CN104721052A - Nanometer drug preparation device - Google Patents

Abstract

The invention discloses a nano medicine preparation device. It is composed of a constant volume injector, a DC high voltage generator, a reactor, a constant temperature electromagnetic stirrer, and a central controller; the mixed solution of nano-medicine preparation raw materials is sprayed into the reactor from the top of the capillary of the constant volume injector; the DC high voltage The electric generator generates a DC high-voltage electric field between the positive and negative electrodes, and the high-voltage generated by it is loaded on the positive and negative electrodes located at the upper and lower ends of the reactor; the mixed solution is atomized into fine droplets under the action of the high-voltage electric field, and flows Under the action of the constant temperature electromagnetic stirrer, the atomized droplets form nano drug micelles in the solvent and solidify into nano drug particles. The prepared nano drug has uniform particle size, high drug loading rate and encapsulation rate, and high yield. And by adjusting the voltage of the DC high-voltage electric field, the flow rate of the constant sample injection, and the concentration of the sample solution, nano-medicines with different particle sizes can be prepared.

Description

A device for preparing nanomedicine

technical field

The invention specifically relates to a nano drug preparation device.

Background technique

At present, there are many preparation methods for nanomedicine, including chemical preparation techniques such as liquid phase reaction and vapor deposition, and physical preparation techniques such as mechanical pulverization. The commonly used nano-medicine preparation methods include dialysis and solvent evaporation method, precipitation method, emulsion method, microemulsion method, liposome method, supercritical fluid technology and other technologies.

Spray drying technology is a drying technology that uses compressed air to spray the emulsion or solution dissolved with drugs and wall materials into small mist droplets, quickly dry them into powder particles at a higher temperature, and then separate the drugs through a separation device. The shape and particle size of the drug can be adjusted by the air flow rate, air temperature, raw material concentration, pumping volume and adding various excipients. Spray drying technology can also be applied to the preparation of porous drug-loaded nanoparticles and microencapsulation of insoluble drugs. Disadvantages of the spray-drying method: ①The particle size of the prepared particles is usually on the micron scale; ②It is not suitable for temperature-sensitive drugs; ③The spray-drying method is mostly used for embedding oil-soluble drugs, and for water-soluble drugs, the prepared particles have obvious Burst effect. Therefore, these shortcomings limit the application of spray drying technology in the field of nanomedicine.

The high-pressure homogenization method is to extrude the drug solution through pores with a diameter of about 25 μm under high pressure (above 1.5×10 ⁵ Kpa). decrease. According to Bernoulli's equation, a sharp increase in dynamic pressure causes a sharp decrease in static pressure, lowering the boiling point of water below room temperature. The result is water boiling violently at room temperature and producing cavitation and micro-bursts, where the instantaneous high pressure of the burst breaks the particles into smaller micropowders. Through multiple (10-15) continuous high-pressure homogenization operations, the nano-suspension drug with a particle size in the range of 100 to 1000 nm and a solid content of 10% to 20% can be obtained.

Supercritical fluid technology is a technology in which drugs are dissolved in supercritical liquid, and when the liquid is decompressed and atomized through a nozzle with a small aperture, with the rapid gasification of the supercritical liquid, solid nanoparticles are precipitated immediately. Supercritical fluid technology has significant advantages: ①Ease of industrialization, adjustable product properties; ②High diffusivity, low viscosity; ③Low interfacial tension, strong solvency. The disadvantages of this method are: ① it can only be applied to the preparation of polylactic acid nanoparticles with a relative molecular mass below 10,000, and it is not suitable for polylactic acid with a larger molecular weight; ② it is possible for the drug to be in at least one solvent soluble, and the solvent must be miscible with a non-solvent. However, it is difficult for the newly developed compounds to meet the above conditions at the same time, so they cannot be prepared by supercritical fluid technology.

The dialysis and solvent evaporation method is to dissolve the drug or carrier in oil (or water), then add the obtained drug or carrier solution into water (or oil) to disperse, evaporate or dialysis to remove the organic solvent, and the drug or carrier in water (or oil) ) aggregates and nucleates due to a sharp decrease in solubility. The precipitation method is to generate particle precipitation in the solution through chemical reaction, and control the growth of the particle size of the precipitation through the control of various reaction conditions, so as to prepare nano-medicine.

