WO2022171200A1 - Resmetirom的晶型及其制备方法和用途 - Google Patents

Resmetirom的晶型及其制备方法和用途 Download PDF

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WO2022171200A1
WO2022171200A1 PCT/CN2022/079946 CN2022079946W WO2022171200A1 WO 2022171200 A1 WO2022171200 A1 WO 2022171200A1 CN 2022079946 W CN2022079946 W CN 2022079946W WO 2022171200 A1 WO2022171200 A1 WO 2022171200A1
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crystal form
resmetirom
solvent
present disclosure
crystal
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English (en)
French (fr)
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盛晓红
盛晓霞
代宇
吕康乐
胡晨阳
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杭州领业医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present disclosure generally relates to the field of medicinal chemical synthesis.
  • the present disclosure relates to a new crystal form of resmetirom (MGL-3196), a preparation method and use thereof, and a pharmaceutical composition comprising the new crystal form.
  • Resmetirom also known as resmetirom, is a thyroid hormone receptor (THR)-beta selective agonist developed by Madrigal Pharmaceuticals. resmetirom is currently in Phase III clinical trials to evaluate its effects in patients with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), and its structural formula is shown in formula (I):
  • CN105008335B discloses a crystal form I of resmetirom in Example 6, which is a light yellow solid, and crystal form I needs to be purified and prepared through at least 4 steps of reaction, and the process is complicated; The crystal form transformation occurred in about 2 days in the competitive crystal slurry, indicating that the stability of crystal form I also has some problems.
  • the purpose of the present disclosure is to provide novel crystalline forms of resmetirom with improved significance and pharmaceutically acceptable, as well as preparation methods and uses thereof.
  • the crystalline forms provided by the present disclosure have at least one of the following improved properties: stability, crystallinity, hygroscopicity, particle size distribution, fluidity, formulation processability, dissolution, solubility, and bioavailability,
  • the invention meets medicinal requirements, can be stored stably, has a simple preparation method, and is of great value to the optimization and further development of medicines.
  • the present disclosure provides crystal form 3 of resmetirom (hereinafter referred to as crystal form 3), which is an anhydrate.
  • crystal form 3 which is an anhydrate.
  • the structural formula of Resmetirom is shown in formula (I):
  • the X-ray powder diffraction pattern of the crystalline form 3 in 2 ⁇ angles has the following characteristic peaks: 10.7 ⁇ 0.2°, 16.2 ⁇ 0.2°, 18.0 ⁇ 0.2°, 24.1 ⁇ 0.2° and 24.3 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the crystalline Form 3 in 2 ⁇ angle further has the following characteristic peaks: 11.3 ⁇ 0.2°, 12.0 ⁇ 0.2°, 14.4 ⁇ 0.2°, 15.6 ⁇ 0.2° and 22.4 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline Form 3 at 2 ⁇ angle further has at least three of the following characteristic diffraction peaks: 17.3 ⁇ 0.2°, 17.6 ⁇ 0.2°, 19.5 ⁇ 0.2°, 20.0 ⁇ 0.2°, 26.7 ⁇ 0.2°, 26.9 ⁇ 0.2° and 28.7 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form 3 has characteristic peaks and their relative intensities at the following diffraction angles 2 ⁇ :
  • the Form 3 has substantially the X-ray powder diffraction (XRPD) pattern shown in FIG. 2 .
  • the Fourier Transform Infrared Spectroscopy (FT-IR) of Form 3 is at 1718 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 1190 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 1180 cm ⁇ 1 ⁇ 2 cm ⁇ 1 , 908 cm ⁇ 1 At least one of 1 ⁇ 2 cm -1 and 896 cm -1 ⁇ 2 cm -1 has a characteristic peak.
  • the Fourier Transform Infrared Spectroscopy (FT-IR) of the Form 3 is at 1603 cm -1 ⁇ 2 cm -1 , 1461 cm -1 ⁇ 2 cm -1 , 1406 cm -1 ⁇ 2 cm -1 , At least one of 1337cm -1 ⁇ 2cm -1 , 1230cm -1 ⁇ 2cm -1 , 952cm -1 ⁇ 2cm -1 , 908cm -1 ⁇ 2cm -1 and 896cm -1 ⁇ 2cm -1 has a characteristic peak.
  • FT-IR Fourier Transform Infrared Spectroscopy
  • the TGA pattern of the crystal form 3 is substantially as shown in FIG. 3, with a weight loss of 0.3% before 100°C, and a decomposition temperature of 320°C.
  • the DSC pattern of the crystal form 3 is substantially as shown in FIG. 4, and the melting point is 324°C.
  • the DVS pattern of the crystalline form 3 is substantially as shown in FIG. 5 , with a weight gain of 0.2% (w/w) in a 0%RH-80%RH environment, and is slightly hygroscopic.
  • the PLM spectrum of the crystal form 3 is substantially as shown in FIG. 6 , and the fine particles are substantially below 10 ⁇ m in size and uniformly distributed.
  • the FT-IR spectrum of the Form 3 is substantially as shown in FIG. 7 .
  • the present disclosure also provides a preparation method of resmetirom crystal form 3, the preparation method comprising:
  • the volatilization is performed under seeding of Form 3.
  • the alcohol is any one of methanol, isopropanol, n-propanol, or a combination thereof.
  • the solvent is an alcohol
  • the temperature of the solution is between 40°C and 65°C.
  • the temperature of the cooling and stirring crystallization is 2°C to 15°C.
  • Form 3 seeds may be added after the solution is cooled.
  • the alcohol is any one of methanol, isopropanol, n-propanol, or a combination thereof.
  • the solvent is selected from alcohols, mixed solvents of alcohols and water, and mixed solvents of acetonitrile and water.
  • the alcohols are C3-C6 alcohols.
  • the alcohol is any one of isopropanol, n-propanol, or a combination thereof.
  • the resmetirom used in the preparation method is selected from any solid form of resmetirom that is not a crystal form of the present disclosure, including but not limited to free amorphous, free crystal form I, free state and other prior art records One or a combination of two or more of the crystalline form and resmetirom solvate, preferably the solvate of resmetirom.
