Solid dispersions comprising amorphous 2-[3-[4-(1H-indazol-5-ylamino)quinazolin-2-yl]phenoxy]-N-propan-2-yl-acetamide

Abstract

The present disclosure relates to a solid dispersion comprising amorphous bermosudil. The present disclosure also provides a pharmaceutical dosage form comprising the solid dispersion comprising amorphous bermosudil as an active pharmaceutical ingredient, and a method of using the pharmaceutical dosage form for treating a disease or disorder modulated by ROCK.

Description

[Technical Field]

[0001] The present disclosure relates to solid dispersions comprising amorphous 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide (also known as belmosudil and KD025). The disclosure further relates to methods for preparing the solid dispersions comprising amorphous belmosudil, pharmaceutical compositions comprising one or more of the solid dispersions described herein, and methods of using the pharmaceutical compositions to treat diseases and conditions modulated by Rho-associated coiled-coil kinase (ROCK). [Background technology]

[0002] Belmosudil, known chemically as 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide, has the following formula I: [ka] is expressed by

[0003] Belmosudil (also known as KD025) is an inhibitor of Rho-associated coiled-coil kinase (ROCK). Belmosudil binds to and inhibits the serine / threonine kinase activity of ROCK1 and ROCK2, making it useful for treating diseases, disorders, and conditions regulated by ROCK, such as autoimmune and fibrotic disorders, acute and chronic graft-versus-host disease (GVHD), idiopathic pulmonary fibrosis, and moderate to severe psoriasis, among other indications. Belmosudil mesylate is currently marketed in the United States and other countries under the trade name REZUROCK® (Kadmon Corp. / Sanofi) for the treatment of patients with chronic GVHD (cGVHD), in some cases after the failure of at least two prior systemic therapies.

[0004] A method for preparing berumosudil is disclosed in U.S. Pat. No. 8,357,693 (the '693 patent), specifically in Example 82 thereof. The method disclosed in the '693 patent provides berumosudil as a crude product purified by high performance liquid chromatography (HPLC). Methods for producing berumosudil and the compound are also described in U.S. Pat. Nos. 9,815,820, 10,183,931, and 10,696,660.

[0005] Belmosudil is a weakly basic compound that is barely soluble in water. The method of administering belmosudil involves formulating belmosudil mesylate into pharmaceutically acceptable capsules and tablets for oral administration. Given the low water solubility of belmosudil, the compound tends to precipitate when it transitions from the acidic gastric environment and early digestive pathway to the more neutral pH of the intestinal environment. Therefore, the low solubility of belmosudil may affect the manner and timing of its bioabsorption and pharmacokinetic properties. Furthermore, the low solubility of belmosudil may limit the use of conventional excipients and wet granulation methods.

[0006] The low solubility and variable pharmacokinetic properties of Belmosudil present a challenge in developing alternative formulations. For example, Belmosudil formulations with enhanced solubility would provide greater flexibility and broader options in developing different administration regimens, formulations and modes for delivering the compound to subjects. Summary of the Invention [Problem to be solved by the invention]

[0007] Therefore, there remains a need for formulations containing belmosudil that can address these challenges. [Means for solving the problem]

[0008] In one aspect, the present disclosure provides a solid dispersion comprising an amorphous form of berumosudil. In some embodiments, the amorphous form of berumosudil is disposed in a solid dispersion comprising a matrix carrier material. The use of amorphous berumosudil in a solid dispersion enhances its solubility and improves its biological performance, providing an expanded method for formulating and delivering drugs.

[0009] In some embodiments, the present disclosure provides an amorphous solid dispersion comprising bermosudil, optionally prepared using spray drying techniques.

[0010] In some embodiments, the amorphous form of belmosudil is provided as an amorphous solid dispersion of belmosudil formulated with at least one polymer, optionally, for example, a pharmaceutically acceptable polymer.

[0011] Another aspect of the present disclosure provides a method for preparing a solid dispersion containing amorphous bermosudil. To prepare a solid dispersion containing amorphous bermosudil, a solvent evaporation method such as spray drying may be used. A solid dispersion containing amorphous bermosudil can be prepared by dissolving bermosudil in a suitable solvent; adding one or more carrier matrix materials; and removing the solvent by spray drying, thereby providing the solid dispersion containing amorphous bermosudil in the carrier matrix materials.

[0012] A solid dispersion containing amorphous belmosudil can be used to prepare solid pharmaceutical dosage forms such as tablets and capsules. Pharmaceutical compositions containing an effective amount of amorphous belmosudil are useful for treating diseases, disorders, and conditions regulated by ROCK, as further described herein. [Brief explanation of the drawings]

[0013] [Figure 1] FIG. 1 shows scanning electron microscope (SEM) images of the solid dispersions of Example 1 (specifically, Nos. 1.1, 1.2, and 1.3 in Table 5) captured at 1500x and 5000x magnification. [Figure 2] FIG. 2 shows the XRPD results for the six spray-dried formulations prepared as in Example 1. [Figure 3] 1 shows two-phase dissolution data for the six spray-dried belmosudil formulations of Example 1 compared to the crystalline mesylate form of belmosudil. [Figure 4] FIG. 4 is an enlarged view of a portion of the data in FIG. 3. [Figure 5] FIG. 5 shows the XRPD results for the three solid dispersions of Example 3. [Figure 6] FIG. 6 shows SEM images of the three solid dispersions of Example 3 (Formulations F1, F2 and F3) captured at 1500x and 5000x magnification. [Figure 7] FIG. 7 shows particle size data for the three solid dispersions of Example 3 (Formulations F1, F2 and F3). [Figure 8] FIG. 8 shows modulated differential scanning calorimetry (mDSC) evaluation of Tg for homogeneity determination after one cooling cycle (upper contour) and one heating cycle (lower contour) for the three solid dispersions of Example 3 (formulations F1, F2, and F3). [Figure 9] FIG. 9 shows the non-sink dissolution data of the three solid dispersions of Example 3 (Formulations F1, F2 and F3) compared to the crystalline mesylate form of belmosudil. [Figure 10] FIG. 10 shows the assay and impurity data for the three solid dispersions of Example 3 (Formulations F1, F2, and F3) compared with the crystalline mesylate form of belmosudil and the diluent as described in Example 4. [Figure 11A] 11A-11C show XRPD diffractograms of the three solid dispersions of Example 3 after 8 weeks of stability testing, as described in Example 5 (FIG. 11A: F1 [20:80 KD025:PPPEG]; FIG. 11B: F2 [20:80 KD025:PVPVA]; and FIG. 11C: F3 [40:60 KD025:PPPEG]). [Figure 11B]11A-11C show XRPD diffractograms of the three solid dispersions of Example 3 after 8 weeks of stability testing, as described in Example 5 (FIG. 11A: F1 [20:80 KD025:PPPEG]; FIG. 11B: F2 [20:80 KD025:PVPVA]; and FIG. 11C: F3 [40:60 KD025:PPPEG]). [Figure 11C] 11A-11C show XRPD diffractograms of the three solid dispersions of Example 3 after 8 weeks of stability testing, as described in Example 5 (FIG. 11A: F1 [20:80 KD025:PPPEG]; FIG. 11B: F2 [20:80 KD025:PVPVA]; and FIG. 11C: F3 [40:60 KD025:PPPEG]). [Figure 12] FIG. 12 shows polarized light microscope images (5x magnification) of 25 mgA / mL suspensions of the solid dispersions of Example 3 (F1, F2, and F3) in 0.5 wt % Methocel A4M (aqueous solution). [Figure 13] Figure 13 shows the in vivo plasma concentration (ng / mL) versus time profile of belmosudil following administration of belmosudil as described in Example 6 for: (a) tablet formulation - fasted; (b) F2 (20:80 KD025:PVPVA) - fasted; (c) tablet formulation - fed; (d) F2 (20:80 KD025:PVPVA) - fed. DETAILED DESCRIPTION OF THE INVENTION