Emulsion method is a method for preparing nano-medicine in emulsion. Generally, the dispersing effect of the surfactant and the shearing effect of the external force are used to form small droplets, and the reaction nucleation occurs on the surface or inside of the droplets to obtain small particles. There are also self-assembled nuclei using amphoteric polymers in emulsions. The specific methods include emulsion polymerization, emulsion self-assembly nucleation method, emulsification cross-linking method and membrane emulsification method.

Although both microemulsions and emulsions are dispersion systems formed by oil phase and water phase, there are fundamental differences between them. Microemulsion is a thermodynamically stable transparent or translucent dispersion system that can be formed spontaneously or by a slight external force. The emulsion is unstable, and it will separate after standing for a period of time. Microemulsions can form small pools of nanometer scale. If various reactions are limited in this small pool, it is conceivable that the reaction products are also nanometer. Moreover, the reaction conditions of the microemulsion method are very mild. By changing the formula of the microemulsion and changing the external conditions, the phase change of the microemulsion (oil-in-water, water-in-oil, bicontinuous phase) can be easily changed, and the shape of the small pool (spherical, rod, Layered, etc.), so as to obtain products with different nanostructures. The most attractive part of microemulsion is that it can solubilize a large amount of water and a large amount of oil at the same time, so that water-soluble substances and oil-soluble substances can be fully mixed, and the reaction efficiency is greatly improved. According to the type of microemulsion, it can be divided into direct phase microemulsion method (O/W) and reverse phase microemulsion method (W/O).

Nanoliposome preparation methods mainly include thin film evaporation method, reverse phase evaporation method, thin film ultrasonic dispersion method and so on. Thin film evaporation method. Dissolve the drug, cholesterol, and phospholipids in an organic solvent, evaporate the solvent to form a uniform lipid film on the wall of the flask with film-forming materials such as the drug and phospholipids, and then add washing solution to wash the film to obtain a liposome suspension. The reverse-phase evaporation method is to mix lecithin, cholesterol and an organic solvent, add an aqueous solution in which the drug is dissolved in the formed organic solution to form a relatively stable W/O emulsion, and then evaporate the organic solvent under reduced pressure to achieve a colloidal state. , add phosphate buffer solution, hydrate, and continue to evaporate under reduced pressure for a short time to obtain a light milky yellow liposome suspension. Thin-film ultrasonic dispersion method is to prepare phospholipid bimolecular membrane first, and then ultrasonically hydrate and disperse liposomes.

However, the nanomedicine prepared by these methods has the disadvantages of poor reproducibility, uneven particle size, low drug loading and encapsulation efficiency, low yield, unstable process, and difficulty in expanding production.

Contents of the invention

The purpose of the present invention is to provide a nano-medicine preparation device, which is used for large-scale preparation of various nano- or micro-spherical drug with uniform particle size and stability.

A nano-medicine preparation device, which is composed of a constant volume injector, a DC high-voltage generator, a reactor, a constant temperature electromagnetic stirrer, and a central controller; the mixed solution of nano-medicine preparation raw materials is sprayed from the top of the capillary of the constant volume injector In the reactor; the DC high-voltage electric generator generates a DC high-voltage electric field between the positive and negative electrodes, and the high voltage generated by it is loaded on the positive and negative electrodes at the upper and lower ends of the reactor; the mixed solution sprayed into the reactor is Under the action of a high-voltage electric field, it is atomized into fine droplets, and moves downward into the solvent in the reactor; under the action of a constant temperature electromagnetic stirrer, the atomized droplets form nano-drug micelles in the solvent, and further solidify into nano-particles. Drug particles, and dispersed evenly.

According to the above scheme, the magnitude and time of the voltage of the DC high voltage generator are controlled and adjusted by the sub-controller of the DC high voltage generator in the central controller, and the data are displayed.

According to the above scheme, the flow rate and injection time of the mixed solution are operated and managed by the sub-controller of the constant sample injector in the central controller, and the data are displayed.

According to the above scheme, the pressure, temperature and solvent volume in the reactor are controlled and regulated by the sub-controller of the reactor in the central controller, and the data are displayed.

According to the above scheme, the temperature of the solvent, the speed of heating and cooling, and the stirring speed are controlled and regulated by the sub-controller of the constant temperature electromagnetic stirrer in the central controller, and the data are displayed.

The application of the above-mentioned nano drug preparation device in the preparation of polymer carriers, inorganic non-metallic materials, nano or microsphere drugs, and capsule drugs.

