Preparation device of polylactic acid microspheres

Abstract

The utility model discloses a preparation device of polylactic acid microspheres. The preparation device comprises a reaction kettle body, a reaction kettle cover which is arranged on the reaction kettle body and covers an upper opening of the reaction kettle body, and a solvent recovery distillation device which is connected with the reaction kettle cover, the polylactic acid microsphere preparation device disclosed by the utility model can be used for rapidly preparing polylactic acid microspheres with concentrated particle size distribution on a large scale, and when the polylactic acid microspheres are heated and cured, volatilized dichloromethane or trichloromethane gas can continuously condense and recover a volatilized solvent through the solvent distillation and recovery device, so that the polylactic acid microspheres can be rapidly prepared. The toxic action on production personnel and the damage to the environment are avoided, and the reutilization of the solvent can also be realized.

Description

Technical Field

[0001] The utility model relates to a medical beauty product, in particular to a preparation device for polylactic acid microspheres. Background Art

[0002] Biodegradable polymer microspheres represented by polylactic acid are widely used in the field of medical cosmetology due to their good biocompatibility and biodegradability. The intermediate product of polylactic acid degradation is lactic acid, which can eventually be degraded into carbon dioxide and water that are harmless to the human body and the environment. During the degradation process of polylactic acid, lactic acid will be gradually released, which will increase the activity of fibroblast transforming growth factor TGF-β, proline hydroxylase and matrix metalloproteinase inhibitors, stimulate the proliferation, differentiation and metabolism of fibroblasts, and promote collagen secretion until polylactic acid is completely degraded. Therefore, the collagen stimulating filler prepared with polylactic acid microspheres as the main material can ensure a longer filling effect.

[0003] The main preparation methods of polylactic acid microspheres include spray drying, phase separation, emulsification solvent evaporation, etc. The spray drying method sprays the suspension or emulsion into hot air, so that the solvent evaporates quickly in a few seconds and converts into solid particles, and the hot air temperature needs to be strictly controlled. The phase separation method makes use of the physical and chemical properties of the polymer to add a non-solvent liquid to the polymer solution so that the polymer precipitates and forms, but the consumption of organic solvents is huge. The emulsification-solvent evaporation method has the advantages of convenient operation, simple process, and easy to expand production, and is suitable for wide application. The emulsification-solvent evaporation method often adjusts the emulsification speed, solvent type, emulsification temperature and time to achieve particle size regulation. However, if the process conditions are not well controlled, the polylactic acid microspheres will have irregular morphology, agglomeration and adhesion between microspheres, and a wide distribution of microsphere sizes, which will seriously affect the application of microspheres.

[0004] CN116139790A uses the principle of emulsification-solvent evaporation method and uses a microfluidic device to prepare polylactic acid microspheres with uniform particle size, but the microfluidic device has high requirements for precision and low yield of microsphere preparation, making it difficult to apply to industrial production on a large scale. CN115531607A, CN114931554A, and CN108653817A all use the emulsification-solvent evaporation method to prepare microspheres, but the removal methods of the organic solvents used to dissolve polyester materials are all natural evaporation or heated evaporation, which poses great harm to the environment and production personnel. The microsphere preparation device and microsphere preparation method of the utility model of the patent use a solvent recovery distillation device to achieve complete recycling of the organic solvent, greatly reducing the harm to the environment and production personnel, and are significantly innovative.