  • the resmetirom Form 3 of the present disclosure has the following beneficial effects:
  • the resmetirom crystal form 3 of the present disclosure has good stability.
  • the chemical stability of a medicinal product is directly related to its purity and impurities.
  • the purity of drug crystal forms is of great significance for ensuring the efficacy and safety of drugs and preventing the occurrence of adverse drug reactions.
  • the impurities contained in the crystal form of the drug are the main factors affecting the purity. If the impurities exceed the limit, the physical and chemical constants may change, the appearance and properties may vary, and the chemical stability of the drug will be affected; the increase of impurities will also make the drug content obvious. On the low side or the activity is reduced, the toxic and side effects are significantly increased.
  • the crystal form 3 of the present disclosure remained unchanged for 10 months under long-term (25°C-65%RH, open) and accelerated (40°C-75%RH, open) conditions, respectively. Under the condition of light (25°C/4500lx/sealing) for 14 days, the crystal form remained unchanged, and the chemical purity of crystal form 3 remained basically unchanged before and after storage. It shows that the crystal form 3 of resmetirom disclosed in the present disclosure has unexpected and unconventional storage stability, can avoid changes in drug dissolution rate and bioavailability due to crystal form changes, and has a great reality for ensuring the efficacy and safety of drugs. significance.
  • the resmetirom crystal form 3 of the present disclosure is more stable.
  • the crystal form 1 was converted into the crystal form 3 disclosed in the present disclosure in a competitive test with the crystal form 3 of the present disclosure, indicating that the crystal form 3 is more stable.
  • the resmetirom crystal form 3 of the present disclosure has better mechanical stability under grinding conditions. In the process of preparation processing, it is often necessary to grind and pulverize the API. Good mechanical stability can reduce the change of the crystallinity of the API and the risk of crystal transformation during the preparation process.
  • the resmetirom crystal form 3 of the present disclosure has low hygroscopicity, does not require strict humidity control, and is more suitable for industrial production.
  • the crystal form 3 of the present disclosure has better dissolution rate and higher dissolution rate, which is beneficial to improve the bioavailability of the drug.
  • the crystal form 3 of the present disclosure can be directly obtained by solvent cooling crystallization or suspension stirring, the preparation method is simple, the steps are simple and feasible, and it is convenient for large-scale industrial production.
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form 3 of resmetirom of the present disclosure and at least one pharmaceutically acceptable carrier.
  • the pharmaceutical composition may also comprise other pharmaceutically acceptable salts or crystalline and amorphous forms of resmetirom.
  • the dosage form for administration of a compound used in the methods of the present disclosure can be determined by the particular compound selected, the type of pharmacokinetic profile desired for the route of administration, and the state of the patient.
  • the pharmaceutically acceptable carrier is selected from the group consisting of fillers, absorption enhancers, wetting agents, binders, disintegrants, glidants, lubricants, colorants, and the like.
  • the pharmaceutically acceptable carrier in the pharmaceutical composition is well known to those skilled in the art and includes, for example, fillers such as sugars, cellulose and derivatives thereof, starch or modified starch ; Absorption enhancers such as calcium phosphate, dicalcium hydrogen phosphate, hydroxyapatite, calcium sulfate, calcium carbonate; Wetting agents such as water or ethanol; Binders such as microcrystalline cellulose, ethyl cellulose, hydroxymethyl cellulose , hydroxypropyl methylcellulose, hydroxyethylcellulose; glidants such as colloidal silicon dioxide, light anhydrous silicic acid, crystalline cellulose, talc or magnesium stearate; disintegrating agents such as glycolic acid Sodium starch, crospovidone, croscarmellose, sodium carboxymethyl cellulose, dry corn starch; lubricants such as stearic acid, magnesium stearate, sodium stearoyl fumarate, polyethylene glycol Alcohols; colorants such as titanium dioxide
  • the route of administration of the pharmaceutical composition includes oral, subcutaneous, intravenous, intramuscular, transdermal, rectal, nasal, and the like.
  • the pharmaceutical composition can be prepared into a certain dosage form according to the route of administration, which can be solid or liquid.
  • Solid oral dosage forms for example, include tablets, granules, powders, enteric-coated tablets, pills, and capsules. Typically, tablets may be coated using a fluid bed dryer or air suspension coating.
  • HPMCP hydroxypropyl methylcellulose phthalate
  • PVAP cellulose acetate phthalate
  • CAT cellulose acetate trimellitate
  • HPMCAS hypromellose succinate
  • methacrylic acid copolymers such as various types of Eudragit copolymers, eg Eudragit L and S, and Eudragit L30D, etc.
  • liquid oral dosage forms including, for example, solutions, syrups, suspensions, dispersions and emulsions
  • injectable dosage forms including solutions, emulsions and lyophilisates.
  • the formulations may be suitable for immediate, sustained or controlled release of the pharmaceutically active ingredient.
  • Pharmaceutical compositions can be conventional, dispersible, chewable, orally dissolving or fast-melting formulations.
  • the route of administration of the pharmaceutical composition is oral; the solid oral dosage form is a tablet.
  • the pharmaceutical compositions can be prepared using techniques known in the art.
  • the crystalline form 3 of resmetirom of the present disclosure is mixed with at least one pharmaceutically acceptable carrier, and optionally mixed with other crystalline forms, salt forms and amorphous substances of pharmaceutically acceptable resmetirom, Optionally mixed with one or more other pharmaceutically active ingredients.
  • Solid preparations can be prepared into oral, subcutaneous, intravenous, intramuscular, transdermal, rectal, nasal, and other dosage forms by direct mixing, granulation, tableting or dissolving processes.
  • the present disclosure also provides the use of the resmetirom crystal form 3 or the pharmaceutical composition of the present disclosure in the preparation of a medicament for the treatment and/or prevention of diseases or adverse symptoms regulated by thyroid hormone analogs.
  • the present disclosure also provides a method of treatment of a disease or adverse condition mediated by a thyroid hormone analog comprising administering to an individual in need of the method a therapeutically and/or prophylactically effective amount of a resmetirom crystal of the present disclosure Type 3 or a pharmaceutical composition of the present disclosure.
