients with sickle cell disease (SCD) who require regular chelation therapy. Voskaridou et al., Ann. Hematol. 2005 Jul, 84(7):434-40, incorporated herein by reference in its entirety. Although sickle cell disease is a different hemoglobinopathy, patients with sickle cell disease who require blood transfusion to ensure viability also suffer from iron toxicity. This also applies to patients with myelodysplasia who require repeated blood transfusions.

In some embodiments, the medical condition being treated with a composition, such as a delayed release tablet, of the present invention is iron overload. In some aspects, the medical condition being treated with the composition, such as a delayed release tablet, is transfusional iron overload in a subject whose prior chelation therapy has been inadequate. In some aspects, the medical condition being treated with the composition, eg, a delayed release tablet, is transfusion iron overload in a subject who has a T2* cardiac MRI of 20 ms or less (eg, 10 ms). In some embodiments, the medical condition being treated with the composition, eg, delayed release tablet, of the present invention is present in patients with thalassemia who have undergone a transfusion. In some embodiments, a composition, such as a delayed release tablet, of the present invention is used to treat transfusional iron overload in patients with sickle cell disease. In some embodiments, the tablet (eg, deferiprone risky delayed release tablet) of the present invention is used to treat transfusional iron overload in patients with myelodysplasia.

Compositions, such as delayed release tablets, of the present invention may also be particularly useful in patients with a neurodegenerative disease such as Parkinson's disease, amyotrophic lateral sclerosis (ALS) or Huntington's disease, since the tablets do not dissolve in the stomach, which in some cases reduces to minimize gastric upset, accompanied by nausea and vomiting, which is especially pronounced in patients who start taking deferiprone. Equally important, the DR tablets of the present invention are absorbed less rapidly than the IR tablets and other known deferiprone tablets, resulting in less nausea and vomiting, which may contribute to the onset of a GI disorder. Still DR pills present

- 18 042135 inventions are rapidly absorbed after reaching the duodenum to allow rapid penetration into the brain, which allows deferiprone to show its beneficial effects in Parkinson's disease, ALS, Huntington's disease and other neurodegenerative diseases, where localized accumulation of iron contributes to the pathology of the disease.

Parkinson's disease is a degenerative disease of the central nervous system. The motor symptoms of Parkinson's disease result from the death of dopamine-generating cells in the substantia nigra, an area of the midbrain. In the early stages of the disease, the most obvious symptoms are associated with movement, such as tremors, rigidity, slowness, and difficulty walking and gait. Problems with thinking and behavior may occur later in the course of the disease, dementia usually occurs late in the disease, and depression is the most common psychiatric symptom. Other symptoms include sensory problems, sleep problems, and emotional problems. Parkinson's disease is more common in older people, with most cases occurring after age 50.

The pathology of Parkinson's disease is characterized by the accumulation of a protein called alphasynuclein in inclusions called Lewy bodies in neurons, along with insufficient formation and activity of dopamine produced by certain neurons in parts of the midbrain. The anatomical distribution of Lewy bodies is often directly related to the expression and extent of each individual's clinical symptoms. Diagnosis of typical cases is mainly based on symptoms, with tests such as neuroimaging used for confirmation.

Early motor symptoms of the disease are usually relieved by treatment with L-DOPA and dopamine agonists. As the disease progresses and the loss of dopaminergic neurons continues, these drugs eventually become ineffective in treating symptoms and at the same time cause a complication called dyskinesia, which is marked by involuntary writhing movements. Diet and exercise and some forms of rehabilitation have shown some effectiveness in alleviating symptoms. Surgery and deep brain stimulation have been used to reduce motor symptoms as a last resort in severe cases where medications are ineffective. There is no cure for Parkinson's disease.

Huntington's disease is a progressive brain disease caused by a defective gene (HTT) on chromosome 4 that codes for a protein called huntingtin. The defect causes the expansion of CAG triplet repeats (cytosine-adenine-guanine) in the gene encoding huntingtin, which damages brain cells. A diagnostic genetic test for the defective huntingtin gene is available.

Symptoms of Huntington's disease usually develop between the ages of 30 and 50 and include uncontrolled movement of the arms, legs, head, face, and upper body. Huntington's disease also causes a decline in thinking and reasoning skills, including memory, concentration, judgment, and the ability to plan and organize.

There is no cure for Huntington's disease, and treatment is directed at treating the symptoms of Huntington's disease. For example, antipsychotics such as olanzapine are used to treat chorea (involuntary movements), antipsychotics or selective serotonin reuptake inhibitors are used to treat irritability, and selective serotonin reuptake inhibitors are used to treat obsessive-compulsive thoughts or actions.

Amyotrophic Lateral Sclerosis (ALS) is a disease that causes the death of neurons that control voluntary muscles. ALS is also known as Lou Gehrig's disease or motor neuron disease (MND). ALS is characterized by stiff muscles, muscle twitching, and gradual weakening of the muscles due to reduced muscle size. This leads to difficulty speaking, swallowing and breathing. The cause is unknown in 90-95% of ALS cases, while approximately 5-10% of ALS cases are inherited genetically. The diagnosis of ALS is based on the person's signs and symptoms, with testing performed to rule out other potential causes.

There is no cure for ALS. Non-invasive ventilation can improve the quality and length of life. Riluzole, a sodium channel blocking drug, may delay the onset of dependence on the need for a ventilator or tracheostomy and may increase life expectancy by about 2 to 3 months. However, the average life expectancy from onset to death is typically 2-4 years.

In some embodiments, the medical condition being treated with the composition, eg, tablet (eg, deferiprone risky delayed release tablet) described herein, is a neurodegenerative disease. In some embodiments, the neurodegenerative disease is Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, pantothenate kinase-associated neurodegeneration, or Friedreich's ataxia.

Accordingly, some embodiments of the invention relate to methods for treating a neurodegenerative disease, comprising the composition described herein. In some embodiments, the neurodegenerative disease is a disease

- 19 042135

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). Some embodiments relate to methods for reducing or slowing the progression of disability associated with ALS. In some embodiments, the subject is additionally administered riluzole. In some embodiments, deferiprone is administered before, after, or simultaneously with administration of riluzole to a subject. In some embodiments, the total daily dose of riluzole is from about 20 mg/day to about 500 mg/day.

