Delayed release deferasirox tablets and methods of use thereof

Abstract

The present invention relates to pharmaceutical compositions such as tablets that exhibit delayed release properties when administered as whole or half tablets. The present invention also relates to delayed release tablets comprising deferiprone for oral administration that are bioequivalent to the same daily dose of immediate release tablets administered three times a day with twice a day administration. The present invention also relates to methods of making and using the same.

Description

[0001] This invention is a divisional application of Chinese Patent Application No. 201880069331.7, filed on January 25, 2018, whose original invention was entitled "Delayed-release deferiphenone tablets and method of use thereof".

[0002] Reference to relevant applications

[0003] This application claims priority to U.S. Provisional Application No. 62 / 577,055, filed October 25, 2017 and U.S. Provisional Application No. 62 / 596,043, filed December 7, 2017, each of which is incorporated herein by reference in its entirety. Background Technology

[0004] Deferoxone is an iron chelator used to treat generalized iron overload, particularly in cases of iron overload caused by frequent transfusions, including, for example, thalassemia (Renzo Galanello, Ther Clin RiskManag. Oct 2007; 3(5):795-805), sickle cell disease (Ware and Kwiatkowski, Pediatr ClinNorth Am. Dec 2013; 60(6):1393-406) and spinal dysplasia (Sheth, Curr OpinHematol. May 2014; 21(3):179-85) (each article is incorporated herein by reference in its entirety). Deferiprone can also be used in cases of localized tissue or cellular iron overload, even in the absence of generalized iron overload, such as in neurodegenerative diseases where inadequate cellular iron management is a prominent feature, including, for example, Friedreich's Ataxia, Parkinson's disease, pantothenic acid kinase-associated neurodegeneration (PKAN) and other forms of neurodegeneration with brain iron accumulation (NBIA), multiple sclerosis, age-related macular degeneration, and superficial iron pneumoconiosis. See Kakhlon et al., Can JPhysiol Pharmacol. Mar 2010; 88(3):187-96; Cabantchik et al., Front Pharmacol. Dec 2013; 4:167; Cossu et al., Parkinsonism. Relat Disord., Jun 2014; 20(6):651-4; Weigel et al., ASN Neuro. Jan 2014; 6(1); Song et al., Free Radic Biol Med. July 2012; 53(l):64-71; and Levy and Llinas, Stroke. Jan 2012; 43(1):120-4 (each is incorporated into this paper in its entirety by citation).

[0005] Deferiphenone is sold in the United States and elsewhere in the form of immediately-release (IR) 500mg tablets, for example, under the trade name... In certain jurisdictions, it is also available as an IR 1000mg tablet and a 100mg / mL liquid formulation. Summary of the Invention

[0006] Certain aspects of this disclosure relate to delayed-release tablets containing deferoxone for oral administration to human subjects, wherein twice-daily administration of the delayed-release tablets at steady state is bioequivalent to the same daily dose of an immediately-release tablet containing deferoxone administered three times daily.

[0007] In another aspect, this disclosure relates to a tablet for oral administration of an active pharmaceutical ingredient (specifically, deferiphenone) to a human subject, wherein the tablet comprises: (a) a core containing a therapeutically effective amount of the active pharmaceutical ingredient and an enteric polymer, and (b) an enteric coating, wherein the tablet has notches that allow it to be administered as a whole tablet or a half tablet, and wherein if the tablet is administered as one or more half tablets, the half tablet is bioequivalent to the whole tablet, for example in a single-dose study, in a fasting state, a feeding state, or both.

[0008] In another aspect, this disclosure relates to a tablet for oral administration of an active pharmaceutical ingredient, comprising: (a) a core containing a therapeutically effective amount of the active pharmaceutical ingredient and an enteric polymer, and (b) an enteric coating, said tablet having notches to facilitate breakage into half tablets, wherein the whole tablet and half tablets exhibit a delayed-release dissolution profile.

[0009] In another aspect, this disclosure relates to a tablet for oral administration comprising: (a) a core containing a therapeutically effective amount of deferiphenone and an enteric polymer; and (b) an enteric coating containing the enteric polymer, wherein the tablet is suitable for administration twice daily.

[0010] In another aspect, this disclosure relates to a tablet containing deferiphenone for oral administration twice daily to human subjects, wherein a single dose of said tablet provides a mean AUC between 3.5 hours and 6.0 hours in both fasting and eating states. ∞ / C max ratio.

[0011] In another aspect, this disclosure relates to a tablet for oral administration comprising: (a) a core containing 1000 mg or 600 mg of deferiphenone, an enteric polymer, a pH adjuster, a flow aid, and a lubricant; and (b) an enteric coating containing a plasticizer, a diluent, an anti-adhesion agent, and an enteric polymer, said tablet being a whole tablet having notches to facilitate the tablet breaking into half tablets.

[0012] In another aspect, this disclosure relates to a method for treating a subject with iron overload or a neurodegenerative disease (e.g., Huntington's disease or amyotrophic lateral sclerosis), the method comprising orally administering to the subject in need of such treatment a deferoxone tablet (e.g., a delayed-release tablet) disclosed herein.

[0013] In some respects, this disclosure relates to a method of treating Huntington's disease in a subject with this need, the method comprising administering to the subject a composition comprising deferiphenone.

[0014] In some aspects, this disclosure relates to a method of treating amyotrophic lateral sclerosis (ALS) in a subject with this need, the method comprising administering to the subject a composition comprising deferiphenone. Some embodiments relate to methods of mitigating or slowing the progression of ALS-related disability. In some embodiments, the subject is further administered riluzole.

[0015] In some respects, this disclosure relates to a method for treating human subjects with iron overload, the method comprising orally administering 3000 mg / day of deferoxone to the subject in need, wherein the deferoxone is administered to the subject twice daily.

[0016] In some respects, this disclosure relates to a method for treating human subjects with iron overload, the method comprising orally administering 1200 mg / day of deferoxone to the subject in need, wherein the deferoxone is administered to the subject twice daily. Attached Figure Description

[0017] Figure 1 The dissolution of whole and half delayed-release (DR) tablets in 0.1N HCl is shown, reflecting dissolution in gastric acid.

[0018] Figure 2 The dissolution of whole and half DR tablets at pH 6.8 is shown, reflecting dissolution in the jejunum and ileum.

[0019] Figure 3 The dissolution of whole and half DR tablets at pH 4.5 is shown, reflecting dissolution in the duodenum.

[0020] Figure 4 Mean serum concentration distribution curves for deferoxone DR and immediate release (IR) tablets are shown. Invention Details

[0021] I. Definition

[0022] The indefinite article “a” or “an” as used in this document should be understood to mean “one or more” of any enumerated or listed components. For example, “a tablet” means one or more tablets.

[0023] As used in this article, “and / or” means and covers any and all possible combinations of one or more of the related listed items, as well as the lack of combinations when interpreted in an alternative manner (“or”).

[0024] When the term “about” is used in conjunction with a numerical value or range, it modifies the numerical value or range by extending the boundaries above and below said numerical value. The term “about” is used herein to modify numerical values ​​that are above or below said value by a variance of more or less than 10% (i.e., ±10%), unless a different variance is specified (e.g., ±30%, ±20%, ±5%, ±1%, etc.).

[0025] Wherever this document uses the term "comprising" to describe an aspect, other similar aspects described in the manner of "consisting of" and / or "substantially consisting of" are also provided. In connection with the use of the term "comprising" in the specification or claims, it is intended to be included in a similar manner to the term "comprising," as the term is interpreted as a transitional word in the statement when adopted.

[0026] As used in this article, "deferone" refers to deferone or its pharmaceutically acceptable salt.

[0027] The term "pharmaceutically acceptable salt" for a given compound means a salt that retains the biological potency and properties of the given compound and is not undesirable biologically or otherwise. "Pharmaceutically acceptable salt" includes, for example, salts with inorganic acids and salts with organic acids. Salts of deferoxones can include pharmaceutically acceptable salts, particularly salts with bases, such as suitable alkali metal or alkaline earth metal salts, e.g., sodium, potassium, or magnesium salts; pharmaceutically acceptable transition metal salts, such as zinc salts; or salts with organic amines, such as cyclic amines, such as mono-, di-, or tri-lower alkylamines, such as hydroxy-lower alkylamines, e.g., 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, ethylamine and tert-butylamine; di-lower alkylamines are, for example, diethylamine and diisopropylamine; and tri-lower alkylamines are, for example, trimethylamine and triethylamine. Suitable hydroxy-lower alkylamines are, for example, mono-, di-, and triethanolamines; hydroxy-lower alkyl-lower alkylamines are, for example, N,N-dimethylaminoethanol and N,N-diethylaminoethanol; suitable polyhydroxy-lower alkylamines are, for example, glucosamine.

[0028] As used herein, the “core” or “tablet core” comprises an active ingredient (e.g., deferiphenone) and one or more excipients, which are compressed into an uncoated tablet. The core may be coated with various coatings, including enteric coatings.

[0029] As used herein, “delayed release” or “DR” means protecting the active ingredient (e.g., deferoxone) from rapid release at acidic pH (e.g., in the stomach, at least during fasting), while allowing the active ingredient to be released at a higher rate at higher pH (e.g., in the intestine). In some embodiments, DR will be understood to mean that, when tested at 75 rpm in USP device 2, the degree of dissolution in 0.1N HCl will be less than 20% over 1 hour, and the dissolution rate in phosphate buffer with pH 6.8 will be significantly higher than the dissolution rate in 0.1N HCl (e.g., more than 30%, for example, more than 40% over 1 hour).

[0030] As used in this article, “disintegrant” refers to an excipient that is insoluble in water but swells when wetted to cause tablet disintegration.

[0031] In this article, "dissolution" refers to the process by which a solute forms a solution in a solvent.

[0032] As used herein, "enteric coating" or "enteric coating" refers to a coating containing an enteric polymer. Enteric coating can be used to prevent or delay the dissolution or disintegration of tablets in the gastric environment.

[0033] "Enteric-coated tablets" refer to tablets containing an active ingredient that are coated with an enteric coating.

[0034] As used herein, “enteric polymer” is understood to mean a polymer that is relatively insoluble at the acidic pH of the fasting stomach (e.g., about pH 1 to about pH 4), but soluble at higher pH (e.g., about pH 4.5 to about pH 8, which corresponds to the pH in the small intestine, or thereafter, especially in the duodenum or ileum).

[0035] The term "fasting state" as used in this article refers to food withdrawal for a limited period of time after a meal (typically, at least a few hours after a meal, for example, 4 or 6 hours).

[0036] As used in this article, “feeding state” means administration with a meal or shortly after a meal (e.g., within about 1 hour).

[0037] As used in this article, “stomach discomfort” refers to gastrointestinal (GI) discomfort, such as pain, cramps, bloating, nausea, indigestion, heartburn, and gas.

[0038] As used herein, "half a tablet" refers to either of the two parts of a tablet obtained by dividing a tablet into two parts of equal or approximately equal weight. In some embodiments, a half tablet is about 40% to about 60% of the weight of the whole tablet from which said half tablet is derived. In some embodiments, the approximately equal weight of each half tablet is about 45-55% of the total weight of the whole tablet.

[0039] As used in this article, “percentage” or “%” means weight percentage (w / w) unless otherwise specified.

[0040] As used herein, "score tablet" refers to a tablet with one or more score lines (also called "score lines") to facilitate tablet splitting (e.g., enabling the administration of half a tablet). In some embodiments, the tablet may have two, three, four, or more score lines.

[0041] As used herein, “tablet” refers to a solid oral medication dosage form. In some embodiments, the tablet is a compressed tablet.

[0042] "Whole tablet" refers to a complete tablet, that is, one that is not broken or split into multiple parts.

[0043] Terms such as “treatment,” “improvement,” or “relief” can refer to: 1) therapeutic measures that cure, slow, reverse, and / or stop the progression of a diagnosed pathological condition or disorder or alleviate its symptoms; and 2) preventive or preventative measures that prevent a targeted pathological condition or disorder, reduce its incidence, lower its risk, and / or slow its development. Therefore, those who require treatment include those who already suffer from the disorder; those who are susceptible to the disorder; and those who need to prevent the disorder. Beneficial or desired clinical outcomes include, but are not limited to, relief of symptoms, reduction of the severity of the disease, stabilization (i.e., no worsening) of the disease state, delay or slowing of disease progression, improvement or relief of the disease state, and relief (partial or complete), whether detectable or undetectable. “Treatment” can also refer to prolonged survival compared to expected survival without treatment. Those who require treatment include those who already suffer from the condition or disorder, those who are susceptible to the condition or disorder, or those in whom the condition or disorder will be prevented or its incidence reduced.

[0044] "Subject" or "individual" or "patient" means any human subject who requires diagnosis, prognosis, treatment or therapy.

[0045] "Therapeutic effective dose or amount" or "effective amount" refers to the amount of such an active pharmaceutical ingredient (e.g., deferiphenone) that, when administered, would achieve a positive therapeutic response in relation to the treatment of a disease or the reduction of risk in the subject to be treated.

[0046] It should be understood that the deferiphenone IR tablets used as a “reference” or “reference product” in this document are FDA-approved and marketed in the United States. Tablets (500mg). For example, "reference" or "reference product" in this document could be such a... The tablets have: (1) a core containing 500 mg of deferoxone, microcrystalline cellulose, colloidal silica and magnesium stearate; and (2) a coating containing hydroxypropyl methylcellulose, polyethylene glycol and titanium dioxide.

[0047] II. Tablets

[0048] In some aspects, this application relates to a delayed-release tablet comprising deferoxone in its core. Delayed release (e.g., provided by enteric coating) is used to delay the dissolution of the active ingredient (e.g., deferoxone) from the tablet core. In some embodiments, delayed release is desirable in cases where the release of a pharmaceutical ingredient in a fasting stomach would cause gastric irritation, and / or in cases where a pharmaceutical ingredient is acid-labile and would degrade if released in a fasting stomach.

