CN106632564B - Obeticholic acid salt, amorphous substance and pharmaceutical composition thereof - Google Patents
Obeticholic acid salt, amorphous substance and pharmaceutical composition thereof Download PDFInfo
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Abstract
The present invention relates to obeticholic acid salts and amorphous forms thereof, and more particularly to sodium, potassium, magnesium and calcium obeticholic acid salts and amorphous forms thereof. The amorphous substance of obeticholic acid salt is suitable for preparing medicines and compositions of Farnesoid X Receptor (FXR) agonists, and can be used for treating or preventing nonalcoholic steatohepatitis, nonalcoholic fatty liver diseases, gallstones, primary biliary cirrhosis, liver cirrhosis, cholesterol and triglyceride reduction and the like.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an amorphous substance of obeticholate, a preparation method thereof, a medicine and a composition containing the amorphous substance of obeticholate, and therapeutic application of the medicine.
Background
Chenodeoxycholic acid and its derivatives are agonists of farnesol X receptor. A series of chenodeoxycholic acid derivatives are disclosed in patents WO2010059859 and WO2005082925, wherein the compound Obeticholic acid (Obeticholic acid) is a selective farnesoid X receptor agonist, chemically named 3,7-dihydroxy-6-ethyl-5-cholan-24-oic acid (3,7-dihydroxy-6-ethyl-5-cholan-24-oic acid), and are expected to be developed as a drug for treating nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, gallstones, primary biliary cirrhosis, liver cirrhosis, hepatic fibrosis, diabetes, hypercholesterolemia, atherosclerosis, obesity, hypercholesterolemia, hypertriglyceridemia, and the like.
The structure of obeticholic acid is shown as formula A:
the polymorphs Form C, Form F, Form G and Form 1 of obeticholic acid (compound of formula a) are disclosed in international patent WO2013192097 and a process for the preparation of Form 1 by conversion of the polymorph Form C. The pharmacokinetic behavior of polymorphic forms Form F and Form 1 was studied in rats and showed that polymorphic Form F had higher plasma exposure and better bioavailability than Form 1, but polymorphic Form F could only be crystallized from explosive and toxic nitromethane solvents.
Different crystal forms and salt forms of the drug may influence the dissolution and absorption of the drug in vivo, and further may influence the clinical efficacy and safety of the drug to a certain extent. In order to improve bioavailability, stability and safety, the development of a crystal form and a salt form of the compound of formula a, which have high purity, high bioavailability, easy collection and high stability, is urgently needed in the art.
Disclosure of Invention
The first aspect of the invention provides an amorphous substance of a salt with a structure shown in a formula X:
wherein n is 1 or 2, M is NH4 +Alkali metal ions, alkaline earth metal ions or transition metal ions.
In another preferred embodiment, M may be selected from the group consisting of: NH (NH)4 +Sodium ions, potassium ions, magnesium ions, calcium ions, iron ions and zinc ions.
In another preferred embodiment, M may be selected from the group consisting of: sodium ions, potassium ions and magnesium ions.
In another preferred embodiment, the compound of formula X has the following characteristics: the melting point of the compound of formula X is at least 5-40 deg.C, preferably 10-40 deg.C, higher than that of obeticholic acid.
In another preferred embodiment, compounds of formula X are of the following formulae I-IV:
in another preferred embodiment, the amorphous substance is an amorphous substance of the compound of formula I-IV.
In another preferred embodiment, the amorphous form I has an X-ray powder diffraction pattern substantially as shown in FIG. 1 a.
In another preferred embodiment, the amorphous I has a specific halo pattern at 2 ° to 6 ° and 8 ° to 20 ° of the X-ray powder diffraction pattern.
In another preferred embodiment, the amorphous I has the following characteristics: in a differential scanning calorimetry analysis chart, the initial temperature is 59 ℃, and the peak is maximum at 93 +/-2 ℃.
In another preferred embodiment, the amorphous I DSC profile is substantially as characterized in FIG. 1 b.
In another preferred embodiment, the amorphous I has an absorption peak selected from the group consisting of 5, 7, 9 or all of the following infrared spectra: 3423 + -5 cm-1、2958±5cm-1、2935±5cm-1、2871±5cm-1、1640±5cm-1、1559±5cm-1、1451±5cm-1、1406±5cm-1、1378±5cm-1、1160±5cm-1、1065±5cm-1And 603. + -.5 cm-1。
In another preferred embodiment, the infrared spectrum of the amorphous I is substantially as shown in FIG. 1 d.
In another preferred embodiment, the ratio of obeticholic acid ions to sodium ions in the amorphous material I is 1: form 1.
In another preferred embodiment, the amorphous form II has an X-ray powder diffraction pattern substantially as characterized in figure 2 a.
In another preferred embodiment, the amorphous form II has a specific halo pattern at 4 ° to 7 ° and 8 ° to 20 ° of the X-ray powder diffraction pattern.
In another preferred embodiment, the amorphous material II has the following characteristics: in a differential scanning calorimetry analysis chart, the initial temperature is 75 ℃, and the maximum peak is at 108 +/-2 ℃.
In another preferred embodiment, the amorphous form II differential scanning calorimetry analysis pattern is substantially as characterized in FIG. 2 b.
In another preferred embodiment, the amorphous form II further has absorption peaks in 5, 7, 9 or all of the following infrared spectra: 3409 +/-5 cm-1、2935±5cm-1、2871±5cm-1、1643±5cm-1、1555±5cm-1、1465±5cm-1、1451±5cm-1、1404±5cm-1、1378±5cm-1、1338±5cm-1、1159±5cm-1、1065±5cm-1And 603. + -.5 cm-1。
In another preferred embodiment, the infrared spectrum of the amorphous material II is substantially as shown in figure 2 d.
In another preferred embodiment, the amorphous substance II is an amorphous substance with a ratio of obeticholic acid ions to potassium ions of 1: form 1.
In another preferred embodiment, the amorphous form III has an X-ray powder diffraction pattern substantially as characterized in figure 3 a.
