A sequential sustained-release drug-loaded nanosalt and its preparation method and application

Abstract

The present invention discloses a sequential sustained-release drug-loaded nano salt and a preparation method and application thereof, belonging to the field of medical technology. The drug-loaded nano salt prepared by the present invention has a nano-scale microstructure, and is loaded with tetracaine and dexamethasone at the same time during the preparation process. Through different drug loading methods, the drug sequential release is realized, so as to achieve the purpose of regulating the immune microenvironment of damaged tissue and relieving pain at different stages of wound healing. The drug-loaded nano salt prepared by the present invention is sprayed on the wound surface while closing the surgical incision, and through the sequential sustained release of the loaded drug, the dexamethasone is first quickly released when sprayed on the wound, and the acute inflammatory response of the incision microenvironment is regulated, and then the analgesic drug tetracaine is continuously released to achieve the purpose of relieving incision pain in the acute period after surgery.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a sequential sustained-release drug-loaded nano salt and a preparation method and application thereof. Background Art

[0002] Acute incision pain is one of the most common symptoms of patients after surgery. Many patients suffer from severe incision pain that affects postoperative recovery and psychological state. Currently, anesthetics and analgesics are often taken orally, intramuscularly, or intravenously to relieve acute postoperative pain. However, due to the rapid metabolism of drugs, the analgesic effect is often poor, and repeated administration is required, which not only increases the patient's dependence on analgesics, but also increases stimulation and trauma. To this end, the present invention provides a sequential sustained-release drug-loaded nano salt and its preparation method and application. Summary of the invention

[0003] The present invention provides a sequential sustained-release drug-loaded nanosalt and a preparation method and application thereof, which realizes sequential drug release through different drug loading modes, thereby achieving the purpose of regulating the immune microenvironment of damaged tissue and relieving pain at different stages of wound healing, thereby effectively reducing the dependence of surgical patients on additional analgesics.

[0004] The first object of the present invention is to provide a method for preparing a sequential sustained-release drug-loaded nanosalt, which is characterized by comprising the following steps:

[0005] Dissolving gelatin and polylactic acid-glycolic acid copolymer in a hexafluoroisopropanol solution to obtain a spinning solution, dissolving tetracaine in the spinning solution, stirring to obtain a drug-loaded spinning stock solution, electrospinning, and drying at room temperature to obtain a drug-loaded fiber membrane; powdering the drug-loaded fiber membrane, adding tert-butyl alcohol, breaking it up to obtain a tert-butyl alcohol dispersion of drug-loaded short fibers; freeze-drying the tert-butyl alcohol dispersion of the drug-loaded short fibers to obtain a tetracaine-loaded nano-short fiber rod powder, soaking the amethocaine-loaded nano-short fiber rod powder in a glutaraldehyde anhydrous ethanol solution, cross-linking at room temperature, washing, and freeze-drying to obtain a cross-linked short fiber powder;

[0006] Adding the dexamethasone methanol solution to the polyamide-amine polymer material aqueous solution, stirring, and centrifuging to obtain a drug-loaded complex solution;

[0007] The cross-linked short fiber powder is immersed in the drug-loaded complex solution, incubated on a shaker at room temperature, centrifuged, and freeze-dried to obtain a sequential sustained-release drug-loaded nano salt.

[0008] As a preferred embodiment, the mass ratio of the gelatin, the polylactic acid-glycolic acid copolymer and tetracaine is 15:15:1-2.

[0009] As a preferred embodiment, the concentration of tetracaine in the drug-loaded spinning solution is 5-10 mg / mL.

[0010] As a preferred embodiment, in the tert-butyl alcohol dispersion of the drug-loaded short fibers, the mass concentration of the drug-loaded short fibers is 1% to 4%.

[0011] As a preferred embodiment, the volume percentage of glutaraldehyde in the glutaraldehyde anhydrous ethanol solution is 10%, and the dosage ratio of the tetracaine-loaded nano short fiber rod powder to the glutaraldehyde anhydrous ethanol solution is 1 g:10 mL.

[0012] As a preferred embodiment, in the drug-loaded complex solution, the molar ratio of dexamethasone to the polyamide-amine polymer material is 20:1.

[0013] As a preferred embodiment, the dosage ratio of the cross-linked short fiber powder to the drug-loaded complex solution is 1 g:10 mL.