  • the method may be administered once a day, twice a day or more.
  • the single dose can be 0.1mg-100mg/kg/day, and the specific dose will be determined according to the actual situation of the patient.
  • the methods of the present disclosure can be used alone or in combination with other drugs.
  • the method is once-daily administration, and the single dose is 10, 20, 40, 60, 80 or 100 mg of resmetirom Form 3 orally.
  • the disease or adverse condition modulated by the thyroid hormone analog includes, but is not limited to, metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia and diabetes, other diseases such as NASH (non-alcoholic fatty liver), atherosclerosis, cardiovascular disease, hypothyroidism, and thyroid cancer.
  • metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia and diabetes
  • other diseases such as NASH (non-alcoholic fatty liver), atherosclerosis, cardiovascular disease, hypothyroidism, and thyroid cancer.
  • the thyroid hormone analog modulated disease is non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).
  • the present disclosure also provides the combined application of the resmetirom crystal form 3 of the present disclosure or its pharmaceutical composition with other drugs.
  • room temperature in the present disclosure refers to a temperature of 10-30°C.
  • stirring conventional methods in the art can be used, for example, stirring methods include magnetic stirring, mechanical stirring, and the like.
  • the "separation" can be carried out by conventional methods in the art, such as centrifugation or filtration.
  • the filtration under reduced pressure is generally carried out at room temperature with suction filtration at a pressure lower than atmospheric pressure.
  • drying can be accomplished by using conventional techniques in the art, such as drying at room temperature, air drying or drying under reduced pressure; it can be under reduced pressure or normal pressure.
  • the drying apparatus and method are not limited, and can be a fume hood, a forced air oven, a spray dryer, a fluidized bed drying or a vacuum oven; it can also be carried out under reduced or no reduced pressure.
  • Crystal form refers to a compound having a uniquely ordered molecular arrangement or configuration within the crystal lattice as evidenced by the characterization of the X-ray powder diffraction pattern shown. It is well known to those skilled in the art that the experimental errors therein depend upon instrumental conditions, sample preparation and sample purity.
  • the 2-theta angles of peaks in XRPD patterns typically vary slightly from instrument to sample. The difference of peak angle may differ by 1°, 0.8°, 0.5°, 03°, 0.1°, etc.
  • the allowable error is ⁇ 0.2°
  • the allowable error of some hydrates and solvent compounds is often greater than ⁇ 0.2 °, so the difference in peak angle cannot be used as the only criterion.
  • the relative intensities of peaks may vary with sample, sample preparation, and other experimental conditions, so the order of peak intensities cannot be the sole or decisive factor.
  • the influence of experimental factors such as sample height will cause the overall shift of the peak angle, and a certain shift is usually allowed.
  • the shape of the peaks will also vary from case to case, with peaks in the same crystal form appearing as a single peak in some cases, and in others as a bifurcation, doublet, triplet, or singlet with a shoulder. Appear.
  • Single crystalline form means a single crystalline form detected by X-ray powder diffraction.
  • Fig. 1 is the XRPD figure of patent crystal form I in preparation example 1 of the disclosure
  • Fig. 2 is the XRPD pattern of crystal form 3 prepared in Example 1 of the disclosure
  • Fig. 4 is the DSC chart of crystal form 3 prepared in Example 1 of the disclosure.
  • FIG. 5 is a DVS diagram of crystal form 3 prepared in Example 1 of the present disclosure.
  • FIG. 6 is a PLM diagram of crystal form 3 prepared in Example 1 of the disclosure.
  • Fig. 7 is the FT-IR image of crystal form 3 prepared in Example 1 of the present disclosure.
  • Fig. 8 is the XRPD figure before and after placing the stability of crystal form 3 prepared in Example 1 of the present disclosure under long-term, accelerated and light conditions;
  • Fig. 9 is the XRPD result graph of the competitive test of the crystal form 3 prepared in Example 1 of the present disclosure and the crystal form I in the preparation example 1 in a mixed solvent;
  • FIG. 10 is the XRPD overlay of the crystal form 3 prepared in Example 1 of the present disclosure before and after grinding.
  • FIG. 11 is an XRPD overlay of the prepared crystal form I prepared in Preparation Example 1 of the present disclosure before and after grinding.
  • X-ray powder diffraction (XRPD): The instrument is a Bruker D8 Advance diffractometer. The detection conditions are as follows: room temperature, angle range: 3-40° 2 ⁇ , step size: 0.02° 2 ⁇ , speed: 0.2 sec/step.
  • Differential thermal analysis data were obtained from TA Instruments Q200 MDSC.
  • the detection method is as follows: take 1-10 mg of the sample and place it in a small hole aluminum crucible, and raise the sample from room temperature to 200-250 °C at a heating rate of 10 °C/min under the protection of 40 mL/min of dry N2 .
  • Thermogravimetric analysis data were obtained from TA Instruments Q500 TGA.
  • the detection method is as follows: take 5-15mg of the sample and place it in a platinum crucible, adopt the method of segmented high-resolution detection, and raise the sample from room temperature to 40mL/min under the protection of dry N2 at a heating rate of 10°C/min. 350°C.
  • DSC Different Calorimetry Scanner test conditions are: equilibrated at 0°C, ramped to 350°C at 10°C/min; for the DSC chart, keep the temperature point and enthalpy value.
  • DVS test conditions are: taken from TA Instruments Q5000 TGA, control software Thermal Advantage, analysis software Universal Analysis; usually 1-10 mg of sample is placed in a platinum crucible, and TA software records the relative humidity of the sample from 0% to 80% Weight change during to 0% change. Depending on the specific conditions of the sample, different adsorption and desorption steps are also applied to the sample.
  • FT-IR Fourier Infrared Spectroscopy
  • the X-ray powder diffraction pattern is shown in FIG. 1 : the solid form of the resmetirom prepared according to the method described in the examples in the patent document CN105008335B is crystal form I.
  • Example 2-1 The solvent in Example 2-1 is replaced with the solvent and temperature in the following table, the seed crystal can be selected from any of the examples in Example 1, and the crystal form 3 can also be obtained.
