Amorphous solid dispersion of belinostat, process for preparing the amorphous solid dispersion of belinostat and pharmaceutical composition.

Abstract

This application relates to new belinostat formulations suitable for oral administration, their preparation process, the pharmaceutical compositions comprising said formulations, and their uses.

Description

"Amorphous solid dispersion of belinostat, process for preparing the amorphous solid dispersion of belinostat and pharmaceutical composition"

[001] The present invention relates to a new oral formulation for belinostat. Background of the Invention

[002] Belinostat is a histone deacetylase inhibitor (HDAC inhibitor) with a sulfonamide-hydroxymide structure. The chemical name of belinostat is: (2E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide. Its structural formula is as follows:

[003] Belinostat is marketed as Beleodaq®, a sterile, lyophilized yellow powder for injection containing 500 mg of belinostat as the active ingredient. Each vial also contains 1000 mg of L-Arginine, USP as an inactive ingredient. It is intended for intravenous administration after reconstitution with water: The powder is mixed with 9 mL of sterile water for injection, and the reconstituted solution is further diluted in 250 mL of sterile 0.9% sodium chloride injection solution before infusion. Beleodaq® is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). The recommended dose is 1000 mg / m² administered over minutes by intravenous infusion, once daily on days 1 to 5 of a 21-day cycle. Cycles may be repeated every 21 days until disease progression or unacceptable toxicity.

[004] Administration by injection is uncomfortable for patients and an oral form is generally preferred to facilitate patient adherence to Petition 870260066733, dated 06 / 07 / 2026, page 12 / 105 2 / 42 treatment.

[005] To allow for flexible dosing and combination regimens, an oral formulation (crystalline drug in capsules) of belinostat was developed and tested in clinical studies. Despite showing clinical promise, the use of belinostat powder capsules has been limited due to variability in exposure across the entire dose range of 250 mg to 2000 mg. Additionally, high variability in belinostat clearance was reported by Steele et al. (Cancer Chemother. Pharmacol. 2011, 67:1273-1279), who studied the pharmacokinetic and pharmacodynamic properties of belinostat administered orally as a crystalline powder in capsules at high doses of oral belinostat (up to 1000 mg / m2 BID (twice daily) for 5 consecutive days).

[006] This may be related to the poor physicochemical properties of belinostat, which exhibits low solubility in water (0.14 mg / mL). In addition, belinostat is also significantly metabolized (especially by glucuronidation by UGT1A1 enzymes), thus also inducing significant potential variability (Wang et al, PLoS One. 2013;8(1):e54522).

[007] By comparison, other clinically advanced hydroxamic acid-based HDAC inhibitors were initially developed as intravenous (IV) products, but they were later developed and marketed as oral solid dosage forms.

[008] Vorinostate is noteworthy: the

[009] Vorinostat exhibits poor solubility in water (0.19 Petition 870260066733, dated 06 / 07 / 2026, page 13 / 105 Vorinostat exhibits a bioavailability of 3 / 42 mg / mL, moderate permeability, and extensive first-pass metabolism reported in animal and human studies. The main metabolic pathways of vorinostat involve glucuronidation and hydrolysis, followed by β-oxidation. In a Phase I trial, an absolute oral bioavailability of 43% was reported.

[010] Vorinostate (Zolinza ®) is marketed as 100 mg capsules containing microcrystalline cellulose, croscaemellose sodium and magnesium stearate (Vorinostate package insert).

[011] Panobinostat lactate (Farydak®) is another hydroxamic-based HDAC inhibitor:

[012] Anhydrous panobinostat lactate is slightly soluble in water. The aqueous solubility of panobinostat lactate is pH dependent, with maximum solubility at pH 2 or 3 (approximately 5 mg / mL), low solubility at neutral pH (0.3 mg / mL at pH 6.8), and very low solubility at pH 7.6 (0.07 mg / mL). It is highly permeable but is extensively metabolized through reduction, hydrolysis, oxidation, and glucuronidation processes. The absolute oral bioavailability of Farydak® is approximately 21%.

[013] Panobinostat is marketed as 10, 15 and 20 mg capsules containing magnesium stearate, mannitol, microcrystalline cellulose and pregelatinized starch (Panobinostat package insert).

[014] Despite the fact that these molecules exhibit physicochemical and pharmacokinetic properties such as belinostat (solubility Petition 870260066733, dated 06 / 07 / 2026, page 14 / 105 4 / 42 weak, high metabolism and low to moderate oral bioavailability), they have been successfully marketed for oral administration using conventional solid dosage forms such as simple powder blends in capsules.

[015] Due to the specific variability in exposure and limited bioavailability observed for higher doses of crystalline belinostat in capsules, there is a need for a specific oral dosage form that will provide increased bioavailability and, consequently, increased potential therapeutic effect.

[016] To overcome this property of poor solubility of belinostat, which is a limiting factor for absorption, several solubilization strategies have been attempted. Among pH modification, cosolvent system, cyclodextrin complexation, in situ acidic or basic salts, and combinations of these techniques, in situ salting was suitable for obtaining an increase in the solubility of belinostat to a satisfactory level. However, the use of this approach is not pharmaceutically acceptable as an oral dosage form, due to the fact that the pH of the saturated solution is above 9. Furthermore, the poor chemical stability of belinostat in liquid solution above pH 8.5 was reported by Finn et al. (2016), The Discovery and Development of belinostat, in Successful Drug Discovery (eds. J. Fischer and W.E. Childers), Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, chapter 3.Early-stage preclinical formulations using a cosolvent showed improved exposure compared to the crystalline form, but they are also not pharmaceutically acceptable for repeated dosing due to the high amount of cosolvent.

[017] Therefore, it is very difficult to obtain an oral formulation of belinostat that is physically and chemically stable and also increases the oral dissolution and bioavailability of belinostat. But there is a need for an effective and stable delivery system that can provide clinically viable oral administration of belinostat. Thus, it was an object Petition 870260066733, dated 06 / 07 / 2026, page 15 / 105 5 / 42 of the present invention provides compositions comprising belinostat for oral administration, which compositions have advantageous characteristics with respect to solubility, bioavailability and / or stability. Brief Description of the Invention

[018] Surprisingly, it has been found that this object can be obtained by providing a solid dispersion comprising belinostate in amorphous form and at least one non-ionizable (neutral) non-cellulosic polymer, such as a polyvinyl lactam polymer.

[019] The challenge was to find a composition that would prevent recrystallization over time (good physical stability) and good chemical stability, since molecules in an amorphous state can be prone to instability during storage due to the higher mobility of molecules in the amorphous state. In addition to good stability in the solid state, the composition should also enhance the dissolution profile by inhibiting the crystallization of the supersaturated solution generated by the dissolution of the amorphous material.

[020] As described below, it has been surprisingly found that only a particular category of matrix compounds (polymers), especially non-ionizable (neutral) non-cellulosic polymers, leads to increased belinostate solubility, along with satisfactory physical and chemical stability, and increased bioavailability. Detailed Description

[021] According to a first object, the present invention provides an amorphous solid dispersion (ASD) of belinostate, comprising: a) Belinostat or a pharmaceutically acceptable salt, solvate or ester thereof; b) At least one non-ionizable (neutral) non-cellulosic polymer; and Petition 870260066733, dated 06 / 07 / 2026, page 16 / 105 6 / 42 c) Optionally, at least one additive.

[022] The term “solid dispersion” refers to a composition in a solid state, that is, a state that is neither liquid nor gaseous, in which belinostate is dispersed in at least one pharmaceutically acceptable polymer comprised in the solid dispersion. The term “solid dispersion,” as used in the present application, encompasses all known categories of solid dispersions, that is, mixtures, simple eutectics, solid solutions, such as continuous solid solutions, discontinuous solid solutions, substitutional crystalline solutions, interstitial crystalline solutions and amorphous solid solutions, glassy solutions and amorphous precipitations in crystalline carriers. According to the invention, the solid dispersion is an amorphous solid dispersion (ASD).

[023] As used in the present application, the term “amorphous solid dispersion” (ASD) refers to a drug dispersion in a solid polymer in an amorphous state. The term “amorphous solid dispersion” refers to solid dispersions comprising belinostat in a substantially amorphous solid form. Preferably, the amorphous particles of belinostat are dispersed in the polymer. The term “substantially amorphous solid form” is intended to mean that at least 80% by weight, typically at least 85% by weight, preferably at least 90% by weight, more preferably at least 95% by weight, even more preferably at least 96% by weight, even more preferably at least 97% by weight, more preferably at least 98% by weight, more preferably at least 99% by weight, more preferably at least 99.9% by weight, most preferably all belinostat, is present in the amorphous form.ASD consists of mixing the drug substance with a polymer to stabilize the amorphous drug.