[0014] As a preferred embodiment, the electrospinning is specifically as follows: the drug-loaded spinning solution is placed in a medical syringe with a needle specification of 22G, which is placed on a syringe pump, and tin foil is wrapped around the receiving roller as a receiving screen, and spinning is performed at a voltage of 15kv, a flow rate of 3ml / , and a spinneret bundling distance of 15cm.

[0015] The second object of the present invention is to provide a sequential sustained-release drug-loaded nano salt prepared by the above preparation method.

[0016] The third object of the present invention is to provide an application of the above-mentioned sequential sustained-release drug-loaded nanosalt in the preparation of a drug for improving severe postoperative pain in patients.

[0017] Compared with the prior art, the present invention has the following beneficial effects:

[0018] The present invention provides a sequential sustained-release drug-loaded nano salt and its preparation method and application. The drug-loaded nano salt prepared by the present invention has a nanoscale microstructure, and tetracaine and dexamethasone are loaded simultaneously during the preparation process. Through different drug loading methods, the sequential release of drugs is realized, so as to achieve the regulation of the immune microenvironment of damaged tissues and relieve pain at different stages of wound healing. The drug-loaded nano salt prepared by the present invention is sprayed on the wound surface while closing the surgical incision. Through the sequential sustained release of the loaded drug, the dexamethasone sprayed on the wound is first released quickly, and the acute inflammatory response of the incision microenvironment is regulated, and then the analgesic drug tetracaine is continuously released to achieve the purpose of relieving incision pain in the acute phase after surgery. The present invention can avoid repeated application of analgesics and anesthetic drugs, and the nano salt can absorb wound exudate in the early stage of wound healing, collect inflammatory factors in the wound microenvironment, inhibit the inflammatory factor storm, and weaken the acute inflammatory response; and after passing the acute phase, the stored inflammatory factors can be gradually released to stimulate the wound surface to heal and repair, and reduce the dependence of surgical patients on additional analgesics after surgery. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 This is a comparison chart of the proportion of open arm time when the rats in different treatment groups perform the cross elevated test when the rats are opened and the incision is closed;

[0020] Figure 2 This is a comparison chart of the number of times rats in different treatment groups entered the food area three days after surgery when the rats had their abdomens opened and the incisions closed;

[0021] Figure 3 This is a comparison chart of the cold pain stimulation time thresholds of rats in different treatment groups when the rats had their abdomens opened and their incisions closed;

[0022] Figure 4 These are pictures of the laparotomy and incision closure of the blank control group of the present invention; among them, pictures A and C are before sampling; picture B is before modeling; picture D is after modeling;

[0023] Figure 5 These are pictures of the laparotomy and incision closure of the rats in the tetracaine treatment group of the present invention; among them, pictures A and C are before sampling; picture B is before modeling; picture D is after modeling;

[0024] Figure 6 These are pictures of the laparotomy and incision closure of rats in the tetracaine+DEX treatment group of the present invention; among them, Figure A and Figure C are before sampling; Figure B is before modeling; and Figure D is after modeling. DETAILED DESCRIPTION

[0025] In order to enable those skilled in the art to better understand the technical solution of the present invention and implement it, the present invention is further described below in conjunction with specific embodiments and drawings, but the embodiments are not intended to limit the present invention. The following test methods and detection methods, unless otherwise specified, are conventional methods; the reagents and raw materials, unless otherwise specified, are commercially available.

[0026] In view of the technical problem that the existing oral, intramuscular, or intravenous anesthetics and analgesics can relieve the acute pain of postoperative incisions, the analgesic effect is often poor due to the rapid metabolism of the drugs, and repeated administration is required, which not only increases the patient's dependence on analgesics, but also increases the stimulation and trauma. The present invention prepares a sequential sustained-release drug-loaded nano salt, wherein gelatin and polylactic acid-glycolic acid copolymer are dissolved in a hexafluoroisopropanol solution to obtain a spinning solution, tetracaine is dissolved in the spinning solution, stirred to obtain a drug-loaded spinning stock solution, electrospun, and dried at room temperature to obtain a drug-loaded fiber membrane; the drug-loaded fiber membrane is powdered , add tert-butanol, break to obtain tert-butanol dispersion of drug-loaded short fibers; freeze-dry the tert-butanol dispersion of drug-loaded short fibers to obtain adicaine-loaded nano-short fiber rod powder; soak the adicaine-loaded nano-short fiber rod powder in glutaraldehyde anhydrous ethanol solution, cross-link at room temperature, wash, freeze-dry to obtain cross-linked short fiber powder; add the dexamethasone methanol solution to the polyamide-amine type polymer material aqueous solution, stir, centrifuge to obtain a drug-loaded complex solution; soak the cross-linked short fiber powder in the drug-loaded complex solution, incubate on a shaker at room temperature, centrifuge, freeze-dry to obtain a sequential sustained-release drug-loaded nano salt.

