CN105175473A - Obeticholic acid crystal form I, preparation method, pharmaceutical composition, and application thereof - Google Patents
Obeticholic acid crystal form I, preparation method, pharmaceutical composition, and application thereof Download PDFInfo
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- CN105175473A CN105175473A CN201510520721.XA CN201510520721A CN105175473A CN 105175473 A CN105175473 A CN 105175473A CN 201510520721 A CN201510520721 A CN 201510520721A CN 105175473 A CN105175473 A CN 105175473A
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Abstract
The invention relates to obeticholic acid crystal form I, which is represented in the description, and a preparation method. The preparation method comprises the following steps: dissolving obeticholic acid in an organic solvent to form a solution, wherein the organic solvent is halogenated alkane or ester, and volatilizing the solution until all solvent is completely volatilized so as to obtain the obeticholic acid crystal form I. Compared with the known solid forms of obeticholic acid, the novel crystal form is more stable and is more suitable for being applied to industrial production. The invention also relates to a pharmaceutical composition of the novel crystal form and an application thereof in the preparation of drugs for treating and/or preventing FXR mediated impaired adjustment, cardiovascular disease, cholestatic liver disease, high HDL cholesterol, high triglyceride, and fibrosis diseases.
Description
Technical field
The invention belongs to pharmaceutical chemistry crystallization technique field.In particular to one shellfish cholic acid difficult to understand crystal formation I, also relate to the preparation method of described crystal formation I, its pharmaceutical composition and purposes.
Background technology
Shellfish cholic acid difficult to understand is a kind of farnesoid X receptor (farnesoidXreceptor) potent agonist, plays a role in adjustment bile acid levels.Animal experiment has proved its effect improving insulin resistant (IR) and alleviate hepatic fat content.Later phase clinical test shows, shellfish cholic acid difficult to understand improves significantly to the rare hepatic diseases sign of the one mainly occurred in middle-aged women, and reduce liver transplantation demand and the mortality risk of patient, in addition, it is also used for the treatment of nonalcoholic steatohepatitis.
Shellfish cholic acid difficult to understand is a kind of chenodeoxycholic acid derivative, and its chemical name is 6-ethyl Chenodiol, and English name is ObeticholicAcid, has another name called OCA, and its structural formula is as follows:
Conceptual phase before Medicine prescription, usually needs the solid form selecting medicine according to the character of medicine and the requirement of target formulation.The difference of medical solid form can cause physico-chemical property, as the difference of stability, solubleness, dissolution rate, water absorbability etc., and then affect its drug effect and Pharmacology, the selection of medical solid form is the important factor will considered in preparation research, therefore needs to find the high shellfish cholic acid crystalline form difficult to understand of a kind of stability.
Patent documentation WO2013192097A1 discloses the crystalline form 1 (unformed) of shellfish cholic acid difficult to understand, crystal form A, crystalline form C, crystalline form D, crystalline form F and crystalline form G, wherein crystal form A, C, D are the crystalline form of the mixed type hydrate/solvate containing water and certain limit organic solvent, above-mentioned crystal formation still existence and stability poor problem, Nitromethane 99Min., acetonitrile equal solvent is used, contaminate environment in crystalline form F, G preparation process.
Summary of the invention
For the deficiencies in the prior art, the object of this invention is to provide a kind of shellfish cholic acid new crystal I difficult to understand.The crystal formation I that the present invention relates to has the higher feature of stability.The invention still further relates to the preparation method of described crystal formation I, its pharmaceutical composition and purposes.
According to object of the present invention, the crystal formation I that the invention provides shellfish cholic acid difficult to understand is an anhydride, and its structural formula is as follows:
In one embodiment of the invention, use Cu-K α radiation, the X-ray powder diffraction pattern that described crystal formation I represents with 2 θ angles has characteristic peak with upper/lower positions: 5.1 ± 0.2 °, 5.4 ± 0.2 °, 6.3 ± 0.2 °, 12.7 ± 0.2 °, 16.7 ± 0.2 ° and 19.4 ± 0.2 °.