[0014] The present disclosure provides a solid dispersion containing an amorphous form of belmosudil, which enhances solubility and improves the biological performance of the compound. Reliable administration and absorption of belmosudil is important to ensure consistent systemic exposure. Therefore, the development of a reproducible drug delivery system and the characterization of its associated dissolution profile provide advantages in ensuring consistent and effective administration of belmosudil.

[0015] To prepare a solid dispersion containing amorphous bermosudil, a solvent evaporation method such as spray drying may be used. This technique involves dissolving or suspending bermosudil in a polymer matrix carrier, followed by spraying the mixture. The solvent is removed by spray drying to obtain a solid dispersion containing amorphous bermosudil dispersed in the polymer matrix carrier.

[0016] Spray drying technology is applied to convert belmosudil into an amorphous state dispersed in a polymer matrix carrier. The amorphous belmosudil prepared by the method disclosed herein provides enhanced dissolution due to particle size reduction and elimination of the crystal lattice. The absence of crystallinity does not result in crystal lattice energy that must be overcome for belmosudil to dissolve. The carrier material can further aid dissolution by improving the wetting, solubility, and stability properties of belmosudil in supersaturated solutions. Spray-dried solid dispersions containing amorphous belmosudil provide good physicochemical properties, such as controlled particle size and flowability, which are useful for downstream processing such as tablet compression.

[0017] Furthermore, pharmaceutical compositions comprising solid dispersions containing amorphous bermosudil exhibit increased dissolution rates compared to compositions containing crystalline forms of bermosudil; in some embodiments, significant increases in dissolution rates are obtained using the solid dispersions herein. The improved solubility of solid dispersions containing amorphous bermosudil provides advantages and greater flexibility in formulation development and drug delivery.

[0018] definition The term belmosudil (or KD025) as used herein refers to 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide, represented by formula I below. [ka]

[0019] In some embodiments, the amorphous bermosudil is in free base form.

[0020] It should be understood that when the term "belmosudil" is used herein, unless the context clearly indicates otherwise, this term can encompass any form of the compound belmosudil as well as its pharmaceutically acceptable salts. The term "belmosudil" refers to both the compound belmosudil (e.g., free base form, amorphous form, or crystalline form), pharmaceutically acceptable salts of belmosudil, such as the mesylate form used as REZUROCK™, and any form of belmosudil that can be used in a formulation or pharmaceutical composition for administering the compound to a patient.

[0021] The term "pharmaceutically acceptable salts" refers to non-toxic, inorganic and organic acid addition salts of belmosudil. In some embodiments, the pharmaceutically acceptable salt of belmosudil herein is the mesylate salt.

[0022] As used herein, "about" includes the exact amount modified by the term "about," as well as an amount that is expected to be within experimental error, such as within 15%, 10%, or 5%. For example, "about 5 mg" means "5 mg," and also refers to a range of mg that is within experimental error, such as ±15%, 10%, or 5% of 5 mg. As used herein, the term "about" can be used to modify ranges and specific values.

[0023] The acronym API, as used herein, refers to "active pharmaceutical ingredient," which is synonymous with the definition of belmosudil (or KD025) and its pharmaceutically acceptable salts, optionally the mesylate salt of belmosudil.

[0024] As used herein, "administering" or "administered" refers to the act of prescribing a medication containing an API for ingestion by a subject during treatment, dispensing the medication to a subject, and / or physically receiving or ingesting the medication. Thus, the API (belmosudil) may be administered by a physician or other healthcare professional who writes a prescription for the medication; and / or a pharmacist who fills the prescription and / or dispenses the medication to the subject; and / or by a patient or subject who ingests the medication and / or their partner or caregiver who provides the medication to the subject.

[0025] As used herein, the term "solid dispersion" refers to a system in which an API is dispersed throughout a solid carrier, in some embodiments, a solid matrix carrier. In some embodiments, the carrier comprises a small molecule and / or a polymer or copolymer, optionally a polymer. Thus, a solid dispersion comprises at least two components, one component being the API and the other component being the carrier. Additional additives may optionally be included (e.g., surfactants). Optionally, in a solid dispersion, the API is dispersed homogeneously or uniformly throughout the carrier matrix.

[0026] As used herein, the term "solid amorphous dispersion" refers to a single-phase amorphous system in which an API is molecularly dispersed or dissolved in a carrier matrix, optionally a polymer matrix.

[0027] In some embodiments herein, the ratio of bermosudil to carrier matrix material in the solid dispersion can be about 10:90 to 90:10 by weight; or about 20:80 to 80:20 by weight; or about 25:75 to 75:25 by weight; or about 40:60 to 60:40 by weight.

[0028] Unless otherwise specified, the terms "amorphous" or "amorphous form" mean that a substance or component is in a substantially non-crystalline, disordered solid form, i.e., a solid form that substantially lacks long-range crystalline order as determined by XRPD data. A substantially amorphous state comprises at least about 50% by weight, optionally at least about 60% by weight, optionally at least about 70% by weight, optionally at least about 80% by weight, optionally at least about 90% by weight, optionally at least 95% by weight, or optionally at least 99% by weight of the API in amorphous form compared to other forms of the substance or component.

[0029] In some embodiments, amorphous bermosdil is a solid form of bermosdil that is substantially amorphous; in some embodiments, it is a form that contains at least about 95% amorphous bermosdil; in some embodiments, at least 98% of the bermosdil is amorphous. Whether bermosdil is in amorphous form can be characterized, for example, by XRPD techniques as described herein or as otherwise known to those skilled in the art.

