CN109896992A - Prepare the method and its application of ionic liquid - Google Patents
Prepare the method and its application of ionic liquid Download PDFInfo
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- CN109896992A CN109896992A CN201711295697.XA CN201711295697A CN109896992A CN 109896992 A CN109896992 A CN 109896992A CN 201711295697 A CN201711295697 A CN 201711295697A CN 109896992 A CN109896992 A CN 109896992A
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Abstract
The invention discloses the method and its application for preparing ionic liquid.Wherein, which includes: to mix chirocaine and salicylic acid compounds with solvent, to obtain mixed solution；The pH value of the mixed solution is adjusted, to obtain the solution after adjusting pH value；L-TARTARIC ACID is mixed and filtered with the solution after the adjusting pH value, to obtain filtered solution；The filtered solution is subjected to extraction processing, to obtain solution extracted；And revolving processing is dried in the solution extracted, to obtain ionic liquid, the ionic liquid includes: chirocaine cation and salicylic acid anion.The ionic liquid that this method is prepared has Levobupivacaine HCL and antipyretic-antalgic dual function.
Description
Technical field
The present invention relates to field of medicaments, and in particular, to the method and its application of ionic liquid is prepared, more specifically, relating to
And prepare the method for ionic liquid and the ionic liquid using this method preparation.
Background technique
Levobupivacaine HCL is the levo form of long-acting amides local anesthetic bupivacaine HCl, is mainly used for surgery
Epidural anesthesia, in March, 2000 show its pharmacological characteristics in U.S.'s Initial Public Offering, through zoopery and clinical application
Similar with Bupivacaine, anesthesia efficiency is close, then after removing R (+) type optical isomer, and nerve and cardiac toxic obviously drop
Low, use is safer, has good application value in clinical treatment.Salicylic acid compounds are using earliest non-steroidal
Anti-inflammatory agent (NSAIDS), clinical use the most extensively and it is lasting be aspirin and salicylic acid, aspirin and salicylic acid exist
It is susceptible to hydrolysis rotten in preparation process, influence the quality of drug.
Chirocaine and salicylic acid compounds have much room for improvement as a result,.
Summary of the invention
The present invention is directed at least solve one of the technical problems existing in the prior art.For this purpose, one object of the present invention
It is to propose a kind of method for preparing ionic liquid, the ionic liquid that this method is prepared is conciliate with Levobupivacaine HCL
Heat analgesia dual function, also, Levobupivacaine HCL is levo form, nerve is low with cardiac toxic, caused by avoiding raceme
Toxic effect.
It should be noted that the present invention is the following work based on inventor and completes:
Ionic liquid refers in room temperature or close to liquid, the salt as composed by zwitterion completely is presented at room temperature,
Referred to as low temperature molten salt.For ionic liquid as ionic compound, lower melting-point main cause is taken because certain in its structure
The asymmetry of Dai Ji prevents ion from being regularly piled into caused by crystal.
Property ionic liquid can be synthesized by adjusting zwitterion by suitable MOLECULE DESIGN, and inventor passes through to a large amount of
Compound is screened, it is found that Levobupivacaine HCL and salicylic acid compounds can form stable ionic liquid, also,
The ionic liquid has Levobupivacaine HCL and antipyretic-antalgic dual function, in addition, ionic liquid is in a liquid state, is convenient for external application,
It can be used for external anti-inflammatory analgetic.Levobupivacaine HCL and salicylic acid compounds ion-exchange reactions it is high-efficient, only
Need 10~60 minutes, generally required more than for 24 hours relative to existing ion-exchange synthesis ionic liquid in addition 2~3 days or
More long generated time, combined coefficient significantly improve.And the method for synthesizing ionic liquid effectively prevents chemical synthesis process
The racemization of middle Levobupivacaine HCL or the problem of change optical activity, the Levobupivacaine HCL in ionic liquid is left-handed
Body, nerve is low with cardiac toxic, avoids toxic effect caused by raceme, and by selecting suitable solvent, extractant and instead
Temperature is answered, salicylic acid compounds is effectively prevented and hydrolyzes generation impurity during the preparation process, influence the quality of drug.
As a result, using chirocaine and salicylic acid compounds as Material synthesis ionic liquid, ion exchange is rapid, synthesis
Time is shorter.The polytropism that obtained ionic liquid eliminates raw material is synthesized, salicylic acid is avoided and is easy decomposed metamorphic
The problem of, while solving the problems, such as that Levobupivacaine HCL optically-active sexually revises.