[0005] According to the beneficial effects of the utility model patent, in addition to the above contents, the microsphere preparation method of the utility model controls the volume ratio of the continuous phase to the dispersed phase, the mass ratio of polyvinyl alcohol to polylactic acid, the stirring speed and the emulsification speed, the removal temperature of the organic solvent, etc. CN115531607A only controls the mass fraction of the surfactant and the stirring and shearing homogenization rates; CN114931554A lacks the mass ratio of the degradable polymer to the surfactant. The microsphere preparation method of the utility model controls multiple parameters that affect the quality of the finished polylactic acid microspheres, effectively ensuring the availability of the finished polylactic acid microspheres. Utility Model Content

[0006] In view of the problems existing in the prior art, the utility model has made improvements to the prior art and provides a preparation device for polylactic acid microspheres. The utility model is achieved through the following technical solutions:

[0007] The utility model discloses a preparation device for polylactic acid microspheres, comprising: a reaction kettle body, a reaction kettle cover arranged on the reaction kettle body to cover an opening on the reaction kettle body, and a solvent recovery distillation device connected to the reaction kettle cover;

[0008] The reactor body comprises an inner cylinder, an outer cylinder, an interlayer formed between the inner cylinder and the outer cylinder, an interlayer inlet and outlet opened on the outer surface of the interlayer, a tank bottom valve located below the reactor body, and a high-temperature circulation device connected to the interlayer inlet and outlet;

[0009] The reactor cover comprises a feed port, a distillation port, a stirring device and an emulsifying device which are provided on the surface of the reactor cover. The stirring device comprises a stirring motor and a stirring rod connected to the stirring motor. The stirring motor is located at the center above the reactor cover. The stirring rod extends into the inner cylinder of the reactor body to achieve stirring of the reaction liquid. The emulsifying device comprises an emulsifying motor located above the reactor cover and an emulsifying head connected to the emulsifying motor. The emulsifying head extends into the inner cylinder of the reactor body to generate polylactic acid microsphere droplets through shear force.

[0010] The solvent recovery distillation device comprises a condenser, a circulation inlet and outlet opened on the surface of the condenser, a low-temperature circulation device connected to the condensation circulation inlet and outlet, a reflux head arranged at the bottom of the condenser, and a collecting bottle connected below the reflux head.

[0011] As a further improvement, the high-temperature circulation device described in the utility model circulates the circulating liquid of the high-temperature circulation device through the interlayer inlet and outlet, and supplies heat to the reaction kettle body in real time, so that the solvent in the polylactic acid microsphere droplets evaporates and solidifies into polylactic acid microspheres; the tank bottom valve is used to release the reaction liquid in the inner cylinder.

[0012] As a further improvement, the reflux head described in the utility model is provided with three open ends, one end of which is connected to the distillation port, one end is connected to the bottom of the condenser, and the last end is connected to the collecting bottle, so as to realize the diversion of the volatile solvent from the inner cylinder to the condenser and the collection of the condensed solvent. The collecting bottle collects the condensed solvent. The condenser has a double-layer structure and is connected to the low-temperature circulation device to realize the condensation of the volatile solvent.

[0013] As a further improvement, the reactor body and the reactor cover described in the utility model are connected by a sealing ring, a screw or a clamp, and the reactor body, the reactor cover and the solvent recovery distillation device are made of corrosion-resistant material, preferably 316 stainless steel.

[0014] The beneficial effects of the utility model are:

[0015] 1. The polylactic acid microsphere preparation device of the utility model uses a stirring device and an emulsifying device at the same time, and is used in conjunction with the microsphere preparation method, so that the dispersed phase polylactic acid solution can be efficiently and evenly dispersed into polylactic acid droplets, and polylactic acid microspheres with concentrated particle size distribution can be prepared in large quantities and quickly.

[0016] 2. The polylactic acid microsphere preparation device of the utility model uses the interlayer formed between the inner cylinder and the outer cylinder to circulate the circulating liquid heated by the high-temperature circulation device, so as to realize water bath heating of the reaction liquid, thereby avoiding the temperature fluctuation caused by directly heating the reaction liquid; when the polylactic acid microspheres are heated and cured, the volatilized dichloromethane or chloroform gas can be passed through the solvent recovery distillation device to continuously condense and recover the volatilized solvent, thereby avoiding the toxic effects on the production personnel and the damage to the environment, and also realizing the reuse of the solvent.