In the preferred embodiment of the present invention, use Cu-K α radiation, the X-ray powder diffraction pattern that described crystal formation I represents with 2 θ angles has characteristic peak with upper/lower positions: 4.2 ± 0.2 °, 5.1 ± 0.2 °, 5.4 ± 0.2 °, 6.3 ± 0.2 °, 9.4 ± 0.2 °, 10.2 ± 0.2 °, 12.5 ± 0.2 °, 12.7 ± 0.2 °, 15.6 ± 0.2 °, 16.3 ± 0.2 °, 16.7 ± 0.2 ° and 19.4 ± 0.2 °.
In the preferred embodiment of the present invention, use Cu-K α radiation, the X-ray powder diffraction pattern that described crystal formation I represents with 2 θ angles has characteristic peak and relative intensity thereof with upper/lower positions:
Without limitation, a representative instance of described crystal formation I has X-ray powder diffraction pattern as shown in Figure 2.
The monocrystalline of described crystal formation I, measures at the temperature of 100K, has following monocrystalline unit cell parameters: axial length is
interfacial angle is α=92.788 (2) °, β=90.398 (2) °, γ=97.281 (2) °; Spacer: P1 (1); Each structure cell includes 8 shellfish cholic acid molecules difficult to understand; Unit cell volume is
structure cell density is 0.825505g/cm
3; Flack parameter is 0.018 (136).
In one embodiment of the invention, the FTIR spectrum of described crystal formation I is 2930,1707,1450,1364,1262,1242,1161,1121,1062,1045,973,954 and 808cm in wave number
-1place has characteristic peak.
The DSC collection of illustrative plates display of described crystal formation I: have an endotherm(ic)peak at 60 ~ 90 DEG C.
The fusing point of described crystal formation I is 77 DEG C
The TGA collection of illustrative plates display of described crystal formation I: had 7.07% weightlessness before 100 DEG C, had 11.79% weightlessness before 150 DEG C.
The adsorption isothermal curve changes in weight be presented in 20% ~ 80% RH range of described crystal formation I is 0.57%.
Compared with known shellfish cholic acid solid form difficult to understand, crystal formation I of the present invention has good stability, and technique is simply easy to the feature of industrialization.
According to object of the present invention, the preparation method that the invention provides crystal formation I comprises the following steps: form shellfish cholic acid difficult to understand solution in organic solvent, described organic solvent is selected from halogenated alkane or ester, evaporates into dry, obtains described crystal formation I;
Preferably, described halogenated alkane elects methylene dichloride and trichloromethane as, is more preferably methylene dichloride; Described ester elects C as
3~ C
6ester, is more preferably n-butyl acetate;
Preferably, the concentration of described shellfish cholic acid difficult to understand solution is in organic solvent 10 ~ 200mg/mL;
Preferably, the service temperature of described preparation method is 10 ~ 50 DEG C, is more preferably room temperature.
In above-mentioned preparation method, described " C
3~ C
6ester " refer to C number that formic acid, acetic acid, propionic acid, butyric acid and methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, sec-butyl alcohol, the trimethyl carbinol formed 3 ~ 6 all esters.
The crystal formation I that above-mentioned preparation method obtains, adopts the ordinary method of this area to carry out drying.Described " drying " method, such as forced air drying, drying under reduced pressure etc.; Drying plant adopts stink cupboard, convection oven or vacuum drying oven; In decompression or can carry out drying under not reducing pressure, preferred pressure is less than 0.09MPa; Drying temperature is 10 ~ 40 DEG C, is preferably room temperature; Time of drying is 1 ~ 72 hour, is preferably 1 ~ 10 hour, is more preferably 1 ~ 2 hour.
Preparation method's step of crystal formation I of the present invention is simple, easy handling.
In the present invention, " room temperature " refers to about 10 ~ 30 DEG C.