In some embodiments, the composition is a tablet, a delayed release tablet, a scored delayed release tablet, a whole tablet, a half tablet, or a combination thereof. In some embodiments, the implementation of the composition is administered in accordance with the dosing regimen described herein. In some embodiments, the composition is administered in a fasted or postprandial state.

Some aspects of the invention relate to a method of treating a human subject with iron overload, comprising oral administration to the subject in need of 3000 mg/day or 1200 mg/day of deferiprone, where the subject is administered deferiprone twice a day. In some embodiments, the subject suffers from thalassemia or myelodysplasia. In some embodiments, the subject is suffering from a neurogenic disorder. In some embodiments, 3000 mg/day of deferiprone is administered at a dose of 1500 mg twice daily (eg, one and half of a 1000 mg DR tablet; or three halves of a 1000 mg DR tablet). In some embodiments, the subject exhibits a C _{max of} 48.5-10.5 μg/ml at steady state. In some embodiments, the subject exhibits an AUC( ₀ _ ₂₄ ) of 75-95 µg-h/ml at steady state. In some embodiments, 1200 mg/day of deferiprone is administered at a dose of 600 mg twice daily. In some embodiments, 1200 mg/day of deferiprone is administered at a dose of 1200 mg once daily. In some embodiments, the subject exhibits a C _max of 4.00 to 13.558 μg/mL following postprandial administration of 600 mg deferiprone. In some embodiments, the subject exhibits a C _max of 5.880 to 13.690 μg/mL following administration of 600 mg of deferiprone on an empty stomach. In some embodiments, the subject exhibits a T _max of 1.333 to 8,000 hours after administration of 1200 mg of deferiprone. In some embodiments, the subject exhibits an AUC _I /C _max of 3.265 to 6.765 hours after administration of 1200 mg of deferiprone.

In some embodiments of these methods, the subject suffers from Parkinson's disease. In some embodiments of these methods, the subject suffers from Huntington's disease. In some embodiments of these methods, the subject suffers from amyotrophic lateral sclerosis (ALS).

VIII. Bioavailability.

Pharmacokinetic (PK) parameters (eg, C _max , T _max , AUCT, AUCI, Kel, Ti/ ₂ ) can be assessed for subjects who are administered the tablet described herein. In some embodiments, PK parameters are determined using a single dose study. In some embodiments, PK parameters are determined using a multi-dose or steady state study.

In some embodiments, the tablet described herein provides an average AUCn/C _max ratio of 3.5 to 6.0 hours in single dose bioequivalence studies in both the fasted and postprandial state when the tablet is administered. as a whole tablet and when administered as a half tablet.

Although the present application is illustrated by a description of its embodiments and although the embodiments are described in considerable detail, Applicants do not intend to reduce or otherwise limit the scope of the appended claims to such detail. Additional advantages and modifications will be apparent to those skilled in the art having the advantages of the present application. Therefore, the application in its broader aspects is not limited to the specific details described by the illustrative examples or by any of the devices mentioned. Deviations may be made from such details, examples and devices without departing from the spirit or scope of the general idea of the invention.

Examples

The use of the invention may be better understood from the following examples, which are intended to illustrate and not limit the scope of the invention.

- 20 042135

Example 1 Preparation of delayed release enteric coated tablets.

Table 1

Deferiprone delayed release tablet (1000 and 600 mg)

Component Function Amount (1000 mg) Amount (600 mg) mg % mg % Deferiprone Active substance 1000 89.6 600 88.7 HPMCAS-LF enteric 28 2.51 29.5 4.36 polymer magnesium oxide pH adjuster 50 4.48 24.5 3.62 colloidal dioxide silicon (part 1) Glidant 2.6 0.23 1 0.15 Subtotal 1080.6 96.8 655 96.8 After compaction magnesium stearate lubricant 17.2 1.54 4 0.59 colloidal dioxide silicon (part 2) Glidant 2.2 0.20 1 0.15 Total 1100 98.5 660 97.6 Coating triethyl citrate plasticizer 1.03 0.09 1.03 0.15 sucrose Diluent 3.09 0.28 3.09 0.46 Talc obstructive adhesion agent 3.09 0.28 3.09 0.46 * Dispersion of methacrylic acid copolymer Enteric polymer 31 0.83 ^# 31 1.37 ^# ** purified water 124 - 126.8 Whole film-coated tablet 1116.5 100 676.5 100

* Contains 30% solids.

** Evaporates during coating process.

# Weight percentage of methacrylic acid copolymer in the coating when the coating dries.

Deferiprone, HPMCAS, magnesium oxide and colloidal silicon dioxide (part 1) were mixed together to form the tablet core and the mixture was compacted and ground into granules. Magnesium stearate and colloidal silicon dioxide (part 2) were added to and mixed with the granules and the resulting mixture was compressed into a tablet core weighing approximately 1100 mg or approximately 660 mg on a capsule-shaped tool halved on both sides.

The enteric coating suspension was sprayed onto the deferiprone tablet cores in a side vent coating machine until the tablets had a target weight gain of approximately 1.5% for the 1000 mg tablets and 2.5% for the 600 mg tablets. The resulting delayed release tablet was designed to have negligible dissolution in the stomach but rapidly dissolve in the duodenum to prevent gastric upset. These properties apply to the whole tablet and half of the tablet.

Example 2 Dissolution characteristics of a delayed release deferiprone tablet (whole and half).

The dissolution characteristics of the 1000 mg delayed release deferiprone tablet prepared in Example 1 were tested in vitro using both whole and half tablets.

Dissolution tests were carried out in USP device 2 at 75 rpm in 900 ml of 0.1N. hydrochloric acid (HCl), 0.5 M phosphate buffer at pH 4.5 and 0.5 M phosphate buffer at pH 6.8. Tablets 1000

- 21 042135 mg from example 1 showed the following dissolution characteristics for both whole tablets and half tablets:

Dissolution was below 20% after 180 min in 0.1N. HCl [Fig. 1].

Dissolution was below 60% after 60 minutes at pH 6.8 [FIG. 2].

Dissolution was above 80% after 60 minutes at pH 4.5 [FIG. 3].

Example 3 Comparison of Dissolution Rates for Deferiprone Delayed Release Tablets vs. with enteric coating.

The dissolution profile for the whole and half of the 1000 mg delayed-release tablet prepared in Example 1 was compared with the dissolution profile for the whole and half of the enteric-coated (EC) tablets (Avicenna Lab, Iranian Patent Application No. 90-07-27-71996) .

