CN108096190B - Quzhazhigan long-circulating liposome and preparation method thereof - Google Patents
Quzhazhigan long-circulating liposome and preparation method thereof Download PDFInfo
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Abstract
The invention relates to the technical field of medicines, in particular to a quzhazhigan long-circulating liposome and a preparation method thereof. The Quzhazhigan long-circulating liposome provided by the invention comprises Quzhazhigan, phospholipid, cholesterol and Tween-80. Also comprises a freeze-drying protective agent lactose. The formula is reasonable, and the encapsulation and the controlled release of the medicine can be realized. In addition, the invention also provides a preparation method of the Quzhazhigan long-circulating liposome, and the process adopts a film dispersion method, is simple to operate and has proper parameters, so that ideal encapsulation efficiency and liposome morphology are obtained. Experiments show that the liposome provided by the invention is spherical or sphere-like under a transmission electron microscope, has good dispersibility, a Zeta potential of-39.34 mV, an average particle size of 161.95nm, a dispersion index PDI of 0.3097 and an entrapment rate of 54.5%. After freeze-drying and rehydration, the properties are still stable.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a quzhazhigan long-circulating liposome and a preparation method thereof.
Background
Quzhazlactone (Piceatannol-3 '-O-beta-D-glucopyranoside), also known as Piceatannol-3' -O-beta-glucopyranoside, is an effective component extracted, separated and purified from the root or rhizome of Rheum lhasaense A.J.Li et P.K.Hsiao, a plant of Polygonaceae. Quzhazhigan is the active ingredient of natural medicine, and the pharmacodynamics research before clinic shows that it can effectively block many links of cerebral ischemia pathological mechanism, and the action range covers the blood vessel-nerve unit, and also has the regulation function (inhibiting ACE, protecting the function of blood vessel endothelium, inhibiting the aggregation of blood platelet, reducing the blood viscosity) to the peripheral body circulation system, thus having stronger anti-cerebral ischemia function. Research shows that the quzhazhigan has a certain protection effect on a rat focal cerebral ischemia reperfusion injury model induced by a wire embolism method, can obviously reduce the cerebral infarction percentage and improve the ethological score, and has the effect equivalent to that of edaravone.
However, the treatment time window of the model of the thrombus-induced rat focal cerebral ischemia-reperfusion injury is within 3 hours when the quzhazhigan is administered for multiple times, and the administration 6 hours after ischemia has no obvious reduction effect on the percent of cerebral infarction. After the rats are injected with 1, 3 and 9mg/kg of Quzhazhigan by vein, the elimination half-life of the Quzhazhigan in plasma is 18-32.7 min. The distribution of the quzhazhigan in the rat brain is increased to a certain extent, the quzhazhigan can be detected in the brain after the rat is injected with the quzhazhigan for 5min intravenously, but the content of the quzhazhigan in the brain is rapidly reduced along with the reduction of blood concentration. Therefore, the half-life period of the quzhazhigan is prolonged, the distribution of the quzhazhigan in the brain is increased, and the research on increasing the curative effect and reducing the toxicity to other organs is focused.
Liposomes (liposomes) refer to the microvesicles formed by encapsulating a drug within a lipid bilayer. As a drug carrier, the liposome can protect the carried drug, control the release of the drug, improve the therapeutic index of the drug, reduce the therapeutic dose of the drug and reduce the toxicity of the drug. Long circulating liposomes (long circulating liposomes) also become stealth liposomes or sterically stabilized liposomes, and can reduce the uptake of liposomes by the reticuloendothelial system, thus slowing the clearance rate of liposomes in vivo and prolonging the residence time in blood, thereby prolonging the action time of the drug carried by liposomes in vivo.
Therefore, the preparation of the long-circulating liposome of the quzhazhigan has good application prospect.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a quzhazhigan long-circulating liposome and a preparation method thereof, wherein the quzhazhigan long-circulating liposome provided by the present invention has the advantages of small average particle size, uniform particle size dispersion and high encapsulation efficiency.
