Morphology of lencofilstat in solid state

Abstract

This invention relates to lencofilstat (RCF) in solid form, a pharmaceutical composition containing the same, and a method for producing a pharmaceutical dosage form using the same.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 63 / 471,879, filed 8 June 2023, the disclosure of which is incorporated herein by reference in whole.

[0002] The present invention relates to the solid form of lencofilstat (also known as RCF, CRV431), its preparation process, and its pharmaceutical composition. [Background technology]

[0003] RCF is a small molecule cyclophyllin inhibitor in clinical development for the treatment of liver diseases, including hepatic fibrosis and hepatocellular carcinoma. In preclinical studies, RCF has demonstrated antiviral activity against numerous viruses, including hepatitis B, hepatitis C, and HIV, as well as antifibrotic activity in the liver in numerous in vivo models. RCF (shown in Figure 1B) is a neutral cyclic peptide composed of 11 amino acids, a derivative of cyclosporine A (CsA) (shown in Figure 1A), where amino acids 1 and 3 are chemically modified as shown in Figure 1B.

[0004] Compared to CsA, RCF preferably exhibits reduced immunosuppressive activity or no immunosuppressive activity at all, while showing improved binding to cyclophyllin (CyP) and inhibition of CyP.

[0005] U.S. Patent No. 9,200,038 and U.S. Patent Application No. 63 / 486,959, both of which are incorporated herein by reference in their entirety, describe laboratory-scale and commercial-scale methods for preparing RCF, respectively.

[0006] Polymorphism, the manifestation of various crystalline forms, is a property of some molecules and molecular complexes. Individual compounds such as RCF exhibit properties such as melting point, thermal behavior (e.g., measured by thermogravimetric analysis ("TGA") or differential scanning calorimeter ("DSC")), powder X-ray diffraction (PXRD) pattern, infrared absorption fingerprint, Raman absorption fingerprint, and solid state. 13 Various polymorphisms with unique crystal structures and physical properties, such as 1C- NMR spectra, can be generated. Using one or more of these techniques, different polymorphic forms of a compound can be distinguished.

[0007] Active drug components in various solid states (including solvated forms) can have a variety of properties. Such differences in the properties of various solid states and solvates can provide a foundation for improving formulations, for example, by promoting better processing or handling characteristics, improving the dissolution profile, or improving stability and shelf life. These differences in the properties of various solid states can also provide improvements to the final dosage form, for example, by contributing to improved bioavailability. Various solid states and solvates of active drug components can also give rise to various polymorphisms or crystalline forms, thereby providing further opportunities to utilize variants in the properties and characteristics of solid active drug components to provide improved products.

[0008] Discovering new solid-state forms and solvates of pharmaceutical products can provide materials as desirable intermediate crystalline forms that possess desirable processing characteristics such as ease of handling, ease of processing, storage stability, and ease of purification, or that facilitate conversion to other polymorphic forms. Novel polymorphic forms and solvates of pharmaceutically useful compounds can also provide opportunities to improve the performance characteristics of pharmaceutical products (e.g., dissolution profile, bioavailability). This expands the repertoire of materials available to pharmaceutical scientists for formulation optimization, for example, by providing products with various properties such as different crystal habits, higher crystallinity, or polymorphic stability, which may result in better processing or handling characteristics, improved dissolution profiles, or improved shelf life.

[0009] For these reasons at least, RCF in solid form (including solvated form) is required. [Overview of the project]

[0010] This disclosure relates to solid-state forms of RCF and pharmaceutical compositions comprising these solid-state forms.

[0011] In a first embodiment, the present invention provides a solid-state lencofilstat represented as Form 1, characterized by data selected from one or more of the following: (a) Powder X-ray diffraction (PXRD) pattern with the following peaks when measured at an angle of 2θ ± 0.2°: [Table 1-1] [Table 1-2] (b) A PXRD pattern, substantially as shown in Figure 2; (c) Solid state with characteristic peaks at 186.54, 184.52, and 181.38 ppm ± 0.2 ppm. 13 ¹¹C NMR spectrum; (d) 86.00 ppm ± 1 ppm: The following absolute differences in chemical shifts exist from the reference peaks at 100.54, 98.52, and 95.38 ppm ± 0.1 ppm, indicating a solid or non-solid body. 13 ¹¹C NMR spectrum; (e) Solid state with peaks at 186.54, 184.52, 182.94, 181.38, 86.00, 71.69, 68.74, 66.22, 62.51, 61.58, 58.47, 56.13, 52.31, 51.22, 50.08, 48.39, 45.60, 44.20, 42.45, 41.66, 40.73, 39.52, 38.29, 36.28, 35.46, 34.41, 33.59, 32.69, 31.42, 30.66, 28.34, 26.44, and 22.38 ppm ± 0.2 ppm. 13 ¹¹C NMR spectrum; (f) The solid state as shown in Figure 5 13 ¹¹C NMR spectrum; (g) 533.72, 583.13, 632.43, 781.53, 864.27, 942.13, 1002.76, 1031.85, 1086.67, 1126.54, 1222.31, 1269.69, 1305.09, 1388.37, 1407.96, 1463.79, 1544.55, 1623.19, 1654.41, 1674.28, 1686.39, 2871.76, 2926.28, 2956.64, 3296.78, 3333.48, 3430.73, and 3477.32 cm -1 ±4cm -1 FI-IR spectrum with a peak at [location]; A combination of two or more of (h), (a), ~ (g).

