CN109776649A - A kind of refining methd of natrium taurocholicum - Google Patents
A kind of refining methd of natrium taurocholicum Download PDFInfo
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- CN109776649A CN109776649A CN201910195136.5A CN201910195136A CN109776649A CN 109776649 A CN109776649 A CN 109776649A CN 201910195136 A CN201910195136 A CN 201910195136A CN 109776649 A CN109776649 A CN 109776649A
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Abstract
The invention discloses a kind of refining methd of natrium taurocholicum, this method natrium taurocholicum crude product dissolves in alcohols solvent, and esters solvent is added while hot, filters after cooling, is dried under reduced pressure to obtain the natrium taurocholicum of high-purity.Compared with prior art, the present invention has the advantage that refining methd is easy to operate, the relatively higher esters solvent of boiling point is used, solvent volatilization can be reduced, avoid the acetone and low boiling point ether using irritant smell, it is safer in operation, it is convenient for industrialized production；This method high income and good product purity; yield >=91%; natrium taurocholicum purity area normalization method detection 100% after purification; ELSD detects HPLC purity >=99.00%; wherein HPLC purity reaches as high as 99.91%, single miscellaneous A content < 0.30%, impurity B content < 0.8%; and dopant species significantly reduce, the final products after purification C free from foreign meter and impurity D.
Description
Technical field
The invention belongs to field of medicinal chemistry, and in particular to a kind of refining methd of natrium taurocholicum.
Background technique
Taurocholate (taurocholic acid, TCA) be primary bile acid in fel bovis and its effective component it
One.It is to combine a kind of conjugated bile acids formed by cholic acid and taurine.It is dynamic that TCA is widely present in ox, sheep, snake, rabbit etc.
In the bile of object, it is important effective component.To its pharmacodynamic study show the substance have cholagogue, antibechic, eliminating the phlegm, relieving asthma
Effect, while have the effects that sterilization it is anti-inflammatory.Also have an impact to cardiovascular system, it can be with blood pressure lowering, reduction heart contraction width
Degree and frequency, it has been reported that it also has certain therapeutic effect to cancer.It can be seen that taurocholate has development and application prospect
Drug.
The chemical name of taurocholate be 3 α, 7 α, -5 β of 12 α-trihydroxy-cholestane -24- carboxylic acid -24- taurine amide,
Molecular formula is C26H45NO7S, molecular weight 515.6, be pale yellow powder, odorless is water-soluble, be soluble in chloroform, methanol,
In the organic solvents such as ethyl alcohol, isopropanol.The structure of natrium taurocholicum is as follows:
Currently, both at home and abroad by purification after taurocholate or Taurocholic acid sodium salt (cholic acid conjugate), yield is low, purity
It is low.Existing document CN101307088B, CN101503454A, CN103755764B disclose the refining methd of cholic acid conjugate.This
A little refining methds can be divided into following several:
Method one: CN101503454A
The ethyl acetate concentrate of cholic acid conjugate is adjusted to pH 1~2 with concentrated hydrochloric acid and a small amount of crystal seed is added, and stirs in 0~5 DEG C
2h is mixed, filters, a small amount of acetone washing of filter cake, then dissolved with acetone-water single_phase system, it is white to be recrystallized to give taurocholate
Color powder, yield only 78.7%.
Method two: CN101307088B
Taurocholate is dissolved in the methanol aqueous solution containing sodium bicarbonate, and ether is then added, and cooling crystallization obtains ox sulphur
The sodium salt of cholic acid.
Method three: CN103755764B
Methanol rising temperature for dissolving is added in cholic acid conjugate, and acetone is added, and stirs decrease temperature crystalline.
Report these methods used common disadvantage is that yield is not high, only 90% or less；Purity is low, HPLC area
Normalization method detection only 99% or less.The commercially available cholic acid conjugate of purchase is detected using ELSD detector, purity is general only
Have 90% hereinafter, dopant species are more, such as contains impurity A (a molecule cholic acid reacts generation with a molecule natrium taurocholicum), B simultaneously
(sodium taurochenodeoxycholate), C (sodium taurodeoxycholate) and D (other unknown impurities), and single miscellaneous content is high.Wherein impurity A
For new impurity, structural formula is as follows:
Therefore, this field still needs to develop easy to operate, high income, the refining methd of purity is high.
