CN117731640A - Polymer composite microsphere and preparation method thereof - Google Patents
Polymer composite microsphere and preparation method thereof Download PDFInfo
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- CN117731640A CN117731640A CN202311674691.9A CN202311674691A CN117731640A CN 117731640 A CN117731640 A CN 117731640A CN 202311674691 A CN202311674691 A CN 202311674691A CN 117731640 A CN117731640 A CN 117731640A
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- 229920000642 polymer Polymers 0.000 title claims abstract description 148
- 239000002131 composite material Substances 0.000 title claims abstract description 93
- 239000004005 microsphere Substances 0.000 title claims abstract description 72
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 58
- 229940079593 drug Drugs 0.000 claims abstract description 41
- 239000002077 nanosphere Substances 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 67
- 239000012071 phase Substances 0.000 claims description 55
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 52
- 229920000954 Polyglycolide Polymers 0.000 claims description 46
- 239000004633 polyglycolic acid Substances 0.000 claims description 46
- 239000004530 micro-emulsion Substances 0.000 claims description 35
- 229920002635 polyurethane Polymers 0.000 claims description 34
- 239000004814 polyurethane Substances 0.000 claims description 34
- 238000003756 stirring Methods 0.000 claims description 22
- 239000008367 deionised water Substances 0.000 claims description 21
- 229910021641 deionized water Inorganic materials 0.000 claims description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 20
- 239000008346 aqueous phase Substances 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 14
- 229920001661 Chitosan Polymers 0.000 claims description 13
- 239000004088 foaming agent Substances 0.000 claims description 11
- 239000000463 material Substances 0.000 claims description 11
- 239000004094 surface-active agent Substances 0.000 claims description 11
- 239000000377 silicon dioxide Substances 0.000 claims description 10
- 239000012530 fluid Substances 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- 238000004108 freeze drying Methods 0.000 claims description 8
- 239000000725 suspension Substances 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 239000002245 particle Substances 0.000 claims description 7
- 229920001610 polycaprolactone Polymers 0.000 claims description 6
- 239000004632 polycaprolactone Substances 0.000 claims description 6
- 239000003361 porogen Substances 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 4
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims description 3
- 102000009027 Albumins Human genes 0.000 claims description 3
- 108010088751 Albumins Proteins 0.000 claims description 3
- 229920002307 Dextran Polymers 0.000 claims description 3
- 229920002732 Polyanhydride Polymers 0.000 claims description 3
- 229940072056 alginate Drugs 0.000 claims description 3
- 229920000615 alginic acid Polymers 0.000 claims description 3
- 235000010443 alginic acid Nutrition 0.000 claims description 3
- 229920001577 copolymer Polymers 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229920002627 poly(phosphazenes) Polymers 0.000 claims description 3
- 229920000728 polyester Polymers 0.000 claims description 3
- 239000004626 polylactic acid Substances 0.000 claims description 3
- 239000002244 precipitate Substances 0.000 claims description 3
- 238000001556 precipitation Methods 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 abstract description 12
- 230000000694 effects Effects 0.000 abstract description 8
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 238000005538 encapsulation Methods 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 71
- 239000004372 Polyvinyl alcohol Substances 0.000 description 22
- 229920002451 polyvinyl alcohol Polymers 0.000 description 22
- 238000002347 injection Methods 0.000 description 18
- 239000007924 injection Substances 0.000 description 18
- 230000000052 comparative effect Effects 0.000 description 11
- 239000011259 mixed solution Substances 0.000 description 10
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 8
- 238000001514 detection method Methods 0.000 description 6
- 239000008385 outer phase Substances 0.000 description 5
- 239000001530 fumaric acid Substances 0.000 description 4
- 238000001878 scanning electron micrograph Methods 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 238000013270 controlled release Methods 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000011807 nanoball Substances 0.000 description 1
- 239000002114 nanocomposite Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
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- 210000001519 tissue Anatomy 0.000 description 1
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- 230000002588 toxic effect Effects 0.000 description 1
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- Medicinal Preparation (AREA)
- Manufacturing Of Micro-Capsules (AREA)
Abstract
The invention discloses a polymer composite microsphere and a preparation method thereof, wherein the polymer composite microsphere comprises a nanosphere core of an inner core region and a high polymer layer of an outer shell region, the nanosphere core is loaded with a drug, 5% -50% of high polymer with a PH value regulator is attached to the surface of the nanosphere core, the porosity of the high polymer layer is 5% -30%, the mass percentage of the nanosphere core is 70% -90%, and the mass percentage of the high polymer layer is 10% -30%. According to the invention, through reasonable component proportion and structure regulation, the release rate of the drug can be regulated and controlled through the thickness and the porosity of the shell layer, so that when the polymer composite microsphere is used for drug slow release, the accurate regulation and control effect on the drug slow release process is realized, local burst release in the slow release process is prevented, and the high polymer layer shell structure of the shell region is also beneficial to improving the encapsulation rate of the drug.