[0012] In a further embodiment, the solid-state form of lenchophyll stat represented as Form 1 has peaks at 4.7083, 8.6831, 10.2239, 16.9995, and 17.6441° 2θ ± ° 2θ, and any one, two, three, four, or five additional peaks at 7.3994, 15.7326, 16.1205, 19.5894, and 24.0205° 2θ ± 0.2° 2θ, and is characterized by a PXRD pattern.

[0013] In a further embodiment, the present invention provides a solid-state form of lenchophyll stat represented as Form 2, characterized by data selected from one or more of the following: (a) A PXRD pattern having the following peaks when measured at an angle of 2θ ± 0.2° 2θ: [Table 2] (b) A PXRD pattern substantially as shown in Figure 3; (c) A solid-state 13 C NMR spectrum having characteristic peaks at 187.29, 184.49, 182.82, and 181.68; (d) A solid-state 13 C NMR spectrum having an absolute difference in chemical shift from the reference peaks at 85.81 ppm ± 1 ppm: at 101.48, 98.68, 97.01, and 95.87 ppm ± 0.1 ppm; (e) A solid-state 13 C NMR spectrum having peaks at 187.29, 185.80, 184.49, 183.51, 182.82, 181.68, 85.81, 79.48, 71.66, 69.64, 67.97, 66.02, 64.79, 62.20, 61.35, 59.89, 55.78, 52.15, 49.64, 47.18, 45.69, 44.04, 42.38, 41.19, 40.21, 38.88, 36.00, 34.79, 34.06, 33.12, 32.35, 30.82, 30.00, 28.50, 25.91, 25.09, and 22.40 ppm ± 0.2 ppm; (f) Substantially in the solid state as shown in Figure 6 13 C NMR spectrum; (g) FI-IR spectrum having peaks at 536.28, 571.41, 596.14, 645.23, 769.57, 859.78, 942.97, 1090.73, 1263.66, 1381.97, 1411.63, 1466.98, 1536.14, 1621.07, 1676.31, 1721.79, 1737.08, 2871.91, 2932.36, 2957.01, 3301.60, and 3487.45 cm -1 ±4 cm -1 and having peaks at (h) A combination of any two or more of (a) to (g).

[0014] In another embodiment, the solid-state form of lenchofilstat represented as Form 2 has peaks at 4.6736, 7.9550, 9.4833, 11.8725, and 17.5943° 2θ ± ° 2θ, and also has any 1, 2, 3, 4, or 5 additional peaks at 5.8747, 7.6125, 15.2227, 18.1623, and 19.1112° 2θ ± 0.2° 2θ, and is characterized by a PXRD pattern.

[0015] In yet another embodiment, the present disclosure preferably includes a pharmaceutical formulation for oral administration in dosage forms such as tablets, capsules, etc., comprising the solid-state form of the above-mentioned RCF and at least one pharmaceutically acceptable excipient.

[0016] In a further embodiment, the present invention provides a method for manufacturing a pharmaceutical dosage form based on a self-microemulsifying drug delivery system (SMEDDS) or a spray-dried dispersion.

[0017] In a preferred embodiment, the SMEDDS dosage form of the present invention is prepared by solubilizing crystalline (preferably of form 1) RCF in a mixture of vitamin E, glyceryl monolinoleate, propylene glycol, diethylene glycol monoethyl ether, ethanol, and polyoxyl castor oil, where vitamin E, glyceryl monolinoleate, propylene glycol, diethylene glycol monoethyl ether, ethanol, and polyoxyl castor oil are present in weight ratios of approximately (0.75-1.5) / (0.5-2) / (2-5) / (2-5) / (2-2.4) / (4-8), respectively.

[0018] In another preferred embodiment, the spray-drying dispersion formulation of the present invention is prepared by mixing crystalline (preferably of Form 1) RCF with a pharmaceutically acceptable polymer, dissolving the mixture in an organic solvent, forming liquid droplets of the dissolved mixture, spraying the liquid droplets onto a receiving surface, and then drying the sprayed mixture to remove any residual solvent. [Brief explanation of the drawing]

[0019] [Figure 1A] The chemical structure of cyclosporine A is shown. [Figure 1B] The chemical structure of CRV431(RCF) is shown. [Figure 2] This shows the powder X-ray diffraction ("powder XRD" or "PXRD") pattern of RCF form 1. [Figure 3] The PXRD pattern of RCF type 2 is shown. [Figure 4] The FT-IR spectra of RCF forms 1 and 2 are shown, respectively. [Figure 5] The solid-state 13C NMR spectrum (in the range of 200 to 0 ppm) of RCF form 1 is shown. [Figure 6] The solid-state 13C NMR spectrum (in the range of 200 to 0 ppm) of RCF form 2 is shown. [Modes for carrying out the invention]

[0020] Two forms of RCF in a solid state are disclosed herein. Form 1 is an anhydrous form having a melting point of about 230°C to 233°C and a heat of fusion of 72.3 J / g.

[0021] Form 2 appears to be an isomorphic nonstoichiometric solvate with a melting point of 130–145°C, depending on its composition. Form 2 can be stabilized with, for example, isopropyl acetate (iProAc), 1,4-dioxane, 2-propanol, methyl tert-butyl ether, toluene, benzyl alcohol, or diethylamine. Although moderately hygroscopic, Form 2 does not exist as a stable hydrate. Importantly, Form 2 is not stabilized by acetonitrile (ACN) or methyl isobutyl ketone (MIBK).