The EC tablet (Avicenna Lab) used for comparison included a tablet core of 500 mg deferiprone, 290 mg microcrystalline cellulose, 1 mg colloidal silicon dioxide, and 9 mg magnesium stearate (800 mg total core weight). The EC tablet (Avicenna Lab) also included a coating of 34.68 mg methacrylic acid copolymer, 15.56 mg talc, 3.61 mg PEG 6000, 4.38 mg titanium dioxide, 4.93 mg hypromellose, 6 cm Poaz, and 0 .82 mg sodium bicarbonate (total coating weight 63.98 mg). The weight of the coating is approximately 7.4% of the total weight of the EC tablet.

Dissolution testing was performed in a USP Apparatus II at 75 rpm using 900 ml of 0.1N. HCl for 180 min. Samples were collected at 5 minute intervals to characterize the dissolution profile of the tablets.

In general, the whole and halves of the delayed release deferiprone tablet of Example 1 had a dissolution below 20% at 60, 90, 120, 150 and 180 minutes in 0.1N. HCl (which is the pH of the stomach). No dissolution was observed in 0.1 N. HCl for a whole EC tablet (Avicenna Lab), but fast and complete dissolution was observed in buffered solutions: 95% dissolved after 30 min in pH 4.5 solution; 94% dissolved after 30 minutes in a pH 6.0 solution; and 88% dissolved after 30 minutes in a pH 6.8 solution. However, half of the EC tablets (Avicenna Lab) dissolved rapidly, thus losing their enteric coating properties.

Thus, the delayed release formulation of Example 1 showed an advantage over other enteric-coated deferipronon tablets. In particular, the 1000 mg delayed release tablet of Example 1 exhibits delayed release in an environment representing the pH of gastric acid, but has superior performance to that provided by the enteric coating. In particular, the novel delayed release tablet of the invention provides the same dissolution rate for half and whole tablets, regardless of the pH of the dissolution medium. Those. a delayed release tablet captures certain properties of an enteric-coated tablet without its drawbacks such that the tablets can be split in half to allow dosage adjustments to administer half tablets.

Examples 4 and 5 24 hour bioequivalence studies.

Examples 4 and 5 refer to bioequivalence studies in human subjects using 1000 mg deferiprone delayed release tablets in Example 1 and Ferriprox® IR tablets.

The first study (Example 4) was a single dose study which showed a delay in absorption of DR tablets but no increase in terminal half-life, and that half tablets had the same rate and extent of absorption as whole tablets whether or not they were administered. with food.

The second study (Example 5) was a multiple dose study of equivalent daily doses of DR and IR tablets. This study showed that, at steady state, DR tablets were bioequivalent at steady state to IR tablets.

Example 4 Pharmacokinetic study of a single dose of deferiprone delayed-release tablets under fasting conditions and after a meal compared with Ferriprox® immediate-release tablets after a meal in healthy volunteers.

This was a randomized, single dose, open label, 4-period, 4-sequence crossover study in healthy male and female volunteers. Subjects were randomized to receive single doses of the following treatments in various sequences with a 7-day washout period between treatments:

one whole tablet 1000 mg deferiprone DR under fasting conditions (n=23);

one whole tablet 1000 mg deferiprone DR under postprandial conditions (n=21);

two half tablets (total 1000 mg) of deferiprone DR under postprandial conditions (n=26); and two 500 mg Ferriprox® IR tablets under postprandial conditions (n=24).

The objectives of the study were to evaluate the effect of food on the PK profile of a single dose DR of deferiprone, to compare the PK profile of a half tablet to that of a whole tablet, to compare the PK profile of deferiprone DR to that of Ferriprox® IR, and to evaluate the safety and tolerability of a single dose of deferiprone DR.

The main PK parameters of this study are shown in Table. 2, and relative bioavailability

- 22 042135 is shown in table. 3. Under postprandial conditions, the time (T _max ) to reach peak serum concentration (C _max ) of deferiprone was longer with the DR formulation (3.00 h) compared to the IR formulation (1.33 h). The C _max for the DR formulation was approximately 65% of that for the IR formulation. Serum drug levels after absorption decreased at a similar rate, and the half-life was approximately 1.8 hours for both formulations. In addition, there was no significant difference in drug exposure (AUC) between the two formulations.

When the DR tablet was administered as half a tablet, neither Cmax nor AUC were significantly different from the values for the whole tablet. With regard to the effect of food, the bioavailability of the DR formulation was the same regardless of whether it was administered on an empty stomach or after a meal. Since the same total dose was given for the DR and IR tablets, C _max was expected to be higher for the IR tablets. However, these results indicated that 50% more deferiprone could be given in the DR tablet to achieve the same C _max as the IR tablet.

For each subject of the pharmacokinetic study, the ratio of AUC _0-inf to C _max was calculated (Table 4). The resulting ratio was transformed by determining the natural logarithm of the ratio. The mean of the log-transformed relationships between subjects in the study was calculated, and then the mean of the logarithm was then converted back to the normal scale by determining the antilogarithm of the mean.

table 2

Summary of pharmacokinetic parameters

Parameter (units) Deferiprone DR fasting Deferiprone DR after meals Deferiprone DR, half tablets, after meals Deferiprone IR, after meals C _mai (µg/mL) mean (range) 6.133 (2.670-13.232) 6.089 (2.908-9.514) 6.620 (3.236-12.419) 9.621 (3.731-19.125) Standard Deviation (SD) 2.246 1.954 2.326 3.860 Tmax (hours) mean median (range) 2.286 2.33 (1.33-4.00) 3.673 3.00 (2.00-8.00) 3.273 2.67(1.33-6.03) 1.886 1.33(0.50-8.00) AUCT (mcg'h/ml) 27.48 (29.2) 27.63 (25.6) 28.52(25.9) 29.64 (27.4) AUCI (mcg h/mL) 27.86 (29.2) 28.41 (25.6) 29.05(26.2) 30.26(27.6) Thalf (hours) 1.83 (11.7) 1.80(16.5) 1.77 (13.7) 1.79(14.8)

Table 3

Relative bioavailability of deferiprone delayed-release tablets

Parameter(units) Ratio (90% CI) Deferiprone DR after meals vs. on an empty stomach Deferiprone DR after a whole meal vs. half Deferiprone DRvs. TR, after eating Stakh (MKG/ML) 98.7(86.6-112.4) 89.0(78.5-100.9) 65.5 (57.6-74.5) AUCT (mcg h/mL) 99.0(95.2-102.9) 96.7 (93.2-100.4) 92.4 (88.9-96.0) AUCI (mcg h/ml) 100.0 (96.3 - 103.8) 97.5 (94.1 -101.1) 93.1 (89.7-96.7)

Table 4

AUCI/Cmax

1 Attitude DR 1000 mg tablet - fasting DR 1000 mg tablet - after meals DR 1000 mg roll tablets - after eating IR 500 mg tablet - after meals AUCI/Cmax (h) (range) 4.735 (2.858 - 6.596) 4.763 (3.225- 8.506) 4.423 (3.174- 6.529) 3.225 (2.073- 4.497)

Example 5 Comparative Steady Bioavailability Study of Deferiprone Delayed Release (DR) Tablets vs. immediate release (IR) tablets at steady state in healthy volunteers.