In the present invention, the method that shellfish cholic acid form A difficult to understand can react 6 descriptions with reference to patent documentation W02013192097A1 embodiment 1 prepares or is available commercially.
Crystal formation I of the present invention is pure, single, does not substantially mix any other crystal, crystal formation or non-crystalline state." substantially do not have " to refer to that other crystal, crystal formation or the non-crystalline state wherein contained is less than 20% (weight), more refer to be less than 10% (weight), especially be less than 5% (weight), refer to especially and be less than 1% (weight).
According to object of the present invention, the invention provides a kind of pharmaceutical composition, described pharmaceutical composition comprises the above-mentioned crystal formation I that the active constituents of medicine treating and/or preventing significant quantity is selected from crystal formation I of the present invention or is obtained by preparation method of the present invention, and the pharmaceutically acceptable carrier of at least one or auxiliary agent.Described pharmaceutical composition comprises usually, by weight the shellfish cholic acid crystal formation I of the present invention difficult to understand of about 1% ~ 99%, and by weight about 99% ~ 1% the pharmaceutically acceptable suitable carrier of at least one or auxiliary agent.In addition, described pharmaceutical composition can also comprise other pharmaceutically useful salt of shellfish cholic acid difficult to understand, solvate, the crystal of hydrate or non-crystalline state.Optionally, described pharmaceutical composition can also comprise one or more other active constituents of medicine.
Described pharmaceutical composition can be prepared as the formulation of solid-state, semi-solid state or liquid state, and solid oral dosage form, such as, comprise tablet, capsule, granule, pill and powder; Liquid oral dosage form, such as, comprise solution, syrup, suspensoid, dispersion agent and emulsion; Injectable formulation, such as, comprise solution, dispersion agent and be re-dubbed the lyophilized powder of solution.Formula can be suitable for the quick-release of active constituents of medicine, slowly-releasing or controlled release, can be preparation that is conventional, dispersible, masticable, Orally dissolving or rapid melting.Route of administration comprises oral, intravenous injection, subcutaneous injection, transdermal administration, rectal administration, intranasal administration etc.Keep crystal formation of the present invention during in order to prepare, pharmaceutical composition of the present invention is preferably solid oral dosage form, and it comprises tablet, capsule, granule, pill and powder, and being more preferably can the solid oral dosage form of slowly-releasing or realizing controlled-release.
When solid dosage, pharmaceutically acceptable carrier of the present invention or auxiliary agent include but not limited to: thinner, such as starch, pregelatinized Starch, lactose, Solka-floc, Microcrystalline Cellulose, secondary calcium phosphate, tricalcium phosphate, N.F,USP MANNITOL, sorbyl alcohol, sugar etc.; Tackiness agent, such as gum arabic, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropylcellulose, Vltra tears, polyoxyethylene glycol etc.; Disintegrating agent, such as starch, sodium starch glycollate, pregelatinized Starch, polyvinylpolypyrrolidone, croscarmellose sodium, colloid silica etc.; Lubricant, such as stearic acid, Magnesium Stearate, Zinic stearas, Sodium Benzoate, sodium acetate etc.; Glidant, such as colloid silica etc.; Complex forming agents, the cyclodextrin of such as various rank and resin; Release rate control agent, such as hydroxypropylcellulose, Walocel MT 20.000PV, Vltra tears, ethyl cellulose, methylcellulose gum, methyl methacrylate, wax etc.Other available pharmaceutically acceptable carriers or auxiliary agent include but not limited to membrane-forming agent, softening agent, tinting material, seasonings, viscosity modifier, sanitas, antioxidant etc.
Described pharmaceutical composition can use in prior art the method that well known to a person skilled in the art to prepare.By the crystal formation I of shellfish cholic acid difficult to understand of the present invention and one or more pharmaceutically acceptable carrier or auxiliary agent during preparation, one or more optional other activeconstituentss mix mutually.Solid preparation can by directly mixing, prepared by the technique such as granulation.
