WO2024254480A2 - Formes à l'état solide de rencofilstat - Google Patents

Formes à l'état solide de rencofilstat Download PDF

Info

Publication number
WO2024254480A2
WO2024254480A2 PCT/US2024/033050 US2024033050W WO2024254480A2 WO 2024254480 A2 WO2024254480 A2 WO 2024254480A2 US 2024033050 W US2024033050 W US 2024033050W WO 2024254480 A2 WO2024254480 A2 WO 2024254480A2
Authority
WO
WIPO (PCT)
Prior art keywords
solid state
theta
degrees
rencofilstat
peaks
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2024/033050
Other languages
English (en)
Other versions
WO2024254480A3 (fr
Inventor
Robert Thomas FOSTER
Daniel Joseph TREPANIER
Thomas PAUL ZABAWA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hepion Pharmaceuticals Inc
Original Assignee
Hepion Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hepion Pharmaceuticals Inc filed Critical Hepion Pharmaceuticals Inc
Priority to AU2024285817A priority Critical patent/AU2024285817A1/en
Publication of WO2024254480A2 publication Critical patent/WO2024254480A2/fr
Publication of WO2024254480A3 publication Critical patent/WO2024254480A3/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • C07K7/645—Cyclosporins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to solid state forms of Rencofilstat (RCF, also known as CRV431), processes for preparation thereof and pharmaceutical compositions thereof.
  • RCF Rencofilstat
  • RCF is a small molecule cyclophilin inhibitor under clinical development for the treatment of liver diseases including liver fibrosis and hepatocellular carcinoma. In preclinical studies, RCF has shown anti-viral activity against a number of viruses including hepatitis B, hepatitis C, and HIV, and anti-fibrotic activity in the liver in a number of in vivo models.
  • RCF (shown in FIG. IB) is a derivative of cyclosporine A (CsA) (shown in FIG. 1 A), a neutral cyclic peptide consisting of eleven amino acids, wherein amino acids 1 and 3 have been chemically modified as shown in FIG. IB.
  • CsA cyclosporine A
  • RCF desirably has reduced or no immunosuppressive activity, with improved binding for, and inhibition of, cyclophilin (CyP).
  • Polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes.
  • a single compound like RCF, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis — "TGA”, or differential scanning calorimetry — “DSC”), powder X-ray diffraction (PXRD) pattern, infrared absorption fingerprint, Raman absorption fingerprint, and solid state ( 13 C-) NMR spectrum.
  • Different solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, improving the dissolution profile, or improving stability and shelf-life. These variations in the properties of different solid state forms may also provide improvements to the final dosage form, for instance, if these serve to improve bioavailability. Different solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to use variations in the properties and characteristics of a solid active pharmaceutical ingredient for providing an improved product.
  • Discovering new solid state forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms.
  • New polymorphic forms and solvates of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product (dissolution profile, bioavailability, etc.). This enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example, by providing a product with different properties, e.g., a different crystal habit, higher crystallinity or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life.
  • the present disclosure relates to solid state forms of RCF and to pharmaceutical compositions comprising these solid state forms.
  • the invention provides a solid state form of Rencofilstat designated as Form 1, characterized by data selected from one or more of the following:
  • the solid state form of Rencofilstat designated as Form 1 is characterized by a PXRD pattern having peaks at: 4.7083, 8.6831, 10.2239, 16.9995 and 17.6441 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks at: 7.3994, 15.7326, 16.1205, 19.5894 and 24.0205 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • the invention provides a solid state form of Rencofilstat designated as Form 2, characterized by data selected from one or more of the following:
  • the solid state form of Rencofilstat designated as Form 2 is characterized by a PXRD pattern having peaks at: 4.6736, 7.9550, 9.4833, 11.8725 and 17.5943 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks at: 5.8747, 7.6125, 15.2227, 18.1623, and 19.1112 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • the present disclosure encompasses pharmaceutical formulations comprising the above described solid state forms of RCF and at least one pharmaceutically acceptable excipient, preferably for oral administration in dosage forms such as tablets, capsules etc.