  • Example 1 of the present disclosure The crystal form 3 samples prepared in Example 1 of the present disclosure were weighed, and the samples were subjected to long-term (25°C-65%RH, open), accelerated (40°C-75%RH, open) and light (25°C/4500lx/sealed) ) conditions, XRPD and HPLC were regularly detected, the results are shown in Table 4 and Figure 8.
  • the crystal form 3 can be kept stable for at least 10 months under long-term (25°C-65%RH, open) and accelerated (40°C-75%RH, open) conditions. It can be kept stable for at least 14 days under the condition of /sealing), and the chemical purity of crystal form 3 remains basically unchanged before and after being placed.
  • the samples of crystal form 3 and crystal form I prepared in the present disclosure were prepared into saturated solutions with FaSSIF (simulating intestinal fluid in fasting state) (preparation of FaSSIF: 3 mmol of sodium taurocholate, 0.75 mmol of lecithin, and dihydrogen phosphate were added to 1 L of water. Potassium 3.9 g, potassium chloride 7.7 g, pH was adjusted to about 6.5 with sodium hydroxide), samples were taken at fixed time points and the content of the samples in the saturated solution was determined by high performance liquid chromatography (HPLC). The experimental results are shown in Table 5:
  • the crystal form 3 has significantly superior solubility compared with the crystal form I, and the solubility at 1 h is 172% higher than that of the existing crystal form I, resulting in unexpected effects.
  • the intestine is the main site of drug absorption, and the significantly improved solubility of crystalline form 3 in FaSSIF is beneficial to improve the absorption of the drug in the intestine and increase the bioavailability of resmetirom.
  • the resmetirom crystal form 3 and the resmetirom crystal form 1 were respectively mixed with the raw materials shown in Table 6, and were pressed with a single-punch tablet machine (pressure 10MPa, time 2min) to prepare crystal form 3 tablets with a tablet weight of 120 mg and Form I tablets.
  • the tablet containing crystal form 3 and crystal form I prepared according to the above-mentioned prescription and process is subjected to dissolution test, and the conditions are as follows:
  • Dissolution Apparatus RC12AD Tianda Tianfa Dissolution Apparatus
  • Dissolution medium pH 6.8 phosphate buffer
  • Dissolution method basket method
  • the release degree of crystal form 3 reached 42.53% after 15 minutes, almost all of it was released after 2 hours, while the release degree of crystal form I was still less than 50% after 2 hours. Therefore, compared with the crystal form I, the crystal form 3 has better dissolution rate and higher dissolution rate, which is beneficial to improve the bioavailability of the drug.
  • the resmetirom crystal form 3 and the raw and auxiliary materials shown in Table 8 are mixed uniformly and filled into capsules to obtain 3 capsules of different specifications.