[0027] The present invention simultaneously loads tetracaine and dexamethasone on nanofibers, and realizes sequential drug release through different drug loading modes, thereby achieving the purpose of regulating the immune microenvironment of damaged tissue and relieving pain at different stages of wound healing. While closing the surgical incision, the sequential sustained-release drug-loaded nano salt of the present invention is sprayed on the wound surface, and through the sequential sustained release of the loaded drugs, dexamethasone is first released rapidly to regulate the acute phase inflammatory response of the incision microenvironment, and then the analgesic drug tetracaine is continuously released to achieve the purpose of relieving incision pain in the acute phase after surgery.

[0028] The present invention will be specifically described below by means of the following examples and comparative examples.

[0029] Example 1

[0030] A method for preparing a sequential sustained-release drug-loaded nanosalt comprises the following steps:

[0031] S1, dissolving 750 mg of type B gelatin powder and 750 mg of polylactic acid-co-glycolic acid (PLGA) powder in 10 mL of hexafluoroisopropanol, and magnetically stirring for 24 hours to obtain a spinning solution, dissolving 100 mg of tetracaine powder in the spinning solution, and magnetically stirring again for 2 hours to obtain a drug-loaded spinning stock solution, placing the drug-loaded spinning stock solution in a medical syringe with a needle specification of 22G, placing it on a syringe pump, and wrapping tin foil as a receiving screen on a receiving roller, spinning at a voltage of 15 kV, a flow rate of 3 ml / , and a spinneret clustering distance of 15 cm, and drying at room temperature for 72 hours to obtain a drug-loaded fiber membrane;

[0032] The drug-loaded fiber membrane is cut into powder, weighed and placed in a 50 mL centrifuge tube, and tert-butanol is added to completely immerse the powder of the drug-loaded fiber membrane, and the powder is broken in a 13000 rpm homogenizer for 15 minutes to obtain a tert-butanol dispersion of drug-loaded short fibers, wherein the mass concentration of the drug-loaded short fibers in the tert-butanol dispersion of the drug-loaded short fibers is 4%; the drug-loaded short fiber dispersion is dispensed into 6-well plates, frozen at -80°C for 24 hours, and then placed in a vacuum freeze dryer for further freeze drying for 48 hours to remove residual organic solvents to obtain a nano short fiber rod powder loaded with tetracaine.

[0033] The nanometer short fiber rod powder loaded with tetracaine is immersed in anhydrous ethanol solution of glutaraldehyde, cross-linked at room temperature for 30 minutes to obtain a cross-linked product, wherein the anhydrous ethanol solution of glutaraldehyde is prepared by adding 9mL of anhydrous ethanol to 1mL of 50% glutaraldehyde solution. After cross-linking is completed, the cross-linked product is rinsed 5 times with deionized water, and then soaked in a 5% glutamic acid hydrochloric acid solution (prepared by adding 4.2mL of 36% concentrated hydrochloric acid to 95.8mL of deionized water and then adding 5g of glutamic acid powder), and placed on a shaking table at room temperature for continuous rinsing for 48 hours to neutralize free aldehyde groups, during which fresh glutamic acid hydrochloric acid solution is replaced once every 12 hours, and then deionized water is used to continue rinsing for 12 hours, and then vacuum freeze-dried to obtain a cross-linked short fiber powder.

[0034] S2, slowly dropping the dexamethasone methanol solution into the vigorously stirred polyamide-amine dendritic polymer material (PAMAM) aqueous solution, stirring overnight to allow the methanol to fully evaporate, centrifuging at 8000 rpm for 5 minutes the next day, and taking the supernatant, which is the drug-loaded complex solution (PAMAM aqueous solution loaded with dexamethasone); wherein the molar ratio of dexamethasone to polyamide-amine polymer material is 20:1;

[0035] The polyamidoamine dendrimer material (PAMAM) aqueous solution is specifically prepared by weighing 100 mg of PAMAM powder and dissolving it in 10 mL of double distilled water, and stirring evenly.