Drugs, polymers and other carriers, various additives, etc. are dissolved in a solvent to form a mixed solution of a certain concentration, and the mixed solution is sprayed into the reactor at a certain flow rate through the top of a capillary with a certain aperture. Under the action of high voltage, the mixed solution sprayed into the reactor is atomized into fine droplets, and moves down into different solvents. Under the action of a certain temperature and a certain stirring speed, the atomized droplets are in the solvent Form nano-drug micelles, further solidify into nano-drug particles, and disperse evenly.

Compared with the current traditional nano-medicine preparation method, the nano-medicine preparation device of the present invention can fully mix and atomize a mixed solution of a certain concentration of drugs, polymers and other carriers, various auxiliary agents, etc. under the action of high voltage. The required various tiny droplets enter different solvents to form nano-drug micelles, which are further solidified into nano-drug particles with uniform particle size.

The beneficial effects of the present invention are:

(1) The particle size of the prepared nano-medicine is uniform, the drug loading rate and encapsulation rate are high, and the yield is high.

(2) The particle size of the prepared nano-medicine is controllable. By adjusting the voltage of the DC high-voltage electric field, the flow rate of constant sample injection, and the concentration of the sample solution, nano-medicines with different particle sizes can be prepared.

(3) The particle size of the prepared nano drug has good reproducibility, stability and easy operation.

Description of drawings

Figure 1: Schematic diagram of nanomedicine preparation device;

Fig. 2: TEM photograph 35nm of embodiment 1 nanoparticle;

Fig. 3: TEM photograph 100nm of embodiment 1 nanoparticle;

Fig. 4: TEM photograph 80nm of embodiment 1 nanoparticle;

1-Constant sample injector; 2-DC high voltage generator; 3-Reactor; 4-Constant temperature electromagnetic stirrer; 5, 6-Positive and negative electrodes; 7-Central controller; 8-Feeding port; 9- Outlet; among them, 7-1-constant sampler sub-controller; 7-2-DC high voltage generator sub-controller; 7-3-reactor sub-controller; 7-4-constant temperature electromagnetic stirrer sub-controller controller.

Detailed ways

The following examples further illustrate the technical solutions of the present invention, but are not intended to limit the protection scope of the present invention.

Nano drug preparation device of the present invention, with reference to shown in accompanying drawing 1, is made up of constant sample injector 1, DC high-voltage electric generator 2, reactor 3, constant temperature electromagnetic stirrer 4, central controller 7; Nano drug preparation raw material The mixed solution is sprayed into the reactor 3 from the top of the capillary of the constant volume injector 1; On the positive and negative electrodes (5, 6) at the end; the mixed solution sprayed into the reactor 3 is atomized into fine droplets under the action of a high-voltage electric field, and moves downward into the solvent in the reactor; Under the action of the agitator 4, the atomized liquid droplets form nano-medicine micelles in the solvent, which are further solidified into nano-medicine particles and dispersed uniformly. At the same time, the reactor 7 is also provided with a feed port 8 and a feed port 9 up and down.

Wherein, the magnitude and time of the DC high voltage generator voltage are controlled and adjusted by the DC high voltage generator sub-controller 7-2 in the central controller, and display data; the voltage range is 0-40000V.

The flow rate and injection time of the mixed solution are operated and managed by the sub-controller 7-1 of the constant sample injector in the central controller, and the data is displayed; the flow rate range is 0.001-5000mL/min.

According to the above scheme, the pressure, temperature, and solvent volume in the reactor are controlled and regulated by the sub-controller 7-3 of the reactor in the central controller, and display data; the feed port of the reactor is regulated and controlled by a metering control valve; The discharge port is regulated by the metering control valve. .

The temperature of the solvent, the heating and cooling speed, and the stirring speed are controlled and regulated by the sub-controller 7-4 of the constant temperature electromagnetic stirrer in the central controller, and the data is displayed; the speed range is 0-10000rpm.

The central controller is equipped with four independent parameter control color LCD screens, touch-sensitive screens, manual knobs, gear adjustment devices, or other display screens, which are the controller screens for adjusting and controlling the corresponding devices, and are used to adjust and control the corresponding devices. various operating parameters.

The above-mentioned nano-medicine preparation device can be used to prepare various nano- or micro-spherical particle materials such as nano- or micro-spherical drugs, capsule-type drugs, etc. from the composites of polymer carriers, inorganic non-metallic materials and various drugs. The diameter range of the nanometer particle is 0.1-100nm, the diameter range of the nanometer particle is 0.1-100nm, and the diameter range of the microsphere particle is 0.1μm-1mm.