[0017] 3. In the device for preparing polylactic acid microspheres of the utility model, when polylactic acid droplets are heated and solidified into polylactic acid microspheres, the volatilized dichloromethane or chloroform gas can be directed to the condenser through the guide of the reflux head, and the volatilized solvent is continuously condensed; the condensed solvent is then collected in the collection bottle through the reflux head, thereby achieving complete recovery and reuse of the organic solvent, avoiding toxic effects on production personnel and damage to the environment, and also achieving solvent reuse.

[0018] 5. The polylactic acid microspheres prepared by the device of the utility model have better ball-forming effect, higher yield and more concentrated particle size distribution.

[0019] 6. The polylactic acid microspheres prepared by the utility model have high biocompatibility, can stimulate collagen regeneration, and can be used as a component of a filler. They can be suspended with an aqueous solution of sodium carboxymethyl cellulose and mannitol, and freeze-dried for use in the field of medical beauty injections. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 is a schematic diagram of an embodiment of a device for preparing polylactic acid microspheres;

[0021] Figure 2 is a particle size distribution diagram of polylactic acid microspheres prepared by the microsphere preparation method;

[0022] Figure 3 This is a photo of polylactic acid microspheres with a particle size range of 10 to 50 μm prepared by the microsphere preparation method;

[0023] Figure 4 This is a tissue section diagram of the polylactic acid microspheres prepared by the utility model, which were implanted subcutaneously in rabbits for 3 months to stimulate the production of collagen;

[0024] Figure 5 This is a tissue section diagram of the polylactic acid microspheres prepared by the utility model, which were implanted subcutaneously in rabbits for 6 months to stimulate the production of collagen;

[0025] In the figure, 11 is an inner tube, 12 is an outer tube, 13 is an interlayer inlet and outlet, 14 is a tank bottom valve, and 15 is a high temperature circulation device;

[0026] 21 feed port, 22 distillation port, 23 emulsification motor, 24 emulsification head, 25 stirring motor, 26 stirring rod blade;

[0027] 31 condenser, 32 condensation circulation inlet and outlet, 33 low temperature circulation device, 34 reflux head, 35 collection bottle. DETAILED DESCRIPTION

[0028] The present invention is further described below in conjunction with specific embodiments and drawings. More details are elaborated in the following description to facilitate a full understanding of the present invention. However, the present invention can obviously be implemented in a variety of other ways different from the description. Those skilled in the art can make similar generalizations and deductions based on actual application situations without violating the connotation of the present invention. Therefore, the protection scope of the present invention should not be limited by the content of this specific embodiment.

[0029] It should be noted that these and other subsequent drawings are only examples and are not drawn in proportion, and should not be used as a limitation on the actual scope of protection required by the present utility model.

[0030] like Figure 1 As shown, the preparation device of polylactic acid microspheres includes a reaction kettle body 10, a reaction kettle cover 20 disposed on the reaction kettle body to cover the opening of the reaction kettle body, and a solvent recovery distillation device 30 connected to the reaction kettle cover;

[0031] like Figure 1 As shown, the reactor body 10 includes an inner cylinder 11, an outer cylinder 12, an interlayer 13 formed between the inner cylinder and the outer cylinder, an interlayer inlet and outlet 14 opened on the outer surface of the interlayer, a tank bottom valve 15 located below the reactor body, and a high-temperature circulation device 16 connected to the interlayer inlet and outlet;

[0032] like Figure 1 As shown, the reactor cover 20 includes a feed port 21, a distillation port 22, a stirring device, and an emulsifying device, which are opened on the surface of the reactor cover. The stirring device includes a stirring motor 23 and a stirring rod 24 connected to the stirring motor. The stirring motor 23 is located in the center above the reactor cover. The stirring rod 24 extends into the inner cylinder 11 of the reactor body 10 to achieve stirring of the reaction liquid. The emulsifying device is composed of an emulsifying motor 25 located above the reactor cover and an emulsifying head 26 connected to the emulsifying motor. The emulsifying head 26 extends into the inner cylinder 10 of the reactor body to generate polylactic acid microsphere droplets through shear force.