Thus, according to an aspect of the present invention, the present invention provides a kind of methods for preparing ionic liquid.According to this hair
Bright embodiment, this method comprises: chirocaine and salicylic acid compounds are mixed with solvent, it is molten to obtain mixing
Liquid；The pH value of the mixed solution is adjusted, to obtain the solution after adjusting pH value；After L-TARTARIC ACID and the adjusting pH value
Solution mix and filter, to obtain filtered solution；The filtered solution is subjected to extraction processing, to obtain
Solution extracted；And revolving processing is dried in the solution extracted, to obtain ionic liquid, the ion
Liquid includes: chirocaine cation and salicylic acid anion.
Inventor has surprisingly found that the ionic liquid that this method is prepared has Levobupivacaine HCL and antipyretic-antalgic
Dual function, wherein Levobupivacaine HCL is levo form, and nerve is low with cardiac toxic, and toxicity caused by raceme is avoided to make
With, and avoid salicylic acid compounds and hydrolyze generation impurity during the preparation process, influence the quality of drug.Also, this method
Cost it is low, yield is high, easy to operate.
In addition, ionic liquid according to the above embodiment of the present invention can also have the following additional technical features:
According to an embodiment of the invention, the molar ratio of the chirocaine and the salicylic acid compounds is 1:(0.8
~2.0).
According to an embodiment of the invention, the salicylic acid compounds are salicylic acid and/or acetylsalicylic acid.
According to an embodiment of the invention, the molar ratio of the salicylic acid and the acetylsalicylic acid is (0.8~2.0): 1.
According to an embodiment of the invention, the total concentration of the salicylic acid and the acetylsalicylic acid be 0.1mol/l~
0.5mol/l。
According to an embodiment of the invention, the solvent is selected from acetone, ethyl alcohol, ethyl acetate, water, methanol, methylene chloride
At least one of with chloroform.
According to an embodiment of the invention, the chirocaine and the salicylic acid compounds mix 10 with the solvent
~60 minutes.
According to an embodiment of the invention, the pH value for adjusting the solution after pH value is 6~8.
According to an embodiment of the invention, the method for preparing ionic liquid is carried out under conditions of 0~35 degree Celsius
's.Preferred embodiment in accordance with the present invention, the method for preparing ionic liquid are carried out under conditions of 5~10 degrees Celsius
's.
On this basis, present invention further proposes a kind of ionic liquids.According to an embodiment of the invention, the ion
Liquid is prepared using method above-mentioned, and the ionic liquid includes: chirocaine cation；With salicylic acid yin from
Son.The ionic liquid has Levobupivacaine HCL and antipyretic-antalgic dual function as a result, wherein Levobupivacaine HCL is
Levo form, nerve is low with cardiac toxic, avoids toxic effect caused by raceme, and avoid salicylic acid compounds and preparing
Hydrolysis generates impurity in the process, influences the quality of drug.
According to an embodiment of the invention, the salicylic acid anion is anionic salicylate and/or acetylsalicylic acid yin
Ion.
Additional aspect and advantage of the invention will be set forth in part in the description, and will partially become from the following description
Obviously, or practice through the invention is recognized.
Detailed description of the invention
Above-mentioned and/or additional aspect of the invention and advantage will become from the description of the embodiment in conjunction with the following figures
Obviously and it is readily appreciated that, in which:
Fig. 1 shows the flow diagram of the method according to an embodiment of the invention for preparing ionic liquid；
Fig. 2 shows ionic liquid infrared spectroscopy schematic diagram according to an embodiment of the invention.
Specific embodiment
The embodiment of the present invention is described below in detail, examples of the embodiments are shown in the accompanying drawings, wherein from beginning to end
Same or similar label indicates same or similar element or element with the same or similar functions.Below with reference to attached
The embodiment of figure description is exemplary, and for explaining only the invention, and is not considered as limiting the invention.
In the description of the present invention, term " longitudinal direction ", " transverse direction ", "upper", "lower", "front", "rear", "left", "right", " perpendicular
Directly ", the orientation or positional relationship of the instructions such as "horizontal", "top", "bottom" is to be based on the orientation or positional relationship shown in the drawings, and is only
For ease of description the present invention rather than require the present invention that must be constructed and operated in a specific orientation, therefore should not be understood as pair
Limitation of the invention.