[0049] Some oral medication tablets are coated with an enteric coating to provide delayed release. Some other oral medication tablets have scoring lines to make it easy for patients to divide the tablet into two roughly equal parts, allowing for half-tablet administration, for example, for dosage flexibility. However, it is difficult to combine both features into a single tablet; that is, to prepare a tablet with an enteric coating that can be divided into two parts without compromising the delayed release feature. This is because the surface at the interface 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 broken tablet will dissolve in gastric acid faster than the whole tablet, thus losing its protection against gastric irritation; (2) alternatively, if the unprotected core tablet disintegrates and / or dissolves slowly enough to prevent gastric irritation, even without the protection of the enteric coating, dissolution and absorption in the intestine may also be relatively slow, resulting in a decrease in the degree of absorption and / or peak serum levels; and (3) the broken tablet no longer delivers the drug at the same rate and possibly to the same extent as the unbroken tablet. These issues can lead to a lack of bioequivalence between half-tablets and whole tablets. For example, Iranian Patent Application 90-07-27-71996 discloses a deferiphenone formulation with an enteric coating. It discloses protection against stomach upset by using a methacrylic acid copolymer as the enteric coating for deferiphenone tablets, wherein the coating comprises approximately 7.4% of the total weight of the tablet (an 800mg core tablet containing 500mg of deferiphenone). When the tablet is cut in half or split in two, the enteric-coated tablet formulation disclosed in Iranian Patent Application 90-07-27-71996 loses the benefits of the enteric coating. The EC tablet from Iranian patent application 90-07-27-71996 (Avicenna Lab) comprises a core tablet of 500 mg deferiphenone, 290 mg microcrystalline cellulose, 1 mg colloidal silica, 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 hydroxypropyl methylcellulose, 6 cm Poaz, and 0.82 mg sodium bicarbonate (63.98 mg total coating weight). The coating weight is approximately 7.4% of the total weight of the EC tablet. In some embodiments, the tablet of this application differs from the EC tablet from Iranian patent application 90-07-27-71996.For example, in some embodiments, the DR tablets disclosed herein do not contain 290 mg of microcrystalline cellulose, 1 mg of colloidal silica, and / or 9 mg of magnesium stearate (800 mg total core weight); and in some embodiments, the coating of the DR tablets disclosed herein does not contain 34.68 mg of methacrylic acid copolymer, 15.56 mg of talc, 3.61 mg of PEG 6000, 4.38 mg of titanium dioxide, 4.93 mg of hydroxypropyl methylcellulose, 6 cmPoaz and / or 0.82 mg of sodium bicarbonate (63.98 mg total coating weight). Furthermore, in some embodiments, the coating weight of the DR tablets disclosed herein is not approximately 7.4% of the total weight of the EC tablets.

[0050] In some aspects, this disclosure relates to a deferoxone-containing composition, such as a tablet, for oral administration to a human subject. In one embodiment, the composition is a tablet for oral administration comprising (a) a deferoxone-containing core and (b) an enteric coating. Preferably, the tablet is designed to release deferoxone in the retrogastric portion of the gastrointestinal (GI) tract. In some embodiments, the tablet is substantially non-disintegrating in the stomach or at least in the fasting stomach, i.e., the tablet is substantially non-dissolving before reaching the intestine. 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.

[0051] In some embodiments, the tablet is administered as a whole tablet. In some embodiments, the tablet has notches to administer approximately half the amount of a whole tablet. In some embodiments, the tablet is administered as a half tablet. In some embodiments, the tablet is administered in combination with one or more half tablets.

[0052] In some aspects, tablets of this disclosure are formulated to have relatively low (e.g., less than 20%, if any) dissolution in a fasted stomach, but will dissolve more rapidly in the intestine, and thus can be referred to as delayed-release compositions. In some embodiments, tablets of this disclosure impart similar dissolution rates to half-tablets and whole tablets, independent of the pH of the dissolution medium. In some aspects, tablets of this disclosure have the properties of enteric-coated tablets without their drawbacks, allowing the tablets to be split in half so that dosage fine-tuning can be applied to whole tablets, half tablets, or any combination thereof. Half-tablets of this disclosure are as resistant to dissolution in acidic media (0.1N HCl) as whole tablets, representing fasted stomach contents; and at higher pH values ​​(representing small intestinal contents), they also exhibit similar dissolution rates to whole tablets.

[0053] 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 weight of the tablets. In some embodiments, the coating 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 tablets; and / or the coating is more than 1% of the total weight of the tablets. In some embodiments, the coating 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%, about 1.8%, about 1.9%, about 2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, or about 3.0% of the total weight of the tablets, or a range between any two of the above values, for example, 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 tablets. In some embodiments, the coating is about 1.5% of the total weight of the tablets. In other embodiments, the coating is approximately 2.5% of the total weight of the tablet.

[0054] III. Core

[0055] This disclosure relates to a composition comprising a core, such as a delayed-release tablet, the core comprising an active pharmaceutical ingredient, such as deferiphenone or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, the tablet core comprises about 100 mg to about 1500 mg, about 250 mg to about 1250 mg, or about 900 mg to about 1100 mg of deferone. In some embodiments, the tablet comprises 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 deferone. In some embodiments, the tablet comprises about 1000 mg of deferone.

[0057] In some embodiments, the active pharmaceutical ingredient (e.g., deferoxone) comprises about 75-95% (e.g., 80-95% or 85-95%) of the total core weight. In some embodiments, the active ingredient (e.g., deferoxone) comprises about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, or about 95% of the total core weight.

[0058] In some embodiments, the core of a DR tablet for once, twice, or three times daily contains 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 of deferiphenone. In some embodiments, the core of a DR tablet for once, twice, or three times daily contains at least about 600 mg of deferiphenone. In some embodiments, the core of a DR tablet for once, twice, or three times daily contains at least about 500 mg of deferiphenone. In some embodiments, the tablet core comprises about 200 mg to about 1500 mg, about 300 mg to about 900 mg, about 300 mg to about 700 mg, about 500 mg to about 700 mg, about 500 mg 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 about 1500 mg of deferoxone. In some embodiments, a tablet core comprising 600 mg or 1000 mg of deferoxone is preferred.

[0059] In some embodiments, the core of a DR tablet for once, twice, or three times daily contains at least about 200 mg, at least about 300 mg, or at least about 400 mg of deferiphenone. In some embodiments, the core of a DR tablet for once, twice, or three times daily contains 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 deferiphenone. In some embodiments, the core of a DR tablet for twice daily contains at least about 500 mg of deferiphenone. In some embodiments, the tablet core comprises 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 mg to 1500 mg, about 500 mg 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 deferone.

[0060] In some embodiments, the tablet core comprises an enteric polymer as an excipient. Prior to this application, when an enteric-coated tablet was broken in half, for example at a scratch line, the surface at the interface of the broken scratch line was no longer protected by the enteric coating. In some embodiments, including an enteric polymer in the core helps maintain a relatively low dissolution rate of the separated tablets (e.g., half tablets) in 0.1N HCl, thereby limiting dissolution in a fasted stomach while still being able to dissolve more quickly at intestinal pH.

[0061] In some embodiments, the enteric polymer is about 1% to 20%, 1% to 15%, 1% to 10%, or 1% to 5% of the 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% of the weight of the core, or a range between any two of the above values, for example, about 2-2.5%, 2.5-3%, 3-3.5%, 3.5-4%, 4-4.5%, or 4.5-5% of the weight of the core. In some embodiments, the enteric polymer is about 2.5% of the weight of the core. In some embodiments, the enteric polymer is about 4.5% of the weight of the core.

[0062] In some embodiments, the enteric polymer in the core is selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (i.e., HPMCAS), HPMC phthalate, polyvinyl acetate phthalate, methacrylic acid copolymers, derivatives thereof, and combinations thereof. In some embodiments, the enteric polymer in the core is HPMCAS.

[0063] In some embodiments, the tablet core of the tablets disclosed herein (e.g., delayed-release tablets) comprises about 900 mg to about 1100 mg of deferiphenone and about 10 mg to about 80 mg, 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, and about 25 mg to about 35 mg of enteric polymer, such as HPMCAS. In some embodiments, the tablet core of the tablets disclosed herein (e.g., delayed-release tablets) comprises about 500 mg to about 750 mg of deferiphenone and about 10 mg to about 80 mg, 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, and about 25 mg to about 35 mg of enteric polymer, such as HPMCAS. In some embodiments, the tablet core of the tablets disclosed herein (e.g., delayed-release tablets) comprises about 400 mg to about 800 mg of deferiphenone (e.g., about 600 mg) and about 10 mg to about 80 mg, 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 enteric polymer, such as HPMCAS.

[0064] In some embodiments, the tablet core of the tablets disclosed herein (e.g., delayed-release tablets) comprises about 200 mg to about 500 mg of deferiphenone and about 10 mg to about 80 mg, 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 enteric polymer, such as HPMCAS.

[0065] In some embodiments, the tablet core of the tablets disclosed herein (e.g., delayed-release tablets) comprises about 1000 mg of deferoxone and about 30 mg of an enteric polymer, such as HPMCAS. Specifically, the tablet core comprises 1000 mg of deferoxone and 28.5 mg of HPMCAS.

[0066] In some embodiments, the tablet core of the tablets disclosed herein (e.g., delayed-release tablets) comprises about 600 mg of deferoxone and about 30 mg of an enteric polymer, such as HPMCAS. Specifically, the tablet core comprises 600 mg of deferoxone and 29.5 mg of HPMCAS.

[0067] In some embodiments, the tablet core of the tablets disclosed herein (e.g., delayed-release tablets) comprises about 400 mg of deferoxone and about 20 to about 30 mg of an enteric polymer, such as HPMCAS. In some embodiments, the tablet core of the tablets disclosed herein (e.g., delayed-release tablets) comprises about 600 mg of deferoxone and about 20 mg to about 30 mg of an enteric polymer, such as HPMCAS.

[0068] In some embodiments, the core comprises one or more basic excipients. In some embodiments, the basic excipient is selected from meglumine, metal oxides, metal hydroxides, basic salts of weak acids, and combinations thereof. Metal oxides include, but are not limited to, magnesium oxide, aluminum oxide, and zinc oxide. Metal hydroxides include, but are not limited to, sodium hydroxide, potassium hydroxide, magnesium hydroxide, and calcium hydroxide. Basic salts of weak acids include, but are not limited to, sodium or potassium salts of carbonates, bicarbonates, acetates, and citrates. In some embodiments, the basic excipient is magnesium oxide, meglumine, or a combination thereof. In some embodiments, the basic excipient is magnesium oxide.

[0069] In some embodiments, the basic 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%, about 3-4%, or about 4-5% of the total weight of the core. In some embodiments, the tablet core of the tablets disclosed herein (e.g., delayed-release tablets) 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 basic excipient is about 4.5% of the total weight of the core. In some embodiments, the basic excipient is about 3.7% of the total weight of the core.

[0070] In some embodiments, the tablet core of the tablets disclosed herein (e.g., delayed-release tablets) comprises about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 90 mg, or 100 mg of basic excipient, or a range between any two of the above values, such as about 5-100 mg, 5-80 mg, 10-60 mg, 40-60 mg, or 20-30 mg of basic excipient.

[0071] In some embodiments, the tablet core of the tablets disclosed herein (e.g., delayed-release tablets) comprises about 1000 mg of deferoxone and about 50 mg of a basic excipient, such as magnesium oxide. In some embodiments, the tablet core of the tablets disclosed herein (e.g., delayed-release tablets) comprises about 600 mg of deferoxone and about 25 mg of a basic excipient, such as magnesium oxide. In some embodiments, the tablet core of the tablets disclosed herein (e.g., delayed-release tablets) comprises about 400 mg of deferoxone and about 10 to about 20 mg of a basic excipient, such as magnesium oxide.

[0072] In some embodiments, the tablet core does not contain a disintegrant.

[0073] In some embodiments, the tablet core is coated with the enteric coating described herein. In some embodiments, the core contains the same or a different enteric polymer as the enteric polymer in the coating.

[0074] 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 97%, at least 98%, or at least 99% of the total tablet weight.

[0075] 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 adhesion to tools during compression), flow aids such as colloidal silica (e.g., to improve flowability during tableting), and combinations thereof.

[0076] In some embodiments, the core comprises a flow aid such as colloidal silica. In some embodiments, the flow aid is about 1%, 0.5%, 0.45%, 0.4%, 0.35%, 0.3%, 0.25%, 0.2%, 0.1% of the weight of the core, or a range between any two of the above values, for example, about 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% of the weight of the core. In some embodiments, the core comprises about 0.45% by weight of a flow aid (e.g., colloidal silica). In some embodiments, the core comprises about 0.3% by weight of a flow aid (e.g., colloidal silica).

[0077] In some embodiments, the tablet core of the tablets disclosed herein (e.g., delayed-release tablets) comprises about 1000 mg of deferoxone and about 5 mg of a flow aid, such as colloidal silica. In some embodiments, the tablet core of the tablets disclosed herein (e.g., delayed-release tablets) comprises about 600 mg of deferoxone and about 2 mg of a flow aid, such as colloidal silica. In some embodiments, the tablet core of the tablets disclosed herein (e.g., delayed-release tablets) comprises about 400 mg of deferoxone and about 1 mg to about 2 mg of a flow aid, such as colloidal silica.

[0078] In some embodiments, the core comprises a lubricant, such as magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, or talc. In some embodiments, the core comprises magnesium stearate as a lubricant.

[0079] 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% of the core weight, or a range between any two of the above values, for example, 0.5-1%, 0.5-2%, 0.6-2%, 0.7-2%, 1-1.5%, 1.2-1.7%, or 1.5-2% of the core weight. In some embodiments, the core contains about 0.6% by weight of lubricant (e.g., magnesium stearate). In some embodiments, the core contains about 1.5% by weight of lubricant (e.g., magnesium stearate).

[0080] In some embodiments, the tablet core of the tablets disclosed herein (e.g., delayed-release tablets) comprises about 2 mg, 3 mg, 4 mg, 5 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 21 mg, 22 mg, 23 mg, 24 mg, or 25 mg of lubricant, or a range between any two of the above values, such as about 2-25 mg, 2-10 mg, 2-8 mg, 2-6 mg, 7-20 mg, 10-20 mg, or 15-20 mg of lubricant.