[0030] As used herein, "carrier matrix" or "carrier matrix material" refers to a component that stabilizes, suspends, and / or transports the amorphous form of bermosudil when in the solid state. The carrier matrix material may be an amorphous polymer material. The polymer selection for a solid dispersion can play a significant role in the overall attributes of the final product. Polymers for use as a carrier matrix material include povidone derivatives, such as polyvinylpyrrolidone (PVP) and polyvinylpyrrolidone-vinyl acetate copolymer (PVPVA) (such as those sold under the trade name Kollidon VA 64®), polymethacrylate derivatives (such as the Eudragit® series), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PPPEG) (such as those currently sold under the trade name Soluplus®), hydroxypropyl methylcellulose (HPMC), and hydroxypropyl methylcellulose acetate succinate (HPMCAS). Optional carrier matrix materials herein are PVPVA and PPPEG.

[0031] The term "effective amount" in relation to the amorphous form of belmosudil refers to an amount capable of treating or preventing a disorder, disease, or condition disclosed herein, or a symptom thereof. For example, an effective amount of the amorphous form of belmosudil in a pharmaceutical composition may be a level that provides the desired effect; for example, a unit dosage for oral administration may be about 0.5 to 15 mg / kg of a subject's body weight, optionally about 1 to 5 mg / kg of a subject's body weight, and optionally about 3 mg / kg of a patient's body weight. For example, the dosage of belmosudil may be the current therapeutic dose of 200 mg administered daily, or may be a dose ranging from 10 mg to a maximum of 1000 mg, and optionally a dose ranging from 100 mg to 400 mg for an adult patient; or optionally a dose ranging from 100 mg to 200 mg.

[0032] Furthermore, optionally, for pediatric patients, the dose of belmosudil may range from 10 mg to 200 mg. The dose of belmosudil may be adjusted according to the patient's weight. For example, for pediatric patients weighing between about 6 kg and less than 20 kg, the dose may be between about 10 mg and 50 mg administered once daily; in other embodiments, for pediatric patients weighing between about 10 kg and less than 20 kg, the dose may be about 50 mg administered once daily; for pediatric patients weighing between about 20 kg and less than 40 kg, the dose may be about 100 mg administered once daily; and for pediatric patients weighing 40 kg or more, the dose may be 200 mg administered once daily.

[0033] As will be apparent to one of skill in the art, it is expected that the effective amount of the amorphous form of belmosudil disclosed herein may vary depending on the severity of the indication being treated, the route of administration, and / or other drugs, such as proton pump inhibitors or CYP3A inducers, administered to the subject, taking into account drug-drug interactions.

[0034] The phrase "pharmaceutically acceptable carrier," as used herein, means a pharmaceutically acceptable material, composition, or vehicle (e.g., a lubricant, talc, magnesium, calcium, or zinc stearate, or stearic acid). Each carrier must be "acceptable" in the sense of being compatible with the formulation (e.g., containing the API so as not to allow slow crystallization over time), maintaining the stability of the other ingredients of the formulation, and not injurious to the patient.

[0035] As used herein, the term "suitable solvent," when used to dissolve berumosudil in a solvent system containing a carrier matrix material, refers to a solvent or mixture of one or more solvents that is compatible with berumosudil and the carrier matrix material and can sufficiently dissolve berumosudil and one or more carrier matrix materials to enable the use of spray-drying techniques. The term "suitable solvent" may also include a mixture of solvents and is therefore interchangeable with "suitable solvent system." The solubility of the API and / or carrier matrix material can be confirmed by filtration and HPLC analysis or by visual observation (e.g., producing a clear or substantially clear solution upon visual observation). A solvent being "suitable" also means that the solvent does not exhibit unacceptable toxicity or environmental hazards and is acceptable for use in the manufacture of pharmaceuticals for human consumption.

[0036] "Or" is used in its inclusive sense (equivalent to "and / or") unless the context requires otherwise.

[0037] General Preparation and Use A solid dispersion comprising amorphous bermosudil can be prepared by dissolving bermosudil in a suitable solvent; adding one or more carrier matrix materials to the bermosudil solution; and removing or substantially removing the solvent to provide amorphous bermosudil dispersed in the carrier matrix.

[0038] In the first step of the process, which involves adding berumosudil to a suitable solvent, berumosudil may be in various forms, for example, any polymorphic crystalline form, or may be a solvate. Berumosudil may be in the form of a salt or a free base. When berumosudil is in the form of an acid addition salt and amorphous berumosudil in the form of a free base is desired, a sufficient amount of base may be added to the solvent to form berumosudil free base. The base may be an inorganic base such as an alkali metal hydroxide, or an amine such as diethylamine or triethylamine.

[0039] Within the context of this method, solvent selection is an important consideration when preparing amorphous solid dispersions, and a combination of solvents may be used to achieve the desired solvent parameters. As described in Example 1 herein, extensive solvent screening experiments were conducted to arrive at a solvent system useful for dissolving bermosudil and the carrier matrix material to enable the use of spray-drying techniques. Following these solubility experiments, it was discovered that a suitable solvent system for preparing amorphous bermosudil by spray-drying comprises a mixture of triethylamine (TEA) and acetone. In comparison, solvent systems including acetone, ethyl acetate, acetonitrile (ACN), tetrahydrofuran, methanol, dichloromethane (DCM), dimethylformamide (DMF), isopropanol (IPA), methyl ethyl ketone, methyl isobutyl ketone (MIBK), methyl tert-butyl ether (MTBD), n-heptane, toluene, mixtures of DCM and methanol, mixtures of ethanol and hexane, and mixtures of aqueous solutions with acetone or ACN were determined to be ineffective at dissolving belmosudil, and / or belmosudil was determined to be substantially insoluble or slightly soluble in these solvents such that these solvents are not "suitable solvents" as defined herein.

[0040] For example, WO 2021 / 129589 A1 reportedly identifies solvents alleged to be "good solvents" for use in dissolving berumosudil to prepare its amorphous form. WO 2021 / 129589 A1 provides an example (Example 22) of the preparation of amorphous KD025, which involves the use of DMF as a solvent. However, the applicant discovered that berumosudil is only slightly soluble in DMF and therefore is not a suitable solvent. WO 2021 / 129589 A1 further identifies recommended solvents for use in preparing the amorphous form of berumosudil, which are allegedly selected from one or more of methanol, acetone, methyl ethyl ketone, DMF, dimethyl sulfoxide (DMSO), n-methylpyrrolidone, and ethylene glycol dimethyl ether. However, WO 2021 / 129589 A1 does not provide examples illustrating the use of these solvents. The applicant has discovered through the working examples described herein that the solvents identified in WO 2021 / 129589 A1 are not suitable solvents as defined herein due to either the low solubility of bermosudil and / or the carrier matrix in the solvents and / or their incompatibility in spray drying and / or drug development processes.

