WO2023083293A1 - 依利格鲁司他可药用盐及其晶型 - Google Patents
依利格鲁司他可药用盐及其晶型 Download PDFInfo
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- WO2023083293A1 WO2023083293A1 PCT/CN2022/131323 CN2022131323W WO2023083293A1 WO 2023083293 A1 WO2023083293 A1 WO 2023083293A1 CN 2022131323 W CN2022131323 W CN 2022131323W WO 2023083293 A1 WO2023083293 A1 WO 2023083293A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- eliglustat
- pharmaceutically acceptable
- acceptable salt
- salt
- naphthalene disulfonate
- Prior art date
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- 229960002856 eliglustat Drugs 0.000 title claims abstract description 193
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- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims abstract description 37
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Classifications
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
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- C—CHEMISTRY; METALLURGY
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- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
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- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/33—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of six-membered aromatic rings being part of condensed ring systems
- C07C309/34—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of six-membered aromatic rings being part of condensed ring systems formed by two rings
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Definitions
- the invention relates to a pharmaceutically acceptable salt of eliglustat and its crystal form, a preparation method, a pharmaceutical composition containing the crystal form and its use, belonging to the technical field of medicine.
- Eliglustat the chemical name is N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxan-6-yl)-2-hydroxy- 1-(1-Pyrrolidinemethyl)ethyl]octylamide, a potent and highly specific ceramide analog inhibitor, reduces glucosylceramide production by targeting glucosylceramide synthetase.
- Eliglustat Capsules It was approved by the US FDA in 2014 for the long-term treatment of first-line treatment of adult patients with type 1 Gaucher disease.
- Eliglustat Capsules Combination with CYP2D6 and CYP3A4 inhibitor drugs may significantly increase the exposure of the drug and cause PR, QTc, and/or prolongation of the QRS cardiac interval, resulting in arrhythmia; when the plasma concentration of eliglustat reaches 500ng/mL, Pharmacokinetic/pharmacodynamic models predicted mean increases in PR, QRS, and QTcF intervals of 22 (26), 7 (10), and 13 (19) milliseconds.
- Eliglustat Capsules Compared with the dosage of 84 mg orally twice a day for CYP2D6 extensive and intermediate metabolizers, for CYP2D6 poor metabolizers, the dosage of Eliglustat Capsules was lowered to 84 mg orally once a day to avoid the risk of arrhythmia for CYP2D6 poor metabolizers side effect. Based on the above factors, the marketed Eliglustat Capsules There are many inconveniences in clinical use.
- Eliglustat and its preparation method are described in US6916802B2, and the "pharmaceutically acceptable salt” is briefly described as inorganic acids, such as sulfuric acid, hydrochloric acid, phosphoric acid, etc., or organic acids, such as acetate. No studies were conducted on the physicochemical properties of the pharmaceutically acceptable salts, nor on the crystal forms of the salts.
- WO2011066325A1 describes that salts of eliglustat include citrate, malate, fumarate, methanesulfonate and acetate, but these salts cannot be obtained in solid form; although they can be obtained in solid form
- the hydrochloride salt and the 1:1 tartrate salt were obtained, but both were not in crystalline form and were too hygroscopic for formulation.
- Eliglustat hemitartrate is easier to formulate and synthesize than the free base and other salts.
- eliglustat hemitartrate and its crystal form are crystalline, non-hygroscopic, water-soluble and have better fluidity than the corresponding free base and other salts, and are suitable for large-scale preparation.
- 6.6°, 10.7°, 1 1.0°, 15.9°, and 2 ⁇ of 21.7° exist main X-ray powder diffraction peaks.
- CN107445938A another L-hemitartrate crystal form of eliglustat is described, and X-ray powder diffraction has Main characteristic peaks, DSC spectrum shows that there is an endothermic peak at 161 ° C ⁇ 162 ° C.
- the invention provides a new eliglustat salt and its crystal form, which can exist in a stable solid form.
- eliglustat hemi-tartrate crystal form A eliglustat 1,5-naphthalene disulfonate and its crystal form have lower hygroscopicity, and the solubility difference in water and simulated gastric juice is small, It is expected to have a more gentle plasma drug concentration after oral administration, and reduce the adverse reactions of arrhythmia caused by increasing the dose.
- the invention provides a pharmaceutically acceptable salt, solvate and crystal form thereof of eliglustat that can exist in a stable solid form.
- the solubility of the pharmaceutically acceptable salts, solvates and crystal forms thereof of eliglustat in water and simulated gastric juice is less than or equal to 6.0 mg/mL.
- the pharmaceutically acceptable salt of eliglustat is naphthalene disulfonate, mucate, glutarate.
- the naphthalene disulfonate salt of eliglustat may be selected from 1,5-naphthalene disulfonate, 1,6-naphthalene disulfonic acid, 1,7-naphthalene disulfonic acid, 2, 6-naphthalene disulfonate or 2,7-naphthalene disulfonate.
- the molar ratio of 1,5-naphthalene disulfonic acid to eligrusat is 1:1 or 1:2.
- the pharmaceutically acceptable salt of eliglustat is a hydrate or an ansolvate of 1,5-naphthalenedisulfonate.
- the hydrates of 1,5-naphthalene disulfonate are hemihydrate, monohydrate, and dihydrate.
- the crystalline form D of the 1,5-naphthalene disulfonate of eliglustat further has X-ray powder diffraction peaks at 2 ⁇ angles ( ⁇ 0.2°) of 7.0°, 10.4°, and 24.7°.
- the crystalline form D of 1,5-naphthalene disulfonate of eliglustat further has X-ray powder diffraction peaks at 2 ⁇ angles ( ⁇ 0.2°) of 14.2° and 16.2°.
- the crystalline form D of the 1,5-naphthalene disulfonate salt of eliglustat has an X-ray powder diffraction pattern substantially similar to that in Figure 3A.
- the crystalline form B of 1,5-naphthalene disulfonate of eliglustat further has X-ray powder diffraction peaks at 22.8°, 21.0°, and 20.8° at 2 ⁇ angles ( ⁇ 0.2°).
- the crystalline form B of 1,5-naphthalene disulfonate of eliglustat further has X-ray powder diffraction peaks at 2 ⁇ angles ( ⁇ 0.2°) of 13.1°, 3.3°, and 15.1°.
- the crystalline form B of the 1,5-naphthalene disulfonate salt of eliglustat has an X-ray powder diffraction pattern substantially similar to that in Figure 4A.
- a crystalline form C of eliglustat 1,5-naphthalene disulfonate having a 2 ⁇ angle ( ⁇ 0.2°) at 9.4°, 13.6°, 20.1°, 12.1° X-ray powder diffraction peaks.
- the crystalline form C of 1,5-naphthalene disulfonate of eliglustat further has X-ray powder diffraction peaks at 2 ⁇ angles ( ⁇ 0.2°) at 24.3°, 12.8°, and 19.6°.
- the crystalline form C of 1,5-naphthalene disulfonate of eliglustat further has X-ray powder diffraction peaks at 2 ⁇ angles ( ⁇ 0.2°) of 6.2° and 14.0°.
- the crystalline form C of the 1,5-naphthalene disulfonate salt of eliglustat has an X-ray powder diffraction pattern substantially similar to that in FIG. 5A .
- a crystalline form A of eliglustat oxalate which has X-ray powder diffraction peaks at 2 ⁇ angles ( ⁇ 0.2°) at 7.5°, 15.5°, and 19.0°.
- the crystalline form A of the oxalate salt of eliglustat further has X-ray powder diffraction peaks at 2 ⁇ angles ( ⁇ 0.2°) of 10.0°, 22.3°, and 23.3°.
- Form A of eligglustat oxalate has an X-ray powder diffraction pattern substantially similar to that of Figure 6A.
- a crystalline form A of eliglustat glutarate which has X-ray powder diffraction peaks at 2 ⁇ angles ( ⁇ 0.2°) at 5.1°, 19.3°, and 21.3°.
- the crystalline form A of the glutaric acid salt of eliglustat further has X-ray powder diffraction peaks at 2 ⁇ angles ( ⁇ 0.2°) of 15.5°, 6.4°, and 10.6°.
- the crystalline form A of the glutaric acid salt of eliglustat further has X-ray powder diffraction peaks at 2 ⁇ angles ( ⁇ 0.2°) at 18.6°, 21.9°, and 13.1°.
- Form A of eliglustat glutarate has an X-ray powder diffraction pattern substantially similar to that of Figure 7A.
- a crystalline form A of eliglustat mucate salt which has X-ray powder diffraction peaks at 2 ⁇ angles ( ⁇ 0.2°) at 6.4°, 8.4°, and 20.7°.
- the crystalline form A of the mucate salt of eliglustat further has X-ray powder diffraction peaks at 2 ⁇ angles ( ⁇ 0.2°) of 5.3°, 14.0°, and 12.4°.
- the crystalline form A of mucate salt of eliglustat further has X-ray powder diffraction peaks at 2 ⁇ angles ( ⁇ 0.2°) of 17.0, 19.6, 17.9 ⁇ 0.2°.
- Form A of eliglustat mucate salt has an X-ray powder diffraction pattern substantially similar to that of Figure 8A.
- the pharmaceutically acceptable salt of eliglustat of the present invention wherein the compound is at least 60% by weight in a single crystal form, at least 70% in a single crystal form, at least 80% in a single crystal form , at least 90% monomorph, at least 95% monomorph, or at least 99% monomorph.
- the present invention also provides a pharmaceutical composition, the active ingredient of which includes a pharmaceutically acceptable salt of eliglustat, hydrate of eliglustat 1,5-naphthalene disulfonate, eliglustat 1,5 - Naphthalene disulfonate crystal form D, Eliglustat 1,5-naphthalene disulfonate crystal form B, Eliglustat 1,5-naphthalene disulfonate crystal form C, Eliglustat He oxalate crystalline form A, eliglustat glutarate crystalline form A, or eliglustat mucate crystalline form A, and a pharmaceutically acceptable carrier.
- a pharmaceutically acceptable salt of eliglustat hydrate of eliglustat 1,5-naphthalene disulfonate, eliglustat 1,5 - Naphthalene disulfonate crystal form D
- Eliglustat 1,5-naphthalene disulfonate crystal form B Eliglustat 1,5-naphthalene disulfonate crystal form C
- compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, transmucosally or in ophthalmic formulations.
- parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
- the pharmaceutical composition provided by the present invention is orally administered in an orally acceptable dosage form, including but not limited to capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.
- a pharmaceutically acceptable carrier refers to a non-toxic carrier, adjuvant or carrier, which will not adversely affect the pharmacological activity of the compound formulated with it, and is also safe for human use.
- the pharmaceutical composition provided herein contains one or more selected from diluents, disintegrants, binders, surfactants, glidants and lubricants.
- the present invention also provides a preparation method of crystalline form D of eliglustat 1,5-naphthalene disulfonate.
- the following steps are included: dissolving eliglurus free base and 1-1.1 equivalents of 1,5-naphthalene disulfonic acid in methyl tert-butyl ether, and placing the mixture system at room temperature with magnetic stirring After centrifugation, the resulting solid was vacuum-dried overnight at room temperature to obtain the crystal form D of eliglustat 1,5-naphthalene disulfonate.
- the preparation method of crystalline form D of eliglustat 1,5-naphthalene disulfonate comprises the following steps, combining eliglustat free base and 1-1.1 equivalents of 1,5-naphthalene disulfonate
- the sulfonic acid was dissolved in methyl tert-butyl ether, and the mixture was magnetically stirred at room temperature for 1-3 days and then centrifuged, and the obtained solid was vacuum-dried overnight at room temperature.
- the 1,5-naphthalene disulfonic acid can be an ansolvate or a hydrate, specifically 1,5-naphthalene disulfonic acid tetrahydrate.
- the present invention also provides a method for preparing crystal form B of eliglustat 1,5-naphthalene disulfonate.
- the following steps are included: dissolving Eliglux free base and 0.5 equivalent of 1,5-naphthalene disulfonic acid in tetrahydrofuran/n-heptane, continuously suspending and stirring, and drying the precipitated solid to obtain Eliglux free base Form B of gluconate 1,5-naphthalene disulfonate.
- the preparation method of crystalline form B of eliglustat 1,5-naphthalene disulfonic acid salt comprises the following steps, combining eliglustat free base with 0.5 equivalent of 1,5-naphthalene disulfonic acid Dissolve in tetrahydrofuran/n-heptane (1:9, v:v), continuously suspend and stir at 20-40°C, and dry the precipitated solid to obtain eliglustat 1,5-naphthalene disulfonate Crystalline Form B.
- the invention provides a method for preparing crystal form C of eliglustat 1,5-naphthalene disulfonate. In some embodiments, the following steps are included: adding H 2 O to 1,5-naphthalene disulfonate crystal form B, stirring at room temperature, separating the solid, and drying with calcium oxide to obtain Eliglustat 1,5 - Form C of naphthalene disulfonate.
- the preparation method of crystalline form C of eliglustat 1,5-naphthalene disulfonate comprises the following steps, adding 10 times the weight of H to 1,5-naphthalene disulfonate crystal form B 2 O, stirred overnight at room temperature, separated the solid, and dried it in a desiccator filled with calcium oxide for 24 hours to obtain crystalline form C of eliglustat 1,5-naphthalene disulfonate.
- the present invention also provides a preparation method of eliglustat oxalate crystal form A.
- the following steps are included: dissolving eliglurus free base and 0.5 equivalent of oxalic acid in methyl tert-butyl ether, continuously suspending and stirring at 15-50° C., and drying the precipitated solid to obtain eligluux Grusastat 1,5-naphthalene disulfonate oxalate crystal form A.
- the preparation method of eliglustat oxalate crystal form A comprises the following steps, dissolving eliglustat free base in methyl tert-butyl ether, adding 0.5 equivalents of oxalic acid in batches under stirring, Suspended and stirred at 40°C, reacted overnight, separated the solid by suction filtration, and dried in vacuo at room temperature to obtain crystalline form A of eliglustat 1,5-naphthalene disulfonate oxalate.
- the present invention also provides a preparation method of eliglustat glutarate crystal form A.
- a preparation method of eliglustat glutarate crystal form A comprising the step of dissolving eliglurus free base with 0.5 equivalents of glutaric acid in isopropyl acetate/n-heptane (1:5, v:v) at 20-40°C Continuously suspend and stir at high temperature, and dry the precipitated solid to obtain eliglustat glutarate crystal form A
- the preparation method of eliglustat glutarate crystal form A comprises the following steps, dissolving eliglustat free base and 0.5 equivalent of glutaric acid in isopropyl acetate/n-heptane ( 1:5, v:v), after suspending and stirring at room temperature for 1 day and 40°C for 2 days, the precipitated solid was dried to obtain eliglustat glutarate crystal form A.
- the present invention also provides a preparation method of eliglustat mucate salt crystal form A.
- a preparation method of eliglustat mucate salt crystal form A comprising the step of dispersing eliglurus free base and 0.5 equivalents of mucic acid in acetone/n-heptane (1:9, v:v) for continuous suspension at a temperature of 35-45°C Stir, and dry the precipitated solid to obtain crystalline form A of eliglustat mucate salt.
- the preparation method of eliglustat mucate salt crystalline form A comprises the following steps, adding eliglustat free base into acetone/n-heptane (1:9, v:v), Add 0.5 equivalent of mucic acid in batches under stirring, and circulate the system at 50°C to 5°C for 2-4 times, separate the solid, wash it with n-heptane, and dry it under vacuum at room temperature to obtain eliglustat mucate salt crystals Type A.
- the present invention also provides a pharmaceutically acceptable salt of eliglustat, 1,5-naphthalene disulfonate hydrate of eliglustat, and crystal form of 1,5-naphthalene disulfonate of eliglustat D.
- Eliglustat 1,5-naphthalene disulfonate crystal form B Eliglustat 1,5-naphthalene disulfonate crystal form C
- Eliglustat oxalate crystal form A Use of Eliglustat glutarate crystal form A and Eliglustat mucate crystal form A in treating Gaucher disease, Fabry disease and polycystic kidney disease.
- the present invention also provides a pharmaceutically acceptable salt of eliglustat, 1,5-naphthalene disulfonate hydrate of eliglustat, and crystal form of 1,5-naphthalene disulfonate of eliglustat D.
- Eliglustat 1,5-naphthalene disulfonate crystal form B Eliglustat 1,5-naphthalene disulfonate crystal form C
- Eliglustat oxalate crystal form A Use of eliglustat glutarate crystal form A and eliglustat mucate crystal form A in the preparation of drugs for treating Gaucher disease, Fabry disease and polycystic kidney disease.
- the patient with the disease is a CYP2D6 extensive metabolizer, intermediate metabolizer, or poor metabolizer.
- the Gaucher disease is Gaucher disease type 1 and the polycystic kidney disease is autosomal dominant polycystic kidney disease.
- crystalline refers to a solid form of eliglustat, or a pharmaceutically acceptable salt thereof, in which there is a long-range atomic order of atomic positions.
- the crystalline nature of a solid can be confirmed, for example, by examining an X-ray powder diffraction pattern. If the XRPD shows a sharp intensity peak in the XRPD, the compound is crystalline.
- crystalline is a fully crystalline or partially crystalline solid, and includes solids that are at least 80% crystalline, 85% crystalline, 90% crystalline, 95% crystalline, and 99% crystalline by weight.
- solvate means that a stoichiometric or non-stoichiometric amount of a solvent or solvent mixture is incorporated into a crystal structure.
- hydrate refers to the incorporation of stoichiometric or non-stoichiometric amounts of water into the crystal structure.
- a hydrate is a solvate in which the solvent incorporated into the crystal structure is water.
- anhydrous when used with reference to a compound refers to substantially no solvent incorporated into the crystal structure, eg, less than 0.1% by weight as determined by TGA, Karl Fischer analysis, single crystal data. Compounds that are anhydrous are referred to herein as "anhydrates.”
- major peaks refers to the three strongest peaks in a pattern of XRPD data, or to a peak having at least 50% of the 100% relative intensity of the strongest peaks.
- the specific values of °2 ⁇ in the XRPD list of each crystal form in this paper retain four decimal places, and the values with one, two, three or four decimal places for each data are regarded as the specific data disclosed in this application and are included in this application in the public content of .
- the 2-theta values of the X-ray powder diffraction patterns of the crystalline forms described herein may vary slightly from instrument to instrument, and are also dependent on variance in sample preparation and batch-to-batch variability. Accordingly, unless otherwise defined, XRPD patterns and/or 2-theta peaks described herein should not be interpreted as absolute and may vary by ⁇ 0.2 degrees.
- the 2-theta values presented here were obtained using Cu K ⁇ 1 radiation.
- Temperature values may vary slightly from instrument to instrument and are also dependent on variations in sample preparation, rate of temperature ramp during the experiment, batch-to-batch variation in material, and other environmental factors . Therefore, unless otherwise defined, the temperature values stated herein should not be interpreted as absolute and may vary by ⁇ 5°.
- substantially identical XRPD patterns or “substantially similar X-ray powder diffraction patterns” means that, for comparison purposes, at least 90% of the peaks shown are present. It is further understood that some variation, eg, ⁇ 0.2 degrees, is allowed for the 2-theta peak position from the position shown for comparison purposes. It should be understood that when the expression “X-ray powder diffraction peaks characterized by 2-theta angles ( ⁇ 0.2°)" is followed by a listing of 2-theta peak positions at ⁇ 0.2°, it applies to each peak position listed.
- Crystalline and amorphous forms were prepared following the following general procedures, as described in the Examples below.
- the XRPD pattern was collected on an X-ray powder diffraction analyzer produced by PANalytacal, and Table 2 lists the XRPD parameters.
- thermogravimetric analyzer TA Q2000/Discovery 2500
- Dynamic moisture sorption (DVS) curves were collected on DVS Intrinsic of SMS (Surface Measurement Systems). The relative humidity at 25°C was corrected for the deliquescence points of LiCl, Mg( NO3 )2 and KCl. Table 4 lists the parameters of the DVS assay.
- Liquid NMR spectra were collected on a Bruker 400M NMR instrument, and DMSO-d 6 was used as a solvent.