[0022] Form 2 transforms into Form 1 when it is in the slurry of ACN, ACN / water blends, or when heated above 150°C. Form 2 melts above approximately 137°C and then recrystallizes to Form 1 at approximately 147°C. Following this recrystallization event, melting of Form 1 continues at approximately 230°C.

[0023] definition Crystal morphologies may be referred to herein as those characterized by graphic data "described" or "shown" in the figures. Such data include, for example, powder X-ray diffraction patterns and solid-state NMR spectra. As is well known in the art, graphic data potentially provides additional technical information and further defines the corresponding solid-state morphology (the so-called "fingerprint"), which is not necessarily limited to descriptions by numerical values ​​or peak positions alone. In any case, as is well known to those skilled in the art, such graphical representations of data may be subject to small variations, for example, in peak relative intensity and peak position, due to factors such as differences in instrument response and differences in sample concentration and purity. Nevertheless, it will be readily possible for those skilled in the art to compare the graphic data in the figures herein with graphic data generated for an unknown crystal morphology and to determine whether corresponding sets of graphic data characterize the same crystal morphology or two different crystal morphologies. Therefore, a crystal morphology RCF, which may be referred to herein as one characterized by graphic data "described" or "shown" in the figure, will be understood to include any crystal morphology RCF characterized by graphic data having such minor differences as will be known to those skilled in the art when compared to the figure.

[0024] A solid-state form (or polymorphism) may be referred to herein as polymorphically pure or substantially free of any other solid-state (or polymorphic) form. In this context, as used herein, the expression “substantially free of any other form” will be understood to mean that the solid-state form contains about 20% or less, about 10% or less, about 5% or less, about 2% or less, about 1% or less, or about 0% of any other form of the compound in question, as measured, for example, by PXRD.

[0025] Therefore, the RCF of a solid state described herein as substantially free of any other solid state form is understood to contain about 80% (w / w), about 90% (w / w), about 95% (w / w), about 98% (w / w), about 99% (w / w), or about 100 (w / w) of the RCF of the solid state form in question. Accordingly, in some embodiments of this disclosure, the RCF of a solid state form described may contain about 1% to about 20% (w / w), about 5% to about 20% (w / w), or about 5% to about 10% (w / w) of one or more other solid state forms of RCF.

[0026] When used herein, unless otherwise stated, the PXRD peaks reported herein are CuK α It can be measured using radiation, λ = 1.5418 Å.

[0027] In this specification, percentages are weight percent (wt%) unless otherwise specified.

[0028] A process or step may be said to be carried out "overnight" as herein. This means a time interval for the process or step that spans the night when the process or step cannot be actively observed. This time interval is approximately 8 to 20 hours, or approximately 10 to 18 hours, and usually about 16 hours.

[0029] This specification describes the use of various solvents, mostly represented by the corresponding abbreviations shown in Table 1 below: [Table 3]

[0030] In this specification, the amount of solvent used in a chemical process, such as a reaction or crystallization, can be referred to as a number of “volumes” or “vol” or “V”. For example, it can be said that a material is suspended in 10 volumes (or 10 vol or 10 V) of solvent. In this context, this expression is understood to mean several hundred milliliters of solvent per gram of suspended material, so that 5 grams of material is suspended in 10 volumes of solvent means that the solvent is used at an amount of 10 milliliters per gram of suspended material, or in this example, 50 mL of solvent. In another context, the term “v / v” can be used to indicate the number of volumes of solvent added to a liquid mixture based on the volume of the mixture. For example, adding methyl tert-butyl ether ("MTBE") (1.5 v / v) to 100 mL of a reaction mixture means that 150 mL of MTBE was added.

[0031] As used herein, the term "reduced pressure" refers to a pressure of approximately 10 mbar to approximately 50 mbar.

[0032] Pharmaceutical preparations This disclosure also provides the use of RCF in a solid state form for preparing other solid state forms of RCF.

[0033] The present invention further conceivable the use of the above-described solid forms of RCF, individually or in combination, to prepare pharmaceutical compositions and / or formulations, preferably oral formulations, such as tablets or capsules. Accordingly, the present disclosure encompasses pharmaceutical formulations comprising at least one or a combination thereof of the above-described solid forms of RCF and at least one pharmaceutically acceptable excipient.

[0034] Pharmacokinetically acceptable excipients can be added to the formulations of the present invention for various purposes.

[0035] Diluents can increase the bulk of solid pharmaceutical compositions and facilitate the handling of pharmaceutical dosage forms containing the composition by patients and caregivers. Examples of diluents for solid compositions include microcrystalline cellulose (e.g., Avicel®), microcellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugars, dextrose, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylate (e.g., Eudraigit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[0036] Solid pharmaceutical compositions, which are compressed into dosage forms such as tablets, may contain excipients that have the function of assisting the binding of the active ingredient with other excipients after compression. Examples of binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g., Carbopol), sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), hydroxypropylmethylcellulose (e.g., Methocel®), liquid glucose, aluminum magnesium silicate, maltodextrin, methylcellulose, polymethacrylate, povidone (e.g., Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.

[0037] By adding a disintegrant to the composition, the dissolution rate of the compressed solid pharmaceutical composition in the patient's stomach can be increased. Examples of disintegrants include alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose (e.g., Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, sodium croscarmellose, crospovidone (e.g., Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, potassium polariphosphate, powdered cellulose, pregelatinized starch, sodium alginate, sodium glycolate starch (e.g., Explotab®), and starch.