[0041] The amorphous solid dispersions containing bermosudil can be used to prepare solid pharmaceutical dosage forms such as tablets and capsules.

[0042] In one aspect, the present disclosure provides a pharmaceutically acceptable composition comprising a therapeutically effective amount of an amorphous form of belmosudil formulated with one or more pharmaceutical excipients. The pharmaceutical composition is specially formulated for administration in solid form and can be adapted for administration to a patient in a manner suitable for use of the solid form of the API, for example, by oral administration with a tablet or capsule.

[0043] In some embodiments, the present disclosure provides solid pharmaceutical dosage forms (capsules, tablets, pills, powders, granules, etc.) comprising an amorphous solid dispersion of bermosudil for oral administration mixed with a pharmaceutically acceptable carrier, such as sodium citrate or dicalcium phosphate, and / or one or more pharmaceutically acceptable excipients, including any of the following: (1) a filler or extender, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) a binder, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) a humectant, such as glycerol; (4) agar, calcium carbonate, potato, or tapioca starch, Disintegrating agents such as alginic acid, certain silicates, and sodium carbonate; (5) solution retardants such as paraffin; (6) absorption enhancers, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as cetyl alcohol, glycerol monostearate, and nonionic surfactants; (8) absorbents such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled-release agents, such as crospovidone or ethylcellulose. In the case of capsules, tablets, and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard-shell gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0044] Tablets may be made by compression or molding (including melt extrusion), optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents, or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0045] Tablets and other solid dosage forms of the pharmaceutical compositions of the present disclosure, such as capsules, pills, and granules, can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They can also be formulated to provide sustained or controlled release of the active ingredient therein, for example, using hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres in various proportions to provide the desired release profile. They can also be formulated for rapid release, e.g., lyophilization. These compositions can also optionally contain opacifying agents and can be compositions that optionally release only the active ingredient or active compounds in a specific part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, where appropriate, with one or more of the above-mentioned excipients.

[0046] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0047] Pharmaceutical compositions comprising an effective amount of the amorphous form of belmosudil are useful for inhibiting ROCK1 and ROCK2, preferentially ROCK2, and are therefore useful for treating diseases modulated by ROCK enzymes, such as autoimmune disorders and / or fibrotic disorders including GVHD (chronic and acute), pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, radiation-induced fibrosis, or arterial, cardiac, endomyocardial, renal, or hepatic fibrosis; moderate to severe psoriasis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), Crohn's disease, dermatitis (e.g., atopic dermatitis), and eczema, among other indications.

[0048] The compositions provided herein may further be useful in treating bronchiolitis obliterans syndrome (BOS), a potentially serious complication following lung transplantation or allogeneic hematopoietic stem cell transplantation (allo-HSCT). [Example]

[0049] The following abbreviations may be useful as reference in light of the present disclosure:

[0050] [Table 1]

[0051] device: The following instruments and procedures may be used to collect the data described in the Examples herein, unless other instrumental details are provided in the Examples below. Those skilled in the art will appreciate that alternative instruments and procedures may optionally be used to collect characterization data, such as PLM, XRPD, TGA, DSC / TGA, and PSD.

[0052] XRPD, PSD and MDSC data were collected using the instruments and procedures shown below in Tables 1, 2 and 3, respectively.

[0053] [Table 2]

[0054] [Table 3]

[0055] [Table 4]

[0056] Example 1 1.1 Solvent Screening The purpose of the experiments described in this example was to explore amorphous solid dispersions using spray drying technology to increase the solubility of berumosudil and improve its biological performance. However, spray drying technology requires an appropriate solvent system that is compatible with berumosudil and the polymer matrix material.

[0057] To determine suitable solvent systems for use with Vermosudil and polymer matrix materials, the organic solvent systems described in this section (Tables 4A, 4B, and 4C) were prepared and evaluated.

[0058] A. Solubility evaluation using HPLC The solubility (w / v) of belmosudil in various solvents was measured using HPLC. Saturated solutions of belmosudil were prepared in 5 mL amber vials using approximately 99–105 mg of belmosudil and 2.0 mL of solvent, as shown in Table 4A below. The solutions were thoroughly shaken and loaded onto a laboratory rotator at 200 rpm for 24 hours of constant rotation. The resulting samples were filtered through a 0.45 μm filter, and the filtrate was used for quantification of belmosudil by HPLC using the linearity method. Samples containing IPA, acetonitrile, ethyl acetate, DCM, toluene, MIBK, acetone, n-heptane, and methyl tert-butyl ether (MTBE) were injected into the HPLC without further dilution. Samples containing methanol, DMF, and DMSO were further diluted before injection into the HPLC; for the methanol, DMF, and DMSO solutions, 0.1 mL of the filtered solution was transferred to a 100 mL volumetric flask and diluted to volume with diluent before injection. The solubilities are reported in mg / mL in Table 4A.

[0059] [Table 5]

[0060] B. pH-Based Solubility Assessment The solubility of brumosodil in various pH buffer solutions, namely, buffer solutions at pH 1.2, 3.5, 4.5, 6.8, 7.4, and 10, was investigated. To prepare the buffer solutions, stock solutions were prepared for pH adjustment as follows: 0.2 M HCl solution was prepared by transferring 17.0 mL of 35% HCl to 500 mL of water, mixing well, and diluting the solution to 1000 mL with water; 2 M acetic acid solution was prepared by transferring 116.0 mL of acetic acid to 500 mL of water, mixing well, and diluting to 1000 mL with water; 0.2 M NaOH solution was prepared by transferring 4.01492 g of sodium hydroxide pellets to 250 mL of water, dissolving, and diluting to 500 mL with water; and phosphate buffer stock solution was prepared by transferring approximately 2.72 g of potassium hydrogen phosphate buffer to a 100 mL volumetric flask, dissolving, and diluting with water.

[0061] A buffer solution containing the sample (Belmosudil) was prepared as follows.

[0062] Sample pH 1.2 buffer. 1.53145 g of potassium chloride was transferred to a 100 mL volumetric flask, dissolved, and diluted to volume with water. 25.0 mL of this solution was transferred to a 100 mL volumetric flask; 42.5 mL of 0.2 M hydrochloric acid solution was added, and the solution was diluted to volume with water. 2.0 mL of this pH 1.2 buffer was added to a 5 mL amber vial containing 100.15 mg of vermosudil.

[0063] Sample pH 3.5 buffer. 4.11871 g of potassium phthalate was transferred to a 100 mL volumetric flask, dissolved, and diluted to volume with water. 25.0 mL of this solution was transferred to a 100 mL volumetric flask, to which 8.3 mL of 0.2 M hydrochloric acid was added, and the solution was diluted to volume with water. 2.0 mL of this buffer was added to a 5 mL amber vial containing 100.52 mg of vermosudil.