[0081] In some embodiments, the tablet core of the tablets disclosed herein (e.g., delayed-release tablets) comprises about 1000 mg of deferoxone and about 17 mg of lubricant, such as magnesium stearate. In some embodiments, the tablet core of the tablets disclosed herein (e.g., delayed-release tablets) comprises about 600 mg of deferoxone and about 4 mg of lubricant, such as magnesium stearate. In some embodiments, the tablet core of the tablets disclosed herein (e.g., delayed-release tablets) comprises about 400 mg of deferoxone and about 1 mg to about 4 mg of lubricant, such as magnesium stearate.

[0082] In some embodiments, the core comprises hydroxypropyl methylcellulose acetate succinate, magnesium oxide, colloidal silica, magnesium stearate, and approximately 1000 mg of deferoxone.

[0083] In some embodiments, the core comprises hydroxypropyl methylcellulose acetate succinate, magnesium oxide, colloidal silica, magnesium stearate, and approximately 600 mg of deferoxone.

[0084] In some embodiments, the core comprises hydroxypropyl methylcellulose acetate succinate, magnesium oxide, colloidal silica, magnesium stearate, and approximately 400 mg of deferoxone.

[0085] IV. Enteric coating

[0086] In some aspects of this disclosure, the composition, such as a tablet, may comprise an enteric coating. Such a coating can be used to reduce gastric irritation. The enteric coating can delay dissolution from the tablet core until the tablet reaches the intestine. This disclosure relates to a composition, such as a delayed-release tablet, comprising a core and an enteric coating, said core comprising an active pharmaceutical ingredient, such as deferiphenone or a pharmaceutically acceptable salt thereof.

[0087] Suitable enteric polymers for enteric coating include, for example, hydroxypropyl methylcellulose acetate succinate (also known as hydroxypropyl methylcellulose acetate succinate or HPMCAs), HPMC phthalate (also known as hydroxypropyl methylcellulose phthalate), polyvinyl acetate phthalate, cellulose acetate trimellitate, lac, zein, methacrylic acid copolymers (e.g., 30% C-type dispersion of methacrylic acid copolymer), their derivatives, and combinations thereof.

[0088] In some embodiments, the preferred enteric polymer in the enteric coating is a copolymer of hydroxypropyl methylcellulose acetate succinate and methacrylic acid, for example, a type C copolymer of methacrylic acid in an aqueous dispersion.

[0089] 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% of the tablet weight, or a range between any two of the above values, for example... 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% of the tablet weight. In some embodiments, the enteric polymer in the coating (e.g., a methacrylic acid copolymer) is about 0.8% of the tablet weight. In some embodiments, the enteric polymer in the coating (e.g., a methacrylic acid copolymer) is about 1.4% of the tablet weight (e.g., a methacrylic acid copolymer).

[0090] In some embodiments, the enteric coating comprises about 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, or 30 mg of enteric polymer, or a range between any two of the above values, such as about 5-20 mg, 7-20 mg, 7-30 mg, 8-15 mg, or 8-10 mg of enteric polymer.

[0091] In some embodiments, the tablets disclosed herein (e.g., delayed-release DR tablets) comprise about 1000 mg of deferiphenone and about 9 mg of an enteric polymer, such as a methacrylic acid copolymer (from about 31 mg of dispersion), in the coating. In some embodiments, the tablet core of the tablets disclosed herein (e.g., delayed-release tablets) comprises about 600 mg of deferiphenone and about 9 mg of an enteric polymer, such as a methacrylic acid copolymer (from about 31 mg of dispersion), in the coating. In some embodiments, the tablet core of the tablets disclosed herein (e.g., delayed-release tablets) comprises about 400 mg of deferiphenone and about 9 mg of an enteric polymer, such as a methacrylic acid copolymer (from about 31 mg of dispersion), in the coating.

[0092] In some embodiments, in addition to the enteric polymer, the enteric coating may also contain other excipients, including, for example, plasticizers, lubricants or anti-sticking agents such as talc, opacifiers, colorants, diluents or any combination thereof.

[0093] In some embodiments, the enteric coating plasticizer is diethyl phthalate, citrate (e.g., triethyl citrate), polyethylene glycol, glycerol, acetylated glyceryl esters, acetylated citrate esters, dibutyl sebacate, castor oil, or any combination thereof.

[0094] In some embodiments, the enteric coating contains about 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, or 5 mg of plasticizer, or a range between any two of the above values, such as about 0.5-5 mg, 0.7-2 mg, or 0.8-1.2 mg of plasticizer.

[0095] In some embodiments, the enteric coating comprises a diluent (e.g., lactose, sucrose, fructose, mannitol, or combinations thereof). In some embodiments, the enteric coating comprises talc as a lubricant or anti-sticking agent.

[0096] Certain aspects of this application relate to compositions comprising a core and a coating (e.g., delayed-release tablets), wherein the core comprises 1000 mg deferoxone, an enteric polymer, a pH adjuster, a flow aid, and a lubricant, and the coating comprises a plasticizer, a diluent, an anti-adhesion agent, and an enteric polymer. In some embodiments, the core comprises 1000 mg deferoxone, HPMCAS-LF, magnesium oxide, colloidal silica, and magnesium stearate; and the coating comprises triethyl citrate, sucrose, talc, and a methacrylic acid copolymer dispersion. In another embodiment, the composition (e.g., delayed-release tablets) comprises 1000 mg deferoxone, 28 mg HPMCAS-LF, 50 mg magnesium oxide, 4.8 mg (2.6 mg + 2.2 mg) colloidal silica, and 17.2 mg magnesium stearate in the core; and the coating comprises 1.03 mg triethyl citrate, 3.09 mg sucrose, 3.09 mg talc, and 31 mg methacrylic acid copolymer dispersion.

[0097] Certain aspects of this application relate to compositions comprising a core and a coating (e.g., delayed-release tablets), wherein the core comprises 600 mg of deferoxone, an enteric polymer, a pH adjuster, a flow aid, and a lubricant, and the coating comprises a plasticizer, a diluent, an anti-adhesion agent, and an enteric polymer. In some embodiments, the core comprises 600 mg of deferoxone, HPMCAS-LF, magnesium oxide, colloidal silica, and magnesium stearate; and the coating comprises triethyl citrate, sucrose, talc, and a methacrylic acid copolymer dispersion. In another embodiment, the core comprises 600 mg of deferoxone, 29.5 mg of HPMCAS-LF, 24.5 mg of magnesium oxide, 2 mg (1 mg + 1 mg) colloidal silica, and 4 mg of magnesium stearate; and the coating comprises 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.

[0098] In some embodiments, the core comprises 600 mg deferoxone, hydroxypropyl methylcellulose acetate succinate AS-LF, light magnesium oxide, colloidal silica, and magnesium stearate; and the coating comprises triethyl citrate, sucrose, talc, a methacrylic acid copolymer dispersion, and titanium dioxide. In another embodiment, the core comprises 600 mg deferoxone, 29.5 mg hydroxypropyl methylcellulose acetate succinate AS-LF, 24.5 mg light magnesium oxide, 2 mg (1 mg + 1 mg) colloidal silica, and 4 mg magnesium stearate; and the coating comprises 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.

[0099] 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 weight of the tablets. 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 tablets. In some embodiments, the enteric coating is between 0.5% and 5% of the total tablet weight. In some embodiments, the enteric coating is between 0.5% and 3% of the total tablet weight. In some embodiments, the enteric coating is between 0.5% and 2% of the total tablet weight. In some embodiments, the enteric coating is between 0.5% and 1.5% of the total tablet weight. In some embodiments, the coating 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 tablets.

[0100] In some embodiments, the coating is about 1.5% of the total weight of the tablet. In some embodiments, the coating is about 2.5% of the total weight of the tablet.

[0101] In some embodiments, the tablets disclosed herein (e.g., delayed-release tablets) comprise about 1000 mg of deferoxone and about 1.5% of the tablet's weight in enteric coating. In some embodiments, the tablets disclosed herein (e.g., delayed-release tablets) comprise about 600 mg of deferoxone and about 2.5% of the tablet's weight in enteric coating.

[0102] Another aspect of this disclosure relates to a method for delayed release of deferone in a human subject, the method comprising administering a tablet of this disclosure to the subject, wherein the tablet comprises the core and enteric coating disclosed herein and is administered as a whole tablet, half tablet, or a combination thereof.

[0103] Another aspect of this disclosure relates to a method for relieving gastric discomfort in a human subject requiring deferiprone treatment, the method comprising administering a tablet of this disclosure to the subject, wherein the tablet comprises the core and enteric coating disclosed herein, and the tablet is administered as a whole tablet, half tablet, or a combination thereof.

[0104] V. Administration

[0105] This disclosure provides a dosing regimen that can be used with methods of using the pharmaceutical compositions described herein (e.g., delayed-release tablets). In some embodiments, the deferiphenone composition of this disclosure is administered once, twice, or three times daily to a subject in need. Specifically, the deferiphenone composition of this disclosure is administered twice daily to a subject in need.

[0106] In some implementations, the subjects in need suffer from iron overload (e.g., transfusional iron overload, such as in subjects with thalassemia, spinal dysplasia, or sickle cell disease). In some implementations, the subjects in need suffer from neurodegenerative diseases (e.g., Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, Friedreich's ataxia, pantothenate kinase-associated neurodegeneration (PKAN), or neurodegeneration with brain iron accumulation (NBIA)).

[0107] In some implementations, the iron overload suffered by the subject requiring this is transfusion iron overload. In some aspects, the subject suffers from transfusion iron overload and their prior chelation therapy is inadequate. In some aspects, the subject suffers from transfusion iron overload and has a cardiac MRI T2* of 20 ms or less (e.g., 10 ms).

[0108] In some embodiments, the pharmaceutical composition is for oral delivery, for example, a tablet as disclosed herein.

[0109] In some respects, the DR deferone composition (specifically, the tablet composition) of this disclosure is administered twice daily. IR deferone tablets are inconvenient for patients because they require three-times-daily dosing (TID). Patients generally prefer a twice-daily (BID) or once-daily dosing regimen. One reason for requiring TID dosing is that the elimination half-life of deferone is only about 2 hours. After ingestion of a deferone IR tablet, the deferone contents are rapidly absorbed from the upper gastrointestinal tract and appear in the bloodstream within 5 to 10 minutes of oral administration. In fasting healthy subjects and patients, peak serum concentrations occur approximately 1 hour after the single dose, while in the fed state, peak concentrations occur up to 2 hours after the single dose. Because of the short elimination half-life, if the dosing frequency is less than TID, serum concentrations will decrease to well below therapeutically effective levels before the next dose.

[0110] Another issue associated with deferoxone is acute gastrointestinal upset, which can last for several days or longer. This is a limiting adverse event for many patients, such as those who discontinue the medication in the first few days due to gastrointestinal upset and thus forgo the benefits of deferoxone.

[0111] Extended-release (ER) formulations have been developed to allow certain drugs to be administered twice daily or once daily. These formulations are designed to gradually release the active drug contents over a longer period, typically about 5–10 hours for twice-daily dosing and more than 8–20 hours for once-daily dosing. This is usually only done for drugs absorbed via the ileum and duodenum to ensure that the gradual release of the formulation as it passes through the intestines does not impair absorption.

[0112] Issues with ER formulations and maximum (or peak) serum concentrations (C max This is related to the fact that, by prolonging the absorption time, for example, by using extended-release formulations, C max Ultimately, it will be much lower than IR tablets. This could be a problem for achieving the desired effect of certain drugs (such as iron chelators), where C max The area under the graph of serum concentration versus time (AUC) can affect efficacy.

[0113] Certain aspects of this disclosure relate to deferiphenone tablets for twice-daily (BID) dosing that are bioequivalent at steady state to IR tablets for TID dosing using the same total daily dose. In some embodiments, BID is bioequivalent at steady state, wherein the mean AUC ratio (over 24 hours) and mean C of the tablets for BID dosing are [not specified in the original text]. max The ratio relative to the IR tablets used for TID was between 80% and 125%. The tablets used for twice-daily dosing then provided subjects with the same chelating benefits as the IR tablets, but with some advantages of twice-daily dosing. In addition to the promotion of BID dosing, this regimen also enhances patient compliance, for example, by selecting patients who do not take the midday dose to school or work, thus missing out on the full-day dose benefits of deferiprone.

[0114] In some respects, the disclosed formulations are used to target specific serum concentration-time curves and achieve the improved performance disclosed herein.

[0115] Some aspects of this disclosure relate to overcoming problems associated with TID dosing without sacrificing the achievement of C max The benefits, provided by offering tablets for twice-daily administration, compared to IR tablets administered with the same total daily dose via TID, are as follows:

[0116] i. Similar absorption rate to IR tablets, and therefore similar mean serum concentrations; and

[0117] ii. Similar peak serum concentrations, but peaks occur twice daily instead of three times daily.

[0118] Some aspects of this disclosure relate to overcoming problems associated with TID dosing without sacrificing the achievement of C max The benefits, provided by offering tablets for twice-daily administration, compared to IR tablets administered with the same total daily dose via TID, are as follows:

[0119] i. Equivalent absorption to IR tablets, and therefore similar mean serum concentrations; and

[0120] ii. Equivalent peak serum concentration, but the peak occurs twice a day instead of three times a day.

[0121] Another aspect of this disclosure is the provision of a tablet formulation containing deferone for twice-daily administration, exhibiting a delayed release onset and an extended release duration without affecting the terminal half-life, thereby enabling the achievement of peak and trough concentrations in serum. This advantage applies 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; therefore, half tablets are bioequivalent to whole tablets in single-dose bioequivalence studies under both fasting and fed conditions.

[0122] The results presented in this paper also confirm that, under steady-state conditions, the delayed-release tablets of this disclosure, when administered with BID, can achieve the same effect as... The same maximum peak concentration (C) as IR tablets (when IR tablets are administered three times daily). max Both products had the same total absorption capacity (AUC) over 24 hours. Therefore, the benefits of twice-daily dosing were obtained, with less gastrointestinal discomfort in some cases, without compromising efficacy.