- the free form A was prepared by the following method: Weigh about 200 mg of the starting tartrate salt form A in a beaker, add 2 mL of deionized water to dissolve, quickly add 20 mL of saturated NaHCO 3 solution to the solution, and stir at room temperature for 1.5 After 2 hours, the obtained solid was collected by suction filtration, and after vacuum drying at room temperature overnight, the XRPD of the obtained sample was tested.
- Figure 2A shows that the sample was in a crystalline state, named as free crystal form A, and its XRPD result is shown in Figure 2A.
- TGA/DSC results (Fig. 2B) showed that the sample had a weight loss of 0.8% when heated to 80°C, and an endothermic peak was observed at 88.9°C (peak temperature).
- 1 H NMR was measured in DMSO-d 6 , and the results are shown in Fig. 2C, no obvious organic solvent residue was found.
- the obtained clear solution was transferred to 5°C for stirring or anti-solvent (n-heptane) was added to induce the precipitation of solids, and the still clear solution was volatilized at room temperature to obtain solids; the obtained jelly was transferred to 50°C-5°C for temperature cycle (One cycle: heating up to 50°C at 4.5°C/min, constant temperature at 50°C for 2 hours; cooling down to 5°C at 0.1°C/min; constant temperature at 5°C for 2 hours).
- anti-solvent n-heptane
- the obtained solid XRPD was tested, and the results showed that a total of 11 salt forms were obtained in the three-stage XRPD screening test, including 1,5-naphthalene disulfonate crystal form A or B, oxalate crystal form A, mucate salt crystal form A, Form A or B of malate, form A of glutarate, form A of succinate, form A of phosphate, form A of hydrochloride and form A of fumarate.
- the XRPD, TGA, DSC and 1 H NMR or IC/HPLC characterizations of the 11 salt crystal forms are summarized in Table 7-1 to Table 7-4.
- a jelly was obtained after stirring at 40°C, and a solid was obtained after temperature cycling (50°C-5°C) for XRPD testing.
- the two salt-type samples are a mixture of salt-type and free-state samples.
- 1,5-naphthalene disulfonate crystal form A was confirmed as a mixture in subsequent research, and a stable 1,5-naphthalene disulfonate salt crystal form D was obtained in crystal form screening.
- Free form A and 0.5 equivalent of 1,5-naphthalene disulfonic acid were suspended in THF/n-heptane (1:9, v:v) for 1 day at room temperature and 2 days at 40°C, and the solid was separated by centrifugation , and the free crystal form A was obtained after vacuum drying.
- Sample XRPD results are shown in Figure 4A.
- the TGA/DSC curve is shown in Figure 4B, and the results show that the weight loss is 1.5% when heated to 150°C, and an endothermic signal is observed at 75.9, 167.9°C (peak temperature).
- the 1 H NMR spectrum was tested in DMSO-d 6 and is shown in Figure 4C. The results showed that the molar ratio of ligand acid to API was about 0.5, and no residual solvent was observed.
- the XRPD results are presented in Figure 5A.
- the TGA and DSC results are shown in Figure 5B.
- the TGA results showed that the weight loss was 6.6% when heated from room temperature to 150° C.; the DSC curve observed endothermic peaks at 73.5 and 171.4° C. (peak temperature).
- 1 H NMR was measured in DMSO-d 6 , and the results are shown in Figure 5C.
- the molar ratio of ligand acid and API in the sample was 0.5, and no obvious residues of THF and n-heptane were detected.
- the crystal form C of 1,5-naphthalene disulfonate was identified by heating test.
- the 1,5-naphthalene disulfonate crystal form C is converted into 1,5-naphthalene disulfonate crystal form B after heating to 100°C under nitrogen protection and cooling to room temperature. Combining the weight loss of the TGA curve, liquid NMR results and heating test results, the crystal form C of 1,5-naphthalene disulfonate is a dihydrate.
- the XRPD results are presented in Figure 6A.
- the TGA and DSC results are shown in Figure 6B.
- the TGA results showed that the weight loss was 7.4% when heated from room temperature to 150° C.; the DSC curve observed endothermic peaks at 90.1 and 116.0° C. (peak temperature).
- 1 H NMR was measured in DMSO-d 6 , and the results are shown in Figure 6C. No obvious MTBE residue was detected in the sample.
- IC/HPLC test results showed that the molar ratio of ligand acid to API in the sample was 0.5.
- Free form A and 0.5 equivalent of L-malic acid were obtained by suspending and stirring in EtOAc for 1 day at room temperature. The solid was separated by centrifugation, and malate salt form A was obtained after vacuum drying. Due to the obvious deliquescence of the sample under room humidity conditions, no other characterization data were collected.