[0038] By adding lubricants, the fluidity of incompressible solid compositions can be improved, thereby enhancing the accuracy of administration. Examples of excipients that can function as lubricants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

[0039] When dosage forms such as tablets are produced by compressing a powdered composition, the composition is subjected to pressure from a punch and a dye. Some excipients and active ingredients tend to adhere to the surfaces of the punch and dye, which can cause pitting and other surface irregularities in the product. However, lubricants can be added to the composition to reduce adhesion and facilitate the removal of the product from the dye. Suitable lubricants include, for example, magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.

[0040] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the compositions of this disclosure include, for example, maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0041] Solid and liquid compositions can be stained with any pharmaceutically acceptable colorant to improve their appearance and / or facilitate patient identification at the product and unit dosage form level.

[0042] In the liquid pharmaceutical compositions of this disclosure, the active ingredient and any other solid excipients can be dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.

[0043] Liquid pharmaceutical compositions may also contain emulsifiers for uniformly dispersing insoluble active ingredients or other excipients throughout the composition. Examples of emulsifiers usable in the liquid compositions of this disclosure include gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, hornwort, pectin, methylcellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

[0044] The liquid pharmaceutical compositions of this disclosure may also contain thickeners for improving the mouthfeel of the product and / or for coating the inside of the gastrointestinal tract. Examples of such agents include acacia, bentonite alginate, carbomer, calcium or sodium carboxymethylcellulose, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xanthan gum.

[0045] Sweeteners such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can also be added to improve the taste.

[0046] To improve storage stability, preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole, and ethylenediaminetetraacetic acid may be added in amounts safe for consumption.

[0047] According to this disclosure, the liquid composition may also contain buffering agents such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate.

[0048] The selection of excipients and the amounts used can be readily determined by a pharmaceutical scientist based on standard procedures in the art and the experience and considerations of references such as Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed., whose entire disclosure is incorporated herein by reference.

[0049] Dosage The solid compositions of this disclosure may include powders, granules, aggregates, and compressed compositions. Dosages may be suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalation, and intraocular administration. In any given case, the most suitable administration depends on the nature and severity of the condition being treated, but in preferred embodiments, the route of administration is oral.

[0050] The dosage can be conveniently presented in unit dosage form and can be prepared by any method well known in the field of pharmacy.

[0051] Possible dosage forms include tablets, powders, capsules, suppositories, sachets, lozenges, and solid dosage forms such as liquid syrups, suspensions, and elixirs.

[0052] The dosage forms of the present disclosure may be capsules containing a predetermined amount of the composition disclosed herein, either as a powder or granules; or as a solution or suspension in an aqueous or non-aqueous liquid contained within a hard or soft shell. The shell may be made of gelatin and may optionally contain a plasticizer such as glycerin, and optionally an opacifying agent and / or a coloring agent.

[0053] Compositions for tableting or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then mixed in the presence of a liquid, usually water, that binds the powders together to form granules. The granules are screened and / or milled, dried, and then screened and / or milled again to the desired particle size. The granules can then be tableted, or other excipients such as lubricants and / or other additives can be added before tableting.

[0054] Tabletized compositions can be prepared conventionally by dry blending. For example, a blended composition of active drug components and excipients can be compressed into a slag or sheet, and then further compressed into granules. The compressed granules are then compressed into tablets.

[0055] Instead of dry granulation, direct compression technology can be used to compress the blended composition directly into a compressible form. Direct compression produces a more uniform tablet that does not contain granules. Excipients particularly well suited for direct compression tableting include, for example, microcrystalline cellulose, spray-dried lactose, dicalcium phosphate dihydrate, and colloidal silica.

[0056] The capsule filling of the present invention may include either of the above-described blends and granules, as described with reference to tableting, but these are not subjected to the final tableting step.

[0057] The pharmaceutical formulations conceived herein may be formulated for administration to mammals, preferably humans. The compositions disclosed herein may be formulated, for example, as a viscous liquid or suspension, or a clear solution, for injection. The formulations may contain one or more solvents. Suitable solvents can be selected by considering the physical and chemical stability of the solvent in various pH levels (to enable injectability), fluidity, boiling point, miscibility, and purity. Suitable solvents include, for example, alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and castor oil USP. Additional substances, particularly buffers, solubilizers, and antioxidants, may be added to the formulations.

[0058] This specification will be further described by referring to the following examples, which detail the preparation and analysis of the compositions of the present invention.

[0059] Method for producing a preferred dosage form The present invention also encompasses methods for producing pharmaceutical dosage forms based on self-emulsifying drug delivery systems (SMEDDS) or spray-dried dispersions.

[0060] SMEDDS (Self-Emulsifying Drug Delivery Systems) are homogeneous mixtures of hydrophilic surfactants, cosolvents, and oils that form oil-in-water (o / w) microemulsifications immediately after gentle stirring and dilution in an aqueous medium. This type of supersaturated environment has been shown to improve the solubility and absorption of drugs.

[0061] The SMEDDS dosage form of the present invention is prepared by solubilizing crystalline (preferably of form 1) RCF in a mixture of vitamin E, glyceryl monolinoleate, propylene glycol, diethylene glycol monoethyl ether, ethanol, and polyoxyl castor oil, where vitamin E, glyceryl monolinoleate, propylene glycol, diethylene glycol monoethyl ether, ethanol, and polyoxyl castor oil are present in weight ratios of approximately (0.75-1.5) / (0.5-2) / (2-5) / (2-5) / (2-2.4) / (4-8), respectively.