According to object of the present invention, the crystal formation I that the invention provides shellfish cholic acid difficult to understand of the present invention is mediating insufficiency of accommodation, cardiovascular disorder or cholestatic liver disease for the preparation for the treatment of and/or preventing FXR, and the purposes in the medicine of high HDL cholesterol, high triglyceride and fibrosis conditions.
According to object of the present invention, the invention provides one and treat and/or prevent FXR mediation insufficiency of accommodation, cardiovascular disorder or cholestatic liver disease, and the method for high HDL cholesterol, high triglyceride and fibrosis conditions, described method comprises the crystal formation I or foregoing pharmaceutical composition of the present invention that the crystal formation I of the present invention of the patient treatment that gives needs and/or prevention significant quantity or method produced according to the present invention obtain; Described patient refers to the Mammals comprising the mankind.In some embodiments, dosage range can be per kg body weight per day about 0.01 milligram to about 100 milligrams, dosage schemes every day that can be easy to use.The type of the visual illness of dosage and degree, the general health of patient, the characteristic of formula and route of administration etc. and regulate.
Above-mentioned FXR mediates insufficiency of accommodation, cardiovascular disorder or cholestatic liver disease, and the hepatic disorder that high HDL cholesterol, high triglyceride and fibrosis conditions include but not limited to biliary atresia, cholestatic liver disease, chronic hepatopathy, nonalcoholic fatty liver disease (NASH), C type virus infection, alcoholic liver disease, primary biliary cirrhosis (PBC), cause due to Progressive symmetric erythrokeratodermia fibrosis, hepatic fibrosis and cardiovascular disorder (comprising atherosclerosis, arteriosclerosis, hypercholesterolemia and hyperlipidemia).
Accompanying drawing explanation
Fig. 1 is the XRPD figure of shellfish cholic acid form A difficult to understand disclosed in WO2013192097A1
Fig. 2 is the XRPD figure of shellfish cholic acid crystal formation I difficult to understand prepared by embodiment 1
Fig. 3 is the TGA figure of shellfish cholic acid crystal formation I difficult to understand prepared by embodiment 1
Fig. 4 is the DSC figure of shellfish cholic acid crystal formation I difficult to understand prepared by embodiment 1
Fig. 5 is the DVS figure of shellfish cholic acid crystal formation I difficult to understand prepared by embodiment 1
Fig. 6 is the adsorption isothermal curve of shellfish cholic acid crystal formation I difficult to understand prepared by embodiment 1
Fig. 7 is the IR figure of shellfish cholic acid crystal formation I difficult to understand prepared by embodiment 1
Embodiment
The present invention is with further reference to following examples, and described embodiment describes crystal formation I of the present invention, its preparation method and application in detail.It will be apparent for a person skilled in the art that the many changes for both materials and methods can be implemented without departing from the present invention.
Detecting instrument and method:
X-ray powder diffraction (XRPD): instrument is BrukerD8Advancediffractometer, copper target wavelength is adopted to be the KaX-ray of 1.54nm, under the operational condition of 40kV and 40mA, θ-2 θ goniometer, Mo monochromator, Lynxeye detector.Instrument is calibrated with silicon carbide before use.Acquisition software is DiffracPlusXRDCommander.Sample is at room temperature tested, and is placed on by sample on no reflection events plate.Testing conditions is: angular range: 3-40 ° of 2 θ, step-length: 0.02 ° of 2 θ, speed: 0.2 second/step.
Differential thermal analysis (DSC) data acquisition is certainly in TAInstrumentsQ200MDSC, and instrument control software is ThermalAdvantage, and analysis software is UniversalAnalysis.Usually the sample getting 1 ~ 10 milligram is positioned over does not add a cover in the aluminium crucible of (unless stated otherwise), with the heat-up rate of 10 DEG C/min at the dry N of 50mL/min
2protection under sample is risen to 250 DEG C from room temperature, the simultaneously thermal change of TA software records sample in temperature-rise period.In this application, fusing point is reported by starting temperature.