[0123] "Bioequivalence" means that there is no significant difference in the bioavailability (i.e., extent of absorption and peak concentration) between two drug products (e.g., the investigation product and the reference product) over a period of time at the same dose and under the same conditions.

[0124] A study (called a bioequivalence or comparative bioavailability study) conducted under controlled conditions on a cohort of subjects (typically about 18-36 subjects or more) determines whether the test product is bioequivalent to a reference product.

[0125] The study can be conducted with a "crossover" design, meaning it can be completed in two or more phases, typically spaced at least one week apart, depending in part on the drug's half-life. In the first phase, half of the participants are randomly assigned to take the test product first, while the other half takes the control product first. In the second phase, each participant takes an alternate product.

[0126] At each stage, blood samples were drawn from each subject according to a predetermined schedule after ingestion of the test product. The blood samples were then analyzed to determine the serum concentration of the drug (test product, e.g., deferiphenone) at each time point. The results from each subject for both the test product and the reference product were then combined to determine the following:

[0127] • AUC - Defined as the area under the curve of serum concentration versus time over a selected time period (e.g., 24 hours) after ingestion.

[0128] ·AUCT or AUC T - Defined as the area under the curve of serum concentration versus time from intake time to last sampling time.

[0129] ·AUCI or AUC I - Defined as the area under the curve of serum concentration versus time from the time of intake to infinity, using AUC. T And terminal clearance rate estimation.

[0130] ·C max - Defined as peak serum concentration.

[0131] • AUC ratio - defined as the ratio of the AUC of the test product to the AUC of the reference product, calculated for each subject.

[0132] ·C max The ratio - defined as the C of the test product also calculated from each subject max Compared with the reference product C max ratio

[0133] • Mean AUC ratio - defined as the inverse logarithm of the mean of the logarithms of the AUC ratios of all subjects.

[0134] ·Average C max The ratio - defined as the C of all subjects max The inverse logarithm of the mean of the logarithms of ratios.

[0135] "Equivalent absorption extent" is defined as the average AUC ratio of the investigational product to the reference product, calculated in studies typically involving 18 or more subjects, between 80% and 125%.

[0136] "Equivalent peak concentration" is defined as the average Cg of the test product relative to the reference product, calculated as between 80% and 125% in studies typically conducted in 18 or more subjects. max ratio.

[0137] Only when equivalent absorption level and equivalent peak concentration are achieved can it be considered bioequivalent.

[0138] For any bioavailability parameter, the “true” average ratio of the parameter measured in the test product to that measured in the reference product is defined as the average ratio found in studies involving a large number of subjects. Since studies involving a large number of subjects are impossible, 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, the average ratio result generally provides a better estimate of the true average ratio. Unless otherwise stated herein, references to products having a specific parameter ratio to a reference product are understood to mean the average determined in studies involving at least 18 subjects.

[0139] Bioequivalence studies can be conducted as single-dose studies in either a fasting or eating state. In a study conducted in a fasting state, the product is typically ingested at least several hours before or after a meal without food. If the study is conducted in a eating state, the product is ingested with or shortly after a meal. In some implementations, bioequivalence studies can be single-dose or steady-state studies. In a single-dose study, each subject receives only one dose of the product ingested at each stage, although this dose may include more than one tablet, depending on the size of the dose being studied. In a steady-state study, subjects are given the dose according to the tested dosing regimen (e.g., twice or three times daily) for at least several doses until steady-state is reached, and then blood samples are taken at predetermined time intervals (usually more than one day). To evaluate formulations with modulated release (whether delayed or extended release), studies are often conducted in the presence of food and steady-state is reached after several doses (to simulate effects over a long period of dosing).

[0140] Administering tablets to patients who have just eaten can alter the rate and extent of absorption, and if the medication is to be taken with food, it may be important to characterize the rate and extent of absorption of delayed-release tablets taken with food, relative to IR tablets taken with food.

[0141] Bioequivalence studies can also be conducted as multiple-dose studies over a period of at least several days to determine whether the two products are bioequivalent at "steady state" after several days of administration. "Steady state," as used herein, is reached when the rate of drug delivery equals the rate of drug elimination (as determined by the absence of further increases in drug concentration in subjects after repeated dose administration). "Bioequivalence at steady state" should be understood as meaning that, at least three days after administration of the test product, the mean ratio of AUC (over 24 hours) and C... max The average ratio is between 80% and 125% of the corresponding value of the reference product.

[0142] In some embodiments, this disclosure provides compositions for twice-daily administration, such as delayed-release tablets, which are bioequivalent in steady state to the same daily dose of an IR tablet administered three times daily, for example, as illustrated in the examples below.

[0143] Certain aspects of this disclosure relate to tablets containing deferoxone for oral administration, which, when administered twice daily, provide at least equivalent absorption in steady-state studies compared to the same total daily dose administered three times daily as an IR tablet.

[0144] Certain aspects of this disclosure relate to tablets containing deferiphenone for oral administration, which, when administered twice daily, provide equivalent peak serum concentrations in steady-state studies compared to the same total daily dose administered three times daily as IR tablets.

[0145] Certain aspects of this disclosure relate to deferoxone-containing tablets for BID oral administration, whose equivalent absorption extent and / or absorption rate characteristics, as described above, are satisfied not only for whole tablets but also for half tablets, thereby allowing the administration of half tablets. In some embodiments, the tablets preferably have score lines to facilitate splitting into half tablets. For example, if a whole tablet contains about 1000 mg of deferoxone, and a half tablet contains about 500 mg of deferoxone, then a dose of about 1500 mg can be administered as one whole tablet + one half tablet, and a total daily dose of 3000 mg can be achieved with BID administration.

[0146] In some embodiments, to achieve the desired absorption characteristics, the tablets of this disclosure are formulated to exhibit a desired dissolution rate, as demonstrated by in vitro dissolution tests. Reference to dissolution tests herein should be understood as tests conducted at 75 rpm in 900 mL of medium (i.e., 0.1 N hydrochloric acid (HCl), 0.5 M pH 4.5 phosphate buffer, and 0.5 M pH 6.8 phosphate buffer) in a USP device 2, unless otherwise indicated. The dissolution results should be understood as the average result for 6 or more tablets.

[0147] Some aspects of this disclosure relate to half or whole tablets for oral administration to human subjects, comprising a core containing deferiphenone, said core having a dissolution rate of about 55% to about 90%, about 60% to about 90%, or about 65% to about 85% at pH 4.5 for 60 minutes.

[0148] Some aspects of this disclosure relate to half or whole tablets for oral administration to human subjects, comprising a core containing deferiphenone, said core having a dissolution rate of about 55% to about 90%, about 60% to about 90%, or about 65% to about 85% at pH 6.8 for 60 minutes.

[0149] In some respects, when measured at 75 rpm in 900 mL using the USP Device II paddle method at pH 6.8 or 4.5, approximately 100% of the deferone is released within about 90 minutes. In other respects, when measured at 75 rpm in 900 mL using the USP Device II paddle method at pH 6.8 or 4.5, approximately 50% of the deferone is released within about 30 minutes.

[0150] Furthermore, certain aspects of this disclosure relate to half or whole tablets for oral administration to human subjects, comprising a core containing deferiphenone, which has a dissolution rate of less than 20% or less than 10% in 0.1N HCl at 60 minutes.

[0151] In some embodiments, when the tablets are administered to human subjects, a single dose of the tablets of this disclosure provides a mean AUC between 3.5 hours and 6.0 hours in a fasting state. ∞ / C max ratio.

[0152] In some embodiments, when the tablets are administered to human subjects, a single dose of the tablets of this disclosure provides a mean AUC between 3.5 hours and 6.0 hours in an oral state. ∞ / C max Ratio. In some embodiments, the tablet contains 1000 mg of deferone. In some embodiments, the tablet contains 600 mg of deferone. In some embodiments, when the tablet is administered to a human subject, the average C... max It ranges from 2.670 to 13.232 μg / mL. In some embodiments, when the tablets are administered to human subjects, the median T... max The median time to recovery is between 1.33 and 4.00 hours. In some embodiments, when the tablet is administered to a human subject, the median time to recovery is between 1.33 and 4.00 hours. max The median time to recovery is between 2.00 and 8.00 hours. In some embodiments, when the tablet is administered to a human subject, the median time to recovery is between 2.00 and 8.00 hours. max The AUC is between 1.33 and 6.03 hours. In some embodiments, when the tablet is administered to a human subject, the AUC... I / C max The ratio is between 2.858 and 6.596 hours. In some embodiments, when the tablet is administered to a human subject, the AUC... I / C max The ratio is between 3.225 and 8.506 hours.

[0153] In some embodiments, the administration is for treating a subject suffering from iron overload (e.g., transfusion-induced iron overload, such as in a subject suffering from thalassemia, spinal dysplasia, or sickle cell disease). Certain aspects of this disclosure relate to dosing regimens that can be used in the methods for treating iron overload described herein. In some embodiments of the method for treating iron overload, the total daily dose of deferiphenone is about 1 mg / kg / day to about 200 mg / kg / day, about 1 mg / kg / day to about 150 mg / kg / day, about 20 mg / kg / day to about 150 mg / kg / day, about 50 mg / kg / day to about 125 mg / kg / day, or about 50 mg / kg / day to about 100 mg / kg / day. In some embodiments, the administration is once, twice, or three times daily. In some implementations, the dosage for treating iron overload is about 1 mg / kg to about 150 mg / kg, about 20 mg / kg to about 150 mg / kg, 25 mg / kg to about 125 mg / kg, or about 50 mg / kg to about 100 mg / kg twice daily (BID).

[0154] In some embodiments, the administration is for treating a subject suffering from a neurodegenerative disease, such as Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, Friedreich's ataxia, pantothenic kinase-associated neurodegeneration (PKAN), or neurodegeneration with brain iron accumulation (NBIA). In some embodiments, the deferiphenone composition (IR or DR composition) of this disclosure is administered once, twice, or three times daily to a subject suffering from a neurodegenerative disease, such as Parkinson's disease, ALS, Huntington's disease, Friedreich's ataxia, pantothenic kinase-associated neurodegeneration (PKAN), or neurodegeneration with brain iron accumulation (NBIA). In some embodiments, the subject suffers from ALS. In some embodiments, the subject suffers from Huntington's disease. In some embodiments, the subject suffers from Parkinson's disease.

[0155] Certain aspects of this disclosure relate to dosing regimens that can be used in the methods for treating neurodegenerative diseases described herein. In some embodiments of the methods for treating neurodegenerative diseases, the total daily dose of deferiphenone is about 1 mg / kg / day to about 200 mg / kg / day, about 1 mg / kg / day to about 150 mg / kg / day, about 1 mg / kg / day to about 100 mg / kg / day, about 1 mg / kg / day to about 50 mg / kg / day, 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, about 1 mg / kg / day to about 10 mg / kg / day, or about 1 mg / kg / day to about 5 mg / kg / day. In some embodiments, the administration is once, twice, or three times daily. In some embodiments, the administration for treating neurodegenerative diseases is about 1 mg / kg to about 100 mg / kg, about 1 mg / kg to about 50 mg / kg, about 1 mg / kg to about 40 mg / kg, about 1 mg / kg to about 25 mg / kg, or about 1 mg / kg to about 20 mg / kg twice daily (BID).

[0156] In some embodiments of the method, the amount of deferone in the composition (e.g., tablets) is about 100 mg to about 1500 mg, about 200 mg to about 1500 mg, about 400 mg to about 1500 mg, about 600 mg to about 1500 mg, about 800 mg to about 1500 mg, about 1200 mg to about 1500 mg, about 200 mg to about 1200 mg, about 400 mg to about 1200 mg, about 600 mg to about 1... 200 mg, about 800 mg to about 1200 mg, about 200 mg to about 1000 mg, about 400 mg to about 1000 mg, about 600 mg to about 1000 mg, about 800 mg to about 1000 mg, about 200 mg to about 800 mg, about 400 mg to about 800 mg, about 600 mg to about 800 mg, 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 method, the amount of deferiphenone in the composition (e.g., tablets) is any range of 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 values ​​thereof. Specifically, the amount of deferiphenone in the composition (e.g., tablets) is 600 mg or 1000 mg. In some embodiments, the amount of deferiphenone in the tablets is 1000 mg. In some embodiments, the amount of deferiphenone in the tablets is 600 mg.

[0157] In some embodiments of the method, the total daily dose of deferoxone is about 100 mg / day to about 3000 mg / day, about 200 mg / day to about 3000 mg / day, about 400 mg / day to about 2400 mg / day, about 600 mg / day to about 2400 mg / day, about 800 mg / day to about 2400 mg / day, about 1200 mg / day to about 2400 mg / day, about 1600 mg / day to about 2400 mg / day, approximately 1800 mg / day to approximately 2400 mg / day, approximately 2000 mg / day to approximately 2400 mg / day, approximately 400 mg / day to approximately 2000 mg / day, approximately 600 mg / day to approximately 2000 mg / day, approximately 800 mg / day to approximately 2000 mg / day, approximately 1200 mg / day to approximately 2000 mg / day, approximately 1600 mg / day to approximately 2000 mg / day, approximately 180 mg / day 0 mg / day to approximately 2000 mg / day, approximately 400 mg / day to approximately 1800 mg / day, approximately 600 mg / day to approximately 1800 mg / day, approximately 800 mg / day to approximately 1800 mg / day, approximately 1200 mg / day to approximately 1800 mg / day, approximately 1600 mg / day to approximately 1800 mg / day, approximately 400 mg / day to approximately 1600 mg / day, approximately 600 mg / day to approximately 1600 mg / day Approximately 800 mg / day to approximately 1600 mg / day, approximately 1200 mg / day to approximately 1600 mg / day, approximately 400 mg / day to approximately 1200 mg / day, approximately 600 mg / day to approximately 1200 mg / day, approximately 800 mg / day to approximately 1200 mg / day, approximately 400 mg / day to approximately 800 mg / day, approximately 600 mg / day to approximately 800 mg / day, or approximately 400 mg / day to approximately 600 mg / day. In some embodiments of the method, the total daily dose of deferoxone 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, about 1600 mg / day, about 1800 mg / day, about 2000 mg / day, about 2200 mg / day, about 2400 mg / day, about 2600 mg / day, about 2800 mg / day, about 3000 mg / day, or any range of values ​​thereof.

