A device for preparing microdroplets and a method for preparing chitosan microspheres

Abstract

The present invention relates to the field of microfluidics, and in particular to a device for preparing microdroplets and a method for preparing chitosan microspheres. The device provided by the present invention comprises a piezoelectric ceramic stacking structure, a piezoelectric base, a collecting tank, a cavity and a needle; a first opening is provided at the top of the piezoelectric base, and a polytetrafluoroethylene film is provided at the first opening; the piezoelectric ceramic stacking structure is located above the piezoelectric base, and the piezoelectric ceramic stacking structure is in contact with the polytetrafluoroethylene film; a second opening is provided at the bottom of the piezoelectric base; the second opening is connected to the needle; a droplet phase inlet is provided on one side of the piezoelectric base in the horizontal direction; the cavity is located below the piezoelectric base, and the needle is placed in the cavity; the collecting tank is located below the cavity. The device can prepare chitosan microspheres with controllable microsphere particle size.

Description

Technical Field

[0001] The invention relates to the technical field of microfluidics, and in particular to a device for preparing microdroplets and a method for preparing chitosan microspheres. Background Art

[0002] The formation process of droplets intuitively illustrates the complexity of microfluidic processing. The relatively small forces associated with surface tension produce a high degree of nonlinearity in the droplet formation process and are extremely sensitive to external disturbances. In order to form droplets from a continuous liquid phase, energy needs to be introduced and then converted into surface energy after the droplets are formed. Depending on the type of external input energy, the active control generation of droplets is mainly divided into: thermal control, magnetic control, gas drive / liquid drive control and piezoelectric control. Since piezoelectric drive has a very fast response, generally up to 200μs, research on the preparation of microdroplets by piezoelectric active excitation has received increasing attention. At present, the introduction of piezoelectric perturbations is mainly aimed at microfluidic chips, but the microdroplets generated by two-dimensional microfluidic chip technology often come into contact with the cavity wall and deform, resulting in uncontrollable microspheres prepared subsequently.

[0003] At the same time, chitosan is a deacetylated product of chitin in the shells of crabs and shrimps. Due to its good biocompatibility, biodegradability, bioadhesion and other characteristics, it has broad application prospects in the fields of medicine and bioengineering materials. Chitosan microspheres have a large surface area to volume ratio. As a drug carrier, they can increase the water solubility and stability of drugs, control the release of drugs, and improve the bioavailability of drugs. Therefore, the preparation of chitosan microspheres that meet the requirements can make high value-added use of chitosan, a natural resource.

[0004] At present, the preparation methods of chitosan microspheres mainly include emulsification dispersion cross-linking method, solvent evaporation method, coagulation method and spray drying method. Emulsification dispersion cross-linking method is the most widely used method in microsphere preparation, but this method must introduce cross-linking agents such as formaldehyde and glutaraldehyde. Many documents report microsphere preparations cross-linked with glutaraldehyde. Whether a small amount of glutaraldehyde produced after the microspheres are degraded in vivo is still questioned. In the process of preparing chitosan microspheres, the solvent evaporation method will add organic solvents that are harmful to the human body, and the residual organic solvent will inevitably bring safety problems to the use of chitosan microspheres prepared by this method. Coagulation method is to add anionic gelling aqueous solution to chitosan solution to form insoluble chitosan derivatives. The mechanical strength of the product obtained by this method is not high, and the spherical shape is not good. Spray drying method is to dissolve chitosan and disperse it in an acidic solution, and then spray it in a hot air flow to evaporate the solvent rapidly into gas to form chitosan microspheres. This method is simple to operate, but the particle size of the prepared microspheres is difficult to control and is not suitable for some drugs that are sensitive to temperature.

[0005] Therefore, it is of great significance to obtain chitosan microspheres with controllable particle size by preparing microdroplets. Summary of the invention

[0006] The purpose of the present invention is to provide a device for preparing micro-droplets and a method for preparing chitosan microspheres. The device can achieve controllable particle size of microspheres.