  • the cores and coatings were prepared according to conventional methods, and then the aqueous solution/suspension of the coating was applied to the cores to obtain 4 film-coated tablets of different sizes.

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Abstract

公开了resmetirom的晶型及其制备方法和用途，以及包含所述晶型的药物组合物。

Description

Resmetirom的晶型及其制备方法和用途
相关申请的引用
本公开要求于2021年2月10日向中华人民共和国国家知识产权局提交的申请号为202110183231.0的发明专利申请以及于2022年1月28日向中华人民共和国国家知识产权局提交的申请号为202210098713.0的全部权益，并通过引用的方式将其全部内容并入本公开。
领域
本公开大体上涉及药物化学合成领域。具体而言，本公开涉及resmetirom(MGL-3196)的新晶型及其制备方法和用途，以及包含所述新晶型的药物组合物。
背景
Resmetirom，又名瑞司美替罗，是Madrigal制药公司开发的一款甲状腺激素受体(THR)-β选择性激动剂。resmetirom目前处于临床III期，用于评估其在非酒精性脂肪性肝病(NAFLD)和非酒精性脂肪性肝炎(NASH)患者中的作用,其结构式如下式(I)所示：
Figure PCTCN2022079946-appb-000001
CN105008335B在实施例6中公开了resmetirom的一种晶型I，为浅黄色固体，晶型I需要经过至少4步反应来进行纯化制备，过程复杂；此外，经过发明人研究发现，晶型I在竞争性晶浆中2天左右发生晶型转化，表明晶型I的稳定性也存在一定问题。
概述
本公开的目的是提供具有改善意义的、可药用的resmetirom的新晶型及其制备方法和用途。
在某些实施方案中，本公开提供的晶型至少具有以下一种改进的特性：稳定性、结晶度、吸湿性、粒度分布、流动性、制剂可加工性、溶出、溶解度及生物利用度，符合药用要求，能稳定储存，制备方法简便，对药物的优化和进一步开发具有重要价值。
一方面，本公开提供resmetirom的晶型3(以下简称晶型3)，其为无水物。Resmetirom的结构式如式(I)所示：
Figure PCTCN2022079946-appb-000002
使用Cu-Kα辐射，所述晶型3以2θ角度表示的X-射线粉末衍射图具有以下特征峰：10.7±0.2°、16.2±0.2°、18.0±0.2°、24.1±0.2°和24.3±0.2°。
在某些实施方案中，所述晶型3以2θ角度表示的X-射线粉末衍射图还具有以下特征峰：11.3±0.2°、12.0±0.2°、14.4±0.2°、15.6±0.2°和22.4±0.2°。
在某些实施方案中，所述晶型3以2θ角度表示的X-射线粉末衍射图还具有以下特征衍射峰中的至少三个：17.3±0.2°、17.6±0.2°、19.5±0.2°、20.0±0.2°、26.7±0.2°、26.9±0.2°和28.7±0.2°。
在某些实施方案中，所述的晶型3的X-射线粉末衍射图谱在以下衍射角2θ处具有特征峰及其相对强度：
Figure PCTCN2022079946-appb-000003
Figure PCTCN2022079946-appb-000004
在某些实施方案中，所述晶型3基本具有如图2所示的X-射线粉末衍射(XRPD)图谱。
在某些实施方案中，所述晶型3的傅里叶红外光谱(FT-IR)在1718cm -1±2cm -1、1190cm -1±2cm -1、1180cm -1±2cm -1、908cm -1±2cm -1和896cm -1±2cm -1中的至少一处具有特征峰。
在某些实施方案中，所述晶型3的傅里叶红外光谱(FT-IR)在还在1603cm -1±2cm -1、1461cm -1±2cm -1、1406cm -1±2cm -1、1337cm -1±2cm -1、1230cm -1±2cm -1、952cm -1±2cm -1、908cm -1±2cm -1和896cm -1±2cm -1中的至少一处具有特征峰。
在某些实施方案中，所述晶型3的TGA图谱基本如图3所示，在100℃前有0.3％的重量损失，分解温度为320℃。
在某些实施方案中，所述晶型3的DSC图谱基本如图4所示，熔点为324℃。
在某些实施方案中，所述晶型3的DVS图谱基本如图5所示，在0％RH-80％RH环境下增重0.2％(w/w)，略有引湿性。
在某些实施方案中，所述晶型3的PLM图谱如基本如图6所示，细小颗粒，粒径基本在10μm以下，分布均匀。
在某些实施方案中，所述晶型3的FT-IR图谱如基本如图7所示。
另一方面，本本公开还提供了resmetirom晶型3的制备方法，所述制备方法包括：
1)将resmetirom溶清于溶剂中，挥发析晶得到晶型3的固体，其中，所述溶剂为醇类，所述挥发在室温下进行。
在某些实施方案中，所述挥发在加晶型3晶种下进行。
在某些实施方案中，所述醇类为甲醇、异丙醇、正丙醇中的任一种或其组合。
或者
2)将resmetirom溶清于溶剂中形成溶液，冷却，搅拌析晶，分离，干燥得到晶型3的固体。
在某些实施方案中，所述溶剂为醇类。
在某些实施方案中，所述溶清的温度在40℃-65℃之间。
在某些实施方案中，所述冷却搅拌析晶的温度为2℃-15℃。
在某些实施方案中，所述溶液冷却后可添加晶型3晶种。
在某些实施方案中，所述醇类为甲醇、异丙醇、正丙醇中的任一种或其组合。
或者
3)将resmetirom和单一溶剂或混合溶剂混合形成悬浮液，搅拌，分离，干燥，得到所述晶型3。
在某些实施方案中，所述溶剂选自醇类、醇类和水混合溶剂、乙腈和水的混合溶剂。
在某些实施方案中，所述醇类为C3-C6醇。
在某些实施方案中，所述醇类为异丙醇、正丙醇中的任一种或其组合。
在某些实施方案中，所述制备方法中采用的resmetirom选自resmetirom非本公开的晶型的任一固体形态，包括但不限于游离态无定型物、游离态晶型I、游离态其他现有技术记载的晶型、resmetirom溶剂合物中的一种或两种以上组合，优选resmetiron的溶剂化合物。
在某些实施方案中，本公开的resmetirom晶型3具有以下有益效果：