In another preferred embodiment, the amorphous III has specific halo patterns at 4 to 6 and 6 to 20 of the X-ray powder diffraction pattern
In another preferred embodiment, the amorphous material III has the following characteristics: in the differential scanning calorimetry analysis chart, the initial temperature is 57 ℃, and the peak is maximum at 93 +/-2 ℃.
In another preferred embodiment, the amorphous III DSC profile is substantially as characterized in FIG. 3 b.
In another preferred embodiment, the amorphous form III further has absorption peaks in 5, 7, 9 or all of the following infrared spectra: 3401 +/-5 cm-1、2935±5cm-1、2871±5cm-1、1555±5cm-1、1449±5cm-1、1414±5cm-1、1377±5cm-1、1159±5cm-1、1064±5cm-1And 603. + -.5 cm-1。
In another preferred embodiment, the infrared spectrum of the amorphous III is substantially as shown in FIG. 3 d.
In another preferred embodiment, the amorphous substance III is an obeticholic acid ion and magnesium ion with the ratio of 2: form 1.
In another preferred embodiment, the amorphous form IV has an X-ray powder diffraction pattern substantially as shown in figure 4 a.
In another preferred embodiment, the amorphous IV has a specific halo pattern at 4 to 6 and 6 to 18 of the X-ray powder diffraction pattern.
In another preferred embodiment, the amorphous material IV has the following characteristics: in the differential scanning calorimetry analysis chart, the initial temperature is 50 ℃, and the peak is maximum at 87 +/-2 ℃.
In another preferred embodiment, the amorphous IV DSC profile is substantially as characterized in FIG. 4 b.
In another preferred embodiment, the amorphous form IV further has absorption peaks in 5, 7, 9 or all of the following infrared spectra: 3407 +/-5 cm-1、2935±5cm-1、2871±5cm-1、1553±5cm-1、1447±5cm-1、1417±5cm-1、1377±5cm-1、1159±5cm-1、1064±5cm-1And 603. + -.5 cm-1。
In another preferred embodiment, the infrared spectrum of the amorphous material IV is substantially as shown in FIG. 4 d.
In another preferred embodiment, the amorphous material IV is an amorphous material with the ratio of obeticholic acid ions to calcium ions being 2: 1 salt form.
A second aspect of the invention provides a process for preparing an amorphous form of a salt according to the first aspect of the invention,
(I) when M is sodium or potassium, the method comprises the steps of:
(1) dissolving obeticholic acid in an inert solvent, adding sodium hydroxide or potassium hydroxide, and concentrating to obtain a solid; and
(2) suspending the solid in an inert solvent and slurrying to obtain an amorphous form according to the first aspect of the invention;
(II) when M is magnesium or calcium, the process comprises the steps of:
(1) dissolving obeticholic acid in a sodium hydroxide or potassium hydroxide aqueous solution, and dissolving; and
(2) adding an aqueous solution of magnesium chloride or an aqueous solution of calcium chloride, stirring to precipitate a solid, and filtering to obtain an amorphous form according to the first aspect of the present invention;
(III) when M is magnesium or calcium, the process comprises the steps of:
(1) dissolving sodium obeticholic acid or potassium obeticholic acid salt in an aqueous solution, and dissolving;
(2) adding an aqueous solution of magnesium chloride or an aqueous solution of calcium chloride, stirring to precipitate a solid, and filtering to obtain an amorphous form according to the first aspect of the present invention.
In another preferred embodiment, the inert solvent is selected from the group consisting of: refers to methanol, ethanol, isopropanol, acetone, acetonitrile, ethyl acetate, butyl acetate, 1, 4-dioxane, methyl tert-butyl ether, water, and combinations thereof.
In a third aspect, the present invention provides a use of the amorphous substance according to the first aspect of the present invention for preparing a farnesoid X receptor agonist and a composition thereof or a medicament for preventing and treating liver and gallbladder related diseases and cardiovascular diseases.
In another preferred embodiment, the related disease is selected from the group consisting of: non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, gallstone, primary biliary cirrhosis, liver fibrosis, diabetes, atherosclerosis and obesity.
In a fourth aspect, the present invention provides a pharmaceutical composition comprising:
(a) an amorphous form according to the first aspect of the present invention; and
(b) a pharmaceutically acceptable carrier.
In another preferred embodiment, the mode of administration of the pharmaceutical composition is oral.
In another preferred embodiment, the pharmaceutical composition is a solid dosage form.
In another preferred embodiment, the pharmaceutical composition is in a liquid dosage form.
In a fifth aspect, the present invention provides a use of a pharmaceutical composition according to the fourth aspect of the present invention for the preparation of a medicament for the treatment and prevention of: non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, gallstone, primary biliary cirrhosis, liver fibrosis, diabetes, atherosclerosis and obesity.
Drawings
FIG. 1a shows the X-ray powder diffraction pattern of amorphous form I.
FIG. 1b shows a differential scanning calorimetry trace of amorphous I.
FIG. 1c shows amorphous I1HNMR map.
FIG. 1d shows the infrared spectrum of amorphous I.
FIG. 2a shows the X-ray powder diffraction pattern of amorphous II.
FIG. 2b shows a differential scanning calorimetry trace of amorphous II.
FIG. 2c shows amorphous II1HNMR map.
FIG. 2d shows the infrared spectrum of amorphous II.
FIG. 3a shows the X-ray powder diffraction pattern of amorphous form III.
FIG. 3b shows a differential scanning calorimetry trace of amorphous III.
FIG. 3c shows amorphous III1HNMR map.
FIG. 3d shows the infrared spectrum of amorphous III.
FIG. 4a shows the X-ray powder diffraction pattern of amorphous IV.
FIG. 4b shows a differential scanning calorimetry trace of amorphous IV.
FIG. 4c shows amorphous IV1HNMR map.
FIG. 4d shows the infrared spectrum of amorphous IV.
In each of the above figures, onset represents an initial value (initial value), and peak represents a peak (peak value).