Summary of the invention
Place that purpose of the invention is to overcome the shortcomings in the prior art, provides a kind of purification of natrium taurocholicum
New process solves the problems, such as that yield existing in the prior art is low, purity is not high.
In order to achieve the above object, the present invention uses following scheme, a kind of refining method of natrium taurocholicum: by ox sulphur
Sodium taurocholate crude product is added in alcohols solvent, is warming up to 40-60 DEG C, and stirring and dissolving is added esters solvent, is added dropwise, is cooled to
0-40 DEG C of crystallization, filtering, is dried to obtain the natrium taurocholicum of purification.
Good solvent of the alcohols solvent of the present invention in mixed solvent recrystallization system as natrium taurocholicum, it is main
It is used to dissolve natrium taurocholicum.
Poor solvent of the heretofore described esters solvent in mixed solvent recrystallization system as natrium taurocholicum,
It is primarily to facilitate the crystallization of natrium taurocholicum.
As a further improvement of the present invention, the alcohols solvent includes methanol, ethyl alcohol, propyl alcohol or butanol；The esters
Solvent includes methyl acetate, ethyl acetate, propyl acetate, butyl acetate, ethyl propionate, ethyl butyrate or ethyl valerate；It is described
Alcohols solvent is more preferably methanol or ethyl alcohol；The esters solvent is more preferably methyl acetate or ethyl acetate.
As a further improvement of the present invention, wherein the volume mass ratio of alcohols solvent and natrium taurocholicum crude product is 2:1
The volume mass ratio of~10:1, esters solvent and natrium taurocholicum crude product is 2:1~20:1.
As a further improvement of the present invention, wherein the volume mass of alcohols solvent and natrium taurocholicum crude product ratio is further
Preferably 3:1~6:1.The volume mass of esters solvent and natrium taurocholicum crude product is than being more preferably 4:1~8:1.
As a further improvement of the present invention, wherein the solution temperature of natrium taurocholicum crude product is more preferably 50-55
℃。
As a further improvement of the present invention, wherein further preferred 20-30 DEG C of the crystallization temperature of natrium taurocholicum.
As a further improvement of the present invention, wherein ethyl acetate is added to the first of natrium taurocholicum crude product in a manner of being added dropwise
In alcoholic solution, further preferably alcohols solvent alcohol solution that 40-60 DEG C of natrium taurocholicum crude product is added in a manner of being added dropwise
In.
As a further improvement of the present invention, wherein ethyl acetate: methanol: the volume mass ratio of natrium taurocholicum crude product is
6:4:1(v/v/w)。
As a further improvement of the present invention, natrium taurocholicum crude product of the present invention can be prepared as follows,
Include the following steps:
(a) by N, N '-dimethyl formamide is added in reaction kettle, is warming up to 70~110 DEG C, puts into cholic acid, stirring is to admittedly
All dissolution obtains reaction solution to body；2- ethyoxyl -1- ethoxy carbonic acyl radical -1,2- dihydroquinoline is added into above-mentioned reaction solution
(EEDQ), triethylamine (TEA) and taurine are stirred to react 0.5~4h at 70~110 DEG C；
(b) it is cooled to after room temperature and methyl tertiary butyl ether(MTBE) precipitation solid, filtering is added into reaction kettle；Obtained solid is dissolved in
In methanol, sodium hydroxide is added, is stirred at room temperature, methyl tertiary butyl ether(MTBE) is added into reaction kettle, filter, 50~70 DEG C of vacuum are dry
It is dry, obtain natrium taurocholicum crude product；
(c) above-mentioned natrium taurocholicum crude product is added in methanol, is warming up to 40-60 DEG C, then acetic acid is added in stirring and dissolving
Ethyl ester is cooled to 0-40 DEG C of crystallization, and filtering is dried to obtain the natrium taurocholicum of purification.
Wherein the structure of cholic acid is as follows:
The route for preparing natrium taurocholicum from cholic acid is as follows:
Natrium taurocholicum crude product of the present invention oneself can be prepared, and commercially available or food grade materials can also be bought.Its
His raw material be all it is conventional use of, can be bought from market.