1)本公开的resmetirom晶型3的稳定性好。
本领域技术人员均知药物化学稳定性与其纯度及杂质有直接关系。药物晶型的纯度对于保证药物的疗效和安全性,防止药物不良反应的发生具有重要意义。并且，药物晶型中含有的杂质是影响纯度的主要因素，如含有超过限量的杂质,就有可能使理化常数变动，外观性状产生变异，影响药物的化学稳定性；杂质增多也使药物含量明显偏低或活性降低，毒副作用显著增加。
本公开的晶型3分别在长期(25℃-65％RH，敞口)和加速(40℃-75％RH，敞口)条件下放置10个月晶型保持不变。在光照(25℃/4500lx/密封)条件下放置14天晶型保持不变，且放置前后晶型3 的化学纯度基本保持不变。说明本公开的resmetirom晶型3具有意想不到的超常规的放置稳定性，能够避免由于晶型改变而导致的药物溶出速率和生物利用度改变，对于保证药物的疗效和安全性具有很大的现实意义。
2)与resmetirom晶型I相比，本公开的resmetirom晶型3更加稳定。经对比研究发现，晶型I在与本公开的晶型3在竞争性试验中转为转变成本公开的晶型3，说明晶型3更稳定。
3)与resmetirom晶型I相比，本公开的resmetirom晶型3在研磨条件下具有更好的机械稳定性。制剂加工过程中常常需要将原料药进行研磨粉碎，良好的机械稳定性可以降低制剂加工过程中原料药晶型结晶度的改变和转晶的风险。
4)本公开的resmetirom晶型3引湿性低，无需严格控制湿度，更适合工业化生产。
5)与resmetirom晶型I相比，本公开的resmetirom晶型3在FaSSIF中的溶解度提高了172％，提高了药物在肠的吸收和增加了resmetirom的生物利用度。
6)与resmetirom晶型I相比，本公开的晶型3的溶出度更好且溶出速率更高，有利于提高药物的生物利用度。
7)与resmetirom晶型I相比，本公开的晶型3的可以直接通过溶剂冷却结晶或悬浮液搅拌得到，制备方法简便，步骤简单易行，便于大规模化工业生产。
又一方面，本公开还提供了药物组合物，所述药物组合物包含治疗有效量的本公开的resmetirom的晶型3以及至少一种药学上可接受的载体。
在某些实施方案中，所述药物组合物还可以包含resmetirom的其它可药用盐或晶型及无定型。
在某些实施方案中，本公开方法中使用的化合物的给药剂型可以通过所选择的特定化合物、给药途径要求的药物动力学分布类型及患者的状态来确定。
在某些实施方案中，所述药学上可接受的载体选自填充剂、吸收促进剂、润湿剂、粘合剂、崩解剂、助流剂、润滑剂和着色剂等。
在某些实施方案中，所述药物组合物中所述药学上可接受的载体，是本领域技术人员公知的，例如包括填充剂如糖类，纤维素及其衍生物，淀粉或改性淀粉；吸收促进剂如磷酸钙、磷酸氢二钙、羟基磷灰石、硫酸钙、碳酸钙；润湿剂如水或乙醇；粘合剂如微晶纤维素、乙基纤维素、羟甲基纤维素、羟丙基甲基纤维素、羟乙基纤维素；助流剂如胶态二氧化硅、轻质无水硅酸、结晶纤维素、滑石粉或硬脂酸镁；崩解剂如乙醇酸淀粉钠、交聚维酮、交联羧甲基纤维素、羧甲基纤维素钠、干玉米淀粉；润滑剂如硬脂酸、硬脂酸镁、硬脂酰富马酸钠、 聚乙二醇；着色剂如二氧化钛、落日黄、亚甲蓝、药用氧化铁红。
在某些实施方案中，所述药物组合物的给药途径包括口服、皮下注射、静脉注射给药、肌肉注射、透皮给药、直肠给药、鼻腔给药等。所述药物组合物可以根据给药途径，制备成一定的剂型，可为固态或液态。固体口服剂型，例如包括片剂、颗粒剂、散剂、肠溶片、丸剂和胶囊剂，通常，片剂可以使用流化床干燥器或空气悬浮包衣进行包衣。肠溶衣中使用的常用物质是邻苯二甲酸羟丙基甲基纤维素(HPMCP)、醋酸邻苯二甲酸纤维素(PVAP)、邻苯二甲酸酰基酯(diethyl phthalate)、醋酸邻苯二甲酸纤维素(cellulose acetate phthalate)、醋酸偏苯三酸纤维素(CAT)、羟丙甲纤维素琥珀酸酯(HPMCAS)、甲基丙烯酸共聚物如各种类型的尤特奇共聚物，例如Eudragit L和S，以及Eudragit L30D等；液体口服剂型，例如包括溶液剂、糖浆剂、混悬剂、分散剂和乳剂；可注射制剂型包括溶液剂、乳剂和冻干剂。配方可适于药物活性成分的速释、缓释或可控释放。药物组合物可以是常规的、可分散的、可咀嚼的、口腔溶解的或快速熔化的制剂。
在某些实施方案中，所述药物组合物的给药途径为口服；所述固体口服剂型为片剂。
在某些实施方案中，所述药物组合物可以使用本领域公知技术来制备。制备药物组合物时，将本公开的resmetirom晶型3与至少一种药学上可接受的载体相混合，任选地与可药用的resmetirom的其它晶型、盐型、无定型物相混合，任选地与一种或多种其他的药物活性成分相混合。固体制剂可以通过直接混合、制粒、压片或溶解等工艺制备成口服、皮下注射、静脉注射给药、肌肉注射、透皮给药、直肠给药、鼻腔给药等剂型。
又一方面，本公开还提供了本公开的resmetirom晶型3或所述的药物组合物在制备用于治疗和/或预防甲状腺激素类似物调节的疾病或不良症状的药物中的用途。
另一方面，本公开还提供了治疗和/或甲状腺激素类似物调节的疾病或不良症状的治疗方法，其包括向需要所述方法的个体给予治疗和/或预防有效量的本公开的resmetirom晶型3或本公开的药物组合物。
在某些实施方案中，所述方法可以是一天一次，一天两次或以上给药。单次剂量可以是0.1mg-100mg/kg/天，具体的剂量将根据病人的实际情况决定。
在某些实施方案中，本公开的方法可以单用或和其他药物联用。
在某些实施方案中，所述方法为每日一次给药，单次剂量为口服10、20、40、60、80或100mg resmetirom晶型3。
在某些实施方案中，所述甲状腺激素类似物调节的疾病或不良症状包括但不限于代谢疾病，如肥胖、高脂血症、高胆固醇血症和糖尿病，其他疾病如NASH(非酒精性的脂肪肝)、动脉粥样硬化、心血管疾 病、甲状腺功能减退和甲状腺癌。
在某些实施方案中，所述甲状腺激素类似物调节的疾病为非酒精性脂肪性肝病(NAFLD)和非酒精性脂肪性肝炎(NASH)。
本公开还提供了本公开的resmetirom晶型3或其药物组合物与其他药物的联合应用。
除非特殊注明，本公开所述的“室温”是指10-30℃的温度。
所述“搅拌”，可以采用本领域的常规方法，例如搅拌方式包括磁力搅拌、机械搅拌等。
所述“分离”可以采用本领域的常规方法，例如离心或过滤。其中减压过滤，一般是在室温下以小于大气压的压力进行抽滤。
所述“干燥”，可以采用本领域的常规技术完成，例如常温干燥、鼓风干燥或减压干燥；可以减压或常压。干燥仪器和方法不受限制，可以是通风橱、鼓风烘箱、喷雾干燥器、流化床干燥或真空烘箱；亦可以在减压或不减压下进行。