[0064] Sample pH 4.5 Buffer. 25.0 mL of pH 3.5 buffer (from the previous paragraph) was added to a 100 mL volumetric flask. An additional 10 mL of 0.2 M sodium hydroxide was added, and the solution was diluted to volume with water. 2.0 mL of this pH 4.5 buffer was added to a 5 mL amber vial containing 101.53 mg of vermosudil.

[0065] Sample pH 6.8 buffer. 25.0 mL of phosphate buffer stock was transferred to a 100 mL volumetric flask; 23 mL of 0.2 M sodium hydroxide was added, and the solution was diluted to volume with water. 2.0 mL of this pH 6.8 buffer was added to a 5 mL amber vial containing 100.18 mg of vermosudil.

[0066] Sample pH 7.4 buffer. 25.0 mL of phosphate buffer stock was transferred to a 100 mL volumetric flask; 41 mL of 0.2 M sodium hydroxide was added, and the solution was diluted to volume with water. 2.0 mL of this pH 7.4 buffer was added to a 5 mL amber vial containing 100.52 mg of vermosudil.

[0067] Sample pH 10.0 buffer. 1.52493 g of potassium chloride and 1.21879 g of boric acid were added to a 100 mL volumetric flask, dissolved, and diluted to volume with water. 25.0 mL of this solution was transferred to a 100 mL volumetric flask; 22 mL of 0.2 M sodium hydroxide was added, and the solution was diluted to volume with water. 2.0 mL of this pH 10.0 buffer was added to a 5 mL amber vial containing 103.8 mg of vermosudil.

[0068] Each sample pH buffer solution prepared according to the previous paragraph was thoroughly shaken and loaded onto a laboratory rotator at 200 rpm for constant rotation for 24 hours. In all cases, undissolved sample was observed in the vial after 24 hours. The resulting sample solution was filtered through a 0.45 μ syringe filter, and the filtrate was collected and injected into the HPLC without further dilution. The pH was monitored after 24 hours of equilibration at 25°C. The results are shown in Table 4B.

[0069] [Table 6]

[0070] C. Solubility Evaluation - Visual Observation Further solubility evaluations were performed in each solvent system listed in Table 4C using 25 mg of vermosudil for each sample.

[0071] [Table 7]

[0072] All solutions were prepared at 10 wt% bermudil and then diluted to 1 wt% bermudil. Under these conditions, bermudil did not dissolve in any of the solvent systems listed in Table 4C. All solutions were then heated to 40°C, but no improvement with heating was observed. Therefore, the solvent systems listed in Table 4C were not suitable for dissolving bermudil and the polymeric carrier matrix material to enable the technique for preparing the amorphous form. After further experimentation, a mixture of bermudil, triethylamine (TEA), and acetone in a ratio of 3:1 (molar equivalents of TEA:acetone) provided a clear solution at 5 wt% bermudil. Therefore, a mixture of TEA and acetone was designated as the solvent system for formulating the solid dispersions used in the following examples.

[0073] 1.2 Polymer Carrier Matrix and Ratio Selection Three polymers were selected to prepare six formulations: (1) vinylpyrrolidone-vinyl acetate copolymer (PVPVA) (sold under the trade name Kollidon® VA 64); (2) polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG, or "PPPEG" herein) (sold under the trade name Soluplus® and available from BASF); and (3) hypromellose acetate succinate (HPMCAS-M, or HPMC) (Shin-Etsu Chemical Co., Ltd.).

[0074] The ratios (by weight) of bermosudil to polymeric carrier matrix were selected for evaluation as follows:

[0075] [Table 8]

[0076] 1.3 Preparation of spray-dried dispersions An acetone suspension of berumosil and TEA was first prepared, and then the three polymeric carrier matrix materials in Table 5 were added using the berumosil:polymer ratios listed in Table 5. Spray drying of the suspension then proceeded as follows.

[0077] A Buchi B-290 spray dryer was used in this study. Nitrogen was used as the drying gas. The solution feed rate (mL / min) and atomization pressure (Psi) were adjusted to 17.5 and 26, respectively. The inlet temperature ranged from 84 to 101°C, and the outlet temperature was adjusted to a range of 49 to 51°C. The spray-dried formulation was oven-dried at 50°C for 24 hours, and residual solvent was removed using a convection tray dryer.

[0078] Example 2 All six formulations in Example 1 were characterized for surface morphology, crystallinity, and dissolution, as described in this Example 2. All six formulations yielded solid products that were deemed acceptable for further evaluation according to their morphology and amorphous state. However, after analysis and characterization of surface morphology, crystallinity, and dissolution, as described in Sections 2.1-2.3 below, Example 1.2 (20:80 KD025:PVPVA), Example 1.3 (20:80 KD025:PPPEG), and Example 1.6 (40:60 KD025:PPPEG) were selected as preferred candidates for further evaluation, as described in Examples 3-6.

[0079] 2.1 Scanning electron microscopy Dispersions from Examples 1.1, 1.2, and 1.3 were selected for visual observation using scanning electron microscopy (SEM). Samples were prepared by dispensing samples onto adhesive carbon-coated sample stubs and coating them with a thin conductive layer of gold using a Cressington 108 Auto. Samples were analyzed using an FEI Quanta 200 SEM equipped with an Everhart-Thornley (secondary electron) detector operating in high vacuum mode. The results are shown in Figure 1 herein. The typical morphology characteristic of solid dispersions was observed to consist of whole and collapsed spheres with smooth surfaces. However, this evaluation revealed that the use of a polymer carrier matrix containing PVPVA and PPPEG had advantages over HPMC, as the dispersion containing HPMC appeared to have some long filaments, while the dispersion containing PVPVA and PPPEG produced a more uniform matrix of vermosudil suspended in the polymer matrix.

[0080] 2.2 Powder X-ray diffraction X-ray powder diffraction (XRPD) was used to evaluate the crystalline morphology of the six dispersions of Example 1 (using a Rigaku Miniflex 6G X-ray diffractometer). Samples were irradiated with monochromated CuKα radiation and analyzed in continuous scan mode between 5° and 40°. Samples were rotated during analysis to minimize preferred orientation effects. Figure 2 shows the XRPD results for each of Examples 1.1-1.6. These results confirm that each solid dispersion of Example 1 exists in an amorphous state, as reflected by the lack of crystalline peaks.