[0033] like Figure 1 As shown, the solvent recovery distillation device 30 includes a condenser 31, a circulation inlet and outlet 32 ​​opened on the surface of the condenser, a low-temperature circulation device 33 connected to the condensation circulation inlet and outlet, a reflux head 34 arranged at the bottom of the condenser, and a collection bottle 35 connected below the reflux head.

[0034] In one or more embodiments, the high-temperature circulation device 15 circulates the circulating liquid of the high-temperature circulation device through the interlayer inlet and outlet 13 to supply heat to the reactor body 10 in real time, so that the solvent in the polylactic acid microsphere droplets evaporates and solidifies into polylactic acid microspheres; the tank bottom valve 14 is used to release the reaction liquid in the inner tube 11.

[0035] In one or more embodiments, the reflux head 34 is provided with three open ends, one end of which is connected to the distillation port 22, one end is connected to the bottom of the condenser 31, and the last end is connected to the collecting bottle 35, so as to realize the diversion of the volatile solvent from the inner cylinder 11 to the condenser 31 and the collection of the condensed solvent. The collecting bottle 35 collects the condensed solvent. The condenser 31 is a double-layer structure, which is connected to the low-temperature circulation device 33 to realize the condensation of the volatile solvent.

[0036] In one or more embodiments, the reactor body 10 is connected to the reactor cover 20 via a sealing ring, screws or clamps. The reactor body 10, the reactor cover 20 and the solvent recovery distillation device 30 are made of corrosion-resistant material, preferably 316 stainless steel.

[0037] In one or more embodiments, the dispersed phase is continuously added to the mobile phase through the feed port 21 at a uniform low speed to improve the uniformity of the prepared polylactic acid microspheres.

[0038] In one or more embodiments, the continuous phase is an aqueous system containing a polyvinyl alcohol surfactant; the dispersed phase is an organic solvent system containing polylactic acid, and the organic solvent is preferably one of dichloromethane or chloroform or a mixture of the two. Due to the corrosiveness, flammability and explosiveness of organic solvents, the reactor is preferably explosion-proof equipment, and the material is preferably 316 stainless steel.

[0039] Combined with the above introduction to the polylactic acid microsphere preparation device, a preparation method for preparing polylactic acid microspheres with concentrated particle size distribution can also be understood. The preparation method mainly includes the following steps:

[0040] A continuous phase polyvinyl alcohol solution and a dispersed phase polylactic acid solution are prepared respectively; the continuous phase polyvinyl alcohol solution is first put into the inner cylinder 11 of the reactor, and then the dispersed phase polylactic acid solution is slowly added to the continuous phase polyvinyl alcohol solution to form a reaction solution; at the same time, a stirring motor 25 is used to drive a stirring rod 26 to make the reaction solution flow, and an emulsifying motor 23 is used to drive an emulsifying head 24 to generate a continuous shear force acting on the reaction solution to generate polylactic acid microsphere droplets; the emulsifying motor 23 is turned off, the stirring motor 25 is kept turned on, and a high-temperature circulation device 15 is used to heat the reaction solution in real time to volatilize the solvent in the polylactic acid microsphere droplets and solidify them into polylactic acid microspheres; at the same time, a low-temperature circulation device 33 is used to cool the volatilized solvent in real time, so that it is condensed and collected in a collecting bottle 35 through a reflux head 34; after the solvent distillation is completed, a reaction solution containing a crude polylactic acid microsphere is obtained, and the crude polylactic acid microsphere is washed and dried to obtain a finished polylactic acid microsphere.

[0041] In one or more embodiments, the continuous phase polyvinyl alcohol solution is prepared by adding polyvinyl alcohol to water for injection and stirring to dissolve it, and the concentration range is 0.05 to 0.1 g / ml; the dispersed phase polylactic acid solution is prepared by adding polylactic acid to one or both of dichloromethane or chloroform, stirring and dissolving it under closed conditions, and the concentration range is 0.1 to 0.2 g / ml.

