CN112808122A - Application of multi-channel mixer and method for continuously preparing liposome in batch - Google Patents
Application of multi-channel mixer and method for continuously preparing liposome in batch Download PDFInfo
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- CN112808122A CN112808122A CN202011580475.4A CN202011580475A CN112808122A CN 112808122 A CN112808122 A CN 112808122A CN 202011580475 A CN202011580475 A CN 202011580475A CN 112808122 A CN112808122 A CN 112808122A
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F33/00—Other mixers; Mixing plants; Combinations of mixers
- B01F33/30—Micromixers
- B01F33/301—Micromixers using specific means for arranging the streams to be mixed, e.g. channel geometries or dispositions
- B01F33/3017—Mixing chamber
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
- B01F23/40—Mixing liquids with liquids; Emulsifying
- B01F23/45—Mixing liquids with liquids; Emulsifying using flow mixing
- B01F23/451—Mixing liquids with liquids; Emulsifying using flow mixing by injecting one liquid into another
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F2101/00—Mixing characterised by the nature of the mixed materials or by the application field
- B01F2101/22—Mixing of ingredients for pharmaceutical or medical compositions
Abstract
The invention discloses an application of a multi-channel mixer in the process of continuously preparing liposome in batches; the invention also discloses a method for continuously preparing the liposome in batches by using the multi-channel mixer, which comprises the following steps: dissolving liposome-preparing raw materials such as phospholipid in a good solvent, stirring at room temperature to dissolve completely to form a good solvent solution of liposome-preparing raw materials such as phospholipid; and introducing a good solvent solution into one or more channels of the multi-channel mixer, and introducing an anti-solvent or an anti-solvent solution formed by the anti-solvent and the hydrophilic substance into the other channels, so that the liposome can be rapidly self-assembled in a mixing cavity of the multi-channel mixer. The invention prepares liposome by a multi-channel mixer, and can continuously and rapidly prepare liposome with uniform and controllable size in large batch.
Description
Technical Field
The invention relates to the technical field of liposome preparation. More particularly, the invention relates to the use of a multi-channel mixer and a method for continuous batch preparation of liposomes.
Background
Fully closed unilamellar or multilamellar vesicles, which are bilayers formed from lipids such as phospholipids, are called liposomes and are structurally and compositionally similar to cell membranes. The liposome membrane can be inserted into the lipid layer of the cell membrane and then release the inclusion into the cell, which raises the concentration of the inclusion around the cell and slowly permeates into the cell by diffusion, especially when its constituent lipids are from natural sources. Liposomes have been shown to be biocompatible, biodegradable, non-toxic or mildly toxic, flexible and non-immunogenic, and are widely used in pharmaceutical formulations, skin care formulations, nutraceutical formulations, etc. for in vivo and in vitro administration for the entrapment and delivery of biologically active hydrophobic and hydrophilic molecules.
The traditional method for producing liposome is a thin film hydration method, a solvent evaporation method, an ethanol injection method and the like, and then the procedures of high-pressure homogenization, membrane filtration and the like are carried out to reduce the size of the liposome and improve the monodispersity of the liposome. These conventional methods are complicated, long-lasting, yield-dependent on batch volume, and require high energy input such as ultrasound and high pressure during the manufacturing process. In industrial production and practical application scenes, a method for rapidly preparing the liposome is urgently needed, so that the cost is reduced, the production is continuous, and the requirements of different application scenes are met.
In order to solve the problems, a plurality of liposome preparation methods based on ethanol injection (anti-solvent mixing) and special mixing modes are provided at present, including coaxial injection, microfluidic method and the like, and the continuous batch preparation of the liposome is realized to a certain extent. The micro-fluidic method needs to accurately control the appearance of a micro-channel, adopts slow micro-fluidic mixing and has low preparation efficiency. The coaxial injection method is a method newly developed in recent years, and a phospholipid/cholesterol ethanol solution and water are mixed by a coaxial rapid injection method to continuously prepare particles and liposomes. The coaxial injection method requires that a phospholipid ethanol solution channel and an anti-solvent channel are positioned at the same axis, and the two liquids can be mixed only during mixing, so that the mixing of more than two liquids cannot be realized. Meanwhile, this mixing method requires a long injection mixing channel, and cannot achieve efficient and rapid mixing within a small distance and space limitation range. Moreover, the above method is not ideal in the effect of embedding hydrophilic substances, and it is difficult to achieve a high encapsulation efficiency and a high loading rate.