[0007] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0008] The present invention provides a device for preparing micro-droplets, comprising a piezoelectric ceramic stacking structure 5, a piezoelectric base 1, a collecting tank 8, a cavity 7 and a needle 9;

[0009] The top of the piezoelectric base 1 is provided with a first opening 11, and a polytetrafluoroethylene film 2 is provided at the first opening 11;

[0010] The piezoelectric ceramic stacking structure 5 is located above the piezoelectric base 1, and the piezoelectric ceramic stacking structure 5 is in contact with the polytetrafluoroethylene film 2;

[0011] The bottom of the piezoelectric base 1 is provided with a second opening 12;

[0012] The second opening 12 is connected to the needle 9;

[0013] A droplet phase inlet 6 is provided on one side of the piezoelectric base 1 in the horizontal direction;

[0014] The cavity 7 is located below the piezoelectric base, and the needle 9 is placed in the cavity 7;

[0015] The collecting tank 8 is located below the cavity 7 .

[0016] Preferably, it also includes a fixing seat 3 and a fixing bracket 4;

[0017] The two ends of the fixing bracket 4 are respectively connected to the fixing base 3 and the piezoelectric base 1;

[0018] The piezoelectric ceramic stack structure 5 is fixed by a fixing seat 3 and a fixing bracket 4 .

[0019] Preferably, the piezoelectric ceramic stacking structure 5 includes a threaded base 13, a coaxial cable 14, a stainless steel housing 15, a pre-tightening mechanical structure 17, a piezoelectric ceramic 16 and a moving end 18;

[0020] The piezoelectric ceramic stack structure 5 is connected to the fixing seat 3 via a threaded base 13;

[0021] The coaxial cable 14 is connected to the piezoelectric ceramic 16;

[0022] The mobile end 18 is connected to the piezoelectric ceramic 16;

[0023] The pre-tightening mechanical structure 17 is located at the bottom of the stainless steel housing 15 and connected to the moving end 18 to achieve vibration of the moving end 18 .

[0024] Preferably, the piezoelectric ceramic stack structure 5 is connected to a parameter control module 19 via a coaxial cable 14;

[0025] A signal generator 20 and a power amplifier 21 are sequentially arranged between the parameter control module 19 and the piezoelectric ceramic stack structure 5 .

[0026] Preferably, the parameter control module 19 is also electrically connected to the droplet phase inlet 6; a micro-injection pump 22 is provided between the parameter control module 19 and the droplet phase inlet 6;

[0027] The parameter control module 19 is also electrically connected to the cavity 7 ; a high-pressure gas cylinder 23 is provided between the parameter control module 19 and the cavity 7 .

[0028] The present invention also provides a method for preparing chitosan microspheres using the preparation device described in the above technical solution, comprising the following steps:

[0029] Placing a paraffin oil solution of terephthalaldehyde with a mass concentration of 2% to 4% in the collecting tank 8;

[0030] mixing chitosan and glacial acetic acid to obtain a chitosan solution;

[0031] Nitrogen is introduced into the cavity 7 as a driving gas, and the chitosan solution is injected into the piezoelectric base 1 through the droplet phase inlet 6. The piezoelectric ceramic stacking structure 5 is driven to disturb the chitosan solution through the polytetrafluoroethylene film 2, so that the chitosan solution flowing out through the needle 9 and forming the jet injection 10 is broken to produce chitosan droplets. The chitosan droplets fall into the collecting tank 8 to undergo a cross-linking reaction to obtain the chitosan microspheres.

[0032] Preferably, the mass concentration of the chitosan solution is 4% to 8%; the flow rate of the chitosan solution injected into the piezoelectric base 1 is 60 to 80 mL / h.

[0033] Preferably, the driving voltage of the piezoelectric ceramic stacking structure 5 is 400-1000 mV, and the driving frequency is 2.8-4.2 kHz.

[0034] Preferably, the driving waveform for driving the piezoelectric ceramic stacking structure 5 is a sine wave, a square wave or a sawtooth wave.

[0035] Preferably, the pressure of the cavity 7 is >0.5 kPa;

[0036] The cross-linking reaction time is 30 minutes.