[0036] The dexamethasone methanol solution is specifically prepared by weighing 27.2 mg of dexamethasone powder and dissolving it in 1 mL of methanol solution (stock solution), and stirring the mixture evenly.

[0037] 1 g of the cross-linked short fiber powder was immersed in 10 mL of the dexamethasone-loaded PAMAM aqueous solution, incubated on a shaker for 12 hours at room temperature, centrifuged at 1500 rpm for 5 minutes, and vacuum-freeze-dried for 24 hours to obtain sequential sustained-release drug-loaded nanosalt.

[0038] In order to further illustrate the technical effect of the present invention, the present invention also provides a comparative example, which is as follows:

[0039] Comparative Example 1

[0040] A method for preparing a tetracaine-loaded nano short fiber rod powder comprises the following steps:

[0041] 750 mg of type B gelatin powder and 750 mg of polylactic acid-co-glycolic acid (PLGA) powder were dissolved in 10 mL of hexafluoroisopropanol, and magnetically stirred for 24 hours to obtain a spinning solution. 100 mg of tetracaine powder was dissolved in the spinning solution, and magnetically stirred again for 2 hours to obtain a drug-loaded spinning stock solution. The drug-loaded spinning stock solution was placed in a medical syringe with a needle specification of 22G, which was placed on a syringe pump, and tin foil was wound on a receiving roller as a receiving screen, and spinning was performed at a voltage of 15 kV, a flow rate of 3 ml / , and a spinneret clustering distance of 15 cm, and dried at room temperature for 72 hours to obtain a drug-loaded fiber membrane;

[0042] The drug-loaded fiber membrane is cut into powder, weighed and placed in a 50 mL centrifuge tube, and tert-butanol is added to completely immerse the powder of the drug-loaded fiber membrane. The powder is broken in a homogenizer at 13000 rpm for 15 minutes to obtain a tert-butanol dispersion of drug-loaded short fibers. The drug-loaded short fiber dispersion is dispensed into 6-well plates, frozen at -80°C for 24 hours, and then placed in a vacuum freeze dryer for further freeze drying for 48 hours to remove residual organic solvents to obtain a nano-short fiber rod powder loaded with tetracaine.

[0043] Comparative Example 2

[0044] A method for preparing nano short fiber rod powder comprises the following steps:

[0045] 750 mg of type B gelatin powder and 750 mg of polylactic acid-co-glycolic acid (PLGA) powder were dissolved in 10 mL of hexafluoroisopropanol, and magnetically stirred for 24 hours to obtain a spinning solution. The spinning solution was placed in a medical syringe with a needle specification of 22G, which was placed on a syringe pump, and tin foil was wound on a receiving roller as a receiving screen. Spinning was performed at a voltage of 15 kV, a flow rate of 3 ml / min, and a spinneret clustering distance of 15 cm, and dried at room temperature for 72 hours to obtain a fiber membrane.

[0046] The fiber membrane is cut into powder, weighed and placed in a 50 mL centrifuge tube, and tert-butanol is added to completely immerse the fiber membrane powder, and the powder is broken in a homogenizer at 13000 rpm for 15 minutes to obtain a tert-butanol dispersion of short fibers; the tert-butanol dispersion of short fibers is dispensed into 6-well plates, frozen at -80°C for 24 hours, and then placed in a vacuum freeze dryer for further freeze drying for 48 hours to remove residual organic solvent to obtain nano short fiber rod powder.

[0047] 1. Establishment of rat skin incision model

[0048] 1. Experimental animals: Adult female SD rats, kept in a clean rat room for 5 days to adapt to the environment;

[0049] 2. All rats were intubated and anesthetized with isoflurane inhalation;

