CN111545087B - Multichannel diversion efficient homogeneous mixing device and application thereof in preparation of drug-loaded nano-particles - Google Patents
Multichannel diversion efficient homogeneous mixing device and application thereof in preparation of drug-loaded nano-particles Download PDFInfo
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- CN111545087B CN111545087B CN202010345433.6A CN202010345433A CN111545087B CN 111545087 B CN111545087 B CN 111545087B CN 202010345433 A CN202010345433 A CN 202010345433A CN 111545087 B CN111545087 B CN 111545087B
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Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
- B01F25/20—Jet mixers, i.e. mixers using high-speed fluid streams
- B01F25/23—Mixing by intersecting jets
- B01F25/231—Mixing by intersecting jets the intersecting jets having the configuration of sheets, cylinders or cones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/713—Double-stranded nucleic acids or oligonucleotides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/23—Calcitonins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5115—Inorganic compounds
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5123—Organic compounds, e.g. fats, sugars
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
- A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5192—Processes
-
- 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 a multichannel diversion efficient mixing and homogenizing device and application thereof in preparation of drug-loaded nano particles. Comprises a shell, a fluid mixing cavity arranged in the shell; the mixing cavity is a cylindrical cavity and is provided with an axial fluid main outlet; at least two fluid main inlets which are in the same clockwise direction and are perpendicular to the axial direction of the cylindrical cavity are arranged in the shell; a channel structure for splitting the fluid of the main inlet is arranged between the main inlet and the mixing cavity, so that each main inlet fluid enters the fluid mixing cavity along the axial vertical direction of the cylindrical cavity through at least two splitting channels; the fluid main outlet and the fluid main inlet are respectively connected with an external pipeline through connecting parts on the shell. The device can remarkably improve the effective contact area of one or more solutions when being mixed in the fluid mixing cavity, so that the solutions can be mixed in a high-efficiency and homogeneous way at a low flow rate, and the device can be used for continuously and massively preparing different drug-loaded nano-particles.
Description
Technical Field
The invention relates to the technical field of preparation devices of nano-drug preparations, in particular to a multichannel diversion efficient homogeneous mixing device and application thereof in preparation of drug-loaded nano-particles.
Background
The nanoparticle has wide application prospect in the field of drug delivery, and the nanoparticle is used as a carrier to deliver drugs, so that the stability can be improved, the targeting property can be enhanced, the bioavailability can be improved, and the large-scale preparation of the drug-loaded nanoparticle with stable quality plays a vital role in clinical transformation. The traditional preparation method of the drug-loaded nano-particles mainly comprises the technologies of a gradual dripping method, a rapid pouring method, an emulsion-solvent volatilizing method and the like, and the drug-loaded nano-particles obtained by utilizing the intermittent preparation methods generally have application bottlenecks of larger particle size, uneven particle size, poor batch reproducibility and the like, so that the technical requirements of clinical transformation on quality control are difficult to meet.
In recent years, continuous flow mixing techniques have received great attention in the pharmaceutical field, which have many advantages in the preparation of drug-loaded nanoparticles. For example, microfluidic technology can achieve precise control of fluids in a tiny confined space, and can be used to continuously prepare drug-loaded nanoparticles of different sizes and surface properties, however, the slower flow rate and lower mixing efficiency of the drug-loaded nanoparticles make nanoparticle yield unsatisfactory. The microreactor device can rapidly realize high-flux preparation of drug-loaded nano-particles under high turbulence mixing conditions, however, the mixing devices must rely on extremely high flow velocity to achieve uniform mixing effect, and the process is easy to cause denaturation or inactivation of biological macromolecular drugs. Therefore, there is a need to develop a novel efficient mixing and homogenizing device, so that the effective contact area of one or more solutions can be remarkably increased, the efficient homogeneous mixing effect can be achieved under the condition of low flow velocity, the influence of bioactive drugs is avoided, and the controllable preparation of different types of drug-carrying nanoparticle preparations, especially the continuous and controllable preparation of polypeptide, protein or nucleic acid macromolecule drug nanoparticle preparations, is realized.