- Glutaric acid salt form A was obtained from free form A and 0.5 equivalents of glutaric acid in IPAc/n-heptane (1:5, v:v) after suspending and stirring at room temperature for 1 day and at 40°C for 2 days. The solid was separated by centrifugation and dried in vacuo for subsequent characterization.
- Sample XRPD results are shown in Figure 7A.
- the TGA/DSC curve is shown in Figure 7B.
- the results show that the weight loss is 3.7% when heated to 150°C, and endothermic signals are observed at 86.7, 101.4, and 177.4°C (peak temperature). Based on this result, it is speculated that it is glutarate Form A and free form A mixture.
- the 1 H NMR spectrum was tested in DMSO-d 6 and is shown in Figure 7C. The results showed that the molar ratio of ligand acid to API was about 0.7, and no residual solvent was observed.
- the sample XRPD results are shown in Table 14.
- the TGA/DSC curve showed a weight loss of 7.3% when heated to 120°C, and endothermic signals were observed at 83.7,169.9°C.
- the 1 H NMR spectrum was tested in DMSO-d 6 , and the results showed that the molar ratio of ligand acid to API was about 0.6, and no residual solvent was observed.
- sample XRPD results are shown in Table 16.
- TGA/DSC results showed a weight loss of 11.7% when heated to 150°C, and an endothermic signal was observed at 48.6, 93.0°C (peak temperature).
- NMR testing was not carried out due to the insufficient amount of samples obtained from the screening.
- Sample IC/HPLC test results showed that the molar ratio of ligand acid to API in the sample was 1.0.
- Embodiment 15 dynamic solubility test
- Embodiment 16 Humidity evaluation
- the tartrate crystal form A sample has a slight hygroscopicity, because the moisture absorption weight gain is 1.11wt% at 25°C/80%RH, and the free crystal form A sample has almost no hygroscopicity3, and the crystal form of the two samples did not change after the DVS test .
- DVS test results are listed in Table 19.
- Embodiment 17 Solid State Stability Evaluation
- 1,5-naphthalene disulfonate form C was left open for 1 week, 3 weeks and 4 weeks under the conditions of 25°C/60%RH and 40°C/75%RH, the physical properties of the samples were detected by XRPD and HPLC. and chemical stability, and the stability data of tartaric acid crystal form A and free crystal form A for 1 week, 2 weeks and 4 weeks were used as a reference.
- the stability of 1,5-naphthalene disulfonate crystal form B and oxalate salt crystal form A was investigated for 1 week under the conditions of 25°C/60%RH and 40°C/75%RH.
- Embodiment 18 Pharmacodynamic study
- SRT substrate-reducing therapy
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Abstract
本发明提供了依利格鲁司他的多种可药用盐,包括萘二磺酸盐、草酸盐、戊二酸盐、粘酸盐,以及他们的各种晶型,还提供了包含这些盐和晶型的药物组合物、其制备方法及其用于治疗戈谢病、法布雷病、多囊性肾病的用途。
Description
本发明涉及依利格鲁司他的可药用盐的及其晶型、制备方法和含有所述晶型的药物组合物及其用途,属于医药技术领域。
依利格鲁司他(Eliglustat),化学名为N-[(1R,2R)-1-(2,3-二氢-1,4-苯并二恶烷-6-基)-2-羟基-1-(1-吡咯烷甲基)乙基]辛酰胺,是一种强效、高度特异性神经酰胺类似物抑制剂,通过靶向葡萄糖神经酰胺合成酶降低葡萄糖神经酰胺的产生。依利格鲁司他胶囊
2014年获美国FDA批准,用于一线治疗1型戈谢病成年患者的长期治疗。临床研究表明,依利格鲁司他胶囊
与CYP2D6和CYP3A4抑制剂药物联用有可能显著增加药物的暴露量而引起PR,QTc,和/或QRS心动间隔的延长,导致心律失常;在依利格鲁司他血浆浓度达到500ng/mL时,药代动力学/药效学模型预测PR、QRS和QTcF间期平均增加22(26)、7(10)和13(19)毫秒。相对于CYP2D6广泛和中间代谢者84毫克一天口服两次的用量,针对CYP2D6代谢不良者,依利格鲁司他胶囊的用量下调至84毫克一天口服一次,以避免对CYP2D6代谢不良者产生心律失常的副作用。基于上述因素,上市的依利格鲁司他胶囊
在临床使用上存在诸多不便。
在US6916802B2中描述了依利格鲁司他及其制备方法,并简单描述了“药学上可接受的盐”例如是无机酸,例如硫酸,盐酸,磷酸等,或有机酸,例如乙酸盐。没有对药用盐的物理化学性质进行研究,也未对盐的晶型进行研究。
在US7196205B2中简单的描述了依利格鲁司他生理上可接受的盐的种类,没有对药用盐的物理化学性质进行研究,也未对盐的晶型进行研究。
受到依利格鲁司他游离碱本身性质影响,获得稳定的固体形式的盐型及其晶型存在技术困难。例如WO2011066325A1中描述了依利格鲁司他的盐包括柠檬酸盐、苹果酸盐、富马酸盐、甲基磺酸盐和醋酸盐,但是这些盐不能以固体形式获得;尽管能以固体形式获得到盐酸盐和1∶1的酒石酸盐,但是两者都不是结晶形态,且对于制剂而言吸湿性太强。依利格鲁司他半酒石酸盐比游离碱和其他盐更容易配制和合成。该专利具体公开了依利格鲁司他半酒石酸盐及其晶型是结晶的、非吸湿性的、水溶性的且流动性好于相应游离碱和其他盐,适于大规模制备,在5.1°,6.6°,10.7°,1 1.0°,15.9°,和21.7°的2θ处存在主要的X-射线粉末衍射峰。在CN107445938A中描述了另一种依利格鲁司他的L-半酒石酸盐晶型,X-射线粉末衍射在2θ角为10.2°、12.4°、13.6°、14.9°、20.1°、22.1°处有主要特征峰,DSC图谱显示在161℃~162℃有吸热峰。
本发明提供一种新的依利格鲁司他盐及其晶型,能够以稳定的固体形式存在。相对依利格鲁司他半酒石酸盐晶型A,依利格鲁司他1,5-萘二磺酸盐及其晶型具有更低的吸湿性,并且在水、模拟胃液中的溶解度差异小,预期口服后具有更平缓的血浆药物浓度,减轻因露剂量增加所导致的心律失常的不良反应。
发明内容
本发明提供一种能够以稳定的固体形式存在的依利格鲁司他的可药用盐、溶剂合物及或其晶型。
在一些实施方案中,依利格鲁司他的可药用盐、溶剂合物及或其晶型在水和模拟胃液中的溶解度小于等于6.0mg/mL。
在一些实施方案中,依利格鲁司他的可药用盐为萘二磺酸盐、粘酸盐、戊二酸盐。
在一些实施方案中,依利格鲁司他的萘二磺酸盐可以选自1,5-萘二磺酸盐、1,6-萘二磺酸、1,7-萘二磺酸、2,6-萘二磺酸盐或2,7-萘二磺酸盐。
在一些实施方案中,依利格鲁司他的1,5-萘二磺酸与依利格鲁司他的摩尔比为1:1或1:2。
在一些实施方案中,依利格鲁司他的可药用盐为1,5-萘二磺酸盐的水合物或非溶剂化物。1,5-萘二磺酸盐的水合物为半水合物、一水合物、二水合物。
在一些实施方案中,提供一种依利格鲁司他1,5-萘二磺酸盐的晶型D,具有在4.9°、5.9°、18.7°的2θ角(±0.2°)的X射线粉末衍射峰。依利格鲁司他的1,5-萘二磺酸盐的晶型D进一步具有在7.0°、10.4°、24.7°的2θ角(±0.2°)的X射线粉末衍射峰。依利格鲁司他的1,5-萘二磺酸盐的晶型D进一步具有在14.2°、16.2°的2θ角(±0.2°)的X射线粉末衍射峰。依利格鲁司他的1,5-萘二磺酸盐的晶型D具有与图3A基本类似的X射线粉末衍射图谱。