[024] “Amorphous” refers to the non-crystalline state of a solid. Amorphous solids generally have short-range molecular arrangements. Petition 870260066733, dated 06 / 07 / 2026, page 17 / 105 7 / 42 similar to a crystal, that is, no long-range order of molecular packing found in crystalline solids. The solid-state form of a solid in solid dispersion can be determined by polarized light microscopy, powder X-ray diffraction, differential scanning calorimetry, or other techniques known to those skilled in the art. The amorphous state of belinostate in solid dispersion can be identified by a distinct broad powder X-ray diffraction pattern, whereas crystalline solids lead to specific isolated peaks. The amorphous state can exist in two states: a rubbery state and a glassy state, where one state converts to the other at the glass transition temperature (Tg).

[025] Belinostat and methods for synthesizing it are described in international patent application document WO 2002 / 30879. The amorphous solid dispersion may comprise any pharmaceutically acceptable form of belinostat, including, without limitation, its free form and its pharmaceutically acceptable salts, solvates or esters thereof.

[026] The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable, preferably non-toxic, bases or acids, including mineral or organic acids, or organic or inorganic bases. These salts are also known as acid addition salts and basic addition salts. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, “Pharmaceutically Acceptable Salts,” J. Pharm. Sci., Vol. 66, pages 1 to 19.

[027] The term “solvate” refers to a molecular complex comprising the drug substance and a stoichiometric or non-stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). The term “hydrate” refers to a solvate comprising the drug substance and a stoichiometric or non-stoichiometric amount of water. Petition 870260066733, dated 06 / 07 / 2026, p. 18 / 105 8 / 42

[028] Alternatively, belinostat can be used in a chemically protected form. The term “chemically protected form” refers to a form of compound in which one or more reactive functional groups are protected from undesirable chemical reactions, i.e., they are in the form of a protected or protecting group (also known as a masking or masking group). With respect to belinostat, a hydroxy group can be protected as an organic or inorganic ester, for example, an acetyl ester (-OC(=O)CH3, -OAc) or a phosphate ester.

[029] As used in the present application, “non-ionizable (neutral) non-cellulosic polymers” refers to vinyl polymers and copolymers having at least one substituent selected from the group consisting of hydroxyl, alkylacyloxy and cyclamide; polyvinyl alcohols having at least a portion of their repeating units in the non-hydrolyzed form (vinyl acetate); copolymers of polyvinyl acetate and polyvinyl alcohol, polyvinylpyrrolidone; polyoxyethylene-polyoxypropylene copolymers, also known as poloxamers; and copolymers of polyvinyl alcohol and polyethylene.

[030] According to one embodiment, “non-ionizable (neutral) non-cellulosic polymers” do not include “non-ionizable (neutral) cellulosic polymers, such as hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose (HPMC) also cited as hypromellose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate and hydroxyethyl ethyl cellulose; and at least partially ionizable cellulosic polymers at physiologically relevant pH, such as hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxyethyl cellulose acetate succinate methyl cellulose, hydroxyethyl methyl cellulose phthalate acetate, carboxyethyl cellulose, carboxymethyl cellulose, carboxymethyl ethyl cellulose, Petition 870260066733, dated 06 / 07 / 2026, page 19 / 1059 / 42 cellulose acetate phthalate (CAP), methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl cellulose acetate succinate phthalate, hydroxypropyl cellulose acetate succinate phthalate, hydroxypropyl cellulose acetate succinate phthalate, cellulose propionate phthalate, hydroxypropyl cellulose acetate butyrate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, cellulose propionate trimellitate, cellulose acetate butyrate trimellitate, cellulose acetate terephthalate, Cellulose acetate isophthalate, cellulose acetate pyridinedicarboxylate, cellulose salicylic acid acetate, hydroxypropyl cellulose salicylic acid acetate.cellulose ethylbenzoic acid acetate, hydroxypropyl cellulose ethylbenzoic acid acetate, ethyl cellulose phthalic acid acetate, ethyl cellulose nicotinic acid acetate and ethyl cellulose picolinic acid acetate.

[031] According to one embodiment, “non-ionizable (neutral) non-cellulosic polymers” do not include ionizable non-cellulosic polymers such as carboxylic acid-functionalized vinyl polymers, such as carboxylic acid-functionalized polymethacrylates and carboxylic acid-functionalized polyacrylates such as Eudragit® manufactured by Evonik; amino-functionalized polyacrylates and polymethacrylates; proteins such as gelatin and albumin; and carboxylic acid-functionalized starches such as starch glycolate.

[032] In a preferred embodiment, the non-ionizable (neutral) non-cellulosic polymer is a vinyl polymer or copolymer substituted with at least one cyclic amide (lactam) group as a substituent, also referred to as a “polyvinyl lactam polymer”. 1. According to one embodiment, the present invention provides an amorphous solid dispersion of belinostate, comprising: Petition 870260066733, dated 06 / 07 / 2026, p. 20 / 105 10 / 42 a) Belinostat or a pharmaceutically acceptable salt, solvate or ester thereof; b) At least one polyvinyl lactam polymer; and c) Optionally, at least one additive.

[033] Preferred polyvinyl lactam polymers refer to polymers and copolymers comprising the following subunits: / (Wm < >° N '' / (I)

[034] Where m is an integer chosen from 1, 2, 3 or 4 (β-, γ- and δ- or ε-lactam) en represents the number of repeating lactam units in the given subunit, which can be between n = 20 and en = 30000.

[035] According to one embodiment, said polymer is soluble in water. According to one embodiment, said polymer is a linear chain polymer.

[036] “Linear chain polymer”, as used in the present application, refers to a straight chain polymer consisting of a long ribbon of repeating units that are joined end-to-end as linkages along said chain.

[037] When in formula (I), m is 2 and the polymer consists of (I) subunits, the said polyvinyl lactam polymer is povidone. Povidone may also be called polyvidone, povidonum, PVP or poly(1-vinyl-2-pyrrolidone). Commercially available povidones are generally pharmaceutical grade products with different nominal K values ​​that characterize their molecular weight, including: Petition 870260066733, dated 06 / 07 / 2026, page 21 / 105 11 / 42

[038] Povidone K12 (Kollidon® 12PF manufactured by BASF), Povidone K17 (Kollidon® 17PF manufactured by BASF; Plasdone® C-15 manufactured by ISP), Povidone K25 (Kollidon® 25 manufactured by BASF; Plasdone® K-25 manufactured by ISP), Povidone K30 (Kollidon® 30 manufactured by BASF, Plasdone® K-29 / 32 manufactured by ISP), Povidone K30 with low peroxide grade (Kollidon® 30 LP), Povidone K90 (Kollidon® 90F manufactured by BASF; Plasdone® K-90, K-90 D and K-90M manufactured by ISP).

[039] Polyvinyl lactam polymers according to the invention also include copolymers comprising subunit (I) above. In particular, they include copolymers comprising subunits (I) where m = 2, and polyethylene acetate subunits of formula:

[040] These copolymers are called copovidone. Copovidone is a water-soluble copolymer with a chain structure made of 6 parts vinylpyrrolidone and 4 parts vinyl acetate. Commercially available copovidones include Kollidon® VA64 (manufactured by BASF), Plasdone® S-630 (manufactured by ISP). Copovidone is also referred to as copovidonum, copolividone, or PCV-VAc copolymer (polyvinylpyrrolidone excipients for pharmaceuticals Bühler et al / 2005, Springer Verlag).

[041] The polyvinyl lactam polymers of the invention also include the polymers and copolymers comprising the subunits (I), where m = 4), (ie), including caprolactam rings.

[042] In particular, they include Soluplus® copolymers such as polyvinyl caprolactam-polyvinyl acetate graft copolymer Petition 870260066733, dated 06 / 07 / 2026, page 22 / 105 12 / 42 polyethylene glycol, also known as PCL-PVAc-PEG (manufactured by BASF) with the formula:

[043] It should also be noted that the crosslinked polymers of formula (I) where m = 2 are called crospovidone or insoluble polyvinylpyrrolidone (Bühler et al., above) and that they are therefore not encompassed by the linear and / or water-soluble polyvinyl lactam polymers of the invention.

[044] According to a particular embodiment, said polyvinyl lactam polymer is selected from chain polymers and copolymers comprising the following subunits: (II)

[045] Where n is defined as in formula (I).