Disclosure of Invention
The invention aims to overcome the defects and shortcomings in the prior art and provide a multichannel diversion efficient mixing and homogenizing device.
The invention further aims to provide an application of the multichannel diversion efficient mixing homogenizing device in preparation of drug-loaded nanoparticles.
The above object of the present invention is achieved by the following technical solutions:
A multichannel diversion efficient mixing homogenizing device comprises a shell, a fluid mixing cavity and a fluid mixing device, wherein the fluid mixing cavity is arranged in the shell; the mixing cavity is a cylindrical cavity and is provided with an axial fluid main outlet; at least two fluid main inlets which are in the same clockwise direction and are perpendicular to the axial direction of the cylindrical cavity are arranged in the shell; a channel structure for splitting the fluid of the main inlet is arranged between the main inlet and the mixing cavity, so that each main inlet fluid enters the fluid mixing cavity along the axial vertical direction of the cylindrical cavity through at least two splitting channels; the fluid main outlet and the fluid main inlet are respectively connected with an external pipeline through connecting parts on the shell.
According to the multichannel diversion efficient mixing and homogenizing device, fluid enters along the same clockwise direction, and is rapidly and uniformly mixed by using vortex; meanwhile, a mode that one main inlet channel is split into a plurality of split inlet channels and then enters the mixing cavity is adopted, each main inlet fluid is split into at least two streams, and then each split stream enters the central mixing cavity respectively, so that the effective contact area of one or more solutions in the cylindrical mixing cavity is remarkably improved, the efficient homogeneous mixing effect of the solutions can be realized under the condition of low flow velocity, the structural damage and inactivation of bioactive macromolecular drugs are avoided, and the method is suitable for controllable preparation of small-size nano particles. In addition, the special diversion structure design of the fluid channel enables the capacity of the internal mixing cavity meeting the uniform mixing condition to be larger, so that the production efficiency of the nano particles is improved.
Preferably, the fluid diversion channel is arranged in the tangential direction of the circular section of the cylindrical cavity; each main inlet fluid is divided into a plurality of branches when passing through the branch channel, and then enters the fluid mixing cavity along the tangential direction of the circular section of the cylindrical cavity.
Preferably, four fluid main inlets which are in the same clockwise direction and are perpendicular to the axial direction of the cylindrical cavity are arranged in the shell, and every two adjacent fluid main inlets are perpendicular to each other.
Further preferably, the four main fluid inlets are in the same plane.
Further preferably, the four fluid main inlets correspond to eight split channels in total, and each fluid main inlet corresponds to two split channels.
Further preferably, the two diversion channels corresponding to each fluid main inlet are arranged along the axial direction of the cylindrical cavity and are in the same plane.
Further preferably, the cross-section of the shunt channel is circular.
Preferably, the diameter of the diversion channel ranges from 0.5 mm to 4mm, the diameter of the main outlet of the cylindrical fluid ranges from 0.5 mm to 4mm, the diameter of the circular section of the cylindrical mixing cavity ranges from 5mm to 12mm, and the height of the cylindrical mixing cavity ranges from 2mm to 10mm.
Preferably, the shell is cuboid or has other geometric shapes, the connecting part connected with the fluid main outlet is arranged on one surface, and the connecting part connected with the fluid main inlet is uniformly arranged on the surface adjacent to the surface of the connecting part connected with the fluid main outlet.
More preferably, the casing has a rectangular parallelepiped structure, the connecting member connected to the fluid main outlet is provided on one of the square surfaces, and the connecting member connected to the fluid main inlet is provided on four surfaces adjacent to the surface on which the connecting member connected to the fluid main outlet is provided.
Further preferably, the housing is integrally formed.
Preferably, the adapter is a hollow bolt; the main fluid inlet is connected with one end of the hollow bolt, the external sampling tube is connected with the other end of the hollow bolt, one end of the main fluid outlet is connected with one end of the hollow bolt, and the external sampling tube is connected with the other end of the hollow bolt.
Still preferably, the bolt is a plastic or metal bolt.
Preferably, the fluid mixing cavity is made of stainless steel, ultra-high molecular weight polyethylene, polypropylene, polytetrafluoroethylene, polyoxymethylene or polyether-ether-ketone.