在一些实施方案中,提供一种依利格鲁司他1,5-萘二磺酸盐的晶型B,具有在7.3°、14.6°、6.5°的2θ角(±0.2°)的X射线粉末衍射峰。依利格鲁司他的1,5-萘二磺酸盐的晶型B进一步具有在22.8°、21.0°、20.8°的2θ角(±0.2°)的X射线粉末衍射峰。依利格鲁司他的1,5-萘二磺酸盐的晶型B进一步具有13.1°、3.3°、15.1°的2θ角(±0.2°)的X射线粉末衍射峰。依利格鲁司他的1,5-萘二磺酸盐的晶型B具有与图4A基本类似的X射线粉末衍射图谱。
在一些实施方案中,提供一种依利格鲁司他1,5-萘二磺酸盐的晶型C,具有在9.4°、13.6°、20.1°、12.1°的2θ角(±0.2°)的X射线粉末衍射峰。依利格鲁司他的1,5-萘二磺酸盐的晶型C进一步具有在24.3°、12.8°、19.6°的2θ角(±0.2°)的X射线粉末衍射峰。依利格鲁司他的1,5-萘二磺酸盐的晶型C进一步具有在6.2°、14.0°的2θ角(±0.2°)的X射线粉末衍射峰。依利格鲁司他的1,5-萘二磺酸盐的晶型C具有与图5A基本类似的X射线粉末衍射图谱。
在一些实施方案中,提供一种依利格鲁司他草酸盐的晶型A,具有在7.5°、15.5°、19.0°的2θ角(±0.2°)的X射线粉末衍射峰。依利格鲁司他的草酸盐的晶型A进一步具有在10.0°、22.3°、23.3°的2θ 角(±0.2°)的X射线粉末衍射峰。依利格鲁司他的可药用盐,其中所述依利格鲁司他的草酸盐的晶型A进一步具有在12.8°,18.3°,20.70°的2θ角(±0.2°)的X射线粉末衍射峰。在一些实施方案中,依利格鲁司他草酸盐的晶型A具有与图6A基本类似的X射线粉末衍射图谱。
在一些实施方案中,提供一种依利格鲁司他戊二酸盐的晶型A,具有在5.1°、19.3°、21.3°的2θ角(±0.2°)的X射线粉末衍射峰。依利格鲁司他的戊二酸盐的晶型A进一步具有在15.5°、6.4°、10.6°的2θ角(±0.2°)的X射线粉末衍射峰。依利格鲁司他的戊二酸盐的晶型A进一步具有在18.6°、21.9°、13.1°的2θ角(±0.2°)的X射线粉末衍射峰。在一些实施方案中,依利格鲁司他戊二酸盐的晶型A具有与图7A基本类似的X射线粉末衍射图谱。
在一些实施方案中,提供一种依利格鲁司他粘酸盐的晶型A,具有在6.4°、8.4°、20.7°的2θ角(±0.2°)的X射线粉末衍射峰。依利格鲁司他的粘酸盐的晶型A进一步具有在5.3°、14.0°、12.4°的2θ角(±0.2°)的X射线粉末衍射峰。依利格鲁司他的粘酸盐的晶型A进一步具有在17.0、19.6、17.9±0.2°的2θ角(±0.2°)的X射线粉末衍射峰。在一些实施方案中,依利格鲁司他粘酸盐的晶型A具有与图8A基本类似的X射线粉末衍射图谱。
在一些实施方案中,本发明的依利格鲁司他的可药用盐,其中的化合物为按重量计至少60%的单晶型、至少70%的单晶型、至少80%的单晶型、至少90%的单晶型、至少95%的单晶型或至少99%的单晶型。
本发明还提供一种药物组合物,活性成分包含依利格鲁司他的可药用盐,依利格鲁司他1,5-萘二磺酸盐的水合物,依利格鲁司他1,5-萘二磺酸盐晶型D,依利格鲁司他1,5-萘二磺酸盐晶型B,依利格鲁司他1,5-萘二磺酸盐晶型C,依利格鲁司他草酸盐晶型A,依利格鲁司他戊二酸盐晶型A,或依利格鲁司他粘酸盐晶型A,和药学上可接受的载体。
本发明所述的组合物可经口、肠胃外、通过吸入喷雾、局部、经 直肠、经鼻、经口腔、经粘膜或在眼用制剂中给药。本文中使用的术语“肠胃外”包括皮下、静脉内、肌内、关节内、滑膜内、胸骨内、鞘内、肝内、病灶内和颅内注射或输注技术。一个方面,本发明提供的药物组合物以口服可接受的剂型口服给药,包括但不限于胶囊、片剂、乳剂和水混悬剂、分散体和溶液。
药学上可接受的载体是指无毒的载体、辅剂或载体,其不会对与其一起配制的化合物的药理活性产生不利影响,并且对人类使用也是安全的。
在一个实施方案中,本文提供的药物组合物包含选自稀释剂、崩解剂、粘合剂、表面活性剂、助流剂和润滑剂中的一种或数种。
本发明还提供一种依利格鲁司他1,5-萘二磺酸盐的晶型D的制备方法。在一些实施方案中,包括以下步骤,将依利格鲁司游离碱及1-1.1当量的1,5-萘二磺酸溶解在甲基叔丁基醚中,将混合物体系置于室温下磁力搅拌后进行离心分离,将所得固体在室温条件下真空干燥过夜后得依利格鲁司他1,5-萘二磺酸盐的晶型D。
在一些实施方案中,依利格鲁司他1,5-萘二磺酸盐的晶型D的制备方法包括以下步骤,将依利格鲁司游离碱及1-1.1当量的1,5-萘二磺酸溶解在甲基叔丁基醚中,将混合物体系置于室温下磁力搅拌1-3天后进行离心分离,将所得固体在室温条件下真空干燥过夜。所述1,5-萘二磺酸可以是非溶剂化物或水合物,具体都选择1,5-萘二磺酸四水合物。
本发明还提供一种依利格鲁司他1,5-萘二磺酸盐的晶型B的制备方法。在一些实施方案中,包括以下步骤,将依利格鲁司游离碱与0.5当量的1,5-萘二磺酸溶解在四氢呋喃/正庚烷中,持续悬浮搅拌,并将析出固体干燥后得依利格鲁司他1,5-萘二磺酸盐的晶型B。
在一些实施方案中,依利格鲁司他1,5-萘二磺酸盐的晶型B的制备方法包括以下步骤,将依利格鲁司游离碱与0.5当量的1,5-萘二磺酸溶解在四氢呋喃/正庚烷(1:9,v:v)中,在20-40℃温度下持续悬浮搅拌,并将析出固体干燥后得依利格鲁司他1,5-萘二磺酸盐的晶型B。
本发明提供一种依利格鲁司他1,5-萘二磺酸盐的晶型C的制备方法。在一些实施方案中,包括以下步骤,将1,5-萘二磺酸盐晶型B加入H
2O后在室温下搅拌,分离固体,使用氧化钙干燥,得依利格鲁司他1,5-萘二磺酸盐的晶型C。
在一些实施方案中,依利格鲁司他1,5-萘二磺酸盐的晶型C的制备方法包括以下步骤,将1,5-萘二磺酸盐晶型B加入10倍重量的H
2O,于室温下搅拌过夜,分离固体,在盛有氧化钙的干燥器中干燥24小时,得依利格鲁司他1,5-萘二磺酸盐的晶型C。
本发明还提供一种依利格鲁司他草酸盐晶型A的制备方法。在一些实施方案中,包括以下步骤,将依利格鲁司游离碱与0.5当量的草酸溶解在甲基叔丁基醚中,在15-50℃下持续悬浮搅拌,并将析出固体干燥,得依利格鲁司他1,5-萘二磺酸盐草酸盐晶型A。
在一些实施方案中,依利格鲁司他草酸盐晶型A的制备方法包括以下步骤,将依利格鲁司游离碱溶解在甲基叔丁基醚中,搅拌下分批加入0.5当量草酸,并置于40℃下悬浮搅拌,反应过夜后,抽滤分离固体,室温真空干燥,得依利格鲁司他1,5-萘二磺酸盐草酸盐晶型A。
本发明还提供一种依利格鲁司他戊二酸盐晶型A的制备方法。在一些实施方案中,包括以下步骤,将依利格鲁司游离碱与0.5当量的戊二酸溶解在乙酸异丙酯/正庚烷(1:5,v:v)中,在20-40℃温度下持续悬浮搅拌,并将析出固体干燥,得依利格鲁司他戊二酸盐晶型A
在一些实施方案中,依利格鲁司他戊二酸盐晶型A的制备方法包括以下步骤,将依利格鲁司游离碱与0.5当量的戊二酸溶解在乙酸异丙酯/正庚烷(1:5,v:v)中经室温悬浮搅拌1天及40℃悬浮搅拌2天,将析出固体干燥,得依利格鲁司他戊二酸盐晶型A。
本发明还提供一种依利格鲁司他粘酸盐晶型A的制备方法。在一些实施方案中,包括以下步骤,将依利格鲁司游离碱与0.5当量的粘酸分散在丙酮/正庚烷(1:9,v:v)中,在35-45℃温度下持续悬浮搅拌,并将析出固体干燥,得依利格鲁司他粘酸盐晶型A。
在一些实施方案中,依利格鲁司他粘酸盐晶型A的制备方法包括以下步骤,将依利格鲁司游离碱加入分散在丙酮/正庚烷(1:9,v:v)中,搅拌下分批加入0.5当量的粘酸,并将体系在50℃~5℃温度循环2-4次,分离固体并以正庚烷洗涤,室温真空干燥,得依利格鲁司他粘酸盐晶型A。
本发明还提供一种依利格鲁司他的可药用盐、依利格鲁司他1,5-萘二磺酸盐水合物、依利格鲁司他1,5-萘二磺酸盐晶型D、依利格鲁司他1,5-萘二磺酸盐晶型B、依利格鲁司他1,5-萘二磺酸盐晶型C、依利格鲁司他草酸盐晶型A、依利格鲁司他戊二酸盐晶型A、依利格鲁司他粘酸盐晶型A在治疗戈谢病、法布雷病、多囊性肾病的用途。
本发明还提供一种依利格鲁司他的可药用盐、依利格鲁司他1,5-萘二磺酸盐水合物、依利格鲁司他1,5-萘二磺酸盐晶型D、依利格鲁司他1,5-萘二磺酸盐晶型B、依利格鲁司他1,5-萘二磺酸盐晶型C、依利格鲁司他草酸盐晶型A、依利格鲁司他戊二酸盐晶型A、依利格鲁司他粘酸盐晶型A在制备治疗戈谢病、法布雷病、多囊性肾病药物中的用途。
在一些实施方案中,疾病的患者为CYP2D6广泛代谢者、中间代谢者或不良者代谢者。
在一些实施方案中,戈谢病为1型戈谢病、所述多囊性肾病为常染色显性多囊性肾病。
定义
当单独使用时,当描述依利格鲁司他的可药用盐,术语“形式A”、“形式B”、“形式C”和分别指依利格鲁司他的可药用盐的晶型A、B和C。在本文中“形式A”和“晶型A”、“形式B”和“晶型B”以及“形式C”和“晶型C”可互换使用。
如本文所用,“结晶”指依利格鲁司他或其可药用盐的固体形式,其中存在着原子位置的长程原子有序。固体的结晶性质可以通过例如检查X射线粉末衍射图谱来确认。如果XRPD显示XRPD中的尖锐 的强度峰,则所述化合物为晶体。作为“结晶”是完全结晶或部分结晶的固体,并且包含按重量计至少80%结晶、85%结晶、90%结晶、95%结晶和99%结晶的固体。
术语“溶剂合物”指化学计量或非化学计量量的溶剂或溶剂混合物被引入晶体结构中。
术语“水合物”指化学计量或非化学计量的水被引入晶体结构中。水合物是一种溶剂合物,其中结合到晶体结构中的溶剂是水。术语“无水的”在用于关于化合物时,指基本上没有结合到晶体结构中的溶剂,例如通过TGA、卡尔·费希尔分析、单晶数据确定的小于0.1重量%。无水的化合物在本文中称为“无水物”。
术语“主峰”指XRPD数据图谱中的三个最强峰,或指具有最强峰的100%相对强度的至少50%的峰。
本文各晶型XRPD列表中具体的°2θ的数值保留了四位小数,各数据保留一位、两位、三位或四位小数的数值都视为本申请公开的具体数据,并纳入本申请的公开内容中。本文所述晶型的X射线粉末衍射图的2-θ值可能因仪器的不同而略有不同,也取决于样品制备的差异和批次之间的差异。因此,除非另有定义,否则本文所述的XRPD图谱和/或2-θ峰值不应被解释为绝对的,并且可以变化±0.2度。本文提供的2-θ值是使用Cu Kα1辐射获得的。
温度值(例如,DSC峰值温度和DSC起始温度)可能因仪器不同而略有不同,并且还取决于样品制备的变化、实验过程中温度的上升速率、材料的批次间变化以及其他环境因素。因此,除非另有定义,否则本文所述的温度值不应被解释为绝对的,并且可以变化±5°。