Thermogravimetric analysis (TGA) data acquisition is certainly in TAInstrumentsQ500TGA, and instrument control software is ThermalAdVantage, and analysis software is UniversalAnalysis.Usually the sample getting 5 ~ 15mg is positioned in platinum crucible; adopt the mode of segmentation high resolution detection; under the protection of the dry N2 of 50mL/min, sample is risen to 300 DEG C from room temperature with the heat-up rate of 10 DEG C/min, simultaneously the changes in weight of TA software records sample in temperature-rise period.
Adsorption isothermal curve data acquisition is certainly in TAInstrumentsQ5000TGA, and instrument control software is ThermalAdvantage, and analysis software is UniversalAnalysis.Usually the sample getting 1 ~ 10mg is positioned in platinum crucible, the changes in weight of TA software records sample relative humidity from 0% to 80% to 0% change procedure.Particular case per sample, also can adopt different absorption and De contamination step to sample.Adsorption isothermal curve can be obtained by analysis software.
Single crystal diffractometer: EosCCD detector, four circle Kappa survey instrument, enhancement type Mo light source and enhancement type Cu light source.Detect parameters: envrionment temperature 100K, enhancement type Cu light source, graphite monochromator, wavelength
data analysis software is Crysalispro.Again through the process of shelxtl software analysis, schematic arrangement can be obtained.
Infrared spectroscopy (IR) data acquisition is certainly in BrukerTensor27, and instrument control software and data analysis software are all OPUS.Usual employing ATR equipment, at 600 ~ 4000cm
-1in scope, gather infrared absorption spectrum, the sweep time of sample and blank background is 16 seconds, instrumental resolution 4cm
-1.
preparation example 1
React 6 obtained shellfish cholic acid form A difficult to understand according to the embodiment 1 of patent documentation WO2013192097A1, concrete operations are as follows:
By 3 Alpha-hydroxy-6 α-ethyl-7-ketone group-5 β-cholane-24-acid (86g, 205.4mmol), mixture and the sodium borohydride (7.77g, 205.4mmol) of water (688mL) and 50% (w/w) sodium hydroxide solution (56.4mL) react to 105 DEG C with 90 DEG C in mixture of 50% (w/w) sodium hydroxide solution (1.5mL) and water (20mL).Stir lower reflux at least 3 hours, after having reacted, reaction solution is cooled to 80 DEG C.Add citric acid (320.2g, anhydrous), n-butyl acetate (860mL) and the mixture of water (491mL) at 30 DEG C to 50 DEG C, ensure that pH value is acid, by aqueous phase separation.Distillation organic phase, distillation obtains residue n-butyl acetate and dilutes, and slowly cools to 15 DEG C to 20 DEG C, centrifuging.Crude product is crystallization from n-butyl acetate.Shellfish cholic acid difficult to understand isolates rear n-butyl acetate (43mL, 4 times) washing, and sample is 80 DEG C of vacuum-dryings.Obtain 67.34g (77.9%) crystalloid form A shellfish cholic acid difficult to understand.
The XRPD collection of illustrative plates of crystal C as shown in Figure 1.
embodiment 1
Get 50mg shellfish cholic acid difficult to understand form A, add 1mL n-butyl acetate and dissolve, volatilizing at 50 DEG C dryly obtains shellfish cholic acid crystal formation I difficult to understand.
The XRPD collection of illustrative plates of crystal formation I as shown in Figure 2.Be shown as crystal form material.
The DSC collection of illustrative plates of crystal formation I as shown in Figure 3.Display fusing point 77 DEG C.
The TGA collection of illustrative plates of crystal formation I as shown in Figure 4.There is 7.07% weightlessness before showing 100 DEG C, before 150 DEG C, have 11.79% weightlessness.