A two-period crossover study was conducted to evaluate the comparative bioavailability of 1000 mg deferiprone DR tablets (as shown in Example 1) and deferiprone IR tablets (Ferriprox®) at steady state in 35 healthy volunteers. Subjects were randomized to receive the next two treatments separated by 5 wash days.

Treatment A: Deferiprone DR 1500 mg (one and half 1000 mg tablets) every 12 hours (BID) (total 3000 mg/day) for 3 days administered after meals; and Treatment B: Ferriprox® IR 1000 mg (two 500 mg tablets) every 8 hours (three times a day (TID)) (3000 mg/day total) for 3 days administered after meals.

Following appropriate screening and baseline testing, subjects were administered deferiprone BID or TID as appropriate on days 1-3. After a washout period, they returned to the site on the evening of the 8th day and received another treatment for 9-11 days and left on the morning of the 12th day.

For each period, blood samples for pharmacokinetic (PK) evaluation were taken prior to the first dose of the day on the first two days of dosing (days 1-2 and 9-10) and then at specified time points after

- 23 042135 dosing within 24 hours on the third day (day 3 and day 11).

PK comparisons between deferiprone DR and Ferriprox® IR were performed at steady state (ie, using data for the 0-24 hour interval on the third day for each treatment).

Statistical analysis for AUC _0-244-ss , C _max-ss , C _min-ss , C _24-ss , T _max-ss is based on an analysis of variance model. A two-sided 90% confidence interval of the difference between treatments was calculated for each parameter. Data AUC _0-244-ss , C _max-ss , C _min-ss and C _24-ss were log-transformed before analysis of variance.

Criteria for bioequivalence at steady state were established by the 90% confidence interval for AUC _0-244-ss and C _max-ss , which should be in the range of 80-125%.

Summary of study outcomes for deferiprone BID DR tablets and TID IR tablets in subjects at steady state are shown in Table 1. 5 and 6 and in FIG. 4.

Table 5

PK results for deferiprone tablets DR BID and IR tablets TID in subjects at steady state

Parameter(units) ' Treatment A (Deferiprone DR) a (n=35) ’ Treatment B (Deferiprone IR)” (n=35) Average (C.V.%) Average (C.V.%) Cmax,ss (µg/ml) 9.587 (21.1) 10.798 (27.9) T _max ,„ (hours) ^and 3.67(1.50-17.00) 9.00(0.50-18.00) AUC ₍₀ -24) _SS ( ^µg 'h/ml) 83.634 (22.4) 83.364(23.3)

^a One and half 1000 mg tablets twice daily (every 12 hours), for a total of 3000 mg/day, for 3 consecutive days.

^b Two 500 mg tablets three times daily (every 8 hours), for a total of 3000 mg/day, for 3 consecutive days.

^c The median (range) is shown.

Tmax was calculated from the 1st dose of the day.

Table 6

Comparison of Steady State Bioequivalence Results of Deferiprone DR Tablets BID and IR Tablets TID

Parameter(units) Attitude 90% confidence limit (%) Lower Upper C _mai , _ss (µg/ml) 88.74 83.00 94.89 AUC ₍ 0-24h) _SS ( ^mcg 'h/ml) 99.31 97.03 101.63

The results show that over a 24-hour period, DR tablets when taken twice a day could reach the same maximum peak concentrations (C _max ) as IR tablets when taken three times a day, and that the total amount absorbed (AUC) was essentially the same for both drugs during the 24-hour period when the total daily dose was the same.

Example 6 Bioavailability of Deferiprone Delayed Release (DR) 600mg Tablets Compared to Oral Solution in Healthy Volunteers.

In this study, healthy subjects were randomized to receive the next four treatments in different orders, with a 7-day washout period between treatments.

Treatment A: deferiprone DR 1200 mg (two 600 mg tablets) single dose under postprandial conditions (n=18);

treatment B: deferiprone DR 1200 mg (two 600 mg tablets) single dose on an empty stomach (n=17);

treatment C: deferiprone DR, 1200 mg (four half-tablets) single dose under postprandial conditions (n=18); and treatment D: oral solution (Ferriprox®, 1200 mg (100 mg/mL) single dose under fasting conditions (n=17).

Blood samples were collected before dosing and within 24 hours after dosing. Parameters PK (C _max and T _max ) are shown in table. 7. The ratio of AUCI to C _max is shown in table. 8. These results show that the C _max for 600 mg DR tablets is approximately half the C _max of oral solution and the AUCI/C _max for 600 mg DR tablets is about twice the ratio for oral solution.

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Table 7

C _max (µg/ml) and T _max (h)

Parameter (units) 'Treatment A (DR600 mg tablets - after meals) Treatment B (DR 600 mg fasting tablet) 'Treatment C (DR 600 mg half tablet after meals ¹ Treatment D (Oral Solution - Fasting) Stach (µg/mL) CvDNve (range) 8.047 (4.300-13.558) 8.214 (5.880-13.690) 7.429 (4.551-12.321) 16.712 (8.613-24.059) SD 2.845 2.181 2.004 4.540 T _t „ (h ) Mean (Range; median) 3.926 (1.333-8.000; 4.000) 2.051 (1.333- 3.500; 2.000) 3.494 (1.333-8.000; 3.108) 0.522 (0.250-1.000; 0.500)

Table 8 AUCI/ _Cmax

Attitude Treatment A (DR 600 mg tablet - after meals) ’ Treatment B (DR600 mg tablets - fasting 'Treatment C (DR600 mg half tablet after meals) Treatment D (Oral solution on an empty stomach) AUCI/C _max (h ) Mean (range) 4.758 (3.265- 6.765) 4.393 (3.511- 5.884) 5.004 (3.567-7.589) 2.490 (1.633-3.277)

Example 7 Preparation of Enteric Coated Delayed Release Tablets.