[0050] 3. Modeling: The animal model of chronic pain after thoracotomy was established by Buvanendran method. Rats were anesthetized by intraperitoneal injection of sodium pentobarbital 40 mg / kg. Subsequently, rats were intubated through the mouth (16G, 51mm venous puncture needle cannula modified) by neck transillumination and connected to a small animal ventilator for mechanical ventilation. After anesthesia, the rats were placed in the left lateral position and a 3 cm long incision was made in the right T4 and T5 intercostal spaces. The intercostal muscles were exposed after separation of the superficial and deep muscles. A 1.5 cm long incision was made on the intercostal muscles and pleura above the 5th rib. A blunt-toothed microretractor was used to move the 4th and 5th ribs 8 mm apart. After 60 minutes, the retractor was removed, the 4th and 5th ribs were closed and fixed with 3-0 catgut ligature. Then a 22G venous puncture needle cannula was left in the chest cavity and a 5 ml syringe was connected to extract the accumulated air in the chest cavity to restore the negative pressure in the chest. Finally, the muscles and skin were sutured in layers with 3-0 catgut and 3-0 nylon respectively. After the operation, the rats regained consciousness and spontaneous breathing was restored, and the endotracheal tube was removed.

[0051] 2. Drug treatment of rats during incision closure after thoracotomy and laparotomy

[0052] 1. Grouping: Rats were randomly divided into 3 groups, 10 rats in each group;

[0053] Blank control group (Control group: closed incision without drug administration, nano short fiber rod powder without drug loading) 200 mg / rat, such as Figure 4 As shown; tetracaine treatment group (tetracaine-loaded nano short fiber rod powder: tetracaine) 200 mg / rat, as Figure 5 As shown; tetracaine + dexamethasone treatment group (short fiber powder loaded with tetracaine and dexamethasone: tetracaine + DEX) 200 mg / rat, as Figure 6 As shown;

[0054] 2. The frequency of administration is single administration. During the operation, when closing the incision, apply each treatment group on the muscle wound surface, the dosage is 200 mg / head, and no repeated administration is required.

[0055] 3. Evaluation of therapeutic effects of rat thoracotomy and laparotomy model

[0056] 1. High-altitude cross test results

[0057] The high-altitude cross test is a behavioral test method to reflect the pain level of animals. In the high-altitude cross test, the longer the time in the open arm, the lower the pain level of the animal. Figure 1 It can be seen that in each group of rats, the time of the rats in the tetracaine + DEX group in the open arm is longer than that of the rats in the tetracaine group, and the time of the rats in the tetracaine group in the open arm is longer than that of the rats in the control group. It can be seen that the nano short fiber powder (i.e., sequential sustained-release drug-loaded nano salt) prepared by the present invention, which is loaded with tetracaine and dexamethasone at the same time, can effectively relieve the pain of the incision after surgery; as the time after surgery increases, the time of the rats in the tetracaine + DEX group in the open arm reaches the maximum value on the 5th day, that is, the pain level of the rats after surgery on the 5th day is low. On the 7th day, although the time of the rats in the open arm decreases to a lower degree, the time of the rats in the tetracaine + DEX group in the open arm is still maintained at a higher level than that in the tetracaine group and the control group, so the pain level of the rats in the tetracaine + DEX group is still low. Therefore, it can be seen from the results of the high-altitude cross test that the sequential sustained-release drug-loaded nano salt prepared by the present invention can efficiently regulate the immune microenvironment of damaged tissues and relieve pain.

[0058] 2. Results of novel food suppression test in rats

[0059] The novel food suppression test is a behavioral test method to reflect the pain level of animals. In the novel food suppression test, the longer the animal enters the food area, the lower the pain level. Figure 2It can be seen that: 3 days after the operation, the rats in the tetracaine+DEX group entered the food area more times than the rats in the tetracaine group, and the rats in the tetracaine group entered the food area more times than the rats in the control group. It can be seen that the nano-short fiber powder loaded with tetracaine and dexamethasone (i.e., sequential sustained-release drug-loaded nanosalt) prepared by the present invention can effectively relieve the pain of the incision after surgery, and maintain the pain level of the surgical incision in rats at a low level.

[0060] 3. Results of cold stimulation pain threshold test in rats

[0061] The cold stimulation pain threshold is a quantitative indicator of the pain level of the animal. The higher the cold stimulation pain threshold, the lower the pain level. Figure 3 shown.