[046] Exemplary polymers of formula (I) are detailed below: Table 1 Status Name Synonym Functional Structure Glass Transition Temperature Tg Exemplified Excipients PVP K30 Polyvinylpyrrolidone, Povidone (K value 30), PVP 29-32 MW-50 000 g / mol Neutral Water-soluble (non-cellulosic) Tg 156°C to 163°C Petition 870260066733, dated 06 / 07 / 2026, page 23 / 105 13 / 42 Status Name Synonym Functional structure Glass transition temperature Tg PVP n PVP VA64 Copovidone, Vinylpyrrolidone-vinyl acetate copolymer MW~45 nnn n / mnl Neutral water-soluble (non-cellulosic) Tg 101 °C UH; Ltl PVF XW Ml 1 o 1 c=o 1 CHj à Y PVP K12 Polyvinylpyrrolidone, Povidone (K value 12), MW 2000 to 2500 g / mol Neutral water-soluble (non-cellulosic) Tg 101 °C PVP K90 Polyvinylpyrrolidone, Povidone (K value 90), MW~1 250 000 K g / mol Neutral water-soluble (non-cellulosic) Tg 177°C Suitable potential excipients to enhance amorphous spray dry dispersion PVP K17 Polyvinylpyrrolidone, Povidone (K value 17), MW 9000 to 10 000 g / mol Neutral water-soluble (non-cellulosic) Tg 136°C PVP K25 Polyvinylpyrrolidone, Povidone (K value 25), MW25,000 to 30,000 g / mol Neutral, water-soluble (non-cellulosic) Tg 152°C Soluplus® HO n\ o JmL 7 0 t HO Polyvinyl caprolactam-polyvinyl acetate graft copolymer Neutral, water-soluble (non-cellulosic) Tg 70°C Petition 870260066733, dated 06 / 07 / 2026, p. 24 / 105 14 / 42 Status Name Synonym Functional Structure Glass Transition Temperature Tg polyethylene glycol, PEG 6000 / vinylcaprolactam / vinyl acetate 13 / 57 / 30 MW ~ 118,000 g / mol

[047] In particular, polyvinyl lactam polymers are chosen from povidone polymers and copovidone copolymers, in particular: Soluplus®, PVP such as PVP K30, PVP K12, PVP K17, PVP K25, PVP K90 and PVP VA64; and any of their mixtures, such as 20 / 80, 30 / 70, 40 / 60, 50 / 50, 60 / 40, 70 / 30 or 80 / 20 mixture of MSRP K30 / MSRP VA64, MSRP K30 / Soluplus, MSRP K30 / MSRP K90.

[048] More particularly, polyvinyl lactam polymers are chosen from PVP K30, PVP K12 and PVP VA64, and mixtures thereof; particularly PVP K30 and PVP VA64 and mixtures thereof.

[049] In one embodiment, the non-ionizable (neutral) non-cellulosic polymer is a polyvinyl alcohol (PVA) polymer.

[050] In one particular embodiment, the PVA polymer is polyvinyl alcohol. In another embodiment, the PVA polymer is the polyvinyl alcohol-polyethylene glycol graft copolymer called Kollicoat® IR. The Kollicoat® IR polymer consists of approximately 75% polyvinyl alcohol units and approximately 25% polyethylene glycol units.

[051] According to one embodiment, the amorphous solid dispersion of belinostate may also comprise at least one additive.

[052] According to one embodiment, said additive may be chosen from usual excipients that are commonly used in oral formulations and / or in solid dispersions. Suitable additives include, in particular, antioxidants, dispersing agents, pH modifiers, stabilizers, solubilizers, disintegrants or any mixture thereof. Petition 870260066733, dated 06 / 07 / 2026, page 25 / 105 15 / 42

[053] pH modifiers such as acids, bases or buffers can be useful for reducing hydrolysis and / or chemical degradation, but they can also modify the rate of dissolution; they include, in particular, KOH, NaOH, CaCO3, L-arginine, meglumine, sodium carbonate, sodium bicarbonate, citric acid or succinic acid, etc.

[054] Antioxidants include, in particular, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium metabisulfite (SMB), propyl gallate (PG), ascorbyl palmitate, dihydroxybenzoic acid, cysteine, ascorbic acid, alpha-tocopherol (Vit-E), etc.

[055] Suitable solubilizers are additives that can enhance the in vitro dissolution profile (higher degree of saturation) and wettability, but can also inhibit crystallization. Solubilizers can be anionic, cationic, amphoteric, or non-ionic surfactants. They include, in particular, polysorbate (e.g., Tween 80), sodium lauryl sulfate (SLS), lauroyl plyoxyl-32 glycerides (Gelucire 44 / 14), D-atocopheryl polyethylene glycol 1000 succinate (TPGS), poloxamers (e.g., Pluronic F127). Solubilizers may also include cyclodextrins such as sulfobutyl ether beta cyclodextrin or hydroxyl propyl beta cyclodextrin.

[056] Stabilizers are additives that can enhance chemical and / or physical stability. Stabilizers include, in particular, amino acids (e.g., L-histidine, L-lysine, L-leucine, L-arginine, glycine, phenylalanine, tryptophan, and tyrosine) or sugars (e.g., sorbitol, glycerol, mannitol, xylitol, sucrose, trehalose).

[057] When these additives are included as part of the dispersion itself, they can comprise up to 25% of the dispersion.

[058] According to one embodiment, the amorphous solid dispersion may comprise: - about 5 to 80% (weight) of belinostat; and Petition 870260066733, dated 06 / 07 / 2026, page 26 / 105 16 / 42 - approximately 20 to 95% (by weight) of said non-cellulosic polymer, non-ionizable as a polyvinyl lactam polymer;

[059] particularly about 15 to 50% of belinostate (by weight) and about 50 to 85% (by weight) of said non-ionizable non-cellulosic polymer, such as a polyvinyl lactam polymer.

[060] The amorphous solid dispersion is physically stable, as belinostat can maintain its substantially amorphous form in the formulation through storage for at least 2 years. To reduce the risk of recrystallization and ensure long-term stability, belinostat ASDs of the inventions can also be stored in water vapor, protective packaging to prevent water absorption into the dispersion.

[061] The amorphous solid dispersions of the invention have also been found to be chemically stable.

[062] It was also discovered that due to its hydroxamide group, belinostat in solution, as well as belinostat in the amorphous state, is very sensitive to hydrolysis and chemical degradation, like other hydroxamic acids based on HDAC inhibitors. In the amorphous state, the main impurities of belinostat are belinostat acid and belinostat dimer.

[063] Belinostat acid ((E)-3-[3-(phenylsulfamoyl)phenyl]prop-2-enoic acid) has the formula:

[064] It is an intermediate in the synthesis of the drug substance belinostat, a degradation product of belinostat via hydrolysis of the hydroxamic acid function and a metabolite (Finn et al. 2016).

[065] Belinostat dimer ((E)-3-(3-(N-Phenylsulfamoyl)phenyl)-NPetition 870260066733, of 07 / 06 / 2026, page 27 / 105 17 / 42 (((E)-3-(3-(N-phenylsulfamoyl)-phenyl)acryloyl)oxy)acrylamide) has the formula:

[066] It is formed by the degradation of belinostat, by loss of hydroxylamine. It is also a synthetic impurity during the synthesis of the drug substance belinostat that is removed during the manufacturing process by a recrystallization step.

[067] When solid dispersions are prepared using ionizable or neutral cellulosic polymers or ionizable non-cellulosic polymers, significant chemical degradation into belinostat acid or belinostat dimer can be observed during storage.

[068] Surprisingly, when neutral non-cellulosic polymers such as polyvinylactam are used, the resulting amorphous solid dispersion of the invention is chemically stable, since the degradation of belinostate into its two main impurities in the amorphous solid dispersion formulation is kept within the following upper limits: Less than 0.2% of belinostat acid and / or belinostat dimer, as determined by a release test; and / or Less than 2% of belinostat acid and / or belinostat dimer through storage for at least 18 months, preferably at least 24 months, with the highest preference at least 36 months, during storage under ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) conditions.

[069] The amorphous solid dispersions of the invention provide improved solubility and dissolution characteristics, compared to the crystalline drug when tested in vitro dissolution assays. Petition 870260066733, dated 06 / 07 / 2026, page 28 / 105 18 / 42

[070] In some embodiments, compositions when tested in vitro at a 5-fold supersaturation level exhibit an increase in the solubility of belinostat at 90 min at least 1.5 times greater compared to the undispersed crystalline drug tested under the same conditions, typically at least 2 times or even at least 2.5 times greater. Given the extremely low aqueous solubility of belinostat, this improvement in solubility with the use of dispersions of the invention is also quite surprising.

[071] Within the scope of the invention, amorphous solid dispersions, which exhibit enhanced in vitro dissolution properties, also significantly improved plasma exposure and in vivo bioavailability.

[072] When tested in vivo, a composition within the scope of the invention exhibits either a Cmax or an AUC at least 1.25 times higher than the corresponding Cmax or AUC exhibited by a composition comprising an equivalent amount of undispersed crystalline drug. Preferably, the Cmax or AUC is at least 1.5 times higher, more preferably 2 times higher.

[073] It can also be said that these compositions have a relative bioavailability of at least about 1.25, compared to the undispersed crystalline drug, typically up to at least 2 times.

[074] According to a second object, the present invention also relates to the process of preparing the amorphous solid dispersion of the invention.

