CN117883414A - Long-acting slow-release capsaicin microsphere, and preparation method and application thereof - Google Patents
Long-acting slow-release capsaicin microsphere, and preparation method and application thereof Download PDFInfo
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- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 title claims abstract description 164
- 239000004005 microsphere Substances 0.000 title claims abstract description 86
- 229960002504 capsaicin Drugs 0.000 title claims abstract description 82
- 235000017663 capsaicin Nutrition 0.000 title claims abstract description 82
- 238000002360 preparation method Methods 0.000 title claims abstract description 37
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- 239000007788 liquid Substances 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 14
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 10
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- 238000000034 method Methods 0.000 claims description 9
- 238000013268 sustained release Methods 0.000 claims description 9
- 239000012730 sustained-release form Substances 0.000 claims description 9
- 230000000202 analgesic effect Effects 0.000 claims description 8
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- 235000014655 lactic acid Nutrition 0.000 claims description 7
- 239000004310 lactic acid Substances 0.000 claims description 7
- 239000012266 salt solution Substances 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- -1 polyoxyethylene Polymers 0.000 claims description 5
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 4
- 239000004094 surface-active agent Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 3
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- 238000013270 controlled release Methods 0.000 claims 2
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- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a long-acting slow-release capsaicin microsphere, and a preparation method and application thereof. The long-acting slow-release capsaicin microsphere provided by the invention comprises capsaicin, polylactic acid-glycolic acid copolymer and release regulator. The polylactic acid-glycolic acid copolymer is used for coating capsaicin to prepare the biodegradable long-acting slow-release microsphere, the microsphere preparation has uniform particle size and long-acting slow-release function, can effectively prolong half-life, can improve drug targeting and therapeutic indexes through local administration, avoid liver first pass effect, reduce irritation, effectively maintain the drug effective concentration through long-acting slow-release of the capsaicin in the microsphere, can reduce administration times, reduce systemic toxic and side effects at the periphery and improve patient compliance, and lays a foundation for developing a novel capsaicin preparation.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a long-acting slow-release capsaicin microsphere, and a preparation method and application thereof.
Background
Capsaicin (CAPSAICIN, CAP) is a vanilloid alkaloid extracted from natural capsicum, and has good chemical stability. The capsaicin can be used as a spice for foods, has potential medicinal values such as antibiosis, antiphlogosis, analgesia, antipruritic, antioxidation, weight reduction and anti-tumor, and has certain prevention and treatment effects on cardiovascular system diseases and digestive system diseases, wherein the capsaicin is unique in long-acting analgesia effect and novel analgesia mechanism.
Capsaicin acts by selectively stimulating the primary afferent neuron terminals and the specific transient receptor potential vanilloid 1 (TRPV 1) on the cell membrane, which is also known as the capsaicin receptor, releasing various neuropeptides to exert analgesic, vasodilatory, antitumor, etc. At present, capsaicin has been clinically tried for treating chronic neuralgia difficult to treat, such as post-herpetic neuralgia, sciatica, diabetic neuralgia, severe rheumatic arthritis and other diseases, with remarkable curative effects. The analgesic effect is stronger than that of opioid analgesics and does not produce the side effects frequently occurring in non-steroidal anti-inflammatory drugs. However, capsaicin has severe liver first pass effects, strong irritation, and short half-life (< 30 min) after oral administration. The existing capsaicin preparation comprises the dosage forms of conventional injection, cream, patch and the like, but the conventional injection has strong irritation, short half-life period, and local administration preparations such as cream, patch and the like are limited to external administration, have certain irritation and need frequent administration. Therefore, the development of a novel capsaicin preparation has important significance for improving the application of capsaicin in the aspect of pain relief.
Disclosure of Invention
In view of the above, the invention aims to provide a long-acting slow-release capsaicin microsphere, a preparation method and application thereof.
In order to achieve the above object, the present invention provides the following technical solutions:
The invention provides a long-acting slow-release capsaicin microsphere, which comprises capsaicin, polylactic acid-glycolic acid copolymer and release regulator.