“基本相同的XRPD图谱”或“基本相似的X射线粉末衍射图谱”是指,为便于比较目的,至少90%的显示的峰存在。应进一步理解,为比较目的,允许2-θ峰值位置与所示位置之间存在一定的变异,例如±0.2度。应当理解,当表述“特征在于2θ角(±0.2°)的X射线粉末衍射峰”后接±0.2°的2-θ峰位置列表时,适用于所列的每一个峰位置。
图1A依利格鲁司他酒石酸盐晶型A的XRPD图谱
图1B依利格鲁司他酒石酸盐晶型A的TGA/DSC曲线
图1C依利格鲁司他酒石酸盐晶型A的
1H HMR图谱
图2A依利格鲁司他游离碱晶型A的XRPD图谱
图2B依利格鲁司他游离碱晶型A的TGA/DSC曲线
图2C依利格鲁司他游离碱晶型A的TGA/DSC曲线
图3A依利格鲁司他1,5-萘二磺酸盐晶型D的XRPD图谱
图3B依利格鲁司他1,5-萘二磺酸盐晶型D的TGA/DSC曲线
图3C依利格鲁司他1,5-萘二磺酸盐晶型D的
1H HMR图谱
图4A依利格鲁司他1,5-萘二磺酸盐晶型B的XRPD图谱
图4B依利格鲁司他1,5-萘二磺酸盐晶型B的TGA/DSC曲线
图4C依利格鲁司他1,5-萘二磺酸盐晶型B的
1H HMR图谱
图5A依利格鲁司他1,5-萘二磺酸盐晶型C的XRPD图谱
图5B依利格鲁司他1,5-萘二磺酸盐晶型C的TGA/DSC曲线
图5C依利格鲁司他1,5-萘二磺酸盐晶型C的
1H HMR图谱
图6A依利格鲁司他草酸盐晶型A的XRPD图谱
图6B依利格鲁司他草酸盐晶型A的TGA/DSC曲线
图6C依利格鲁司他草酸盐晶型A的XRPD图谱
图7A依利格鲁司他戊二酸盐晶型A的XRPD图谱
图7B依利格鲁司他戊二酸盐晶型A的TGA/DSC曲线
图7C依利格鲁司他戊二酸盐晶型A的
1H HMR图谱
图8A依利格鲁司他粘酸盐晶型A的XRPD图谱
图8B依利格鲁司他粘酸盐晶型A的TGA/DSC曲线
图8C依利格鲁司他粘酸盐晶型A的
1H HMR图谱
如以下实施例所述,按照以下一般程序制备结晶和无定形形式。
本发明使用的典型溶剂缩写概述如下:
表1.溶剂缩写
溶液
模拟胃液的配制(SGF)
称取0.2g氯化钠和0.1g曲纳通X-100至100mL容量瓶中,加纯水溶解,搅拌至固体完全溶解后加约1.632mL盐酸(1M),用1M盐酸或1M氢氧化钠调节pH至1.8,最后使用纯水定容。
模拟禁食状态肠液的配制(FaSSIF)
分别称取0.34g磷酸二氢钠(NaH2PO4,无水)、0.042g氢氧化钠、0.62g氯化钠至100-mL容量瓶中,加约48mL纯水溶解,用1M盐酸或1M氢氧化钠调节pH至6.5,用纯水定容得到储备液。取50-mL容量瓶加入0.11g SIF粉末,用上述储备液溶解定容,超声使粉末完全溶解。
XRPD
XRPD图在PANalytacal生产的X射线粉末衍射分析仪上采集,表2列出了XRPD参数。
表2.XRPD参数
TGA和DSC
TGA和DSC图分别在TA Q5000/Discovery 5500热重分析仪和TA Q2000/Discovery 2500
差示扫描量热仪上采集。详细参数见表3。
表3.TGA和DSC参数
动态水分吸附DVS
动态水分吸附(DVS)曲线在SMS(Surface Measurement Systems)的DVS Intrinsic上采集。在25℃时的相对湿度用LiCl,Mg(NO
3)2和KCl的潮解点校正。表4列出了DVS试验的参数。
表4.DVS参数
液态核磁(Solution NMR)
液态核磁谱图在Bruker 400M核磁共振仪上采集,DMSO-d
6作为溶剂。
离子色谱/高效液相色谱(IC/HPLC)
试验中纯度测试、动态溶解度和稳定性测试由安捷伦1260高效液相色谱仪测试完成,离子的成盐摩尔比测试由离子色谱测试完成,分析条件如表5和表6。
表5.高校液相色谱测试条件
表6离子色谱测试条件
实施例1依利格鲁司他酒石酸盐晶型A的制备及表征
通过市售获得格鲁司他酒石酸盐,并测定其XRPD图谱。该依利格鲁司他酒石酸盐的XRPD图谱参见图1A,显示样品为晶态,与WO2011066325A1中说明书附图图1的XRPD图谱数据吻合,在本 发明中描述为依利格鲁司他酒石酸盐晶型A。TGA/DSC结果(图1B)显示,样品加热至150℃时有0.2%的失重,且在165.9℃(峰值温度)观察到吸热峰。
1H NMR在DMSO-d
6中测得,结果参见图1C,结果显示酒石酸与API的摩尔比约为0.5,未见明显有机溶剂残留。
实施例2游离依利格鲁司他的制备及表征
游离态晶型A由以下方法制备得到:在烧杯中称取约200mg起始酒石酸盐晶型A,加入2mL去离子水溶解,向该溶液中快速加入20mL饱和NaHCO
3溶液,并于室温下搅拌1.5小时,抽滤收集所得固体,经室温真空燥过夜后,测试所得样品XRPD,图2A显示样品呈结晶态,命名为游离态晶型A,其XRPD结果如图2A所示。TGA/DSC结果(图2B)显示,样品加热至80℃时有0.8%的失重,且在88.9℃(峰值温度)观察到吸热峰。
1H NMR在DMSO-d
6中测得,结果列于图2C,未见明显有机溶剂残留。
实施例3盐型筛选
以制备得到的游离态晶型A为原料,选用28种酸性配体,分三阶段共设置了154个盐型筛选试验。筛选试验具体步骤如下:称取约20mg游离态晶型A样品和相应配体至HPLC小瓶中,加入0.5mL溶剂混合得到悬浊液。室温悬浮搅拌2天后(第三阶段筛选试验在40℃下进行),离心分离固体并在室温下真空干燥。室温搅拌后所得澄清溶液转至5℃搅拌或反溶剂(正庚烷)添加诱导析出固体,仍澄清的转为室温敞口挥发以得到固体;所得胶状物转至50℃~5℃温度循环(一个循环:4.5℃/min升温至50℃,在50℃恒温2小时;0.1℃/min降温至5℃;在5℃恒温2小时)。测试所得固体XRPD,结果显示,三阶段XRPD筛选试验中共得到11种盐型,包括1,5-萘二磺酸盐晶型A或B、草酸盐晶型A、粘酸盐晶型A、苹果酸盐晶型A或B、戊二酸盐晶型A、琥珀酸盐晶型A、磷酸盐晶型A、盐酸盐晶型A及富马酸盐晶型A。对11种盐晶型的 XRPD、TGA、DSC和
1H NMR或IC/HPLC表征,表征结果汇总于表7-1至表7-4。
表7-1第一轮盐型筛选试验结果总结
*:固体于XRPD测试时发生潮解;
胶状物:样品经低温搅拌、反溶剂添加、温度循环及室温敞口挥发后仍为胶状物;
1:室温搅拌得到澄清溶液,5℃及-20℃搅拌后得到固体进行XRPD测试;
2:室温及5℃搅拌得到澄清溶液,以正庚烷进行反溶剂添加后得到胶状物,经温度循环(50℃~5℃)后得到固体进行XRPD测试;
3:室温搅拌得到胶状物,经温度循环(50℃~5℃)后得到固体进行XRPD测试;
4:室温搅拌得到澄清溶液,5℃搅拌得到胶状物,经温度循环(50℃~5℃)后得到固体进行XRPD测试;
5:室温搅拌得到澄清溶液,以正庚烷进行反溶剂添加后得到油状物,经室温敞口挥发后得到固体进行XRPD测试。
表7-2第二轮盐型筛选试验结果总结
澄清溶液:没有观察到晶体
表7-3第三轮盐型筛选试验结果总结*
*:该轮试验投料摩尔比均为1:2(配体酸/API);NA:未设置。
1:40℃搅拌后得到胶状物,经温度循环(50℃~5℃)后得到固体进行XRPD测试。
2:样品初次XRPD测试得到游离态晶型A,补加0.25eq对应配体酸后继续于40℃下搅拌,得到固体进行测试。
表7-4筛选所得盐型样品表征结的果汇总
*:样品于XRPD测试时观察到潮解;
#:此两盐型样品为盐型与游离态样品的混合物。
--:因样品明显潮解,未收集此表征数据;NA:因筛选所得样品不足,未进行该表征。
+:1,5-萘二磺酸盐晶型A在之后的研究中被确认为混合物,在晶型筛选中获得了稳定的1,5-萘二磺酸盐晶型D。
晶型筛选
实施例4 1,5-萘二磺酸盐晶型D的制备和表征
将49.6mg依利格鲁司游离碱及45.7mg的1,5-萘二磺酸四水合物(1.1当量)溶解在2.0mL的MTBE中,将混合物体系置于室温下磁力搅拌(约750rpm)约3天后进行离心分离(10000rpm,2min),将所得固体在室温条件下真空干燥过夜,得依利格鲁司他1,5-萘二磺酸盐晶型D。
样品XRPD结果如图3A所示。TGA/DSC曲线如图3B所示,结果显示加热至130℃失重为9.82%,且在114.7和159.8℃(峰值温度)观察到吸热信号。
1H NMR谱图在DMSO-d6中测试得到,列于图3C,结果显示,配体酸与API摩尔比约为1.0。
表8依利格鲁司他1,5-萘二磺酸盐晶型D的XRPD峰列表
实施例5 1,5-萘二磺酸盐晶型B的制备和表征
将游离态晶型A与0.5当量的1,5-萘二磺酸于THF/正庚烷(1:9,v:v)中经室温悬浮搅拌1天及40℃悬浮搅拌2天,离心分离固体,真空干燥后得到游离态晶型A。
样品XRPD结果如图4A所示。TGA/DSC曲线如图4B所示,结果显示加热至150℃失重为1.5%,且在75.9,167.9℃(峰值温度)观察到吸热信号。
1H NMR谱图在DMSO-d
6中测试得到,列于图4C,结果显示,配体酸与API摩尔比约为0.5,未观察到残留溶剂。
表9依利格鲁司他1,5-萘二磺酸盐晶型B的XRPD峰列表
实施例6 1,5-萘二磺酸盐晶型C的制备和表征
称取119.9mg 1,5-萘二磺酸盐晶型B样品于3-mL玻璃瓶中,加入2mL H
2O,于室温下磁力搅拌(~750rpm)过夜,离心分离固体,在盛有氧化钙的干燥器中晾干24小时后,收集固体用于表征测试及研究。
XRPD结果列于图5A。TGA及DSC结果列于图5B,TGA结果显示,从室温加热到150℃失重6.6%;DSC曲线于73.5及171.4℃(峰值温度)处观察到吸热峰。
1H NMR在DMSO-d
6中测得,结果列于图5C,样品中配体酸及API摩尔比为0.5,未检测到明显THF及正庚烷残留。通过加热试验对1,5-萘二磺酸盐晶型C进行鉴定。1,5-萘二磺酸盐晶型C在氮气保护下加热至100℃并冷却至室温后,转为1,5-萘二磺酸盐晶型B。结合TGA曲线的失重、液态核磁结果及加热试验结果,1,5-萘二磺酸盐晶型C为二水合物。
表10依利格鲁司他1,5-萘二磺酸盐晶型C的XRPD峰列表
实施例7草酸盐晶型A的制备和表征
称取300.4mg游离态晶型A样品于20-mL玻璃瓶中,加入15mL MTBE溶解。磁力搅拌(~750rpm)下分批加入33.0mg草酸(约0.5当量),并置于40℃下悬浮搅拌。反应过夜后,抽滤分离固体,室温真空干燥并收集固体用于表征测试及研究。
XRPD结果列于图6A。TGA及DSC结果列于图6B,TGA结果显示,从室温加热到150℃失重7.4%;DSC曲线于90.1及116.0℃(峰值温度)处观察到吸热峰。
1H NMR在DMSO-d
6中测 得,结果列于图6C,样品中未检测到明显MTBE残留。IC/HPLC测试结果显示,样品中配体酸与API摩尔比为0.5。
表11依利格鲁司他草酸盐晶型A的XRPD峰列表
实施例8粘酸盐晶型A的制备和表征