Description
Technical Field
The invention relates to the technical field of composite microsphere materials, in particular to a polymer composite microsphere and a preparation method thereof.
Background
The traditional administration mode mainly adopts injection or oral administration and the like, has the defect that the concentration of the drug after administration is rapidly increased and rapidly reduced, lacks effective control of the drug release rate, and particularly needs more precise control of the drug release rate and release time in bone defect filling operation, implant prosthesis revision and other operations in orthopaedics, so that a drug release technology for controlling the drug release rate is generated. The drug-loaded microsphere is one of important branches of a drug sustained-release technology, and refers to a spherical polymer composite microsphere formed by dissolving or dispersing a drug in a high polymer matrix material, wherein the polymer composite microsphere has the properties of large specific surface area, strong adsorptivity, surface reaction capacity and the like, has strong controlled release capacity on the drug, can remarkably prolong the acting time of the drug, realizes local sustained-release drug administration at a treatment position, reduces the drug use times, and can protect the packaged drug from being degraded in vivo prematurely, thereby improving the treatment effect and relieving the toxic and side effects of the drug on human tissues, so the drug-loaded microsphere has long been used for drug delivery application.
The traditional preparation method of the polymer composite microsphere mainly comprises an emulsification/solvent volatilization method, a spray drying method, a supercritical CO2 method and the like, and the differences of the preparation methods lead to the differences of the prepared drug-loaded microsphere, including morphology, structure, drug-loaded performance, drug release performance and the like, and the differences of the performances determine whether the obtained microsphere can effectively realize the slow release and the controlled release of the drug, so the preparation method of the microsphere is very important to the selection and the optimization. However, there are still many problems in drug-loading research and development and market application of the polymer composite microsphere, and it is known that the more uniform the diameter of the polymer composite microsphere is, the more stable the performance is, and the more accurate the controlled release of drug effect is. However, the particle size of the polymer composite microsphere prepared by the traditional preparation method is difficult to control, so that the performance of the polymer composite microsphere is unstable, the slow release control of the drug is not accurate enough, and on the other hand, the whole process of the drug-carrying microsphere which needs to prevent local burst release in the slow release process is difficult to control accurately.
Disclosure of Invention
The invention provides the following technical scheme for solving the technical problems that the particle size of polymer composite microspheres is difficult to control, the performance is unstable, the slow release control of drugs is not accurate enough, and the whole slow release process is difficult to control for drug-carrying microspheres which need to prevent local burst release in the slow release process.
The invention relates to a polymer composite microsphere, which comprises a nanosphere core in an inner core region and a high polymer layer in an outer shell region, wherein the nanosphere core is loaded with a drug, 10% -50% of high polymer with a PH value regulator is attached to the surface of the nanosphere core, the porosity of the high polymer layer is 5% -30%, the mass percentage of the nanosphere core is 70% -90%, and the mass percentage of the high polymer layer is 10% -30%.
As a further technical scheme, the high molecular polymer layer is made of one of polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), polyglycolic acid (PGA) or Polycaprolactone (PCL).
As a further technical scheme, the preparation material of the nanosphere core is one of materials such as dextran, chitosan, alginate, mesoporous silica, albumin or polyester, polyanhydride, polyphosphazene, polyphosphoester and the like.
As a further technical scheme, the particle size of the polymer composite microsphere is 50-250 μm.
