Novel vamorolone formulations exhibiting improved solubility

Abstract

Vamorolone is provided as an amorphous solid composition. The composition of the present invention comprises an amorphous solid dispersion of vamorolone in a polymer matrix, i.e., amorphous vamorolone dispersed in a polymer matrix.

Description

[Background technology]

[0001] Glucocorticoids are the standard treatment for many inflammatory diseases, but their long-term use is associated with various side effects. Recently, Δ9,11 steroid analogs have emerged as a promising source of safer drugs for treating chronic inflammatory diseases.

[0002] Vamorolone is one of these Δ9,11 steroid analogs. Vamorolone is a synthetic glucocorticoid corticosteroid, also known as VB-15, VBP-15, 16α-methyl-9,11-dehydroprednisolone, or 17α,21-dihydroxy-16α-methylpregna-1,4,9(11)-triene-3,20-dione: Also known as TIFF2026504517000001.tif53128.

[0003] Preclinical studies have shown that vamorolone potently binds to the glucocorticoid receptor and has anti-inflammatory effects similar to those of conventional glucocorticoids. When tested in multiple mouse models of inflammatory conditions, it exhibits efficacy similar to prednisolone, with a dramatically improved side effect profile, including abolition of growth stunting and bone fragility. Recent clinical data confirm these beneficial effects.

[0004] US 2020 / 0281942 (Patent Document 1) discloses an aqueous oral pharmaceutical suspension composition containing crystalline vamorolone. Vamorolone has limited solubility in aqueous media. Because it lacks ionizable groups in the physiological pH range, its solubility is relatively independent of pH. Its thermodynamic solubility at 37°C in aqueous buffer is 33-37 μg / ml over the pH range of 1-7.

[0005] To date, the only pharmaceutical dosage form of vamorolone available is an aqueous oral pharmaceutical suspension containing 300 mg of vamorolone per 7.5 ml for pediatric use. Pediatric patients typically receive 100 ml bottles of this aqueous oral suspension. Depending on the patient's weight, one unit of this aqueous oral suspension product may not be sufficient to cover one month of treatment. For these patients, there is a need to develop a more convenient, appropriately sized, immediate-release oral solid dosage form that provides good physical and chemical stability during storage and facilitates simple and accurate dosing.

[0006] It is known that poor solubility in water and slow dissolution rate lead to low bioavailability, adversely affect pharmacokinetic behavior, and limit the orally absorbed dose. Therefore, there is a need for an oral formulation containing vamorolone with improved solubility and dissolution rate that can provide adequate bioavailability in a palatable oral solid dose.

[0007] Overall, there is a need to overcome the problems arising from the vamorolone formulations provided by US 2020 / 0281942. In particular, there is a need to provide higher doses of vamorolone in a convenient pharmaceutical dosage form, preferably an immediate-release solid dosage form, that contains vamorolone with improved solubility and dissolution rate compared to the crystalline drug, is capable of delivering vamorolone in a stable formulation, and further preferably exhibits improved bioavailability at optimized doses. Additionally, there is a need to provide an immediate-release solid oral dosage form containing vamorolone. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] US 2020 / 0281942 Summary of the Invention

[0009] The present invention fulfills this need by providing vamorolone as an amorphous solid composition. The composition of the present invention comprises an amorphous solid dispersion of vamorolone in a polymer matrix, i.e., amorphous vamorolone dispersed in a polymer matrix.

[0010] The terms "composition of the present invention" and "solid amorphous dispersion of the present invention" are used synonymously throughout this specification.

[0011] The mere presence of a polymer in a composition containing vamorolone, rather than as an amorphous solid dispersion of the present invention, does not result in the increased solubility seen in the solid dispersion. Simply mixing vamorolone (whether crystalline or amorphous) with a polymer does not result in the same solubility as amorphous vamorolone alone - see Figure 3.

[0012] Therefore, it was found that the amorphous solid dispersion of the present invention is a formulation with improved dissolution properties and can stabilize the solubility of vamorolone in aqueous media.

[0013] Surprisingly, the compositions of the present invention have been found to exhibit dramatically improved kinetic solubility in aqueous media, which allows for better bioavailability, regardless of co-administration with food, compared to prior art vamorolone compositions.

[0014] Even more surprisingly, it has been found that the composition of the present invention, comprising an amorphous solid dispersion of vamorolone dissolved in an aqueous medium, is stable for extended periods of time in the form of a supersaturated aqueous solution without recrystallization, and as a result, the solubilized form is efficiently absorbed in vivo.

[0015] The composition of the present invention comprising an amorphous solid dispersion of vamorolone is preferably obtained by spray drying. This technique has been found to be superior to other alternatives, such as hot-melt extrusion, because it allows for high drug loading while preventing degradation of the composition and exhibits good processability into pharmaceutical dosage forms.

[0016] To stabilize the amorphous state of vamorolone, a suitable polymer or a mixture of suitable polymers is used.Generally, this polymer is pharmaceutically acceptable.Representative examples of polymers include cellulose or cellulose derivatives, povidone and copovidone, and methacrylic acid and methyl methacrylate derivatives.Such polymers may include copolymers.

[0017] "Cellulose derivatives" include cellulose ethers, cellulose esters, and cellulose ester ethers, or their respective copolymers. Preferred cellulose derivatives are selected from hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose, methylcellulose, ethylcellulose, and cellulose acetate.

[0018] "Derivatives of methacrylic acid, ethyl acrylate, and / or methyl methacrylate" include vinyl polymers composed of acrylate or methacrylate monomers, where the vinyl groups are involved in the polymerization while the carboxyl groups are the target of the derivatization reaction. Thus, "derivatives of methacrylic acid, ethyl acrylate, and / or methyl methacrylate" include vinyl polymers with functionalized carboxyl groups, e.g., esters or carboxylates. Preferred derivatives of methacrylic acid, ethyl acrylate, and / or methyl methacrylate are poly(methacrylic acid) polymers and polyacrylate polymers, or their respective copolymers. More preferred derivatives of methacrylic acid, ethyl acrylate, and / or methyl methacrylate are selected from ethyl acrylate-methyl methacrylate copolymers such as Eudragit® E PO, methacrylic acid-ethyl acrylate copolymers such as Eudragit® L, methacrylic acid-methyl methacrylate copolymers such as Eudragit® S, ethyl acrylate-methyl methacrylate copolymers such as Eudragit® RS, methacrylic acid-ethyl acrylate copolymers such as Eudragit® NE.

[0019] The polymer is preferably selected from hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, and cellulose acetate, more preferably selected from hydroxypropyl methylcellulose (HPMC), copovidone (polyvinylpyrrolidone-vinyl acetate copolymer), and hydroxypropyl methylcellulose acetate succinate (HPMCAS; grades L, M, or H). In a most preferred embodiment, the vamololone polymer is hydroxypropyl methylcellulose acetate succinate.

[0020] In a specific embodiment, the polymer is selected from cellulose derivatives, preferably hydroxypropyl methylcellulose derivatives, more preferably hydroxypropyl methylcellulose acetate succinate grades L, H, or M. In one preferred embodiment, the polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS) grade M, which dissolves at pH values ​​above 6.0. Preferably, HPMCAS grades L, H, or M are characterized by an acetyl content of about 7-11% and a succinoyl content of about 10-14%.

[0021] The kinetic solubility of amorphous vamorolone increases in the presence of one or more of the polymers of the present invention, resulting in a supersaturated solution when dissolved in the composition of the present invention. Such supersaturated solutions of vamorolone are stable for at least 10 hours at concentrations greater than 50 μg / ml, preferably greater than 100 μg / ml, more preferably greater than 150 μg / ml, more preferably greater than 200 μg / ml, more preferably greater than 250 μg / ml, even more preferably greater than 300 μg / ml, and most preferably greater than 350 μg / ml. All of the above concentrations represent solubility in an aqueous medium at 37°C. Typically, the aqueous medium is fasted stated simulated intestinal fluid (FASSIF) at 37°C.