[075] Amorphous solid dispersion can be prepared by any methods known in the art, including spray drying, hot melt extrusion (HME) and precipitation from solution with the addition of a non-solvent. The preferred method is the spray drying method. Petition 870260066733, dated 06 / 07 / 2026, page 29 / 105 19 / 42

[076] According to one embodiment, the said process comprises the following steps: - Prepare a solution of belinostate and said non-ionizable non-cellulosic polymer, such as polyvinyl lactam polymer in a solvent, optionally with said optional additives; and - Dry the said solution by spraying.

[077] Spray drying is a generally well-known method in the art and typically involves transforming a solution into a dry form by spraying the solution into a hot drying medium. The spray-dried product is typically in the form of a powder consisting of single particles or agglomerates, depending on the physical and chemical properties of the formulation and the design and operation of the dryer. The basic technique generally includes the following four steps: a) atomization of the solution into a spray; b) contact with the spray gas; c) drying of the spray; d) separation of the dry product from the drying gas.

[078] Spray drying generally involves atomizing a solution (raw material) into a spray of droplets, and bringing the droplets into contact with hot gas in a drying chamber. The droplets can be produced, for example, with atomizing nozzles. The evaporation of moisture from the produced droplets and the formation of dry particles can proceed under controlled temperature and gas flow conditions. When the droplets are small enough and the chamber is large enough, the droplets generally dry before they reach the chamber wall. The resulting product is collected as a free-flowing material. The powder can be continuously discharged from the drying chamber. Operating conditions and the design of the spray dryer are generally selected according to the drying characteristics of the product and the powder specification. Petition 870260066733, dated 06 / 07 / 2026, page 30 / 105 20 / 42

[079] Spray dryers generally include a feedstock pump, an atomizer, a gas heater, a gas disperser, a drying chamber, and systems for exhaust gas cleaning and dust recovery. An example of a spray drying system includes drying gas introduced into a pre-filter. In one aspect, the drying gas is nitrogen, and the presence of oxygen is avoided. The drying gas then passes through a fan and a heater, which may be an electric heater. The drying gas then passes through an inlet gas temperature gauge that monitors the inlet gas temperature before being introduced into a drying chamber via a gas dispenser in the ceiling. Redundant filtration may be employed to ensure product quality.

[080] The solvent is usually chosen from organic solvents that can solubilize both belinostate and the non-ionizable non-cellulosic polymer, such as polyvinyl lactam polymer. Suitable solvents include methanol, acetone, chloroform, ethanol, dichloromethane, water.

[081] Solutions are usually prepared at 5 to 50% solid weight.

[082] According to an alternative embodiment, the said process comprises the following steps: - Mixing belinostate and said non-ionizable non-cellulosic polymer, such as polyvinyl lactam polymer, possibly with optional additives; and - Extruding the mixture using a temperature-controlled extruder.

[083] According to any of the embodiments of the process, the amounts of belinostate and polymer are generally used in their respective ratios, as desired in the amorphous solid dispersion discussed above. Petition 870260066733, dated 06 / 07 / 2026, page 31 / 105 21 / 42

[084] The amorphous solid dispersion of the invention is suitable for oral administration of belinostat.

[085] According to a third object, the present invention therefore relates to a pharmaceutical composition comprising the amorphous solid dispersion of belinostat of the invention, optionally with one or more pharmaceutically acceptable excipients.

[086] The compositions can be conveniently prepared by any of the methods well known in pharmaceutical technique, for example, as described in Remington: The Science and Practice of Pharmacy, 20th ed.; Gennaro, AR, Ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2000.

[087] Formulations that are suitable for oral administration to a patient include distinct units such as capsules, soft or hard galatin capsules, tablets, each containing a predetermined amount of belinostat and / or the amorphous solid dispersion of belinostat. They also include powders or granules; multiparticulates, suspensions in an aqueous liquid or a non-aqueous liquid. Pharmaceutical compositions may optionally be coated.

[088] “Pharmaceutically” or “pharmaceutically acceptable” refers to molecular entities and compositions that do not produce an adverse, allergic or other undesirable reaction when administered to an animal, or a human, as appropriate.

[089] As used in the present application, “pharmaceutically acceptable excipient” includes, in particular, diluents, adjuvants, carriers or vehicles. The use of these ingredients for pharmaceutical active substances is well known in the art.

[090] The amorphous solid dispersion of belinostat can be administered in unit dose forms, wherein the term “dosage” Petition 870260066733, dated 06 / 07 / 2026, page 32 / 105 "22 / 42 unitary" means a single dose that can be administered to a patient and is easy to handle and package.

[091] The daily dose according to the invention can be obtained by administering half of a unit dosage form, a single unit dosage, or two or more unit dosage forms, according to the commercially available unit dosage form, the daily dose to be administered, and the frequency of administration prescribed by the physician.

[092] According to another object, the present invention also relates to the amorphous solid dispersion of belinostat of the invention for use in the treatment and / or prevention of cancer.

[093] As used in the present application, “cancer” refers to various forms of cancer, including tumors or leukemia. Cancers of the breast, prostate, lung, colon, bladder, brain, stomach, kidney, liver, ovary, mouth, skin, intestine, uterus, head and neck, throat, hematopoietic and lymphoid tissues, and blood are encompassed in the present application. Lymphoma, that is, cancer of blood cells, including Hodgkin lymphomas, non-Hodgkin lymphomas, and multiple myeloma, is particularly targeted, and more particularly relapsed or refractory peripheral T-cell lymphoma (PTCL).

[094] Identifying those subjects who are in need of treatment for the diseases and conditions described in this application is well within the capacity and knowledge of a person skilled in the art. A medical person skilled in the art can easily identify, through the use of clinical tests, physical examination, genetic testing, and medical / family history, those subjects who are in need of such treatment.

[095] Current dosage levels of the belinostat solid dispersion of the invention can be varied in order to obtain an amount of active ingredient that is effective in achieving a desired therapeutic response for a particular composition and method of administration. The dosage level Petition 870260066733, dated 06 / 07 / 2026, page 33 / 105 The 23 / 42 dose selected therefore depends on the desired therapeutic effect, the route of administration, the desired duration of treatment, and other factors, for example, the patient's condition.

[096] A therapeutically effective amount can be easily determined by the physician's diagnosis, as a technician in the subject, by using conventional techniques and observing the results obtained under analogous circumstances. In determining the therapeutically effective amount, a number of factors are considered by the physician's diagnosis, including, but not limited to: the species of subject; their size, age, and general state of health; the specific disease involved; the degree of involvement or severity of the disease; the individual response of the subject; the particular compound administered; the mode of administration; the characteristic bioavailability of the administered preparation; the selected dosage regimen; the use of concomitant medication; and other relevant circumstances.

[097] The amount of amorphous solid dispersion required to achieve the desired biological effect will vary depending on a number of factors, including the dose of drug to be administered, the type and progression of disease, the patient's disease status, and the route of administration.

[098] In the context of the invention, the term “treat” or “treatment”, as used in the present application, means to reverse, alleviate, inhibit the progression of, or prevent the dysfunction or condition to which that term applies, or one or more symptoms of that dysfunction or condition.

[099] “Therapeutically effective quantity” means an amount of a pharmaceutical compound / composition according to the present invention, effective to produce the desired therapeutic effect.

[100] According to the invention, the term “patient” or “patient in need thereof” means a human or non-human mammal affected or likely to be affected by Petition 870260066733, dated 06 / 07 / 2026, page 34 / 105 24 / 42 dysfunctions above. Preferably, the patient is a human. Figures

[101] Figure 1 illustrates the results of comparative pharmacokinetics in dogs, from Example 5.

[102] The following examples are given as an illustration of the present invention. Examples Example 1 Bioavailability of Belinostat Oral Solid Dosage Form

[103] A canine PK study was conducted to compare the plasma exposure and bioavailability of 5 different oral solid dosage forms of belinostat. Formulations A, B, C, D, and E (detailed composition in Table 2) were administered by oral gavage to 5 fasted female Beagle dogs (7.0 to 9.0 kg) at a fixed dose of 50 mg per dog (equivalent to 6.5 to 10.2 mg / kg). The animals were dosed once with each formulation with a one-week washout period between each dosing. Intravenous dosing was performed for absolute bioavailability calculation by slow bolus injection into the cephalic vein.

[104] Blood samples were collected in heparinized tubes after each dose at the following time points: 5, 15 and 30 min, 1, 3, 6, 12, 24 and 36 hours from the saphenous or cephalic veins. Plasma concentrations of belinostat were measured using a validated bioanalytical method (solid phase extraction, UHPLC-MS / MS, concentration range: 2 to 2000 ng / mL).

[105] Pharmacokinetic parameters were derived from individual plasma concentration profiles by non-compartmental analysis using WinNonlin Professional (version 4.1).