The Quzhazhigan long-circulating liposome provided by the invention comprises the following raw materials in parts by mass:
| quzhazhigan | 0.05 to 0.5 portion; |
| phospholipids | 1-8 parts; |
| |
0 to 1 portion; |
| tween-80 | 0.05 to 0.2 portion. |
The different mass ratios of cholesterol and phospholipid affect the encapsulation capacity of the quzhazhigan nanoliposome. Under the condition of a certain amount of the quzhazhigan drug-loading, as the mass ratio of cholesterol to phospholipid is increased from 0 to 2, the encapsulation rate of the quzhazhigan liposome is increased and then reduced. This is probably because the incorporation of cholesterol into the lipid membrane enhances membrane compactness and rigidity, and increases liposome stability during hydration, resulting in increased liposome encapsulation efficiency. After the cholesterol intercalation amount exceeds a certain range, the cholesterol will again interfere with the bilayer structure, resulting in leakage of solute molecules from the liposome. In the invention, the ratio of cholesterol to phospholipid is (0-1): (1-8); preferably 1: 0.25.
As the dosage of the quzhazhigan is increased, the number of the quzhazhigan molecules encapsulated in the liposome is increased, and the drug loading is increased. When the mass ratio of the quzhazhigan to the phospholipid is 1:10, the maximum encapsulation rate of the quzhazhigan long-circulating liposome reaches 65.3%. The medicine-lipid ratio exceeding 1:10 will result in the reduction of the encapsulation efficiency of the quzhazhigan. At lower loadings, the encapsulation probability of the liposome vesicles for the quzhazhigan is also small due to the low concentration of solute molecules. Under certain conditions, the number of liposomes formed from a given phospholipid is limited, so that the encapsulation efficiency decreases as the loading increases. The drug loading is high, the production cost can be reduced, but the encapsulation efficiency can be reduced due to the excessively high drug loading, so that two indexes of the encapsulation efficiency and the drug loading need to be considered, and the encapsulation efficiency is improved as much as possible when the drug loading is selected to be relatively considerable in the experiment.
In some specific embodiments, the quzhazhigan long-circulating liposome comprises the following raw materials in parts by mass:
| quzhazhigan | 0.1 part; |
| |
1 part; |
| cholesterol | 0.25 part; |
| tween-80 | 0.2 part. |
In the invention, the phospholipid consists of egg yolk lecithin and DSPE-PEG2000, wherein the mol percentage of the egg yolk lecithin is 95%.
In order to improve the stability of the liposome, a freeze-drying protective agent is also included, and the freeze-drying protective agent is lactose. Specifically, the preparation also comprises lactose, and the mass fraction of the lactose is 0.1-10 parts. Preferably, the mass fraction of lactose is 1-10 parts.
Experimental results show that the quzhazhigan long-circulating liposome provided by the invention is circular or oval, the encapsulation rate can reach 65.3%, the average particle size of the quzhazhigan long-circulating liposome prepared in the embodiment is 161.95nm, the dispersion index PDI is 0.3097, the Zeta potential is-39.34 mV, and all indexes are good.
The invention also provides a preparation method of the quzhazhigan long-circulating liposome, which comprises the following steps:
step 1: dissolving phospholipid and cholesterol in an organic solvent, and volatilizing the organic solvent to prepare a lipid film;
step 2: dissolving Quzhazhigan and tween-80 in buffer solution to obtain water phase;
and step 3: and (3) mixing the water phase with the lipid membrane prepared in the step (1), and filtering to obtain the quzhazhigan long-circulating liposome suspension after shaking and ultrasound.
The volatilization adopts a decompression rotary evaporation mode.
The choice of organic solvent is critical to the ability to form a uniform film. Common organic solvents are ethanol, chloroform, ethyl acetate, acetone, diethyl ether and the like, and the difference of the organic solvents influences the quality of a formed film and then finally influences the encapsulation efficiency and the particle size. Considering that chloroform is too toxic, this experiment examined the dissolution of lipid materials with a mixture of ethyl acetate, diethyl ether, ethanol and acetone (1:1), respectively, as an organic solvent, and the film-forming effect was observed. The result shows that the solubility of the ethyl acetate to the lipid material is poor, and the film formation is not uniform; dissolving the lipid material with diethyl ether, the dissolution is good, but the solvent is volatilized quickly during rotary evaporation, and the film is formed unevenly; the mixed solution (1:1) of ethanol and acetone is used as a solvent, and has good solubility and film forming property on lipid materials. Therefore, in the embodiment of the present invention, the organic solvent is a mixture of ethanol and acetone, wherein the volume ratio of ethanol to acetone is 1: 1.
in addition, the experiment of the invention shows that after phospholipid is dissolved in the step 1 which is too low or too high, the encapsulation efficiency of the quzhazhigan is reduced by the too high or too low phospholipid concentration. On the other hand, when the phospholipid concentration is too high, the particle size and polydispersity index of the liposome prepared also become large, and the stability is lowered. In the examples, a phospholipid concentration of 1.0% was chosen.