[0062] Spray drying causes the drug molecules and polymer carriers to co-precipitate in a stable amorphous solid dispersion, resulting in improved dissolution rates and enhanced bioavailability of poorly soluble compounds. Spray-dried dispersion (SDD) brings the drug molecules into a polymer-mediated stable state, maintaining this amorphous state during their movement through the patient's gastrointestinal (GI) tract. SDDs can be prepared from solutions in which both the drug molecules and pharmaceutically acceptable polymers are dissolved in a suitable solvent (not limited to, but including, acetone, methanol, methanol / water, or acetone / water mixtures) that is readily evaporable. Examples of pharmaceutically acceptable polymers include, but are not limited to, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), and polyvinylpyrrolidone (PVP).

[0063] In the preparation of SDD, both the drug molecules and polymers must be completely dissolved to avoid the presence of crystalline residues of drug molecules in the final SDD. The resulting solution is then delivered to a spray drying unit, where the solution is rapidly converted into droplets. These droplets dry rapidly in place as they pass through the spray dryer and move out of its outlet to a receiving surface (which may include a three-dimensional shell or mold). The rapid evaporation of the solvent traps the drug-polymer mixture in an amorphous state, creating low-density solid particles. The dried SDD material then goes through a post-drying step to ensure that the solvent is completely removed.

[0064] The SDD dosage form of the present invention is prepared by mixing crystalline (preferably of form 1) RCF with a pharmaceutically acceptable polymer, dissolving the mixture in an organic solvent, forming liquid droplets of the dissolved mixture, spraying the liquid droplets onto a receiving surface, and then drying the sprayed mixture to remove any residual solvent. The polymer is preferably HPMC. The preferred solvent is methanol or a methanol / water mixture. [Examples]

[0065] Analytical method used in the following examples Thermogravimetric analysis (“TGA”) Initial stage: The sample was placed in a pre-tareted 40 μL aluminum pot and loaded into the TA Discovery TGA autosampler. The sample was heated to 300 °C at 20 °C / min.

[0066] Separation from slurry: The sample was placed in a pre-tareted 40 μL aluminum pot and loaded into the TA Discovery TGA autosampler. The sample was heated to 100°C at 3°C / min, and then to 300°C at 20°C / min.

[0067] Recovery from saturated solution: Cooled samples were treated according to the method described for "Isolation from slurry." Samples recovered by evaporation were subjected to temperatures from 10°C to 300°C.

[0068] Differential scanning calorimeter ("DSC") Approximately 3 mg of the sample was placed in an airtight aluminum pot and analyzed using a Mettler Toledo DSC calibrated with indium (temperature) and sapphire (heat capacity). The sample was analyzed using STARe software.

[0069] The RCF morphology 1 sample was heated to 255°C at a rate of 10°C / min, cooled to 0°C at a rate of 10°C / min, and then reheated to 255°C at a rate of 10°C / min.

[0070] The isolated slurry solid and the cooled saturated solution solid were subjected to the same procedure, but only the first thermal cycle was analyzed. The solid recovered by evaporation was subjected to only one heating cycle at 0–255°C at 10°C / min.

[0071] Example 1: Initial Characterization of RCF Form 1 When the RCF sample was heated, it was measured to have a melting point of 231.2°C and a heat of fusion of 72.3 J / g (94.2 kJ / mol). Upon cooling, a small amount of exothermic reaction was observed at 61.1°C (-0.63 J / g). During the second heating cycle, without any additional thermal events, T g This was observed at 16.5℃ (ΔC p = 0.52J g -1 K -1 ).

[0072] Thermogravimetric analysis (TGA): RCF form 1 showed no mass loss through melting and was consistent with an anhydrous substance that was essentially solvent-free. Decomposition began at 262°C.

[0073] Dynamic water vapor adsorption (DVS): During desorption, 0.5% of the mass was lost at 95-0% RH (relative humidity). This indicates that RCF form 1 is a non-hygroscopic crystalline structure that does not readily form hydrates from the solid state at ambient temperature. The initial sorption isotherm showed a 10% mass loss at 50-60% RH, but this was likely an experimental artifact, as characterization after DVS and images obtained during sorption did not show any change in the material. NMR (discussed further below) before and after DVS showed no loss of any peaks or changes in relative intensity, which is consistent. This suggests that form 1 remains unchanged even after exposure to 95% humidity and subsequent drying.

[0074] Example 2: Initial Characterization of RCF Form 2 crystallization RCF form 1 slurries were prepared in 20 different solvents or solvent blends. The slurries were maintained at 0, 25, or 50°C for two weeks with stirring. In 12 of the 20 slurries, the final solid matched a different polymorph (form 2). In the other 8 slurries, the final solid matched the starting material (form 1). These results are summarized in Table 2 below: [Table 4]

[0075] RCF Form 1 did not convert to Form 2 in either acetonitrile or the tested formulation solvents (DEGMEE, propylene glycol, vitamin E). Form 2 was formed with pure solvent, 1,4-dioxane, IPA, iProAc, MTBE, and toluene.

[0076] Most RCF Form 2 samples exhibited endothermic and exothermic reactions at approximately 127 and 145°C, respectively. The only exceptions were 30 / 70 DIPE / BnOH (no apparent transitions in this temperature range) and the solid isolated from iProAc slurried at 0°C (exothermic only). For two samples (iProAc and MTBE at 25°C), exothermic reactions occurred at slightly higher temperatures. All samples melted at 230°C. The DSC was consistent with those previously reported for Form 1, which is consistent with Form 2 having a melting point of approximately 137°C and Form 1 having a melting point of 230°C.