  • the present invention provides methods for manufacturing a pharmaceutical dosage form based on a self-microemulsifying drug delivery system (SMEDDS) or a spray dried dispersion.
  • SMEDDS self-microemulsifying drug delivery system
  • the inventive SMEDDS dosage form is prepared by solubilizing crystalline (preferably Form 1) RCF 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 at a weight ratio, respectively, of about (0.75-1.5)/(0.5-2)/(2-5)/(2-5)/(2-2.4)/(4-8).
  • the inventive spray dried dispersion dosage form is prepared by mixing crystalline (preferably 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 residual solvent.
  • FIG. 1 A shows the chemical structure of cyclosporine A.
  • FIG. IB shows the chemical structure of CRV431 (RCF).
  • FIG. 2 shows a powder X-ray diffraction ("powder XRD” or "PXRD”) pattern of RCF Form 1.
  • FIG. 3 shows a PXRD pattern of RCF Form 2.
  • FIG. 4 shows FT-IR spectra of RCF Forms 1 and 2, respectively.
  • FIG. 5 shows a solid state 13 C NMR spectrum (range from 200-0 ppm) of
  • FIG. 6 shows a solid state 13 C NMR spectrum (range from 200-0 ppm) of RCF Form 2.
  • Form 1 is an anhydrate with a melting point of about 230°C to 233°C and a heat of fusion of 72.3 J/g.
  • Form 2 appears to be an isomorphic, non-stoichiometric solvate with a melting point between 130 and 145 °C depending on its composition.
  • Form 2 can be stabilized by, e.g., isopropyl acetate (iProAc), 1,4-di oxane, 2-propanol, methyl tert-butyl ether, toluene, benzyl alcohol, or diethylamine.
  • Form 2 does not exist as a stable hydrate, though it is moderately hygroscopic.
  • Form 2 is not stabilized by acetonitrile (ACN) or methyl isobutyl ketone (MIBK).
  • ACN acetonitrile
  • MIBK methyl isobutyl ketone
  • Form 2 converts to Form 1 upon slurry in ACN, ACN/water blends, or upon heating above 150°C.
  • Form 2 melts at about 137°C, followed by recrystallization to Form 1 at about 147°C. This recrystallization event is followed by melting of Form 1 at around 230°C.
  • a crystal form may be referred to herein as being characterized by graphical data "as depicted in” or “as shown in” a Figure.
  • Such data include, for example, powder X-ray diffractograms and solid state NMR spectra.
  • the graphical data potentially provide additional technical information to further define the respective solid state form (a so-called "fingerprint"), which can not necessarily be described by reference to numerical values or peak positions alone.
  • fingerprint a so-called “fingerprint”
  • the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to factors such as variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person.
  • a solid state form may be referred to herein as polymorphically pure or substantially free of any other solid state (or polymorphic) forms.
  • the expression “substantially free of any other forms” 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 forms of the subject compound as measured, for example, by PXRD.
  • a process or step may be referred to herein as being carried out “overnight.” This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10 to about 18 hours, typically about 16 hours.
  • the amount of a given solvent employed in a chemical process may be referred to herein as a number of "volumes” or “vol” or “V.”
  • a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent.
  • this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent.
  • v/v may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding methyl tert-butyl ether (“MTBE”) (1.5 v/v) to a 100 ml reaction mixture would indicate that 150 mL of MTBE was added.
  • MTBE methyl tert-butyl ether
  • reduced pressure refers to a pressure of about 10 mbar to about 50 mbar.
  • the present disclosure also provides the use of a solid state form of RCF for preparing other solid state forms of RCF.
  • the present invention further contemplates the use of the above-described solid state forms of RCF, individually or in combination, for the preparation of pharmaceutical compositions and/or formulations, preferably oral formulations, e.g. tablets or capsules. Accordingly, the present disclosure encompasses pharmaceutical formulations comprising at least one of the above described solid state forms of RCF, or combinations thereof, and at least one pharmaceutically acceptable excipient.
  • compositions of the present invention may be added to the formulations of the present invention for a variety of purposes.