Disclosure of Invention
An object of the present invention is to solve at least the above problems and to provide at least the advantages described later.
The invention also aims to provide an application of the multi-channel mixer in continuous batch preparation of the liposome, and also provides a method for the multi-channel mixer in continuous batch preparation of the liposome, and a method for the multi-channel mixer in continuous batch preparation of the liposome. By utilizing the multi-channel mixer, the effect of ultra-fast liposome preparation can be realized, and the prepared liposome has uniform size and is controllable.
To achieve these objects and other advantages in accordance with the present invention, there is provided a use of a multi-channel mixer in a continuous batch liposome preparation process.
The invention also provides a method for continuously preparing the liposome in batches by using the multi-channel mixer, which comprises the following steps:
dissolving liposome-preparing raw materials such as phospholipid in a good solvent, stirring at room temperature to dissolve completely to form a good solvent solution of liposome-preparing raw materials such as phospholipid;
and introducing a good solvent solution into one or more channels of the multi-channel mixer, and introducing an anti-solvent or an anti-solvent solution formed by the anti-solvent and the hydrophilic substance into the other channels, so that the liposome can be rapidly self-assembled in a mixing cavity of the multi-channel mixer.
Preferably, the multi-channel mixer is a mixer containing two or more channels.
Preferably, the multi-channel mixer is a mixer comprising four channels, wherein the same feed rate is used for two opposite channels.
Preferably, the flow rate of the good solvent solution in one channel is 2-6 mL/min.
Preferably, the flow rate of the anti-solvent or the anti-solvent solution in the other channels except the channel opposite to one channel is 18-54 mL/min.
Preferably, the mixing time of the good solvent solution with the anti-solvent or the anti-solvent solution is less than 0.1 second.
Preferably, the dimensions of the mixing chamber of the multi-channel mixer, the rate of introduction of the good solvent solution, the rate of introduction of the anti-solvent or anti-solvent solution are controlled such that the Reynolds number Re > 4000.
The invention also provides the liposome obtained by the method for continuously preparing the liposome in batches by using the multi-channel mixer.
The invention at least comprises the following beneficial effects:
the method uses a micro mixer with multiple channels to prepare the liposome, and has the characteristics of low energy consumption, high efficiency and high speed. The rapid mixing process enables direct and effective mixing at the molecular level, resulting in rapid and uniform supersaturation of liposome-forming substances, efficient process, high yield, and the liposomes prepared by the method have the characteristics of small size, uniform size, and high batch repeatability. And because of mixing evenly, phospholipid is separated out and self-assembly nucleation is rapid, liposome with the particle size less than 100nm can be generated, and the liposome size can be realized by adjusting the mixing rate;
the solution feeding speed of each channel of the multi-channel mixer is independently controllable, so that on one hand, the operation is convenient, and on the other hand, the component proportion, the organic solvent concentration and the like in the final product can be freely controlled, the stability of the liposome is easier to regulate and control, and the influence of the solvent on the embedding substance is reduced;
when the Reynolds number is more than 4000, the mixing rate is higher than the rate of forming the liposome by self-assembly of lecithin, so that the generation process and the appearance of the liposome are not influenced by the increased mixing rate, and the mixing effect is consistent;
the liposome prepared by the method can realize high encapsulation rate (> 80%) and high loading capacity (> 10%) for hydrophilic substances such as water-soluble protein and the like.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.