[0077] When RCF form 2 melts, it appears to recrystallize into form 1 during or immediately after the melting process. In contrast, after RCF form 1 melts, no recrystallization is observed at the same scanning rate during cooling or reheating of the sample. This suggests that form 2 crystallizes a seed crystal of form 1 from the molten material, and / or that forms 1 and 2 have similar crystalline structures, and that they are converted back to form 1 when the solvent is lost from the form 2 structure.

[0078] All isolated solids matching Form 2 undergo measurable mass loss during heating, ranging from 1.8 to 5.5 wt% (0.27 to 0.7 molar ratio) between ambient temperature and 230°C in TGA. In most cases, the mass loss is gradual, and there are no indicators of rapid mass loss in the transition temperature range of 130–160°C, as observed by DSC. All solids are vacuum-dried overnight at 40°C prior to TGA.

[0079] In summary, these data suggest that RCF form 2 is likely a solvate that can adapt to many different solvents and is stable across a wide range of solvents and conditions from 0 to 50°C.

[0080] Example 3: Investigation of RCF form 2 solvates Solvent loss due to heating To further investigate whether RCF form 2 is a solvate, the form 2 sample was heated in a vacuum oven to 70°C for 3 days to remove the solvent. This process removed approximately half of the solvent, resulting in an even more disordered form 2. This suggests that form 2 is unstable in the absence of the solvent, and that the solvent is not readily removed from the crystal.

[0081] Form 2 DVS RCF form 2 is moderately hygroscopic, reversibly absorbing and desorbing water at 25°C, reaching a maximum of 8.9% by weight at 90% RH. This amount of water is equal to a water:RCF molar ratio of 7:1. This is consistent with form 2 being a non-stoichiometric solvate that can incorporate water into its open crystalline structure.

[0082] Stability of Form 2 in a highly water-active solvent blend To understand whether RCF form 2 can exist as a stable hydrate, form 2 was slurryed for 2 days in a saturated ACN / water blend with high water activity. Form 2 was added to an ACN / water blend (70-90% (w / w) water) previously saturated with form 1. (Samples containing form 1 solids were heated to 70°C overnight and then stirred at ambient temperature for 2 days. The remaining solids were still form 1, and these solids were removed by filtration through a 0.45 micrometer PTFE syringe filter.) After stirring these suspensions for 2 days, all remaining solids were form 1. With blends containing 70-74% (w / w) water, the form 2 solids dissolved first, forming two liquid phases (liquid-liquid phase separation, LLP), and after stirring for 2 days, the solid was observed. With 90% (w / w) water, no dissolution of the solid was observed.

[0083] The water activity in these experiments ranged from 0.88 to 0.94. Such high water activity, while the conversion of morph 2 solid to morph 1 solid confirms that morph 2 can contain a large amount of water (as measured by DVS), it is not a stable hydrate.

[0084] Example 4: PXRD analysis of RCF forms 1 and 2 Forms 1 and 2 solids were either loaded into a zero-background (high-index Si crystal) holder (0.2 mm depth) or dropped into the holder and dried directly in the zero-background holder. The samples were analyzed at 40 kV and 15 mA using a Rigaku MiniFlex 600 equipped with a D / tex Ultra 1D detector.

[0085] The PXRD pattern for form 1 is shown in Figure 2. This pattern has the following peaks when measured at an angle of 2θ ± 0.2° 2θ: [Table 5-1] [Table 5-2]

[0086] The PXRD pattern for form 2 is shown in Figure 3. This pattern has the following peaks when measured at an angle of 2θ ± 0.2° 2θ: [Table 6]

[0087] Example 5: Analysis of RCF forms 1 and 2 by FT-IR spectroscopy Infrared spectra were obtained using a Thermo iS-50 equipped with a diamond crystal and a single repulsive attenuated total internal reflection (ATR) detector, for Fourier transform infrared spectroscopy (FT-IR) analysis. (2 cm) -1 64 scans at this resolution were recorded for each spectrum.

[0088] As shown in Figure 4, when comparing the FT-IR spectra of RCF forms 1 and 2, the spectra (600-1400 cm⁻¹) -1 This shows that there are slight differences between the two forms, spanning the fingerprint area of ​​the two forms (1600-1750 cm). Most notably, the two forms (1600-1750 cm) -1There is a clear difference in carbonyl extension compared to ). This is consistent with observations from ssNMR data (see below) and is likely due to differences in hydrogen bond synthons present in the corresponding morphologies.

[0089] Example 6: 13 Analysis of RCF forms 1 and 2 by 13C NMR solid state 13 For the analysis of RCF morphologies 1 and 2 by 13C nuclear magnetic resonance spectroscopy ("ssNMR"), RCF polymorphisms were collected at 23°C using a Bruker 500 MHz spectrometer equipped with a high-resolution HF / X BMax 500 DOTY probe. A standard spectrometer equipped with a spinning sideband suppressor was used. 13 C-cross polarization-magic angle sample rotation (CP-MAS) was performed, and 10,000 scans were collected. Data was collected using MestreNova software.