[106] Cmax, AUC0-24 and bioavailability (F%), calculated for Petition 870260066733, dated 06 / 07 / 2026, page 35 / 105 25 / 42 each dog, and then the average for the test population is calculated, as reported in Table 2. Table 2 Pharmacokinetic Parameters of Different Solid Dosage Forms Belinostat Oral Treatments in Dogs Dosage Formulation of arginine IV Formulation A Pure belinostat in capsule Formulation B Tablet prototype Formulation C Capsule suspension Formulation D Granules in capsule I Formulation E Granules in capsule II Route of dose IV Oral Oral Oral Oral Oral Composition Belinostat solution at 50 mg / mL containing 10% L-arginine in SWFI Non-micronized belinostat 50 mg in capsule Tablets 50 mg (Micronized belinostat 55.56%, Pregelatinized Starch 16%, Microcrystalline Cellulose 16.24%, povidone 2.2%, crospovidone 6%, SLS 3%, colloidal silicon dioxide 0.75%, magnesium stearate 0.75%) Capsules 50 mg (micronized belinostat 10% in suspension in liquid lipid vehicle: Migliol 812N 80% and Lecithin 10%) Capsules 50 mg (micronized belinostat 83%, povidone K12 4.5%, SLS 2.5%, poloxamer 188 10%) Capsules 50 mg (micronized belinostat 60%, maltodextrin 37%,SLS 3%) Cmax (ng / mL) 5830 183 309 154 176 218 AUC 0-24 (ng*h / mL) 2700 428 429 396 345 323 Bioavailability 100% 15.9% 15.9% 14.7% 12.8% 12.0%,

[107] All oral administration methods resulted in similar exposure levels with AUCc-24h being 12% to 16% of the intravenous dosage. The different types of oral administration did not alter the exposure profiles and there was no improved bioavailability compared to pure belinostat in capsules.

[108] The results show that neither the conventional capsule Petition 870260066733, dated 06 / 07 / 2026, p. 36 / 105 Neither 26 / 42 (Formulation A) nor micronized belinostat in tablet / capsule form (Formulations B, D and E) or liquid lipid suspension formulations (Formulation C) are adequate in terms of enhancing the bioavailability of belinostat compared to the crystalline form and justify the need for a specific enabling technology to increase solubility and thus bioavailability. Example 2 Amorphous Solid Dispersion

[109] Different belinostate and polymer ASDs were prepared by spray drying, according to the following procedure:

[110] Solvent solutions of belinostate with different polymers (selected from HPMCAS-L, HPMCAS-M, HPMCAS-H, HPMC E3, PVP K12, PVP K30, PVP VA 64, Eudragit L100, Eudragit E PO, Eudragit S100, HPMCP HP 55S, CAP and a mixture of PVP K30 / PVP K90) were prepared in methanol, methanol / water or acetone (3 to 10% solids by weight in solvent) and spray dried using a Bend Research Custom Built Lab Scale Spray Dryer (Bend Research, Bend OR, Equipment ID No. BRI-EQ-0036) to obtain spray-dried solid dispersion fine particles on the scale of 7.5 to 10 g. Some ASDs with HPMCAS were tested with some additives: pH modifier (KOH, Na2CaCO3 bicarbonate) and ASDs with PVP K30 were tested with antioxidant (BHT) or stabilizers (L-histidine). A mixture of PVP K30 and PVP K90 was also tested in a 75 / 25 ratio. When an additive was used, it was dissolved and mixed with belinostate and polymer in the solvent solution before spray drying.The following conditions were used for all experiments: atomization pressure 100 to 140 psi, gas flow rate: 450 to 475 g / min, solution flow rate: 10 to 30 g / min, inlet temperature: 81 to 166°C.

[111] After secondary drying overnight at 40°C, Petition 870260066733, dated 06 / 07 / 2026, page 37 / 105 27 / 42 In a convection tray dryer, the different ASDs were characterized for physical stability (XRPD, Tg versus relative humidity), chemical stability (impurity by HPLC after 1 week, 40°C / RH 75%) and in vitro dissolution.

[112] The different formulations were prepared and tested as summarized in Table 3 below. Unless otherwise mentioned in Table 3, the ASDs contained 25% belinostat. Some formulations were tested at drug loadings of 15% to 50%. Theoretically, lower or higher drug loadings could be predicted. Example 3 Physical Stability

[113] The amorphous or crystalline state of freshly prepared spray as described in Example 2 was evaluated by X-ray powder diffraction (XRPD). The same analysis was repeated after 1 week of storage at 40°C and 75% relative humidity under open conditions.

[114] XRPD patterns were obtained with a Rigaku MiniFlex 600 X-ray diffractometer operating with a copper anode (Kαί = 1.5060 A; Ka2 = 1.54439 A), generator set at 45 kV and 15 mA, in the 2-theta 3 to 40° 2θ range, digitized at a rate of 2.5° 2Θ per minute in continuous scanning mode, and using a D / teX Ultra velocity detector.

[115] Table 3 describes the Crystalline / Amorphous state of the different ASDs prepared with belinostat. All ASD diffractograms exhibited a broad amorphous halo with the absence of sharp signals as a representative example. The disappearance of belinostat crystal peaks in spray-dried samples demonstrates that the different spray-dried dispersions are substantially amorphous. In contrast, amorphous belinostat, not stabilized with a polymer, undergoes recrystallization upon storage. Petition 870260066733, dated 06 / 07 / 2026, page 38 / 105 28 / 42

[116] After 1 week of storage at 40°C and 75% relative humidity (open), except for spray-dried belinostat (without polymer), all spray-dried dispersions were substantially amorphous. They showed good overall physical stability of belinostat in the amorphous form when dispersed in various polymers.

[117] In addition, to evaluate the physical stability of prepared ASDs, the glass transition temperature (Tg) was determined under two relative humidity (RH) conditions (RH < 5% and 75%) by modulated differential scanning calorimetry (m-DSC).

[118] DSC curves were recorded using a TA Instruments Q2000 differential scanning calorimeter. Samples were heated under a nitrogen flow from 0 to 200°C at 2.5 ± 1.5°C / min in a non-hermetically sealed pan for RH < 5% analysis or from 0 to 130°C at 2.5°C ± 1.5°C / 80 s in hermetically sealed pans for RH 75% analysis.

[119] Table 3 describes Tg of the different ASDs prepared with belinostat.

[120] Amorphous belinostate has a relatively low glass transition temperature (Tg), which is about 53°C. Since molecules, even in a glassy amorphous state, have some mobility, it is known in the art that it is beneficial for the glass transition temperature of ASD to be higher than current storage conditions (at least 20°C higher, and more preferably at least 40°C higher).

[121] Comparing all recorded TG values ​​of spray-dried amorphous dispersions, it was found that PVP K12, PVP K30, PVP VA 64 have satisfactory glass transition temperatures (> 100°C at < 5% RH).

[122] Thus, belinostat ASDs with polyvinyl lactam polymers exhibit good physical stability in the amorphous state. Petition 870260066733, dated 06 / 07 / 2026, p. 39 / 105 29 / 42 Example 4 Chemical Stability

[123] Due to the hydroxamide function, belinostat is easily hydrolyzed, so it is challenging to develop a chemically stable ASD.

[124] The purity of each batch of ASD was tested by HPLC analysis on the sample immediately after preparation and after one week of storage under accelerated stability conditions: 40°C / RH 75% open or closed. Under closed conditions, the ASDs were placed in sealed bottles (heat induction seal) containing a 1g SORB-IT desiccant tube.

[125] HPLC analysis was performed using an Agilent 1100 or 1200 system with a binary or quaternary pump, a diode array detector, a cooled autosampler, and a column oven. Data analysis was performed using Empower 3 software. The column used was Zorbax Extras RP 4.6 x 150 mm (3.5 µm). Acetonitrile / potassium phosphate buffer 20 mM, pH 3.0 was used as the mobile phase with a concentration gradient at a flow rate of 1.0 mL / min; UV detection was used at a wavelength of 220 nm.

[126] Belinostat leads to two main impurities: belinostat acid (Bel-acid) and belinostat dimer (Bel-dimer).

[127] Table 3 summarizes the purity profile of each spray-dried dispersion indicating the % area of ​​total impurities and % area of ​​belinostat (Bel-Acid) and belinostat dimer (Bel-dimer) impurities.

[128] For most prepared ASDs, the dimer impurity content and total impurity values ​​are initially low, but the impurity level increases significantly over time upon storage under accelerated stability conditions. Variability in impurity formation, particularly dimer impurity, is observed depending on the Petition 870260066733, dated 06 / 07 / 2026, page 40 / 105 30 / 42 associated polymer.