[0022] In one embodiment, the amorphous solid dispersion of the present invention comprises at least 20 wt% vamorolone based on the weight of the amorphous solid dispersion and 80 wt% total polymer based on the weight of the amorphous solid dispersion. Some amorphous solid dispersions comprise about 20 wt% to about 80 wt% vamorolone based on the weight of the amorphous solid dispersion. Preferably, the amorphous solid dispersion of the present invention contains about 30 wt% to 70 wt% vamorolone. More preferably, the amorphous solid dispersion contains about 40 wt% to 60 wt% vamorolone. More preferably, the amorphous solid dispersion contains about 45 wt% to 55 wt% vamorolone. The total amount of polymer is preferably 100 wt% minus the amount of vamorolone. For example, if the amount of vamorolone is 20 wt% to 80 wt% of the amorphous solid dispersion, the total amount of polymer is 80 wt% to 20 wt% of the amorphous solid dispersion. The same calculation applies to all the preferred amounts of vamorolone mentioned above. In another preferred embodiment, the present invention relates to an amorphous solid dispersion containing vamorolone in an amount of 50 wt %, in a 1:1 ratio relative to the total amount of polymer.

[0023] Alternatively, in a preferred embodiment, the polymer has an amount equal to 99 wt% minus the amount of vamorolone. For example, when the amount of vamorolone is 20 wt% to 80 wt% of the amorphous solid dispersion, the total polymer amount is 79 wt% to 19 wt% of the amorphous solid dispersion. When the amount of vamorolone is 30 wt% to 70 wt% of the amorphous solid dispersion, the total polymer amount is 69 wt% to 29 wt% of the amorphous solid dispersion. When the amount of vamorolone is 40 wt% to 60 wt% of the amorphous solid dispersion, the total polymer amount is 59 wt% to 39 wt% of the amorphous solid dispersion. When the amount of vamorolone is 45 wt% to 55 wt% of the amorphous solid dispersion, the total polymer amount is 54 wt% to 34 wt% of the amorphous solid dispersion.

[0024] In yet another preferred embodiment, the polymer has an amount obtained by subtracting the amount of vamorolone from 97 wt%. For example, when the amount of vamorolone is 20 wt% to 80 wt% of the amorphous solid dispersion, the total polymer amount is 77 wt% to 17 wt% of the amorphous solid dispersion. When the amount of vamorolone is 30 wt% to 70 wt% of the amorphous solid dispersion, the total polymer amount is 67 wt% to 27 wt% of the amorphous solid dispersion. When the amount of vamorolone is 40 wt% to 60 wt% of the amorphous solid dispersion, the total polymer amount is 57 wt% to 37 wt% of the amorphous solid dispersion. When the amount of vamorolone is 45 wt% to 55 wt% of the amorphous solid dispersion, the total polymer amount is 52 wt% to 32 wt% of the amorphous solid dispersion.

[0025] In yet another preferred embodiment, the present invention relates to an amorphous solid dispersion containing amorphous vamorolone in a polymer matrix together with one or more additional active ingredients.

[0026] A higher amount of vamorolone in the solid dispersion than 67 wt% is associated with physical instability. When exposed to stress conditions (40°C / 75% relative humidity, 1 week) during storage, partial recrystallization of the amorphous form was observed. Furthermore, despite an initial increase in kinetic solubility in water or aqueous media, when the vamorolone loading in the solid dispersion is about 67 wt% or higher, the ability to maintain supersaturation is negatively affected.

[0027] In a preferred embodiment, the composition of the present invention does not contain any additional components except for the polymer and vamorolone. In another embodiment, the composition of the present invention contains up to 3 wt%, or up to 2 wt%, or up to 1 wt% of any additional component based on the total amount. The additional component is, for example, a component for stabilizing vamorolone in the amorphous phase.

[0028] In a further aspect, there is provided a pharmaceutical composition comprising an amorphous solid dispersion of vamorolone and one or more pharmaceutically acceptable excipients. Such pharmaceutical compositions may comprise pharmaceutically acceptable excipients of various functional categories, including but not limited to diluents, binders, disintegrants, lubricants, glidants, surfactants, and polymeric film coating agents.

[0029] In certain embodiments, the pharmaceutical composition is a solid oral dosage form. In more preferred embodiments, the solid dosage form is an immediate release tablet or capsule for oral administration. Such tablets or capsules may contain pharmaceutically acceptable additives of various functional categories, including but not limited to diluents, binders, disintegrants, lubricants, glidants, surfactants, and polymeric film coating agents.

[0030] In a more preferred embodiment, the amorphous vamorolone dispersion of the present invention is prepared by spray drying. Accordingly, the present invention provides a method for preparing the vamorolone composition of the present invention, i.e., vamorolone as a solid dispersion of amorphous vamorolone in a polymer matrix, by spray drying. Spray drying is well known in the art. This method includes, for example, atomizing a solution containing the active ingredient vamorolone and a polymer, optionally with suitable additives, to produce small droplets, which are then introduced into a chamber where they are contacted with a hot drying gas and dried by solvent evaporation to form particles. The particles can then be separated from the drying medium, for example, using a cyclone or bag filter. Thus, the spray drying process includes, for example, atomizing a feed solution containing vamorolone and a polymer or other suitable additives, contacting the resulting droplets with a hot drying medium, drying the droplets into particles, and separating the particles from the drying medium. The resulting powder preferably undergoes a secondary drying step to ensure that residual solvent is removed to an acceptable level.

[0031] Surprisingly, other methods have proven largely unsuccessful in preparing the compositions of the present invention. Experiments using hot-melt extrusion have failed to produce stable amorphous solid dispersions of vamorolone with adequate drug loading. For example, to obtain and stabilize an amorphous form of vamorolone, the drug loading of vamorolone in the dispersion must be about 20 wt% or less. Such drug loading is incompatible with an appropriate tablet size that is convenient for patients in terms of ease of swallowing. Meanwhile, the conditions required for higher drug loadings resulted in significant degradation of the active pharmaceutical ingredient.

[0032] One embodiment of preparing the solid dispersions of the invention using spray drying involves dissolving the drug and polymer in an organic solvent or mixture of organic solvents and spraying the resulting solution into a heated gas stream to remove the organic solvent.

[0033] Spray drying provides a fast drying rate and the ability to capture the drug substance in an amorphous form, allowing the drug substance to be co-precipitated with the polymer to form a stable amorphous solid dispersion.

[0034] In another aspect of the present invention, a pharmaceutical composition comprising the vamorolone of the present invention is provided. More preferably, the present invention provides a solid dosage form, preferably a tablet or a coated tablet. In another embodiment, the solid dosage form is a capsule. The capsule can be filled with a powder, granules, pellets, multiparticulates, or mini-tablets containing the composition of the present invention.

[0035] Further provided is a solid oral pharmaceutical composition comprising the vamorolone composition of the present invention as an amorphous solid dispersion and at least one filler, disintegrant, binder, glidant, wetting agent, and / or lubricant. In a preferred embodiment, a film coating may be added. Also provided is a method for preparing such a solid oral pharmaceutical composition.

[0036] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: a) asthma or chronic obstructive pulmonary disease, b) skin diseases; c) Sjögren's syndrome, d) arthritis, or e) Muscle wasting The present invention provides a vamorolone composition for use in a method for treating a disease selected from the group consisting of:

[0037] Preferably, the muscle wasting disease is muscular dystrophy. In some embodiments, the muscular dystrophy is selected from Duchenne muscular dystrophy, Becker muscular dystrophy, limb-girdle muscular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic muscular dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy, and Emery-Dreifuss muscular dystrophy.

[0038] Most preferably, the muscular dystrophy is Duchenne muscular dystrophy.

