Injectable and degradable composite drug-loaded hydrogel as well as preparation method and application thereof

Abstract

The invention discloses injectable and degradable composite drug-loading hydrogel as well as a preparation method and application thereof. The injectable and degradable composite drug-loading hydrogel comprises sodium alginate hydrogel, piezoelectric nanofibers and triamcinolone acetonide and / or ropivacaine, wherein the piezoelectric nanofibers and the triamcinolone acetonide and / or the ropivacaine are loaded on the sodium alginate hydrogel; the piezoelectric nanofibers are poly-L-lactic acid nanofibers. Through the synergistic effect of controllable release of the medicine and piezoelectric stimulation, the dual effects of continuous analgesia and neural restoration are achieved in the PHN treatment process, more effective treatment selection is provided for a PHN patient, complications caused by a traditional implantable electrode can be avoided, a more minimally invasive, convenient and safe treatment mode can be provided for the patient, and the treatment effect is good. And a theoretical basis is provided for future clinical practice.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and more specifically to an injectable and degradable composite drug-loaded hydrogel and a preparation method and application thereof. Background Art

[0002] At present, the clinical treatment of postherpetic neuralgia (PHN) mainly focuses on controlling its symptoms, such as relieving pain through drugs to improve the quality of life of patients. The treatment drugs mainly include opioids, antiviral drugs, nonsteroidal anti-inflammatory drugs, antiepileptic drugs, anticonvulsants, tricyclic antidepressants, etc. However, simple drug treatment is not effective in controlling PHN and often fails to achieve the expected effect. In addition, due to the long duration of pain or even lifelong pain, long-term medication is required, which often brings various adverse reactions such as cognitive impairment and drug resistance. The use of local anesthetics can extend the therapeutic effect only to the locally affected area, which can effectively reduce the adverse reactions of drugs to the whole body. However, the action time of local anesthetics is relatively short, and repeated administration is required to maintain the therapeutic effect.

[0003] In recent years, the development of sustained-release drug delivery systems has opened up new feasible options for the treatment of PHN. By utilizing specific drug carriers and release mechanisms, slow and sustained release of drugs in the body can be achieved. This method of administration can not only maintain the effective concentration of the drug at the lesion site, reduce the number of administrations and dosages, but also reduce the side effects and toxicity of the drug. However, the drug release rate of the sustained-release drug delivery system is difficult to adjust in real time according to individual differences or changes in the condition. This may result in drug concentrations that are too high or too low in some cases, and the optimal therapeutic effect cannot be achieved. Therefore, it is of great scientific significance to develop more effective, controllable and personalized treatment options for the treatment of PHN.

[0004] In addition, from the perspective of pathophysiological mechanism, PHN is essentially a kind of nerve damage, the main root of which is the invasion and damage of the nerves by the virus. This damage can cause local inflammatory response, interfere with the normal conduction of nerve signals, and ultimately cause patients to suffer from severe pain. Existing treatment methods often ignore the importance of nerve repair and only stay at the level of analgesia, resulting in repeated illness and endless pain for patients. A large number of clinical studies have shown that electrical stimulation can effectively relieve various types of neuropathic pain and effectively promote nerve regeneration. Transcutaneous electrical nerve stimulation (TENS) is a non-invasive treatment method commonly used in clinical practice. It can transmit weak current through electrodes on the surface of the skin to stimulate nerves to relieve pain and promote nerve regeneration. However, most of this electrical stimulation treatment requires external energy input and wired connection, in which the stimulation electrodes, stimulators and controllers are placed outside the body. The system transmits weak current through electrodes on the surface of the skin to stimulate nerves to relieve pain. Long-term treatment is prone to skin inflammation, which limits the clinical application of electrical stimulation treatment. In recent years, wireless power supply stimulation implant materials have provided a promising solution to these challenges, avoiding complex external wiring problems and improving efficacy. Among them, piezoelectric bioactive materials can generate physiologically relevant electrical signals under the action of ultrasound, and have great application prospects in providing stable electrical stimulation. However, implanting such piezoelectric materials requires invasive surgery, and this implant intervention may cause related complications, such as tissue damage, infection and inflammation, delaying the patient's recovery time.