Detailed Description
The inventor unexpectedly discovers a series of amorphous forms of pharmaceutically acceptable salts of the compound shown in the formula A, including amorphous forms of pharmaceutically acceptable salts shown in the formula X, and more preferably sodium salts, potassium salts, magnesium salts and calcium salts shown in the formula I-IV, wherein the amorphous forms have better drug bioavailability, high purity and high stability, and are suitable for preparing pharmaceutical compositions of farnesol X receptor agonists, so that the amorphous forms are more beneficial to treating or preventing diseases such as non-alcoholic fatty hepatitis, non-alcoholic fatty liver disease, gallstones, primary biliary cirrhosis, liver cirrhosis, high cholesterol and hypertriglyceridemia. In addition, the amorphous substance is not easy to raise, collect and waste in the process of manufacturing split-charging and other medicines, and is beneficial to protecting the health of operators. The present invention has been completed based on this finding.
Term(s) for
The compound of the formula I refers to sodium obeticholic acid with a structural formula shown as the formula I.
The compound of the formula II refers to potassium obeticholic acid salt with the structural formula shown in the formula II.
The compound of the formula III refers to obeticholic acid magnesium salt with the structural formula shown in the formula III.
The compound of formula IV is obeticholic acid calcium salt with a structural formula shown as formula IV.
The compound of the formula A refers to obeticholic acid with the structural formula shown in the formula A.
"obeticholic acid" refers to crystalline or amorphous obeticholic acid.
Polymorphic substance
The solid is present either in amorphous or crystalline form. In the case of crystalline forms, the molecules are positioned within three-dimensional lattice sites. When a compound crystallizes from a solution or slurry, it can crystallize in different spatial lattice arrangements (this property is known as "polymorphism"), forming crystals with different crystalline forms, each of which is known as a "polymorph". Different polymorphs of a given substance may differ from each other in one or more physical properties such as solubility and dissolution rate, true specific gravity, crystal form, packing pattern, flowability, and/or solid state stability.
Amorphous or amorphous solids
Amorphous solids or amorphous materials do not have long range ordered structures, and the arrangement of atoms does not have periodicity, so that the arrangement of atoms in the amorphous materials cannot be described with certainty as crystalline materials. The X-ray diffraction experiment shows that the amorphous solid has short-range order, and the probability of finding other atoms in any direction and any distance from one atom is completely the same; another characteristic of the amorphous solid structure is: its structural parameters exhibit a certain statistical distribution and do not have a defined value as in crystals.
Crystallization of
Production scale crystallization can be accomplished by manipulating the solution such that the solubility limit of the compound of interest is exceeded. This can be accomplished by a variety of methods, for example, dissolving the compound at relatively high temperatures and then cooling the solution below the saturation limit. Or by boiling, atmospheric evaporation, vacuum drying, or by some other method to reduce the liquid volume. The solubility of the compound of interest may be reduced by adding an anti-solvent or a solvent in which the compound has low solubility or a mixture of such solvents. Another alternative is to adjust the pH to reduce solubility. For a detailed description of the Crystallization see crystallation, third edition, J W Mullins, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.
If salt formation is desired to occur simultaneously with crystallization, addition of an appropriate acid or base may result in direct crystallization of the desired salt if the salt is less soluble in the reaction medium than the starting material. Also, in media where the final desired form is less soluble than the reactants, completion of the synthesis reaction can result in direct crystallization of the final product.
Optimization of crystallization may include seeding the crystallization medium with crystals of the desired form. In addition, many crystallization methods use a combination of the above strategies. One example is to dissolve the compound of interest in a solvent at elevated temperature, followed by the addition of an appropriate volume of anti-solvent in a controlled manner so that the system is just below the saturation level. At this point, seeds of the desired form may be added (and the integrity of the seeds maintained) and the system cooled to complete crystallization.
As used herein, the term "room temperature" generally means 4-30 deg.C, preferably 20. + -. 5 deg.C.
The obeticholic acid salt of the present invention
A compound of formula X
In the invention, the compound of the formula X is obeticholate, in particular amorphous substance, which has excellent treatment effect on primary biliary cirrhosis, non-alcoholic steatohepatitis and non-alcoholic fatty liver disease.
In the present invention, the pharmaceutically acceptable salt is selected from the group consisting of: NH (NH)4 +Sodium ions, potassium ions, magnesium ions, calcium ions, iron ions and zinc ions.
As used herein, "inert solvent" refers to methanol, ethanol, isopropanol, dimethyl sulfoxide, N-methylpyrrolidone, N, N-dimethylformamide, acetone, acetonitrile, acetic acid, formic acid, N-hexane, N-heptane, toluene, tetrahydrofuran, ethyl acetate, butyl acetate, 1, 4-dioxane, methyl tert-butyl ether, water, or a mixture of the above solvents.
As used herein, the term "obeticholate salt of the present invention" includes the reaction of a compound of formula a with an alkali metal ion, such as lithium, sodium, potassium, rubidium, cesium, and the like; alkaline earth metal ions such as magnesium, calcium, strontium, barium, etc.; transition metal ions such as iron, zinc, etc.; quaternary ammonium ions, e.g. ammonium (NH)4 +) And the like to form obeticholate represented by formula X.
Preferred obeticholate salts of the present invention include (but are not limited to):
(i) sodium salt of obeticholic acid represented by formula I;
(ii) potassium obeticholic acid salt represented by formula II;
(iii) a magnesium salt of obeticholic acid represented by formula III;
(iv) calcium salt of obeticholic acid represented by formula IV.
Amorphous material of the invention
As used herein, the term "amorphous form of the invention" includes amorphous forms of the salt of formula X.
Preferred amorphous materials of the present invention include (but are not limited to):
(i) amorphous form I of obeticholic acid sodium salt shown in formula I;
(ii) amorphous form II of obeticholic acid potassium salt represented by formula II;
(iii) amorphous form III of obeticholic acid magnesium salt represented by formula III;
(iv) amorphous form IV of obeticholic acid calcium salt represented by formula IV.
Identification and Properties of amorphous Material
After preparing an amorphous form of the compound of formula X, the present inventors studied its properties in various ways and apparatuses as follows.