The invention also comprises a preparation method of the polymer composite microsphere, which comprises the following steps:
s1: dispersing a nano ball core manufacturing material in water to prepare uniform suspension serving as an inner water phase and W1 serving as a fluid; dissolving a high molecular polymer in a volatile organic solvent to prepare a high molecular polymer solution serving as an oil phase and serving as a fluid O; dissolving a hydrophilic surfactant in deionized water to obtain an external water phase and W2 as a fluid;
s2: w1, O and W2 are respectively passed through self-assembled three-phase micro-channels to obtain water-in-oil-in-water type microemulsion droplets;
s3: placing the polymer composite microemulsion obtained in the step S2 into a solution containing a pore-forming agent, stirring and standing;
s4: standing for 12-24 h, washing off excessive porogen by using deionized water, performing centrifugal precipitation, and freeze-drying the precipitate to obtain the polymer composite microsphere.
As a further technical scheme, the flow rate of the inner aqueous phase solution W1 is 5ml/h-20ml/h, the flow rate of the oil phase solution O is 5ml/h-20ml/h, and the flow rate of the outer aqueous phase solution W2 is 1ml/h-4ml/h.
As a further technical scheme, the pore-foaming agent in the step S3 is polyurethane, and the concentration of the pore-foaming agent in the polymer composite microemulsion and the pore-foaming agent solution is 0.1wt% to 5wt%.
As a further technical scheme, in the step S1, the volatile organic solvent is dichloromethane, and the concentration of the high molecular polymer in the high molecular polymer organic solvent solution is 2-10wt%.
As a further technical scheme, in the step S1, the concentration of the polymer solution mixed with the nano-sphere core suspension and attached with the PH regulator is 0.02wt% to 0.2wt%.
As a further technical scheme, in the three-phase micro-channel, the diameter of the inner water phase channel is 50-200 μm, and the diameter of the middle oil phase channel is 100-500 μm; the diameter of the external water phase channel is 100-500 μm.
The invention has the beneficial effects that the high molecular polymer with biocompatibility is adopted as a shell area of the composite microsphere, the nano-sphere core with medicine carrying function is adopted as a core area, and the release rate of medicine can be regulated and controlled through the thickness and the porosity of a shell layer by reasonable component proportion and structure regulation, so that when the polymer composite microsphere is used for medicine slow release, the accurate regulation and control effect on the medicine slow release process is realized, the medicine effect of the medicine is improved by a larger surface area-volume ratio of the nano-sphere core, and the space and time of medicine release are controlled; the polymer composite microsphere is produced by adopting a water-in-oil-in-water method, the size and the internal structure of the polymer composite microsphere can be regulated and controlled by the relative size of the three-phase micro-channels and the concentration of the internal water phase, and the thickness of the high polymer layer can be regulated by regulating the concentration of the oil phase, so that the particle size of the polymer composite microsphere is accurately controlled, the drug-carrying slow-release performance is stable, and the accuracy of drug slow-release control is ensured. The high molecular polymer with PH value regulator is attached on the surface of the nanometer sphere core, the PH value can delay the release of the medicine, and the local burst release in the slow release process can be prevented. The high polymer layer outer shell structure of the shell region is also beneficial to improving the encapsulation rate of the medicine.
Drawings
FIG. 1 is an SEM image of polymer composite microspheres of example 1 of the invention;
FIG. 2 is an SEM image of polymer composite microspheres of example 2 of the invention;
FIG. 3 is an SEM image of polymer composite microspheres of example 3 of the invention;
FIG. 4 is an SEM image of a polymer composite microsphere of comparative example 1 of the present invention;
FIG. 5 is a graph showing sustained release of drug delivery for composite microspheres of comparative examples 1-2 and three examples of the present invention;
Detailed Description
In order to make the objects, modes of use, technical solutions and advantages of the present invention more apparent, the present invention will be further described in detail below with reference to the accompanying drawings and examples. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention. In the description of the present invention, it should be noted that technical features in the following description may be combined with each other in the embodiments of the present invention and features in the embodiments without conflict.