Table 9

Deferiprone 600 mg delayed release tablets

Component Function Amount (600 mg) mg % Deferiprone Active substance 600 87.7 Hypromellose acetate succinate (NF) AS-LF Release control polymer 29.5 4.31 magnesium oxide pH adjuster 24.5 3.58 colloidal silicon dioxide (part 1) Glidant 1 0.1462 Subtotal 655 95.7 After compaction magnesium stearate lubricant 4 0.585 colloidal silicon dioxide (part 2) Glidant 1 0.1462 Total 660 96.5 Coating Triethylcitrate NF plasticizer 1.032 0.1509 Sucrose NF (very fine) Coating agent 3.09 0.452 Talc USP 500 mesh non-stick agent 2.09 0.306

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* Dispersion of methacrylic acid copolymer NF Release control polymer 30.96 4.53 Titanium Dioxide USP opalescent component 8.5 1.243 ** purified water 154.3 22.6 Whole film-coated tablet 684 100

* Contains 30% solids.

** Evaporates during coating process.

Deferiprone, hypromellose acetate succinate (NF) AS-LF, light magnesium oxide USP/EP and colloidal silicon dioxide (part 1) were mixed together to form the tablet core, the mixture was compacted and ground into granules. Magnesium stearate and colloidal silicon dioxide (part 2) were added to the granules and mixed with the granules. The resulting mixture was compressed into tablet cores. The tablets were then coated.

In addition to the various embodiments described herein, the present invention includes the following embodiments, numbered E1 to E132. This list of embodiments is presented as an exemplary list, and the application is not limited to these embodiments.

E1. A delayed release tablet containing deferiprone for oral administration to a human subject, wherein twice daily administration of the delayed release tablet is bioequivalent at steady state to the same daily dose of an immediate release tablet containing deferiprone administered three times daily.

E2. A tablet according to E1, where the tablet is a whole tablet which has a score to facilitate breaking into tablet halves.

E3. Tablet according to E2, where half tablets are bioequivalent to a whole tablet, either on an empty stomach or after a meal.

E4. A tablet according to E3, where half a tablet is bioequivalent to a whole tablet both on an empty stomach and after a meal.

E5. A tablet according to any one of E1-E4, wherein the tablet consists of (a) a core containing deferiprone in a therapeutically effective amount; and (b) enteric coating.

E6. Tablet according to E5, wherein the core further comprises an enteric polymer.

E7. A tablet according to E6 wherein the enteric polymer in the core is selected from the group consisting of hydroxypropyl methylcellulose (HPMC) succinate acetate, HPMC phthalate, polyvinyl acetate phthalate, methacrylic acid copolymers, a derivative thereof, and combinations thereof.

E8. A tablet according to E7 wherein the enteric polymer is present in an amount of from about 1% to about 20% by weight of the core.

E9. A tablet according to any one of E1-E8, wherein when the tablet is administered to a human subject, a single dose of the tablet provides an average AUC _W /C _max ratio of 3.5 to 6.0 hours on an empty stomach.

E10. A tablet according to any one of E1-E8, wherein when the tablet is administered to a human subject, a single dose of the tablet provides an average AUC/C _max ratio of 3.5 to 6.0 hours after a meal.

E11. Tablet according to E9 or E10, where the tablet contains 1000 mg of deferiprone.

E12. Tablet according to E9 or E10, where the tablet contains 600 mg of deferiprone.

E13. A tablet according to E11, wherein when the tablet is administered to a human subject, the mean Cmax is between 2.670 and 13.232 µg/mL.

E14. A tablet according to E11, wherein when the tablet is administered to a human subject, the median T _max is 1.33 to 4.00 hours.

E15. A tablet according to E11, wherein when the tablet is administered to a human subject, the median T _max is between 2.00 and 8.00 hours.

E16. A tablet according to E11, wherein when the tablet is administered to a human subject, the median T _max is 1.33 to 6.03 hours.

E17. A tablet according to E11, wherein when the tablet is administered to a human subject, the ratio AUCI/C _max is between 2.858 and 6.596 hours.

E18. A tablet according to E11, wherein when the tablet is administered to a human subject, the ratio AUCI/Cmax is between 3.225 and 8.506 hours.

E19. Tablet for oral administration of an active pharmaceutical ingredient to a subject-

- 26 042135 to a person, where the tablet contains (a) a core containing an active pharmaceutical ingredient in a therapeutically effective amount and an enteric polymer; and (b) enteric coating, where the tablet is scored so that it can be administered as a whole tablet or half a tablet, and where, if the tablet is administered as one or more half tablets, the half tablets are bioequivalent to whole tablets on an empty stomach or after a meal .

E20. A tablet according to E19 wherein the enteric polymer in the core is selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), HPMC phthalate, polyvinyl acetate phthalate, methacrylic acid copolymers, a derivative thereof, and combinations thereof.

E21. A tablet according to E20 wherein the enteric polymer is present in an amount of from about 1% to about 20% by weight of the core.

E22. A tablet according to any one of E19-E21 wherein the active pharmaceutical ingredient is deferiprone.

E23. A tablet according to any of E19-E22, wherein twice daily tablet administration is bioequivalent at steady state to the same daily dose of an immediate release tablet (Ferriprox®) containing deferiprone administered three times daily.

E24. A tablet according to any one of E19-E23, wherein when the tablet is administered to a human subject, a single dose of the tablet provides an average AUCn/C _max ratio of 3.5 to 6.0 hours on an empty stomach.

E25. A tablet according to any one of E19-E23, wherein when the tablet is administered to a human subject, a single dose of the tablet provides an average AUCn/C _max ratio of 3.5 to 6.0 hours postprandial.

E26. Tablet according to E24 or E25, where the tablet contains 1000 mg of deferiprone.

E27. Tablet according to E24 or E25, where the tablet contains 600 mg of deferiprone.

E28. A tablet according to E26, wherein when the tablet is administered to a human subject, the mean C _max is between 2.670 and 13.232 μg/ml.

E29. A tablet according to E26, wherein when the tablet is administered to a human subject, the median T _max is 1.33 to 4.00 hours.