Powder X-ray diffraction
Methods for determining X-ray powder diffraction of crystalline forms are known in the art. The spectra were acquired using a copper radiation target, for example, using a Rigaku D/max 2550VB/PC model X-ray powder diffractometer, at a scanning speed of 2 ° per minute.
The amorphous substance of the compound of the formula I has a specific amorphous form and a specific halo pattern (halo pattern) in an X-ray powder diffraction (XRPD) pattern. The following are preferred:
(1) amorphous material I
The amorphous I has a specific halo pattern (halo pattern) at 2 DEG to 6 DEG and 8 DEG to 20 DEG of an X-ray powder diffraction pattern.
In another preferred embodiment, the amorphous form I has an X-ray powder diffraction pattern substantially as shown in FIG. 1 a.
(2) Amorphous substance II
The amorphous II has a specific halo pattern (halo pattern) at 4 DEG to 7 DEG and 8 DEG to 20 DEG of an X-ray powder diffraction pattern.
In another preferred embodiment, the amorphous form II has an X-ray powder diffraction pattern substantially as shown in figure 2 a.
(3) Amorphous material III
The amorphous III has a specific halo pattern (halo pattern) at 4 DEG to 6 DEG and 6 DEG to 20 DEG of an X-ray powder diffraction pattern.
In another preferred embodiment, the amorphous form III has an X-ray powder diffraction pattern substantially as shown in figure 3 a.
(4) Amorphous IV
The amorphous material IV has a specific halo pattern (halo pattern) at 4 DEG to 6 DEG and 6 DEG to 18 DEG of an X-ray powder diffraction pattern.
In another preferred embodiment, the amorphous form IV has an X-ray powder diffraction pattern substantially as shown in FIG. 4 a.
Differential scanning calorimetry
Also known as Differential Scanning Calorimetry (DSC), is a technique for measuring the relationship between the energy difference between a substance to be measured and a reference substance and the temperature during heating. The position, shape and number of peaks on a DSC spectrum are related to the nature of the substance and can be used qualitatively to identify the substance. The method is commonly used in the field to detect various parameters such as phase transition temperature, glass transition temperature, reaction heat and the like of a substance.
DSC measurement methods are known in the art. The DSC scan pattern of the polymorph or amorphous can be obtained, for example, using a NETZSCH DSC 204F 1 differential scanning calorimeter, with a temperature ramp rate of 10 ℃ per minute, from 25 ℃ to 300 ℃.
The amorphous form of the compound of the formulae I to IV of the present invention has a specific characteristic peak in a Differential Scanning Calorimetry (DSC) chart.
(1) Amorphous material I
The differential scanning calorimetry pattern of amorphous form I has a maximum peak at 93 + -2 deg.C (or + -1 deg.C, or + -0.5 deg.C).
In another preferred embodiment, the amorphous form I has a Differential Scanning Calorimetry (DSC) pattern substantially as shown in figure 1 b.
(2) Amorphous substance II
The differential scanning calorimetry pattern of amorphous form II has a maximum peak at 108 + -2 deg.C (or + -1 deg.C, or + -0.5 deg.C).
In another preferred embodiment, the amorphous form II has a Differential Scanning Calorimetry (DSC) pattern substantially as shown in figure 2 b.
(3) Amorphous material III
The differential scanning calorimetry pattern of amorphous form III showed a maximum peak at 93 + -2 deg.C (or + -1 deg.C, or + -0.5 deg.C).
In another preferred embodiment, the amorphous form III has a differential scanning calorimetry pattern substantially as shown in figure 3 b.
(4) Amorphous IV
The differential scanning calorimetry pattern of amorphous form IV has a maximum peak at 87 + -2 deg.C (or + -1 deg.C, or + -0.5 deg.C).
In another preferred embodiment, the amorphous form IV has a differential scanning calorimetry pattern substantially as shown in figure 4 b.
Nuclear magnetic resonance analysis
Nuclear Magnetic Resonance (NMR) can also be used to aid in the determination of the crystalline structure, the determination of which is known in the art. The invention preferably employs Bruker Avance III plus-400 MHz.
Infrared spectroscopy
Infrared spectroscopy (IR) is a type of molecular absorption spectroscopy that utilizes selective absorption of electromagnetic radiation in the infrared region by substances for structural analysis and for qualitative and quantitative analysis of various infrared absorbing compounds, the methods of which are known in the art. The present invention preferably employs potassium bromide tableting.
The amorphous substance of the compound of the formula I has a specific amorphous form and a specific pattern in an infrared spectrum (IR). The following are preferred:
(1) amorphous material I
The amorphous material I also has absorption peaks selected from 5, 7, 9 or all of the following infrared spectrograms: 3423 + -5 cm-1、2958±5cm-1、2935±5cm-1、2871±5cm-1、1640±5cm-1、1559±5cm-1、1451±5cm-1、1406±5cm-1、1378±5cm-1、1160±5cm-1、1065±5cm-1And 603. + -.5 cm-1。
In another preferred embodiment, the amorphous form I has an ir spectrum substantially as shown in fig. 1 d.
(2) Amorphous substance II
The amorphous substance II also has absorption peaks selected from 5, 7, 9 or all of the following infrared spectrograms: 3409 +/-5 cm-1、2935±5cm-1、2871±5cm-1、1643±5cm-1、1555±5cm-1、1465±5cm-1、1451±5cm-1、1404±5cm-1、1378±5cm-1、1338±5cm-1、1159±5cm-1、1065±5cm-1And 603. + -.5 cm-1。
In another preferred embodiment, the amorphous form II has an infrared spectrum substantially as shown in FIG. 2 d.
(3) Amorphous material III
In another preferred embodiment, the amorphous form III further has absorption peaks in 5, 7, 9 or all of the following infrared spectra: 3401 +/-5 cm-1、2935±5cm-1、2871±5cm-1、1555±5cm-1、1449±5cm-1、1414±5cm-1、1377±5cm-1、1159±5cm-1、1064±5cm-1And 603. + -.5 cm-1。
In another preferred embodiment, the amorphous form III has an infrared spectrum substantially as shown in FIG. 3 d.