The DVS collection of illustrative plates of crystal formation I and adsorption isothermal curve are as shown in Figure 5 and Figure 6.Changes in weight 0.57% in display 20%-80% RH range, omnidistance changes in weight 0.69%.
The infared spectrum of crystal formation I as shown in Figure 7.Display: be 2930,1707,1450,1364,1262,1242,1161,1121,1062,1045,973,954 and 808cm in wave number
-1place has characteristic peak.
embodiment 2
Get 50mg shellfish cholic acid difficult to understand form A, add 0.25mL n-butyl acetate and dissolve, under room temperature, volatilization obtains shellfish cholic acid crystal formation I monocrystalline difficult to understand.
Monocrystalline unit cell parameters is as shown in table 1.
The monocrystalline unit cell parameters of table 1 crystal formation I
In table 1, a, b, c represent structure cell axial length, and α, β, γ represent interfacial angle, and Z represents the number of molecule in each structure cell, and V represents unit cell volume, D
calcrepresent structure cell density.
Correlation parameter resolved by monocrystalline: residual error factor R 1=0.0568, weighted R-values wR2=0.1453, goodness of fit GooF (S)=0.917.R1 value is less than 0.06, wR2 value and is less than 0.15, S value close to 1, illustrates that single crystal data is reasonable.
Result proves that crystal formation I is made up of shellfish cholic acid molecules difficult to understand, is anhydride.
embodiment 3
Get 50mg shellfish cholic acid difficult to understand form A, add 5.0mL methylene dichloride and dissolve, at 10 DEG C, volatilization obtains shellfish cholic acid crystal formation I difficult to understand.
embodiment 4
Get 50mg shellfish cholic acid difficult to understand form A, add 1.0mL trichloromethane and dissolve, under room temperature, volatilization obtains shellfish cholic acid crystal formation I difficult to understand.
embodiment 5
Get 50mg shellfish cholic acid difficult to understand form A, add 1.0mL trichloromethane and dissolve, under room temperature, volatilization obtains shellfish cholic acid crystal formation I difficult to understand.
embodiment 6
Get 50mg shellfish cholic acid difficult to understand form A, add 2.0mL acetic acid ethyl dissolution, under room temperature, volatilization obtains shellfish cholic acid crystal formation I difficult to understand.
embodiment 7
Get 50mg shellfish cholic acid difficult to understand form A, add 2.5mL isopropyl acetate and dissolve, under room temperature, volatilization obtains shellfish cholic acid crystal formation I difficult to understand.
Sample prepared by embodiment 3-embodiment 7 has same or analogous XRPD collection of illustrative plates, TGA collection of illustrative plates, DSC collection of illustrative plates, IR collection of illustrative plates with embodiment 1.Illustrate that the sample of embodiment 3-embodiment 7 and the sample of embodiment 1 are phase homomorphisms.
embodiment 8
Crystal formation I of the present invention is prepared into the tablet of different size in following table.
The concrete operations preparing tablet are: according to the prescription of table 2, get shellfish cholic acid crystal formation I difficult to understand, Microcrystalline Cellulose, Explotab, Magnesium Stearate (the 25mg specification of recipe quantity, add colloidal silica) mix after be pressed into plain sheet, then carry out dressing to target weight with the coating liquid of OpdayII.
Table 2 tablet formulation
The amount of shellfish cholic acid crystal formation I difficult to understand described in table is assumed to be absolutely anhydrous state, and actual amount is weightless based on the surface solvent of different batches raw material, and the shellfish cholic acid activeconstituents difficult to understand ensured in every sheet by the amount reducing corresponding Microcrystalline Cellulose reaches specification requirement.
The above; be only the specific embodiment of the present invention; but protection scope of the present invention is not limited thereto; any those of ordinary skill in the art are in the technical scope disclosed by the present invention; the change can expected without creative work or replacement, all should be encompassed within protection scope of the present invention.