[0081] 2.3 Dissolution evaluation The first step in the dissolution evaluation was to determine the direct solubility of belmosudil in either 0.1 N HCl or FaSSIF biorelevant media, which was found to be greater than 1000 μg / mL and 5 μg / mL, respectively. The dissolution performance of the six dispersions from Example 1 and the crystalline mesylate form of belmosudil was tested by non-sink dissolution (results are shown in Figure 3). A dissolution test was used to measure the improvement in solubility over bulk crystalline belmosudil solubility in the biorelevant FaSSIF medium after 30 minutes of exposure to a low pH environment. During the test, samples were transferred via dilution from 0.1 N HCl (theoretical Cmax = 1000 μg / mL) to FaSSIF (theoretical Cmax = 500 μg / mL). The drug concentrations measured in this test were the drug without SDI, the drug in micelles, and the drug in the drug-polymer colloid complex. The purpose of this experiment was to rank-order and select a lead formulation. Table 6 summarizes the overall two-phase dissolution data.

[0082] [Table 9]

[0083] In general, the Cmax at low pH in the gastric environment was much higher than the Cmax at higher pH for most formulations, but as shown in Table 6, Examples 1.3 and 1.6 (both the 20:80 and 40:60 PPPEG dispersions), along with Example 1.2 (the 20:80 KD025:PVPVA dispersion), outperformed the other three formulations with Cmax of 369.6, 79.7, and 99.9 μgA / mL, respectively. Furthermore, drug concentrations at the end of the dissolution run (210 min) were higher for these formulations compared to crystalline KD025, with values ​​reported of 20.8 μgA / mL (Example 1.2 [20:80 KD025:PVPVA]), 369.6 μgA / mL (Example 1.3 [20:80 KD025:PPPEG]), and 50.4 μgA / mL (Example 1.6 [40:60 KD025:PPPEG]) compared to 6.1 for crystalline KD025. In summary, increased area under the curve (AUC) was observed for Example 1.2 (20:80 KD025:PVPVA), Example 1.3 (20:80 KD025:PPPEG), and Example 1.6 (40:60 KD025:PPPEG) compared to belmosudil (KD025).

[0084] Example 3 Based on the surface morphology, crystallinity, and dissolution studies in Example 2, three formulations were selected for further characterization and in vivo evaluation and experimentation: Example 1.2 (20:80 KD025:PVPVA); Example 1.3 (20:80 KD025:PPPEG); and Example 1.6 (40:60 KD025:PPPEG). For ease of reference, these selected formulations are identified as follows: Formulation 1 [F1]: 20:80 KD025:PPPEG (Example 1.3); Formulation 2 [F2]: 20:80 KD025:PVPVA (Example 1.2); and Formulation 3 [F3]: 40:60 KD025:PPPEG (Example 1.6).

[0085] In this example, F1, F2 and F3 were prepared according to the processing conditions shown in Table 7 below and then analyzed for their amorphous state, surface morphology, residual solvent, particle size distribution and thermal evaluation.

[0086] [Table 10]

[0087] 3.1 Amorphous dispersions XRPD results were obtained for three formulations prepared according to the procedure set forth in Table 7, applying the measurement conditions set forth in Table 1 above. The results are shown in Figure 5. All solid dispersions were confirmed to be amorphous (Figure 5). SEM images of F1, F2, and F3 were also obtained at 1500x and 5000x magnification (following the same procedure as in Example 2.1), and the results are shown in Figure 6. No crystals were observed in any of the three solid dispersions. Formulations F1 and F2 (20:80 dispersion) were swollen with collapsed spheres, while F3 formed mostly swollen spheres that fused into clusters.

[0088] 3.2 Evaluation of residual solvent content After the secondary drying step described in Table 7, GC-HS was used to measure the residual acetone and TEA remaining in the three solid dispersions (F1, F2, and F3). Measurements were performed using an HP 6890 series GC equipped with an Agilent 7697A headspace sampler. A 30 m x 0.32 mm x 1.8 μm capillary column with a 6% cyanopropylphenyl 94% dimethylpolysiloxane GC column was used for the study.

[0089] Residual solvents detected in all formulations are reported in Table 8 below. For all three formulations (F1, F2, and F3), acetone concentrations were not detected. TEA levels were below the limit of quantitation (LOQ) for F1 and F3 (PPPEG formulations) and 1631 ppm for F2 (PVPVA formulation). These levels are below the limits for acetone and TEA (5000 ppm) set by the International Council for Harmonisation (ICH).

[0090] [Table 11]

[0091] 3.3 Particle size distribution The particle size distributions (PSD) of F1, F2, and F3 were measured using the laser diffraction method (Mastersizer 3000 with Aero S unit) with the parameters summarized in Table 2. 200 mg of sample was added to a standard Venturi disperser with a 1.5 mm hopper gap and then fed into the dispersion system. The feed rate (20-40%) was adjusted to maintain a laser obscuration level of 0.1-15%. Compressed air at 1.5 bar was used to transport and suspend the sample particles through the optical cell. The measurement time was 10 seconds, with a background measurement in air for 10 seconds. The Dv10, Dv50, and Dv90 diameters were used to characterize the particle size distribution of the powders.

[0092] The results of the PSD test are shown in Table 9 and Figure 7. F1 and F2 (20:80 bermosudil dispersion) were shown to have fairly similar particle sizes, with Dv50 values ​​less than 10 μm, and a fairly narrow size range for both formulations (Dv10-Dv90 values ​​ranged from about 3 to about 28 for F1 and from about 2 to about 17 for F2). F3 (40% bermosudil dispersion) was found to have a bimodal distribution with larger total particles (Dv10 = 6.54, Dv90 = 187). These results are consistent with SEM observations (Figure 6), which showed particles fused into clusters for F3.

[0093] [Table 12]

[0094] 3.4 Differential scanning calorimetry DSC of F1, F2, and F3 was performed using the equipment described in Table 3 above. Samples were placed in non-hermetic aluminum pans and heated at a constant rate of 2.0 °C / min over the temperature range of 0 to 240 °C. To ensure an inert atmosphere throughout the measurement process, the system was purged with a nitrogen flow at 50 mL / min.

[0095] The results of this thermal analysis (mDSC) are shown in Figure 8. All three formulations F1, F2, and F3 had a single Tg and showed good uniformity (Tg (°C) of 73, 90, and 67 for F1, F2, and F3, respectively). F3 (40% KD025 dispersion) showed a broad Tg with an unclear onset, indicating higher molecular mobility of the dispersion during spray drying.

[0096] Example 4 4.1 In vitro drug release In vitro drug release evaluation of F1, F2, and F3 was performed using a USP Type II Distek 2100 Dissolution Apparatus. A two-stage dissolution study was performed. Preweighed SDI powder was briefly suspended in medium and transferred to a 50 mL preheated (37°C) volume of 0.1 N simulated gastric fluid (SGF) pH approximately 1.0 (without pepsin or bile salts) at a stirring paddle speed of 100 rpm. After 30 minutes of gastric pH exposure, a 2x concentrate (FaSSIF) was added to the SGF to achieve a final pH of 6.8 in FaSSIF (100 mM PBS containing 2.24 mg / mL SIF powder (Biorelevant Inc.)) in a total volume of 100 mL. 1.0 mL samples were withdrawn at designated time points and analyzed using an appropriate HPLC method.