More preferably, the material of the fluid mixing chamber is stainless steel, polypropylene or polyether ether ketone.
The invention also claims the application of the multichannel diversion efficient mixing homogenizing device in preparing drug-loaded nano particles.
The invention also provides a continuous preparation method of the drug-loaded nano-particles, which is to lead the carrier and/or the drug solution to pass through the main fluid inlet and then to be split, flow to the mixing cavity inside the shell through a plurality of split channels for rapid and uniform mixing, and prepare the nano-particles with uniform particle size, high drug encapsulation efficiency and drug loading capacity and high reproducibility by using static electricity, hydrophobic, hydrogen bonds or other acting forces.
The method can obviously improve the effective contact area of one or more solutions in the cylindrical mixing cavity when mixing, so that the solution can achieve the efficient homogeneous mixing effect under the condition of lower flow velocity.
Preferably, the precursor solution is an aqueous solution of a carrier material and/or a drug, or an organic solution of a carrier material and/or a drug.
Preferably, the carrier and/or drug solution is drained through tubing to the mixing chamber inside the housing by the pushing force of a peristaltic or syringe pump.
Preferably, the reynolds number of the fluid in the mixing cavity is between 50 and 200 or 200 and 2000 or 2000 and 20000.
Preferably, the drug is a hydrophilic and/or hydrophobic small molecule drug, a large molecule polypeptide, protein or nucleic acid drug; the carrier material is an inorganic material, an organic small molecule or a high polymer material, and mainly plays a role in stabilizing active ingredients of medicines and/or forming nano particles.
The invention also claims the drug-loaded nano-particles prepared by any one of the methods.
The application of the drug-loaded nano-particles in drug delivery and treatment is also within the scope of the present invention.
Compared with the prior art, the invention has the following beneficial effects:
The invention provides a multichannel diversion efficient mixing homogenizing device, which utilizes vortex flow to perform rapid and uniform mixing, and remarkably improves the effective contact area of one or more solutions in a cylindrical mixing cavity when the solutions are mixed by splitting a main inlet into a plurality of diversion inlets and then entering the mixing cavity, so that the efficient homogenization mixing effect of the solutions can be realized under the condition of low flow velocity, and the structural damage and inactivation of bioactive macromolecular medicaments are avoided. The mixing device can be used for continuously and high-flux preparation of different drug-loaded nano-particles, the prepared drug-loaded nano-particles have the characteristics of uniform particle size, high reproducibility and the like, and the mixing device is particularly suitable for high-efficiency preparation of small-size drug-loaded nano-particles, so that the mixing device has a wide application prospect in the field of drug delivery.
Drawings
Fig. 1 is a schematic structural diagram of a multi-channel split-flow efficient mixing homogenizing device in embodiment 1 of the present invention.
Fig. 2 is a schematic structural diagram of a multi-channel split-flow efficient mixing homogenizing device according to embodiment 1 of the present invention; wherein a and B are schematic diagrams of different viewing angles of the mixer device.
Fig. 3 is an assembly and engineering drawing of a multi-channel split-flow high-efficiency mixing and homogenizing apparatus according to embodiment 1 of the present invention. Wherein A is an assembly drawing of the mixer device, B is an engineering drawing of the mixer device, wherein the diameter phi a of 8 cylindrical diversion channels ranges from 0.5 to 4mm, the diameter phi B of a main cylindrical fluid outlet ranges from 0.5 to 4mm, the diameter phi c of a circular section of a cylindrical fluid mixing cavity ranges from 5 to 12mm, and the height h of the cylindrical fluid mixing cavity ranges from 2 to 10mm.
FIG. 4 is a schematic view of a cylindrical mixing chamber of a mixer apparatus according to example 1 of the present invention.
Fig. 5 is a physical diagram of the mixer apparatus according to example 1 of the present invention with parameters of Φa=0.8 mm, Φb=1.2 mm, Φc=7.0 mm, and h=3.5 mm at different viewing angles.
Fig. 6 is a graph showing particle size and polydispersity index of the preparation of insulin-loaded nanoparticles using a mixing apparatus under different flow rate conditions.