The invention discloses a polymer composite microsphere, which comprises a nanosphere core of an inner core region and a high polymer layer of an outer shell region. The particle size of the polymer composite microsphere is 50-250 mu m according to the actual administration position and the drug carrying components. The preparation material of the nanosphere core is one of materials such as dextran, chitosan, alginate, mesoporous silica, albumin or polyester, polyanhydride, polyphosphazene, polyphosphoester and the like. In the invention, the nanosphere core is loaded with the drug, the specific drug is not particularly limited, different drugs can be loaded according to actual practice, and the sphere diameter of the nanosphere core and the thickness of the high polymer layer can be adjusted. The surface of the nanosphere core is attached with 5% -50% of high molecular polymer with pH value regulator, the pH value regulator can adopt fumaric acid, lactic acid and the like, the release of the drug can be delayed by the pH value, the local solubility of the API is improved by regulating the pH value of the microenvironment, and finally the release speed of the drug is regulated; local burst during the slow release process can be prevented.
The high polymer layer is made of one of polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), polyglycolic acid (PGA) or Polycaprolactone (PCL). The porosity of the high polymer layer is 5% -30%, the mass percentage of the nanosphere core is 70% -90%, and the mass percentage of the high polymer layer is 10% -30%.
The polymer composite microsphere provided by the invention adopts the high molecular polymer with biocompatibility as a shell region of the composite microsphere, adopts the nanosphere core with medicine carrying function as a core region, and enables the release rate of medicine to be regulated and controlled through reasonable component proportion and structure regulation, so that when the polymer composite microsphere is used for medicine slow release, the accurate regulation and control effect on the medicine slow release process is realized, the medicine effect of the medicine is improved through a larger surface area-volume ratio of the nanosphere core, the space and time of medicine release are controlled, and the encapsulation rate of the medicine is also improved through the high molecular polymer layer shell structure of the shell region.
The invention also provides a preparation method of the polymer composite microsphere, which comprises the following steps:
s1: dispersing a nano-sphere core manufacturing material in water to prepare uniform suspension, and mixing a high polymer solution attached with a PH value regulator with the nano-sphere core suspension to obtain an inner water phase serving as a fluid W1; dissolving a high molecular polymer in a volatile organic solvent to prepare a high molecular polymer solution serving as an oil phase and serving as a fluid O; dissolving a hydrophilic surfactant in deionized water to obtain an external water phase and W2 as a fluid;
s2: w1, O and W2 are respectively passed through self-assembled three-phase micro-channels to obtain water-in-oil-in-water type microemulsion droplets;
in the step S2, the flow rate of the inner aqueous phase solution W1 is 5ml/h-20ml/h, the flow rate of the oil phase solution O is 5ml/h-20ml/h, and the flow rate of the outer aqueous phase solution W2 is 1ml/h-4ml/h. Therefore, the flow of W1, O and W2 can be regulated and controlled according to the spherical diameter of the required composite microsphere, the size of the micro emulsion liquid drop is controlled, and the size and the internal structure of the polymer composite microsphere are further controlled.
S3: placing the polymer composite microemulsion obtained in the step S2 into a solution containing a pore-forming agent, stirring and standing;
the pore-forming agent in the step S3 is polyurethane, and the concentration of the pore-forming agent in the polymer composite microemulsion and the pore-forming agent solution is 0.1-5 wt%. Since the hydrophilic surfactant in the outer aqueous phase has the effect of a porogen, the concentration of porogen polyurethane is low in this step. The process of stirring and standing the polymer composite microemulsion obtained in the step S2 in the solution containing the pore-foaming agent is repeatedly and alternately performed, preferably, the polymer composite microemulsion is stirred in the solution containing the pore-foaming agent for 5-10 minutes, and then is kept stand for 30-60 minutes, so that the polymer composite microemulsion is repeatedly and alternately reacted in the solution containing the pore-foaming agent. The stirring speed is limited to a certain extent, and the rotating speed is preferably 60-100 r/min so as to prevent the polymer composite microemulsion from being damaged by the excessively high rotating speed. In the step, the porosity of the high polymer layer can be adjusted to meet different drug loading requirements and slow release speeds.
S4: standing for 12-24 h, washing off excessive porogen by using deionized water, performing centrifugal precipitation, and freeze-drying the precipitate to obtain the polymer composite microsphere.