[0158] In some embodiments of the method, the composition (e.g., tablets) is administered once, twice, or three times daily. In some embodiments, the composition (e.g., tablets) 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, about 2200 mg, or about 2400 mg of deferone and is administered once, twice, or three times daily. In some embodiments, the composition (e.g., tablets) contains about 600 mg of deferone and is administered once or twice daily.

[0159] In some embodiments, the composition (e.g., tablets) contains about 100, 200, 300, or 400 mg of deferiphenone and is administered once, twice, or three times daily. In some embodiments, the composition (e.g., tablets) contains about 400 mg of deferiphenone and is administered once, twice, or three times daily. In some embodiments, the composition (e.g., tablets) contains about 500 mg of deferiphenone and is administered once, twice, or three times daily. In some embodiments, the composition (e.g., tablets) contains about 1000 mg of deferiphenone and is administered once, twice, or three times daily.

[0160] Such implementation methods disclosed herein can be used to avoid or reduce the risk of stomach upset, and / or to treat iron overload or neurodegenerative diseases (e.g., amyotrophic lateral sclerosis) in subjects (e.g., those suffering from thalassemia, spinal dysplasia, or sickle cell disease).

[0161] VI. Preparation Method

[0162] In some embodiments, the pharmaceutical composition is prepared for oral delivery. In some aspects, this disclosure relates to the preparation of the delayed-release deferiphenone tablets disclosed herein.

[0163] In some embodiments, the method for preparing delayed-release deferoxone tablets includes: (a) mixing deferoxone and one or more excipients; (b) compressing the mixture of (a) into a tablet core; and (c) coating the tablet core with an enteric coating suspension or solution. The method may further include (d) scoring the tablet core.

[0164] In some embodiments, the method of coating the core with an enteric coating solution or suspension includes spray coating. When coating by spray coating, it can be operated according to general coating methods, such as fluidized bed coating, pan coating, etc., to spray coat the tablet core with an enteric coating solution or suspension.

[0165] In some embodiments, the enteric-coated solution or suspension comprises 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-coated solution or suspension. In some embodiments, when the coating has dried, the enteric polymer is about 20-80%, about 25-75%, or about 30-70% of the enteric coating. In some embodiments, when the coating has dried, the enteric polymer is about 50-60% of the enteric coating by weight. In some embodiments, when the coating has dried, the enteric polymer is about 55% of the enteric coating by weight.

[0166] In some embodiments, the enteric-coated suspension or solution contains a plasticizer, such as diethyl phthalate, citrate (e.g., triethyl citrate), polyethylene glycol, glycerol, acetylated glyceryl esters, glyceryl fatty acid esters, cetyl alcohol, stearyl alcohol, acetylated citrate, dibutyl sebacate, castor oil, or combinations thereof.

[0167] 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-coated suspension or solution. In some embodiments, when the coating has dried, the plasticizer is about 1-10% or about 4-8% of the enteric coating by weight. In some embodiments, when the coating has dried, the plasticizer is about 6% of the enteric coating by weight.

[0168] In some embodiments, the enteric-coated suspension or solution contains a lubricant or anti-sticking agent (e.g., talc).

[0169] In some embodiments, the lubricant or anti-sticking agent is about 0.5-10%, about 0.5-8%, about 0.5-5%, or about 1-5% of the enteric-coated suspension or solution. In some embodiments, when the coating has dried, the lubricant or anti-sticking agent is about 10-30% or about 15-25% of the enteric coating by weight. In some embodiments, when the coating has dried, the lubricant or anti-sticking agent is about 20% of the enteric coating by weight.

[0170] In some embodiments, the enteric-coated suspension or solution may further contain a diluent, such as sugars (e.g., lactose, sucrose, fructose, mannitol, and mixtures thereof).

[0171] 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-coated suspension or solution. In some embodiments, when the coating has dried, the diluent is about 10-30% or about 15-25% of the enteric coating by weight. In some embodiments, when the coating has dried, the diluent is about 20% of the enteric coating by weight.

[0172] In some embodiments, the enteric coating can be applied as a solution or latex suspension in an organic solvent or an aqueous solvent or a mixture thereof. Solvents such as water, lower alcohols, lower chlorinated hydrocarbons, ketones, or mixtures thereof can be used.

[0173] In some embodiments, the solvent is about 20-80%, about 30-80%, about 40-80%, or about 50-75% of an enteric-coated solution or suspension.

[0174] In some embodiments, at least one ionic, nonionic, or polymeric surfactant may be added as a stabilizer to the enteric-coated suspension or solution. Suitable examples of surfactants include, but are not limited to, diethanolamine, fatty acids, hydroxypropyl methylcellulose, hydroxypropyl cellulose, monoethanolamine, nonylphenyl alcohol ether, octylbenzeneol, oleic acid, poloxamer, polyoxyethylene 50 stearate, polyoxy fatty acids, polyoxyethylene ethers, polysorbates (e.g., polysorbate 80, etc.), povidone, fatty acid salts, sodium lauryl sulfate, dehydrated sorbitol esters, triethanolamine, etc.

[0175] In some embodiments, the enteric-coated solution or suspension contains a plasticizer, a diluent, a lubricant or anti-adhesive, and an enteric polymer.

[0176] After coating, in some implementations, antistatic agents such as talc may also be used.

[0177] By using the methods disclosed herein to coat the tablet core, the immediate dissolution of the physiologically active substance from the enteric-coated particles at acidic pH (e.g., pH 1-4), corresponding to dissolution near the stomach in the early stages after oral administration, is inhibited, and subsequent dissolution of the physiologically active substance at weakly acidic to weakly alkaline pH (e.g., pH 4.5-8), corresponding to dissolution in the small intestine and thereafter, particularly in the duodenum and ileum. Specifically, dissolution can be more tightly controlled in the early stages after administration.

[0178] VII. Instructions for Use

[0179] This disclosure provides methods of 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 (e.g., a delayed-release tablet disclosed herein).

[0180] For example, deferoxone immediate-release tablets The most common adverse event is that it causes severe gastrointestinal upset. This upset can cause patients to refuse medication, leading to a worsening of their condition. In addition, gastrointestinal upset can impair health-related quality of life and cause physical, mental and social distress. Spiegel, Am J Gastroenterol. 2011 Mar; 106(3):380-5, incorporated herein by reference in its entirety. In some embodiments, the compositions of this disclosure (e.g., delayed-release tablets) are formulated to relieve gastrointestinal upset, a problem that occurs in about 15-30% of patients starting treatment with deferiphenone. In some embodiments, the compositions disclosed herein (e.g., delayed-release tablets) have negligible dissolution in the stomach, thereby minimizing gastrointestinal upset, and achieve sufficiently rapid dissolution in the intestine to achieve the desired intestinal release rate. In some embodiments, the compositions disclosed herein (e.g., delayed-release tablets) have negligible dissolution in the stomach, thereby minimizing gastrointestinal upset, and still achieve a similar, but different, serum concentration-time profile in vivo as that of immediate-release deferiphenone tablets, plus a delay of about 1 hour.

[0181] Some embodiments of this disclosure relate to a method for relieving gastric discomfort in human subjects requiring deferiphenone treatment, the method comprising administering a tablet disclosed herein (e.g., a notched delayed-release deferiphenone tablet) (e.g., a whole tablet, half a tablet, or a combination thereof).

[0182] Some embodiments of this disclosure relate to a method for delayed release of deferiphenone in a human subject, the method comprising administering a tablet disclosed herein (e.g., a whole tablet, half a tablet, or a combination thereof). Some embodiments of this disclosure relate to a method for treating a medical condition (e.g., where deferiphenone is required) in a human subject, the method comprising administering a tablet disclosed herein (e.g., a notched delayed release deferiphenone tablet) (e.g., a whole tablet, half a tablet, or a combination thereof).

[0183] The compositions of this disclosure (e.g., delayed-release tablets) may be particularly useful in patients who require blood transfusions for survival (such as those with hemoglobinopathies, including thalassemia and sickle cell disease) or in patients with secondary impairment of their ability to form red blood cells (such as those with spinal dysplasia).

[0184] Deferone Immediate Release Tablets Currently used to minimize the toxicity of high concentrations of iron in the body, tissues, or cells. Thalassemia is a form of inherited autosomal recessive blood disorder characterized by abnormal hemoglobin formation. Abnormal hemoglobin leads to insufficient oxygen transport and an accelerated rate of red blood cell destruction. Compared to normal individuals, people with thalassemia produce less hemoglobin and have fewer circulating red blood cells, resulting in moderate to severe anemia. Patients require lifelong blood transfusions to treat their thalassemia, typically every 2-4 weeks. Each transfusion leads to an increase in iron in the body equivalent to the amount normally absorbed from food in the intestines over 6 months. Because there is no pathway for iron excretion, this excess can cause iron overload, particularly in the liver and other more sensitive tissues, leading to endocrine disorders and iron-induced cardiovascular disease.

[0185] Iron overload occurs in sickle cell disease (SCD) patients requiring 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 distinct hemoglobinopathy, patients with sickle cell disease who require transfusions to survive also suffer from iron toxicity. The same is true for patients with spinal dysplasia who require repeated transfusions.

[0186] In some embodiments, the medical condition treated with the composition of this disclosure (e.g., a delayed-release tablet) is iron overload. In some aspects, the medical condition treated with the composition (e.g., a delayed-release tablet) is transfusion iron overload in subjects whose prior chelation therapy has been insufficient. In some aspects, the medical condition treated with the composition (e.g., a delayed-release tablet) is transfusion iron overload in subjects with a cardiac MRI T2* of 20 ms or less (e.g., 10 ms). In some embodiments, the medical condition treated with the composition of this disclosure (e.g., a delayed-release tablet) is in transfusion patients with thalassemia. In some embodiments, the composition of this disclosure (e.g., a delayed-release tablet) is used to treat transfusion iron overload in patients with sickle cell disease. In some embodiments, tablets of this disclosure (e.g., notched delayed-release deferiphenone tablets) are used to treat transfusion iron overload in patients with spinal dysplasia.

[0187] The compositions of this disclosure (e.g., delayed-release tablets) are also particularly useful in patients with neurodegenerative diseases such as Parkinson's disease, amyotrophic lateral sclerosis (ALS), or Huntington's disease because the tablets do not dissolve in the stomach, thus minimizing gastrointestinal discomfort associated with nausea and vomiting in some cases, especially in patients starting defericon. Equally important, the DR tablets of this disclosure are absorbed more slowly than IR tablets and other known defericon tablets, resulting in less nausea and vomiting (which can lead to gastrointestinal discomfort). However, the DR tablets of this disclosure are absorbed rapidly enough after reaching the duodenum to penetrate into the brain, thereby enabling defericon to exhibit its beneficial effects in Parkinson's disease, ALS, Huntington's disease, and other neurodegenerative diseases in which localized iron accumulation contributes to the pathology of the disease.

[0188] Parkinson's disease is a degenerative disorder of the central nervous system. The motor symptoms of Parkinson's disease originate from the death of dopamine-producing cells in the substantia nigra (a region of the midbrain). In the early stages of the disease, the most obvious symptoms are motor-related, such as swaying, rigidity, bradykinesia, and difficulty walking and gait. In later stages, thinking and behavioral problems can occur; dementia usually occurs in the later stages of the disease, while depression is the most common psychiatric symptom. Other symptoms include sensory, sleep, and mood problems. Parkinson's disease is more common in older adults, with most cases occurring after age 50.

[0189] The pathological features of Parkinson's disease include the accumulation of a protein called α-synuclein in inclusion bodies within neurons (called Lewis bodies), and insufficient formation and activity of dopamine in certain neurons within parts of the midbrain. The anatomical distribution of Lewis bodies is often directly related to the expression and severity of each individual's clinical symptoms. Diagnosis of typical cases is primarily based on symptoms, confirmed using tests such as neuroimaging.

[0190] Early motor symptoms of the disease are typically controlled with L-DOPA and dopamine agonists. As the disease progresses and dopaminergic neurons are continuously lost, these medications eventually become ineffective in treating symptoms, and complications known as motor disorders, characterized by involuntary twisting movements, may occur. Diet and exercise, as well as certain forms of rehabilitation, have shown some efficacy in alleviating symptoms. In severe cases where medication is ineffective, surgery and deep brain stimulation have been used as a last resort to reduce motor symptoms. Parkinson's disease is incurable.

[0191] Huntington's disease is a progressive brain disorder caused by a defective gene (HTT) on chromosome 4 that encodes a protein called huntingtin. This defect leads to an amplification of the CAG (cytosine-adenine-guanine) triplet repeat sequence in the gene encoding huntingtin, which damages cells in the brain. Diagnostic genetic tests for the defective huntingtin gene are available.

[0192] Symptoms of Huntington's disease typically develop between the ages of 30 and 50 and include uncontrolled movements of the arms, legs, head, face, and upper body. Huntington's disease also causes a decline in thinking and reasoning abilities, including memory, concentration, judgment, and the ability to plan and organize. Brain changes in Huntington's disease lead to obsessive thoughts and behaviors, as well as mood changes such as depression, anxiety, anger, and irritability.

[0193] Huntington's disease is incurable; treatment focuses on controlling its symptoms. For example, antipsychotics such as olanzapine are used to treat chorea (involuntary movements), while antipsychotics or selective serotonin reuptake inhibitors (SSRIs) are used to treat irritability, and SRIs are used to treat obsessive thoughts or behaviors.

[0194] Amyotrophic lateral sclerosis (ALS) is a disease that causes the death of neurons that control voluntary muscle movement. ALS is also known as Lou Gehrig's disease or motor neuron disease (MND). ALS is characterized by stiff muscles, muscle twitching, and progressive muscle weakness due to decreased muscle size. This leads to difficulty speaking, swallowing, and eventually breathing. The cause is unknown in 90-95% of ALS cases, while approximately 5-10% are genetically inherited. ALS diagnosis is based on a person's signs and symptoms, and tests are performed to rule out other potential causes.