Figure 7 is a particle size and polydispersity index of salmon calcitonin-loaded nanoparticle prepared using a mixing apparatus under different flow rate conditions.
FIG. 8 is a dynamic light scattering result of the nucleic acid-loaded nanoparticle prepared by using a mixing apparatus at a flow rate of 30 mL/min.
FIG. 9 shows the dynamic light scattering results of PLGA nanoparticles prepared using a mixing device at a flow rate ratio (32 mL/min water: 8mL/minTPGS aqueous solution: 8mL/min PLGA acetonitrile solution).
Drawing and annotating: 1-4 are fluid main inlets respectively connected with an external pipeline, 5 are two split-flow inlet channels, 6 are fluid outlet outside the shell, 7 are cylindrical fluid mixing cavities, 8 are axial direction fluid main outlets connected with the mixing cavities, 9 are plugging bolts above the mixing cavities, and 10 are device shells.
Detailed Description
The invention is further illustrated in the following drawings and specific examples, which are not intended to limit the invention in any way. Unless specifically stated otherwise, the reagents, methods and apparatus employed in the present invention are those conventional in the art.
Reagents and materials used in the following examples are commercially available unless otherwise specified.
Example 1 design, processing and Assembly of Multi-channel flow-splitting efficient mixing homogenizing device
As shown in fig. 1 to 4, a multi-channel split-flow high-efficiency mixing and homogenizing device comprises a cuboid shell 10 (length 33mm, width 33mm and height 27 mm), a cylindrical fluid mixing cavity 7 (diameter phi c of the circular section of the cylindrical cavity ranges from 5mm to 12mm, and height h of the cylindrical cavity ranges from 2mm to 10 mm) arranged in the shell; the cylindrical fluid mixing cavity 7 is provided with an axial cylindrical fluid main outlet 8, the diameter phi b of the main outlet channel ranges from 0.5 mm to 4mm, the fluid main outlet 8 is communicated with a fluid outlet 6 outside the shell through a joint part (a hollow bolt) on the device shell 10, one end of the hollow bolt is connected with the fluid main outlet 8, and the other end of the hollow bolt is connected with the fluid outlet 6 outside; four fluid main inlets 1-4 which are in the same clockwise direction and are perpendicular to the axial direction of the cylindrical fluid mixing cavity 7 are arranged in the shell 10, and two adjacent fluid main inlets are perpendicular to each other; a channel structure for splitting the fluid of the main inlet is arranged between the fluid main inlets 1-4 and the cylindrical fluid mixing cavity 7, so that each fluid main inlet is divided into two splitting channels 5 arranged along the tangential direction of the circular section of the cylindrical fluid mixing cavity 7, 8 splitting channels (the diameter phi a of each splitting channel ranges from 0.5 mm to 4 mm) are totally separated from the four fluid main inlets, and the fluid of the main inlet enters the cylindrical fluid mixing cavity 7 along the tangential direction of the circular section of the cylindrical fluid mixing cavity 7 after being split (as shown in figure 4); the fluid main inlets 1-4 are respectively connected with external sample injection pipes through hollow bolts correspondingly arranged on the shell, the fluid main inlets are connected with one end of the hollow bolts, and the external sample injection pipes are connected with the other end of the hollow bolts. Fig. 5 is a physical diagram of a mixer apparatus with parameters specifically Φa=0.8 mm, Φb=1.2 mm, Φc=7.0 mm, h=3.5 mm at different viewing angles.
When the nano-particle packaging device is used, a peristaltic pump or a syringe pump is used for respectively passing a carrier and/or a drug solution through a fluid main inlet, then the carrier and/or the drug solution is split, the carrier and/or the drug solution is guided to a mixing cavity in the shell through a plurality of split channels for rapid and uniform mixing, and nano-particles with uniform particle size, high drug encapsulation efficiency, drug loading capacity and high reproducibility are prepared by using static electricity, hydrophobic, hydrogen bonds or other acting force to drive and assemble.
In particular, the present invention demonstrates the applicability and advantages of preparing nanoparticles by the following examples using a multi-channel split-flow high-efficiency mixing homogenizing apparatus of the specification or parameters of fig. 5.