E30. A tablet according to E26, wherein when the tablet is administered to a human subject, the median T _max is between 2.00 and 8.00 hours.

E31. A tablet according to E26, wherein when the tablet is administered to a human subject, the median T _max is 1.33 to 6.03 hours.

E32. A tablet according to E26, wherein when the tablet is administered to a human subject, the ratio AUCI/C _max is between 2.858 and 6.596 hours.

E33. A tablet according to E26, wherein when the tablet is administered to a human subject, the ratio AUCI/C _max is between 3.225 and 8.506 hours.

E34. A tablet for oral administration of an active pharmaceutical ingredient, comprising (a) a core containing the active pharmaceutical ingredient in a therapeutically effective amount and an enteric polymer; and (b) an enteric coating, wherein the tablet is a whole tablet that has risks to facilitate breaking the tablet into half tablets, where both the whole and half tablets have a delayed release dissolution profile.

E35. Tablet according to E34, where half tablets are bioequivalent to whole tablets on an empty stomach or after a meal.

E36. A tablet according to E35 wherein the enteric polymer in the core is selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), HPMC phthalate, polyvinyl acetate phthalate, methacrylic acid copolymers, a derivative thereof, and combinations thereof.

E37. A tablet according to E36 wherein the enteric polymer is present in an amount of from about 1% to about 20% by weight of the core.

E38. A tablet according to any one of E34-E37 wherein the active pharmaceutical ingredient is deferiprone.

E39. A tablet according to any one of E34-E38 wherein both the whole and half of the tablets exhibit dissolution below 20% after 60 minutes in 0.1N. HCl.

E40. A tablet according to any one of E34-E39, wherein when the tablet is administered to a human subject, a single dose of the tablet provides an average AUCn/C _max ratio of 3.5 to 6.0 hours on an empty stomach.

E41. A tablet according to any one of E34-E39, wherein when the tablet is administered to a human subject, a single dose of the tablet provides an average AUCn/C _max ratio of 3.5 to 6.0 hours postprandial.

E42. Tablet according to E40 or E41, where the tablet contains 1000 mg of deferiprone.

E43. Tablet according to E40 or E41, where the tablet contains 600 mg of deferiprone.

E44. A tablet in accordance with E42, where when the tablet is administered to a human subject, the average value

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C _max ranges from 2.670 to 13.232 µg/ml.

E45. A tablet according to E42, wherein when the tablet is administered to a human subject, the median T _max is 1.33 to 4.00 hours.

E46. A tablet according to E42, wherein when the tablet is administered to a human subject, the median T _max is between 2.00 and 8.00 hours.

E47. A tablet according to E42, wherein when the tablet is administered to a human subject, the median T _max is 1.33 to 6.03 hours.

E48. A tablet according to E42, wherein when the tablet is administered to a human subject, the ratio AUCI/C _max is between 2.858 and 6.596 hours.

E49. A tablet according to E42, wherein when the tablet is administered to a human subject, the ratio AUCI/C _max is between 3.225 and 8.506 hours.

E50. A tablet for oral administration comprising (a) a core containing a therapeutically effective amount of deferiprone and an enteric polymer; and (b) an enteric coating containing an enteric polymer, wherein the tablet is suitable for administration twice a day.

E51. A tablet according to E50 which has a notch to facilitate the breaking of the tablet into tablet halves.

E52. A tablet according to E51 which can be administered as one or more whole tablets, one or more half tablets or a combination thereof.

E53. A tablet according to any one of E50-E52, wherein the enteric polymer in the core is selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), HPMC phthalate, polyvinyl acetate phthalate, methacrylic acid copolymers, a derivative thereof, and combinations thereof.

E54. A tablet according to E53 wherein the enteric polymer is present in an amount of from about 1% to about 20% by weight of the core.

E55. A tablet according to any one of E50-E54, wherein the enteric polymer in the enteric coating is selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), HPMC phthalate, polyvinyl acetate phthalate, methacrylic acid copolymers, a derivative thereof, and combinations thereof.

E56. A tablet according to any of E50-E55, wherein the core further comprises a base excipient and a glidant.

E57. A tablet according to E56 wherein the main excipient is selected from the group consisting of meglumine, metal oxides, metal hydroxides, basic salts of weak acids, and combinations thereof.

E58. Tablet according to E56 or E57, where the glidant is colloidal silicon dioxide.

E59. A tablet according to any of E56-E58, additionally containing a lubricant.

E60. A tablet according to E59 wherein the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, talc and combinations thereof.

E61. A tablet according to any one of E54-E60 wherein the enteric coating further comprises a plasticizer and an anti-stick agent.

E62. A tablet according to E61 wherein the plasticizer is selected from the group consisting of citric acid ester, diethyl phthalate, polyethylene glycol, glycerol, acetylated glycerides, acetylated citric acid esters, dibutyl sebacate, castor oil, and combinations thereof.

E63. A tablet according to E61 or E62, wherein the tablet further comprises a diluent selected from the group consisting of sucrose, lactose, fructose, mannitol, and combinations thereof.

E64. Tablet according to E61 or E62, wherein the anti-adhesion agent is talc.

E65. A tablet according to any one of E50-E64, wherein, when the tablet is administered to a human subject, a single dose of the tablet provides an average AUCn/C _max ratio of 3.5 to 6.0 hours on an empty stomach.

E66. A tablet according to any one of E50-E64, wherein when the tablet is administered to a human subject, a single dose of the tablet provides an average AUCn/C _max ratio of 3.5 to 6.0 hours postprandial.

E67. Tablet according to E65 or E66, where the tablet contains 1000 mg of deferiprone.

E68. Tablet according to E65 or 66, where the tablet contains 600 mg of deferiprone.

E69. A tablet according to E67, wherein when the tablet is administered to a human subject, the mean C _max is 2.670 to 13.232 μg/ml.

E70. A tablet according to E67, wherein when the tablet is administered to a human subject, the median Tmax is between 1.33 and 4.00 hours.

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E71. A tablet according to E67, wherein when the tablet is administered to a human subject, the median T _max is between 2.00 and 8.00 hours.

E72. A tablet according to E67, wherein when the tablet is administered to a human subject, the median T _max is 1.33 to 6.03 hours.

E73. A tablet according to E67, wherein when the tablet is administered to a human subject, the ratio AUCI/C _max is between 2.858 and 6.596 hours.