According to an aspect of the present invention, the present invention provides a kind of methods for preparing ionic liquid.What this method obtained
Ionic liquid has Levobupivacaine HCL and antipyretic-antalgic dual function, wherein Levobupivacaine HCL is levo form, nerve
It is low with cardiac toxic, toxic effect caused by raceme is avoided, and avoid salicylic acid compounds and hydrolyze during the preparation process
Impurity is generated, the quality of drug is influenced.Also, the cost of this method is low, and yield is high, easy to operate.
With reference to Fig. 1 according to an embodiment of the invention, the method for preparing ionic liquid is explained, this method packet
It includes:
S100 mixing
According to an embodiment of the invention, chirocaine and salicylic acid compounds are mixed with solvent, obtain mixing molten
Liquid.Chirocaine and salicylic acid compounds are reacted in a solvent as a result, and reaction equation is as follows:
According to an embodiment of the invention, the molar ratio of chirocaine and salicylic acid compounds is 1:(0.8~2.0).
As shown in above-mentioned chemical equation, two chirocaines are in conjunction with two salicylic acid compounds, in the molar ratio
Under can make reaction more thoroughly carry out, keep its conversion ratio higher, the obtained less purity of ionic liquid impurity is higher more stable.
According to an embodiment of the invention, salicylic acid compounds can be salicylic acid and/or acetylsalicylic acid.Salicylic acid and
The antipyretic-antalgic effect of acetylsalicylic acid is good, be it is clinically widely applied represent drug, be with salicylic acid and acetylsalicylic acid
The antipyretic-antalgic effect of raw material, ionic liquid is also preferable.
According to an embodiment of the invention, the molar ratio of salicylic acid and acetylsalicylic acid is (0.8~2.0): 1.Due to acetyl
Salicylic acid is light-exposed or heated easy decomposition generates salicylic acid and acetic acid, and the acetate anion in reaction system can destroy ionic liquid
The balance of middle zwitterion, to influence the degree of reaction, conversion ratio, product purity.And the light-exposed then perishable discoloration of salicylic acid
Influence the appearance color of product.Inventor is the study found that when the molar ratio of salicylic acid and acetylsalicylic acid is (0.8~2.0): 1
When, salicylic acid and acetylsalicylic acid can reach balance in reaction solution system, play the role of inhibiting to decompose, thus, it closes
At the conversion ratio of reaction and the purity is high of product.
According to an embodiment of the invention, the total concentration of salicylic acid and acetylsalicylic acid is 0.1mol/l~0.5mol/l,
That is salicylic acid is 0.1mol/l~0.5mol/l plus the summation of the concentration of acetylsalicylic acid.It can in the concentration range
It is enough to guarantee that reaction be rapidly performed by, reach higher conversion ratio, and can be avoided a large amount of of salicylic acid and acetylsalicylic acid
It decomposes, significant loss and impurity is caused to produce.
Since salicylic acid can be dissolved in respectively in water, ethyl alcohol and acetone；Acetylsalicylic acid is slightly soluble in water, be dissolved in ethyl alcohol, methanol,
Methylene chloride and chloroform；Levobupivacaine HCL is dissolved in water, acetone, ethyl alcohol, methanol, methylene chloride and chloroform.Choosing
It takes one such or several as solvent, be dissolved completely in all reactants can in the solvent, with the shape of zwitterion
State exists in the reaction system, is conducive to more rapid carry out ion exchange, improves the reaction efficiency of synthetic reaction, significant to shorten
Synthesize the time of ionic liquid.According to an embodiment of the invention, solvent can be for selected from acetone, ethyl alcohol, ethyl acetate, water, first
At least one of alcohol, methylene chloride and chloroform.Chirocaine and salicylic acid compounds in a solvent molten as a result,
Solution property is good, and reaction efficiency is high, and the time is short, and the volatility of solvent is good, small toxicity.
According to an embodiment of the invention, chirocaine and salicylic acid compounds mix 10~60 minutes with solvent.By
This, is conducive to chirocaine and salicylic acid compounds sufficiently react, if the time is too short, chirocaine and salicylic acid
The reaction of class compound is incomplete, and the yield of overlong time, chirocaine and salicylic acid compounds ionic liquid is without obvious
It improves, influences production efficiency.