In the above step S1, the volatile organic solvent is preferably methylene chloride, and the concentration of the high molecular polymer in the high molecular polymer organic solvent solution is 2wt% to 10wt%. The hydrophilic surfactant adopts polyvinyl alcohol (PVA), and the concentration of the hydrophilic surfactant aqueous solution is 0.2-2 wt%. Meanwhile, in the step S1, the concentration of the polymer solution mixed with the nanosphere core suspension and attached with the PH regulator is 0.02wt% -0.2wt%, at this time, the polymer with the PH regulator may be attached to the surface of the nanosphere core, and the thickness and the attachment area of the polymer solution may be regulated.
Meanwhile, in order to control the size of the micro emulsion liquid drops, the size and the internal structure of the polymer composite microsphere are further controlled. The size and the internal structure of the polymer micro-nano composite microsphere can be regulated and controlled by the relative size of a three-phase micro-channel, wherein the diameter of an internal water channel in the three-phase micro-channel is 50-200 mu m, and the diameter of an intermediate oil phase channel is 100-500 mu m; the diameter of the external water phase channel is 100-500 μm.
The preparation method can regulate the size and the internal structure of the polymer composite microsphere through the relative size of the three-phase micro-channels and the concentration of the internal water phase, and regulate the thickness of the high polymer layer through regulating the concentration of the oil phase, so that the particle size of the polymer composite microsphere is accurately controlled, the drug-carrying slow-release performance is stable, the accuracy of controlling the drug slow-release is ensured, and the local burst release in the slow-release process is prevented.
In examples 1 to 3 and comparative examples 1 to 2 described below, the injection rates of the raw materials in the three-phase microchannels were different and the stirring speeds were different in comparative example 1 and example 1 to 3; comparative example 2 the preparation materials and the process were the same as in example 3 except that no pH adjuster was added.
Example 1:
18mg of mesoporous silica was added to 50ml of deionized water, and a polyglycolic acid (PGA) solution to which fumaric acid was attached was mixed to obtain a mixed solution as an internal aqueous phase; polyglycolic acid (PGA) was dissolved in methylene chloride to prepare a methylene chloride solution of 0.6wt% polyglycolic acid (PGA) as an oil phase; dissolving surfactant polyvinyl alcohol in deionized water to prepare a 2wt% polyvinyl alcohol solution as an external water phase; dissolving a pore-foaming agent polyurethane in water at 60 ℃ to prepare a polyurethane solution with the weight percent of 0.5 percent, wherein the polyurethane solution is used as a pore-foaming solution of the next step of polymer composite microemulsion drops;
injecting the mixed solution into an internal water channel of the microfluid, wherein the diameter of the internal phase channel is set to be 90 mu m, and the injection rate is 5ml/h;0.6wt% polyglycolic acid (PGA) in methylene chloride was injected into the mesophase channels of the microfluidics at an injection rate of 2ml/h;2wt% aqueous polyvinyl alcohol (PVA) solution was injected into the outer aqueous phase channel of the microfluidics, the diameter of the outer phase channel was set to 200 μm, and the injection rate was 2ml/h.
The composite micro-emulsion drop of mesoporous silica with uniform size is prepared in the three-phase micro-channel, methylene dichloride is volatilized after standing and stirring, and then polyurethane solution with the weight percent of 0.5 percent is added, so that the pore-foaming agent polyurethane reacts on the high polymer layer in the shell area of the composite micro-emulsion drop, and the porosity of the high polymer layer is increased. And (3) dripping the polymer composite microemulsion into a polyurethane-containing solution, stirring for 5-10 minutes at a stirring speed of 60r/min, standing for 30-60 minutes, and repeating the steps for 10 times. Centrifuging and washing with deionized water, and freeze-drying for 24 hours to obtain polymer composite microspheres; through detection, the spherical diameter size of the polymer composite microsphere loaded with mesoporous silica is consistent, the diameter is about 50 mu m, the mass percentage of the nano-sphere core to the high polymer layer is 9:1, and the porosity of the high polymer layer is 10%.