In the embodiment of the invention, the buffer solution is phosphate buffer solution. Experiments show that the solubility of the quzhazhigan in PBS is increased along with the increase of pH, and the phospholipid is most stable at pH6.5 in combination with literature data. Meanwhile, in consideration of the stability of the quzhazhigan in neutral and weakly acidic solutions and the solubility in PBS with different pH values, the pH value of the PBS buffer solution adopted in the embodiment of the invention is 7.4.
The ionic strength of the hydration medium (buffer) has an influence on the encapsulation efficiency of the quzhazhigan liposome. The experimental result shows that the ionic strength of the phosphate buffer solution is lower than 0.1 mol.L-1And the influence on the entrapment rate of the quzhazhigan liposome is not significant. But results in a decrease in encapsulation efficiency at higher ionic strength. This may be due to a decrease in encapsulation efficiency due to competition between phospholipid hydration and electrolytes for hydrated molecules. Therefore, the smaller the ionic strength, the better the ionic strength, while ensuring sufficient buffering capacity. The ionic strength determined in the experiment is 0.05 mol.L-1。
The purpose of shaking was to disperse the lipid film with phosphate buffer for drug encapsulation. The experimental result shows that the encapsulation rate of the quzhazhigan liposome is increased and then reduced along with the increase of the drug-loading temperature, the increase of the temperature is favorable for the encapsulation of the drug, but the high temperature can cause the damage of the liposome, so that the proper temperature is needed for obtaining the high encapsulation efficiency. After the oscillation time exceeds one hour, the drug loading time is increased, and the influence on the encapsulation efficiency is small. One hour may be selected as the drug loading time in view of efficiency issues. Therefore, the oscillation temperature adopted by the invention is 40 ℃, and the oscillation time is 1-4 h. In view of time saving, the oscillation time is preferably 1 h.
The purpose of ultrasonic treatment is to carry out finishing, the ultrasonic time has certain influence on the encapsulation efficiency and the particle size of the liposome, the particle size can be reduced by moderate ultrasonic treatment, but the ultrasonic time is too long, or a lipid membrane is damaged, so that the leakage of the medicament is caused, and the encapsulation efficiency is reduced, so that the encapsulation efficiency and the particle size are comprehensively considered, and the ultrasonic time is 10min in the embodiment of the invention. The ultrasonic wave is operated for 1s at an interval of 1s during 40-200W.
In the invention, the filtration refers to two times of filtration respectively through 045 mu m and 0.22 mu m filter membranes.
In one embodiment, the Quzhazhigan long-circulating liposome is prepared by dissolving lipid material with phospholipid concentration of 1.0% and cholesterol/phospholipid ratio of 1/4 with ethanol and acetone (1:1), rotary evaporating solvent in a rotary evaporator under reduced pressure in a water bath at 40 deg.C, and removing residual solvent completely with an oil pump. Adding Tween-80 (to phospholipid ratio of 1/5) and QUZHAQIGAN (medicinal lipid ratio of 1:10) in PBS (pH7.0, ionic strength of 0.05 mol. L-1) Carrying out ultrasonic medicine loading for 1h at 40 ℃, intermittently carrying out ultrasonic treatment for 10min by using a probe, and respectively filtering twice by using filtration membranes of 045 mu m and 0.22 mu m to obtain a quzhazhigan long-circulating liposome suspension.
Under the condition of room temperature, the quzhazhigan long-circulating liposome suspension gradually reduces in appearance transparency, encapsulation efficiency and pH along with the prolonging of the standing time, and the particle size gradually increases. The results show that the quzhazhigan long-circulating liposome suspension has poor stability at room temperature and is not suitable for storage at room temperature. Therefore, the filtration also comprises a step of freeze-drying the quzhazhigan long-circulating liposome suspension.
The freeze-drying protective agent has great influence on the appearance and the redispersibility of the quzhazhigan long-circulating liposome freeze-dried powder, and not only needs to be added with the freeze-drying protective agent, but also needs to select a proper protective agent. The freeze-dried product using lactose as the freeze-drying protective agent has better appearance, good redispersibility after redissolution and more important low drug leakage rate. In the examples of the present invention, lactose was used as a protective agent for lyophilization.