Preferably, the molecular weight of the polylactic acid-glycolic acid copolymer is 30-100 kDa;
the polylactic acid-glycolic acid copolymer is obtained by polycondensation of lactic acid and glycolic acid, and the molar ratio of the lactic acid to the glycolic acid is (25-85) (15-75); the polylactic acid-glycolic acid copolymer comprises an ester-terminated polylactic acid-glycolic acid copolymer, a carboxyl-terminated polylactic acid-glycolic acid copolymer or a hydroxyl-terminated polylactic acid-glycolic acid copolymer.
The invention also provides the long-acting slow-release capsaicin microsphere, and the mass ratio of the capsaicin to the polylactic acid-glycolic acid copolymer is 1 (3-10).
Preferably, the release modifier is a nonionic polyoxyethylene surfactant.
Preferably, the mass of the release regulator is 0.1-2% of the mass of the polylactic acid-glycolic acid copolymer.
Preferably, the diameter of the long-acting slow-release capsaicin microsphere is 50-300 mu m.
The invention also provides a preparation method of the long-acting slow-release capsaicin microsphere, which comprises the following steps:
mixing capsaicin, polylactic acid-glycolic acid copolymer, release regulator and organic solvent to obtain dispersed phase;
Shearing the disperse phase by using a continuous phase, collecting the obtained spherical liquid drops into a salt solution, removing an organic solvent, and solidifying to obtain the long-acting slow-release capsaicin microsphere.
Preferably, the organic solvent comprises one or more of dichloromethane, ethyl acetate, chloroform and isopropanol.
Preferably, the continuous phase is a polyvinyl alcohol solution; the mass concentration of the polyvinyl alcohol solution is 0.2-3%.
The invention also provides the long-acting slow-release capsaicin microsphere prepared by the technical scheme or the long-acting slow-release capsaicin microsphere prepared by the preparation method of the technical scheme, and the application of the long-acting slow-release capsaicin microsphere in preparing a long-acting analgesic.
The invention provides a long-acting slow-release capsaicin microsphere, which comprises capsaicin, polylactic acid-glycolic acid copolymer and release regulator. The biodegradable long-acting slow-release microsphere is prepared by using the biodegradable high polymer material polylactic acid-glycolic acid copolymer as a carrier material to wrap capsaicin, and the microsphere preparation has good roundness and uniform particle size, and a large amount of capsaicin encapsulated in the microsphere is slowly released through an internal water-based channel. Therefore, the long-acting slow-release capsaicin microsphere provided by the invention has a long-acting slow-release effect, can effectively prolong half-life, can improve drug targeting and therapeutic index through local administration, avoid liver first pass effect, reduce irritation, effectively maintain drug effective concentration, reduce administration times, reduce peripheral systemic toxic and side effects and improve patient compliance, and lays a foundation for developing novel capsaicin preparations. The results of the examples show that the long-acting slow-release capsaicin microsphere provided by the invention has good stability under the storage condition of 4 , can realize long-acting slow release in vitro for 3 weeks, can obviously reduce the administration times of capsaicin drugs, and continuously plays a long-acting analgesic role.
The invention also provides a preparation method of the long-acting sustained-release capsaicin microsphere, and the preparation method utilizes a novel microfluidic technology to prepare the biodegradable long-acting sustained-release microsphere by wrapping capsaicin with a polymer material polylactic acid-glycolic acid copolymer, and the preparation process is simple, convenient and feasible, and the condition is mild and easy to control.
Drawings
FIG. 1 is an optical microscope image of the long-acting sustained-release capsaicin microsphere prepared in example 1;
FIG. 2 is a scanning electron microscope image of the long-acting slow-release capsaicin microsphere prepared in example 1;
FIG. 3 is an in vitro cumulative release profile of the long-acting sustained release capsaicin microsphere prepared in example 1;
FIG. 4 is a graph of the in-vivo degradation fluorescence of DiR@M simulated long-acting slow-release capsaicin microsphere prepared in example 1.
Detailed Description
The invention provides a long-acting slow-release capsaicin microsphere, which comprises capsaicin, polylactic acid-glycolic acid copolymer and release regulator.
The present invention is not limited to the specific source of the raw materials used, and may be commercially available products known to those skilled in the art, unless otherwise specified.