[0195] ALS is incurable. Non-invasive ventilation can improve quality of life and lifespan. Riluzole (a sodium channel blocker) can delay the onset of ventilator dependence or tracheostomy and may extend survival by about 2-3 months. However, the average survival from onset to death is typically 2-4 years.

[0196] In some embodiments, the medical condition treated with the compositions disclosed herein (e.g., tablets, such as notched delayed-release deferiphenone tablets) is a neurodegenerative disease. In some embodiments, the neurodegenerative disease is Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, pantothenic acid kinase-associated neurodegeneration, or Friedreich's ataxia.

[0197] Therefore, certain embodiments of this disclosure relate to methods of treating neurodegenerative diseases using the compositions described herein. In some embodiments, the neurodegenerative disease is Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, Friedreich's ataxia, pantothenic acid kinase-associated neurodegeneration (PKAN), or neurodegeneration with iron accumulation in the brain (NBIA). Some embodiments relate to methods of mitigating or slowing the progression of ALS-related disability. In some embodiments, the subject is further administered riluzole. In some embodiments, deferiphenone is administered before, after, or simultaneously with the administration of riluzole to the subject. In some embodiments, the total daily dose of riluzole is from about 20 mg / day to about 500 mg / day.

[0198] 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 composition is administered using the dosing regimen described herein. In some embodiments, the composition is administered in a fasting or eating state.

[0199] Some aspects of this disclosure relate to a method for treating human subjects with iron overload, the method comprising orally administering deferiprone 3000 mg / day or 1200 mg / day to the subject in need, wherein deferiprone is administered twice daily. In some embodiments, the subject suffers from thalassemia or spinal dysplasia. In some embodiments, the subject suffers from a neurogenic disease. In some embodiments, deferiprone 3000 mg / day is administered twice daily at a dose of 1500 mg (e.g., one and a half 1000 mg DR tablets; or half a tablet of three 1000 mg DR tablets). In some embodiments, the subject exhibits a C4 level of 48.5–10.5 μg / mL at steady state. max In some implementations, the subject exhibits an AUC of 75-95 μg·h / mL at steady state. (0-24) In some embodiments, deferoxone is administered at a dose of 600 mg twice daily, totaling 1200 mg / day. In some embodiments, deferoxone is administered at a dose of 1200 mg once daily. In some embodiments, the subject, after administration of 600 mg deferoxone while in a fed state, exhibited a C4 level of 4.00 to 13.558 μg / mL. max In some embodiments, the subjects, after administration of 600 mg deferone in a fasting state, exhibited C values ​​ranging from 5.880 to 13.690 μg / mL. max In some embodiments, the subjects exhibited a T value of 1.333 to 8.000 hours after administration of 1200 mg deferoxone. maxIn some implementations, the subjects exhibited an AUC of 3.265 to 6.765 hours after administration of 1200 mg deferoxone. I / C max .

[0200] 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).

[0201] VIII. Bioavailability

[0202] For subjects administering the tablets disclosed herein, pharmacokinetic (PK) parameters (e.g., C60 ... max T max AUCT, AUCI, K el T 1 / 2 In some implementations, PK parameters are determined through single-dose studies. In other implementations, PK parameters are determined through multiple-dose or steady-state studies.

[0203] In some embodiments, when the tablets are administered as a whole tablet and when administered as a half tablet, the tablets disclosed herein provide a mean AUC between 3.5 hours and 6.0 hours in single-dose bioequivalence studies in both fasting and fed states. ∞ / C max ratio.

[0204] Although this application has been explained by description of its embodiments, and although the embodiments have been described in detail, the applicant does not intend to limit the scope of the appended claims to or in any way restrict it to such details. Other advantages and modifications will readily become apparent to those skilled in the art from this application. Therefore, in a broader sense, this application is not limited to the specific details, illustrative examples shown, or any devices mentioned. Deviations from such details, examples, and devices may be made without departing from the spirit or scope of the overall inventive concept. Example

[0205] The work of the present invention can be better understood from the following embodiments, which are intended to be exemplary and do not limit the scope of the invention.

[0206] Example 1: Preparation of enteric-coated delayed-release tablets

[0207] Table 1: Deferoxone Delayed-Release Tablets (1000mg and 600mg)

[0208]

[0209]

[0210] *Contains 30% solids.

[0211] **Evaporation during the coating process.

[0212] #Weight percentage of the methacrylic acid copolymer in the coating when the coating has dried.

[0213] To prepare the tablet core, deferiphenone, HPMCAS, magnesium oxide, and colloidal silica (part 1) were mixed together, and the mixture was compacted and ground into granules. Magnesium stearate and colloidal silica (part 2) were added to the granules and mixed, and the resulting mixture was pressed into a capsule-shaped mold to form a core tablet of approximately 1100 mg or approximately 660 mg in weight, which was then divided in half.

[0214] The enteric-coated suspension is sprayed onto deferiphenone-core tablets in a side-ventilated coating pan until the tablets exhibit a target weight increase of approximately 1.5% (for 1000 mg tablets) and 2.5% (for 600 mg tablets). The resulting delayed-release tablets are designed to have negligible dissolution in the stomach but rapid dissolution in the duodenum to prevent gastric upset. These properties apply to both whole and half tablets.

[0215] Example 2: Dissolution characteristics of delayed deferiphenone tablets (whole and half tablets)

[0216] The dissolution characteristics of the 1000 mg delayed-release deferone tablets prepared in Example 1 were tested in vitro using whole and half tablets.

[0217] Dissolution tests were performed at 75 rpm in USP device 2 in 900 mL of 0.1 N hydrochloric acid (HCl), 0.5 M pH 4.5 phosphate buffer, and 0.5 M pH 6.8 phosphate buffer. For both whole and half tablets, the 1000 mg tablets of Example 1 exhibited the following dissolution characteristics:

[0218] Dissolution in 0.1N HCl was less than 20% after 180 minutes. Figure 1 ].

[0219] At pH 6.8, dissolution was above 60% after 60 minutes. Figure 2 ].

[0220] At pH 4.5, dissolution was above 80% within 60 minutes. Figure 3 ].

[0221] Example 3: Comparison of dissolution rate of delayed-release tablets relative to enteric-coated deferiphenone tablets

[0222] The dissolution profiles of the whole and half delayed-release 1000 mg tablets prepared in Example 1 were compared with those of the whole and half enteric-coated (EC) tablets (Avicenna Lab, Iranian Patent Application No. 90-07-27-71996).

[0223] The EC tablets (Avicenna Lab) used for comparison consisted of a core tablet containing 500 mg deferiphenone, 290 mg microcrystalline cellulose, 1 mg colloidal silica, and 9 mg magnesium stearate (800 mg total core weight). The EC tablets (Avicenna Lab) also consisted of a coating containing 34.68 mg methacrylic acid copolymer, 15.56 mg talc, 3.61 mg PEG 6000, 4.38 mg titanium dioxide, 4.93 mg hydroxypropyl methylcellulose, 6 cm Poaz, and 0.82 mg sodium bicarbonate (63.98 mg total coating weight). The coating weight was approximately 7.4% of the total weight of the EC tablets.

[0224] Dissolution tests were performed for 180 minutes at 75 rpm using 900 mL of 0.1 N HCl in a USP device II. Samples were collected every 5 minutes to characterize the dissolution profile of the tablets.

[0225] In summary, the whole and half delayed-release deferiphenone tablets from Example 1 exhibited less than 20% dissolution in 0.1N HCl (representing the pH of the stomach) at 60, 90, 120, 150, and 180 minutes. For the whole EC tablet (Avicenna Lab), no dissolution was observed in 0.1N HCl, but rapid and complete dissolution was observed in buffer solutions: 95% dissolution in pH 4.5 solution at 30 minutes; 94% dissolution in pH 6.0 solution at 30 minutes; and 88% dissolution in pH 6.8 solution at 30 minutes. However, the half EC tablet (Avicenna Lab) dissolved rapidly, thus losing its enteric coating properties.

[0226] Therefore, the delayed-release formulation of Example 1 exhibits advantages over other enteric-coated deferone tablets. Specifically, the 1000 mg delayed-release tablet of Example 1 exhibits delayed release in an environment representing gastric acid pH, but possesses properties exceeding those provided by enteric coating. Specifically, the novel delayed-release tablet of the present invention imparts a dissolution rate similar to half-tablets and whole tablets, independent of the pH of the dissolution medium. That is, the delayed-release tablet possesses some of the properties of enteric-coated tablets without their disadvantages, so the tablet can be divided in half to allow for fine-tuning of the dosage by administering half a tablet.

[0227] Examples 4-5: 24-hour bioequivalence study

[0228] Examples 4-5 relate to bioequivalence studies in human subjects, using the 1000 mg deferone delayed-release tablets from Example 1 and tablet.

[0229] The first study (Example 4) was a single-dose study that showed a delay in the absorption of DR tablets, but no increase in the terminal half-life, and also showed that half tablets had a similar rate and extent of absorption as whole tablets, regardless of whether they were administered with food.

[0230] The second study (Example 5) was a multi-dose study of equivalent daily doses of DR and IR tablets. This study demonstrated that, at steady state, DR tablets are bioequivalent to IR tablets.

[0231] Example 4: Deferoxone delayed-release tablets under fasting and feeding conditions versus under feeding conditions in healthy volunteers Single-dose pharmacokinetic studies of immediately released tablets

[0232] This is a randomized, single-dose, open-label, 4-cycle, 4-sequence crossover study in healthy male and female volunteers. Subjects were randomly assigned to receive a single dose of the following treatments in different sequences, with a 7-day clearance period between drug administrations:

[0233] One complete 1000mg deferone DR tablet (n=23) under fasting conditions;

[0234] One whole 1000mg deferoxone DR tablet (n=21) under oral conditions;

[0235] Two half tablets of deferiphenone DR (total 1000 mg) (n=26) under dietary conditions; and

[0236] Two under feeding conditions The formulation consists of 500mg tablets (n=24).

[0237] The aim of this study was to evaluate the effect of food on the pharmacokinetic (PK) curves of a single dose of deferone DR, comparing the PK curves of half-tablets and whole tablets, and comparing deferone DR with... The p-p ...

[0238] The main pharmacokinetic parameters of this study are shown in Table 2, and the relative bioavailability is shown in Table 3. Under feeding conditions, the DR formulation (3.00 hours) reached the maximum serum concentration of deferiphenone (C0.00) compared to the IR formulation (1.33 hours). max ) time (T) max (Longer.) DR formulations have a longer C max C for IR formulationsmax Approximately 65% ​​of the drug was absorbed by both formulations. Serum drug levels decreased at similar rates after absorption, with a half-life of approximately 1.8 hours. Furthermore, there was no significant difference in drug exposure limits (AUC) between the two formulations.

[0239] When DR tablets are administered as half a tablet, C max Both AUC and CUC showed no significant difference from the whole tablet value. Regarding the effect of food, the bioavailability of the DR formulation was the same regardless of whether it was administered under fasting or feeding conditions. Since the total dose of DR and IR tablets is the same, the CUC of the IR tablet is expected to be... max It will be higher. However, these results confirm that the deferiphenone content in DR tablets can be increased by 50% to achieve the same C10 concentration as IR tablets. max .

[0240] For each subject of the pharmacokinetic study, the AUC was calculated. 0-inf With C max The ratios (Table 4) were used to transform the resulting ratios by determining the natural logarithm of the ratios. The mean of the log-transformed ratios for the subjects in the study was calculated, and then the mean log value was inversely converted to a normal scale by determining the inverse logarithm of the mean.

[0241] Table 2: Summary of Pharmacokinetic Parameters

[0242]

[0243] Table 3: Relative bioavailability of deferone delayed-release tablets

[0244]

[0245] Table 4: AUCI / C max

[0246]

[0247] Example 5: Steady-state comparative bioavailability study of delayed-release (DR) tablets versus immediate-release (IR) tablets in healthy volunteers.

[0248] A two-phase crossover study was conducted in 35 healthy volunteers to evaluate the effects of 1000 mg deferoxone DR tablets (as shown in Example 1) and deferoxone at steady state. Comparative bioavailability of IR tablets. Subjects were randomly assigned to receive either of the following two treatments, with a clearance period 5 days apart:

[0249] Treatment A: Deferoxone DR, 1500 mg every 12 hours (one and a half 1000 mg tablets) (total 3000 mg / day), for 3 days, administered with food; and

[0250] Treatment B: 1000 mg (two 500 mg tablets) every 8 hours (TID) (total 3000 mg / day) for 3 days, administered with food.

[0251] Following appropriate screening and baseline testing, subjects were given deferiprone via appropriate BID or TID on days 1–3. After the clearance period, they returned to the field on the evening of day 8 and received further treatment on days 9–11, with a check-up on the morning of day 12.

[0252] For each phase, blood samples were collected on the first day before the first dose for pharmacokinetic (PK) assessment during the first two days of administration (days 1-2 and 9-10), and then blood samples were collected at designated time points after administration during the 24-hour period on the third day (days 3 and 11).

[0253] Deferoxone DR and The comparison between them (i.e., for each treatment, data from the 0-24 hour interval on the third day).

[0254] AUC 0-24hr-ss C max-ss C min-ss C 24-ss T max-ss The statistical analysis was based on the ANOVA model. Two-sided 90% confidence intervals were calculated for the differences between treatments for each parameter. Prior to ANOVA, AUC was analyzed. 0-24hr-ss C max-ss C min-ss and C 24-ss The data undergoes a logarithmic transformation.

[0255] Through AUC 0-24hr-ss and C max-ss The 90% confidence interval establishes the standard for bioequivalence at steady state, which needs to be within the range of 80-125%.

[0256] Tables 5 and 6 and Figure 4 This study summarizes the findings of the DR deferoxone tablet BID and IR tablet TID studies in subjects under steady-state conditions.

[0257] Table 5: PK results of deferoxone DR tablet BID and IR tablet TID in subjects under steady state.