The lyoprotectant may be added to the aqueous phase or to the finally prepared suspension, which is not limited in the present invention. When the concentration of the freeze-dried suspension is increased from 2.5 percent to 5 percent, the appearance and the redispersibility of the freeze-dried product are improved; the concentration of the protective agent is increased to have little influence on the result, the principle of adding auxiliary materials as little as possible is followed, and the concentration of the freeze-drying protective agent is selected to be 5%.
Through the investigation on the appearance and the moisture of the freeze-dried powder, the freeze-drying process of the quzhazhigan liposome freeze-dried powder is finally determined as follows: pre-freezing at-40 deg.C for 3h, and drying for 18h, and freeze-drying in the same manner as shown in FIG. 4.
The invention provides a quzhazhigan long-circulating liposome and a preparation method thereof, and the quzhazhigan long-circulating liposome provided by the invention comprises quzhazhigan, phospholipid, cholesterol and tween-80. Also comprises a freeze-drying protective agent lactose. The formula is reasonable, and the encapsulation and the controlled release of the medicine can be realized. In addition, the invention also provides a preparation method of the Quzhazhigan long-circulating liposome, and the process adopts a film dispersion method, is simple to operate and has proper parameters, so that ideal encapsulation efficiency and liposome morphology are obtained. Experiments show that the liposome provided by the method is spherical or sphere-like under a transmission electron microscope, the dispersibility is good, the Zeta potential is-39.34 mV, the average particle size is 161.95nm, the dispersion index PDI is 0.3097, and the entrapment rate reaches 65.3%. After freeze-drying and rehydration, the properties are still stable.
Drawings
FIG. 1 transmission electron micrograph of Quzhazhigan liposome;
FIG. 2 Zeta potential diagram of Quzhazhigan liposome;
FIG. 3 is a distribution diagram of the particle size of Quzhazhigan liposome;
figure 4 freeze-drying profile of quzhazhigan liposomes;
figure 5 in vitro release curves of quzhazhigan and quzhazhigan liposomes.
Detailed Description
The invention provides a Quzhazhigan long-circulating liposome and a preparation method thereof, and a person skilled in the art can realize the preparation by properly improving process parameters by referring to the content. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.
The instruments adopted by the invention are all common commercial products and can be purchased in the market. Wherein:
quzhazhigan bulk drug (supplied by Kunzhi group, Inc., lot number 20131003);
quzhazhigan control (20140813 available from Kunzhi group pharmaceutical research institute);
egg yolk lecithin for injection (PC-98T Nippon Kyoto Co., Ltd., EL 12004-13023);
cholesterol (GENVIEW 2713010236);
distearoylphosphatidylethanolamine-polyethylene glycol 2000(DSPE-PEG2000, shanghai yanyi biotechnology ltd 20140415);
tween-80 (tianjin feng ship chemical reagents science and technology ltd 20130504);
the invention is further illustrated by the following examples:
examples 1-38 preparation of Quzhazhigan Long-circulating liposome suspensions
The prescription is shown in table 1:
TABLE 1 examples 1 to 38
Dissolving phospholipid (95 mol% egg yolk lecithin, 5 mol% DSPE-PEG2000) and cholesterol in 25% ethanol water solution, evaporating under reduced pressure in water bath at 40 deg.C in round-bottomed flask to form a uniform lipid film on the wall of round-bottomed flask. The vacuum rotary evaporation was continued to remove residual ethanol. Adding phosphate buffer solution containing Tween-80 and Quzhazhigan, shaking in constant temperature water bath shaking apparatus, hydrating, and filtering with 0.22 μm filter membrane for 3 times by probe ultrasound (power 40%, ultrasound 1s, interval 1s), wherein the filtrate is long-circulating liposome suspension.
The quzhazhigan long-circulating liposome suspension prepared in the embodiments 1-38 of the invention is placed at 4 ℃ for 10 days, and the appearance and the encapsulation rate are compared with those on the 0 th day. The results showed that no precipitation occurred within 10 days.
Wherein, the quzhazhigan long-circulating liposome prepared in example 35 is spherical or sphere-like under a transmission electron microscope, the dispersibility is good (figure 1), the Zeta potential is-39.34 mV (figure 2), the average particle diameter is 161.95nm, the dispersion index PDI is 0.3097 (figure 3), the encapsulation efficiency reaches 65.3%, and all indexes are good.
EXAMPLE 39 Freeze drying
Lyophilization can increase the physical stability (i.e., reduce the tendency for particle size to increase) and chemical stability (i.e., prevent chemical reactions such as oxidation or hydrolysis) of liposomes, and thus in order to increase the stability of the suspension of the mazatilbene liposomes.