[129] Cellulosic-based ASDs (HPMCAS, HPMC, HPMCP, CAP) (formulations 3 to 12) provided rapid chemical degradation. To overcome a possible acid-catalyzed hydrolysis of the hydroxyl amide by the acid function of the HPMCAS-M polymer, pH-modifying additives were tested (formulations 5 and 6). As this resulted in higher chemical degradation, this approach was also unsatisfactory. Other (non-cellulosic ionizable) polymers, such as Eudragit® (formulations 23 to 25), were unsatisfactory as they lead to increased chemical degradation.

[130] However, the results show that only non-ionizable (neutral) non-cellulosic polymers, such as polyvinyl lactam polymers (such as PVP VA64, PVP K12 and PVP K30 alone, mixed with PVP K90 or with an additive, such as a stabilizer) can significantly prevent / reduce dimer formation as opposed to other polymers (formulations 13 to 22). Example 5 Non-Sink In Vitro Dissolution

[131] The dissolution of spray-dried belinostat materials has been tested in vitro, under non-sink conditions, in order to evaluate the ability of formulations to achieve supersaturation and the sustainability of supersaturation in relation to the crystalline drug.

[132] Dissolution was evaluated using the microcentrifuge method (Curatolo et al. Pharm Res 2009:26(6):1419-1431). The microcentrifuge dissolution method consisted of introducing an equivalent of 1.8 mg of belinostat as ASD into an empty microcentrifuge tube and adding 1.8 mL of total volume dissolution medium (PBS pH 6.5 with 0.5% by weight of Simulated Intestinal Fluid) to obtain a maximum theoretical concentration of belinostat in solution of 1000 pg / mL). For some formulations Petition 870260066733, dated 06 / 07 / 2026, page 41 / 105 31 / 42 (marked with * in Table 3), the ASDs were first exposed in gastric medium pH 2.0 at 2000 μg / mL for 30 min before being transferred to PBS pH 6.5 with 0.5% by weight of Simulated Bowel Fluid at a final theoretical maximum concentration of belinostat in solution of 1000 μg / mL. The tubes were placed at 37°C. Aliquots (50 μL) of supernatant were collected after centrifugation of 15,800 g for 1 min at each time point (5, 10, 20, 45, 90 and 1200 minutes). Between each time point, solids in the centrifuge tube were resuspended by continuously mixing the sample in the vortex mixer for 30 min and the tube was placed back at 37°C. Aliquot samples were diluted using acetonitrile, and the drug concentration was determined by HPLC.

[133] Table 3 summarizes C90 min and C1200 min which represent the concentrations in the dissolution medium obtained after 90 min and 1200 minutes.

[134] With the use of the ASDs of the invention, the concentration of belinostat in solution after 90 minutes is 2 to 3.5 times higher compared to the undispersed crystalline drug. Similar solubility values ​​are obtained after 1200 min and show the ability of the selected polymers to maintain a good supersaturated level over time. Table 3 Summary of the Physical Stability, Chemical Stability, and Dissolution Results of Different Amorphous Solid Dispersions (ASD) of Belinostate Formulations Physical Stability Chemical Stability (% impurity area) Dissolution Tg (°C) < 5% RHa Tg (°C) 75% RHb Initial XRPD XRPD 1 week open 40 / 75 Initial 1 week open 40 / 75 1 week closed 40 / 75 Dissolution Cgomin pg / mL Dissolution C20h pg / mL Controls 1 Crystalline NA NA Crystalline Acid Crystal / / 270 310 Petition 870260066733, dated 06 / 07 / 2026, page 42 / 105 32 / 42 Formulations Physical Stability Chemical Stability (% impurity area) Dissolution Tg (°C) < 5% RHa Tg (°C) 75% RHb Initial XRPD XRPD 1 week open 40 / 75 Initial 1 week open 40 / 75 1 week closed 40 / 75 Dissolution CgQmin pg / mL Dissolution C20h pg / mL oino o Bel < 0.05 Dimer Bel NA Total imp. < 0.05 2 Belinost spray-dried 53 Not found Partially crystalline Crystalline Acid Bel 0.05 Dimer Bel 0.48 Total imp. 0.59 Acid Bel 0.10 Dimer Bel 0.25 Total imp. 0.42 Recrystallization observed Bel Acid 0.10 Bel Dimer 1.34 Total imp. 1.49 363 Recrystallization observed 387 Cellulosic polymers (Non-ionizable and ionizable) based on ASD 3 HPMCA SL 81 37 Amorphous Amorphous Bel Acid ND Bel Dimer 0.19 Total imp. 0.45 Bel Acid 0.14 Bel Dimer 2.07 Total imp. 2.44 Not performed 980 920 4 HPMCA SM 83 38 Amorphous Amorphous Bel Acid ND Bel Dimer 0.20 Total imp. 0.39 Bel Acid 0.10 Bel Dimer 1.77 Total imp.2.11 Does not perform 950 920 5 HPMCA 87 37 Amorphous Amorphous Acid Acid Bel Acid 785 770. Petition 870260066733, dated 06 / 07 / 2026, p. 43 / 105 33 / 42 Formulations Physical Stability Chemical Stability (% impurity area) Dissolution Tg (°C) < 5% RHa Tg (°C) 75% RHb Initial XRPD Initial XRPD 1 week 40 / 75 open Initial 1 week 40 / 75 open 1 week 40 / 75 closed Dissolution C90min pg / mL Dissolution C20h pg / mL SM + IMeq.K OH to Bel ND Dimer Bel 0.09 Total imp. 1.95 2.86 Dimer Bel 2.21 Total imp. 8.80 Bel 0.19 Dimer Bel 0.32 Total imp. 2.12 6 HPMCA SM + CaCO3 2% 80 33 Amorphous Amorphous Acid Bel 0.09 Dimer Bel 0.99 Total imp. 1.72 Acid Bel 0.17 Dimer Bel 1.85 Total imp. 2.81 Acid Bel 0.09 Dimer Bel 1.23 Total imp. 2.12 896 883 7 HPMCA SM (API 50%) 71 42 Amorphous Amorphous Acid Bel ND Dime ro Bel 0.17 Total imp. 0.45 Acid Bel 0.13 Dimer Bel 1.76 Total imp. 1.98 Acid Bel ND Dimer Bel 0.71 Total imp. 0.81 922 909 8 HPMCA SM (API 75%) 60 27 Amorphous Amorphous Acid Bel ND Dime ro Bel 0.21 Total imp. 0.59 Acid Bel 0.22 Dimer Bel 1.88 Total imp.2.40 Acid Bel 0.08 Dimer Bel 0.87 Total imp. 1.14 774 789 9 HPMCA SH 80 42 Amorphous Amorphous Acid Bel 0.04 Dime Acid Bel 0.16 Dimer Bel 1.37 Acid Bel 0.07 Dimer 602 596. Petition 870260066733, dated 06 / 07 / 2026, p. 44 / 105 34 / 42 Formulations Physical Stability Chemical Stability (% impurity area) Dissolution Tg (°C) < 5% RHa Tg (°C) 75% RHb Initial XRPD XRPD 1 week open 40 / 75 Initial 1 week open 40 / 75 1 week closed 40 / 75 Dissolution CgQmin pg / mL Dissolution C2Oh pg / mL ro Bel 0.18 Total imp. 0.28 Total imp. 1.69 o Bel 0.83 Total imp. 0.95 1 0 HPMC E3 93 30 Amorphous Amorphous Acid o Bel ND Dimer ro Bel 0.10 Total imp. 0.30 Acid Bel 0.19 Dimer Bel 0.62 Total imp. 1.18 Does not perform 700 780 1 1 HPMCP HP55S 100 46 Amorphous Amorphous Acid Bel 0.04 Dime ro Bel 0.17 Total imp. 0.27 Acid Bel 0.38 Dimer Bel 1.53 Total imp. 1.96 Acid Bel 0.06 Dimer Bel 0.84 Total imp. 0.94 751 759 1 2 CAP 110 46 Amorphous Amorphous Acid Bel 0.03 Dime ro Bel 0.22 Total imp. 0.31 Acid Bel 0.27 Dimer Bel 2.14 Total imp. 2.46 Acid Bel 0.06 Dimer o Bel 0.68 Total imp.0.78 723 715 Non-ionizable (neutral) non-cellulosic polymers based on ASD 1 3 PVP K30 (API 15%) 146 30 Amorphous Amorphous Acid Bel 0.04 Dimer Bel Acid Bel 0.14 Dimer Bel 0.18 Total imp. 0.56 Acid Bel 0.05 Dimer Bel 0.04 965 1020. Petition 870260066733, dated 06 / 07 / 2026, p. 45 / 105 35 / 42 Formulations Physical Stability Chemical Stability (% impurity area) Dissolution Tg (°C) < 5% RHa Tg (°C) 75% RHb Initial XRPD Initial XRPD 1 week 40 / 75 open 1 week 40 / 75 closed Dissolution CgQmin pg / mL Dissolution C20h pg / mL 0.03 Total imp. 0.24 Total imp. 0.31 1 4 PVP K30 (API 25%) 139 43 Amorphous Amorphous Acid Bel 0.04 Dimer Bel 0.05 Total imp. 0.15 Acid Bel 0.14 Dimer Bel 0.30 Total imp. 0.52 Bel acid 0.05 Bel dimer 0.13 Total imp. 0.24 806 837 1 5 PVP K30 (API 50%) 107 49 Amorphous Amorphous Acid Bel 0.04 Dimer Bel 0.04 Total Imp. 0.26 Bel acid 0.10 Bel dimer 0.46 Total imp. 0.83 Bel acid 0.05 Bel dimer 0.18 Total imp. 0.44 813 809 1 6 PVP K30 low peroxide grade 140 39 Amorphous Amorphous Acid Bel 0.03 Dimer Bel 0.03 Total imp. 0.27 Bel acid 0.09 Bel dimer 0.20 Total imp. 0.55 Bel acid 0.05 Bel dimer 0.06 Total imp.0.33 933 975 1 7 PVP K30 + BHT 2% 135 41 Amorphous Amorphous Bel Acid 0.03 Bel Dimer 0.03 Total Bel Acid 0.11 Bel Dimer 0.20 Total Imp. 0.56 Acid Bel 0.05 Dimer o Bel 0.05 Total imp. 960 1006. Petition 870260066733, dated 06 / 07 / 2026, page 46 / 105 36 / 42 Formulations Physical Stability Chemical Stability (% impurity area) Dissolution Tg (°C) < 5% RHa Tg (°C) 75% RHb Initial XRPD Initial XRPD 1 week 40 / 75 open Initial 1 week 40 / 75 open 1 week 40 / 75 closed Dissolution C90min pg / mL Dissolution C20h pg / mL imp. 0.24 0.29 1 8 PVPK3 0 + NaHCO3 2% 141 38 Amorphous Amorphous Acid Bel 0.07 Dimer Bel 0.03 Total imp. 0.32 Acid Bel 0.26 Dimer Bel 0.15 Total imp. 0.85 Acid Bel 0.11 Dimer Bel 0.03 Total imp. 0.47 1000 979 1 9 PVP VA64 108 36 Amorphous Amorphous Acid Bel ND Dimer Bel 0.04 Total imp. 0.20 Acid Bel 0.07 Dimer Bel 0.31 Total imp. 0.58 Not performed 530 570 2 0 PVP K12 100 0 Amorphous Amorphous Acid Bel < 0.05 Dimer Bel < 0.05 Total imp. 0.11 Acid Bel 0.06 Dimer Bel 0.21 Total imp. 0.33 Acid Bel < 0.05 Dimer Bel 0.10 Total imp. 0.24 597* 714* 2 1 PVP K30 + Lhistidin 5% 121 33 Amorphous Amorphous Acid Bel < 0.05 Dime ro Bel < 0.05 Total imp. Acid Bel 0.07 Dimer Bel 0.17 Total imp.0.33 Acid Bel 0.06 Dimer Bel 0.12 Total imp. 0.25 788* 815*. Petition 870260066733, dated 06 / 07 / 2026, p. 47 / 105 37 / 42 Formulations Physical Stability Chemical Stability (% impurity area) Dissolution Tg (°C) < 5% RHa Tg (°C) 75% RHb Initial XRPD Initial XRPD 1 week 40 / 75 open 1 week 40 / 75 closed Dissolution CgQmin pg / mL Dissolution C20h pg / mL 0.06 2 2 PVP K30 / PV P K90 131 24 Amorphous Amorphous Acid Bel < 0.05 Dimer Bel 0.09 Total imp. 0.15 Acid Bel 0.06 Dimer Bel 0.31 Total imp. 0.44 Acid Bel 0.05 Dimer Bel 0.18 Total imp. 0.31 577* 727* Ionizable non-cellulosic polymers based on ASD 2 3 Eudragi t L100 151 Amorphous Phase Separator Amorphous Bel Acid ND Bel Dimer 0.22 Total imp. 0.86 Bel Acid 0.44 Bel Dimer 1.33 Total imp. 1.93 Not realized 960 940 2 4 Eudragi t E PO 62 33 Amorphous Amorphous Bel Acid ND Bel Dimer 0.06 Total imp. 0.74 Bel Acid 0.79 Bel Dimer 0.29 Total imp. 1.84 Bel Acid 0.13 Bel Dimer 0.23 Total imp.0.83 173 211 2 5 Eudragi t S100 Not determinable Not determinable Amorphous Amorphous Acid Bel 0.05 Dimer Bel 0.26 Total imp. Acid Bel 0.54 Dimer Bel 1.08 Total imp. 1.67 Acid Bel 0.10 Dimer Bel 0.75 Total imp. 0.89 921 876. Petition 870260066733, dated 06 / 07 / 2026, page 48 / 105 38 / 42 Formulations Physical Stability Chemical Stability (% impurity area) Dissolution Tg (°C) < 5% RHa Tg (°C) 75% RHb Initial XRPD XRPD 1 week open 40 / 75 Initial 1 week open 40 / 75 1 week closed 40 / 75 Dissolution Cgomin pg / mL Dissolution C20h pg / mL 0.37 ND: not detected *formulations for which in vitro dissolution was first performed in gastric medium pH 2.0 for 30 min before being diluted in PBS medium pH 6.5. Conclusions