[0258]

[0259] a One and a half 1000mg tablets twice daily (every 12 hours), for a total of 3000mg / day, for 3 consecutive days.

[0260] b Two 500mg tablets three times a day (tid, every 8 hours), for a total of 3000mg / day, for 3 consecutive days.

[0261] c The median (range) is presented. T is calculated from the first dose of the day. max .

[0262] Table 6: Comparison of steady-state bioequivalence results of deferiphenone DR tablets (BID) and IR tablets (TID)

[0263]

[0264] The results confirmed that, over a 24-hour period, DR tablets, when administered twice daily, achieved the same peak concentration (C0) as IR tablets, administered three times daily. max Furthermore, when the total daily dose is the same, the total amount absorbed (AUC) of the two products over a 24-hour period is substantially the same.

[0265] Example 6: Bioavailability of deferiphenone delayed-release (DR) 600 mg tablets relative to oral solution in healthy volunteers

[0266] In this study, healthy subjects were randomly assigned to receive treatment in four different sequences, with a 7-day clearance period between treatments:

[0267] Treatment A: Deferoxone DR, 1200mg (two 600mg tablets) single dose, under eating conditions (n=18);

[0268] Treatment B: Deferoxetine DR, 1200mg (two 600mg tablets) single dose, under fasting conditions (n=17);

[0269] Treatment C: Deferoxone DR, 1200mg (four and a half tablets) single dose, under eating conditions (n=18); and

[0270] Treatment D: Oral solution ( A single dose of 1200 mg (100 mg / mL) was administered under fasting conditions (n ​​= 17).

[0271] Blood samples were collected before administration and within 24 hours after administration. PK parameters (C max and T max As shown in Table 7. AUCI and C max The ratios are shown in Table 8. These results indicate that the C of the 600 mg DR tablet is... max It is the C of the oral solution. max Approximately half the AUC1 / C of 600mg DR tabletsmax It is about twice the ratio of oral solutions.

[0272] Table 7.C max (μg / mL) and T max (Hour)

[0273]

[0274] Table 8. AUCI / C max

[0275]

[0276] Example 7: Preparation of enteric-coated delayed-release tablets

[0277] Table 9: 600mg deferone delayed-release tablets

[0278]

[0279] *Contains 30% solids.

[0280] **Evaporation during the coating process.

[0281] To prepare the tablet core, deferoxone, hydroxypropyl methylcellulose succinate (NF) AS-LF, light magnesium oxide USP / EP, and colloidal silica (part 1) were mixed together, and the mixture was compacted and ground into granules. Magnesium stearate and colloidal silica (part 2) were added to the granules and mixed. The resulting mixture was compressed into core tablets. The tablets were then coated.

[0282] In addition to the various embodiments described herein, this disclosure also includes the following embodiments numbered E1 through E132. This list of embodiments is presented as an exemplary list, and this application is not limited to these embodiments.

[0283] E1. Delayed-release tablets containing deferoxone for oral administration to human subjects, wherein twice-daily administration of the delayed-release tablets in steady state is bioequivalent to the same daily dose of an immediately-release tablet containing deferoxone administered three times daily.

[0284] E2. The tablet according to E1, wherein the tablet is a whole tablet with notches to facilitate breaking into half tablets.

[0285] E3. The tablet according to E2, wherein the half tablet is bioequivalent to the whole tablet in a fasting or eating state.

[0286] E4. According to E3, half a tablet is bioequivalent to a whole tablet in both fasting and eating states.

[0287] E5. A tablet according to any one of E1 to E4, wherein the tablet comprises: (a) a core containing a therapeutically effective amount of deferiphenone and (b) an enteric coating.

[0288] E6. The tablet according to E5, wherein the core further comprises an enteric polymer.

[0289] E7. The tablet according to E6, wherein the enteric polymer in the core is selected from hydroxypropyl methylcellulose (HPMC) succinate, HPMC phthalate, polyvinyl acetate phthalate, methacrylic acid copolymer, derivatives thereof, and combinations thereof.

[0290] E8. The tablet according to E7, wherein the enteric polymer is present in an amount of about 1% to about 20% of the weight of the core.

[0291] E9. A tablet according to any one of E1 to E8, wherein when said tablet is administered to a human subject, a single dose of said tablet provides a mean AUC between 3.5 hours and 6.0 hours in a fasting state. ∞ / C max ratio.

[0292] E10. A tablet according to any one of E1 to E8, wherein when said tablet is administered to a human subject, a single dose of said tablet provides a mean AUC between 3.5 hours and 6.0 hours in an oral state. ∞ / C max ratio.

[0293] E11. Tablets according to E9 or E10, wherein the tablet contains 1000 mg of deferoxone.

[0294] E12. Tablets according to E9 or E10, wherein the tablets contain 600 mg of deferoxone.

[0295] E13. The tablet according to E11, wherein when said tablet is administered to a human subject, the average C max It ranges from 2.670 to 13.232 μg / mL.

[0296] E14. The tablet according to E11, wherein when said tablet is administered to a human subject, the median T... max It is between 1.33 and 4.00 hours.

[0297] E15. The tablet according to E11, wherein when said tablet is administered to a human subject, the median T... max It is between 2.00 and 8.00 hours.

[0298] E16. The tablet according to E11, wherein when said tablet is administered to a human subject, the median T... max It is between 1.33 and 6.03 hours.

[0299] E17. A tablet according to E11, wherein when said tablet is administered to a human subject, AUCI / C max The ratio is between 2.858 and 6.596 hours.

[0300] E18. A tablet according to E11, wherein when said tablet is administered to a human subject, AUCI / C max The ratio is between 3.225 and 8.506 hours.

[0301] E19. A tablet for oral administration of an active pharmaceutical ingredient to a human subject, wherein the tablet comprises: (a) a core containing a therapeutically effective amount of the active pharmaceutical ingredient and an enteric polymer, and (b) an enteric coating, wherein the tablet has a notch that allows it to be administered as a whole tablet or a half tablet, and wherein if the tablet is administered as one or more half tablets, the half tablet is bioequivalent to the whole tablet in a fasting or feeding state.

[0302] Tablets of E20 and E19, wherein the enteric polymer in the core is selected from hydroxypropyl methylcellulose succinate (HPMCAS), HPMC phthalate, polyvinyl acetate phthalate, methacrylic acid copolymer, derivatives thereof, and combinations thereof.

[0303] E21.E20 tablets, wherein the enteric polymer is present in an amount of about 1% to about 20% of the weight of the core.

[0304] E22. A tablet according to any one of E19 to E21, wherein the active pharmaceutical ingredient is deferoxone.

[0305] E23. A tablet according to any one of E19 to E22, wherein the tablet is administered twice daily in a steady state and the tablet is administered three times daily for immediate release of deferone. The same daily dose of tablets is bioequivalent.

[0306] E24. A tablet according to any one of E19 to E23, wherein when said tablet is administered to a human subject, a single dose of said tablet provides a mean AUC between 3.5 hours and 6.0 hours in a fasting state. ∞ / C max ratio.

[0307] E25. A tablet according to any one of E19 to E23, wherein when said tablet is administered to a human subject, a single dose of said tablet provides a mean AUC between 3.5 hours and 6.0 hours in an oral state. ∞ / C max ratio.

[0308] E26. Tablets according to E24 or E25, wherein the tablets contain 1000 mg of deferoxone.

[0309] E27. Tablets according to E24 or E25, wherein the tablets contain 600 mg of deferoxone.

[0310] E28. The tablet according to E26, wherein when said tablet is administered to a human subject, the average C max It ranges from 2.670 to 13.232 μg / mL.

[0311] E29. The tablet according to E26, wherein when said tablet is administered to a human subject, the median T... max It is between 1.33 and 4.00 hours.

[0312] E30. The tablet according to E26, wherein when said tablet is administered to a human subject, the median T... max It is between 2.00 and 8.00 hours.

[0313] E31. The tablet according to E26, wherein when said tablet is administered to a human subject, the median T... max It is between 1.33 and 6.03 hours.

[0314] E32. The tablet according to E26, wherein when said tablet is administered to a human subject, AUCI / C max The ratio is between 2.858 and 6.596 hours.

[0315] E33. The tablet according to E26, wherein when said tablet is administered to a human subject, AUCI / C max The ratio is between 3.225 and 8.506 hours.

[0316] E34. A tablet for oral administration of an active pharmaceutical ingredient, comprising: (a) a core containing a therapeutically effective amount of the active pharmaceutical ingredient and an enteric polymer, and (b) an enteric coating, said tablet being a whole tablet having notches to facilitate the tablet breaking into half tablets, wherein the whole tablet and half tablets exhibit delayed-release dissolution profiles.

[0317] E35. A tablet according to E34, wherein a half tablet is bioequivalent to a whole tablet in a fasting or feeding state.

[0318] E36. The tablet according to E35, wherein the enteric polymer in the core is selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS), HPMC phthalate, polyvinyl acetate phthalate, methacrylic acid copolymer, derivatives thereof, and combinations thereof.

[0319] E37. The tablet according to E36, wherein the enteric polymer is present in an amount of about 1% to about 20% of the weight of the core.

[0320] E38. A tablet according to any one of E34 to E37, wherein the active pharmaceutical ingredient is deferoxone.

[0321] E39. Tablets according to any one of E34 to E38, wherein whole tablets and half tablets show less than 20% dissolution in 0.1N HCl at 60 minutes.

[0322] E40. A tablet according to any one of E34 to E39, wherein when said tablet is administered to a human subject, a single dose of said tablet provides a mean AUC between 3.5 hours and 6.0 hours in a fasting state. ∞ / C max ratio.

[0323] E41. A tablet according to any one of E34 to E39, wherein when said tablet is administered to a human subject, a single dose of said tablet provides a mean AUC between 3.5 hours and 6.0 hours in an oral state. ∞ / C max ratio.

[0324] E42. Tablets according to E40 or E41, wherein the tablets contain 1000 mg of deferoxone.

[0325] E43 refers to tablets based on E40 or E41, wherein the tablets contain 600 mg of deferoxone.

[0326] E44. A tablet according to E42, wherein when said tablet is administered to a human subject, the average C max It ranges from 2.670 to 13.232 μg / mL.

[0327] E45. A tablet according to E42, wherein when said tablet is administered to a human subject, the median T... max It is between 1.33 and 4.00 hours.

[0328] E46. The tablet according to E42, wherein when said tablet is administered to a human subject, the median T... max It is between 2.00 and 8.00 hours.

[0329] E47. A tablet according to E42, wherein when said tablet is administered to a human subject, the median T... max It is between 1.33 and 6.03 hours.

[0330] E48. A tablet according to E42, wherein when said tablet is administered to a human subject, AUCI / C max The ratio is between 2.858 and 6.596 hours.

[0331] E49. A tablet according to E42, wherein when said tablet is administered to a human subject, AUCI / C max The ratio is between 3.225 and 8.506 hours.

[0332] E50. A tablet for oral administration comprising: (a) a core containing a therapeutically effective amount of deferiphenone and an enteric polymer; and (b) an enteric coating containing the enteric polymer, wherein the tablet is suitable for administration twice daily.

[0333] E51.E50 tablets have notches to facilitate the tablet breaking into half.

[0334] E52 and E51 tablets can be administered as one or more whole tablets, one or more half tablets, or a combination thereof.

[0335] E53. A tablet according to any one of E50 to E52, wherein the enteric polymer in the core is selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS), HPMC phthalate, polyvinyl acetate phthalate, methacrylic acid copolymer, derivatives thereof, and combinations thereof.

[0336] E54. The tablet according to E53, wherein the enteric polymer is present in an amount of about 1% to about 20% of the weight of the core.

[0337] E55. A tablet according to any one of E50 to E54, wherein the enteric polymer in the enteric coating is selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS), HPMC phthalate, polyvinyl acetate phthalate, methacrylic acid copolymer, derivatives thereof, and combinations thereof.

[0338] E56. A tablet according to any one of E50 to E55, wherein the core further comprises an alkaline excipient and a flow aid.

[0339] E57. The tablet according to E56, wherein the basic excipient is selected from meglumine, metal oxides, metal hydroxides, base salts of weak acids, and combinations thereof.

[0340] E58. Tablets according to E56 or E57, wherein the flow aid is colloidal silica.

[0341] E59. A tablet according to any one of E56 to E58, further comprising a lubricant.

[0342] E60. The tablet according to E59, wherein the lubricant is selected from magnesium stearate, calcium stearate, stearic acid, sodium stearoyl fumarate, talc, and combinations thereof.

[0343] E61. A tablet according to any one of E54 to E60, wherein the enteric coating further comprises a plasticizer and an anti-adhesion agent.

[0344] E62. The tablet according to E61, wherein the plasticizer is selected from citrate, diethyl phthalate, polyethylene glycol, glycerol, acetylated glyceryl ester, acetylated citrate, dibutyl sebacate, castor oil, and combinations thereof.

[0345] E63. A tablet according to E61 or E62, wherein the tablet further comprises a diluent selected from sucrose, lactose, fructose, mannitol and combinations thereof.

[0346] E64. Tablets according to E61 or E62, wherein the anti-adhesion agent is talc.

[0347] E65. A tablet according to any one of E50 to E64, wherein when said tablet is administered to a human subject, a single dose of said tablet provides a mean AUC between 3.5 hours and 6.0 hours in a fasting state. ∞ / C max ratio.

[0348] E66. A tablet according to any one of E50 to E64, wherein when said tablet is administered to a human subject, a single dose of said tablet provides a mean AUC between 3.5 hours and 6.0 hours in an oral state. ∞ / C max ratio.

[0349] E67. Tablets according to E65 or E66, wherein the tablet contains 1000 mg of deferoxone.

[0350] E68. Tablets according to E65 or 66, wherein the tablet contains 600 mg of deferoxone.

[0351] E69. The tablet according to E67, wherein when said tablet is administered to a human subject, the average C max It ranges from 2.670 to 13.232 μg / mL.

[0352] E70. The tablet according to E67, wherein when said tablet is administered to a human subject, the median T... max It is between 1.33 and 4.00 hours.