(4) Amorphous IV
In another preferred embodiment, the amorphous form IV further has absorption peaks in 5, 7, 9 or all of the following infrared spectra: 3407 +/-5 cm-1、2935±5cm-1、2871±5cm-1、1553±5cm-1、1447±5cm-1、1417±5cm-1、1377±5cm-1、1159±5cm-1、1064±5cm-1And 603. + -.5 cm-1。
In another preferred embodiment, the amorphous form IV has an infrared spectrum substantially as shown in FIG. 4 d.
Active ingredient
As used herein, the term "active ingredient" or "active compound" refers to the obeticholate salts of the present invention and amorphous forms thereof, i.e., amorphous forms of the compounds of formulae I-IV.
Bioavailability of
A rat bioavailability study of crystalline obeticholic acid form F (see published patent WO2013192097 for preparation) with amorphous forms of obeticholic acid salt X of the present invention was performed. Pharmacokinetic behavior and drug absorption tests for oral administration were performed according to methods known in the art, i.e. orally administering crystalline obeticholic acid form F or amorphous form I, II, III or IV of the obeticholic acid salt of the present invention, blood concentrations at various time points were measured by LC/MS method, and Tma, Cmax, T1/2 and plasma exposure AUC were calculated. Compared with the crystalline obeticholic acid, the obeticholic acid salt amorphous forms I-IV have higher plasma exposure and better bioavailability in animals.
Pharmaceutical compositions and methods of administration
Since the amorphous substance of the present invention has excellent farnesoid X receptor agonistic activity, the amorphous substance of the present invention and a pharmaceutical composition comprising the amorphous substance of the present invention as a main active ingredient can be used for treating, preventing and alleviating a disease mediated by farnesoid X receptor. According to the prior art, the amorphous substance of the invention can be used for treating the following diseases: non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, gallstone, primary biliary cirrhosis, hypercholesterolemia, hypertriglyceridemia, and the like.
The pharmaceutical composition of the present invention comprises the amorphous form of the present invention in a safe and effective amount range and a pharmaceutically acceptable excipient or carrier.
Wherein "safe and effective amount" means: the amount of the compound (or amorphous form) is sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1 to 2000mg of the amorphous substance of the present invention per dose, more preferably, 1 to 100mg of the amorphous substance of the present invention per dose. Preferably, said "dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must be sufficientSufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of being combined with the active ingredients of the present invention and with each other without significantly diminishing the efficacy of the active ingredient. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g. tween, etc.)
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the amorphous substance or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following: (a) fillers or extenders, for example, microcrystalline cellulose, starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, sodium carbonate, crospovidone, croscarmellose sodium; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active ingredient in such compositions may be delayed in a certain portion of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active ingredient may also be in microencapsulated form with one or more of the above excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, especially cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active ingredients, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these materials, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the amorphous form of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The amorphous form of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When the pharmaceutical composition is used, a safe and effective amount of the amorphous form of the present invention is suitably used for mammals (e.g., humans) in need of treatment, wherein the dose at the time of administration is a pharmaceutically considered effective dose, and for a human of 60kg body weight, the daily dose is usually 1 to 2000mg, preferably 1 to 200 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The main advantages of the invention include:
1. the amorphous material of the present invention has a higher melting point than the free acid form and is excellent in stability.
2. The amorphous substance has better drug bioavailability and very high purity, thereby being more beneficial to treating or preventing diseases such as non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, gallstone, primary biliary cirrhosis, liver cirrhosis, hypercholesterolemia, hypertriglyceridemia and the like.
3. Compared with the preparation of crystal forms, the preparation process of the amorphous substance is easier and the process is easy to control.
4. The amorphous substance is not easy to raise, collect and waste in the manufacturing process of split charging and other medicines, and is beneficial to protecting the health of operators.
The invention is further illustrated with reference to specific embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Example 1: preparation of amorphous Obeticholic acid sodium salt I
The method comprises the following steps:
5.0g obeticholic acid solid, 10ml absolute methanol was added, stirred to dissolve, slowly dropped into sodium hydroxide methanol solution (1.0eq NaOH in 2.0ml methanol), and stirred at room temperature for 2 h. Vacuum concentrating at 40 deg.C, adding acetone (15ml × 3), concentrating, adding 30ml acetone, pulping for 2 hr, filtering, and vacuum drying at room temperature for 8 hr.
Sampling channel1Detection by H NMR, Ion Chromatography (IC), X-ray powder diffraction, DSC, infrared spectroscopy (IR), etc. confirmed that the title compound was obtained in 4.6g of a white solid in yield: 87% and the purity is 99.1%.
1H NMR(400MHz,DMSO-d6)δ:4.38(s,1H),4.08(s,1H),3.50(s,1H),3.17-3.13(m,1H),1.93-0.81(m,36H),0.61(s,3H)。
Characteristic absorption peak of infrared spectrogram (IR): 3423 + -5 cm-1、2958±5cm-1、2935±5cm-1、2871±5cm-1、1640±5cm-1、1559±5cm-1、1451±5cm-1、1406±5cm-1、1378±5cm-1、1160±5cm-1、1065±5cm-1And 603. + -.5 cm-1。
Ion chromatography IC (Na)+) 5.19% (theoretical value: 5.19%).
Its X-ray powder diffraction pattern is shown in FIG. 1a, Differential Scanning Calorimetry (DSC) pattern is shown in FIG. 1b,1the spectrum of H NMR is shown in 1c, and the infrared spectrum (IR) is shown in 1 d.
The method 2 comprises the following steps:
2.0g of obeticholic acid solid is taken, 10ml of anhydrous methanol is added for dissolving, 1.05eq of NaOH solid is added, and stirring is carried out for 2 hours. The mixture is divided into 4 parts, 1 part of the mixture is concentrated to be dry in vacuum at 40 ℃, 8ml of ethyl acetate is added into the residue to be pulped for 0.5h, and the mixture is filtered and drained. The title amorphous form was obtained as a white solid, weighing 420mg, yield: 84 percent and the purity is 99.3 percent.