Example 2:
40mg of chitosan was added to 50ml of deionized water, and a polyglycolic acid (PGA) solution to which fumaric acid was attached was mixed to obtain a mixed solution as an internal aqueous phase; polyglycolic acid (PGA) was dissolved in methylene chloride to prepare a methylene chloride solution of 3wt% polyglycolic acid (PGA) as an oil phase; dissolving surfactant polyvinyl alcohol in deionized water to prepare a 2wt% polyvinyl alcohol solution as an external water phase; dissolving a pore-forming agent polyurethane into water at 80 ℃ to prepare a polyurethane solution with the weight percent of 2 percent, wherein the polyurethane solution is used as a pore-forming solution of the next step of polymer composite microemulsion drops;
injecting the mixed solution into an internal water channel of the microfluid, wherein the diameter of the internal phase channel is set to be 150 mu m, and the injection rate is 20ml/h; a 3wt% solution of polyglycolic acid (PGA) in methylene chloride was injected into the mesophase channel of the microfluid at an injection rate of 20ml/h;2wt% aqueous polyvinyl alcohol (PVA) solution was injected into the outer aqueous phase channel of the microfluidics, the diameter of the outer phase channel was set to 500 μm, and the injection rate was 2ml/h.
And (3) preparing composite microemulsion drops of uniformly-sized loaded chitosan in the three-phase micro-channels, standing and stirring, volatilizing dichloromethane, adding into a polyurethane solution with the weight percent of 2%, and reacting the shell region high polymer layer of the composite microemulsion drops by using pore-forming agent polyurethane to increase the porosity of the high polymer layer. And (3) dripping the polymer composite microemulsion into a polyurethane-containing solution, stirring for 5-10 minutes at a stirring speed of 90r/min, standing for 30-60 minutes, and repeating the steps for 10 times. Centrifuging and washing with deionized water, and freeze-drying for 24 hours to obtain polymer composite microspheres; through detection, the spherical diameter size of the polymer composite microsphere loaded with mesoporous silica is consistent, the diameter is about 110 mu m, the mass percentage of the nano-sphere core to the high polymer layer is 8.5:1.5, and the porosity of the high polymer layer is 15%.
Example 3:
50mg of chitosan was added to 50ml of deionized water, and a polyglycolic acid (PGA) solution to which fumaric acid was attached was mixed to prepare a mixed solution as an internal aqueous phase; polyglycolic acid (PGA) was dissolved in methylene chloride to prepare a methylene chloride solution of 5wt% polyglycolic acid (PGA) as an oil phase; dissolving surfactant polyvinyl alcohol in deionized water to prepare a 2wt% polyvinyl alcohol solution as an external water phase; dissolving a pore-forming agent polyurethane into water at 90 ℃ to prepare a polyurethane solution with the weight percent of 2 percent, wherein the polyurethane solution is used as a pore-forming solution of the next step of polymer composite microemulsion drops;
injecting the mixed solution into an internal water channel of the microfluid, wherein the diameter of the internal phase channel is set to be 200 mu m, and the injection rate is 6ml/h; a 5wt% solution of polyglycolic acid (PGA) in methylene chloride was injected into the mesophase channel of the microfluid at an injection rate of 5ml/h;2wt% aqueous polyvinyl alcohol (PVA) solution was injected into the outer aqueous phase channel of the microfluidics, the diameter of the outer phase channel was set to 300 μm, and the injection rate was 2ml/h.
And (3) preparing composite microemulsion drops of uniformly-sized loaded chitosan in the three-phase micro-channels, standing and stirring, volatilizing dichloromethane, adding into a polyurethane solution with the weight percent of 2%, and reacting the shell region high polymer layer of the composite microemulsion drops by using pore-forming agent polyurethane to increase the porosity of the high polymer layer. And (3) dripping the polymer composite microemulsion into a polyurethane-containing solution, stirring for 5-10 minutes at the stirring speed of 80r/min, standing for 30-60 minutes, and repeating the steps for 10 times. Centrifuging and washing with deionized water, and freeze-drying for 24 hours to obtain polymer composite microspheres; through detection, the spherical diameter size of the polymer composite microsphere loaded with mesoporous silica is consistent, the diameter is about 250 mu m, the mass percentage of the nano-sphere core to the high polymer layer is 7:3, and the porosity of the high polymer layer is 30%.