[0039] Further provided is the use of a polymer to improve the solubility of vamorolone in aqueous media by dispersing the solid amorphous form of vamorolone in the polymer. In this aspect of the invention, at least 50 wt% of the total amount of vamorolone should be dispersed amorphous vamorolone; more preferably, at least 60 wt% of the total amount of vamorolone should be dispersed amorphous vamorolone; even more preferably, at least 70 wt% of the total amount of vamorolone should be dispersed amorphous vamorolone; even more preferably, at least 80 wt% of the total amount of vamorolone should be dispersed amorphous vamorolone; even more preferably, at least 90 wt% of the total amount of vamorolone should be dispersed amorphous vamorolone; even more preferably, at least 95 wt% of the total amount of vamorolone should be dispersed amorphous vamorolone; even more preferably, at least 97 wt% of the total amount of vamorolone should be dispersed amorphous vamorolone; most preferably, at least 99 wt% of the total amount of vamorolone should be dispersed amorphous vamorolone. All amounts are the amount of amorphous vamorolone relative to the total vamorolone. The vamorolone dispersion is preferably obtained by spray drying. The vamorolone is preferably vamorolone in the composition of the present invention as defined in any of the above embodiments. [Brief explanation of the drawings]

[0040] [Figure 1A]Figures 1A and 1B show X-ray diffraction patterns obtained for solid dispersion prototypes obtained by hot-melt extrusion (1A) and spray drying (1B). Figure 1A shows the XRPD pattern of the HME prototype (40% vamorolone in VA64). Figure 1B shows the XRPD patterns of the SDD prototypes: (1) vamorolone: ​​Kollidon VA64 (1:2); (2) vamorolone: ​​HPMC E3 (1:2); (3) vamorolone: ​​HPMC E3 (1:1); (4) vamorolone: ​​HPMCAS M (1:2); (5) vamorolone: ​​HPMCAS M (1:1); (6) vamorolone: ​​HPMCAS M (2:1). For hot-melt extrusion, the selection of the polymer (Copovidone VA64) was based on the results of a preliminary blending study (miscibility experiment) in which the following polymers were evaluated using differential scanning calorimetry (DSC): Copovidone VA64, a Copovidone VA64 / poloxamer blend, a Copovidone VA64 / HPMC E3 blend, HPMCAS-L, and HPMCAS-M. The hot-melt extrusion results with the polymer that showed the best miscibility were unsatisfactory, as the diffractograms showed clear signs of crystallization at drug loadings above 40%. Furthermore, HPLC analysis of this sample confirmed degradation of the drug substance. However, spray drying yielded XR patterns typical of amorphous materials for several polymers: HPMCAS-M (drug loadings 67%, 50%, and 33%), HPMC E3 (drug loadings 50% and 33%), and Copovidone VA64 (drug loading 33%), suggesting that the conditions applied during spray drying were particularly advantageous for obtaining stable amorphous solid dispersions of vamorolone compared to hot-melt extrusion. [Figure 1B] See legend to Figure 1A. [Figure 2]Figure 2 shows the kinetic solubility of SDD prototypes in FaSSIF pH 6.5 compared to crystalline vamorolone. Figure 2 shows an overlay of the kinetic solubility profiles obtained for eight spray-dried amorphous solid dispersion prototypes in fasting simulated intestinal fluid (FaSSIF). For comparison, the solubility profile of micronized crystalline vamorolone is also included. While all prototypes showed increased solubility compared to crystalline vamorolone, the performance of different polymers was unexpectedly diverse and ranked as follows: HPMC-AS M > HPMC-E3 > Kollidon VA64. Furthermore, the ability of vamorolone to remain dissolved by the polymer in supersaturated solution was affected by different drug loadings. For the best-performing polymer, HPMC-AS M, solubilization was maintained at higher polymer loadings (hence, lower API loadings), and no vamorolone precipitation was observed. As the drug loading increases beyond approximately 67%, the risk of vamorolone precipitation increases significantly because the drug-to-polymer ratio decreases and less polymer is available to stabilize the drug. [Figure 3] Figure 3 shows the kinetic solubility of the SDD prototype in FaSSIF pH 6.5 compared to crystalline vamorolone and a mixture of crystalline vamorolone and HPMCAS-M. Figure 3 compares the kinetic solubility profiles obtained for crystalline vamorolone, a spray-dried amorphous solid dispersion prototype (vamorolone:HPMCAS-M (1:1)), and a physical mixture of vamorolone and HPMCAS M (1:1). The presence of polymer alone does not result in the increased solubility seen in the solid dispersion. [Figure 4] Figure 4 shows the XRPD patterns of stability samples after 4 weeks of storage in 25 / 60 (closed) and 40 / 75 (open). Figure 4 shows the XRPD stability data obtained for the spray-dried prototypes. The prototype obtained with HPMC E3 and the prototype with the highest drug loading (2:1 API:HPMCAS-M) showed clear signs of crystallization after 4 weeks in 40 / 75. DETAILED DESCRIPTION OF THE INVENTION

[0041] Detailed Description As used herein, the term "vamorolone" refers to 17α,21-dihydroxy-16α-methylpregna-1,4,9(11)-triene-3,20-dione (also known as VBP15), which has the following structure: I have TIFF2026504517000002.tif54128.

[0042] The term "crystalline vamorolone" refers to a drug substance that contains vamorolone crystals in an amount that can be detected by electron microscopy or XRPD. XRPD (X-ray powder diffraction) is an experimental technique that uses X-ray diffraction on powdered or microcrystalline samples for structural characterization of materials analysis.

[0043] The term "amorphous vamorolone" refers to vamorolone drug substance that exists primarily in an amorphous state, i.e., does not contain any amount of crystalline vamorolone detectable by XRPD. Preferably, the amount of crystalline vamorolone in the amorphous vamorolone is less than 10 wt%, more preferably less than 5 wt%, more preferably less than 3 wt%, more preferably less than 2 wt%, or most preferably less than 1 wt%. Ideally, the amorphous vamorolone is free of any crystalline form.

[0044] The term "administering" means providing a compound or other treatment, therapy, or procedure such that the individual internalizes the compound.

[0045] As used herein, the term "disease" is intended to be generally synonymous with, and used interchangeably with, the terms "disorder" and "condition" (e.g., medical condition), all of which reflect an abnormal condition of the human or animal body or parts thereof that impairs normal function and is typically manifested by characteristic signs and symptoms, resulting in a decrease in the lifespan or quality of life of the human or animal.

[0046] Vamorolone is used to treat any type of NF-κB-mediated disease. As used herein, the term "NF-κB-mediated disease" refers to a disease that has a significant pathological inflammatory component that can be addressed by inhibiting NF-κB. The term "NF-κB-mediated disease" also refers to the following diseases, even though the compounds disclosed herein exert their effects through biological pathways and / or processes other than NF-κB: muscular dystrophy, arthritis, traumatic brain injury, spinal cord injury, sepsis, rheumatic disease, cancer, atherosclerosis, type 1 diabetes, type 2 diabetes, leptospirosis nephropathy, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic metabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, ischemia / reperfusion, stroke, cerebral aneurysm, angina pectoris, lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, asthma, chronic obstructive pulmonary disease, Sjogren's syndrome, hyaline membrane disease, renal Diseases, glomerular diseases, alcoholic liver disease, intestinal diseases, peritoneal endometriosis, skin diseases, sinusitis, mesothelioma, anhidrotic ectodermal dysplasia-ID, Behçet's disease, incontinentia pigmenti, tuberculosis, asthma, Crohn's disease, colitis, ocular allergies, appendicitis, Paget's disease, pancreatitis, periodontitis, endometriosis, inflammatory bowel disease, inflammatory lung disease, silica-induced disease, sleep apnea, AIDS, HIV-1, autoimmune diseases, antiphospholipid syndrome, lupus, lupus nephritis, familial Mediterranean fever, hereditary periodic fever syndromes, psychosocial stress disorders, neuropathological diseases, familial amyloidotic polyneuropathy, inflammatory neuropathies, Parkinson's disease, multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, cataracts, and hearing loss.

[0047] As used herein, the term "pharmaceutical composition" means a composition containing at least one active ingredient, such as vamorolone, whereby the composition is suitable for investigation or study for a particular efficacious outcome in a mammal (e.g., but not limited to, a human).