Example 2 preparation of protein-loaded drug nanoparticles using a high efficiency mixing homogenizing apparatus
Insulin was selected as a protein drug model and dissolved in aqueous ph=2.8 hydrochloric acid to give an insulin solution at a concentration of 0.5 mg/mL. Chitosan (90 kda,85% deacetylation degree) was dissolved in 0.2% aqueous acetic acid to give a chitosan solution with a concentration of 1mg/mL, and the pH of the chitosan solution was adjusted to 5.3 using sodium hydroxide solution. Sodium tripolyphosphate was dissolved in 25mM HEPES buffer solution to give a sodium tripolyphosphate solution at a concentration of 0.2mg/mL, and the final nanoparticle suspension solution obtained by adjusting the initial pH of the solution was controlled to pH 6.5. And controlling the flow rate of fluid by using a syringe pump, respectively passing the insulin solution, the sodium tripolyphosphate solution, the chitosan solution and the double distilled water through four main fluid inlets of the mixing device shown in fig. 5, then realizing efficient and homogeneous mixing in a cylindrical mixing cavity, and then collecting nanoparticle solution from a fluid outlet to obtain the loaded insulin nanoparticle suspension. As shown in FIG. 6, under the same preparation parameter conditions, the reported preparation method of the loaded insulin nanoparticle suspension by using a four-channel microreactor mixing device (Biomaterials 2017,130,28-41; chinese patent application No. 201780016821.6) is compared, and the multi-channel split-flow high-efficiency mixing homogenizing device can be used for obtaining the loaded insulin nanoparticle with small size (less than 60 nm) and narrow particle size distribution under the condition of lower flow rate (10 mL/min), so that the effective contact area of a plurality of solution mixing processes can be remarkably improved, and therefore, the high-efficiency homogenizing mixing effect is realized under the lower flow rate, and the nanoparticle with controllable quality is obtained. The invention characterizes the loaded insulin nano-particles obtained under the flow rate condition of 25mL/min in detail, the particle diameter is about 50nm, the polydispersity index is lower than 0.2, the zeta potential of the nano-particles is about 9.6mV, the insulin encapsulation efficiency is about 89%, and the drug loading rate of the nano-particles is about 27%. The device provided by the invention can be used for preparing the drug-loaded nano-particles with small particle size and narrow particle size distribution under the condition of lower flow rate.
Example 3 preparation of polypeptide drug-loaded nanoparticles Using efficient mixing homogenizing apparatus
The salmon calcitonin is selected as a polypeptide drug model, glycol chitosan and salmon calcitonin are respectively dissolved in 0.2% acetic acid aqueous solution to obtain 1mg/mL and 0.5mg/mL mother liquor, the two mother liquor are mixed according to equal volume to obtain a glycol chitosan/salmon calcitonin mixed solution (hereinafter referred to as mixed solution), the pH value of the mixed solution is regulated to 5.8, the concentration of the glycol chitosan in the mixed solution is 0.5mg/mL, and the concentration of the salmon calcitonin in the mixed solution is 0.25mg/mL. The sulfonated glucan was dissolved in double distilled water to give an aqueous sulfonated glucan solution with a concentration of 0.2 mg/mL. The two main fluid inlets of the mixing device of fig. 5 were used to introduce the mixed solution, the other two main fluid inlets were used to introduce the aqueous sulfonated dextran solution, and the prepared salmon calcitonin nanoparticle loaded suspension was collected from the fluid outlet. As a result, as shown in FIG. 7, drug-loaded nanoparticles having a particle diameter of about 140 to 60nm can be obtained by controlling the flow rate of the fluid from 2 to 50 mL/min. When the flow rate of the fluid is controlled to be 20mL/min, the particle size of the prepared drug-loaded nano-particles is about 67nm, the polydispersity index is about 0.17, the zeta potential of the particles is about 18.2mV, the encapsulation efficiency of salmon calcitonin is about 69%, and the drug loading rate is about 16.5%. The invention shows that the medicine carrying nano particles with small particle size and narrow particle size distribution can be prepared and obtained under the condition of lower flow rate by the mixing and homogenizing device, and the medicine carrying nano particles with different particle sizes can be obtained by regulating the flow rate.