[0037] The present invention provides a device for preparing micro-droplets, comprising a piezoelectric ceramic stacking structure 5, a piezoelectric base 1, a collecting tank 8, a cavity 7 and a needle 9; a first opening 11 is arranged at the top of the piezoelectric base 1, and a polytetrafluoroethylene film 2 is arranged at the first opening 11; the piezoelectric ceramic stacking structure 5 is located above the piezoelectric base 1, and the piezoelectric ceramic stacking structure 5 is in contact with the polytetrafluoroethylene film 2; a second opening 12 is arranged at the bottom of the piezoelectric base 1; the second opening 12 is connected to the needle 9; a micro-droplet phase inlet 6 is arranged on one side of the piezoelectric base 1 in the horizontal direction; the cavity 7 is located below the piezoelectric base, and the needle 9 is placed in the cavity 7; the collecting tank 8 is located below the cavity 7. The device described in the present invention arranges a piezoelectric ceramic stacking structure at the first opening of the piezoelectric base, and transmits the vibration energy of the piezoelectric ceramic to the chitosan solution in the piezoelectric base through a polytetrafluoroethylene film. The vibration energy is disturbed during the process of forming a cone and a jet injection, thereby preparing chitosan microdroplets, and the size and generation frequency of the microdroplets generated by the jet column breakup are controlled by controlling the driving conditions of the piezoelectric ceramic stacking structure; the chitosan microdroplets fall into a collecting tank, undergo a cross-linking reaction with a curing agent in the collecting tank, and obtain chitosan microspheres with controllable microsphere particle size. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 This is a schematic diagram of the structure of the device for preparing micro-droplets according to the present invention;

[0039] Figure 2 is a schematic diagram of the piezoelectric ceramic stacking structure of the present invention;

[0040] Among them, 1- piezoelectric base, 2-polytetrafluoroethylene film, 3-fixed seat, 4-fixed bracket, 5-piezoelectric ceramic stacking structure, 6-droplet phase inlet, 7-cavity, 8-collecting container, 9-needle, 10-jet column, 11-first opening, 12-second opening, 13-threaded base, 14-coaxial cable, 15-stainless steel shell, 16-piezoelectric ceramic, 17-pretightening mechanical structure, 18-mobile terminal, 19-parameter control module, 20-signal generator, 21-power amplifier, 22-micro injection pump, 23-high-pressure gas cylinder. DETAILED DESCRIPTION

[0041] The present invention provides a device for preparing micro-droplets, comprising a piezoelectric ceramic stacking structure 5, a piezoelectric base 1, a collecting tank 8, a cavity 7 and a needle 9;

[0042] The top of the piezoelectric base 1 is provided with a first opening 11, and a polytetrafluoroethylene film 2 is provided at the first opening 11;

[0043] The piezoelectric ceramic stacking structure 5 is located above the piezoelectric base 1, and the piezoelectric ceramic stacking structure 5 is in contact with the polytetrafluoroethylene film 2;

[0044] The bottom of the piezoelectric base 1 is provided with a second opening 12;

[0045] The second opening 12 is connected to the needle 9;

[0046] A droplet phase inlet 6 is provided on one side of the piezoelectric base 1 in the horizontal direction;

[0047] The cavity 7 is located below the piezoelectric base, and the needle 9 is placed in the cavity 7;

[0048] The collecting tank 8 is located below the cavity 7 .

[0049] As an embodiment of the present invention, it also includes a fixing seat 3 and a fixing bracket 4;

[0050] The two ends of the fixing bracket 4 are respectively connected to the fixing base 3 and the piezoelectric base 1;

[0051] The piezoelectric ceramic stack structure 5 is fixed by a fixing seat 3 and a fixing bracket 4 .

[0052] As an embodiment of the present invention, the piezoelectric ceramic stack structure 5 includes a threaded base 13, a coaxial cable 14, a stainless steel housing 15, a pre-tightening mechanical structure 17, a piezoelectric ceramic 16 and a moving end 18;

[0053] The piezoelectric ceramic stack structure 5 is connected to the fixing seat 3 via a threaded base 13;

[0054] The coaxial cable 14 is connected to the piezoelectric ceramic 16;

[0055] The mobile end 18 is connected to the piezoelectric ceramic 16;

[0056] The pre-tightening mechanical structure 17 is located at the bottom of the stainless steel housing 15 and connected to the moving end 18 to achieve vibration of the moving end 18 .

[0057] As an embodiment of the present invention, the piezoelectric ceramic stack structure 5 is connected to a parameter control module 19 via a coaxial cable 14;

[0058] A signal generator 20 and a power amplifier 21 are sequentially arranged between the parameter control module 19 and the piezoelectric ceramic stack structure 5 .

[0059] As an embodiment of the present invention, the parameter control module 19 is also electrically connected to the droplet phase inlet 6; a micro-injection pump 22 is provided between the parameter control module 19 and the droplet phase inlet 6;

[0060] The parameter control module 19 is also electrically connected to the cavity 7 ; a high-pressure gas cylinder 23 is provided between the parameter control module 19 and the cavity 7 .