[0048] As used herein, the term "pure" refers to a compound that is about 90-100%, preferably 95-100%, more preferably 98-100% (wt / wt), or 99-100% (wt / wt) pure, e.g., containing less than about 10%, less than about 5%, less than about 2%, or less than about 1% of impurities. Such impurities include, for example, degradation products, oxidation products, epimers, solvents, and / or other undesirable impurities. In practice, drug substance specifications include 98.0-102.0 wt% as measured by conventional methods.

[0049] As used herein, the term "therapeutically acceptable" refers to a compound (or salt, prodrug, tautomer, zwitterionic form, etc.) that is suitable for use in contact with the tissues of a patient without undue toxicity, irritation, or allergic response, is commensurate with a reasonable benefit / risk ratio, and is effective for its intended use.

[0050] As used herein, the phrase "therapeutically effective" is intended to qualify the amount of active ingredient used to treat a disease or disorder. It refers to a dose effective for a patient to reduce or eliminate the symptoms of the disease being treated.

[0051] As used herein, the terms "treat," "treatment," and the like refer to improving a disease so as to reduce or eliminate one or more of the causes, progression, severity, or symptoms of the disease in a subject, or otherwise beneficially alter the disease. Treatment may be preemptive in nature, i.e., include prophylaxis of the disease in a subject exposed to or at risk of the disease. Prevention of a disease may include complete protection from the disease, such as preventing infection by a pathogen, or may include preventing disease progression, such as from prediabetes to diabetes. For example, prevention of a disease may refer to preventing disease symptoms to a clinically significant or detectable level, rather than completely eliminating all effects associated with the disease at any level. Prevention of a disease may also refer to preventing the progression of the disease.

[0052] The term "amorphous solid dispersion" (ASD) refers to a system in which an active pharmaceutical ingredient (API), such as vamorolone, is embedded in a solid matrix of one or more polymers in a predominantly amorphous state, preferably without any crystalline form. In the present invention, preferably, at least 95 wt% of the total amount of vamorolone is dispersed amorphous vamorolone, and most preferably, at least 99 wt% of the total amount of vamorolone is dispersed amorphous vamorolone. Ideally, 100 wt% of the total amount of vamorolone is dispersed amorphous vamorolone. All of these amounts are based on the amount of amorphous vamorolone relative to the total amount of vamorolone.

[0053] Spray drying (SD) is a technique that involves converting a liquid material (solution or suspension) into a solid form, and involves drying a solution that has been previously atomized into small droplets.

[0054] Hot melt extrusion (HME) involves mixing an active compound and excipients (mainly thermoplastic polymers) under thermal and mechanical stress, followed by extrusion through a die, often with the aim of melting or dispersing the drug in the polymer excipient to obtain a product in which the active compound is in an amorphous state.

[0055] Vamorolone as a solid dispersion in polymers The present invention provides a composition comprising amorphous vamorolone. Vamorolone can be prepared, for example, according to US 2020 / 0281942.

[0056] The compositions of the present invention comprise amorphous vamorolone in an amorphous solid dispersion with a polymer.

[0057] In a more preferred embodiment, the amorphous vamorolone of the present invention is prepared by spray drying.

[0058] In a more preferred embodiment, the compositions of the present invention are stable for at least two weeks when stored in an open container at 40°C / 75% relative humidity.

[0059] In a further preferred embodiment, the composition of the present invention comprises at least 20 wt% vamorolone, preferably at least 30 wt%, more preferably at least 40 wt%, and even more preferably at least 50 wt% vamorolone, based on the weight of the composition. In any of these embodiments, the composition of the present invention is preferably an amorphous solid dispersion comprising vamorolone and a polymer or polymer mixture. In another preferred embodiment, the composition of the present invention further comprises a wetting agent.

[0060] In further preferred embodiments, the compositions of the present invention comprise 80 wt% or less vamorolone, preferably 70 wt% or less vamorolone, more preferably 67 wt% or less vamorolone, and even more preferably 60 wt% or less vamorolone, based on the weight of the composition. In any of these embodiments, the compositions of the present invention are preferably amorphous solid dispersions comprising vamorolone and a polymer.

[0061] In one aspect of the present invention, the particle size distribution of vamorolone in the vamorolone composition of the present invention, i.e., the amorphous solid dispersion with polymer, is defined as follows: d10: up to 6 μm, d50: up to 15 μm, and d90: up to 35 μm.

[0062] In another aspect of the present invention, the amorphous solid dispersion composition of the present invention has a BET surface area of ​​800 to 1,200 m 2 / g, preferably 900 to 1.00 m 2 / g.

[0063] Pharmaceutical compositions containing vamorolone In another aspect of the present invention, there is provided a pharmaceutical composition comprising vamorolone as the amorphous solid dispersion of the present invention.

[0064] Preferably, the present invention provides an oral pharmaceutical composition comprising vamorolone.

[0065] In some embodiments, the oral pharmaceutical composition comprises vamorolone as an amorphous solid dispersion (ASD) in an amount of about 20 wt% to about 80 wt% of the ASD relative to the total weight of the pharmaceutical composition. In some embodiments, the oral pharmaceutical composition comprises vamorolone in an amount of about 25% to about 75 wt% of the ASD relative to the total weight of the pharmaceutical composition. In some embodiments, the oral pharmaceutical composition comprises vamorolone in an amount of about 30 wt% to about 70 wt% of the ASD relative to the total weight of the pharmaceutical composition. In some embodiments, the oral pharmaceutical composition comprises vamorolone in an amount of about 40 wt% to about 60 wt% of the ASD relative to the total weight of the pharmaceutical composition. Preferably, in the pharmaceutical composition, the amount of amorphous vamorolone in the ASD is 40 wt% to 60 wt% of the ASD relative to the total weight of the pharmaceutical composition. More preferably, in the pharmaceutical composition, the amount of amorphous vamorolone in the pharmaceutical composition is 20 wt% to 40 wt% based on the total amount of the pharmaceutical composition.

[0066] In some embodiments, the ASD is used to prepare a pharmaceutical composition further comprising at least one pharmaceutically acceptable ingredient, such as a filler. In some embodiments, the filler is selected from lactose, calcium phosphate, sorbitol, mannitol, maltitol, lactitol, cellulose, microcrystalline cellulose, starch, pregelatinized starch, sucrose, or any combination thereof. In one embodiment, the pharmaceutical composition comprises at least one pharmaceutically acceptable ingredient, such as a filler, in an amount of up to 70 wt%, up to 50 wt%, up to 35 wt%, up to 25 wt%, and most preferably up to 10 wt%, based on the total weight of the pharmaceutical composition.

[0067] The pharmaceutical compositions of the present invention can also include a pharmaceutically acceptable binder, such as cellulose, microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyethylene glycol, maltodextrin, pregelatinized starch, or a combination thereof, to impart cohesiveness to the powder and thereby provide the binding properties necessary to form granules that, under compression, form a dense mass, such as a tablet. In one embodiment, the pharmaceutical composition includes at least one binder in an amount of up to 50 wt%, up to 25 wt%, up to 10 wt%, and most preferably up to 5 wt%, based on the total weight of the pharmaceutical composition.

[0068] The pharmaceutical compositions of the present invention can also include a pharmaceutically acceptable disintegrant, such as croscarmellose sodium, sodium starch glycolate, crospovidone, or a combination thereof, to facilitate disintegration of the solid dosage form. In one embodiment, the pharmaceutical composition includes at least one disintegrant in an amount of up to 20 wt%, up to 15 wt%, up to 10 wt%, and most preferably up to 5 wt%, based on the total weight of the pharmaceutical composition.

[0069] In some embodiments, the pharmaceutical composition further contains a pharmaceutically acceptable glidant, such as colloidal silicon dioxide, talc, or a combination thereof, to improve the flowability of the blend. In one embodiment, the pharmaceutical composition comprises at least one glidant in an amount of up to 15 wt%, up to 10 wt%, up to 5 wt%, and most preferably up to 1 wt%, based on the total weight of the pharmaceutical composition.