The present invention uses liquid chromatography testing product purity, and wherein detector is evaporative light scattering detector (ELSD).
Compared with prior art, relatively higher using boiling point the present invention has the advantage that refining methd is easy to operate
Esters solvent can reduce solvent volatilization, avoid the acetone and low boiling point ether using irritant smell, more pacify in operation
Entirely, it is convenient for industrialized production；This method high income and good product purity, yield >=91%, the natrium taurocholicum purity after purification
Area normalization method detects 100%, ELSD and detects HPLC purity >=99.00%, and wherein HPLC purity reaches as high as 99.91%,
Single miscellaneous A content < 0.30%, impurity B content < 0.8%, and dopant species significantly reduce, and the final products after purification are free of
Impurity C and impurity D.
Detailed description of the invention
Fig. 1 is the HPLC map of two products obtained therefrom of embodiment.
Fig. 2 is the mass spectrogram of two gained impurity A of embodiment.
Fig. 3 is the HPLC map of three products obtained therefrom of embodiment.
Fig. 4 is the HPLC map of example IV products obtained therefrom.
Fig. 5 is the HPLC map of five products obtained therefrom of embodiment.
Fig. 6 is the HPLC map of six products obtained therefrom of embodiment.
Fig. 7 is the HPLC map of seven products obtained therefrom of embodiment.
Fig. 8 is the HPLC map of eight products obtained therefrom of embodiment.
Fig. 9 is the HPLC map of nine products obtained therefrom of embodiment.
Figure 10 is the HPLC map of one products obtained therefrom of comparative example.
Specific embodiment
Embodiment one:
The preparation of natrium taurocholicum: measuring 5L N, and N '-dimethyl formamide is added in reaction kettle, is warming up to 90 DEG C, investment
Cholic acid, stirring to solid are all dissolved.0.7kg 2- ethyoxyl -1- ethoxy carbonic acyl radical -1,2- dihydroquinoline, 0.3kg tri- is added
Ethamine, 0.36kg taurine are stirred to react 2h at 90 DEG C.The addition 25L methyl tertiary butyl ether(MTBE) into reaction kettle is cooled to after room temperature
Solid, filtering is precipitated.Obtained solid is dissolved in 5L methanol, 0.07kg sodium hydroxide is added, 1h is stirred at room temperature.Into reaction kettle
25L methyl tertiary butyl ether(MTBE), filtering is added, 60 DEG C of vacuum drying obtain natrium taurocholicum crude product.
Embodiment two:
20g natrium taurocholicum crude product (self-control, HPLC content 93.78%, largest single impurity are added in 250ml reaction flask
2.53%) 50 DEG C of dissolutions and 80ml methanol, are heated to, 120ml ethyl acetate is added while hot, is cooled to 25 DEG C of stirred crystallizations, mistake
Filter, is dried under reduced pressure to obtain natrium taurocholicum finished product 18.2g, yield 91%, HPLC content 99.91%, largest single impurity A content
0.09%.As shown in Fig. 1: the peak that appearance time is 9.96min is natrium taurocholicum, and the peak that appearance time is 20.04min is
Impurity A, mass spectrum is as shown in Fig. 2, molecular weight is 904.59.
Embodiment three:
20g natrium taurocholicum crude product (self-control, HPLC purity 93.78%, largest single impurity are added in 250ml reaction flask
2.53%) 50 DEG C of dissolutions and 60ml methanol, are heated to, 120ml ethyl acetate is added while hot, is cooled to 25 DEG C of stirred crystallizations, mistake
Filter, be dried under reduced pressure natrium taurocholicum finished product 19g, yield 95%, HPLC content 99.71%, largest single impurity B content are
0.29%.As shown in Fig. 3: the peak that appearance time is 9.77min is natrium taurocholicum, and the peak that appearance time is 11.43min is
Impurity B: sodium taurochenodeoxycholate.