In the invention, the molecular weight of the polylactic acid-glycolic acid copolymer is preferably 30-100 kDa, more preferably 50-80 kDa; the polylactic acid-glycolic acid copolymer is obtained by polycondensation of lactic acid and glycolic acid, and the molar ratio of the lactic acid to the glycolic acid is preferably (25-85): (15-75), more preferably (50-85): (15-50); the polylactic acid-glycolic acid copolymer preferably includes an ester-terminated polylactic acid-glycolic acid copolymer, a carboxyl-terminated polylactic acid-glycolic acid copolymer or a hydroxyl-terminated polylactic acid-glycolic acid copolymer, more preferably a hydroxyl-terminated polylactic acid-glycolic acid copolymer; the mass ratio of the capsaicin to the polylactic acid-glycolic acid copolymer is preferably 1 (3-10), more preferably 1 (5-8).
In the present invention, the release regulator is preferably a nonionic polyoxyethylene surfactant; the nonionic polyoxyethylene surfactant is preferably pluronic F127; the release regulator preferably accounts for 0.1-2% of the weight of the polylactic acid-glycolic acid copolymer, and more preferably 0.2-1%.
The release regulator used in the invention can regulate and control the release of the microsphere and regulate the release of the microsphere in the middle and later stage of the platform stage; the release regulator has pore-forming effect, so that tiny water-based pore channels in the microsphere are increased or uniform, and the integral release curve of the microsphere is regulated to be closer to zero-order release.
In the invention, the diameter of the long-acting slow-release capsaicin microsphere is preferably 50-300 mu m, more preferably 100-200 mu m; the encapsulation rate of the long-acting slow-release capsaicin microsphere is preferably more than 70%, more preferably more than 80%.
The long-acting slow-release capsaicin microsphere provided by the invention is composed of polylactic acid-glycolic acid copolymer, has high specific surface area, and provides a larger medicine carrying space inside, so that capsaicin can be wrapped inside the microsphere or adsorbed on the surface of the microsphere, and medicine is slowly released through diffusion and an aqueous channel inside the microsphere after administration, thereby realizing long-acting slow-release. The microsphere has good biocompatibility and stability, does not cause obvious immune reaction or other adverse reactions, and has good physical and chemical stability to maintain the stability of the structure, so that the microsphere can maintain a long-acting slow release effect in vivo.
The invention also provides a preparation method of the long-acting slow-release capsaicin microsphere, which comprises the following steps:
mixing capsaicin, polylactic acid-glycolic acid copolymer, release regulator and organic solvent to obtain dispersed phase;
Shearing the disperse phase by using a continuous phase, collecting the obtained spherical liquid drops into a salt solution, removing an organic solvent, and solidifying to obtain the long-acting slow-release capsaicin microsphere.
According to the invention, capsaicin, polylactic acid-glycolic acid copolymer, release regulator and organic solvent are mixed to obtain a disperse phase.
In the present invention, the organic solvent includes one or more of dichloromethane, ethyl acetate, chloroform and isopropanol, more preferably dichloromethane or ethyl acetate.
In the invention, capsaicin, polylactic acid-glycolic acid copolymer, release regulator and organic solvent are mixed, preferably capsaicin and polylactic acid-glycolic acid copolymer are dissolved in organic solvent, and then release regulator is added to obtain dispersed phase; the mass concentration of the polylactic acid-glycolic acid copolymer in the disperse phase is preferably 100-250 mg/mL, more preferably 150-200 mg/mL.
After the disperse phase is obtained, spherical liquid drops obtained by shearing the disperse phase by using a continuous phase are collected into a salt solution, and the long-acting slow-release capsaicin microsphere is obtained by volatilizing an organic solvent for solidification.
In the present invention, the continuous phase is preferably a polyvinyl alcohol solution; the molecular weight of the polyvinyl alcohol in the polyvinyl alcohol solution is preferably 85-124 kDa, more preferably 90-120 kDa; the mass concentration of the polyvinyl alcohol solution is preferably 0.2-3%, more preferably 0.5-2.5%.