Comparative example 1:
adding 30mg of chitosan into 50ml of deionized water, and mixing polyglycolic acid (PGA) solution with the chitosan to obtain a mixed solution as an internal water phase; polyglycolic acid (PGA) was dissolved in methylene chloride to prepare a methylene chloride solution of 5wt% polyglycolic acid (PGA) as an oil phase; dissolving surfactant polyvinyl alcohol in deionized water to prepare a 2wt% polyvinyl alcohol solution as an external water phase; dissolving a pore-forming agent polyurethane into water at 90 ℃ to prepare a polyurethane solution with the weight percent of 2 percent, wherein the polyurethane solution is used as a pore-forming solution of the next step of polymer composite microemulsion drops;
injecting the mixed solution into an internal water channel of the microfluid, wherein the diameter of the internal phase channel is set to be 200 mu m, and the injection rate is 12ml/h; a 5wt% solution of polyglycolic acid (PGA) in methylene chloride was injected into the mesophase channel of the microfluid at an injection rate of 2ml/h;2wt% aqueous polyvinyl alcohol (PVA) solution was injected into the outer aqueous phase channel of the microfluidics, the diameter of the outer phase channel was set to 300 μm, and the injection rate was 8ml/h.
And (3) preparing composite microemulsion drops of uniformly-sized loaded chitosan in the three-phase micro-channels, standing and stirring, volatilizing dichloromethane, adding into a polyurethane solution with the weight percent of 2%, and reacting the shell region high polymer layer of the composite microemulsion drops by using pore-forming agent polyurethane to increase the porosity of the high polymer layer. And (3) dripping the polymer composite microemulsion into a polyurethane-containing solution, stirring for 5-10 minutes at a stirring speed of 150r/min, standing for 30-60 minutes, and repeating the steps for 10 times. Centrifuging and washing with deionized water, and freeze-drying for 24 hours to obtain polymer composite microspheres; through detection, the polymer composite microspheres loaded with mesoporous silica have different sphere diameter sizes, most of the diameters are between 90 and 480 mu m, the sphere diameter is nonuniform, the mass percentage of the nano sphere core to the high polymer layer is 7:3, and the porosity of the high polymer layer is 52%.
Comparative example 2:
adding 50mg of chitosan into 50ml of deionized water, and mixing polyglycolic acid (PGA) solution with the chitosan to obtain a mixed solution as an internal water phase; polyglycolic acid (PGA) was dissolved in methylene chloride to prepare a methylene chloride solution of 5wt% polyglycolic acid (PGA) as an oil phase; dissolving surfactant polyvinyl alcohol in deionized water to prepare a 2wt% polyvinyl alcohol solution as an external water phase; dissolving a pore-forming agent polyurethane into water at 90 ℃ to prepare a polyurethane solution with the weight percent of 2 percent, wherein the polyurethane solution is used as a pore-forming solution of the next step of polymer composite microemulsion drops;
injecting the mixed solution into an internal water channel of the microfluid, wherein the diameter of the internal phase channel is set to be 200 mu m, and the injection rate is 6ml/h; a 5wt% solution of polyglycolic acid (PGA) in methylene chloride was injected into the mesophase channel of the microfluid at an injection rate of 5ml/h;2wt% aqueous polyvinyl alcohol (PVA) solution was injected into the outer aqueous phase channel of the microfluidics, the diameter of the outer phase channel was set to 300 μm, and the injection rate was 2ml/h.
And (3) preparing composite microemulsion drops of uniformly-sized loaded chitosan in the three-phase micro-channels, standing and stirring, volatilizing dichloromethane, adding into a polyurethane solution with the weight percent of 2%, and reacting the shell region high polymer layer of the composite microemulsion drops by using pore-forming agent polyurethane to increase the porosity of the high polymer layer. And (3) dripping the polymer composite microemulsion into a polyurethane-containing solution, stirring for 5-10 minutes at the stirring speed of 80r/min, standing for 30-60 minutes, and repeating the steps for 10 times. Centrifuging and washing with deionized water, and freeze-drying for 24 hours to obtain polymer composite microspheres; through detection, the spherical diameter size of the polymer composite microsphere loaded with mesoporous silica is consistent, the diameter is about 250 mu m, the mass percentage of the nano-sphere core to the high polymer layer is 7:3, and the porosity of the high polymer layer is 30%.