Claims (10)
1. shellfish cholic acid (ObeticholicAcid) the crystal formation I difficult to understand that structural formula is as follows
2. shellfish cholic acid crystal formation I difficult to understand according to claim 1, it is characterized in that, use Cu-K α radiation, the X-ray powder diffraction pattern that described crystal formation I represents with 2 θ angles has characteristic peak with upper/lower positions: 5.1 ± 0.2 °, 5.4 ± 0.2 °, 6.3 ± 0.2 °, 12.7 ± 0.2 °, 16.7 ± 0.2 ° and 19.4 ± 0.2 °.
3. shellfish cholic acid crystal formation I difficult to understand according to claim 2, it is characterized in that, the X-ray powder diffraction pattern that described crystal formation I represents with 2 θ angles has characteristic peak with upper/lower positions: 4.2 ± 0.2 °, 5.1 ± 0.2 °, 5.4 ± 0.2 °, 6.3 ± 0.2 °, 9.4 ± 0.2 °, 10.2 ± 0.2 °, 12.5 ± 0.2 °, 12.7 ± 0.2 °, 15.6 ± 0.2 °, 16.3 ± 0.2 °, 16.7 ± 0.2 ° and 19.4 ± 0.2 °.
4. shellfish cholic acid crystal formation I difficult to understand according to claim 3, it is characterized in that, the X-ray powder diffraction pattern that described crystal formation I represents with 2 θ angles has characteristic peak and relative intensity thereof with upper/lower positions:
5. the shellfish cholic acid crystal formation I difficult to understand according to any one of claim 1-4, it is characterized in that, the monocrystalline of described crystal formation I is measured at the temperature of 100K, has following monocrystalline unit cell parameters: axial length is
interfacial angle is α=92.788 (2) °, β=90.398 (2) °, γ=97.281 (2) °; Spacer: P1 (1).
6. the shellfish cholic acid crystal formation I difficult to understand according to any one of claim 1-4, it is characterized in that, the FTIR spectrum of described crystal formation I is 2930,1707,1450,1364,1262,1242,1161,1121,1062,1045,973,954 and 808cm in wave number
-1place has characteristic peak.
7. the preparation method of the shellfish cholic acid crystal formation I difficult to understand according to any one of claim 1-6, it is characterized in that, described preparation method comprises the following steps: form shellfish cholic acid difficult to understand solution in organic solvent, described organic solvent is selected from halogenated alkane or ester, evaporate into dry, the service temperature of described preparation method is 10 ~ 50 DEG C, obtains described crystal formation I, wherein said halogenated alkane elects methylene dichloride and trichloromethane as, and described ester elects C as
3~ C
6ester.
8. the preparation method of shellfish cholic acid crystal formation I difficult to understand according to claim 7, it is characterized in that, described halogenated alkane elects methylene dichloride as, and described ester elects n-butyl acetate as.
9. a pharmaceutical composition, comprises the active constituents of medicine treating and/or preventing significant quantity and is selected from shellfish cholic acid crystal formation I difficult to understand according to any one of claim 1-6, and the pharmaceutically acceptable carrier of at least one or auxiliary agent.
10. the shellfish cholic acid crystal formation I difficult to understand according to any one of claim 1-6 is mediating insufficiency of accommodation, cardiovascular disorder or cholestatic liver disease for the preparation for the treatment of and/or preventing FXR, and the purposes in the medicine of high HDL cholesterol, high triglyceride and fibrosis conditions; Described FXR mediates insufficiency of accommodation, cardiovascular disorder or cholestatic liver disease, and high HDL cholesterol, high triglyceride and fibrotic illness are selected from biliary atresia, cholestatic liver disease, chronic hepatopathy, nonalcoholic fatty liver disease (NASH), C type virus infection, alcoholic liver disease, primary biliary cirrhosis (PBC), the hepatic disorder that causes due to Progressive symmetric erythrokeratodermia fibrosis, hepatic fibrosis and cardiovascular disorder (comprising atherosclerosis, arteriosclerosis, hypercholesterolemia and hyperlipidemia).
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