[0097] The results are shown in Table 10 and Figure 9. As reflected in Figure 9, the in vitro performance results showed that F1, F2, and F3 exhibited improved dissolution performance compared to the crystalline mesylate salt of belmosudil. The data indicate that F1, F2, and F3 are viable options for achieving higher relative solubility while maintaining acceptable chemical and physical stability.

[0098] [Table 13]

[0099] 4.2 Assay Evaluation Reverse-phase high-performance liquid chromatography (RPHPLC) (Agilent 1200 Series LC (1220 s and 1260 s)) was used to determine and assay impurities in F1, F2, and F3 during processing, compared to the mesylate form of belmosudil. The HPLC was equipped with a diode array detector. A gradient method using a Zorbax SB-CN column was used. The mobile phase consisted of (A) 50 mM potassium phosphate buffer and (B) acetonitrile, pumped at a flow rate of 1.4 mL / min at ambient temperature with a detection wavelength of 250 nm. The mobile phase gradient was maintained as follows (min, %B): (0, 20.0); (20.0, 30.0); (30.0, 60); (40.0, 60).

[0100] The results of this assay are reported in Table 11 below and shown in Figure 10. The impurity profile is similar to the mesylate form of belmosudil. No degradation was observed during processing.

[0101] [Table 14]

[0102] Example 5 5.1 Stability assessment To evaluate the physical and chemical stability of formulations F1, F2, and F3, the three formulations were aged for up to 8 weeks at 25°C / 60% relative humidity (RH) in open packaging and at 40°C / 75% RH in open and closed packaging. F1, F2, and F3 were evaluated for physical and chemical stability by appearance and XRPD. The collected XRPD patterns are shown in Figure 11A (F1), Figure 11B (F2), and Figure 11C (F3).

[0103] Overall, F2 (20:80 KD025:PVPVA) formed a hard solid at all conditions by 8 weeks, and the dispersions remained amorphous at all conditions, with the observed physical changes shown in Figure 11B. As shown in Figure 11A, F1 (20:80 PPPEG dispersion) remained amorphous when opened at 25°C / 60% RH and closed at 40°C / 75% RH. When opened at 40°C / 75% RH, F1 formed hard agglomerates. As shown in Figure 11C, F3 remained amorphous at 40°C / 75% RH and formed crystals when opened at 25°C / 60% RH and opened at 40°C / 75% RH. This study was instructive regarding the time and storage conditions required for pre-manufacturing of the final dosage form (i.e., tablet compression, suspension, etc.).

[0104] Example 6 The pharmacokinetics (PK) of F1, F2, and F3 were evaluated in male beagle dogs after oral (PO) administration as described in this Example 6.

[0105] 6.1 Suspension Formulations for In Vivo Administration Suspension formulations were developed for administration of F1, F2, and F3 in a PK canine model. Suspensions were prepared at 25 mgA / mL at 0.5% wt. % Methocel A4M containing F1, F2, and F3, respectively, and evaluated for visual appearance, injectability, and crystallinity by PLM. Methylcellulose A4M was added to purified, preheated water (65±5°C) until completely dispersed in the water. The mixture was then cooled to room temperature under continuous mixing. Based on the desired dosage, the amount of solid dispersion (F1, F2, F3), powder, was slowly added. A wet paste initially formed, which transformed into a suspension with continued mixing. The suspensions were evaluated using PLM (5x magnification) at T=0, T=1 hour, and T=2.5 hours. Images are shown in Figure 12.

[0106] The F1 dispersion (20:80 KD025:PPPEG) was homogeneous, without aggregates or crystals, and remained unchanged over 2.5 hours. The F1 formulation remained stable in suspension for at least 4.5 hours with stirring at room temperature. Both F2 (20:80 KD025:PVPVA) and F3 (40:60 KD025:PPPEG) showed aggregation due to PLM at T=0, which grew over time; however, no crystals were observed, and the suspension remained injectable (injected via a 20-gauge stomach tube).

[0107] Although a suspension formulation has been successfully developed and selected for easy administration for the dog PK model, solid dosage forms are also contemplated.Solid dosage forms such as tablets are relatively easy to manufacture, package, and transport, are more stable than liquids, and can be formulated with coatings and moldings to facilitate swallowing.Therefore, those skilled in the art may contemplate the use of solid dosage forms as an alternative to the liquid suspension used in this dog study.

[0108] 6.2 In vivo PK evaluation in dogs Male beagle dogs were selected for the biological performance evaluation of F1, F2, and F3. The study was conducted under a protocol approved by the Pharmaron Institutional Animal Care and Use Committee. Twenty male beagle dogs, aged 1 to 1.5 years, were assigned to dosing and feeding conditions that maintained body weights at 11 to 12 kg throughout the study period. All animals were housed in a 12-hour light-dark cycle environment. F1, F2, and F3 were tested under fasted and fed conditions and compared with belmosudil free base powder and immediate-release (IR) tablets containing the crystalline mesylate salt of belmosudil, which served as controls. In the fasted group, dogs were fasted overnight and administered the drug in the morning under fasted conditions. Food was returned to the dogs after plasma collection 4 hours after dosing. In the fed group, dogs were fasted overnight and fed 1 hour before dosing. All dogs had access to water throughout the study. All samples were administered orally (PO); tablets were administered as is. After tablet administration, 5 mL of vehicle was used to help the dogs swallow the tablets. Formulations 1, 2, 3, and the free base sample were administered by oral gavage using a 0.5 wt% Methocel A4M suspension. After suspension administration, the dogs were given 5 mL of vehicle to ensure all of the suspension was flushed into the stomach.

[0109] 6.3 Study Design A total of 20 beagle dogs were dosed using the dosing regimen summarized in Table 12. Four dogs were assigned to each group A-J. Groups A / F, B / G, C / H, D / I, and E / J shared the same animals. Animals in groups A-E were dosed first. After a 7-day washout period, animals in groups F-J were dosed. Dosing in each case was by PO administration. Four males were dosed in each group.

[0110] [Table 15]

[0111] 6.4 Sampling Blood samples were collected from each animal at predetermined time points before administration and at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 18, 24, 30, and 36 hours after administration. Blood samples (1 mL) were collected from each animal via the jugular vein. These blood samples were placed in tubes containing dipotassium ethylenediaminetetraacetic acid and centrifuged at 2000 g for 10 minutes at 2-8°C to obtain plasma.