[135] In terms of chemical stability, the formation of dimer impurities was variable depending on the polymers used.

[136] In vitro dissolution data of the various spray-dried amorphous belinostat dispersions of the invention with a non-ionizable (neutral) non-cellulosic polymer, such as a polyvinyl lactam polymer, exhibit a large improvement in solubility compared to undispersed crystalline belinostat and show that the dispersions significantly enhanced the drug dissolution rate.

[137] It appears that polymers belonging to the polyvinyl lactam group provide good chemical stability of belinostate in the amorphous state. It is expected that other polyvinyl lactam polymers such as Soluplus®, other molecular weights of PVP (PVP K17, PVP K25) will also be suitable.

[138] The above results show that only polymers of the polyvinyl lactam class lead to excellent chemical stability, along with an adequate Tg, good physical stability and a satisfactory dissolution profile.

[139] Polyvinyl lactam polymers were unexpectedly found to have good dissolution, along with rates Petition 870260066733, dated 06 / 07 / 2026, p. 49 / 105 39 / 42 smaller dimer formation.

[140] Three ASDs were also tested for longer stability duration (1, 3 and 6 months at 5°C and real time (25 / 60 open and closed) and accelerated stability conditions (30 / 65 closed) (see Table 4 below). Table 4 Chemical Stability Support for 6 Months of ASD PVP VA64, PVP K30 and HPMCAS-M Chemical Stability (% of impurity area) 25°C, RH 60% dated (desiccant) 25°C, RH 60% open 30°C, RH 65% dated (desiccant) Refrigerator 2 to 8°C (open) Weeks PVP VA 64 0 Bel Acid 0.05 Bel Dimer 0.06 Total impurity 0.16 Bel Acid 0.05 Bel Dimer 0.06 Total impurity 0.16 Bel Acid 0.05 Bel Dimer 0.06 Total impurity 0.16 Bel Acid 0.05 Bel Dimer 0.06 Total impurity 0.16 4 Bel Acid < 0.05 Bel Dimer 0.10 Total impurity 0.20 Bel Acid < 0.05 Bel Dimer 0.12 Total imp. 0.22 Bel Acid 0.04 Bel Dimer 0.11 Total imp. 0.21 Bel Acid 0.03 Bel Dimer 0.04 Total imp. 0.12 12 Bel Acid 0.06 Bel Dimer 0.16 Total imp. 0.26 Bel Acid 0.07 Bel Dimer 0.22 Total imp. 0.33 Bel Acid 0.07 Bel Dimer 0.21 Total imp. 0.33 Bel Acid not tested Bel Dimer not tested Total imp. not tested 24 Bel Acid 0.05 Bel Dimer 0.23 Total imp. 0.44 Bel Acid 0.12 Bel Dimer 0.34 Total Imp. 0.63 Bel Acid 0.07 Bel Dimer 0.37 Total Imp.0.62 Bel Acid 0.04 Bel Dimer 0.06 Total Imp. 0.35 Week s hpmcas-m 0 Bel Acid 0.04 Bel Dimer 0.22 Total Imp. 0.31 Bel Acid 0.04 Bel Dimer 0.22 Total Imp. 0.31 Bel Acid 0.04 Bel Dimer 0.22 Total Imp. 0.31 Bel Acid 0.04 Bel Dimer 0.22 Total Imp. 0.31 4 Bel Acid 0.05 Bel Dimer 0.59 Total Imp. 0.69 Bel Acid 0.08 Bel Dimer 0.84 Total Imp. 0.98 Bel Acid 0.03 Bel Dimer 0.74 Total Imp. 0.83 Bel Acid 0.04 Bel Dimer 0.27 Total Imp. 0.36 12 Bel Acid 0.07 Bel Dimer 0.88 Total of imp. 1.00 Bel Acid 0.14 Bel Dimer 1.48 Total of imp. 1.69 Bel Acid 0.09 Bel Dimer 1.28 Total of imp. 1.42 Bel Acid not tested Bel Dimer not tested Total of imp. not tested 24 Bel Acid 0.08 Bel Dimer 1.48 Bel Acid 0.33 Bel Dimer 2.69 Bel Acid 0.16 Bel Dimer 2.58 Bel Acid 0.05 Bel Dimer 0.36. Petition 870260066733, dated 07 / 06 / 2026, page. 50 / 105 40 / 42 Chemical Stability (% of impurity area) 25°C, RH 60% dated (desiccant) 25°C, RH 60% open 30°C, RH 65% dated (desiccant) Refrigerator 2 to 8°C (open) Total impurities 1.65 Total impurities 3.14 Total impurities 2.85 Total impurities 0.53 Weeks PVPK30 0 Bel Acid 0.04 Bel Dimer 0.05 Total impurities 0.15 Bel Acid 0.04 Bel Dimer 0.05 Total impurities 0.15 Bel Acid 0.04 Bel Dimer 0.05 Total impurities 0.15 Bel Acid 0.04 Bel Dimer 0.05 Total impurities 0.15 4 Bel Acid 0.04 Bel Dimer 0.08 Total Imp. 0.18 Bel Acid 0.07 Bel Dimer 0.13 Total Imp. 0.27 Bel Acid 0.04 Bel Dimer 0.12 Total Imp. 0.23 Bel Acid 0.03 Bel Dimer 0.03 Total Imp. 0.12 12 Bel Acid 0.05 Bel Dimer 0.15 Total Imp. 0.38 Bel Acid 0.09 Bel Dimer 0.18 Total Imp. 0.48 Bel Acid 0.07 Bel Dimer 0.22 Total Imp. 0.50 Bel Acid 0.04 Bel Dimer 0.04 Total Imp. 0.26 24 Bel Acid 0.07 Bel Dimer 0.25 Total Imp. 0.47 Bel Acid 0.17 Bel Dimer 0.28 Total imp.0.65 Bel acid 0.12 Bel dimer 0.44 Total imp. 0.73 Bel acid 0.04 Bel dimer 0.06 Total imp. 0.31.