Example IV:
20g natrium taurocholicum crude product (self-control, HPLC purity 93.78%, largest single impurity are added in 250ml reaction flask
2.53%) 55 DEG C of dissolutions and 120ml methanol, are heated to, 160ml ethyl acetate is added while hot, is cooled to 20 DEG C of stirred crystallizations, mistake
Filter, is dried under reduced pressure to obtain natrium taurocholicum finished product 18.8g, yield 94%.As shown in Fig. 4: the peak that appearance time is 9.72min is
Natrium taurocholicum, HPLC purity 99.00%；The peak that appearance time is 11.44min is impurity B: sodium taurochenodeoxycholate contains
Amount is 0.73%；The peak that appearance time is 17.70min is impurity A, content 0.27%.
Embodiment five:
20g natrium taurocholicum crude product (self-control, HPLC purity 93.78%, largest single impurity are added in 250ml reaction flask
2.53%) 40 DEG C of dissolutions and 200ml methanol, are heated to, 400ml ethyl acetate is added while hot, is cooled to 0 DEG C of stirred crystallization, mistake
Filter, is dried under reduced pressure to obtain natrium taurocholicum finished product 18.6g, yield 93%.As shown in Fig. 5: the peak that appearance time is 9.44min is
Natrium taurocholicum, HPLC purity 99.00%；The peak that appearance time is 11.45min is impurity B: sodium taurochenodeoxycholate contains
Amount is 0.71%；The peak that appearance time is 17.71min is impurity A, content 0.26%.
Embodiment six:
20g natrium taurocholicum crude product (self-control, HPLC purity 93.78%, largest single impurity are added in 250ml reaction flask
2.53%) 60 DEG C of dissolutions and 40ml methanol, are heated to, 40ml ethyl acetate is added while hot, is cooled to 30 DEG C of stirred crystallizations, mistake
Filter, is dried under reduced pressure to obtain natrium taurocholicum finished product 18.4g, yield 92%.As shown in Fig. 6: the peak that appearance time is 9.65min is
Natrium taurocholicum, HPLC purity 99.01%；The peak that appearance time is 11.44min is impurity B: sodium taurochenodeoxycholate contains
Amount is 0.71%；The peak that appearance time is 17.70min is impurity A, content 0.28%.
Embodiment seven:
20g natrium taurocholicum crude product (self-control, HPLC content 93.78%, largest single impurity are added in 250ml reaction flask
2.53%) 50 DEG C of dissolutions and 80ml ethyl alcohol, are heated to, 120ml methyl acetate is added while hot, is cooled to 25 DEG C of stirred crystallizations, mistake
Filter, is dried under reduced pressure to obtain natrium taurocholicum finished product 18.8g, yield 94%.As shown in Fig. 7: the peak that appearance time is 9.43min is
Natrium taurocholicum, HPLC purity 99.00%；The peak that appearance time is 11.44min is impurity B: sodium taurochenodeoxycholate contains
Amount is 0.72%；The peak that appearance time is 17.69min is impurity A, content 0.28%.
Embodiment eight:
20g natrium taurocholicum crude product (self-control, HPLC content 93.78%, largest single impurity are added in 250ml reaction flask
2.53%) 50 DEG C of dissolutions and 80ml propyl alcohol, are heated to, 120ml propyl acetate is added while hot, is cooled to 25 DEG C of stirred crystallizations, mistake
Filter, is dried under reduced pressure to obtain natrium taurocholicum finished product 18.4g, yield 92%.As shown in Fig. 8: the peak that appearance time is 9.57min is
Natrium taurocholicum, HPLC purity 99.00%；The peak that appearance time is 11.45min is impurity B: sodium taurochenodeoxycholate contains
Amount is 0.73%；The peak that appearance time is 17.70min is impurity A, content 0.27%.
Embodiment nine:
20g natrium taurocholicum crude product (self-control, HPLC content 93.78%, largest single impurity are added in 250ml reaction flask
2.53%) 50 DEG C of dissolutions and 80ml butanol, are heated to, 120ml ethyl propionate is added while hot, is cooled to 25 DEG C of stirred crystallizations, mistake
Filter, is dried under reduced pressure to obtain natrium taurocholicum finished product 18.6g, yield 93%.As shown in Fig. 9: the peak that appearance time is 9.43min is
Natrium taurocholicum, HPLC purity 99.00%；The peak that appearance time is 11.44min is impurity B: sodium taurochenodeoxycholate contains
Amount is 0.72%；The peak that appearance time is 17.69min is impurity A, content 0.28%.