S200 adjusts pH value
According to an embodiment of the invention, adjusting the pH value of mixed solution, obtain adjusting the solution after pH value.It prevents as a result,
Salicylic acid compound ionizes in the solution, and avoiding hydrolysis from generating impurity causes reaction system in buff.
According to an embodiment of the invention, the pH value for adjusting the solution after pH value is 6~8.In the pH value range, salicylic acid
Degree of ionization is low in the solution for compound, and being effectively prevented from hydrolysis generation impurity causes reaction system in buff, reactant
System is in colorless and transparent, and the drug effect of chirocaine and salicylic acid compounds ionic liquid is more preferably.
According to an embodiment of the invention, utilize alkaline solution adjust pH value, wherein the alkaline solution be selected from sodium carbonate,
At least one of sodium bicarbonate and sodium hydroxide.The effect for adjusting pH as a result, is good, does not introduce foreign ion.Specifically, alkaline
Solution can take dropwise addition mode, and rate of addition is 0.5~3s/ drop.PH value to accurately adjust solution is prevented to 6~8
It is added dropwise excessive, causes the pH value of solution excessively high, when pH value not will lead to the partially or completely decomposition of salicylic acid anion at that time,
Keep no product generation or impurity more.
S300 filtering
According to an embodiment of the invention, mixing and filtering L-TARTARIC ACID with the solution after the adjusting pH value, it is obtained
Solution after filter.The a small amount of dextrorotation Bupivacaine by-product generated in reaction is passed through into precipitating by the way that L-TARTARIC ACID is added as a result,
Mode remove.At the same time it can also prevent the aspirin in reaction system from hydrolyzing during washing extraction, hydrolyze
Reaction system be will lead in buff, generate impurity.
S400 extraction
According to an embodiment of the invention, filtered solution is carried out extraction processing, solution extracted is obtained.As a result,
Chirocaine and salicylic acid compounds ionic liquid are separated from reaction solution.
The dry revolving of S500
According to an embodiment of the invention, revolving processing is dried in solution extracted, ionic liquid, the ion are obtained
Liquid includes: chirocaine cation and salicylic acid anion.It is extracted molten by dry revolving processing removal as a result,
Solvent in liquid obtains pure ionic liquid, which is colorless transparent viscous liquid.
The appearance color of the light-exposed then perishable coloured effect product of salicylic acid is chemically reacted as shown in reaction equation 2.Inventor
The study found that cryogenic conditions can inhibit the hydrolysis of salicylic acid compounds to generate the impurity such as acetic acid, and acetate anion meeting
The balance for destroying zwitterion in ionic liquid causes reaction system in buff, and influences the degree of reaction, conversion ratio, medicine
The effect and purity of object.According to an embodiment of the invention, the method for preparing ionic liquid be under conditions of 0~35 degree Celsius into
Capable.The percent hydrolysis of salicylic acid compounds is low as a result, and the color of reaction system is transparent.Preferred embodiment in accordance with the present invention,
The method for preparing ionic liquid is carried out under conditions of 5~10 degrees Celsius.Inhibit the hydrolysis of salicylic acid compounds as a result,
Effect it is good, the color clarity of reaction system is high, and effect of drugs is good.
On this basis, present invention further proposes a kind of ionic liquids.According to an embodiment of the invention, the ionic liquid
Body is prepared using method above-mentioned, which includes: chirocaine cation and salicylic acid anion.By
This, which has Levobupivacaine HCL and antipyretic-antalgic dual function, wherein Levobupivacaine HCL is left-handed
Body, nerve is low with cardiac toxic, avoids toxic effect caused by raceme, and avoid salicylic acid compounds in preparation process
Middle hydrolysis generates impurity, influences the quality of drug.
According to an embodiment of the invention, the molar ratio of chirocaine and salicylic acid anion is 1:(0.8~2.0).
As shown in above-mentioned chemical equation, a chirocaine is in conjunction with two salicylic acid compounds, in the molar ratio
Under can make raw material reaction it is more complete, conversion ratio is higher, and the less purity of ionic liquid impurity made is higher more stable.
According to an embodiment of the invention, salicylic acid anion is anionic salicylate and/or acetyl salicylic acid anion.
The antipyretic-antalgic effect of salicylic acid and acetylsalicylic acid is good, be it is clinically widely applied represent drug, with salicylic acid and acetyl
Salicylic acid is raw material, and the antipyretic-antalgic effect of ionic liquid is also preferable.