The X-ray powder diffraction pattern is the same as that of figure 1a, and the Differential Scanning Calorimetry (DSC) pattern is the same as that of figure 1 b.
Example 2: preparation of amorphous Obeticholic acid Potassium salt II
5.0g of obeticholic acid solid is added with 10ml of methanol, stirred and dissolved to be clear, and then slowly dropped into potassium hydroxide methanol solution (0.65g of NaOH is dissolved in 2.0ml of methanol), and stirred for 2 hours at room temperature; vacuum concentrating at 40 deg.C, adding acetone (10ml x 3) for concentrating, pulping residue with 30ml acetone for 1.5 hr, filtering, and vacuum drying at room temperature for 8 hr to obtain white solid 4.9 g; yield: 90% and the purity is 99%.
Sampling channel1Detection by H NMR, Ion Chromatography (IC), X-ray powder diffraction, DSC, infrared spectroscopy (IR), etc. confirmed that the title compound was obtained in 4.9g of a white solid in yield: 90 percent.
1H NMR(400MHz,DMSO-d6)δ:4.51(s,1H),4.18(s,1H),3.50(s,1H),3.15-3.10(m,1H),1.93-0.81(m,36H),0.60(s,3H)；
Characteristic absorption peak of infrared spectrogram (IR): 3409 +/-5 cm-1、2935±5cm-1、2871±5cm-1、1643±5cm-1、1555±5cm-1、1465±5cm-1、1451±5cm-1、1404±5cm-1、1378±5cm-1、1338±5cm-1、1159±5cm-1、1065±5cm-1And 603. + -.5 cm-。
Ion chromatography IC (K)+) 8.50% (theoretical value: 8.52%).
Its X-ray powder diffraction pattern is shown in FIG. 2a, Differential Scanning Calorimetry (DSC) pattern is shown in FIG. 2b,1the spectrum of H NMR is shown in 2c, and the infrared spectrum (IR) is shown in 2 d.
Example 3: preparation of amorphous form III of obeticholic acid magnesium salt
The method comprises the following steps:
taking 840mg obeticholic acid solid, adding 2.5ml water and sodium hydroxide aqueous solution (1.0eq NaOH is dissolved in 1.0ml water), stirring and dissolving to be clear; slowly adding magnesium chloride hexahydrate aqueous solution (820mg solid dissolved in 2.0ml water) dropwise to precipitate solid, filtering, washing with pure water, pumping off, and vacuum drying at 35 deg.C for 8 h.
Sampling channel1Detection by H NMR, Ion Chromatography (IC), X-ray powder diffraction, DSC, infrared spectroscopy (IR), etc. confirmed that the title compound was obtained in 720mg of a white solid in a yield of: 84 percent and the purity is 99.2 percent.
1H NMR(400MHz,DMSO-d6)δ:4.32(s,1H),4.03(d,J＝4.0Hz,1H),3.50(s,1H),3.13(s,1H),1.93-0.81(m,36H),0.61(s,3H)
Characteristic absorption peak of infrared spectrogram (IR): 3401 +/-5 cm-1、2935±5cm-1、2871±5cm-1、1555±5cm-1、1449±5cm-1、1414±5cm-1、1377±5cm-1、1159±5cm-1、1064±5cm-1And 603. + -.5 cm-1。
Ion chromatography (Mg)2+) 2.82% (theoretical value: 2.81%).
Its X-ray powder diffraction pattern is shown in FIG. 3a, Differential Scanning Calorimetry (DSC) pattern is shown in FIG. 3b,1the spectrum of H NMR is shown in 3c, and the infrared spectrum (IR) is shown in 3 d.
The method 2 comprises the following steps:
taking 200mg of obeticholic acid sodium salt solid, adding 2.0ml of water, and stirring to dissolve the solid clearly; magnesium chloride hexahydrate aqueous solution (45mg solid dissolved in 0.5ml water) was added dropwise to precipitate a solid, stirred for 3 hours, filtered, washed with pure water, and dried at room temperature to obtain a white solid as the title amorphous substance, weighing 150mg, yield: 77% and the purity is 99.2%. The X-ray powder diffraction pattern is the same as that of FIG. 3a, and the Differential Scanning Calorimetry (DSC) pattern is the same as that of FIG. 3 b.
The method 3 comprises the following steps:
taking 200mg of obeticholic acid potassium salt solid, adding 2.0ml of water, and stirring to dissolve the solid clearly; magnesium chloride hexahydrate aqueous solution (45mg solid dissolved in 0.5ml water) was added dropwise to precipitate a solid, stirred for 3 hours, filtered, washed with pure water, and dried at room temperature to obtain a white solid as the title amorphous substance, and 152mg was weighed, yield: 81% and the purity is 99.3%. The X-ray powder diffraction pattern is the same as that of FIG. 3a, and the Differential Scanning Calorimetry (DSC) pattern is the same as that of FIG. 3 b.
Example 4: preparation of amorphous Obeticholic acid calcium salt IV
The method comprises the following steps:
taking 840mg obeticholic acid solid, adding 3.0ml water and sodium hydroxide water solution (85mg solid is dissolved in 2.0ml water), and stirring to dissolve the solid; dropwise adding calcium chloride water solution (888mg solid dissolved in 2.5ml water), precipitating solid, stirring at room temperature for 16h, filtering, washing with pure water, draining, and vacuum drying at room temperature for 8 h.
Sampling channel1H NMR, Ion Chromatography (IC), X-ray powder diffraction, DSC, and infrared spectrogram (IR) etc. proved that the title compound was obtained in 735mg of a white solid in a yield of: 84 percent and the purity is 99.1 percent.