Comparative example one:
The method according to disclosed in CN103755764B, in 250ml reaction flask be added 20g natrium taurocholicum crude product (self-control,
HPLC purity 93.78%, largest single impurity 2.53%) and 80ml methanol, 50 DEG C of dissolutions are heated to, 120ml acetone, drop are added while hot
Temperature is to 25 DEG C of stirred crystallizations, filtering, is dried under reduced pressure to obtain natrium taurocholicum finished product 18.4g, yield 92%, HPLC content 98.39%,
Largest single impurity B content is 0.70%.As shown in Fig. 10: the peak that appearance time is 9.97min is natrium taurocholicum, appearance time
Peak for 11.82min is impurity B sodium taurochenodeoxycholate；The peak that appearance time is 12.22min is impurity C ox sulphur deoxidation gallbladder
Sour sodium, content 0.11%；The peak that appearance time is 14.10min is unknown impuritie D, content 0.04%；Appearance time is
The peak of 17.94min is that a molecule cholic acid reacts the impurity A generated, content 0.27% with a molecule natrium taurocholicum.
Comparative example two:
The method according to disclosed in CN101503454A, in 250ml reaction flask be added 20g natrium taurocholicum crude product (self-control,
HPLC purity 93.78%, largest single impurity 2.53%), 185ml acetone and 15ml water is added, is heated to 50 DEG C of dissolutions, is cooled to 25
DEG C stirred crystallization, filtering, is dried under reduced pressure, and obtains natrium taurocholicum finished product 15g, yield 75%, HPLC content only 94.9%.
Comparative example three:
20g taurocholate crude product is added in 250ml reaction flask, is dissolved in for the method according to disclosed in CN101307088B
It in 1.7g sodium bicarbonate and 50ml methanol mixed solution, is stirred at room temperature 10 minutes, 100ml ether, 0 DEG C of cool overnight, mistake is added
Filter washs filter cake with a small amount of ice-cold ether, dry, obtains 18.3g taurocholate white solid powder, yield 88%, HPLC contains
Amount only 78.5%.
Basic principles and main features and advantages of the present invention of the invention have been shown and described above.The skill of the industry
Art personnel it should be appreciated that the present invention is not limited to the above embodiments, the above embodiments and description only describe
The principle of the present invention, without departing from the spirit and scope of the present invention, various changes and improvements may be made to the invention, these
Changes and improvements will be fallen into scope of the claimed invention.The claimed scope of the invention is by appended claims
And its equivalent thereof.
Claims (10)
1. a kind of refining methd of natrium taurocholicum, it is characterised in that: natrium taurocholicum crude product is added in alcohols solvent, heating
To 40-60 DEG C, then esters solvent is added in stirring and dissolving, is cooled to 0-40 DEG C of crystallization, and filtering is dried to obtain the ox sulphur of purification
Sodium taurocholate, structure are as follows:
2. refining methd according to claim 1, it is characterised in that: the alcohols solvent include methanol, ethyl alcohol, propyl alcohol or
Butanol；The esters solvent include methyl acetate, ethyl acetate, propyl acetate, butyl acetate, ethyl propionate, ethyl butyrate or
Ethyl valerate.
3. refining methd according to claim 2, it is characterised in that: the alcohols solvent includes methanol or ethyl alcohol；It is described
Esters solvent includes methyl acetate or ethyl acetate.
4. refining methd according to claim 1, it is characterised in that: the body of the alcohols solvent and natrium taurocholicum crude product
Mass ratio is accumulated as 2:1~10:1, the volume mass ratio of esters solvent and natrium taurocholicum crude product is 2:1~20:1.
5. refining methd according to claim 4, it is characterised in that: the body of the alcohols solvent and natrium taurocholicum crude product
Mass ratio is accumulated as 3:1~6:1, the volume mass ratio of esters solvent and natrium taurocholicum crude product is 4:1~8:1.
6. refining methd according to claim 1, it is characterised in that: the solution temperature of the natrium taurocholicum crude product is
50-55℃。
7. refining methd according to claim 1, it is characterised in that: the crystallization temperature of the natrium taurocholicum is 20-30
℃。
8. refining methd according to claim 1, it is characterised in that: the alcohols solvent is added to 40- in a manner of being added dropwise
In the alcohol solution of 60 DEG C of natrium taurocholicum crude products.