[0005] Therefore, constructing an injectable piezoelectric stimulation system is an important topic that needs to be studied urgently. Summary of the invention

[0006] In view of the problems of poor clinical treatment effect and easy recurrence of postherpetic neuralgia (PHN), the present invention provides an injectable and degradable composite drug-loaded hydrogel and a preparation method and application thereof. Through the synergistic effect of controlled drug release and piezoelectric stimulation, the dual effects of sustained analgesia and nerve repair are achieved in the treatment of PHN, providing a more effective treatment option for PHN patients, not only avoiding the complications caused by traditional implantable electrodes, but also providing patients with a more minimally invasive, convenient and safe treatment method, and providing a theoretical basis for future clinical practice.

[0007] To achieve the above object, the technical solution of the present invention is as follows:

[0008] Disclosed is an injectable and degradable composite drug-loaded hydrogel, which comprises a sodium alginate hydrogel and piezoelectric nanofibers and triamcinolone acetonide and / or ropivacaine loaded on the sodium alginate hydrogel; the piezoelectric nanofibers are L-polylactic acid nanofibers.

[0009] Optionally, the length of the left-handed polylactic acid nanofiber is 20 μm to 25 μm, and the diameter is 100 nm to 800 nm.

[0010] Optionally, the loading amount of triamcinolone acetonide in the injectable and degradable composite drug-loaded hydrogel is 0.2wt% to 0.5wt%.

[0011] Optionally, the loading amount of ropivacaine in the injectable and degradable composite drug-loaded hydrogel is 0.5wt% to 1wt%.

[0012] Optionally, the loading amount of the piezoelectric nanofibers in the injectable and degradable composite drug-loaded hydrogel is 1 wt% to 3 wt%.

[0013] Optionally, the mass ratio of the ropivacaine to the triamcinolone acetonide is (5-10):(2-5).

[0014] The present invention also discloses a method for preparing the injectable and degradable composite drug-loaded hydrogel as described above, which is characterized by comprising the following steps:

[0015] (1) dissolving L-polylactic acid in an organic solvent to obtain a L-polylactic acid solution;

[0016] (2) using the L-polylactic acid solution to perform electrospinning to obtain the L-polylactic acid nanofiber membrane;

[0017] (3) freeze-drying the left-handed polylactic acid nanofiber membrane and then slicing it along a direction perpendicular to the fiber to obtain the piezoelectric nanofiber;

[0018] (4) adding the piezoelectric nanofibers into a calcium chloride solution and mixing to obtain a first mixed solution;

[0019] (5) adding polyvinyl alcohol to ultrapure water and mixing to obtain a second mixed solution;

[0020] (6) mixing sodium alginate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 3-aminophenylboronic acid with water, reacting and dialyzing in sequence, and mixing the obtained sodium alginate-phenylboronic acid hydrogel precursor with ropivacaine and / or triamcinolone acetonide to obtain a pre-gel solution;

[0021] (7) Mixing the first mixed solution, the second mixed solution and the pre-gel solution to obtain the injectable and degradable composite drug-loaded hydrogel.

[0022] Optionally, in step (1), the mass fraction of the poly(L-lactic acid) in the poly(L-lactic acid) solution is 8% to 12%; and the organic solvent comprises one or both of chloroform and N,N-dimethylformamide.

[0023] Optionally, in step (2), the electrospinning is specifically as follows: collecting by a rotating collector, the DC voltage applied for electrospinning is 10 kV to 15 kV, the collection drum speed is 100 rpm to 3000 rpm, the collection distance between the syringe needle and the drum is 8 cm to 12 cm, the feed rate is 1 mL / h to 1.5 mL / h, the ambient temperature is 20°C to 35°C, and the humidity is 25% to 40%.

[0024] Optionally, in step (4), the concentration of the calcium chloride solution is 20 mM to 80 mM; and the concentration of the piezoelectric nanofibers in the first mixed solution is 80 mg / mL to 220 mg / mL.

[0025] Optionally, in step (5), the mixing temperature is 80° C. to 100° C.; and the mass concentration of polyvinyl alcohol in the second mixed liquid is 4% to 8%.

[0026] Optionally, in step (6), the mass volume ratio of the sodium alginate, water, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 3-aminophenylboronic acid is (50 mg to 100 mg): (5 ml to 10 ml): (45 mg to 90 mg): (40 mg to 85 mg); the molecular weight cutoff of the dialysis bag used for dialysis is 3500 KDa to 8000 KDa, and the dialysis time is 5 to 7 days.