[0353] E71. The tablet according to E67, wherein when said tablet is administered to a human subject, the median T... max It is between 2.00 and 8.00 hours.

[0354] E72. The tablet according to E67, wherein when said tablet is administered to a human subject, the median T... max It is between 1.33 and 6.03 hours.

[0355] E73. A tablet according to E67, wherein when said tablet is administered to a human subject, AUCI / C max The ratio is between 2.858 and 6.596 hours.

[0356] E74. A tablet according to E67, wherein when said tablet is administered to a human subject, AUCI / C max The ratio is between 3.225 and 8.506 hours.

[0357] E75. A tablet containing deferoxone for twice-daily oral administration, wherein a single dose of the tablet provides a mean AUC between 3.5 hours and 6.0 hours in both fasting and eating states when administered as a whole tablet and as half a tablet to a human subject. ∞ / C max ratio.

[0358] E76. The tablet according to E75, wherein the average AUC ∞ / C max The ratio is approximately 4.0 hours to approximately 5.5 hours.

[0359] E77. Tablets according to E75 or E76, wherein the active pharmaceutical ingredient or the deferiphenone is present in an amount of about 100 mg to about 1500 mg per tablet.

[0360] E78. A tablet according to any one of E75 to E77, wherein the total daily dose of said active pharmaceutical ingredient or said deferoxone is about 100 mg / day, about 200 mg / day, about 300 mg / day, about 400 mg / day, about 500 mg / day, about 600 mg / day, about 700 mg / day, about 800 mg / day, about 900 mg / day, about 1000 mg / day, about 1200 mg / day, about 1500 mg / day, about 1800 mg / day, about 2000 mg / day, about 2100 mg / day, or about 24 mg / day. 00mg / day, approximately 2500mg / day, approximately 2700mg / day, approximately 3000mg / day, approximately 3300mg / day, approximately 3500mg / day, approximately 4000mg / day, approximately 4500mg / day, approximately 5000mg / day, approximately 5500mg / day, approximately 6000mg / day, approximately 6500mg / day, approximately 7000mg / day, approximately 7500mg / day, approximately 8000mg / day, approximately 8500mg / day, approximately 9000mg / day, approximately 9500mg / day, or approximately 10,000mg / day.

[0361] E79. A tablet according to any one of E74 to E78, wherein the active pharmaceutical ingredient or the deferiphenone has 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.

[0362] E80. A tablet according to E79, comprising a core containing about 1000 mg or about 600 mg of deferiphenone, about 20 mg to about 80 mg of enteric polymer, and about 5 mg to about 100 mg of basic excipient.

[0363] E81. According to the E80 tablets, it further contains a lubricant in an amount of about 7 mg to about 20 mg.

[0364] E82. Tablets according to E80 or E81, comprising an enteric coating containing about 7 mg to about 20 mg of enteric polymer and about 0.5 mg to about 5 mg of plasticizer.

[0365] E83. A tablet according to E79, comprising a core containing about 600 mg of deferiphenone, about 20 mg to about 80 mg of enteric polymer and about 5 mg to about 100 mg of basic excipient.

[0366] E84. Tablets according to E83 further contain a lubricant in an amount of about 2 mg to about 10 mg.

[0367] E85. Tablets according to E83 or E84, comprising an enteric coating containing about 5 mg to about 20 mg of enteric polymer and about 0.5 mg to about 5 mg of plasticizer.

[0368] E86. A tablet according to any one of E75 to E85, wherein the tablet contains 1000 mg of deferoxone.

[0369] E87. A tablet according to any one of E75 to E85, wherein the tablet contains 600 mg of deferoxone.

[0370] E88. The tablet according to E86, wherein when said tablet is administered to a human subject, the average C max It ranges from 2.670 to 13.232 μg / mL.

[0371] E89. The tablet according to E86, wherein when said tablet is administered to a human subject, the median T... max It is between 1.33 and 4.00 hours.

[0372] E90. The tablet according to E86, wherein when said tablet is administered to a human subject, the median T... max It is between 2.00 and 8.00 hours.

[0373] E91. The tablet according to E86, wherein when said tablet is administered to a human subject, the median T... max It is between 1.33 and 6.03 hours.

[0374] E92. Tablets according to E86, wherein when said tablets are administered to a human subject, AUCI / C max The ratio is between 2.858 and 6.596 hours.

[0375] E93. Tablets according to E86, wherein when said tablets are administered to a human subject, AUCI / C max The ratio is between 3.225 and 8.506 hours.

[0376] E94. A tablet according to any one of E1 to E93, having notches to facilitate the tablet breaking into half tablets, and which may be administered to a human subject as one or more whole tablets, one or more half tablets, or any combination thereof.

[0377] E95. A tablet according to any one of E1 to E94, wherein, when measured by a USP device type II flat paddle method at 75 rpm in 900 mL of water at 37 ± 0.5 °C, the tablet releases less than about 80% of deferiphenone within 60 minutes.

[0378] E96. Tablets according to E95, wherein approximately 100% of deferone is released within approximately 90 minutes when measured at 75 rpm in 900 mL at pH 6.8 or 4.5 using a USP device type II flat paddle method.

[0379] E97. Tablets according to E96, wherein approximately 50% of deferone is released within approximately 30 minutes when measured at 75 rpm in 900 mL at pH 6.8 or 4.5 using a USP device type II flat paddle method.

[0380] E98. A method for treating a subject with iron overload, the method comprising orally administering a tablet of any one of E1 to E97 to the subject in need.

[0381] E99. According to the method of E98, wherein the subject suffers from thalassemia or spinal dysplasia.

[0382] E100. According to the method of E98, wherein the subject suffers from transfusion iron overload and his / her prior chelation therapy is inadequate.

[0383] E101. According to the method of E98, wherein the subject suffered transfusion iron overload and had cardiac MRI T2* of 20 ms or less.

[0384] E102. A method for treating a subject with a neurodegenerative disease, the method comprising orally administering a tablet of any one of E1 to E97 to the subject in need.

[0385] Methods E103 and E102, wherein the subject suffers from Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, Friedreich's ataxia, pantothenic acid kinase-associated neurodegeneration (PKAN), or neurodegeneration with brain iron accumulation (NBIA).

[0386] E104. The method according to any one of E98 to E103, including a regimen of administration once daily or twice daily (BID).

[0387] E105. The method according to any one of E98 to E104, wherein the tablet is administered to the subject as one or more whole tablets, one or more half tablets, or a combination thereof.

[0388] E106. The method according to any one of E98 to E105, wherein the tablet is administered to the subject in a fasting or eating state.

[0389] E107. The method according to any one of E98 to E106, wherein the deferiphenone has an amount of about 100 mg to about 800 mg per tablet.

[0390] E108. The method according to any one of E98 to E107, wherein the deferiphenone has an amount of about 400 mg per tablet.

[0391] E109. According to the method of any one of E98 to E108, wherein the total daily dose of deferoxone is about 200 mg / day to about 2400 mg / day.

[0392] E110. According to the method of any one of E98 to E109, wherein the total daily dose of deferoxone is about 400 mg / day to about 1200 mg / day.

[0393] E111. The method according to any one of E98 to E110, wherein the tablet is administered once or twice daily.

[0394] E112. The method according to any one of E98 to E111, wherein 1, 2 or 3 tablets are administered once or twice daily.

[0395] E113. The method according to any one of E98 to E112, wherein 1, 2 or 3 tablets are administered once, twice or three times daily.

[0396] E113. The method according to any one of E103 to E112, wherein the subject suffers from amyotrophic lateral sclerosis (ALS).

[0397] E114. The method according to any one of E103 to E113, wherein the treatment reduces or slows the progression of ALS-related disability in the subject.

[0398] E115. The method according to E113 or E114 further includes administering riluzole to the subject.

[0399] E116. A method for treating a human subject with iron overload, the method comprising orally administering 3000 mg / day of deferoxone to the subject in need, wherein the deferoxone is administered to the subject twice daily.

[0400] E117. According to the method of E116, wherein the subject suffers from thalassemia or spinal dysplasia.

[0401] E118. According to the method of E116 or E117, deferoxone is administered twice daily at a dose of 1500 mg, totaling 3000 mg / day.

[0402] E119. The method according to any one of E116 to E118, wherein the subject exhibits a steady-state C0.5 of 48.5–10.5 μg / mL. max .

[0403] E120. The method according to any one of E116 to E119, wherein the subject exhibits an AUC of 75-95 μg·h / mL at steady state. (0-24) .

[0404] E121. The method according to any one of E98 to E120, wherein the subject is given a tablet of any one of E1 to E97.

[0405] E122. A method for treating a human subject with iron overload, the method comprising orally administering 1200 mg / day of deferoxone to the subject in need, wherein the deferoxone is administered to the subject twice daily.

[0406] E123. The method according to E122, wherein the subject suffers from a neurogenic disease.

[0407] E124. According to the method of E122 or E123, 1200 mg / day of deferoxone is administered twice daily at a dose of 600 mg.

[0408] E125. According to the method of either E122 or E124, wherein 1200 mg / day of deferoxone is administered once daily.

[0409] E126. According to the method of any one of E122 to E125, wherein after administration of 600 mg deferoxone in a fed state, the subject exhibited a C4 level of 4.00 to 13.558 μg / mL. max .

[0410] E127. According to the method of any one of E122 to E126, wherein after administration of 600 mg deferoxone in a fasting state, the subject exhibited a C saturation level of 5.880 to 13.690 μg / mL. max .

[0411] E128. According to the method of any one of E122 to E127, wherein the subject showed a T value of 1.333 to 8.000 hours after administration of 1200 mg deferoxone. max .

[0412] E129. According to the method of any one of E122 to E128, wherein the subject showed an AUCI / C of 3.265 to 6.765 hours after administration of 1200 mg deferoxone. max .

[0413] E130. The method according to any one of E122 to E129, wherein the subject suffers from transfusion iron overload and his / her prior chelation therapy is inadequate.

[0414] E131. The method according to any one of E122 to E129, wherein the subject suffers from transfusion iron overload and has cardiac MRI T2* of 20 ms or less.

[0415] E132. The method according to any one of E122 to E131, wherein the subject is given a tablet of any one of E1 to E97.

[0416] E133. A tablet for oral administration comprising: (a) a core containing 1000 mg or 600 mg deferiphenone, an enteric polymer, a pH adjuster, a flow aid, and a lubricant; and (b) an enteric coating containing a plasticizer, a diluent, an anti-adhesion agent, and an enteric polymer, wherein the tablet is suitable for administration twice daily, and the tablet is a whole tablet having notches to facilitate the tablet breaking into half tablets.

Claims

1. Use of tablets in the preparation of a medicament for treating iron overload in subjects suffering from thalassemia or sickle cell disease, including oral administration of the medicament to subjects in need, wherein the tablet comprises: (a) containing about 1000 (a) a core comprising 1% to 5% by weight of deferoxone and a core containing an enteric polymer, a pH adjuster, and a glidant; and (b) an enteric coating comprising a plasticizer, an anti-adhesion agent, and an enteric polymer, wherein the enteric polymer in the core is selected from hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, methacrylic acid copolymers, derivatives thereof, and combinations thereof, wherein the enteric polymer in the enteric coating is selected from hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, methacrylic acid copolymers, cellulose acetate, cellulose acetate-1,2,4-benzenetricarboxylic acid, shellac, zein, derivatives thereof, and combinations thereof, and the enteric coating is 0.5-2% of the total weight of the tablet, wherein approximately refers to ±10%.

2. The use according to claim 1, wherein the iron overload is transfusion iron overload.

3. The use according to claim 1, wherein the pH adjuster is selected from meglumine, metal oxides, metal hydroxides, base salts of weak acids, and combinations thereof.

4. The use according to claim 1, wherein the flow aid is colloidal silica.

5. The use according to claim 1, wherein the core further comprises a lubricant selected from magnesium stearate, calcium stearate, stearic acid, sodium stearoyl fumarate, talc, and combinations thereof.

6. The use according to claim 1, wherein the core comprises: (i) Approximately 1000 mg of deferoxone; (ii) 1% to 5% of the weight of the core enteric polymer; (iii) A pH adjuster in an amount of 2% to 8% of the core weight; (iv) A flow aid in an amount of 0.1% to 0.5% of the core weight; and (v) Lubricant in an amount of 0.5% to 2% of the core weight.

7. The use according to claim 1, wherein the plasticizer is diethyl phthalate, citrate, polyethylene glycol, glycerol, acetylated glyceryl ester, acetylated citrate, dibutyl sebacate, castor oil, or any combination thereof.

8. The use according to claim 1, wherein the core comprises: (i) Approximately 1000 mg of deferoxone; (ii) 1% to 5% of the weight of the core of hydroxypropyl methylcellulose succinate. (iii) Magnesium oxide; (iv) Colloidal silica; and (v) Magnesium stearate.

9. The use according to claim 1, wherein the core comprises: (i) Approximately 1000 mg of deferoxone; (ii) 1% to 5% of the weight of the core of hydroxypropyl methylcellulose succinate. (iii) Magnesium oxide in amounts of 2% to 8% of the core weight; (iv) Colloidal silica in an amount of 0.1% to 0.5% by weight of the core; and (v) Magnesium stearate in amounts of 0.5% to 2% of the core weight.

10. The use according to claim 9, wherein the enteric coating is about 1.5% of the total weight of the tablet, wherein "about" means ±10%.

11. The use according to claim 1, wherein the core comprises: (i) Approximately 1000 mg of deferoxone; (ii) 25 mg to 35 mg hydroxypropyl methylcellulose acetate succinate; (iii) 40 mg to 60 mg magnesium oxide; (iv) Approximately 5 mg of colloidal silica; and (v) 15 mg to 20 mg magnesium stearate, The "approximately" here refers to ±10%.

12. The use according to claim 1, wherein the total daily dose of deferiphenone is from 50 mg / kg to 100 mg / kg.

13. The use according to claim 1, wherein the tablet is scored to facilitate the tablet breaking into halves.

14. The use according to claim 13, wherein the drug is administered to the subject as one or more whole tablets, one or more half tablets, or a combination thereof.

Images