In the present invention, shearing the dispersed phase with the continuous phase is preferably: and installing the syringes respectively provided with the disperse phase and the continuous phase on a microfluidic injection pump, connecting the syringes to a T-shaped microfluidic chip, enabling the flow directions of the continuous phase and the disperse phase to flow in a T shape, and shearing the continuous phase relative to the disperse phase. In the invention, the inner diameter of the T-shaped micro-fluidic chip is preferably 50-300 mu m, more preferably 100-200 mu m; the flow rate ratio of the dispersed phase to the continuous phase is preferably 1 (1.5 to 15), more preferably 1 (2 to 10). In the embodiment of the invention, the flow rate of the disperse phase is specifically 50 mu L/min, and the flow rate of the continuous phase is specifically 120 mu L/min.
The invention relates to a method for generating a spherical liquid drop by using a T-shaped microfluidic chip liquid drop, wherein two immiscible fluids meet at the intersection of a vertical T-shaped pipeline in a T-shaped channel, and a continuous phase intercepts a dispersed phase under the action of pressure and shearing force, so that the liquid drop is formed.
In the present invention, the salt solution is preferably a sodium chloride solution; the concentration of the salt solution is preferably 0.5-2 mol/L, more preferably 1-1.5 mol/L; the volume of the salt solution is preferably 10-100 times of the volume of the spherical liquid drops, more preferably 20-50 times; the curing time is preferably 2-6 hours, more preferably 3-5 hours; the curing is preferably carried out under stirring at normal pressure; the rotation speed of the normal pressure stirring is preferably 100-200 rpm, more preferably 100-150 rpm.
After solidification, the invention preferably carries out solid-liquid separation, washing and freeze drying on the solidified mixed solution in sequence to obtain the long-acting slow-release capsaicin microsphere.
In the present invention, the solid-liquid separation is preferably centrifugation; the process of the centrifugation is not particularly limited, and the solid-liquid separation may be carried out by using a centrifugation process well known in the art.
In the present invention, the washing liquid used for the washing is preferably deionized water; the number of times of washing is preferably 3; after the washing, the mixed solution obtained by the washing is preferably centrifuged; the process of the centrifugation is not particularly limited, and the solid-liquid separation may be carried out by using a centrifugation process well known in the art.
The process of freeze-drying is not particularly limited, and the solid-liquid separation may be carried out by freeze-drying, which is well known in the art.
The invention can realize the high controllability of liquid drops: the microsphere prepared by micro-flow control can accurately control the particle size of liquid drops by changing parameters such as a chip, flow speed and the like, and the characteristics of accurately controlling the particle size, roundness and the like of the microsphere can be realized by simple adjustment operation. Microsphere particle size high uniformity prepared by the invention: the microfluidic preparation technology can realize high uniformity control of microsphere particle size, so that the microsphere has smaller difference, and is suitable for experiments and applications requiring uniformity.
The invention also provides the long-acting slow-release capsaicin microsphere prepared by the technical scheme or the long-acting slow-release capsaicin microsphere prepared by the preparation method of the technical scheme, and the application of the long-acting slow-release capsaicin microsphere in preparing a long-acting analgesic.
The application of the long-acting slow-release capsaicin microsphere in preparing a long-acting analgesic is not particularly limited, and the long-acting slow-release capsaicin microsphere can be prepared by adopting an application mode well known in the art.
The technical solutions of the present invention will be clearly and completely described in conjunction with the embodiments of the present invention, but they should not be construed as limiting the scope of the present invention.