称取500.8mg游离态晶型A样品于20-mL玻璃瓶中,加入15mL acetone/正庚烷(1:9,v:v)分散。磁力搅拌(~750rpm)下分批加入129.8mg粘酸(约0.5当量),并将体系置于50℃下反应。反应过夜后,体系上部溶液澄清,底部固体呈粘稠胶状。将体系转至温度循环(50℃~5℃),两次循环后,反应体系转为白色悬浊液。反应过夜后,抽滤分离固体并以正庚烷洗涤,室温真空干燥2天后,收集固体用于表征测试及研究。
XRPD测试结果列于图8A。TGA及DSC结果列于图8B。
1H NMR在DMSO-d
6中测得,结果列于图8C,样品中未检测到明显MTBE残留。
表12依利格鲁司他粘酸盐晶型A的XRPD峰列表
实施例9苹果酸盐晶型A/B的制备和表征
将游离态晶型A与0.5当量的L-苹果酸于EtOAc中经1天室温悬浮搅拌后得到。离心分离固体,真空干燥后得到苹果酸盐晶型A。因样品在室湿条件下明显潮解,未收集其他表征数据。
由游离态晶型A与0.5当量的L-苹果酸于IPAc/正庚烷(1:5,v:v)中经室温悬浮搅拌1天及40℃悬浮搅拌2天后,离心分离固体,真空干燥后得到苹果酸盐晶型B。因样品于室湿下剧烈吸湿,未对其进行后续表征。
实施例10戊二酸盐晶型A的制备和表征
戊二酸盐晶型A由游离态晶型A与0.5当量的戊二酸于IPAc/正庚烷(1:5,v:v)中经室温悬浮搅拌1天及40℃悬浮搅拌2天后得到。离心分离固体,真空干燥后用于后续表征。
样品XRPD结果如图7A所示。TGA/DSC曲线如图7B所示,结果显示加热至150℃失重为3.7%,且在86.7,101.4,177.4℃(峰值温度)观察到吸热信号,据此结果,推测其为戊二酸盐晶型A与游离态晶型A混合物。
1H NMR谱图在DMSO-d
6中测试得到,列于图7C,结果显示,配体酸与API摩尔比约为0.7,未观察到残留溶剂。
表13依利格鲁司他戊二酸盐晶型A的XRPD峰列表
实施例11琥珀酸盐晶型A的制备和表征
将游离态晶型A与0.5当量的琥珀酸于IPAc/正庚烷(1:5,v:v)中室温悬浮搅拌1天及40℃悬浮搅拌2天后,所得固体为游离态晶型A。额外补加0.25当量琥珀酸后,继续于40℃下悬浮搅拌一周,离心分离得到固体,真空干燥后用于后续表征。
样品XRPD结果如表14所示。TGA/DSC曲线显示加热至120℃失重为7.3%,且在83.7,169.9℃观察到吸热信号。
1H NMR谱图在DMSO-d
6中测试得到,结果显示,配体酸与API摩尔比约为0.6,未观察到残留溶剂。
表14依利格鲁司他琥珀酸盐晶型A的XRPD峰列表
实施例12磷酸盐晶型A的制备和表征
由游离态晶型A与1当量的磷酸(85%)于MTBE中经室温悬浮搅拌1天后得到。离心分离固体,真空干燥后用于后续表征。
样品XRPD结果如表15所示。TGA/DSC显示加热至100℃失重为4.4%,且在79.7,106.4,131.5℃(峰值温度)观察到吸热信号。
1H NMR谱图在DMSO-d
6中测试得到,结果显示,未观察到残留溶剂。IC/HPLC测试结果显示样品中配体酸与API摩尔比为1.4。
表15依利格鲁司他磷酸盐晶型A的XRPD峰列表
实施例13盐酸盐晶型A的制备和表征
将游离态晶型A样品与等当量的盐酸于EtOAc中室温悬浮搅拌得到澄清溶液,再经正庚烷反溶剂添加后形成胶状物。将该胶状物样品转至50℃至5℃温度循环,2天后得到固体样品,离心分离并真空干燥后用于后续表征。
样品XRPD结果如表16所示。TGA/DSC结果显示加热至150℃失重为11.7%,且在48.6,93.0℃(峰值温度)观察到吸热信号。因筛选所得样品量不足,未进行核磁测试。样品IC/HPLC测试结果显示,样品中配体酸与API摩尔比为1.0。
表16依利格鲁司他盐酸盐晶型A的XRPD峰列表
实施例14富马酸盐晶型A的制备和表征
将游离态晶型A样品与0.5当量的富马酸于EtOH/正庚烷(1:1,v:v)中室温悬浮搅拌后得到澄清溶液,再经正庚烷反溶剂添加后得到油状物,室温敞口挥发后得到固体,真空干燥后用于后续表征。样品XRPD结果如表17所示。TGA/DSC曲线显示加热至100℃失重为9.1%,且在54.6,86.8,134.1℃(峰值温度)观察到吸热信号。
1H NMR谱图在DMSO-d
6中测试得到,结果显示,配体酸与API摩尔比约为0.5,未观察到残留溶剂。
表17依利格鲁司他富马酸盐晶型A的XRPD峰列表
实施例15动态溶解度测试
取1,5-萘二磺酸盐晶型B/晶型C、草酸盐晶型A、酒石酸盐晶型A及游离态晶型A在水和三种生物溶媒中的动态溶解度进行了评估。
试验中,以~10mg/mL的固体投料浓度(~40mg固体投入4mL溶剂中)在37℃下旋转混合,并在不同时间点(1、4和24小时)测定各样品在水、SGF、FaSSIF和FeSSIF1四种体系中的溶解度。每个时间点取样后经离心过滤(0.45μm PTFE过滤头),测定滤液中的游离态浓度和pH值,离心后的固体样品测试XRPD。溶解度试验结果总结于表18。
表18溶解度测试结果总结
S:溶解度(mg/mL,游离态浓度);FC:晶型变化;NA:因样品溶清,未作XRPD表征;
实施例16引湿性评估
通过DVS对1,5-萘二磺酸盐晶型B/晶型C、草酸盐晶型A、酒石酸盐晶型A及游离态晶型A进行了引湿性评估。
结果显示,25℃下湿度高于80%RH时,1,5-萘二磺酸盐晶型B会发生明显吸湿增重,并在DVS测试后转为晶型C;1,5-萘二磺酸盐晶型C于25℃/80%RH吸湿增重为0.33wt%,且未在DVS测试后出现晶型变化;草酸盐晶型A于25℃/80%RH吸湿增重为7.64wt%,在湿度低于10%RH时观察到明显失重,且未在DVS测试后发现晶型变化。酒石酸盐晶型A样品略有引湿性,在于25℃/80%RH吸湿增重为1.11wt%,游离态晶型A样品几乎无引湿性3,且在DVS测试后两样品均未发生晶型变化。DVS测试结果列于表19。
表19引湿性测定结果
晶型 | 25℃/80%RH吸湿增重 | 晶型变化 |
1,5-萘二磺酸盐晶型B | 0.59% | 转化成晶型C |
1,5-萘二磺酸盐晶型C | 0.33% | 无变化 |
草酸盐晶型A | 7.64% | 无变化 |
酒石酸盐晶型A | 1.11% | 无变化 |
游离态晶型A | 0.01% | 无变化 |
实施例17固态稳定性评估
将1,5-萘二磺酸盐晶型C在25℃/60%RH和40℃/75%RH条件下敞口放置1周、3周及4周后,通过XRPD和HPLC检测样品的物理和化学稳定性,并以酒石酸晶型A及游离态晶型A 1周、2周及4周的稳定性数据作为参照。同时,对1,5-萘二磺酸盐晶型B及草酸盐晶型A进行了25℃/60%RH和40℃/75%RH条件下敞口放置1周的稳定性考察。结果显示,1,5-萘二磺酸盐晶型C、酒石酸盐晶型A及游离态晶型A样品在对应条件下敞口放置4周后,均未观察到晶型变化或HPLC纯度的下降。对于1,5-萘二磺酸盐晶型B及草酸盐晶型A样品,在对应条件下敞口放置1周后未观察到HPLC纯度的下降,但1,5-萘二磺酸盐晶型B于40℃/75%RH条件下敞口放置一周后部分转变为晶型C。
实施例18药效研究
葡萄糖神经酰胺(GL-1)的血浆水平被认为是戈谢患者底物减少疗法(SRT)的生物标志物和法布雷患者SRT的替代生物标志物,以评估新发现的盐在临床前物种中的生物学效应。
虽然已经描述了多个实施方案,但是本公开的范围将由所附权利要求书来限定,而不是由已经通过示例方式表示的特定实施方案来限定。本申请全文引用的所有参考文献(包括文献参考、已公布专利、已公开专利申请和共同未决专利申请)的内容在此通过引用全部明确纳入本申请。除非另有定义,本申请中使用的所有科技术语均具有本领域普通技术人员所熟知的含义。
Claims (44)
- 一种依利格鲁司他的可药用盐,其特征在于,所述可药用盐在水和模拟胃液中的溶解度小于等于6.0mg/mL。
- 一种依利格鲁司他的可药用盐,其特征在于,所述可药用盐为萘二磺酸盐、粘酸盐、戊二酸盐。
- 一种依利格鲁司他的可药用盐,其特征在于,所述萘二磺酸盐为1,5-萘二磺酸盐。
- 权利要求3所述的依利格鲁司他的可药用盐,其中1,5-萘二磺酸与依利格鲁司他的摩尔比为1:1或1:2。
- 权利要求4所述的依利格鲁司他的可药用盐,其中所述可药用盐为1,5-萘二磺酸盐的水合物或非溶剂化物。
- 权利要求5所述的依利格鲁司他的可药用盐,所述1,5-萘二磺酸盐的水合物为半水合物、一水合物、二水合物。
- 权利要求1-6中任意一项所述的依利格鲁司他的可药用盐,其中所述盐为1,5-萘二磺酸盐的晶型D,具有在4.9°、5.9°、18.7°的2θ角(±0.2°)的X射线粉末衍射峰。
- 权利要求7所述的依利格鲁司他的可药用盐,其中所述依利格鲁司他的1,5-萘二磺酸盐的晶型D进一步具有在7.0°、10.4°、24.7°的2θ角(±0.2°)的X射线粉末衍射峰。
- 权利要求8所述的依利格鲁司他的可药用盐,其中所述依利格鲁司他的1,5-萘二磺酸盐的晶型D进一步具有在14.2°、16.2°的2θ角(±0.2°)的X射线粉末衍射峰。
- 权利要求7所述的依利格鲁司他的可药用盐,其中所述依利格鲁司他的1,5-萘二磺酸盐的晶型D具有与图3A基本类似的X射线粉末衍射图谱。
- 权利要求1-6中任意一项所述的依利格鲁司他的可药用盐,其中所述盐为1,5-萘二磺酸盐的晶型B,具有在7.3°、14.6°、6.5°的2θ角(±0.2°)的X射线粉末衍射峰。
- 权利要求11所述的依利格鲁司他的可药用盐,其中所述依利格鲁司他的1,5-萘二磺酸盐的晶型B进一步具有在22.8°、21.0°、20.8°的2θ角(±0.2°)的X射线粉末衍射峰。
- 权利要求12所述的依利格鲁司他的可药用盐,其中所述依利格鲁司他的1,5-萘二磺酸盐的晶型B进一步具有13.1°、3.3°、15.1°的2θ角(±0.2°)的X射线粉末衍射峰。
- 权利要求13所述的依利格鲁司他的可药用盐,其中所述依利格鲁司他的1,5-萘二磺酸盐的晶型B具有与图4A基本类似的X射线粉末衍射图谱。
- 权利要求1-6中任意一项所述的依利格鲁司他的可药用盐,其中所述盐为1,5-萘二磺酸盐的晶型C,具有在9.4°、13.6°、20.1°、12.1°的2θ角(±0.2°)的X射线粉末衍射峰。
- 权利要求15所述的依利格鲁司他的可药用盐,其中所述依利格鲁司他的1,5-萘二磺酸盐的晶型C进一步具有在24.3°、12.8°、19.6°的2θ角(±0.2°)的X射线粉末衍射峰。
- 权利要求16所述的依利格鲁司他的可药用盐,其中所述依利格鲁司他的1,5-萘二磺酸盐的晶型C进一步具有在6.2°、14.0°的2θ角(±0.2°)的X射线粉末衍射峰。
- 权利要求15所述的依利格鲁司他的可药用盐,其中所述依利格鲁司他的1,5-萘二磺酸盐的晶型C具有与图5A基本类似的X射线粉末衍射图谱。