[0042] In one or more embodiments, the volume ratio of the continuous phase to the dispersed phase is 5:1 to 50:1, the mass ratio of polyvinyl alcohol to polylactic acid is 1:0.1 to 1:2, the stirring speed is 30 to 150 rpm, and the emulsification speed is 100 to 3000 rpm.

[0043] In one or more embodiments, the volume ratio of the continuous phase to the dispersed phase is 8:1 to 20:1, the mass ratio of polyvinyl alcohol to polylactic acid is 1:0.3 to 1:0.7, the stirring speed is 60-90 rpm, and the emulsification speed is 500 to 1500 rpm.

[0044] In one or more embodiments, in the method for preparing polylactic acid microspheres, the removal of the solvent in the polylactic acid microsphere droplets is achieved by heating, wherein the heating temperature is 30 to 50°C, preferably 40 to 50°C.

[0045] The specific steps of the preparation method of the microspheres prepared by the device of the utility model are as follows:

[0046] Embodiment 1:

[0047] (1) Dissolve poly-L-lactic acid in dichloromethane to prepare a dispersed phase solution with a concentration of 0.5 g / ml, seal and stir to dissolve to prevent dichloromethane from volatilizing, and obtain a dispersed phase. Add polyvinyl alcohol to purified water to prepare a continuous phase solution with a concentration of 0.06 g / ml.

[0048] (2) First add the continuous phase into the inner cylinder so that it covers the stirring blades and the emulsifying head, turn on the stirring motor and set the speed to 50 rpm; turn on the emulsifying motor and set the speed to 750 rpm. Add the dispersed phase to the continuous phase continuously at a low speed so that the final ratio of the continuous phase to the dispersed phase is 10:1, and emulsify for 30 minutes.

[0049] (3) After emulsification is completed, the emulsification motor is turned off, and the high-temperature circulation device is turned on to heat the reaction liquid. The temperature is set to 40° C. to evaporate the solvent in the polylactic acid microsphere droplets and solidify them into polylactic acid microspheres; a solvent recovery distillation device is used to continuously condense and recover the evaporated solvent.

[0050] (4) Collecting the solidified microspheres, washing and drying them to obtain finished polylactic acid microspheres.

[0051] Microsphere property determination:

[0052] like Figure 3 As shown, the microspheres obtained in this embodiment are observed to be regular circles using an optical microscope; the microspheres obtained in this embodiment are measured using a Mastersize 3000 laser particle size analyzer by dry method, as shown Figure 2 The volume distribution range of the particle size of the microspheres is 10-50 μm, of which the microspheres with a particle size range of 15-45 μm account for more than 90%; the residual content of dichloromethane is less than 0.01%, and the residual content of polyvinyl alcohol is less than 0.5%.

[0053] Embodiment 2:

[0054] Compared with Example 1, the concentration of the dispersed phase solution is 0.2 g / ml.

[0055] Microsphere property determination:

[0056] The microspheres obtained in this embodiment were observed to be regular circles using an optical microscope. The microspheres obtained in this embodiment were measured using a Mastersize 3000 laser particle size analyzer by dry method. Figure 2 The volume distribution range of the microsphere particle size is 25-110 μm, of which the microspheres with a particle size range of 40-80 μm account for more than 90%; the residual dichloromethane is less than 0.01%, and the residual polyvinyl alcohol is less than 0.5%.

[0057] Embodiment 3:

[0058] Compared with Example 1, the speed of the emulsifying motor is 1000 rpm.

[0059] Microsphere property determination:

[0060] The microspheres obtained in this embodiment were observed to be regular circles using an optical microscope. The microspheres obtained in this embodiment were measured using a Mastersize 3000 laser particle size analyzer by dry method. Figure 2 The volume distribution range of the particle size of the microspheres is 10-40 μm, of which the microspheres with a particle size range of 15-30 μm account for more than 90%; the residual content of dichloromethane is less than 0.01%, and the residual content of polyvinyl alcohol is less than 0.5%.