  • Diluents increase the bulk of a solid pharmaceutical composition, and can make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle.
  • Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.
  • microcrystalline cellulose e.g. Avicel®
  • microfine cellulose lactose
  • starch pregelatinized starch
  • calcium carbonate calcium sulfate
  • sugar dextrates
  • dextrin de
  • Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet can include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
  • Binders for solid pharmaceutical compositions include, for example, acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g.
  • Methocel® liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.
  • povidone e.g. Kollidon®, Plasdone®
  • pregelatinized starch sodium alginate, and starch.
  • the dissolution rate of a compacted solid pharmaceutical composition in the patient’s stomach can be increased by the addition of a disintegrant to the composition.
  • Disintegrants include, for example, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab®), and starch.
  • alginic acid carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®), gu
  • Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing.
  • Excipients that can function as glidants include, for example, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
  • a dosage form such as a tablet is made by the compaction of a powdered composition
  • the composition is subjected to pressure from a punch and dye.
  • Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
  • a lubricant can be added to the composition to reduce adhesion and ease the release 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.
  • Flavoring agents and flavor enhancers make the dosage form more palatable to the patient.
  • Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present disclosure include, for example, maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
  • Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
  • liquid pharmaceutical compositions of the present disclosure the active ingredient and any other solid excipients may be dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
  • a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
  • Liquid pharmaceutical compositions also may contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier.
  • Emulsifying agents that can be useful in liquid compositions of the present disclosure include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.
  • Liquid pharmaceutical compositions of the present disclosure can also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract.
  • a viscosity enhancing agent may include, for example, acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xanthan gum.
  • Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame,
  • fructose, mannitol, and invert sugar also can be added to improve taste.
  • Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stability.
  • a liquid composition can also contain a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate.
  • a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate.
  • the solid compositions of the present disclosure may include powders, granulates, aggregates, and compacted compositions.
  • the dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, in a preferred embodiment the route of administration is oral.
  • the dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
  • Dosage forms may include solid dosage forms such as tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.
  • the dosage form of the present disclosure can be a capsule comprising a predetermined amount of a composition disclosed herein; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid, contained within either a hard or soft shell.
  • the shell can be made from gelatin and optionally may contain a plasticizer such as glycerin, and optionally sorbitol, an opacifying agent and/or colorant.
  • a composition for tableting or capsule filling can be prepared by wet granulation.
  • wet granulation some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, which causes the powders to clump into granules.
  • the granulate is screened and/or milled, dried, and then screened and/or milled to the desired particle size.
  • the granulate can then be tableted, or other excipients can be added prior to tableting, such as a glidant and/or a lubricant.
  • a tableting composition can be prepared conventionally by dry blending.
  • the blended composition of the active pharmaceutical ingredients and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can subsequently be compressed into a tablet.
  • a blended composition can be compressed directly into a compacted dosage form using direct compression techniques.