Drawings
FIG. 1(A) is a schematic diagram of a three-channel mixer according to one embodiment of the present invention;
FIG. 1(B) is a schematic diagram of a two-channel mixer according to one embodiment of the present invention;
FIG. 1(C) is a schematic structural diagram of a four-channel mixer according to one embodiment of the present invention;
FIG. 2 is a schematic diagram of an injection mixing process of a four-channel mixer of example 1 of the present invention;
FIG. 3(A) is a graph showing particle size and PDI of liposomes formed by self-assembly in example 1 of the present invention;
FIG. 3(B) is a graph showing the light scattering intensity of liposomes formed by self-assembly in example 1 of the present invention;
FIG. 4(A) is a graph of particle size and PDI of liposomes formed from lecithin and cholesterol at various ratios according to example 2 of the present invention;
FIG. 4(B) is a graph showing the light scattering intensity of liposomes formed from lecithin and cholesterol in various proportions in example 2 of the present invention;
FIG. 5(A) is a cryo-transmission electron micrograph of liposomes prepared by self-assembly of lecithin according to example 2;
fig. 5(B) is example 2 lecithin: a cryo-electron micrograph with a cholesterol mass ratio of 60: 40;
fig. 6(a) is example 3 lecithin: a liposome strength distribution diagram prepared when the mass ratio of the ginsenoside is 60: 40;
fig. 6(B) is example 3 lecithin: a cryoelectron micrograph of the prepared liposome when the mass ratio of the ginsenoside is 60: 40;
fig. 7 is example 4 lecithin: encapsulation efficiency and loading capacity of the encapsulated bovine serum albumin are attempted when the molar ratio of cholesterol is 5: 3.
Detailed Description
The present invention is further described in detail below with reference to examples so that those skilled in the art can practice the invention with reference to the description.
It is to be noted that the experimental methods described in the following embodiments are all conventional methods unless otherwise specified, and the reagents and materials are commercially available unless otherwise specified.
The invention provides a multi-channel mixer, which can be a three-channel mixer, a two-channel mixer and a four-channel mixer, as shown in fig. 1(a), fig. 1(B) and fig. 1(C), respectively.
< example 1>
A method for preparing liposome in batches continuously by a multi-channel mixer comprises the following steps:
(1) preparation of a good solvent solution of phospholipids: weighing 900mg of lecithin, dissolving the lecithin in 30mL of absolute ethanol, stirring for 1h at room temperature until the lecithin is completely dissolved to form lecithin ethanol solution, and then respectively sucking the prepared lecithin ethanol solution and the anti-solvent deionized water into a syringe.
(2) Preparing liposome: the prepared lecithin ethanol solution and deionized water are respectively connected with channels 1 and 3 of a multi-channel mixer through a digital injection pump, the same deionized water is respectively introduced into channels 2 and 4, the introduction speeds of the channels 1 and 3 are respectively 1, 2, 3, 4, 5 and 6mL/min, the introduction speeds of the channels 2 and 4 are respectively 9, 18, 27, 36, 45 and 54mL/min, and the obtained liposome flows out of an outlet and is received by a container. Reynolds number Re >4000 during mixing.
The preparation process is shown in figure 2. The liposome was characterized by a Malvern particle sizer, and the results are shown in FIG. 3, where the mean diameter of the liposome and the Polymer Dispersibility Index (PDI) decreased with increasing total flow rate until the total flow rate reached 60mL/min (Re-4000), the particle size was 65nm, the stable PDI dispersibility index was 0.25, and the batch reproducibility was good. Meanwhile, the light scattering intensity of the material is reduced along with the increase of the total flow rate until the total flow rate reaches 60mL/min (Re-4000).
< example 2>
A method for preparing liposome in batches continuously by a multi-channel mixer comprises the following steps:
(1) preparation of good solvent solution of raw materials for preparing liposome, such as phospholipid: respectively taking lecithin: dissolving cholesterol (100: 0), (90: 10), (80: 20), (70: 30) and (60: 40) in absolute ethyl alcohol together in a mass ratio, stirring for 1h at room temperature until the cholesterol is completely dissolved, preparing a lecithin cholesterol ethanol solution, wherein the total concentration of lecithin and cholesterol in the lecithin cholesterol ethanol solution is 50mg/mL, and then respectively sucking the prepared lecithin cholesterol ethanol solution and an anti-solvent deionized water into a syringe.