Example 1

Preparation of polycarbonate nanomedicine:

10 mg of polycarbonate copolymer and 1 mg of 5-fluorouracil were dissolved in 2 mL of dimethyl sulfoxide (DMSO), which were placed in a mother liquor bottle, and polymer nanomedicine was prepared by high-voltage electric field electrospray method. The prepared nano-medicine is deposited in absolute ethanol, and after the solvent is drained, distilled water is used to dissolve and disperse the micelles. The size of polymer nanoparticles was determined by a ZetasizerNano ZS particle size analyzer.

In the process of preparing nano micelles by high-voltage electric atomization method, the influence of sample concentration, capillary loading voltage and flow rate on the size of micelles was further studied by using the method of orthogonal experiment. The results in Table 1 show that increasing the loading voltage of the capillary or reducing the sample concentration is conducive to the preparation of micelles with smaller particle sizes; and increasing the input flow rate of the sample will also increase the particle size of the prepared drug particles. By comparing the two methods of preparing nano-medicines, dialysis and high-voltage electric field electrospraying, it can be seen that the particle size of nano-drugs prepared by high-voltage electric field electrospraying is much smaller than that prepared by dialysis.

Table 1

Example 2:

100 mg of hydroxyl-containing polycarbonate copolymer and 10 mg of doxorubicin were dissolved in 20 mL of dimethyl sulfoxide (DMSO), placed in a mother liquor bottle, and polymer nanomedicine was prepared by high-voltage electric field electrospray method. The prepared nano-medicine is deposited in absolute ethanol, and after the solvent is drained, distilled water is used to dissolve and disperse the micelles.

The morphology of polymer nanomicelle was determined by Tecnai G220 transmission electron microscope and atomic force microscope. The size of the nanomicelles was determined using a Zetasizer Nano ZS particle size analyzer.

The variable working parameters of liquid electrospray include: liquid type, capillary loading voltage, liquid flow rate, and electrode distance. The viscosity, surface tension, conductivity, and dielectric constant of a liquid are related to the type of liquid. The electric field strength and capacitance are related to the electrode distance. Liquid charge is related to liquid flow. The above parameters affect the droplet diameter size. Copolymer nanomedicine was prepared by high-voltage electric field electrospray method, and the effects of polymer feed ratio, capillary loading voltage, liquid flow rate and solution concentration were mainly studied. The influence of the above factors on the polymer nanomicelle is shown in Table 2.

Table 2

It can be seen from Table 2 that reducing the sample concentration or increasing the loading voltage of the capillary is conducive to the preparation of micelles with smaller particle sizes; while increasing the input flow rate of the sample, the particle size of the prepared drug particles becomes larger.

Referring to Figures 1, 2, and 3, from the observation results of the transmission electron microscope, high-voltage electric field electrospraying produces spherical nano-medicines of relatively uniform size, and there is no adhesion between them.

Claims (6)

1. a Nano medication preparation facilities, is characterized in that being made up of constant injector, high direct voltage electric generator, reactor, thermostatic electromagnetic agitator, central controller; The mixed solution of Nano medication raw materials sprays in reactor by the capillary tip of constant injector; Described high direct voltage electric generator produces DC high voltage electric field between positive and negative electrode, its produce high tension voltage be carried in be positioned at the upper and lower two ends of reactor positive and negative electrode on; Spray into the mixed solution in reactor under the effect of high voltage electric field, be atomized into tiny drop, and move downward in the solvent entered in reactor; Under the effect of thermostatic electromagnetic agitator, atomized drop forms Nano medication micelle at solvent, is solidified into Nano medication granule further, and is uniformly dispersed.

2. Nano medication preparation facilities as claimed in claim 1, is characterized in that the size of described high direct voltage electric generator voltage, the time carries out control and regulation by high direct voltage electric generator sub-controller in central controller, and video data.

3. Nano medication preparation facilities as claimed in claim 1, is characterized in that the flow velocity of described mixed solution, sample injection time are undertaken operating by constant injector sub-controller in central controller and manage, and video data.

4. Nano medication preparation facilities as claimed in claim 1, is characterized in that pressure in described reactor, temperature, solvent volume carry out control and regulation by reactor sub-controller in central controller, and video data.

5. Nano medication preparation facilities as claimed in claim 1, is characterized in that the temperature of described solvent, rises heat with cooling rate, mixing speed by thermostatic electromagnetic agitator sub-controller control and regulation in central controller, and video data.

6. the application of Nano medication preparation facilities described in claim 1 in macromolecule carrier, Inorganic Non-metallic Materials, nanometer or microsphere drug, the preparation of capsule-type medicine.