[0090] The ssNMR spectra for RCF forms 1 and 2 are shown in Figures 5 and 6, respectively. 13 A small shift is present in the C peak, but the difference is most pronounced for the carbonyl group (peak above 180 ppm). Form 2 has an additional peak in the carbonyl region, which is likely due to the difference in the hydrogen bond synthon associated with the carbonyl group. A list of the peaks is shown in Table 3 below: [Table 7]

[0091] Example 7: Production of SMEDDS-based soft gelatin capsules The manufacturing process for soft gelatin capsules is divided into five unit operations: A. Preparation of filling material B. Gel preparation C. Encapsulation D. Dried capsules E. Capsule cleaning

[0092] A. Preparation of filling materials First, the RCF in crystalline form 1 is weighed in an isolator and transferred to an intermediate batch container (IBC) until it is ready to be added to the main mix, thereby performing an activated packing mix.

[0093] A by-mixture of glyceryl monolinoleate and vitamin E (dl-α-tocopherol) is prepared using a mixer. In parallel, diethylene glycol monoethyl ether and propylene glycol are added to the main mixing vessel and mixed using a stirrer and homogenizer. The RCF is then transferred to the main mixing vessel under vacuum and the IBC is rinsed with additional diethylene glycol monoethyl ether. The vessel temperature is then set to 23°C and the materials are mixed using a stirrer and homogenizer for the target 20 minutes.

[0094] Next, the glyceryl monolinoleate and vitamin E secondary mixture is transferred under vacuum to the main mixing container and the mixture is mixed for at least 10 minutes. Then, the polyoxyl 40 hydrogenated castor oil is transferred under vacuum while mixing for at least 10 minutes. Finally, the mixture is degassed for the target 20 minutes.

[0095] After degassing, re-establish a vacuum, then transfer anhydrous ethanol to the main mixing container under vacuum. Homogenize the mix for at least 90 minutes. After 60 minutes, take a sample of the filled material using a sampling device and visually inspect it to confirm whether the RCF is sufficiently dissolved.

[0096] After 90 minutes or more, and once it is clearly confirmed that there is undissolved RCF in the mixture, the mix is ​​then released into the receiver. The receiver is then blanketed with nitrogen.

[0097] B and C. Gel preparation and encapsulation Standard pharmaceutical gel materials are prepared before encapsulation. The filler material is encapsulated inside the gel material to form soft gelatin capsules. Throughout the encapsulation process, samples are drawn and tested for filler weight, shell weight, seal thickness, and print quality (if necessary).

[0098] D. capsule drying Immediately following a series of encapsulation steps in a tumble dryer basket, the capsules are dried. The capsules are then transferred to shallow trays, which are stacked and placed in a drying tunnel operating under specific temperature and humidity conditions. The hardness of the capsules is tested throughout the drying process. To produce the final dosage form, the capsules are dried within a specific hardness range.

[0099] E. Capsule cleaning Fractionated coconut oil and a fractionated coconut oil / lecithin blend (0.1%), used to lubricate the gelatin ribbon on the encapsulation machine, are removed from the capsules during the washing step using an anhydrous liquid phospholipid concentrate, preferably phosphatidylcholine in medium-chain triglycerides (content: 53.0% or more; available as Phosal 53 MCT, Lipoid GmbH, Ludwigshafen, Germany), and denatured ethanol sprayed directly onto the capsules. The washing solvent is removed by tumble drying.

[0100] While the present invention has been described in relation to certain preferred embodiments, other embodiments will become apparent to those skilled in the art by considering the specification. It will be apparent to those skilled in the art that many modifications to both materials and methods can be implemented without departing from the scope of the present invention.

Claims

1. The solid-state form of lencofilstat, represented as Form 1, is characterized by data selected from one or more of the following: (a) Powder X-ray diffraction (PXRD) pattern with the following peaks when measured at an angle of 2θ ± 0.2°: Table 1-1 Table 1-2 (b) A PXRD pattern substantially as shown in Figure 2; (c) Solid state with characteristic peaks at 186.54, 184.52, and 181.38 ppm ± 0.2 ppm 13 13C NMR spectrum; (d) Solids and above have the following absolute differences in chemical shift from the reference peaks at 86.00 ppm ± 1 ppm: 100.54, 98.52, and 95.38 ppm ± 0.1 ppm. 13 13C NMR spectrum; (e) Solid state with peaks at 186.54, 184.52, 182.94, 181.38, 86.00, 71.69, 68.74, 66.22, 62.51, 61.58, 58.47, 56.13, 52.31, 51.22, 50.08, 48.39, 45.60, 44.20, 42.45, 41.66, 40.73, 39.52, 38.29, 36.28, 35.46, 34.41, 33.59, 32.69, 31.42, 30.66, 28.34, 26.44, and 22.38 ppm ± 0.2 ppm 13 13C NMR spectrum; (f) The solid state, which is essentially as shown in Figure 5. 13 13C NMR spectrum; (g) 533.72, 583.13, 632.43, 781.53, 864.27, 942.13, 1002.76, 1031.85, 1086.67, 1126.54, 1222.31, 1269.69, 1305.09, 1388.37, 1407.96, 1463.79, 1544.55, 1623.19, 1654.41, 1674.28, 1686.39, 2871.76, 2926.28, 2956.64, 3296.78, 3333.48, 3430.73, and 3477.32 cm -1 ±4cm -1 FI-IR spectrum having a peak at; A combination of two or more of (h), (a) through (g).

2. Lenkofilstat in solid form according to claim 1, characterized by a PXRD pattern having peaks at 4.7083, 8.6831, 10.2239, 16.9995, and 17.6441°2θ±°2θ, and also having one, two, three, four, or five additional peaks at 7.3994, 15.7326, 16.1205, 19.5894, and 24.0205°2θ±0.2°2θ.