本公开中所述的“晶型”是指化合物被所示X-射线粉末衍射图谱表征所证实的，在晶格内具有独特有序的分子排列或构型。本领域技术人员公知，其中的实验误差取决于仪器条件、样品准备和样品纯度。XRPD图谱中的峰的2θ角度通常会随着仪器和样品不同而略有不同。峰角度的差值根据不同仪器，不同样品等可能相差1°，0.8°，0.5°，03°，0.1°等，通常允许误差±0.2°，有些水合物和溶剂化合物允许的误差常大于±0.2°，所以峰角度的差别不能作为唯一标准。峰的相对强度可能随样品、样品制备和其他实验条件而变化，所以峰强度的顺序不能作为唯一或决定性因素。样品高度等实验因素的影响会造成峰角度整体偏移，通常允许一定的偏移。峰的形状也会因具体情况而有所差别，同一晶型中有的峰在一些情况下显示为单峰，在另一些情况下以分叉、双峰、三峰或单峰加峰肩等形式出现。因而，本领域技术人员可以理解的是，任何具有与本公开X射线粉末衍射图谱相同或相似特征峰的晶型均属于本公开的范畴。“单一晶型”是指经X-射线粉末衍射检测为单一晶型。
附图简要说明
图1为本公开制备例1中专利晶型I的XRPD图；
图2为本公开实施例1制备的晶型3的XRPD图；
图3为本公开实施例1制备的晶型3的TGA图；
图4为本公开实施例1制备的晶型3的DSC图；
图5为本公开实施例1制备的晶型3的DVS图；
图6为本公开实施例1制备的晶型3的PLM图；
图7为本公开实施例1制备的晶型3的FT-IR图；
图8为本公开实施例1制备的晶型3稳定性在长期、加速和光照条件 下放置前后的XRPD图；
图9为本公开实施例1制备的晶型3和制备例1中的晶型I在混合溶剂中竞争性试验的XRPD结果图；
图10为本公开实施例1制备的晶型3研磨前后的XRPD叠图；以及
图11为本公开制备例1的制备的晶型I研磨前后的XRPD叠图。
详述
通过下述实施例将有助于进一步理解本公开，但是不用于限制本公开的内容。
检测仪器及方法：
X-射线粉末衍射(XRPD)：仪器为Bruker D8 Advance diffractometer。检测条件如下：室温，角度范围：3-40°2θ，步长：0.02°2θ，速度：0.2秒/步。
差热分析数据采自于TA Instruments Q200 MDSC。检测方法为：取1-10毫克的样品放置于小孔铝坩埚内，以10℃/min的升温速度在40mL/min干燥N 2的保护下将样品从室温升至200-250℃。
热重分析数据采自于TA Instruments Q500 TGA。检测方法为：取5-15mg的样品放置于白金坩埚内，采用分段高分辨检测的方式，以10℃/min的升温速度在40mL/min干燥N 2的保护下将样品从室温升至350℃。
DSC(差示量热扫描仪)测试条件为：平衡在0℃，以10℃/min升至350℃；对于DSC图，保留温度点及热焓值。
DVS测试条件为：采自于TA Instruments Q5000 TGA，控制软件Thermal Advantage，分析软件Universal Analysis；通常取1-10毫克的样品放置于白金坩埚内，TA软件记录样品在相对湿度从0％到80％到0％变化过程中的重量变化。根据样品的具体情况，也会对样品采用不同的吸附和脱吸附步骤。
傅里叶红外光谱(FT-IR)数据采自于Bruker Tensor 27。参数如下：检测方法：ATR法；采集范围：600cm -1-4000cm -1；分辨率：4.0cm -1。
高效液相色谱(HPLC):
色谱柱：Titank-C183μm(100*4.6mm)
洗脱程序：
Figure PCTCN2022079946-appb-000005
Figure PCTCN2022079946-appb-000006
柱温：40℃
检测波长：254nm
流速：1.0mL/min
流动相A：0.1％TFA in H 2O
流动相B：0.1％TFA in ACN
制备例1
根据专利文献CN105008335B中实施例6所描述的方法制备得到resmetirom固体形态。
X射线粉末衍射图谱如图1所示显示：根据专利文献CN105008335B中实施例所描述的方法制备得到的resmetirom固体形态为晶型I。
实施例1-1
取20毫克制备例1的resmetirom在0.5mL正丙醇中形成混悬液，室温晶浆5天后，离心，置于室温真空干燥24小时，得到晶型3。
其X-射线粉末衍射图谱基本如图2所示。
其TGA图谱基本如图3所示，在100℃前有0.3％的重量损失，分解温度为320℃。
其DSC图谱基本如图4所示，熔点为324℃。
其DVS图谱基本如图5所示，在0％RH-80％RH环境下增重0.2％(w/w)，略有引湿性。
其PLM图谱基本如图6所示，细小颗粒，粒径基本在10μm以下，分布均匀。
其FT-IR图谱如基本如图7所示。
实施例1-2
取51.80毫克制备例1的resmetirom在1.0mL正丙醇中形成混悬液，室温晶浆2天后，离心，置于室温真空干燥24小时，得到晶型3。
实施例1-3
取200毫克制备例1的resmetirom在3mL正丙醇中形成混悬液，室温晶浆3天后，离心，置于室温真空干燥24小时，得到晶型3。
实施例1-4
取500毫克制备例1的resmetirom，在3.5mL正丙醇中形成混悬液，室温晶浆16小时后，过滤，置于室温真空干燥67小时，得到晶型3。 实施例2-1
取20.15毫克制备例1的resmetirom在60℃条件下溶清于2mL正丙醇中，过滤，加入3毫克实施例1制备的晶型3作为晶种，置于4℃下搅拌1天后，离心，置于室温真空干燥24小时，得到晶型3。
实施例2-2
将实施例2-1中的溶剂替换成下表中的溶剂和温度，晶种选自实施例1中任意实施例均可，同样可得到晶型3。
表2.晶型3制备实施例替换实验2
Figure PCTCN2022079946-appb-000007
实施例3-1
取20.92毫克resmetirom在7mL正丙醇中超声溶清后过滤，加入3毫克实施例1制备的晶型3作为晶种，室温敞口挥发2天后，得到晶型3。
实施例6：稳定性
称取本公开实施例1制备的晶型3样品，分别在长期(25℃-65％RH，敞口)、加速(40℃-75％RH，敞口)和光照(25℃/4500lx/密封)条件下放置，定期检测XRPD和HPLC，结果如表4和图8所示。
表4.稳定性数据
Figure PCTCN2022079946-appb-000008
结果表明：晶型3分别在长期(25℃-65％RH，敞口)和加速(40℃-75％RH，敞口)条件下放置至少可以稳定10个月，在光照(25℃/4500lx/密封)条件下放置至少可以稳定14天，且放置前后晶型3的化学纯度基本保持不变。
实施例7：竞争稳定性