  • Direct compression produces a more uniform tablet without granules.
  • Excipients that are particularly well suited for direct compression tableting include, for example, microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica.
  • a capsule filling of the present invention can comprise any of the aforementioned blends and granulates that were described with reference to tableting, but these are not subjected to a final tableting step.
  • a pharmaceutical formulation as contemplated herein may be formulated for administration to a mammal, preferably a human.
  • the compositions disclosed herein can be formulated, for example, as a viscous liquid solution or suspension, or a clear solution, for injection.
  • the formulation can contain one or more solvents.
  • a suitable solvent can be selected by considering the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability), 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 can be added to the formulation such as buffers, solubilizers, and antioxidants, among others.
  • the present invention also encompasses methods for manufacturing a pharmaceutical dosage form based on a self-microemulsifying drug delivery system (SMEDDS) or a spray dried dispersion.
  • SMEDDS self-microemulsifying drug delivery system
  • SMEDDS self-microemulsifying drug delivery systems
  • hydrophilic surfactant hydrophilic surfactant
  • co-solvents hydrophilic surfactant
  • oil-in-water (o/w) microemulsion quickly after gentle agitation and dilution in an aqueous medium. This type of supersaturated environment has been shown to improve drug solubility and absorption.
  • a SMEDDS dosage form of the invention is prepared by solubilizing crystalline (preferably Form 1) RCF 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 at a weight ratio, respectively, of about (0.75-1.5)/(0.5-2)/(2- 5)/(2-5)/(2-2.4)/(4-8).
  • Spray drying co-precipitates a drug molecule and a polymer carrier in a stable amorphous solid dispersion, resulting in improved dissolution rates and enhanced bioavailability of poorly soluble compounds.
  • a spray-dried dispersion places a drug molecule in a polymer-mediated, solubilized state and maintains that amorphous state during transition through the patient’s gastrointestinal (GI) tract.
  • SDDs can be prepared from a solution wherein both the drug molecule and a pharmaceutically acceptable polymer are dissolved in a suitable solvent that can be readily evaporated (including, without limitation, acetone, methanol, methanol/water, or acetone/water mixtures).
  • Pharmaceutically acceptable polymers include, without limitation, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), and polyvinylpyrrolidone (PVP).
  • both the drug molecule and the polymer must be completely dissolved, in order to avoid the inclusion of crystalline residues of the drug molecule in the final SDD.
  • the resulting solution is then delivered into a spray drying unit, which quickly converts the solution into droplets. These droplets dry rapidly in-flight as they travel through, and from the exit of, the spray dryer to a receiving surface (which may include a three- dimensional shell or mold).
  • the solvent’s rapid evaporation traps the drug-polymer mixture in the amorphous state and produces a low-density solid particle.
  • the dried SDD material then goes through a post-drying step to ensure complete removal of the solvent.
  • An SDD dosage form of the invention is prepared by mixing crystalline (preferably 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 residual solvent.
  • crystalline preferably Form 1
  • a pharmaceutically acceptable polymer preferably HPMC.
  • Preferred solvents are methanol or a methanol/water mixture.
  • TGA Thermogravimetric Analysis
  • Isolated from Slurry Samples were placed in pre-tared 40 pL aluminum pans and loaded onto the autosampler of a TA Discovery TGA. Samples were heated at 3°C/min to 100 °C and then 20°C/min to 300°C.
  • DSC Differential scanning calorimetry
  • RCF Form 1 sample was heated at 10°C/min to 255°C, cooled at 10°C/min to 0°C, and finally re-heated at 10°C/min to 255 °C.
  • DSC Differential Scanning Calorimetry
  • RCF Form 1 did not convert to Form 2 in acetonitrile or in any of the formulation solvents tested (DEGMEE, propylene glycol, vitamin E).
  • Form 2 formed in the pure solvents 1,4-di oxane, IP A, iProAc, MTBE, and toluene.
  • RCF Form 2 is likely a solvate that can accommodate many different solvents and is stable over a wide range of solvents and conditions between 0 and 50 °C.