Example 1
Weighing 100mg of polylactic acid-glycolic acid copolymer (molecular weight is 80kDa, the molar ratio of lactic acid to glycolic acid in the used preparation raw materials is 75:25, carboxyl-terminated polylactic acid-glycolic acid copolymer) and 20mg of capsaicin (Cap) to be dissolved in 1mL of dichloromethane together, then adding a release regulator (pluronic F127) accounting for 0.5% of the mass of the polylactic acid-glycolic acid copolymer to be used as a disperse phase, placing the disperse phase and the continuous phase into a 5mL syringe respectively, mounting the syringe on a microfluidic injection pump, connecting the syringe on a T-shaped microfluidic chip (inner diameter is 150 mu m), enabling the continuous phase and the disperse phase to flow out in a T-shaped manner, adjusting the flow rate of the disperse phase to be 50 mu L/min, obtaining dispersed spherical droplets by shearing an oil phase in the continuous phase, collecting the droplets into a 0.5mol/L sodium chloride solution with the volume of 50 times of the spherical droplets, volatilizing the continuous phase to be 1wt% of polyvinyl alcohol (PVA, the molecular weight is 100 kDa), placing the disperse phase and the continuous phase into a 5M solution for solidification by a stirring machine, obtaining the microspheres by cooling the microspheres, and finally obtaining the microspheres by centrifugation, cooling the microspheres after the microspheres are solidified by a centrifugal drying time of the microspheres, namely obtaining the microspheres, and obtaining the microspheres after the microspheres are subjected to be subjected to centrifugation and solidified for 3 m.
Examples 2 to 6
The difference from example 1 is that the flow rate ratio of the dispersed phase and the continuous phase is different, see in particular Table 1, and the remainder are the same as in example 1.
TABLE 1 preparation of Cap@M at different flow rates for examples 2-6
| Examples | Flow ratio of the dispersed phase to the continuous phase | Average particle diameter/. Mu.m | Yield/% | Encapsulation efficiency/% |
| Example 2 | 30200 | 82.1618.51 | 80.08 | 80.25 |
| Example 3 | 50200 | 99.368.08 | 81.44 | 79.43 |
| Example 4 | 70200 | 107.014.34 | 80.23 | 83.14 |
| Example 5 | 100200 | 111.504.59 | 82.64 | 82.55 |
| Example 6 | 120200 | 135.253.92 | 85.75 | 83.96 |
Performance testing
(1) The preparation of example 1 was subjected to microscopic characterization, and the results are shown in fig. 1 and 2.
Through testing, the particle size of Cap@M obtained in example 1 is 155.67 +/-5.51 mu m, and the microsphere is uniform in particle size, good in roundness and smooth in surface and good in dispersibility as can be seen from a microscope characterization chart (shown in figures 1 and 2).
(2) Cap@M in vitro cumulative release investigation
The invention adopts the most commonly used direct release method of microsphere preparation to examine the in vitro release of cap@M, namely the microsphere preparation is directly placed in a release medium, and then the supernatant is centrifugally taken at a specific time point to determine the content of the drug in the microsphere preparation. First, 20mg of the long-acting sustained-release capsaicin microsphere prepared in example 1 (cap@M) was precisely weighed, directly placed in a dialysis medium (PBS, pH7.4, containing 0.25% SDS), and placed in an oscillation tank at 37for oscillation at 100 rpm. At a preset time point, taking supernatant after centrifugation, and measuring the content of Cap by adopting a high performance liquid chromatography. And the release medium is replenished at the same time, and the volume of the release medium is kept unchanged. The measurement results are shown in FIG. 3.
From fig. 3, it is clear that, when the in vitro release test is performed on the sustained release microsphere preparation of example 1, the cumulative release amount of capsaicin in the initial 2 hours is 12.59% and the cumulative release amount in 3 weeks is 80%, and thus it is found that the cap@m can release capsaicin rapidly in the initial stage and release the drug slowly and continuously in the subsequent 3 weeks, thereby exerting the sustained analgesic effect.
(3) In vivo degradation experiment investigation of simulated Cap@M
The present invention uses near infrared fluorescent lipophilic Dye (DiR) to replace capsaicin, and a microsphere preparation (DiR@M) containing DiR is prepared according to the method in the example 1. And (3) examining the change of the in-vivo fluorescence intensity of the DiR by adopting a living body imaging method, thereby reflecting the degradation behavior of the long-acting slow-release microsphere preparation in vivo. First, a single administration of the dispersed microsphere preparation to the left armpit of a mouse is performed, and a living body imaging chart is taken at a specific time point, so that the change of the intensity of fluorescence in the preparation and the distribution behavior of the fluorescence in the preparation in the body are observed, and the degradation behavior of the preparation in the body of the mouse is reflected. The measurement results are shown in FIG. 4.