As shown in fig. 5, in examples 1 to 3 and comparative examples 1 to 2, the injection rate of the raw materials in the three-phase micro-channel was different from that in comparative example 1 and example 1 to 3, and the stirring speed was different, resulting in non-uniform sphere diameter of the microspheres in the detection results, and thus the drug release rate was difficult to grasp, and the drug release was too fast. The comparative example 2 was the same as example 3 except that no pH adjuster was added, and it was clearly found that the same drug release rate as in comparative example 2 was high, and the release process was likely to occur local burst, and the drug release rate was difficult to grasp. It follows that examples 1-3 of the present invention can increase the local solubility of API by adjusting the pH of the microenvironment and ultimately adjust the release rate of the drug.
While the preferred embodiments and examples of the present invention have been described in detail with reference to the accompanying drawings, the present invention is not limited to the embodiments and examples described above, and various changes and equivalent substitutions can be made therein without departing from the spirit of the present invention within the knowledge of those skilled in the art, and therefore, the present invention is not limited to the embodiments and examples disclosed herein, and all examples falling within the scope of the claims of the present application are intended to be included in the scope of the present invention.
Claims (10)
1. A polymer composite microsphere, characterized in that: the nanometer ball comprises a nanometer ball core of an inner core area and a high polymer layer of an outer shell area, wherein the nanometer ball core is loaded with a drug, 5% -50% of high polymer with a PH value regulator is attached to the surface of the nanometer ball core, the porosity of the high polymer layer is 5% -30%, the mass percentage of the nanometer ball core is 70% -90%, and the mass percentage of the high polymer layer is 10% -30%.
2. The polymer composite microsphere according to claim 1, wherein: the high polymer layer is made of one of polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), polyglycolic acid (PGA) or Polycaprolactone (PCL).
3. The polymer composite microsphere according to claim 1, wherein: the preparation material of the nanosphere core is one of materials such as dextran, chitosan, alginate, mesoporous silica, albumin or polyester, polyanhydride, polyphosphazene, polyphosphoester and the like.
4. The polymer composite microsphere according to claim 1, wherein: the particle size of the polymer composite microsphere is 50-250 mu m.
5. The preparation method of the polymer composite microsphere is characterized by comprising the following steps:
s1: dispersing a nano-sphere core manufacturing material in water to prepare uniform suspension, and mixing a high polymer solution attached with a PH value regulator with the nano-sphere core suspension to obtain an inner water phase serving as a fluid W1; dissolving a high molecular polymer in a volatile organic solvent to prepare a high molecular polymer solution serving as an oil phase and serving as a fluid O; dissolving a hydrophilic surfactant in deionized water to obtain an external water phase and W2 as a fluid;
s2: w1, O and W2 are respectively passed through self-assembled three-phase micro-channels to obtain water-in-oil-in-water type microemulsion droplets;
s3: placing the polymer composite microemulsion obtained in the step S2 into a solution containing a pore-forming agent, stirring and standing;
s4: standing for 12-24 h, washing off excessive porogen by using deionized water, performing centrifugal precipitation, and freeze-drying the precipitate to obtain the polymer composite microsphere.
6. The method for preparing polymer composite microspheres according to claim 5, wherein: the flow rate of the inner aqueous phase solution W1 is 5ml/h-20ml/h, the flow rate of the oil phase solution O is 5ml/h-20ml/h, and the flow rate of the outer aqueous phase solution W2 is 1ml/h-4ml/h.
7. The method for preparing polymer composite microspheres according to claim 5, wherein: the pore-foaming agent in the step S3 is polyurethane, and the concentration of the pore-foaming agent in the polymer composite microemulsion and the pore-foaming agent solution is 0.1-5 wt%.
8. The method for preparing polymer composite microspheres according to claim 5, wherein: in the step S1, the volatile organic solvent is methylene dichloride, and the concentration of the high molecular polymer in the high molecular polymer organic solvent solution is 2-10wt%.
9. The method for preparing polymer composite microspheres according to claim 5, wherein: in the step S1, the concentration of the high polymer solution which is mixed with the nano-sphere core suspension and is attached with the PH value regulator is 0.02 to 0.2 weight percent.
10. The method for preparing polymer composite microspheres according to claim 5, wherein: in the three-phase micro-channel, the diameter of the inner water channel is 50-200 μm, and the diameter of the middle oil channel is 100-500 μm; the diameter of the external water phase channel is 100-500 μm.
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