  • RCF Form 2 is moderately hygroscopic and reversibly sorbs and desorbs water at 25°C up to 8.9 wt% water at 90% RH. This amount of water is equivalent to a 7: 1 molar ratio of water to RCF. This is consistent with Form 2 being a non-stoichiometric solvate that can incorporate water into its open crystal structure.
  • Form 2 was slurried in saturated ACN/water blends with high water activity for 2 days.
  • Form 2 was added to ACN/water blends (70 - 90% (w/w) water) previously saturated with Form 1.
  • Samples containing Form 1 solids had been heated to 70°C overnight and then stirred at ambient temperature for 2 days. Remaining solids were still of Form 1, and these solids were removed via filtration through a 0.45 micron PTFE syringe filter.) After stirring these suspensions for 2 days, all remaining solids were of Form 1.
  • the water activity in these experiments is between 0.88 and 0.94.
  • the conversion of Form 2 solids to Form 1 solids at such high water activity confirms that while Form 2 can accommodate a large amount of water (as determined by DVS), it is not a stable hydrate.
  • Form 1 and Form 2 solids were either loaded onto a zero background (high index Si crystal) holder (0.2 mm deep) or dried directly on a zero background holder by drop casting a slurry onto the holder. Samples were analyzed on a Rigaku MiniFlex 600 at 40 kV and 15 mA with a D/tex Ultra ID detector.
  • the PXRD pattern for Form 1 is depicted in FIG. 2, and has the following peaks when measured at an angle of 2-theta ⁇ 0.2 degrees 2-theta:
  • the PXRD pattern for Form 2 is depicted in FIG. 3, and has the following peaks when measured at an angle of 2-theta ⁇ 0.2 degrees 2-theta:
  • FT-IR Fourier transform infrared spectroscopy
  • ATR single bounce attenuated total reflectance
  • the active fill mix is done by first weighing off crystalline Form 1 RCF in an isolator and transferring it into an intermediate batch container (IBC) until ready to be added to the main mix.
  • IBC intermediate batch container
  • a side mixture of Glyceryl Monolinoleate and Vitamin E (dl-alpha Tocopherol) is prepared, using a mixer.
  • Diethylene glycol monoethyl Ether and Propylene Glycol are added to a primary mixing vessel, and are mixed using an agitator and homogenizer.
  • the RCF is then vacuum transferred to the primary mixing vessel, 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 the agitator and homogenizer for a target of 20 minutes.
  • the Glyceryl Monolinoleate and Vitamin E side mix is then vacuum transferred to the primary mixing vessel, and the mixture is mixed for not less than 10 minutes.
  • Polyoxyl 40 Hydrogenated Castor Oil is then vacuum transferred with mixing for not less than 10 minutes.
  • the mixture is then de-aerated for a target of 20 minutes.
  • a standard pharmaceutical gel material is prepared prior to encapsulation. Fill material is encapsulated inside the gel material in order to form the soft gelatin capsules. Throughout the encapsulation process, samples are pulled and tested for fill weight, shell weight, seal thickness and print inspection (if necessary).
  • Capsules are dried immediately after encapsulation in a series of tumble dryer baskets. Capsules are then transferred to shallow trays which are stacked and placed inside drying tunnels operating at specified temperature and humidity conditions. Throughout the drying process, capsules are tested for hardness. Capsules are dried within a specified hardness range in order to produce the final dosage form. E. Capsule Washing
  • 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 a washing step using a liquid, water-free phospholipid concentrate, preferably phosphatidylcholine in medium-chain triglyceride, content > 53.0 % (available as Phosal 53 MCT, Lipoid GmbH, Ludwigshafen, Germany) and denatured ethanol which is sprayed directly onto capsules. Wash solvent is removed by tumble drying.
  • a liquid, water-free phospholipid concentrate preferably phosphatidylcholine in medium-chain triglyceride, content > 53.0 % (available as Phosal 53 MCT, Lipoid GmbH, Ludwigshafen, Germany) and denatured ethanol which is sprayed directly onto capsules. Wash solvent is removed by tumble drying.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Preparation (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des formes à l'état solide de rencofilstat (RCF), des compositions pharmaceutiques les comprenant, ainsi que des méthodes de fabrication de formes posologiques pharmaceutiques les utilisant.
PCT/US2024/033050 2023-06-08 2024-06-07 Formes à l'état solide de rencofilstat Pending WO2024254480A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2024285817A AU2024285817A1 (en) 2023-06-08 2024-06-07 Solid state forms of rencofilstat