[0061] The present invention also provides a method for preparing chitosan microspheres using the preparation device described in the above technical solution, comprising the following steps:

[0062] Placing a paraffin oil solution of terephthalaldehyde with a mass concentration of 2% to 4% in the collecting tank 8;

[0063] mixing chitosan and glacial acetic acid to obtain a chitosan solution;

[0064] Nitrogen is introduced into the cavity 7 as a driving gas, and the chitosan solution is injected into the piezoelectric base 1 through the droplet phase inlet 6. The piezoelectric ceramic stacking structure 5 is driven to disturb the chitosan solution through the polytetrafluoroethylene film 2, so that the chitosan solution flowing out through the needle 9 and forming the jet injection 10 is broken to produce chitosan droplets. The chitosan droplets fall into the collecting tank 8 to undergo a cross-linking reaction to obtain the chitosan microspheres.

[0065] In the present invention, unless otherwise specified, all preparation raw materials are commercially available products well known to those skilled in the art.

[0066] In the present invention, the mass concentration of the chitosan solution is preferably 4% to 8%, more preferably 5% to 6%.

[0067] In the present invention, the flow rate of the chitosan solution injected into the piezoelectric base 1 is preferably 60-80 mL / h, more preferably 65-75 mL / h. In the present invention, the flow rate of the chitosan solution injected into the piezoelectric base 1 is controlled by the parameter control module 19 .

[0068] In the present invention, the driving voltage of the driving piezoelectric ceramic stacking structure 5 is preferably 400-1000mV, more preferably 400mV; the driving frequency is preferably 2.8-4.2kHz, more preferably 4kHz. In the present invention, the driving waveform of the driving piezoelectric ceramic stacking structure 5 is a sine wave, a square wave or a sawtooth wave. In the present invention, the driving voltage, driving frequency and driving waveform are controlled by the parameter control module 19.

[0069] In the present invention, the pressure of the cavity 7 is >0.5 kPa.

[0070] In the present invention, the cross-linking reaction time is preferably 30 minutes.

[0071] The device for preparing micro-droplets and the method for preparing chitosan microspheres provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0072] Example 1

[0073] Placing a paraffin oil solution of terephthalaldehyde with a mass concentration of 4% in the collecting tank 8;

[0074] Mixing chitosan and glacial acetic acid to obtain a chitosan solution with a mass concentration of 8%;

[0075] Nitrogen is introduced into the cavity 7 as a driving gas, and the pressure of the cavity is 50 kPa; the chitosan solution is injected into the piezoelectric base 1 through the droplet phase inlet 6 at a flow rate of 60 mL / h, and the piezoelectric ceramic stacking structure 5 is driven to disturb the chitosan solution through the polytetrafluoroethylene film 2. The driving voltage is 400 mV, the driving frequency is 2.8 kHz, and the driving waveform is a sine wave; the chitosan solution that flows out through the needle 9 and forms a jet injection 10 is broken to produce chitosan droplets, and the chitosan droplets fall into the collecting tank 8 to undergo a cross-linking reaction for 30 minutes to obtain the chitosan microspheres (particle size is 270 μm).

[0076] Example 2

[0077] Placing a paraffin oil solution of terephthalaldehyde with a mass concentration of 2% in the collecting tank 8;

[0078] Mixing chitosan and glacial acetic acid to obtain a chitosan solution with a mass concentration of 2.5%;

[0079] Nitrogen is introduced into the cavity 7 as a driving gas, and the pressure of the cavity is 50 kPa; the chitosan solution is injected into the piezoelectric base 1 through the droplet phase inlet 6 at a flow rate of 60 mL / h, and the piezoelectric ceramic stacking structure 5 is driven to disturb the chitosan solution through the polytetrafluoroethylene film 2, the driving voltage is 400 mV, the driving frequency is 4 kHz, and the driving waveform is a sine wave; the chitosan solution flowing out through the needle 9 and forming the jet injection 10 is broken to produce chitosan droplets, and the chitosan droplets fall into the collecting tank 8 to undergo a cross-linking reaction for 30 minutes to obtain the chitosan microspheres (particle size is 225 μm).