9. refining methd according to claim 1, it is characterised in that: the ethyl acetate: methanol: natrium taurocholicum crude product
Volume mass ratio be 6:4:1 (v/v/w).
10. refining methd according to claim 1, it is characterised in that include the following steps:
(a) by N, N '-dimethyl formamide is added in reaction kettle, is warming up to 70~110 DEG C, puts into cholic acid, is stirred complete to solid
It dissolves to obtain reaction solution in portion；2- ethyoxyl -1- ethoxy carbonic acyl radical -1,2- dihydroquinoline, triethylamine are added into above-mentioned reaction solution
And taurine, 0.5~4h is stirred to react at 70~110 DEG C；
(b) it is cooled to after room temperature and methyl tertiary butyl ether(MTBE) precipitation solid, filtering is added into reaction kettle；Obtained solid is dissolved in methanol
In, sodium hydroxide is added, is stirred at room temperature, methyl tertiary butyl ether(MTBE) is added into reaction kettle, filters, 50~70 DEG C of vacuum drying obtain
Natrium taurocholicum crude product；
(c) above-mentioned natrium taurocholicum crude product is added in methanol, is warming up to 40-60 DEG C, then acetic acid second is added in stirring and dissolving
Ester is cooled to 0-40 DEG C of crystallization, and filtering is dried to obtain the natrium taurocholicum of purification；
Wherein the structure of cholic acid is as follows:
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910195136.5A CN109776649A (en) | 2019-03-14 | 2019-03-14 | A kind of refining methd of natrium taurocholicum |
| PCT/CN2020/088510 WO2020182228A1 (en) | 2019-03-14 | 2020-04-30 | Method of refining sodium taurocholate |
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| CN201910195136.5A CN109776649A (en) | 2019-03-14 | 2019-03-14 | A kind of refining methd of natrium taurocholicum |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020182228A1 (en) * | 2019-03-14 | 2020-09-17 | 美药星（南京）制药有限公司 | Method of refining sodium taurocholate |
| CN113583079A (en) * | 2021-08-02 | 2021-11-02 | 武汉轻工大学 | Synthetic method of sodium taurocholate and pharmaceutical preparation |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04169597A (en) * | 1990-10-31 | 1992-06-17 | Tokyo Tanabe Co Ltd | Purification of taurine-conjugation-type bile acid |
| CN101307088A (en) * | 2008-07-08 | 2008-11-19 | 四川大学 | Method for preparing cholic acid conjugates |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109776649A (en) * | 2019-03-14 | 2019-05-21 | 美药星（南京）制药有限公司 | A kind of refining methd of natrium taurocholicum |
-
2019
- 2019-03-14 CN CN201910195136.5A patent/CN109776649A/en active Pending
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2020
- 2020-04-30 WO PCT/CN2020/088510 patent/WO2020182228A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04169597A (en) * | 1990-10-31 | 1992-06-17 | Tokyo Tanabe Co Ltd | Purification of taurine-conjugation-type bile acid |
| CN101307088A (en) * | 2008-07-08 | 2008-11-19 | 四川大学 | Method for preparing cholic acid conjugates |
Non-Patent Citations (3)
| Title |
|---|
| FRANCESCO VENTURONI: "Continuous flow synthesis and scale-up of glycine- and taurine-conjugated bile salts", 《ORGANIC ＆ BIOMOLECULAR CHEMISTRY》 * |
| 李沙: "牛磺胆汁酸钠的合成及其镇咳、祛痰作用比较", 《同济医科大学学报》 * |
| 杨健: "牛磺胆酸钠的合成", 《中国医药工业杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020182228A1 (en) * | 2019-03-14 | 2020-09-17 | 美药星（南京）制药有限公司 | Method of refining sodium taurocholate |
| CN113583079A (en) * | 2021-08-02 | 2021-11-02 | 武汉轻工大学 | Synthetic method of sodium taurocholate and pharmaceutical preparation |
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| Publication number | Publication date |
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| WO2020182228A1 (en) | 2020-09-17 |
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Application publication date: 20190521 |