(2) Preparing liposome: and respectively connecting the prepared lecithin cholesterol ethanol solution and the anti-solvent deionized water to channels 1 and 3 of a multi-channel mixer through a digital injection pump, respectively introducing the same deionized water into channels 2 and 4, wherein the introducing speed of the channels 1 and 3 is 6mL/min, the introducing speed of the channels 2 and 4 is 54mL/min, and the obtained liposome flows out of an outlet and is received by a container. Reynolds number Re >4000 during mixing.
The liposome was characterized using a malvern particle sizer, and the results are shown in fig. 4A, where the cholesterol ratio was less than 10%, the liposome particle size and PDI were unchanged from the lecithin self-assembly, the liposome particle size was 170nm, and the PDI was 0.50. Particle size and PDI decrease as cholesterol content increases up to 70: the particle size and PDI stability of the particles are respectively 72nm and 0.22 at 30 hours, and the batch repeatability is good. In fig. 4B, the light scattering intensity increases with increasing cholesterol content, and decreasing particle size increases the light scattering intensity. Also characterized by cryo-electron microscopy as shown in fig. 5A, it can be clearly seen that the lecithin self-assembly is a polydisperse liposome structure, whereas fig. 5B lecithin: cholesterol is 60:40 has small dispersibility and small particle size. The result is consistent with the detection result of the particle analyzer.
< example 3>
A method for preparing liposome in batches continuously by a multi-channel mixer comprises the following steps:
(1) preparation of good solvent solution of raw materials for preparing liposome, such as phospholipid: taking lecithin: the mass ratio of the ginsenoside is 60:40 dissolving in absolute ethanol, stirring at room temperature for 1 hr to dissolve completely, preparing lecithin ginsenoside ethanol solution with total concentration of lecithin and ginsenoside of 30mg/mL, and respectively sucking the prepared lecithin ginsenoside ethanol solution and anti-solvent deionized water into syringe.
(2) Preparing liposome: connecting the prepared lecithin ginsenoside ethanol solution and deionized water with channels 1 and 3 of a multi-channel mixer respectively through a digital injection pump, introducing the same deionized water into channels 2 and 4 respectively, wherein the introduction speed of the channels 1 and 3 is 6mL/min, the introduction speed of the channels 2 and 4 is 54mL/min, and the obtained liposome flows out of an outlet and is received by a container. Reynolds number Re >4000 during mixing.
The liposome was characterized using a Malvern particle sizer, and the results are shown in FIG. 6A, where the liposome particle size was 84. + -. 0.636nm, PDI was 0.193. + -. 0.011, and the batch reproducibility was good. Simultaneously, the characterization by cryo-electron microscopy is shown in fig. 6B, where lecithin: the mass ratio of the ginsenoside is 60:40 the liposomes had a small dispersibility and a particle size of about 90nm, consistent with the results obtained with a granulometer.
< example 4>
A method for preparing liposome in batches continuously by a multi-channel mixer comprises the following steps:
(1) preparation of good solvent solution of raw materials for preparing liposome, such as phospholipid: taking a lecithin and cholesterol molar ratio of 5:3, dissolving the components in absolute ethyl alcohol together, wherein the concentration of the lecithin is 70mg/mL, and stirring the mixture for 1 hour at room temperature until the lecithin and the cholesterol are completely dissolved to prepare a lecithin cholesterol ethyl alcohol solution.
(2) Preparation of anti-solvent bovine serum albumin solution: respectively dissolving 150mg and 225mg of bovine serum albumin in 250mL of water, preparing bovine serum albumin solutions with the concentrations of 0.6mg/mL and 0.9mg/mL respectively, and then respectively sucking the prepared lecithin cholesterol ethanol solution and the anti-solvent bovine serum albumin solution into a syringe.