[0062] Depend on Figure 3 It can be seen that: on the 0th day after surgery, due to the effect of the anesthetic, the cold pain stimulation time of the rats in each treatment group was still maintained at a high level, and the pain level of the rats was still low; with the increase of the number of days after surgery, the cold pain stimulation time of the rats in each treatment group decreased to varying degrees, so the pain level of the rats increased to varying degrees, but compared with the tetracaine group and the control group, the cold pain stimulation time of the rats in the tetracaine + DEX group remained in a larger state, so the pain level of the rats in the tetracaine + DEX group was lower than that of the other two groups of rats, and as the number of days after surgery increased to 5-7 days, the cold pain stimulation time of the rats in the tetracaine + DEX group basically showed a stable trend, so the pain level of the rats in the tetracaine + DEX group has basically been maintained at a low level. Therefore, it can be seen from the results of the cold stimulation pain threshold test that the sequential sustained-release drug-loaded nanosalt prepared by the present invention can efficiently regulate the immune microenvironment of damaged tissues and relieve pain.

[0063] In summary, from the two groups of behavioral tests of the high-altitude cross test and the rat novel food inhibition test and the cold pain stimulation threshold test, it can be seen that the sequential sustained-release drug-loaded nanosalt prepared by the present invention (nano-short fiber powder loaded with tetracaine and dexamethasone at the same time) has a better regulating effect on the immune microenvironment and pain level of damaged tissues in surgical incisions than the nano-short fiber rod powder loaded only with tetracaine in Example 1 and the nano-short fiber rod powder not loaded with drugs in Example 2 on the regulating effect of incision pain levels.

[0064] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A method for preparing a sequential sustained-release drug-loaded nanosalt, characterized in that: The following steps are involved: Dissolving gelatin and poly(lactic acid-co-glycolic acid) copolymer in a hexafluoroisopropanol solution to obtain a spinning solution, dissolving tetracaine in the spinning solution, stirring to obtain a drug-loaded spinning stock solution, electrospinning, and drying at room temperature to obtain a drug-loaded fiber membrane; Powdering the drug-loaded fiber membrane, adding tert-butanol, and breaking it to obtain a tert-butanol dispersion of drug-loaded short fibers; The tert-butyl alcohol dispersion of the drug-loaded short fibers is freeze-dried to obtain a tetracaine-loaded nano-short fiber rod powder, and the a tetracaine-loaded nano-short fiber rod powder is immersed in a glutaraldehyde anhydrous ethanol solution, cross-linked at room temperature, washed, and freeze-dried to obtain a cross-linked short fiber powder; Adding the dexamethasone methanol solution into the polyamide-amine type polymer material aqueous solution, stirring, and centrifuging to obtain a drug-loaded complex solution; The cross-linked short fiber powder is immersed in the drug-loaded complex solution, incubated on a shaker at room temperature, centrifuged, and freeze-dried to obtain a sequential sustained-release drug-loaded nano salt.

2. The preparation method according to claim 1, characterized in that: The mass ratio of the gelatin, the polylactic acid-glycolic acid copolymer and tetracaine is 15:15:1-2.

3. The preparation method according to claim 1, characterized in that: The concentration of tetracaine in the drug-loaded spinning stock solution is 5-10 mg / mL.

4. The preparation method according to claim 1, characterized in that: In the tert-butyl alcohol dispersion of the drug-loaded short fibers, the mass concentration of the drug-loaded short fibers is 1% to 4%.

5. The preparation method according to claim 1, characterized in that: The volume percentage of glutaraldehyde in the glutaraldehyde anhydrous ethanol solution is 10%, and the dosage ratio of the tetracaine-loaded nano short fiber rod powder to the glutaraldehyde anhydrous ethanol solution is 1 g:10 mL.

6. The preparation method according to claim 1, characterized in that: In the drug-loaded complex solution, the molar ratio of dexamethasone to the polyamide-amine polymer material is 20:

1.

7. The preparation method according to claim 1, characterized in that: The dosage ratio of the cross-linked short fiber powder to the drug-loaded complex solution is 1 g:10 mL.

8. The preparation method according to claim 1, characterized in that: The electrospinning is specifically as follows: the drug-loaded spinning solution is placed in a medical syringe with a needle specification of 22G, which is placed on a syringe pump, and tin foil is wound around a receiving roller as a receiving screen, and spinning is performed at a voltage of 15kv, a flow rate of 3ml / , and a spinneret clustering distance of 15cm.

9. A sequential sustained-release drug-loaded nano salt prepared by the preparation method according to any one of claims 1 to 8.

10. Use of the sequential sustained-release drug-loaded nanosalt according to claim 9 in the preparation of a drug for improving postoperative pain in patients.

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