[0070] The pharmaceutical composition of the present invention also contains a pharmaceutically acceptable lubricant to reduce ejection force and prevent sticking during compression. Such lubricants are selected from pharmaceutically acceptable fatty acid esters, such as magnesium stearate, sodium stearyl fumarate, stearic acid, hydrogenated oils, or any combination thereof. In one embodiment, the pharmaceutical composition comprises at least one lubricant in an amount of up to 10 wt%, up to 5 wt%, up to 3 wt%, up to 2 wt%, and most preferably up to 1 wt%, based on the total weight of the pharmaceutical composition.

[0071] The pharmaceutical compositions of the present invention also contain pharmaceutically acceptable film-coating agents, such as film-forming agents, softening agents, wetting agents, opacifying and / or coloring pigments. Such film-forming agents are selected from cellulose derivatives, vinyl polymers, or pharmaceutically acceptable polymers, such as polyacrylate, polyethyl acrylate, or polymethacrylate polymers, to provide non-functional film coatings, film coatings that protect against moisture, or a combination of both. In one embodiment, the pharmaceutical composition contains at least one film-coating agent in an amount of up to 10 wt%, up to 8 wt%, up to 6 wt%, up to 4 wt%, and most preferably up to 2 wt%, based on the total weight of the pharmaceutical composition. Conventional film-coating methods can be used to apply the film coating, for example, by spraying a solution or dispersion of the above ingredients in a suitable solvent (water or organic solvent) onto tablet cores or capsules in a perforated pan coater.

[0072] How to use Also provided is amorphous vamorolone of the present invention for use in a method for treating a disease having a significant pathological inflammatory component that can be addressed by inhibition of NF-κB in a human or animal subject in need thereof, said treatment comprising administering to said subject an amount of the suspension described herein effective to alleviate or prevent said disease in said subject, optionally in combination with at least one additional agent suitable for treating said disease known in the standard of care.

[0073] Specific diseases treated by the compounds, compositions, and methods disclosed herein include: acid-induced lung injury, acne (PAPA), acute respiratory distress syndrome, aging, AIDS, HIV-1, alcoholic hepatitis, alcoholic liver disease, allergic bronchopulmonary aspergillosis, Alzheimer's disease, amyotrophic lateral sclerosis, angina pectoris, anhidrotic ectodermal dysplasia-ID, ankylosing spondylitis, antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis, asthma, allergen-induced asthma, non-allergen-induced asthma, arteriosclerosis, atopic dermatitis, autoimmune diseases. , Behçet's disease, Bell's palsy, Blau syndrome, bronchitis, cancer, cardiac hypertrophy, catabolic metabolic disorders, cataracts, cerebral aneurysm, chronic heart failure, chronic lung disease (including those due to premature birth), chronic obstructive pulmonary disease, colitis, ulcerative colitis, complex regional pain syndrome, connective tissue disease, Crohn's disease, cryopyrin-associated periodic fever syndrome, cryptococcosis, cystic fibrosis, interleukin-1 receptor antagonist molecule deficiency (DIRA), dermatitis, dermatomyositis, endometriosis, endotoxemia, familial amyloidotic polyneuropathy, familial cold urticaria, familial Mediterranean fever, fetal growth retardation, glaucoma, glomerular disease, glomerular Nephritis, bowel disease, head trauma, headache, hearing loss, heart disease, Henoch-Schönlein purpura, hepatitis, hereditary periodic fever syndromes, shingles and herpes simplex, Huntington's disease, hyaline membrane disease, hypercholesterolemia, hyper-IgD syndrome with recurrent fever (HIDS), aplastic anemia and other anemias, incontinentia pigmenti, infectious mononucleosis, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory pain, irritant-induced inflammation, plant irritant-induced inflammation, poison ivy / urushiol oil-induced inflammation, chemical irritant-induced inflammation, bee sting-induced inflammation, insect sting-induced inflammation, ischemia / reperfusion, kidney Disease, kidney damage due to parasitic infection, leptospirosis, leukemia, lung damage, lupus, lupus nephritis, lymphoma, meningitis, mesothelioma, Muckle-Wells syndrome (urticaria, hearing loss, amyloidosis), multiple sclerosis, muscle wasting, muscular dystrophy, mycosis fungoides, myelodysplastic syndrome, myocarditis, myositis, sinusitis, necrotizing enterocolitis, neonatal-onset multisystem inflammatory disease (NOMID), nephrotic syndrome, neuritis, neuropathological diseases, obesity, ocular allergies, osteoarthritis, otitis media, Paget's disease, pain, pancreatitis, Parkinson's disease, pericarditis, periodontitis, peritoneal endometriosis, whooping cough,Pharyngitis and adenitis (PFAPA syndrome), Pneumocystis infection, polyarteritis nodosa, polycystic kidney disease, polymyositis, psoriasis, psychosocial stress disorder, lung disease, pulmonary fibrosis, pulmonary hypertension, pyoderma gangrenosum, suppurative aseptic arthritis, renal disease, retinal disease, rheumatic disease, rheumatoid arthritis, sarcoidosis, seborrhea, sepsis, silica-induced disease, Sjögren's syndrome, skin disease, sleep apnea syndrome, solid tumors, spinal cord injury, stroke, subarachnoid hemorrhage, sunburn, burns, thrombocytopenia, TNF receptor-associated periodic syndrome (TRAPS), post-transplant toxoplasmosis, organ transplant, tissue transplant, traumatic brain injury, tuberculosis, type 1 diabetes, type 2 diabetes, uveitis.

[0074] In some embodiments, the disease is selected from acute lymphocytic leukemia, Addison's disease, adrenal hyperplasia, adrenal insufficiency, allergic conjunctivitis, alopecia, amyloidosis, angioedema, anterior segment inflammation, autoimmune hepatitis, Behcet's syndrome, beryllium disease, bone pain, bursitis, carpal tunnel syndrome, chorioretinitis, chronic lymphocytic leukemia, corneal ulcer, diffuse intrinsic pontine glioma, epicondylitis, erythroblastopenia, gout, gouty arthritis, graft versus host disease, hemolytic anemia, Hodgkin's disease, hypercalcemia, hyperammonemia, aplastic anemia, idiopathic thrombocytopenic purpura, iritis, and juvenile rheumatoid arthritis, keratitis, kidney transplant rejection prophylaxis, Leffler's syndrome, mixed connective tissue disease, myasthenia gravis, mycosis fungoides, optic neuritis, pemphigus, pneumonia, pneumonitis, polychondritis, psoriasis, rheumatic heart disease, severe pain, sickle cell anemia, sickle cell anemia, Stevens-Johnson syndrome, temporal arteritis, tenosynovitis, thyroiditis, urticaria, Wegener's granulomatosis, and weight loss.

[0075] In some embodiments, the disease is asthma or chronic obstructive pulmonary disease.

[0076] In some embodiments, the disease is Sjogren's syndrome.

[0077] In some embodiments, the disease is arthritis.

[0078] In some embodiments, the disease is muscle wasting.

[0079] In some embodiments, the muscle wasting disease is a muscular dystrophy.

[0080] In some embodiments, the muscular dystrophy is selected from Duchenne muscular dystrophy, Becker muscular dystrophy, limb-girdle muscular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic muscular dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy, and Emery-Dreifuss muscular dystrophy.

[0081] In some embodiments, the muscular dystrophy is Duchenne muscular dystrophy.

[0082] In certain embodiments, crystalline vamorolone is administered at a dose of 0.1 to 500 mg / kg per day, preferably 0.5 to 20 mg / kg per day, and more preferably 1 to 10 mg / kg per day. Most preferably, crystalline vamorolone is administered at a dose of 2 to 6 mg / kg per day. In some embodiments, the dose range is 0.25 to 6.0 mg / kg / day, e.g., 0.25 mg / kg / day, 0.75 mg / kg / day, 2.0 mg / kg / day, or 6.0 mg / kg / day. The dose range for adults is generally 5 mg to 2 g / day.