[0112] 6.5 LC / MS conditions KD025 in dog plasma samples was evaluated using an LC-MS / MS system consisting of two Shimadzu LC-30AD pumps, a DGU-20A5R (©) degasser, a rack changer II, and an AB Sciex Triple Quads 5500 LC / MS / MS mass spectrometer. Chromatographic separation was performed on an Agilent ZORBAX XDB-Phenyl 5 μm (50 × 2.1 mm) column at room temperature. The mobile phase consisted of A: 5% acetonitrile in water (0.1% formic acid); B: 95% acetonitrile in water (0.1% formic acid). The flow rate was 0.6 mL / min. The injection volume was 2 μL, and the lower limit of quantitation (LLOQ) was 10 ng / mL.

[0113] 6.6 Data Collection and Statistical Analysis Data acquisition was performed using Sciex Analyst 1.6.3 software (AB Sciex, Forster City, CA). Pharmacokinetic parameters, such as area under the curve (AUC0-36h), maximum plasma concentration (Cmax), and time to Cmax (Tmax), were calculated by non-compartmental analysis (Phoenix™ WinNonlin™ 6.1). A linear trapezoidal algorithm was used for AUC calculation. Data statistics and plasma profiles were performed using Excel 2010 software.

[0114] Table 13 summarizes the mean pharmacokinetic parameters following administration of the test formulations to male beagle dogs at a dose of 40 mg / kg (n=4). Figure 13 plots the plasma concentrations of KD025 as a function of time over 24 data collection periods for the following dog groups: Group A = fasted tablet formulation; Group D = fasted F2 formulation (20:80 KD025:PVPVA); Group F = fed tablet formulation; Group I = fed F2 (20:80 KD025:PVPVA).

[0115] [Table 16]

[0116] When comparing the solid dispersion blends F1, F2, and F3 with tablets, it was surprisingly found that F2 (20:80 KD025:PVPVA) was superior to the other (PPPEG) formulations. For F2, the mean Cmax of the fasted and fed groups was found to be similar, i.e., 2915.0 ng / mL for the fasted group and 3100 ng / mL for the fed group. In contrast, the mean Cmax of the reference tablet in the fasted state was significantly different from that in the fed state, i.e., 2842 ng / mL for the fasted group and 4773 ng / mL for the fed group. This improved control of Cmax by amorphous belmosudil may be advantageous from a pharmacokinetic point of view.

[0117] Furthermore, the F2 (KD025:PVPVA) test group showed lower variability compared to the reference tablet, as characterized by %CV (100 × StDev / Mean). Under fasting conditions, the %CV for the F2 formulation was found to be 28.9, compared to 83.0 for the tablet. When compared to fasting conditions, the percent variability was even lower: 7.5%CV for the F2 formulation and 32.9% for the reference tablet. In summary, with respect to Cmax, the solid dispersion formulation F2 (20:80 KD025:PVPVA) reduced inter-subject variability and minimized the food effect. The AUC observed with the F2 formulation was slightly lower than that of the actual reference tablet. However, variability was better controlled. Under fasting conditions, AUC variability was improved using the %CV of F2 (20:80 KD025:PVPVA) (33.1) compared to the tablet (97.0). In summary, the use of solid dispersion formulation F2 was surprisingly effective in achieving minimal variability, and the feeding effect of F2 was lower than that of the free base tablets. No adverse effects were observed in the animals during, during, or after the study in this example.

Claims

1. A solid dispersion comprising substantially amorphous 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (bermosudil) and one or more carrier materials.

2. 2. The solid dispersion of claim 1, wherein the one or more carrier materials are selected from polymers.

3. 2. The solid dispersion of claim 1, wherein the one or more carrier materials are selected from polyvinylpyrrolidone-vinyl acetate copolymer, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and hypromellose acetate succinate.

4. 4. The solid dispersion of claim 1, 2 or 3, wherein the ratio of the bermosudil to the one or more carrier materials is about 10:90 to 90:10 by weight; or about 20:80 to 80:20 by weight; or about 25:75 to 75:25 by weight; or about 40:60 to 60:40 by weight.

5. The solid dispersion according to any one of claims 1 to 4, wherein the carrier material is a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

6. The solid dispersion according to any one of claims 1 to 4, wherein the carrier material is a vinylpyrrolidone-vinyl acetate copolymer.

7. 7. The solid dispersion of any one of claims 1 to 3 or claims 5 or 6, wherein the ratio of bermosudil to carrier material is about 20:80 by weight.

8. 8. The solid dispersion of claim 1, wherein at least about 95% of the bermosudil in the dispersion is in amorphous form.

9. 8. The solid dispersion of claim 1, wherein at least about 99% of the bermosudil in the dispersion is in amorphous form.

10. 10. The solid dispersion according to claim 8, wherein the solid dispersion comprises solid particles having a particle size of less than 10 μm.

11. A pharmaceutical formulation comprising a therapeutically effective amount of the solid dispersion according to any one of claims 1 to 10.

12. 12. The pharmaceutical formulation of claim 11, wherein the pharmaceutical formulation is a tablet or capsule.

13. A method for treating a disease or disorder regulated by ROCK, comprising administering to a subject in need thereof the solid dispersion of any one of claims 1 to 10, or the pharmaceutical formulation of claim 11 or 12.

14. 14. The method of claim 13, wherein the disease or disorder is graft-versus-host disease (GVHD).

15. 15. The method of claim 14, wherein the GVHD is chronic or acute.

16. 14. The method of claim 13, wherein the disease or disorder is an autoimmune disorder or a fibrotic disorder.

17. 17. The method of claim 16, wherein the autoimmune or fibrotic disorder is pulmonary fibrosis; idiopathic pulmonary fibrosis; cystic fibrosis; radiation-induced fibrosis; arterial, cardiac, endomyocardial, renal, or hepatic fibrosis; moderate to severe psoriasis; rheumatoid arthritis; multiple sclerosis; systemic lupus erythematosus (SLE); Crohn's disease; dermatitis; or eczema.

18. 14. The method of claim 13, wherein the disease or disorder is bronchiolitis obliterans syndrome (BOS).

19. 19. The method of claim 18, wherein the BOS is after lung transplantation or after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

20. A method for preparing an amorphous form of berumosudil, comprising dissolving berumosudil and one or more carrier materials in a suitable solvent to form a solution.

21. 21. The method of claim 20, wherein the suitable solvent comprises a mixture of triethylamine and acetone.

22. 22. The method of claim 20 or 21, further comprising spray drying the solution of bermosudil and one or more carrier materials to remove the suitable solvent.

23. A method according to any one of claims 20 to 22, wherein the carrier material is selected from vinylpyrrolidone-vinyl acetate copolymer and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

Images