3. Lencofilstat in solid form according to claim 1, characterized by data selected from one or more of the following: (a) PXRD pattern with the following peak when measured at an angle of 2θ ± 0.2°: Table 2-1 Table 2-2 (b) A PXRD pattern substantially as shown in Figure 2; and (c) A combination of (a) and (b).

4. Lenkofilstat in solid form according to claim 3, characterized by a PXRD pattern having peaks at 4.7083, 8.6831, 10.2239, 16.9995, and 17.6441°2θ±°2θ, and also having one, two, three, four, or five additional peaks at 7.3994, 15.7326, 16.1205, 19.5894, and 24.0205°2θ±0.2°2θ.

5. Lencofilstat in solid form, represented as form 2, characterized by data selected from one or more of the following: (a) Powder X-ray diffraction (PXRD) pattern with the following peaks when measured at an angle of 2θ ± 0.2°: Table 3 (b) A PXRD pattern substantially as shown in Figure 3; (c) Solid state with characteristic peaks at 187.29, 184.49, 182.82, and 181.68 13 13C NMR spectrum; (d) 85.81 ppm ± 1 ppm: The following absolute differences in chemical shift from the reference peaks at 101.48, 98.68, 97.01, and 95.87 ppm ± 0.1 ppm indicate a solid or non-solid body. 13 13C NMR spectrum; (e) A solid state having peaks at 187.29, 185.80, 184.49, 183.51, 182.82, 181.68, 85.81, 79.48, 71.66, 69.64, 67.97, 66.02, 64.79, 62.20, 61.35, 59.89, 55.78, 52.15, 49.64, 47.18, 45.69, 44.04, 42.38, 41.19, 40.21, 38.88, 36.00, 34.79, 34.06, 33.12, 32.35, 30.82, 30.00, 28.50, 25.91, 25.09, and 22.40 ppm ± 0.2 ppm; 13 C NMR spectrum; (f) The solid state, which is essentially as shown in Figure 6. 13 13C NMR spectrum; (g) 536.28, 571.41, 596.14, 645.23, 769.57, 859.78, 942.97, 1090.73, 1263.66, 1381.97, 1411.63, 1466.98, 1536.14, 1621.07, 1676.31, 1721.79, 1737.08, 2871.91, 2932.36, 2957.01, 3301.60, and 3487.45 cm -1 ±4cm -1 FI-IR spectrum having a peak at; A combination of two or more of (h), (a) through (g).

6. Lenkofilstat in solid form according to claim 5, characterized by a PXRD pattern having peaks at 4.6736, 7.9550, 9.4833, 11.8725, and 17.5943°2θ±°2θ, and also having one, two, three, four, or five additional peaks at 5.8747, 7.6125, 15.2227, 18.1623, and 19.1112°2θ±0.2°2θ.

7. Lencofilstat in solid form according to claim 5, characterized by data selected from one or more of the following: (a) Powder X-ray diffraction (PXRD) pattern with the following peaks when measured at an angle of 2θ ± 0.2°: Table 4 (b) A PXRD pattern substantially as shown in Figure 3; and (c) A combination of (a) and (b).

8. Lenkofilstat in solid form according to claim 7, characterized by a PXRD pattern having peaks at 4.6736, 7.9550, 9.4833, 11.8725, and 17.5943°2θ±°2θ, and also having one, two, three, four, or five additional peaks at 5.8747, 7.6125, 15.2227, 18.1623, and 19.1112°2θ±0.2°2θ.

9. The lencofilstat in solid form according to claim 1, further containing 20% ​​or less, 10% or less, 5% or less, 2% or less, 1% or less, 0.5% or less, or about 0% of any other solid form of lencofilstat.

10. The lencofilstat in solid form according to claim 5, further containing 20% ​​or less, 10% or less, 5% or less, 2% or less, 1% or less, 0.5% or less, or about 0% of any other solid form of lencofilstat.

11. A pharmaceutical composition comprising lencofilstat in the solid state form described in claim 1.

12. A pharmaceutical composition comprising lencofilstat in the solid state form described in claim 5.

13. A pharmaceutical formulation comprising lencofilstat in solid form as described in claim 1, and at least one pharmaceutically acceptable excipient.

14. A pharmaceutical formulation comprising lencofilstat in solid form as described in claim 5, and at least one pharmaceutically acceptable excipient.

15. A method for producing a pharmaceutical dosage form based on a self-emulsifying drug delivery system (SMEDDS), wherein the method is: The method comprising solubilizing lencofilstat in a solid form in a mixture of vitamin E, glyceryl monolinoleate, propylene glycol, diethylene glycol monoethyl ether, ethanol, and polyoxyl castor oil, wherein the vitamin E, glyceryl monolinoleate, propylene glycol, diethylene glycol monoethyl ether, ethanol, and polyoxyl castor oil are present in a weight ratio of approximately (0.75-1.5) / (0.5-2) / (2-5) / (2-5) / (2-2.4) / (4-8).

16. A method for producing a pharmaceutical dosage form based on a spray-dried dispersion, wherein the method is: (i) To provide a mixture of lencofilstat in solid form and a pharmaceutically acceptable polymer, (ii) Dissolving the mixture in an organic solvent, (iii) Forming liquid droplets of the dissolved mixture, (iv) Spraying the liquid droplet onto the receiving surface, (v) The method comprising drying the sprayed mixture to remove any residual solvent.

Images