[0083] The following embodiments are provided herein: 1. An amorphous solid dispersion comprising vamorolone and at least one pharmaceutically acceptable polymer. In this composition, vamorolone is preferably present in an amorphous state embedded in a pharmaceutically acceptable polymer. 2. The amorphous solid dispersion of item 1, wherein vamorolone is present in an amount of at least 20 wt%, at least 30 wt%, preferably at least 40 wt%, more preferably at least 50 wt%, and most preferably 45 wt% to 60 wt%, based on the weight of the amorphous solid dispersion. 3. The amorphous solid dispersion of any of items 1-2, wherein vamorolone is present in an amount of 40 wt% to 60 wt% based on the weight of the amorphous solid dispersion, preferably with a total polymer amount of 40 to 60 wt% based on the weight of the amorphous solid dispersion. In more preferred embodiments, the polymer may be present at 37-57 wt% based on the weight of the amorphous solid dispersion, 38-58 wt% based on the weight of the amorphous solid dispersion, or 39-59 wt% based on the weight of the amorphous solid dispersion. 4. The amorphous solid dispersion of any of items 1 to 3, wherein the composition comprises a polymer selected from cellulose, cellulose derivatives, povidone, copovidone, or derivatives of methacrylic acid, ethyl acrylate, and / or methyl methacrylate. Such polymers may include copolymers. The polymer is preferably selected from hydroxypropyl methylcellulose (HPMC), copovidone (polyvinylpyrrolidone-vinyl acetate copolymer), and hydroxypropyl methylcellulose acetate succinate (HPMCAS; grades L, M, or H). In the most preferred embodiment, the polymer is hydroxypropyl methylcellulose acetate succinate. In a specific embodiment, the polymer is selected from cellulose derivatives, preferably hydroxypropyl methylcellulose derivatives, more preferably hydroxypropyl methylcellulose acetate succinate grades L, H, or M. In one preferred embodiment, the polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS) grade M, which dissolves at pH values ​​above 6.0. Preferably, the amorphous solid dispersion of vamorolone comprises at least one polymer selected from HPMC, HPC, HPMCAS-L, HPMCAS-M, povidone, and copovidone. 5. The amorphous solid dispersion of any one of items 1 to 4, comprising 3 wt% or less of other ingredients based on the weight of the amorphous solid dispersion. The other ingredient may be a stabilizer or a humectant. 6. The amorphous solid dispersion of any of items 1 to 5, wherein the amorphous solid dispersion of vamorolone is obtained by spray drying. 7. A pharmaceutical composition comprising the amorphous solid dispersion of any one of items 1 to 6 and a pharmaceutically acceptable excipient. 8. The pharmaceutical composition of item 7, comprising vamorolone in an amount of at least 20 wt% based on the weight of the pharmaceutical composition, preferably at least 25 wt% based on the weight of the pharmaceutical composition, and most preferably at least 30 wt% based on the weight of the pharmaceutical composition. 9. The pharmaceutical composition of item 7 or 8, further comprising a filler. Preferably, the filler is as defined above. 10. The pharmaceutical composition of any of items 7 to 9, further comprising a binder. Preferably, the binder is as defined above. 11. The pharmaceutical composition of any of items 7 to 10, further comprising a disintegrant. Preferably, the disintegrant is as defined above. 12. The pharmaceutical composition of any of items 7 to 11, further comprising a lubricant. Preferably, the lubricant is as defined above. 13. The pharmaceutical composition of any of items 7 to 12, further comprising a glidant. Preferably, the glidant is as defined above. 14. The pharmaceutical composition of any of items 7 to 13, which is a tablet or capsule. Preferably, a solid dosage form such as a tablet or capsule comprises a film coating as defined above. 15. Use of a polymer to improve the solubility of vamorolone in aqueous media by dispersing amorphous form of vamorolone in the polymer. 16. A method of preparing the amorphous solid dispersion of item 1 by spray drying. Spray drying can be carried out by conventional methods known to those skilled in the art and / or as described herein above. [Example]

[0084] Example 1: Synthesis of vamorolone in US 2020 / 0281942 TIFF2026504517000003.tif163128 Scheme A: Synthetic Route in US 2020 / 0281942

[0085] 1.1 Step 1: Preparation of Compound 2 3-TR (100 g, 273 mmol), dichloromethane (DCM, 500 mL), and tetrahydrofuran (THF, 400 mL) were charged to a reaction flask under nitrogen. To this was added trimethylsilylimidazole (TMS-imidazole, 65.3 g, 466 mmol, 1.7 equiv.). The resulting mixture was stirred at room temperature for 3 hours.

[0086] In a separate flask, copper acetate monohydrate (5.4 g, 27 mmol), tetrahydrofuran (400 mL), and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 53.3 g, 416 mmol) were mixed and stirred at room temperature for approximately 3 hours. The blue mixture was then cooled to -50°C and methylmagnesium chloride solution (27 mL, 3.0 M in THF, 82 mmol) was added dropwise. After 30 minutes, the mixture formed a dark blue, sticky "ball."

[0087] The 3-TR / TMS-imidazole mixture was cooled to -50°C and the copper acetate / DMPU solution was added via cannula. Any remaining sticky mass from the copper acetate / DMPU mixture was dissolved with DCM (50 mL) and this was also transferred.

[0088] To the combined reaction mixture was added methylmagnesium chloride (123.2 mL, 3.0 M solution in THF, 368 mmol) dropwise over 45 min and then stirred at −50° C. for 2 h, after which HPLC analysis indicated complete consumption of the starting material. The mixture was allowed to warm to room temperature with stirring overnight.

[0089] Toluene (800 mL) was added to the mixture, followed by 5% acetic acid solution (600 mL). The aqueous layer was removed and discarded. The acetic acid wash was repeated. The organic layer was washed with brine (400 mL), 5% sodium bicarbonate solution (400 mL x 2), followed by a brine wash (400 mL). The organic solution was dried over sodium sulfate and then concentrated to dryness under reduced pressure. The product was recovered as a viscous, pale golden oil. Mass recovery was 146 grams (119% of theoretical).

[0090] 1.2 Step 2: Preparation of Compound 3 Compound 2 (92 g, 202 mmol) and toluene (1000 mL, 10.9 vol) were charged to a reaction flask under nitrogen, and the solution was cooled to -10 °C. A 32 wt% solution of peracetic acid in acetic acid (60 mL, 283 mmol, 1.4 eq) was added dropwise over approximately 30 min, maintaining the temperature at -10 °C. The reaction was held for approximately 20 h (HPLC indicated 75% compound 3, 1.5% compound 2, 6% diastereomer, and 5% epoxide). Starting at -10 °C, 20% aqueous sodium bisulfite (920 mL, 10 vol) was carefully added via the addition funnel, maintaining the temperature below 10 °C. Trifluoroacetic acid (16 mL, 202 mmol, 1 eq) was added, and the mixture was held at 0–5 °C for 3 h to complete the desilylation (end point by HPLC). The lower aqueous layer was drained, and the organic layer was washed with saturated sodium bicarbonate solution (3 × 250 mL), followed by water (1 × 250 mL) and brine (1 × 150 mL). The organic layer was then dried over NaSO, filtered, and concentrated to a pasty solid (89 g). The residue was taken up in 1.5 volumes of EtOAc and transferred to neat heptane (19 volumes), precipitating crude compound 3 as an off-white solid (50 g, 62.5% yield; HPLC: 79% compound 3, 5.6% epoxide, 1.7% diastereomer). Crude compound 3 (48.5 g) was triturated in acetonitrile (2 volumes) warmed to 60 °C for 4 hours, then allowed to slowly cool to ambient temperature overnight. The mixture was filtered, and the filtrate was reused to rinse and wash the wet cake. After drying, the recovery was 64.3% (31.2 g; HPLC: 93.5% compound 3, 3.3% epoxide). To remove the epoxide impurity, compound 3 was dissolved in DCM (250 mL, 8 vol.) and 48% aqueous HBr (7.5 mL) was added. The mixture was heated at 40 °C for 1 h (HPLC: <0.3% epoxide). The mixture was cooled and transferred to a separatory funnel. The lower aqueous layer (brown) was removed, and the upper organic layer was washed with water (200 mL), saturated NaHCO solution (150 mL), and brine (100 mL). The organic phase was dried over NaSO, filtered, and concentrated to a tan foam (32 g, approximately 100% recovery).Methanol (64 mL, 2 volumes) was added to 32 g of the foam to form a slurry. To this was added a 1:1 solution of MeOH and water (60 mL, 2 volumes) dropwise. The slurry was cooled to slightly below ambient temperature, filtered, and the filtrate was recycled to rinse and wash the wet cake. The solid was dried to constant weight to give 26.1 g of compound 3 (81% recovery, 97.8% HPLC). The overall yield for Step 2 was 32.5%.