1H NMR(400MHz,DMSO-d6)δ:4.32(s,1H),4.02(s,1H),3.50(s,1H),3.14(s，1H)，2.09-0.81(m，36H)，0.61(s，3H)；
Characteristic absorption peak of infrared spectrogram (IR): 3407 +/-5 cm-1、2935±5cm-1、2871±5cm-1、1553±5cm-1、1447±5cm-1、1417±5cm-1、1377±5cm-1、1159±5cm-1、1064±5cm-1And 603. + -.5 cm-1。
Ion chromatography (Ca)2+) 4.58% (theoretical value: 4.56%).
Its X-ray powder diffraction pattern is shown in FIG. 4a, Differential Scanning Calorimetry (DSC) pattern is shown in FIG. 4b,1the spectrum of H NMR is shown in 4c, and the infrared spectrum (IR) is shown in 4 d.
The method 2 comprises the following steps:
taking 200mg of obeticholic acid sodium salt solid, adding 2.0ml of water, and stirring to dissolve the solid clearly; calcium chloride aqueous solution (25mg solid dissolved in 0.5ml water) was dropped to precipitate a solid, which was stirred for 3 hours, filtered, washed with pure water, and dried at room temperature to obtain a white solid as the title amorphous substance, and 170mg was weighed, yield: 85 percent and the purity is 99.3 percent. The X-ray powder diffraction pattern is the same as that of FIG. 4a, and the Differential Scanning Calorimetry (DSC) pattern is the same as that of FIG. 4 b.
The method 3 comprises the following steps:
taking 200mg of obeticholic acid potassium salt solid, adding 2.0ml of water, and stirring to dissolve the solid clearly; an aqueous calcium chloride solution (25mg solid dissolved in 0.5ml water) was added dropwise to precipitate a solid, which was stirred for 3 hours, filtered, washed with pure water, and dried at room temperature to obtain a white solid as the title amorphous substance, and 172mg was weighed, yield: 89% and the purity is 99.3%. The X-ray powder diffraction pattern is the same as that of FIG. 4a, and the Differential Scanning Calorimetry (DSC) pattern is the same as that of FIG. 4 b.
Example 5: stability of amorphous form I of sodium Obelin salt
After 6 months of accelerated testing (test conditions 40. + -. 2 ℃ C., 75%. + -. 5% RH), the results show that: amorphous form I is very stable and the purity of amorphous form I is substantially unchanged, consistently above 99%, no significant degradation impurities are seen, and the XRPD pattern is unchanged compared to freshly prepared (0 month) amorphous form I.
Example 6: stability of obeticholic acid potassium salt amorphous form II
After 6 months of accelerated testing (test conditions 40. + -. 2 ℃ C., 75%. + -. 5% RH), the results show that: amorphous form II was very stable and the purity of amorphous form II was essentially unchanged, consistently above 99%, with no significant degradation of impurities and no change in XRPD pattern compared to freshly prepared (0 month) amorphous form II.
Example 7: stability of amorphous form III of obeticholic acid magnesium salt
After 6 months of accelerated testing (test conditions 40. + -. 2 ℃ C., 75%. + -. 5% RH), the results show that: amorphous form III is very stable and has essentially no change in purity, consistently above 99%, no significant degradation impurities, and no change in XRPD pattern compared to freshly prepared (0 month) amorphous form III.
Example 8: stability of amorphous form IV of calcium salt of obeticholic acid
After 6 months of accelerated testing (test conditions 40. + -. 2 ℃ C., 75%. + -. 5% RH), the results show that: amorphous IV is very stable and the purity of amorphous IV is essentially unchanged, consistently above 99%, no significant degradation impurities are seen and the XRPD pattern is unchanged compared to freshly prepared (0 month) amorphous IV.
Example 9: bioavailability study
Male Sprague-Dawley rats, 7-8 weeks old, weighing about 210g, 6 per group, orally dosed at 30mg/kg of (a) control group: a crystalline Form of obeticholic acid (Form F, see published patent WO2013192097 for preparation methods) or (b) test group: an obeticholic acid salt amorphous form prepared in examples 1-4. The plasma pharmacokinetic differences were compared.
Rats were fed with standard feed and given water. Fasting began 16 hours prior to the experiment. The drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the orbit at 0.083 hr, 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 12 hr and 24 hr post-dose.
The rats were briefly anesthetized after ether inhalation and 300 μ L of blood was collected from the orbit into a test tube. There was 30 μ L of 1% heparin salt solution in the tube. Before use, the tubes were dried overnight at 60 ℃.
Immediately after blood collection, the tubes were gently inverted at least 5 times to ensure mixing and then placed on ice. Blood samples were centrifuged at 5000rpm for 5 minutes at 4 ℃. Aspirate 100 μ L of plasma into a clean plastic centrifuge tube indicating the name of the compound and the time point. Plasma was stored at-80 ℃ before analysis. The concentration of the compounds of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.
From the results, it is seen that the obeticholic acid salt amorphous forms I-IV of the present invention have higher plasma exposure in animals and thus have better pharmacodynamic and therapeutic effects, relative to crystalline forms of obeticholic acid.
Example 10: pharmaceutical composition
50g of amorphous form I of sodium Obeticholic acid or amorphous form II of potassium Obeticholic acid or amorphous form III of magnesium Obeticholic acid or amorphous form IV of calcium Obeticholic acid (examples 1 to 4)
Starch 160g
Microcrystalline cellulose 30g
The materials are evenly mixed according to a conventional method and then are filled into common gelatin capsules to obtain 1000 capsules.
Example 11: pharmaceutical composition
5g of amorphous I or II (example 1-2) of obeticholic acid sodium salt or potassium salt
1000g of water for injection
The above materials are mixed uniformly according to a conventional method to obtain the injection.
Therefore, the amorphous form of the present invention is very suitable for use in pharmaceutical compositions. In addition, the amorphous substance is not easy to raise, collect and waste in the manufacturing process of split charging and other medicines, and is beneficial to protecting the health of operators.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (22)
1. An amorphous form of a salt having the structure of formula X:
wherein the structure of the compound of the formula X is shown as the following formulas I-IV:
wherein, the compound with the structure shown in the formula I is an amorphous substance I, and the X-ray powder diffraction pattern of the amorphous substance I is basically characterized as shown in figure 1 a; the compound with the structure shown in the formula II is an amorphous substance II, and the X-ray powder diffraction pattern of the amorphous substance II is basically characterized as shown in figure 2 a; the compound with the structure shown in the formula I II is an amorphous substance III, and the X-ray powder diffraction pattern of the amorphous substance III is basically characterized as shown in figure 3 a; the compound of formula IV is amorphous form IV having an X-ray powder diffraction pattern substantially as characterized in figure 4 a.