- 一种依利格鲁司他的可药用盐,其中所述盐为草酸盐的晶型A,具有在7.5°、15.5°、19.0°的2θ角(±0.2°)的X射线粉末衍射峰。
- 权利要求19所述的依利格鲁司他的可药用盐,其中所述依利格鲁司他的草酸盐的晶型A进一步具有在10.0°、22.3°、23.3°的2θ角(±0.2°)的X射线粉末衍射峰。
- 权利要求20所述的依利格鲁司他的可药用盐,其中所述依利格鲁司他的草酸盐的晶型A进一步具有在12.8°,18.3°,20.70°的2θ角(±0.2°)的X射线粉末衍射峰。
- 权利要求19所述的依利格鲁司他的可药用盐,其中所述依利格鲁司他的草酸盐的晶型A具有与图6A基本类似的X射线粉末衍射图谱。
- 权利要求1-2中任意一项所述的依利格鲁司他的可药用盐,其中所述盐为戊二酸盐的晶型A,具有在5.1°、19.3°、21.3°的2θ角(±0.2°)的X射线粉末衍射峰。
- 权利要求23所述的依利格鲁司他的可药用盐,其中所述依利格鲁司他的戊二酸盐的晶型A进一步具有在15.5°、6.4°、10.6°的2θ角(±0.2°)的X射线粉末衍射峰。
- 权利要求24所述的依利格鲁司他的可药用盐,其中所述依利格鲁司他的戊二酸盐的晶型A进一步具有在18.6°、21.9°、13.1°的2θ角(±0.2°)的X射线粉末衍射峰。
- 权利要求23所述的依利格鲁司他的可药用盐,其中所述依利格鲁司他的戊二酸盐的晶型A具有与图7A基本类似的X射线粉末衍射图谱。
- 权利要求1-2中任意一项所述的依利格鲁司他的可药用盐,其中所述盐为粘酸盐的晶型A,具有在6.4°、8.4°、20.7°的2θ角(±0.2°)的X射线粉末衍射峰。
- 权利要求27所述的依利格鲁司他的可药用盐,其中所述依利格鲁司他的粘酸盐的晶型A进一步具有在5.3°、14.0°,、12.4°的2θ角(±0.2°)的X射线粉末衍射峰。
- 权利要求28所述的依利格鲁司他的可药用盐,其中所述依利格鲁司他的粘酸盐的晶型A进一步具有在17.0°、19.6°、17.9°的2θ角(±0.2°)的X射线粉末衍射峰。
- 权利要求27所述的依利格鲁司他的可药用盐,其中所述依利格鲁司他的粘酸盐的晶型A具有与图8A基本类似的X射线粉末衍射图谱。
- 权利要求7-30中任一项所述的依利格鲁司他的可药用盐,其中的化合物为按重量计至少60%的单晶型、至少70%的单晶型、至少 80%的单晶型、至少90%的单晶型、至少95%的单晶型或至少99%的单晶型。
- 一种药物组合物,其包含权利要求1-4中任一项所述的依利格鲁司他的可药用盐,或权利要求5-6中任一项所述的依利格鲁司他1,5-萘二磺酸盐的水合物,或利要求7-10中任一项所述的依利格鲁司他1,5-萘二磺酸盐的晶型D,或权利要求11-14中任一项所述的依利格鲁司他1,5-萘二磺酸盐的晶型B,或权利要求15-18中任一项所述的依利格鲁司他1,5-萘二磺酸盐的晶型C,或权利要求19-22中任一项所述的草酸盐晶型A,或权利要求23-26中任一项所述的戊二酸盐晶型A,或权利要求31-34中任一项所述的粘酸盐晶型A,和药学上可接受的载体。
- 一种依利格鲁司他1,5-萘二磺酸盐的晶型D的制备方法,其特征在于,将依利格鲁司游离碱及1-1.1当量的1,5-萘二磺酸溶解在甲基叔丁基醚中,将混合物体系置于室温下磁力搅拌1-3天后进行离心分离,将所得固体在室温条件下真空干燥过夜。
- 一种依利格鲁司他1,5-萘二磺酸盐的晶型B的制备方法,其特征在于,将依利格鲁司游离碱与0.5当量的1,5-萘二磺酸溶解在四氢呋喃/正庚烷(1:9,v:v)中,在20-40℃温度下持续悬浮搅拌,并将析出固体干燥。
- 一种依利格鲁司他1,5-萘二磺酸盐的晶型C的制备方法,其特征在于,将1,5-萘二磺酸盐晶型B加入H 2O后在室温下搅拌,分离固体,使用氧化钙干燥。
- 一种依利格鲁司他草酸盐晶型A的制备方法,其特征在于,将依利格鲁司游离碱与0.5当量的草酸溶解在甲基叔丁基醚中,在15-50℃下持续悬浮搅拌,并将析出固体干燥。
- 一种依利格鲁司他戊二酸盐晶型A的制备方法,其特征在于,将依利格鲁司游离碱与0.5当量的戊二酸溶解在乙酸异丙酯/正庚烷(1:5,v:v)中,在20-40℃温度下持续悬浮搅拌,并将析出固体干燥。
- 一种依利格鲁司他粘酸盐晶型A的制备方法,其特征在于, 将依利格鲁司游离碱与0.5当量的粘酸分散在丙酮/正庚烷(1:9,v:v)中,在35-45℃温度下持续悬浮搅拌,并将析出固体干燥。
- 权利要求1-4中任一项所述的依利格鲁司他的可药用盐,或权利要求5-6中任一项所述的依利格鲁司他1,5-萘二磺酸盐的水合物,或利要求7-10中任一项所述的依利格鲁司他1,5-萘二磺酸盐的晶型D,或权利要求11-14中任一项所述的依利格鲁司他1,5-萘二磺酸盐的晶型B,或权利要求15-18中任一项所述的依利格鲁司他1,5-萘二磺酸盐的晶型C,或权利要求19-22中任一项所述的草酸盐晶型A,或权利要求23-26中任一项所述的戊二酸盐晶型A,或权利要求27-30中任一项所述的粘酸盐晶型A,在治疗戈谢病、法布雷病、多囊性肾病的用途。
- 权利要求39所述的用途,其中疾病的患者为CYP2D6广泛代谢者、中间代谢者或不良者代谢者。
- 权利要求39或40所述的用途,其中所述戈谢病为1型戈谢病,所述多囊性肾病为常染色显性多囊性肾病。
- 权利要求1-4中任一项所述的依利格鲁司他的可药用盐,或权利要求5-6中任一项所述的依利格鲁司他1,5-萘二磺酸盐的水合物,或利要求7-10中任一项所述的依利格鲁司他1,5-萘二磺酸盐的晶型D,或权利要求11-14中任一项所述的依利格鲁司他1,5-萘二磺酸盐的晶型B,或权利要求15-18中任一项所述的依利格鲁司他1,5-萘二磺酸盐的晶型C,或权利要求19-22中任一项所述的草酸盐晶型A,或权利要求23-26中任一项所述的戊二酸盐晶型A,或权利要求27-30中任一项所述的粘酸盐晶型A在制备治疗戈谢病、法布雷病、多囊性肾病的药物中的用途。
- 权利要求42所述的用途,其中疾病的患者为CYP2D6广泛代谢者、中间代谢者或不良者代谢者。
- 权利要求42或43所述的用途,其中所诉戈谢病为1型戈谢病,所述多囊性肾病为常染色显性多囊性肾病。
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US6916802B2 (en) | 2002-04-29 | 2005-07-12 | Genzyme Corporation | Amino ceramide-like compounds and therapeutic methods of use |
US7196205B2 (en) | 2001-07-16 | 2007-03-27 | The Regents Of The University Of Michigan | Synthesis of UDP-glucose: N-acylsphingosine glucosyltransferase inhibitors |
WO2011066325A1 (en) | 2009-11-24 | 2011-06-03 | Qualcomm Incorporated | Method and apparatus for facilitating a layered cell search for long term evolution systems |
WO2011066352A1 (en) | 2009-11-27 | 2011-06-03 | Genzyme Corporation | An amorphous and a crystalline form of genz 112638 hemitartrat as inhibitor of glucosylceramide synthase |
WO2015059679A1 (en) * | 2013-10-25 | 2015-04-30 | Dr. Reddy's Laboratories Limited | Improved process for the preparation of eliglustat |
CN107445938A (zh) | 2016-05-31 | 2017-12-08 | 北京启慧医疗器械有限公司 | 依利格鲁司他半酒石酸盐的结晶形式、制备方法和含有所述结晶形式的药用组合物 |
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US7196205B2 (en) | 2001-07-16 | 2007-03-27 | The Regents Of The University Of Michigan | Synthesis of UDP-glucose: N-acylsphingosine glucosyltransferase inhibitors |
US6916802B2 (en) | 2002-04-29 | 2005-07-12 | Genzyme Corporation | Amino ceramide-like compounds and therapeutic methods of use |
WO2011066325A1 (en) | 2009-11-24 | 2011-06-03 | Qualcomm Incorporated | Method and apparatus for facilitating a layered cell search for long term evolution systems |
WO2011066352A1 (en) | 2009-11-27 | 2011-06-03 | Genzyme Corporation | An amorphous and a crystalline form of genz 112638 hemitartrat as inhibitor of glucosylceramide synthase |
CN102712629A (zh) * | 2009-11-27 | 2012-10-03 | 基酶有限公司 | 作为葡糖神经酰胺合酶的抑制剂的无定型和结晶形式的Genz112638半酒石酸盐 |
WO2015059679A1 (en) * | 2013-10-25 | 2015-04-30 | Dr. Reddy's Laboratories Limited | Improved process for the preparation of eliglustat |
CN107445938A (zh) | 2016-05-31 | 2017-12-08 | 北京启慧医疗器械有限公司 | 依利格鲁司他半酒石酸盐的结晶形式、制备方法和含有所述结晶形式的药用组合物 |
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