According to an embodiment of the invention, the molar ratio of anionic salicylate and acetyl salicylic acid anion be (0.8~
2.0): 1.Since acetylsalicylic acid is light-exposed or heated easy decomposition generates salicylic acid and acetic acid, acetic acid can destroy negative in ionic liquid
The balance of cation, to influence the degree of reaction, conversion ratio, product purity.And the light-exposed then perishable coloured effect of salicylic acid
The color of product.Inventor is the study found that when the molar ratio of salicylic acid and acetylsalicylic acid is (0.8~2.0): when 1, salicylic acid
Balance can be reached in reaction solution system with acetylsalicylic acid, play the role of inhibiting to decompose, thus, synthetic reaction turns
The purity is high of rate and product.
Below with reference to specific embodiment, the present invention will be described, it should be noted that these embodiments are only explanation
Property, and be not considered as limiting the invention.
The solution of the present invention is explained below in conjunction with embodiment.It will be understood to those of skill in the art that following
Embodiment is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.Particular technique or item are not specified in embodiment
Part, it described technology or conditions or is carried out according to the literature in the art according to product description.Agents useful for same or instrument
Production firm person is not specified in device, and being can be with conventional products that are commercially available.
Embodiment 1
Chirocaine-salicylic acid ionic liquid is prepared using the method for the embodiment of the present invention, the specific method is as follows:
1. taking in 4.87g Levobupivacaine HCL, 1.80g aspirin and 0.69g salicylic acid investment 500ml ethanol solution
Stirring and dissolving 40 minutes.
2. controlling reaction temperature at 20 DEG C, 75ml concentration is slowly added dropwise thereto as 2mol/l with the speed of 0.5s/ drop
Na2CO3Solution.After being added dropwise, 15min is stirred, detection solution ph is 7.2, and solution is colorless and transparent.
3. 2.25g is added into the solution of step 2, L-TARTARIC ACID is added acetone stirring, there is a small amount of Precipitation, filters.
4. the extraction of 200ml ethyl acetate is added into the filtrate of step 3, by the 30 DEG C of decompression rotations of extraction gained ethyl acetate layer
It steams to get colorless and transparent thick ionic liquid, which is chirocaine-salicylic acid ionic liquid.
5. the chirocaine that pair step 4 obtains-salicylic acid ionic liquid carries out analysis detection, as a result as follows:
(1) infrared spectroscopy:
Infrared chromatography detection is carried out to the ionic liquid, the map of infrared spectroscopy is as shown in Fig. 2, spectrum resolution is as follows:
Table 1
Parsing
A.2500 the big wide OH stretching vibration for absorbing mainly carboxyl of above V-shaped, then there is the methyl CH more than 3000
With more than 2800 phenyl ring CH stretching vibration；
It b.1672,1558 is C=O stretching vibration；
C.1457, phenyl ring skeletal vibration；
D.757, phenyl ring contraposition replaces；
e.1672cm-1: C=O stretching vibration；1273cm-1: C-N stretching vibration, it was demonstrated that amide containing structure in this product structure；
F.1588,1457cm-1: C=C skeleton stretching vibration, 757,732,702cm-1:=C-H out-of-plane bending vibration, card
Structure containing substituted benzene in bright this product structure；
g.2930cm-1: C-H stretching vibration, 1457,1374cm-1: C-H bending vibration, show in this product structure containing methyl,
Methylene based structures；
By infrared spectroscopy it is found that structures such as amide containing, substituted benzene, methyl and methylene, phenyl ring, carboxyl in this product structure.
Above-mentioned infrared data is consistent with Levobupivacaine HCL and acetylsalicylic acid salicylic acid, structure.
(2) optically-active detects
The ionic liquid optical activity are as follows:
Optical activity is measured at the D line 589.3nm of sodium spectrum using WXG-4 type circle polarimeter by States Pharmacopoeia specifications
Specific rotation is calculated as follows:
Wherein L is measurement pipe range 1dm to solid test sample [α]=100 α/LxC, and C is the concentration g/100mL of solution.
ρ is the density of liquid in liquid test sample [α]=α/Lx ρ formula, and it is 1.083g/ml which, which measures density,.