Example 4 preparation of nucleic acid-loaded nanoparticles Using a high efficiency mixing homogenization apparatus
GWiz-luciferase plasmid deoxyribonucleic acid (pDNA) is selected as a nucleic acid drug model, and plasmid nucleic acid (pDNA) is dissolved in double distilled water to obtain a nucleic acid aqueous solution with the concentration of 1.6 mg/mL; 2-dioleoyl hydroxypropyl-3-N, N, N-trimethylammonium chloride (DOTAP), 1, 2-dioleoyl-sn-glycero-3-phosphorylethanolamine (DOPE) and cholesterol are dissolved together in an ethanol solvent to obtain a lipid mixed solution, wherein the DOTAP concentration is 2.78mg/mL, the DOPE concentration is 1.11mg/mL and the cholesterol concentration is 0.44mg/mL. The two main fluid inlets of the mixing device shown in FIG. 5 are used for introducing double distilled water, the flow rates are 30mL/min, the other two main fluid inlets are used for respectively introducing nucleic acid aqueous solution and lipid mixed solution, the flow rates are 30mL/min, and the prepared nucleic acid nanoparticle-loaded suspension is collected from the fluid outlet. As a result, as shown in FIG. 8, nucleic acid-supporting nanoparticles were prepared with a particle diameter of about 205nm and a polydispersity index of about 0.2 using a mixing apparatus. The invention shows that the nucleic acid medicine carrying nano-particles with uniform size can be prepared under the condition of lower flow rate by the mixing and homogenizing device.
Example 5 preparation of Polymer nanoparticles Using a high efficiency mixing homogenizer
Polylactic acid-glycolic acid copolymer (PLGA) is dissolved in acetonitrile solvent to obtain PLGA solution with concentration of 2 mg/mL; vitamin E polyethylene glycol succinate (TPGS) was dissolved in an aqueous solution to give an aqueous solution of TPGS at a concentration of 5 mg/mL. The two main fluid inlets of the mixing device shown in fig. 5 are used for introducing double distilled water, the flow rates are 32mL/min, the other two main fluid inlets are respectively used for introducing TPGS aqueous solution and PLGA acetonitrile solution, the flow rates are 8mL/min, and the prepared PLGA nano particle suspension can be collected from the fluid outlet. As a result, as shown in FIG. 9, PLGA nanoparticles having a particle diameter of about 60nm and a polydispersity index of 0.17 were prepared. The present invention has been shown to provide a hybrid homogeneous device that can produce small-sized and uniform polymer nanoparticles for drug delivery applications at lower flow rates.
Claims (3)
1. The multichannel diversion efficient mixing and homogenizing device is characterized by comprising a shell and a fluid mixing cavity arranged in the shell; the mixing cavity is a cylindrical cavity and is provided with an axial fluid main outlet; four fluid main inlets which are in the same clockwise direction and are perpendicular to the axial direction of the cylindrical cavity are arranged in the shell, and two adjacent fluid main inlets are perpendicular to each other; a channel structure for splitting the fluid of the main inlet is arranged between the main inlet and the mixing cavity, so that each main inlet fluid enters the fluid mixing cavity along the axial vertical direction of the cylindrical cavity through at least two splitting channels, and the splitting channels are all arranged along the axial direction of the cylindrical cavity and are positioned on the same plane; the fluid main outlet and the fluid main inlet are respectively connected with an external pipeline through connecting parts on the shell; the fluid diversion channel is arranged in the tangential direction of the circular section of the cylindrical cavity; the shell is in a cuboid shape, the connecting parts connected with the fluid main outlet are arranged on one surface, and the connecting parts connected with the fluid main inlet are uniformly arranged on the surface adjacent to the surface where the connecting parts connected with the fluid main outlet are arranged.
2. The device of claim 1, wherein the connecting member is a hollow bolt.
3. The use of the multi-channel split-flow high-efficiency mixing homogenizing device according to any one of claims 1-2 in the preparation of drug-loaded nanoparticles.
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