取等量制备例1制备的resmetirom晶型I，和实施例1中得到的晶型3，加入混合溶剂(V(乙腈:水)＝20:1)中形成悬浮液，搅拌2天，离心，置于室温真空干燥24小时，考察其晶型稳定，其XRPD如图9所示表明，晶浆2天后，制备的resmetirom晶型I转变为本公开所述的resmetirom晶型3，说明参考专利制备的晶型I的晶型稳定度较低，而晶型3具有良好的稳定性。
实施例8：机械稳定性
分别将本公开实施例1的晶型3和制备例1的晶型I置于研钵中，手动研磨10min，研磨前后进行XRPD测试(图10和图11)，结果表明：晶型I结晶度明显降低，晶型3的结晶度无明显变化，说明晶型3具有良好的机械稳定性。
实施例9：溶解度
将本公开制备得到的晶型3与晶型I样品用FaSSIF(模拟空腹状态下肠液)配制成饱和溶液(FaSSIF的配制：向1L水中加入牛黄胆酸钠3mmol、卵磷脂0.75mmol、磷酸二氢钾3.9g、氯化钾7.7g，用氢氧化钠将PH调节至约6.5)，在固定的时间点取样并通过高效液相色谱(HPLC)法测定饱和溶液中样品的含量。实验结果如表5所示：
表5.晶型3和晶型I的溶解度数据
Figure PCTCN2022079946-appb-000009
结果表明，在FaSSIF中，晶型3较晶型I具有明显优越的溶解度，1h时的溶解度比现有晶型I提高了172％，产生了出乎预料的效果。肠道是药物吸收的主要部位，晶型3在FaSSIF中溶解度的显著提高，有利于提高药物在肠的吸收和增加resmetirom的生物利用度。
实施例10：溶出度
片剂的制备：
分别将resmetirom晶型3和resmetirom晶型I与表6所示的原辅料混合均匀，用单冲压片机压片(压力10MPa，时间2min)，制备得到片重为120mg的晶型3片剂和晶型I片剂。
表6.晶型3和晶型I的片剂的处方表
Figure PCTCN2022079946-appb-000010
溶出度测定：
将按照上述处方和工艺制备得到含晶型3和晶型I的片剂进行溶出度测试，条件如下：
溶出仪：RC12AD型天大天发溶出仪
溶出介质：pH 6.8磷酸盐缓冲液
介质体积：900mL
溶出方法：篮法
介质温度：37℃
转速：100rpm
溶出结果如表7所示。
表7.晶型3和晶型I片剂的溶出度检测结果
Figure PCTCN2022079946-appb-000011
结果表明：晶型3在15min后释放度就达到42.53％，2h后几乎全部释放，而晶型I在2h后释放度仍旧小于50％。因此，相对于晶型I，晶型3的溶出度更好且溶出速率更高，有利于提高药物的生物利用度。
实施例11：胶囊剂的制备
将resmetirom晶型3与表8所示的原辅料混合均匀，填充到胶囊中，得到3个不同规格的胶囊剂。
表8.晶型3胶囊剂的处方表
Figure PCTCN2022079946-appb-000012
Figure PCTCN2022079946-appb-000013
实施例12：薄膜包衣片剂的制备
按照常规的方法制备片芯和包衣，然后将包衣的水溶液/悬浮液涂覆在片芯上，得到4个不同规格的薄膜包衣片剂。
片芯：
Figure PCTCN2022079946-appb-000014
包衣：
Figure PCTCN2022079946-appb-000015
以上所述，仅为本公开的具体实施方式，但本公开的保护范围并不局限于此，任何熟悉本领域的技术人员在本公开所揭露的技术范围内，可不经过创造性劳动想到的变化或替换，都应涵盖在本公开的保护范围之内。因此，本公开的保护范围应该以权利要求书所限定的保护范围为准。

Claims (16)

  1. 结构式如式(I)所示的resmetirom晶型3，
    Figure PCTCN2022079946-appb-100001
    其中，所述晶型3以2θ角度表示的X-射线粉末衍射图具有以下特征峰：10.7±0.2°、16.2±0.2°、18.0±0.2°、24.1±0.2°和24.3±0.2°。
  2. 如权利要求1所述的resmetirom晶型3，其中，所述晶型3以2θ角度表示的X-射线粉末衍射图还具有以下特征峰：11.3±0.2°、12.0±0.2°、14.4±0.2°、15.6±0.2°和22.4±0.2°。
  3. 如权利要求1或2所述的resmetirom晶型3，其中，所述晶型3以2θ角度表示的X-射线粉末衍射图还具有以下至少3个特征衍射峰：17.3±0.2°、17.6±0.2°、19.5±0.2°、20.0±0.2°、26.7±0.2°、26.9±0.2°和28.7±0.2°。
  4. 根据权利要求1至3中任一权利要求所述的resmetirom晶型3，其中，所述晶型3以2θ角度表示的X-射线粉末衍射图具有以下特征峰及其相对强度：
    Figure PCTCN2022079946-appb-100002
    Figure PCTCN2022079946-appb-100003
  5. 制备权利要求1至4中任一权利要求所述的resmetirom晶型3的方法，其包括：将resmetirom溶清于溶剂中，挥发析晶得到晶型3的固体。
  6. 如权利要求5所述的方法，其中溶剂为醇类，优选所述醇类为甲醇、异丙醇、正丙醇中的任一种或其组合。
  7. 制备权利要求1至4中任一权利要求所述的resmetirom晶型3的方法，其包括：将resmetirom溶清于溶剂中，冷却，搅拌析晶，分离，干燥得到晶型3的固体。
  8. 如权利要求7所述的方法，其中溶剂为醇类，优选所述醇类为甲醇、异丙醇、正丙醇中的任一种或其组合。
  9. 制备权利要求1至4中任一权利要求所述的resmetirom晶型3的方法，其包括：将resmetirom和单一溶剂或混合溶剂混合形成悬浮液，搅拌，分离，干燥，得到晶型3。
  10. 如权利要求9所述的方法，其中所述溶剂选自醇类、醇类和水的混合溶剂、乙腈和水的混合溶剂，优选所述醇类为C3-C6醇。
  11. 药物组合物，其包含治疗和/或预防有效量的权利要求1至4中任一权利要求所述的resmetirom晶型3以及至少一种药学上可接受的载体。
  12. 如权利要求11所述的药物组合物，其为片剂。
  13. 治疗和/或预防甲状腺激素类似物调节的疾病或不良症状的方法，其包括向需要所述方法的个体给予治疗和/或预防疾病有效量的权利要求1至4中任一权利要求所述的resmetirom晶型3或权利要求11或12所述的药物组合物。
  14. 如权利要求14所述的方法，其中以每日一次给药，单次剂量为口服80或100mg的resmetirom晶型3。
  15. 如权利要求13或14所述的方法，其中所述甲状腺激素类似物调节的疾病选自非酒精性脂肪性肝病和非酒精性脂肪性肝炎。
  16. 如权利要求13至15中任一权利要求所述的方法，其还包括给予另一种药物。
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