[0091] 1.3 Step 3: Preparation of VBP15 Compound 3 (26 g, 65 mmol) and MeOH (156 mL, 6 vol) were mixed in a reaction flask and cooled to 0–5 °C. A solution of K2CO3 (9.9 g, 72 mmol, 1.1 equiv.) in water (65 mL) was added dropwise, and the mixture was allowed to warm gradually to ambient temperature overnight. HPLC analysis indicated 2.5% SM (starting material), so an additional 5 mol% K2CO3 was added, and the mixture was stirred for another day (HPLC endpoint: 1.1% compound 3). The mixture was neutralized to pH 7 with 1.5 M HCl (53 mL), and approximately 25% (30 g) of the MeOH was removed under vacuum to maximize recovery. After stirring for 2 days, the product was isolated by filtration, and the filtrate was recycled and the wet cake was transferred to a separatory funnel. The wet cake was dried under vacuum to give 19.3 g of VBP15 (83% yield) as an off-white powder. HPLC analysis of this solid showed it to be 98.8% pure with 0.6% of compound 3 as the only major impurity.

[0092] Example 2: Preparation of amorphous solid dispersion of vamorolone 2.1 Polymer-stabilized amorphous vamololone The solubility of vamorolone is limited to approximately 40 μg / ml in aqueous solution at 37°C.

[0093] There is a need for stable forms of vamorolone that have improved solubility compared to the crystalline drug in order to reduce the dose administered to patients.

[0094] Since various attempts at improving crystalline vamorolone have failed, the present inventors have investigated how to obtain a stable amorphous form of vamorolone as an amorphous solid dispersion in order to enhance its solubility.

[0095] However, this has proven difficult: amorphous solids tend to crystallize into energetically more stable crystalline forms, which usually poses undesirable stability issues for solid oral formulations.

[0096] In preliminary attempts, amorphous vamorolone could be obtained by cryomilling, but the material was found to recrystallize within a few days at room temperature in a closed container.

[0097] Spray drying and hot melt extrusion are common techniques used to prepare solid amorphous dispersions, in which the amorphous state is stabilized by a suitable polymer.

[0098] 2.2 Screening for optimal polymers in the first stage Furthermore, because spray drying requires dissolving the drug and polymer, we also screened for the optimal solvent system.

[0099] The solubility of micronized vamorolone was evaluated in several common organic solvent systems suitable for use in spray drying.

[0100] A 10 mg amount of vamorolone was dispensed into a 2 mL HPLC vial. The experimental design involved adding the test solvent in 200 μl and 100 μl aliquots. After each aliquot addition, the sample was vortexed for 1 minute and the solubility was assessed visually. Observations were also made 1 hour after solvent addition.

[0101] The results of the solvent solubility screening of the drug substance vamorolone are summarized in Table 1 below.

[0102] (Table 1) Solvent solubility screening TIFF2026504517000004.tif54158

[0103] Both DCM (dichloromethane):methanol (1:1) and (1:3) solvent systems gave clear solutions at 50 mg / ml.

[0104] As a next step, the solubility of the polymer was evaluated in a DCM:methanol (1:3) solvent system. A 10 mg amount of polymer was dispensed into a 2 mL HPLC vial. The experimental design was to add this solvent system in 100 μL aliquots. After each aliquot addition, the sample was vortexed for 1 minute and the solubility was assessed visually.

[0105] The results of the evaluation are summarized in the table below.

[0106] (Table 2) Solubility results TIFF2026504517000005.tif43154

[0107] All polymers resulted in clear solutions at 50 mg / ml.

[0108] 2.3 Spray drying prototype Based on the initial screening activities, a spray drying prototype (SDD) was obtained using conventional parameters.

[0109] Spray drying was performed under an inert atmosphere (N2) on a Büchi B-290 equipped with a Büchi B-295 Inert Loop unit. Each run was performed under the same target spray drying parameters. DCM / methanol (1:3) was used as the solvent for all formulations. A total of 15.0 g of solids was spray dried in each case. Processing details are summarized in Table 3 below. Secondary drying was performed under vacuum at 50°C for 3-4 days.

[0110] (Table 3) Treatment details TIFF2026504517000006.tif57160*The inlet temperature was increased from 50 to 60°C to raise the outlet temperature above 40°C.

[0111] The amorphous state of vamorolone in the SDD prototype was confirmed by XRPD, scanning electron microscopy, and DSC. The particle size distribution of the vamorolone amorphous dispersion was determined by laser diffraction particle size analysis to be d10 1.4 μm, d50 7.5 μm, and d90 17.5 μm. The specific surface area measured by BET surface area analysis was 1.088 m 2 / g.

[0112] 2.4 Kinetic Solubility Data of Spray-Dried Prototypes The SDD prototype was evaluated for kinetic solubility in FaSSIF (fasting simulated intestinal fluid, pH=6.5) using a Pion μDissolution monitor with a tip pathlength of 2 mm. Data were collected over 18 hours in 20 mL of each medium heated to 37±2°C using AUPro software. The stirring rate was 250 rpm throughout the experiment.

[0113] In the case of HPMAS-M, the amorphous solid dispersion of vamorolone exhibited a surprisingly improved kinetic solubility of about 4-fold or more compared to the crystalline drug, as shown in Table 4 below.

[0114] (Table 4) Solubility data TIFF2026504517000007.tif77155

[0115] All SDD formulations were able to achieve higher concentrations of vamorolone in FaSSIF compared to crystalline vamorolone. The performance of each polymer could be ranked as follows: HPMC-AS M>HPMC-E3>Kollidon VA64. The ability of vamorolone to remain dissolved is affected by different drug loadings. For HPMC-AS M with higher polymer loadings (and therefore lower vamorolone loadings), the dissolution profile over time remains flat and no vamorolone precipitation is observed. For SDDs featuring higher vamorolone loadings and lower polymer loadings, vamorolone is at a much higher risk of precipitation, and the stabilizing effect of the polymer in keeping vamorolone dissolved decreases over time.

[0116] Figure 2 shows an overlay of kinetic solubility profiles obtained for eight spray-dried amorphous solid dispersion prototypes of vamorolone ("API") in fasting simulated intestinal fluid (FaSSIF). For comparison, the solubility profile of micronized crystalline vamorolone is also included. While all prototypes demonstrated increased solubility compared to crystalline vamorolone, the performance of the different polymers varied unexpectedly and was ranked as follows: HPMC-AS M > HPMC-E3 > Kollidon VA64. Furthermore, the ability of vamorolone to remain dissolved by the polymer in supersaturated solutions was affected by different drug loadings. For the best-performing polymer, HPMC-AS M, solubilization was maintained at higher polymer loadings (hence, lower API loadings), and no vamorolone precipitation was observed. As drug loadings increased beyond approximately 67%, the drug-to-polymer ratio decreased, leaving less polymer available to stabilize the drug, placing vamorolone at a significant risk of precipitation. Thus, the solubility decreases over time.

[0117] Figure 3 shows a comparison of the kinetic solubility profiles obtained for crystalline vamorolone, a spray-dried amorphous solid dispersion prototype (vamorolone:HPMCAS M (1:1)), and a physical mixture of vamorolone and HPMCAS M (1:1). The presence of polymer alone does not result in the increased solubility seen in the solid dispersion.

[0118] 2.5 HME (Hot Melt Extrusion) The feasibility of preparing amorphous solid dispersions of vamorolone was further evaluated by using hot-melt extrusion. In preliminary studies, miscibility was assessed by DSC (differential scanning calorimetry).