2ml of the quzhazhigan long-circulating liposome suspension prepared in example 38 was taken and put into a 5ml penicillin bottle, and a freeze-drying protective agent was added until the mass fractions were 2.5%, 5% and 10%, respectively. Freeze-drying in LYO-16 vacuum freeze-drying machine, pre-freezing at-40 deg.C for 5 hr, and drying for 15 hr until sublimation interface disappears completely. And (5) heating to 30 ℃, carrying out a secondary drying process for 5h, and finishing the freeze-drying process. The lyophilization profile is shown in FIG. 4.
The results are shown in Table 2:
TABLE 2 Freeze drying Effect
| Protecting agent | Mass fraction of protective agent | Appearance of the product | Redispersibility | EncapsulationPercentage (%) |
| Is free of | -- | Severe atrophy of volume, bottom sticking | Difficult to disperse | 4.2 |
| |
5％ | Slight volume atrophy | Disperse slower | 44.7 |
| Lactose | 2.5％ | Atrophy and unsatisfied feeling | Disperse slower | 40.3 |
| Lactose | 5％ | Maintain original volume | Is easy to disperse | 54.6 |
| Lactose | 10％ | Loose and full | Is easy to disperse | 57.2 |
| |
5％ | Slight volume atrophy | Is easier to disperse | 46.5 |
Wherein, the preparation taking lactose with the mass fraction of 5% as a protective agent is lyophilized and then is rehydrated, and the conditions of particle size, morphology, zeta potential, pH value and encapsulation efficiency before and after rehydration are observed. The results are shown in Table 3:
table 3: rehydration effect
| Before freeze-drying | After rehydration | |
| Particle size | 161.95nm(PDI＝0.3097) | 166.69nm(PDI＝0.385) |
| zeta potential | -35.3mV | -32.9mV |
| pH value | 6.73 | 6.80 |
| Encapsulation efficiency | 54.6％ | 52.7％ |
In addition, the water content of the freeze-dried Quzhazhigan liposome is 2.45%, and the water content is less than 5%, so that the freeze-dried Quzhazhigan liposome meets the process standard. The rezakhstan stilbene glucoside long-circulating liposome after rehydration still presents a sphere-like shape, and the dispersibility is better.
Examination of in vitro release effects:
preparing a quzhazhigan solution: accurately weighing appropriate amount of Quzhazhigan, adding PBS to dissolve, and diluting to 0.5 mg/ml.
Quzhazhigan liposome suspension liquid: freeze-drying the preparation taking lactose with the mass fraction of 5% as a protective agent, re-dissolving the preparation with distilled water, and diluting the re-dissolved preparation until the mass concentration of the quzhazhigan is about 0.5 mg/ml.
Soaking the pretreated dialysis bag in a release medium overnight, respectively placing 4mL of quzhazhigan solution and liposome suspension in the dialysis bag, tightly binding two ends of the dialysis bag with stirring paddles of a dissolution instrument, and allowing the release of the drug in the dissolution medium to meet the leakage tank condition, i.e. the drug concentration in the solution is far lower than the saturation concentration of the drug at the dissolution end point, and the limit is generally 10% saturation solubility. Therefore, the test pieces were put into a dissolution cuvette containing 200 mM PBS (pH7.4) and subjected to in vitro release test under the conditions of a medium of 100r/min and (37. + -. 0.5). degree.C. The concentration was measured by periodically taking 5ml of release medium and supplementing the same volume of release medium, absorbance A was measured at 319nn wavelength and substituted into the above standard curve to calculate the cumulative release amount F (n)%, and each sample was repeated 3 times. The formula is as follows:
cumulative release amount F (%) ═ An+(An-1+……+A2+A1)×V1/V2
V1Fixing the sampling volume for each time point; v2Is the volume of dissolution medium; a. thenMeasured Release amount for the nth time Point
The results are shown in FIG. 5:
as can be seen from figure 5, the free quzhazhigan solution is released in PBS quickly, the release amount reaches about 80% after 4h, the permeation amount reaches 91.7% after 8h, and the permeation is almost complete. (the dialysis bag provides some resistance to the drug entering the release medium). The quzhazhigan liposome suspension is slow in drug release, and the cumulative drug release amount in 24 hours is about 75.3%. In the whole view, the release process of the quzhazhigan liposome solution can be divided into two stages, namely the first stage is that the drug release is fast within 0-4 h, because the unencapsulated free drug is fast released. And the release of the drug in the second stage is smooth in 4-24 hours, because the liposome has a slow release effect on the encapsulated drug.