E74. A tablet according to E67, wherein when the tablet is administered to a human subject, the ratio AUCI/C _max is between 3.225 and 8.506 hours.

E75. A tablet containing deferiprone for oral administration twice a day, where a single administration of the tablet provides an average ratio of AUC n / C _max from 3.5 to 6.0 hours both on an empty stomach and after a meal when the tablet is administered as a whole tablet and when administered to a human subject as half a tablet.

E76. A tablet according to E75 wherein the average AUCn/C _max is from about 4.0 hours to about 5.5 hours.

E77. A tablet according to E75 or E76 wherein the active pharmaceutical ingredient or deferiprone is in an amount of from about 100 mg to about 1500 mg per tablet.

E78. A tablet according to any of E75-E77 wherein the total daily dose of the active pharmaceutical ingredient or deferiprone is about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, approximately 600 mg/day, approximately 700 mg/day, approximately 800 mg/day, approximately 900 mg/day, approximately 1000 mg/day, approximately 1200 mg/day, approximately 1500 mg/day, approximately 1800 mg/day, approximately 2000 mg/day, approximately 2100 mg/day, approximately 2400 mg/day, approximately 2500 mg/day, approximately 2700 mg/day, approximately 3000 mg/day, approximately 3300 mg/day, approximately 3500 mg/day, approximately 4000 mg/day day, approximately 4500 mg/day, approximately 5000 mg/day, approximately 5500 mg/day, approximately 6000 mg/day, approximately 6500 mg/day, approximately 7000 mg/day, approximately 7500 mg/day, approximately 8000 mg/day, arr approximately 8500 mg/day, approximately 9000 mg/day, approximately 9500 mg/day or approximately 10000 mg/day.

E79. Tablet according to any of E74-E78, wherein the active pharmaceutical ingredient or deferiprone is in an amount of about 100 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg , about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg or about 1500 mg per tablet.

E80. A tablet according to E79 which contains a core containing about 1000 mg or about 600 mg of deferiprone, from about 20 mg to about 80 mg of an enteric polymer and from about 5 mg to about 100 mg of a base excipient.

E81. Tablet in accordance with E80, additionally containing a lubricant in an amount of from about 7 mg to about 20 mg.

E82. A tablet according to E80 or E81 which contains an enteric coating containing from about 7 mg to about 20 mg of an enteric polymer and from about 0.5 mg to about 5 mg of a plasticizer.

E83. A tablet according to E79 which contains a core containing about 600 mg of deferiprone, about 20 mg to about 80 mg of an enteric polymer, and about 5 mg to about 100 mg of a base excipient.

E84. Tablet in accordance with E83, additionally containing a lubricant in an amount of from about 2 mg to about 10 mg.

E85. A tablet according to E83 or E84 that contains an enteric coating contains from about 5 mg to about 20 mg of an enteric polymer and from about 0.5 mg to about 5 mg of a plasticizer.

E86. A tablet according to any of E75-E85, wherein the tablet contains 1000 mg of deferiprone.

E87. A tablet according to any of E75-E85, wherein the tablet contains 600 mg of deferiprone.

E88. A tablet according to E86, wherein when the tablet is administered to a human subject, the mean C _max is 2.670 to 13.232 µg/ml.

E89. A tablet according to E86, wherein when the tablet is administered to a human subject, the median T _max is 1.33 to 4.00 hours.

E90. A tablet according to E86, wherein when the tablet is administered to a human subject, the median T _max is between 2.00 and 8.00 hours.

E91. A tablet according to E86, wherein when the tablet is administered to a human subject, the median T _max is 1.33 to 6.03 hours.

E92. A tablet according to E86, wherein when the tablet is administered to a human subject, the ratio

- 29 042135

AUCI / C _max ranges from 2.858 to 6.596 hours.

E93. A tablet according to E86, wherein when the tablet is administered to a human subject, the ratio

AUCI / C _max ranges from 3.225 to 8.506 hours.

E94. A tablet according to any one of E1-E93, which has a risk for facilitating breaking the tablet into half tablets and can be administered to a human as one or more whole tablets, one or more tablet halves, or any combination thereof.

E95. A tablet according to any one of E1-E94, wherein the tablet releases less than about 80% of deferiprone in 60 minutes as measured by the USP Apparatus Type II paddle method at 75 rpm in 900 ml of water at 37 ± 0, 5°C.

E96. A tablet according to E95 wherein approximately 100% deferiprone is released in approximately 90 minutes as measured by the USP Apparatus Type II paddle method at 75 rpm in 900 ml at pH 6.8 or 4.5.

E97. A tablet according to E96 wherein approximately 50% deferiprone is released within approximately 30 minutes as measured by the USP Apparatus Type II paddle method at 75 rpm in 900 ml at pH 6.8 or 4.5.

E98. A method of treating a subject with iron overload comprising orally administering to a subject in need thereof a tablet according to any one of E1-E97.

E99. The method according to E98, wherein the subject suffers from thalassemia or myelodysplasia.

E100. The method according to E98, wherein the subject suffers from transfusional iron overload and whose prior chelation therapy is inadequate.

E101. The method according to E98, wherein the subject suffers from transfusional iron overload and has a T2* cardiac MRI of 20 ms or less.

E102. A method of treating a subject with a neurodegenerative disease comprising orally administering to a subject in need thereof a tablet according to any one of E1-E97.

E103. The method according to E102, wherein the subject suffers from Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, Friedreich's ataxia, pantothenate kinase associated neurodegeneration (PKAN), or brain iron storage neurodegeneration (NBIA).

E104. A method according to any one of E98-E103 comprising a once daily or twice daily (BID) dosing regimen.

E105. The method according to any of E98-E104, wherein the tablet is administered to the subject as one or more whole tablets, one or more half tablets, or a combination thereof.

E106. The method according to any one of E98-E105, wherein the tablet is administered to the subject on an empty stomach or after a meal.

E107. The method according to any of E98-E106, wherein the deferiprone is in an amount of from about 100 mg to about 800 mg per tablet.

E108. The method according to any one of E98-E107 wherein the deferiprone is in an amount of approximately 400 mg per tablet.

E109. The method according to any of E98-E108, wherein the total daily dose of deferiprone is from about 200 mg/day to about 2400 mg/day.

E110. The method according to any of E98-E109, wherein the total daily dose of deferiprone is from about 400 mg/day to about 1200 mg/day.

E111. The method according to any one of E98-E110 wherein the tablet is administered once or twice a day.