(3) Preparing liposome: the prepared lecithin cholesterol ethanol solution and the bovine serum albumin solution are respectively connected with the channels 1 and 3 of the multi-channel mixer through a digital injection pump, the same bovine serum albumin solution is respectively introduced into the channels 2 and 4, the introduction speed of the channels 1 and 3 is 6mL/min, the introduction speed of the channels 2 and 4 is 54mL/min, and the obtained liposome flows out of an outlet and is received by a container. Reynolds number Re >4000 during mixing.
The liposome was characterized using a malvern particle sizer, and the results are shown in table 1, and there was no significant difference between the bovine serum albumin-loaded liposome and the empty liposome in particle size and PDI. Meanwhile, the encapsulation efficiency and the loading capacity of the liposome are determined by ultrafiltration and Coomassie brilliant blue color development methods, as shown in FIG. 7, the encapsulation efficiency and the loading capacity of 0.6mg/mL batch of bovine serum albumin are 81% and 11% respectively, and the encapsulation efficiency and the loading capacity of 0.9mg/mL batch of bovine serum albumin are 85% and 16% respectively. The results show that liposomes prepared by multi-channel mixers can greatly improve the encapsulation and loading capacity of hydrophilic proteins and other molecules.
TABLE 1
While embodiments of the invention have been described above, it is not limited to the applications set forth in the description and the embodiments, which are fully applicable to various fields of endeavor for which the invention may be embodied with additional modifications as would be readily apparent to those skilled in the art, and the invention is therefore not limited to the details given herein and to the embodiments shown and described without departing from the generic concept as defined by the claims and their equivalents.
Claims (9)
1. An application of a multi-channel mixer in continuous batch preparation of liposome is provided.
2. A method for preparing liposome in batches continuously by a multi-channel mixer is characterized by comprising the following steps:
dissolving liposome-preparing raw materials such as phospholipid in a good solvent, stirring at room temperature to dissolve completely to form a good solvent solution of liposome-preparing raw materials such as phospholipid;
and introducing a good solvent solution into one or more channels of the multi-channel mixer, and introducing an anti-solvent or an anti-solvent solution formed by the anti-solvent and the hydrophilic substance into the other channels, so that the liposome can be rapidly self-assembled in a mixing cavity of the multi-channel mixer.
3. The method for continuous batch preparation of liposomes by the multi-channel mixer of claim 2 wherein the multi-channel mixer is a mixer containing two or more channels.
4. The method for continuous batch production of liposomes by the multi-channel mixer of claim 3 wherein the multi-channel mixer is a mixer comprising four channels, wherein the same aeration rate is applied to two opposite channels.
5. The method for continuous batch preparation of liposomes by using a multichannel mixer as claimed in claim 4, wherein the flow rate of the good solvent solution in one of the channels is 2 to 6 mL/min.
6. The method for continuous batch production of liposomes by the multi-channel mixer as claimed in claim 5, wherein the feeding speed of the anti-solvent or the anti-solvent solution to the channels other than the channel opposite to one of the channels is 18 to 54 mL/min.
7. The method for continuous batch production of liposomes by the multi-channel mixer of claim 2 wherein the mixing time of the good solvent solution with the anti-solvent or the anti-solvent solution is less than 0.1 second.
8. The method for continuous batch production of liposomes by multi-channel mixer as claimed in claim 2, wherein the size of the mixing chamber of the multi-channel mixer, the feeding speed of the good solvent solution, the feeding speed of the anti-solvent or the anti-solvent solution are controlled so that the reynolds number Re > 4000.
9. A liposome obtained by the method for continuous batch production of liposome by the multi-channel mixer of any one of claims 2 to 8.
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2020
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| CN101152545A (en) * | 2007-09-29 | 2008-04-02 | 四川大学华西医院 | Turmeric water-solubility saponin liposome, preparing method and uses the same |
| JP2013255912A (en) * | 2012-05-15 | 2013-12-26 | Chiba Univ | Liposome and method of making the same |
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