The effect of the quzhazhigan long-circulating liposome prepared by other embodiments of the invention is not greatly different before and after rehydration after freeze-drying by taking lactose with the mass fraction of 5% as a protective agent, and the release effect is similar to that of the quzhazhigan long-circulating liposome in figure 5.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that it is obvious to those skilled in the art that various modifications and improvements can be made without departing from the principle of the present invention, and these modifications and improvements should also be considered as the protection scope of the present invention.
Claims (8)
1. The quzhazhigan long-circulating liposome is characterized by being prepared from the following raw materials in parts by mass:
the phospholipid consists of egg yolk lecithin and DSPE-PEG2000, wherein the mol percentage of the egg yolk lecithin is 95%.
2. The quzhazhigan long-circulating liposome according to claim 1, further comprising lactose, wherein the mass fraction of lactose is 1-10 parts.
3. A method for producing a mazaki stilbene glycoside long-circulating liposome as defined in any one of claims 1 to 2, comprising:
step 1: dissolving phospholipid and cholesterol in an organic solvent, and volatilizing the organic solvent to prepare a lipid film;
step 2: dissolving Quzhazhigan and tween-80 in buffer solution to obtain water phase;
and step 3: and (3) mixing the water phase with the lipid membrane prepared in the step (1), and filtering to obtain the quzhazhigan long-circulating liposome suspension after shaking and ultrasound.
4. The method according to claim 3, wherein the organic solvent is a mixture of ethanol and acetone, and the volume ratio of ethanol to acetone is 1: 1.
5. the method according to claim 3, wherein the buffer is a phosphate buffer; the pH was 7.4.
6. The method according to claim 3, wherein the shaking temperature is 40 ℃ and the shaking time is 1-4 h.
7. The method for preparing the compound of claim 3, wherein the time of the ultrasonic treatment is 10min 200W, and the ultrasonic treatment is carried out for 1s at intervals of 1 s.
8. A production method according to claim 3, characterized by further comprising, after the filtration, a step of lyophilizing the quzhazhigan long-circulating liposome suspension; the freeze-dried protective agent is lactose.
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| RU2311171C1 (en) * | 2006-05-29 | 2007-11-27 | Автономная некоммерческая организация Научно-технический центр "Фармбиопресс" | Anti-infectious liposomal preparation and pharmaceutical composition based in thereof |
| CN101787061A (en) * | 2010-03-02 | 2010-07-28 | 昆明翔昊科技有限公司 | Application of Quzhazhigan in preparation of preparations for preventing and treating cardiac-cerebral ischemia diseases, and preparation method thereof |
| CN105287406A (en) * | 2015-11-17 | 2016-02-03 | 西安力邦肇新生物科技有限公司 | Propofol liposome freeze-drying preparation and preparation method thereof |
| CN105380906A (en) * | 2015-12-29 | 2016-03-09 | 辅仁药业集团有限公司 | Cabazitaxel tumor targeted liposome injection and preparation method thereof |
-
2018
- 2018-01-12 CN CN201810029280.7A patent/CN108096190B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2311171C1 (en) * | 2006-05-29 | 2007-11-27 | Автономная некоммерческая организация Научно-технический центр "Фармбиопресс" | Anti-infectious liposomal preparation and pharmaceutical composition based in thereof |
| CN101787061A (en) * | 2010-03-02 | 2010-07-28 | 昆明翔昊科技有限公司 | Application of Quzhazhigan in preparation of preparations for preventing and treating cardiac-cerebral ischemia diseases, and preparation method thereof |
| CN105287406A (en) * | 2015-11-17 | 2016-02-03 | 西安力邦肇新生物科技有限公司 | Propofol liposome freeze-drying preparation and preparation method thereof |
| CN105380906A (en) * | 2015-12-29 | 2016-03-09 | 辅仁药业集团有限公司 | Cabazitaxel tumor targeted liposome injection and preparation method thereof |
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Effective date of registration: 20210521 Address after: 650106 No. 166, medical Road, hi tech Industrial Development Zone, Yunnan, Kunming Patentee after: Kunming Pharmaceutical Corp. Patentee after: Shanghai kunheng Medical Technology Co.,Ltd. Address before: 650106 No. 166, medical Road, hi tech Industrial Development Zone, Yunnan, Kunming Patentee before: Kunming Pharmaceutical Corp. |