2. ionic liquid product specific rotation of table
By the measurement to raw material Levobupivacaine HCL and ionic liquid product optical activity show product ion liquid and
Raw material optical activity is negative value, i.e., product is also levo form, remains the original medicinal effects of Levobupivacaine HCL.Due to original
Medicine is expected there are polytropism, polytropism will lead to substance of the same race and show different physics, chemical property, this
The ionic liquid of embodiment synthesis changes the state of raw material reactant, effectively prevents polytropism.Meanwhile Bu Bika
Because being a kind of potent local anesthetics of amide derivatives, but easily cause the side effects such as myocardiac inhibition, Refractory Arrhythmias, Central nervous system
System also has certain toxicity.Its toxicity is mainly caused by R (+) type optical isomer, and S (-) type optical isomer toxicity is smaller.Hydrochloric acid
Chirocaine is Bupivacaine S (-) type optical isomer, which effectively prevents Levobupivacaine HCL and be converted into
Dextrorotation Bupivacaine, so as to avoid toxicity problem caused by R (+) type optical isomer.Further, since the water such as acetylsalicylic acid
Easy decomposed metamorphic, the ionic liquid further improve the labile problem of Salicylates to poplar acids drug in the solution.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show
The description of example " or " some examples " etc. means specific features, structure, material or spy described in conjunction with this embodiment or example
Point is included at least one embodiment or example of the invention.In the present specification, schematic expression of the above terms are not
Centainly refer to identical embodiment or example.Moreover, particular features, structures, materials, or characteristics described can be any
One or more embodiment or examples in can be combined in any suitable manner.
Although an embodiment of the present invention has been shown and described, it will be understood by those skilled in the art that: not
A variety of change, modification, replacement and modification can be carried out to these embodiments in the case where being detached from the principle of the present invention and objective, this
The range of invention is defined by the claims and their equivalents.
Claims (10)
1. a kind of method for preparing ionic liquid characterized by comprising
Chirocaine and salicylic acid compounds are mixed with solvent, to obtain mixed solution；
The pH value of the mixed solution is adjusted, to obtain the solution after adjusting pH value；
L-TARTARIC ACID is mixed and filtered with the solution after the adjusting pH value, to obtain filtered solution；
The filtered solution is subjected to extraction processing, to obtain solution extracted；And
Revolving processing is dried in the solution extracted, to obtain ionic liquid, the ionic liquid includes: left cloth
Than cacaine cation and salicylic acid anion.
2. the method according to claim 1, wherein the chirocaine and the salicylic acid compounds
Molar ratio is 1:(0.8~2.0).
3. the method according to claim 1, wherein the salicylic acid compounds are salicylic acid and/or acetyl
Salicylic acid.
4. according to the method described in claim 3, it is characterized in that, the molar ratio of the salicylic acid and the acetylsalicylic acid is
(0.8~2.0): 1.
5. method according to claim 11 body, which is characterized in that the total concentration of the salicylic acid and the acetylsalicylic acid
For 0.1mol/l~0.5mol/l.
6. the method according to claim 1, wherein the solvent be selected from acetone, ethyl alcohol, ethyl acetate, water,
At least one of methanol, methylene chloride and chloroform.
7. the method according to claim 1, wherein the chirocaine and the salicylic acid compounds with
The solvent mixes 10~60 minutes.
8. the method according to claim 1, wherein the pH value for adjusting the solution after pH value is 6~8.
9. the method according to claim 1, wherein the method for preparing ionic liquid is Celsius 0~35
It is carried out under conditions of degree, it is preferable that be 5-10 degrees Celsius.
10. a kind of ionic liquid, which is characterized in that the ionic liquid is to utilize according to any one of claims 1 to 99 described in any item methods
Preparation, the ionic liquid includes:
Chirocaine cation；With
Salicylic acid anion,
Optionally, the salicylic acid anion is anionic salicylate and/or acetyl salicylic acid anion.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4043007A4 (en) * | 2019-10-11 | 2023-11-08 | Toray Industries, Inc. | Pharmaceutical composition including temperature-responsive ionic liquid |
| CN114306713A (en) * | 2021-12-06 | 2022-04-12 | 武汉软件工程职业学院 | Absorbable hemostatic wound-protecting dressing and preparation method thereof |
| CN114306713B (en) * | 2021-12-06 | 2022-08-12 | 武汉软件工程职业学院 | Absorbable hemostatic wound-protecting dressing and preparation method thereof |
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