[0061] Through the preparation method and embodiments of the polylactic acid microspheres, polylactic acid microspheres with concentrated particle size distribution, smooth surface and low residue can be obtained.

[0062] like Figure 4 As shown in the figure, round granular polylactic acid microspheres can be seen gathering under the dermis, and occasionally a small amount of polylactic acid microspheres are damaged. At the implantation site in the deep dermis of the skin, the collagen fibers are arranged in disorder and the reticular structure disappears. A small amount of fine new collagen is generated, which wraps the polylactic acid microspheres and divides them into several lobules. Figure 5 As shown in the figure, round granular polylactic acid microspheres can be seen gathering under the dermis, the damage of the filler has increased slightly, the collagen fibers are arranged in disorder at the implantation site in the deep dermis, and the reticular structure disappears. The production of fine new collagen increases, and some collagen thickens, wrapping the polylactic acid microspheres.

[0063] Although the utility model is disclosed as above with preferred embodiments, it is not intended to limit the utility model. Any person skilled in the art can make possible changes and modifications without departing from the spirit and scope of the utility model. Therefore, any modification, equivalent change and modification made to the above embodiments based on the technical essence of the utility model without departing from the content of the technical solution of the utility model shall fall within the protection scope defined by the claims of the utility model.

Claims

1. A device for preparing polylactic acid microspheres, characterized in that: include: A reaction kettle body, a reaction kettle cover arranged on the reaction kettle body to cover an opening on the reaction kettle body, and a solvent recovery distillation device connected to the reaction kettle cover; The reactor body comprises an inner cylinder, an outer cylinder, an interlayer formed between the inner cylinder and the outer cylinder, an interlayer inlet and outlet opened on the outer surface of the interlayer, a tank bottom valve located below the reactor body, and a high-temperature circulation device connected to the interlayer inlet and outlet; The reactor cover comprises a feed port, a distillation port, a stirring device and an emulsifying device which are provided on the surface of the reactor cover. The stirring device comprises a stirring motor and a stirring bar connected to the stirring motor. The stirring motor is located at the center above the reactor cover. The stirring bar extends into the inner cylinder of the reactor body to achieve stirring of the reaction liquid. The emulsifying device consists of an emulsifying motor located above the reactor cover and an emulsifying head connected to the emulsifying motor. The emulsifying head extends into the inner cylinder of the reactor body to generate polylactic acid microsphere droplets through shear force. The solvent recovery distillation device comprises a condenser, a circulation inlet and outlet opened on the surface of the condenser, a low-temperature circulation device connected to the condensation circulation inlet and outlet, a reflux head arranged at the bottom of the condenser, and a collection bottle connected below the reflux head.

2. The device for preparing polylactic acid microspheres according to claim 1, characterized in that: The high-temperature circulation device circulates the circulating liquid of the high-temperature circulation device through the interlayer inlet and outlet, and supplies heat to the reactor body in real time, so that the solvent in the polylactic acid microsphere droplets evaporates and solidifies into polylactic acid microspheres; the tank bottom valve is used to release the reaction liquid in the inner cylinder.

3. The device for preparing polylactic acid microspheres according to claim 2, characterized in that: The reflux head is provided with three open ends, one end of which is connected to the distillation port, one end is connected to the bottom of the condenser, and the last end is connected to the collecting bottle, so as to realize the diversion of the volatile solvent from the inner cylinder to the condenser and the collection of the condensed solvent. The collecting bottle collects the condensed solvent. The condenser is a double-layer structure, which is connected to the low-temperature circulation device to realize the condensation of the volatile solvent.

4. The device for preparing polylactic acid microspheres according to claim 1, 2 or 3, characterized in that: The reactor body and the reactor cover are connected via a sealing ring, a screw or a clamp; the reactor body, the reactor cover and the solvent recovery distillation device are made of corrosion-resistant materials.

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