E112. The method according to any of E98-E111 wherein one, two or three tablets are administered once or twice a day.

E113. The method according to any of E98-E112 wherein one, two or three tablets are administered one, two or three times a day.

E113. The method according to any of E103-E112, wherein the subject suffers from amyotrophic lateral sclerosis (ALS).

E114. The method according to any one of E103-E113, wherein the treatment reduces or retards the progression of ALS-related disability in a subject.

E115. The method according to E113 or E114, further comprising administering riluzole to the subject.

E116. A method of treating a human subject with iron overload comprising orally administering 3000 mg/day of deferiprone to a subject in need thereof, wherein the subject is administered deferiprone twice daily.

E117. The method according to E116 wherein the subject suffers from thalassemia or myelodysplasia.

E118. The method according to E116 or E117 wherein 3000 mg/day of deferiprone is administered at a dose of 1500 mg twice daily.

E119. A method according to any of E116-E118, wherein the subject exhibits a Cmax of 48.5-10.5 μg/ml at steady state.

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E120. The method according to any of E116-E119, wherein the subject exhibits an AUC _{( 0-24)} of 75-95 µg-h/ml at steady state.

E121. A method according to any one of E98-E120, wherein the subject is administered a tablet according to any one of E1-E97.

E122. A method of treating a human subject with iron overload comprising orally administering to a subject in need thereof 1200 mg/day of deferiprone, wherein the subject is administered deferiprone twice daily.

E123. The method according to E122, wherein the subject suffers from a neurogenic disease.

E124. The method according to E122 or E123, wherein 1200 mg/day of deferiprone is administered at a dose of 600 mg twice daily.

E125. The method according to any of E122 or E124, wherein 1200 mg/day of deferiprone is administered at a dose of 1200 mg once a day.

E126. The method according to any of E122-E125, wherein the subject exhibits a C _max of 4.00 to 13.558 μg/mL following postprandial administration of 600 mg deferiprone.

E127. The method according to any of E122-E126, wherein the subject exhibits a C _max of 5.880 to 13.690 μg/ml after administration of 600 mg of deferiprone on an empty stomach.

E128. The method according to any of E122-E127, wherein the subject exhibits a T _max of 1.333 to 8,000 hours after administration of 1200 mg of deferiprone.

E129. The method according to any of E122-E128, wherein the subject exhibits an AUCI/C _max of 3.265 to 6.765 hours after administration of 1200 mg deferiprone.

E130. The method according to any of E122-E129, wherein the subject suffers from transfusional iron overload and whose prior chelation therapy is inadequate.

E131. The method according to any of E122-E129, wherein the subject suffers from transfusional iron overload and has a T2* cardiac MRI of 20 ms less.

E132. The method according to any one of E122-E131, wherein the subject is administered a tablet according to any one of E1-E97.

E133. An oral tablet comprising (a) a core containing 1000 or 600 mg of deferiprone, an enteric polymer, a pH adjusting agent, a glidant and a lubricant; and (b) an enteric coating containing a plasticizer, a diluent, an anti-adherent agent, and an enteric polymer, wherein the tablet is suitable for dosing twice a day, wherein the tablet, which is a whole tablet, has risks to facilitate breaking the tablet into tablet halves.

Claims (18)

1. Tablet for oral administration, containing (a) a core containing deferiprone in a therapeutically effective amount and an enteric polymer; and (b) an enteric coating comprising an enteric polymer, wherein the enteric polymer in the core is selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMC), polyvinyl acetate phthalate, methacrylic acid copolymers, and combinations thereof, wherein the enteric polymer in the enteric coating is selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), HPMC phthalate, polyvinyl acetate phthalate, methacrylic acid copolymers and combinations thereof, wherein said tablet is suitable for twice daily dosing, wherein said core contains 600 or 1000 mg of deferiprone, and wherein said the enteric polymer makes up 1 to 5% by weight of the core. 2. Tablet according to claim 1, wherein the core further comprises a base excipient and a glidant. 3. Tablet according to claim 2, wherein the main excipient is selected from the group consisting of meglumine, metal oxides, metal hydroxides, basic salts of weak acids, and combinations thereof. 4. Tablet according to claim 2 or 3, wherein the glidant is colloidal silicon dioxide. 5. Tablet according to any one of claims 2 to 4, additionally containing a lubricant. 6. Tablet according to claim 5, wherein the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, talc, and combinations thereof. 7. Tablet according to any one of claims 1 to 6, wherein the enteric coating further comprises a plasticizer and an anti-stick agent. 8. Tablet according to claim 7, wherein the plasticizer is selected from the group consisting of citric acid ester, diethyl phthalate, polyethylene glycol, glycerin, acetylated glycerides, acetylated citric acid esters, dibutyl sebacate, castor oil, and combinations thereof. 9. Tablet according to claim 7 or 8, wherein the anti-adhesion agent is talc. - 31 042135 10. Tablet according to claim 1, where the specified core contains 600 or 1000 mg of deferiprone, an enteric polymer, a pH adjusting agent, a glidant and a lubricant; and said coating comprises a plasticizer, an anti-tack agent, an enteric polymer, and a diluent. 11. Tablet according to claim 10, where the specified core contains 600 or 1000 mg of deferiprone, HPMCAS-LF, magnesium oxide, colloidal silicon dioxide and magnesium stearate; and said coating comprises triethyl citrate, talc, methacrylic acid copolymer dispersion and sucrose. 12. Tablet according to any one of claims 1 to 11, wherein deferiprone is present in an amount of 75 to 95% of the total weight of the core. 13. A tablet according to any one of claims 1 to 12 for the treatment of iron overload in a subject, wherein said tablet is administered orally. 14. The tablet of claim 13, wherein the iron overload subject suffers from a disease selected from thalassemia, myelodysplasia, and sickle cell disease. 15. The tablet of claim 13, wherein said iron overload is transfusion iron overload. 16. A tablet according to claim 15, wherein the subject's prior chelation therapy is insufficient. 17. The tablet of claim 13, wherein the subject suffers from transfusional iron overload and has a T2* cardiac MRI of 20 ms or less. 18. A method of manufacturing a tablet according to any one of paragraphs.1-12, including (a) mixing deferiprone and one or more excipients; (b) compressing mixture (a) into a tablet core; and (c) coating the tablet core with an enteric coating suspension or solution. Dissolution rates of 1000mg Deferiprone ER tablets