[141] These results show that belinostate ASDs with polyvinyl lactam class polymers exhibit excellent chemical and physical stability, even under long storage conditions, also without crystallization observed when analyzed by XRPD. Example 6 In Vivo Performance in Dogs (PK Profile)

[142] The bioavailability of 3 spray-dried dispersions (ASDs) was evaluated in a preclinical canine PK study. The following formulations, Belinostat 25% in HPMCAS-M, PVPVA64, and PVPK30, were administered by oral gavage to 4 fasted male Beagle dogs (7.0 to 9.0 kg) at a fixed dose of 50 mg per dog (equivalent to approximately 6.25 mg / kg). The animals were dosed once with each formulation with at least a one-week washout period between each dose. Petition 870260066733, dated 06 / 07 / 2026, page 51 / 105 41 / 42 dosage.

[143] Blood samples were collected in heparinized tubes after each dose at the following time points: Pre-dose, 5, 15 and 30 min, 1, 1.5, 2, 4, 6, 8, 12 and 24 hours from the jugular veins. Plasma concentrations of belinostat were measured using a validated bioanalytical method (solid phase extraction, UHPLC-MS / MS, concentration range: 1 to 1000 ng / mL).

[144] The aim of the study was to evaluate whether the gain in solubility observed in in vitro dissolution provides increased bioavailability compared to the crystalline form. The results are illustrated in Figure 1.

[145] IV dosing was performed to calculate absolute bioavailability and two control groups were added: crystalline drug in capsule form as a reference for soluble formulation and an oral solution (IV formulation with L-arginine) as a reference for best possible exposure without solubility limitation. It is important to note that due to the high pH (above pH 9.0) this oral solution is not pharmaceutically acceptable for clinical use.

[146] Belinostat solutions, for IV and oral administration, were prepared at 50 mg / mL belinostat in 100 mg / mL L-arginine solution in water. Crystalline belinostat capsules were prepared by hand-weighing 50 mg belinostat (non-micronized) into size 2 hard gelatin capsules. Belinostat ASDs were administered as suspensions at 40 mg / mL in Methocel 0.5% in aqueous vehicle.

[147] Pharmacokinetic parameters were derived from individual plasma concentration data by non-compartmental analysis using Phoenix WinNonlin (version 6.4).

[148] Cmax, AUCc-12h and bioavailability (F%), calculated for each dog and then averaged for the test population, are Petition 870260066733, dated 06 / 07 / 2026, page 52 / 105 42 / 42 reported in Table 5. Table 5 Pharmacokinetic Parameters of Dry Amorphous Dispersion of Belinostat in Dogs Formulations Current Dose Range (mg / dog) Average Cmax (ng / mL) Average AUC0-12h (h*ng / mL) Average Bioavailability IV 42.2 to 45.9 4210 (C0 7109) 1788 - Belinostat in capsules 50.0 to 50.1 54 154 7% Oral solution (with L-arginine) 52.0 to 53.3 702 562 26% Spray dry dispersion PVP VA64 54.3 to 56.1 409 433 19% Spray dry dispersion HPMCAS-M 43.9 to 45.3 338 443 25% Spray dry dispersion PVP K30 55.3 to 59.2 1053 653 28%

[149] The oral solution is not suitable for oral administration.

[150] The HPMCAS-M formulation is also unsuitable as it is not chemically stable.

[151] For the capsule containing crystalline belinostat, the mean AUC(o-i2h) observed was 154 ngxh / mL. For the suspension containing the belinostat / PVPK30 dispersion, the mean AUC was 4.2 times higher at 653 ngxh / mL.

[152] This example demonstrates that dosing a dry spray dispersion of belinostat / PVPK30 for dogs results in a higher systemic belinostat exposure than that observed after dosing crystalline belinostat.

[153] These amorphous solid dispersion formulations of belinostat with enhanced pharmacokinetic properties were not known until then.

Claims

1. AMORPHOUS SOLID DISPERSION OF BELINOSTATE, characterized by comprising: a) belinostat or a pharmaceutically acceptable salt, solvate or ester thereof; b) at least one polyvinyl lactam polymer; and c) optionally at least one additive.

2. DISPERSION, according to claim 1, characterized in that said polyvinyl lactam polymer is chosen from chain polymers and copolymers comprising the following subunits: / Wm < >ON < (I) wherein m is an integer chosen from 1, 2, 3 or 4 (β-, γ- and δ- or ε-lactam) and en represents the number of lactam repeating units in said subunit.

3. A DISPERSION, according to any one of claims 1 to 2, characterized in that said polyvinyl lactam polymer is soluble in water.

4. DISPERSION, according to any one of claims 1 to 3, characterized in that said polyvinyl lactam polymer is chosen from the group consisting of polyvinylpyrrolidone (PVP “Povidone”), PVP-polyvinyl acetate (Copovidone), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG).

5. DISPERSION, according to any of the claims 1 to 4, characterized in that said polyvinyl lactam polymer is chosen from PVP K30, PVP K12, PVP K25, PVP K90, PVP VA64 and mixtures thereof.

6. DISPERSION, according to any one of claims 1 to 5, characterized by comprising: a) 5 to 80% of belinostate (percentage by weight); and b) 20 to 95% of said polyvinyl lactam polymer (percentage by weight).

7. DISPERSION, according to any one of claims 1 to 6, characterized in that said additive is chosen from the group consisting of: pH modifiers, antioxidants, dispersing agents, solubilizers, stabilizers, disintegrants or any mixture thereof.

8. A DISPERSION, according to any one of claims 1 to 7, characterized in that said additive is histidine.

9. DISPERSION, according to any one of claims 1 to 8, characterized in that said dispersion comprises: - less than 0.2% of belinostat acid and / or belinostat dimer, as determined by a release test; and / or - less than 2% of belinostat acid and / or belinostat dimer as determined by storage for at least 18 months.

10. DISPERSION, according to any one of claims 1 to 9, characterized in that it is for use in the treatment and / or prevention of cancer by oral administration.

11. DISPERSION, according to claim 10, characterized in that it is for the treatment of lymphoma.

12. PROCESS FOR PREPARING THE AMORPHOUS SOLID DISPERSION OF BELINOSSATE, as defined in any of claims 1 to 9, characterized by comprising the steps of: - preparing a solution of belinossistate with said polyvinyl lactam polymer in a solvent; - spray-drying said solution.

13. PHARMACEUTICAL COMPOSITION, characterized by comprising an amorphous solid dispersion of belinostat, as defined in any one of claims 1 to 9, and one or more pharmaceutically acceptable excipients.