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363471879P 2023-06-08 2023-06-08
US63/471,879 2023-06-08

Publications (2)

Publication Number Publication Date
WO2024254480A2 true WO2024254480A2 (fr) 2024-12-12
WO2024254480A3 WO2024254480A3 (fr) 2025-01-16

Family

ID=93794711

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/033050 Pending WO2024254480A2 (fr) 2023-06-08 2024-06-07 Formes à l'état solide de rencofilstat

Country Status (2)

Country Link
AU (1) AU2024285817A1 (fr)
WO (1) WO2024254480A2 (fr)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2013119869A (ru) * 2010-10-12 2014-11-20 Аллерган, Инк. Аналоги циклоспорина
LT2651965T (lt) * 2010-12-15 2019-01-10 Contravir Pharmaceuticals, Inc. Ciklosporino analogo molekulės su modifikuotomis 1 ir 3 aminorūgštimis
CN116829168A (zh) * 2020-11-29 2023-09-29 海必恩制药公司 环孢菌素类似物作为抗血栓形成剂的用途

Also Published As

Publication number Publication date
AU2024285817A1 (en) 2026-01-08
WO2024254480A3 (fr) 2025-01-16

Similar Documents

Publication Publication Date Title
EP3969443B1 (fr) Formes solides de tafamidis et sels associés
US20240246949A1 (en) Solid state forms of lanifibranor and process for preparation thereof
WO2023064519A1 (fr) Formes à l'état solide d'élacestrant et leurs processus de préparation
US11286259B2 (en) Co-crystals of ribociclib and co-crystals of ribociclib monosuccinate, preparation method therefor, compositions thereof, and uses thereof
US12281182B2 (en) Solid state forms of voclosporin
EP4153574A1 (fr) Formes à l'état solide d'aprocitentan et leur procédé de préparation
WO2024254480A2 (fr) Formes à l'état solide de rencofilstat
US20250042864A1 (en) Solid state form of tafamidis
WO2022086899A1 (fr) Formes à l'état solide de pralsetinib et leur procédé de préparation
WO2021119223A1 (fr) Forme à l'état solide du lemborexant
EP4211136B1 (fr) Formes à l'état solide d'at-001 et leur procédé de préparation
EP4051659B1 (fr) Formes à l'état solide de fezagepras et leur procédé de préparation
US20240279167A1 (en) Crystalline polymorphs of rigosertib sodium
US20240173304A1 (en) Solid state forms of tideglusib and process for preparation thereof
WO2026003809A1 (fr) Formes à l'état solide de chlorhydrate d'iptacopan
WO2025224678A1 (fr) Formes à l'état solide de milvexian et procédé de préparation associé
WO2024176164A1 (fr) Forme à l'état solide de pirtobrutinib
EP4594313A1 (fr) Formes à l'état solide de denifanstat
WO2022240802A1 (fr) Formes à l'état solide de sels de sitravatinib et leur procédé de préparation
WO2020154581A1 (fr) Formes à l'état solide d'un co-cristal de fédovapagon-acide salicylique

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: AU2024285817

Country of ref document: AU

ENP Entry into the national phase

Ref document number: 2024285817

Country of ref document: AU

Date of ref document: 20240607

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2024820149

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2024820149

Country of ref document: EP

Effective date: 20260108

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24820149

Country of ref document: EP

Kind code of ref document: A2

ENP Entry into the national phase

Ref document number: 2024820149

Country of ref document: EP

Effective date: 20260108

ENP Entry into the national phase

Ref document number: 2024820149

Country of ref document: EP

Effective date: 20260108

ENP Entry into the national phase

Ref document number: 2024820149

Country of ref document: EP

Effective date: 20260108

ENP Entry into the national phase

Ref document number: 2024820149

Country of ref document: EP

Effective date: 20260108