As can be seen from fig. 4, the in vivo degradation and distribution behavior of the DiR-loaded microsphere and the corresponding microsphere preparation are examined, and the result shows that dir@m always maintains strong fluorescence within three weeks, and the average fluorescence intensity always maintains at a strong level (1.6610 8(p/s/cm2/sr)/(Wcm2)), so that the microsphere preparation has a good long-acting slow release effect and can be released continuously for at least three weeks.
Although the foregoing embodiments have been described in some, but not all, embodiments of the invention, according to which one can obtain other embodiments without inventiveness, these embodiments are all within the scope of the invention.
Claims (9)
1. The long-acting slow release capsaicin microsphere is characterized by comprising capsaicin, polylactic acid-glycolic acid copolymer and release regulator;
The molecular weight of the polylactic acid-glycolic acid copolymer is 30-100 kDa;
the polylactic acid-glycolic acid copolymer is obtained by polycondensation of lactic acid and glycolic acid, and the molar ratio of the lactic acid to the glycolic acid is (25-85) (15-75); the polylactic acid-glycolic acid copolymer comprises an ester-terminated polylactic acid-glycolic acid copolymer, a carboxyl-terminated polylactic acid-glycolic acid copolymer or a hydroxyl-terminated polylactic acid-glycolic acid copolymer.
2. The long-acting sustained-release capsaicin microsphere according to claim 1, wherein the mass ratio of capsaicin to polylactic acid-glycolic acid copolymer is 1 (3-10).
3. The long-acting sustained-release capsaicin microsphere according to claim 1, wherein the release regulator is nonionic polyoxyethylene surfactant.
4. A long-acting sustained-release capsaicin microsphere according to claim 1 or 3, wherein the release regulator is 0.1-2% of the polylactic acid-glycolic acid copolymer.
5. The long-acting controlled-release capsaicin microsphere according to claim 1, wherein the diameter of the long-acting controlled-release capsaicin microsphere is 50-300 [ mu ] m.
6. The method for preparing the long-acting slow-release capsaicin microsphere according to any one of claims 1-5, comprising the following steps:
mixing capsaicin, polylactic acid-glycolic acid copolymer, release regulator and organic solvent to obtain dispersed phase;
Shearing the disperse phase by using a continuous phase, collecting the obtained spherical liquid drops into a salt solution, removing an organic solvent, and solidifying to obtain the long-acting slow-release capsaicin microsphere.
7. The method according to claim 6, wherein the organic solvent comprises one or more of dichloromethane, ethyl acetate, chloroform and isopropanol.
8. The method of claim 6, wherein the continuous phase is a polyvinyl alcohol solution; the mass concentration of the polyvinyl alcohol solution is 0.2-3%.
9. Use of the long-acting slow-release capsaicin microsphere prepared by any one of claims 1-5 or the preparation method of any one of claims 6-8 in the preparation of a long-acting analgesic.
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| CN101773475A (en) * | 2010-01-14 | 2010-07-14 | 中国人民武装警察部队医学院 | Preparation method of capsicine micro spheres |
| CN102068409A (en) * | 2011-01-13 | 2011-05-25 | 清华大学 | Method for preparing mono-disperse microemulsion, liposome and microsphere based on microfluidic technology |
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| US20180042860A1 (en) * | 2015-02-09 | 2018-02-15 | Universidad De Sevilla | Method for producing a pharmaceutical composition of polymeric nanoparticles for treating neuropathic pain caused by peripheral nerve compression |
| CN108367041A (en) * | 2015-10-06 | 2018-08-03 | 弗莱克斯制药股份有限公司 | Method and composition for undesirable or abnormal contraction of muscle |
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| CN101773475A (en) * | 2010-01-14 | 2010-07-14 | 中国人民武装警察部队医学院 | Preparation method of capsicine micro spheres |
| CN102068409A (en) * | 2011-01-13 | 2011-05-25 | 清华大学 | Method for preparing mono-disperse microemulsion, liposome and microsphere based on microfluidic technology |
| CN102211008A (en) * | 2011-03-23 | 2011-10-12 | 浙江大学 | Detachable T-shaped microchannel device and method for preparing monodisperse polymer microspheres by same |
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