[0119] The following polymer systems were chosen because of their wide processing temperature range (large difference between Tg and decomposition temperature): HPMCAS-M (Tg 120℃) HPMCAS-L (Tg 120℃) Kollidon VA64 (Tg 101℃) Corridon VA64 / HPMC-E3 (75 / 25) Kollidon VA64 / Poloxamer 188 (97.5 / 2.5)

[0120] In the case of HPMCAS-M and HPMCAS-L, even the 20% vamorolone blend showed crystallinity after DSC runs. Similar results were observed for the 40% vamorolone blend in HPMC-E3. Therefore, these polymers were found to be unsuitable for further HME experiments.

[0121] The best results were obtained with Kollidon VA64, where vamorolone blends with 50% as well as 60% drug loading were found to be completely amorphous by XRPD after DSC runs, thereby indicating the miscibility of vamorolone up to at least 60% vamorolone loading.

[0122] 2.6. Preparation of HME prototype The manufacturing scale was 30 g of blend. To prepare the blend for extrusion, the required amount of each ingredient was weighed and placed in a mixing vessel. Mixing was performed in a Pharmatech MB005 blender. Hot melt extrusion (HME) was performed in a Thermo Scientific Process 11 extruder equipped with a 2 mm die, and tests were performed using standard twin screw configurations and processing conditions.

[0123] This experiment resulted in opaque / crystalline extrudates in which the drug substance contained had undergone significant degradation. Vamorolone in the VA64 blend exhibited significant crystallization, indicating that HME is an undesirable approach to stabilizing vamorolone in its amorphous form.

[0124] Figure 1a shows the crystallization pattern of vamorolone in the VA64 blend. For comparison, Figure 1b is presented, which shows amorphous vamorolone stabilized in the formulation obtained by spray drying.

[0125] In the case of the vamorolone / VA64 system, HME was not considered a feasible technique for preparing stable amorphous solid dispersions, and other polymers were not attractive enough to be further explored due to the relatively low achievable drug loadings.

[0126] Overall, the HME studies unexpectedly showed significant degradation of the resulting extrudates or a lack of miscibility of vamorolone in the polymer, suggesting that HME is not a viable technique for producing amorphous solid dispersions of vamorolone.

[0127] 2.7. Stability testing of spray-dried (SDD) prototypes Based on the characterization and kinetic solubility data, the following batches of prototype SDD were subjected to a 4-week stability study to investigate the physical and chemical stability of the amorphous solid dispersion of vamorolone:

[0128] (Table 5) Description of SDD TIFF2026504517000008.tif71141

[0129] All samples were subjected to stability conditions of 25°C / 60% relative humidity (closed) and 40°C / 75% relative humidity (open) for the duration of the study. Additionally, samples of 55% and 60% SDD were also subjected to 40°C / 75% relative humidity (closed) to evaluate the effect of humidity (data not shown). SDD was stored in Type I borosilicate glass vials held upright for the duration of the study.

[0130] Figure 4 shows the XRPD data for HPMC-E3(1:1), HPMCAS-M(1:2), HPMCAS-M(1:1), and HPMCAS-M(2:1) after 4 weeks of storage at 25°C and 60% relative humidity (closed) and 40°C and 75% relative humidity (open).

[0131] Of all the SDDs, the 1:1 API / HPMC-E3 SDD showed clear signs of crystallization at 40 °C / 75% relative humidity and showed the worst results in terms of physical stability, followed by the sample corresponding to HPMCAS-M (2:1).

[0132] For HPMCAS-M (1:2) and HPMCAS-M (1:1), no crystallization was observed under all conditions tested.

[0133] Chemical stability was satisfactory in all cases, with total impurity contents below 1.0% in all batches at all conditions after 4 weeks.

[0134] 2.8. Conclusion HME studies showed significant degradation of the resulting extrudates or a lack of miscibility of vamorolone in the polymer, suggesting that HME is not a viable technique for producing amorphous solid dispersions.

[0135] Spray drying studies showed promising results for the SDD prototype under certain conditions. An amorphous solid dispersion containing vamorolone:HPMCAS-M (1:1) was considered to be the optimal balance for further development in terms of stability and drug loading.

[0136] Example 3: Solid Dosage Form The amorphous solid dispersions described above were obtained in the form of fine powders that can be characterized by PSD, density, and other techniques known to those skilled in the art.

[0137] The PSD of the HPMCAS-M (1:1) batch was measured by laser diffraction (dry method, Malvern Mastersizer 3000), and the following representative results were obtained: D10: 1.419 μm, D50: 7.528 μm, and D90: 17.509 μm.

[0138] The true density was measured using an AccuPyc II 1340 pycnometer: 1.27 g / ml. Additionally, a compression simulation test was performed by conducting a Heckel test. The purpose of the Heckel test is to compress a material under controlled conditions to derive the yield stress of the bulk material. A known weight of material is compressed with a flat-faced punch moving at a set speed within a 10 mm diameter die. The force exerted on the punch is measured frequently with high precision, while the punch displacement is used to calculate the powder volume. The yield stress is calculated at low and high punch speeds to assess the time-dependent component of material deformation. Based on this test, the ASD powder (obtained by spray drying, i.e., SDD) was classified as soft and ductile.

[0139] Furthermore, when formulated into tablets, the strength results suggest that vamorolone ASD can contribute to the overall strength of the tablet, so that high concentrations are theoretically possible.

[0140] The ASD produced as described above can be used to produce solid dosage forms such as tablets, coated tablets, minitablets, pellets, granules, capsules, etc. Such dosage forms can be obtained by employing standard manufacturing processes and equipment. Typical unit operations that may be applicable include, but are not limited to, blending, sieving, milling, roller compaction, slugging, tabletting, extrusion and spheronization, capsule filling, and film coating, among others.

[0141] Standard pharmaceutically acceptable excipients are processed together with the ASD to obtain such dosage forms.

[0142] Table 6 below shows the tablet formulations containing an ASD of vamorolone:HPMCAS-M (1:1). The tablets were manufactured by dry granulation and the resulting granules were compressed into different tablet weights to achieve various dose strengths.

[0143] Table 6: Tablet formulation TIFF2026504517000009.tif129157

Claims

1. An amorphous solid dispersion comprising vamorolone and at least one pharmaceutically acceptable polymer.

2. 10. The amorphous solid dispersion of claim 1, wherein vamorolone is present in an amount of at least 20 wt% based on the weight of the amorphous solid dispersion.

3. 3. The amorphous solid dispersion of claim 1, comprising vamorolone in an amount of 40 to 60 wt %, based on the weight of the amorphous solid dispersion, and total polymer in an amount of 40 to 60 wt %, based on the weight of the amorphous solid dispersion.

4. 4. The amorphous solid dispersion of claim 1, wherein the composition comprises a polymer selected from cellulose, cellulose derivatives, povidone, copovidone, derivatives of methacrylic acid and / or methyl methacrylate.

5. 5. The amorphous solid dispersion of claim 1, wherein the composition comprises a polymer selected from HPMC, HPC, HPMCAS-L, HPMCAS-M, povidone, and copovidone.

6. 6. The amorphous solid dispersion of claim 1, comprising other components in an amount of 3 wt % or less, based on the weight of the amorphous solid dispersion.

7. 7. The amorphous solid dispersion of claim 1, wherein said amorphous solid dispersion of vamorolone is obtained by spray drying.

8. A pharmaceutical composition comprising the amorphous solid dispersion according to any one of claims 1 to 7 and a pharmaceutically acceptable excipient.

9. 9. The pharmaceutical composition of claim 8, comprising vamorolone in an amount of at least 20 wt% based on the weight of the pharmaceutical composition.

10. 10. The pharmaceutical composition of claim 8 or 9, further comprising a filler, a binder, a disintegrant, a lubricant, a glidant, and / or a film coating agent.

11. The pharmaceutical composition according to any one of claims 7 to 10, which is a tablet or capsule.

12. Use of a polymer to improve the solubility of vamorolone in an aqueous medium by dispersing the amorphous form of vamorolone in the polymer.

13. A method for preparing the amorphous solid dispersion of any one of claims 1 to 7 by spray drying.

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