[0080] Example 3

[0081] Placing a paraffin oil solution of terephthalaldehyde with a mass concentration of 2% in the collecting tank 8;

[0082] Mixing chitosan and glacial acetic acid to obtain a chitosan solution with a mass concentration of 2.5%;

[0083] Nitrogen is introduced into the cavity 7 as a driving gas, and the pressure of the cavity is 50 kPa; the chitosan solution is injected into the piezoelectric base 1 through the droplet phase inlet 6 at a flow rate of 60 mL / h, and the piezoelectric ceramic stacking structure 5 is driven to disturb the chitosan solution through the polytetrafluoroethylene film 2. The driving voltage is 400 mV, the driving frequency is 4.2 kHz, and the driving waveform is a sine wave; the chitosan solution that flows out through the needle 9 and forms a jet injection 10 is broken to produce chitosan droplets, and the chitosan droplets fall into the collecting tank 8 to undergo a cross-linking reaction for 30 minutes to obtain the chitosan microspheres (particle size is 210 μm).

[0084] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A device for preparing microdroplets, characterized in that: It comprises a piezoelectric ceramic stack structure (5), a piezoelectric base (1), a collecting tank (8), a cavity (7) and a needle (9); A first opening (11) is provided at the top of the piezoelectric base (1), and a polytetrafluoroethylene film (2) is provided at the first opening (11); The piezoelectric ceramic stacking structure (5) is located above the piezoelectric base (1), and the piezoelectric ceramic stacking structure (5) is in contact with the polytetrafluoroethylene film (2); The bottom of the piezoelectric base (1) is provided with a second opening (12); The second opening (12) is connected to the needle (9); A droplet phase inlet (6) is provided on one side of the piezoelectric base (1) in the horizontal direction; The cavity (7) is located below the piezoelectric base, and the needle (9) is placed in the cavity (7); The collecting tank (8) is located below the cavity (7); It also includes a fixing seat (3) and a fixing bracket (4); The two ends of the fixed bracket (4) are respectively connected to the fixed seat (3) and the piezoelectric base (1); The piezoelectric ceramic stack structure (5) is fixed by means of a fixing seat (3) and a fixing bracket (4); The piezoelectric ceramic stack structure (5) comprises a threaded base (13), a coaxial cable (14), a stainless steel housing (15), a pre-tightening mechanical structure (17), a piezoelectric ceramic (16) and a moving end (18); The piezoelectric ceramic stack structure (5) is connected to the fixing seat (3) via a threaded base (13); The coaxial cable (14) is connected to the piezoelectric ceramic (16); The mobile end (18) is connected to the piezoelectric ceramic (16); The pre-tightening mechanical structure (17) is located at the bottom of the stainless steel housing (15) and is connected to the moving end (18) to achieve vibration of the moving end (18); The piezoelectric ceramic stack structure (5) is connected to a parameter control module (19) via a coaxial cable (14). A signal generator (20) and a power amplifier (21) are arranged in sequence between the parameter control module (19) and the piezoelectric ceramic stack structure (5).

2. The device according to claim 1, characterized in that The parameter control module (19) is also electrically connected to the microdroplet phase inlet (6); a microinjection pump (22) is provided between the parameter control module (19) and the microdroplet phase inlet (6); The parameter control module (19) is also electrically connected to the cavity (7); and a high-pressure gas cylinder (23) is provided between the parameter control module (19) and the cavity (7).

3. A method for preparing chitosan microspheres using the device for preparing microdroplets according to claim 1 or 2, characterized in that: The following steps are involved: Placing a paraffin oil solution of terephthalaldehyde having a mass concentration of 2% to 4% in the collecting tank (8); mixing chitosan and glacial acetic acid to obtain a chitosan solution; Nitrogen is introduced into the cavity (7) as a driving gas, and the chitosan solution is injected into the piezoelectric base (1) through the droplet phase inlet (6). The piezoelectric ceramic stack structure (5) is driven to disturb the chitosan solution through the polytetrafluoroethylene film (2), so that the chitosan solution flowing out through the needle (9) and forming a jet injection (10) is broken to produce chitosan droplets. The chitosan droplets fall into the collection tank (8) to undergo a cross-linking reaction, thereby obtaining the chitosan microspheres.

4. The method according to claim 3, characterized in that The mass concentration of the chitosan solution is 4% to 8%; The chitosan solution is injected into the piezoelectric base (1) at a flow rate of 60-80 mL / h.

5. The method according to claim 3, characterized in that The driving voltage of the driving piezoelectric ceramic stack structure (5) is 400-1000 mV, and the driving frequency is 2.8-4.2 kHz.

6. The method according to claim 3 or 5, characterized in that The driving waveform for driving the piezoelectric ceramic stacking structure (5) is a sine wave, a square wave or a sawtooth wave.

7. The method according to claim 3, characterized in that The pressure of the cavity (7) is >0.5 kPa; The cross-linking reaction time is 30 minutes.

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