2. The amorphous form of the salt of claim 1 wherein the compound of formula X has the following characteristics: the melting point of the compound of formula X is at least 5-40 ℃ higher than the melting point of obeticholic acid.
3. The amorphous form of the salt of claim 1 wherein the compound of formula X has the following characteristics: the melting point of the compound of formula X is at least 10-40 ℃ higher than the melting point of obeticholic acid.
4. The amorphous form of a salt according to claim 1,
the amorphous I differential scanning calorimetry analysis pattern is substantially as characterized in figure 1 b.
5. The amorphous form of a salt according to claim 1,
the differential scanning calorimetry analysis pattern of amorphous form II is substantially as characterized in FIG. 2 b.
6. The amorphous form of a salt according to claim 1,
the differential scanning calorimetry analysis pattern of amorphous form II is substantially as characterized in FIG. 2 b.
7. The amorphous form of a salt according to claim 1,
the differential scanning calorimetry analysis of amorphous form III is substantially as characterized in FIG. 3 b.
8. The amorphous form of a salt according to claim 1,
the differential scanning calorimetry analysis pattern of amorphous IV is substantially as characterized in FIG. 4 b.
9. The amorphous form of a salt according to claim 1,
the infrared spectrum of the amorphous I is basically characterized as shown in figure 1 d.
10. The amorphous form of a salt according to claim 1,
the infrared spectrum of the amorphous material II is basically characterized as shown in figure 2 d.
11. The amorphous form of a salt according to claim 1,
the infrared spectrum of the amorphous III is basically characterized as shown in figure 3 d.
12. The amorphous form of a salt according to claim 1,
the infrared spectrum of the amorphous material IV is basically characterized as shown in figure 4 d.
13. A process for preparing an amorphous form of the salt of claim 1,
(I) when M is sodium or potassium, the method comprises the steps of:
(1) dissolving obeticholic acid in an inert solvent, adding sodium hydroxide or potassium hydroxide, and concentrating to obtain a solid; and
(2) suspending the solid in an inert solvent and slurrying to obtain an amorphous form of claim 1;
(II) when M is magnesium or calcium, the process comprises the steps of:
(1) dissolving obeticholic acid in a sodium hydroxide or potassium hydroxide aqueous solution, and dissolving; and
(2) adding an aqueous solution of magnesium chloride or an aqueous solution of calcium chloride, stirring to precipitate a solid, and filtering to obtain an amorphous form according to claim 1;
(III) when M is magnesium or calcium, the process comprises the steps of:
(1) dissolving sodium obeticholic acid or potassium obeticholic acid salt in an aqueous solution, and dissolving;
(2) adding an aqueous magnesium chloride solution or an aqueous calcium chloride solution, stirring to precipitate a solid, and filtering to obtain an amorphous form according to claim 1.
14. The method of claim 13, wherein the inert solvent is selected from the group consisting of: refers to methanol, ethanol, isopropanol, acetone, acetonitrile, ethyl acetate, butyl acetate, 1, 4-dioxane, methyl tert-butyl ether, water, and combinations thereof.
15. Use of the amorphous form of claim 1 for the preparation of a farnesoid X receptor agonist and a composition thereof for the prevention or treatment of liver and gall related diseases and cardiovascular diseases.
16. The use of claim 15, wherein the related disease is selected from the group consisting of: non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, gallstone, primary biliary cirrhosis, liver fibrosis, diabetes, atherosclerosis and obesity.
17. A pharmaceutical composition, comprising:
(a) the amorphous form of claim 1; and
(b) a pharmaceutically acceptable carrier.
18. The pharmaceutical composition of claim 17, wherein the mode of administration of the pharmaceutical composition is oral.
19. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is in a solid dosage form.
20. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is selected from the group consisting of: liquid dosage forms for oral administration, compositions for parenteral injection, or amorphous forms for topical administration.
21. The pharmaceutical composition of claim 20, wherein the composition for parenteral injection comprises a sterile powder for reconstitution into a sterile injectable solution or dispersion.
22. Use of a pharmaceutical composition according to claim 17 for the preparation of a medicament for the treatment and/or prevention of: non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, gallstone, primary biliary cirrhosis, liver fibrosis, diabetes, atherosclerosis and obesity.
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| EP1568706A1 (en) * | 2004-02-26 | 2005-08-31 | Intercept Pharmaceuticals, Inc. | Novel steroid agonist for FXR |
| CN101203526A (en) * | 2005-05-19 | 2008-06-18 | 伊莱吉尔瑞公司 | Process for preparing 3alpha(beta)-7alpha(beta)-dihydroxy-6alpha(beta)-alkyl-5beta-cholanic acid |
| WO2013192097A1 (en) * | 2012-06-19 | 2013-12-27 | Intercept Pharmaceuticals, Inc. | Preparation, uses and solid forms of obeticholic acid |
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| WO2002072598A1 (en) * | 2001-03-12 | 2002-09-19 | Roberto Pellicciari | Steroids as agonists for fxr |
| EP1568706A1 (en) * | 2004-02-26 | 2005-08-31 | Intercept Pharmaceuticals, Inc. | Novel steroid agonist for FXR |
| CN101203526A (en) * | 2005-05-19 | 2008-06-18 | 伊莱吉尔瑞公司 | Process for preparing 3alpha(beta)-7alpha(beta)-dihydroxy-6alpha(beta)-alkyl-5beta-cholanic acid |
| WO2013192097A1 (en) * | 2012-06-19 | 2013-12-27 | Intercept Pharmaceuticals, Inc. | Preparation, uses and solid forms of obeticholic acid |
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