[0027] Optionally, in step (6), the mass ratio of the sodium alginate-phenylboric acid hydrogel precursor to ropivacaine is (100-200):1; the mass ratio of the sodium alginate-phenylboric acid hydrogel precursor to triamcinolone acetonide is (200-500):1.

[0028] Optionally, in step (7), the first mixed solution, the second mixed solution and the pre-gel solution are mixed in a volume ratio of (100-200):(200-300):(400-600) to obtain the injectable and degradable composite drug-loaded hydrogel.

[0029] Optionally, the injectable and degradable composite drug-loaded hydrogel of the present invention can be minimally invasively injected into the diseased area through a syringe, and the hydrogel can be degraded under physiological conditions. The specific method of use is: injecting into the affected area with a syringe, under the stimulation of ultrasound, the internal structure of the injectable and degradable composite drug-loaded hydrogel undergoes a phase change, and the piezoelectric nanofibers and drugs ropivacaine and / or triamcinolone acetonide are released on demand; a better analgesic effect is achieved through the synergistic effect of the drugs; at the same time, the electrical stimulation triggered by ultrasound can effectively repair damaged nerves, providing PHN patients with effective treatment experience and quality of life.

[0030] The present invention also discloses the injectable and degradable composite drug-loaded hydrogel as described above, or the use of the injectable and degradable composite drug-loaded hydrogel prepared by the preparation method as described above in a drug delivery system.

[0031] Specifically, the working principle of the injectable and degradable composite drug-loaded hydrogel of the present invention is as follows: For patients with postherpetic neuralgia, on-demand administration is the key to achieving personalized analgesia. Piezoelectric nanofibers and drugs are loaded into sodium alginate hydrogels, and the combination between sodium alginate hydrogels and drugs is adjusted to adjust the size of ultrasonic frequency and intensity, which is expected to achieve controllable and sustained drug release. The present invention loads ropivacaine and / or triamcinolone acetonide onto injectable sodium alginate hydrogels. On the one hand, considering that sodium alginate hydrogels as alginate systems have good biocompatibility and fast degradation rate compared to other hydrogels, the introduction of phenylboronic acid can make the hydrogel have boric acid groups, and then polyvinyl alcohol (PVA) is added to form borate ester bonds, so that the hydrogel has dynamic covalent bonds inside and has self-healing properties; on the other hand, the injectable and degradable composite drug-loaded hydrogel realizes a reversible phase change of the internal structure under the action of ultrasound, thereby controllably releasing drugs; at the same time, the piezoelectric effect excited by ultrasound can also stimulate nerves well, effectively repair damaged nerves, and reduce the recurrence of patients' illnesses.

[0032] The present invention also discloses the injectable and degradable composite drug-loaded hydrogel as described above, or the use of the injectable and degradable composite drug-loaded hydrogel prepared by the preparation method as described above in an injection drug delivery system.

[0033] Specifically, the present invention implants the piezoelectric stimulation system into the body by injection, and under the action of ultrasound, it can achieve the effect of on-demand analgesia in the early stage; then, the local electrical stimulation triggered by ultrasound promotes the repair of damaged nerves. This cascade therapy provides PHN patients with a new and potential treatment method, which is expected to bring revolutionary progress to the treatment of PHN.

[0034] Implementing the embodiments of the present invention will have the following beneficial effects:

[0035] 1. In view of the problem that the current drug delivery system for treating PHN usually cannot achieve on-demand and controllable drug delivery according to the patient's condition, the present invention innovatively proposes an injectable and degradable composite drug-loaded hydrogel, which loads ropivacaine and triamcinolone acetonide on a sodium alginate hydrogel, realizes controlled release of the drugs under the stimulation of ultrasound, and brings a more personalized and comfortable treatment experience for PHN patients.

[0036] 2. Aiming at the problem that PHN patients often suffer from pain due to the difficulty in repairing nerve damage and their condition is erratic, the present invention innovatively proposes an injectable and degradable composite drug-loaded hydrogel. By embedding piezoelectric PLLA nanofibers into sodium alginate hydrogel, the electrical stimulation generated by the hydrogel under the action of ultrasound can activate the signal transduction pathway in the cells, promote the proliferation, migration and differentiation of nerve cells, thereby efficiently repairing damaged nerves and bringing better prognosis for PHN patients.

[0037] 3. In response to the problem that piezoelectric materials are difficult to degrade and cannot be injected, the present invention innovatively proposes an injectable and degradable composite drug-loaded hydrogel. By regulating the content of PLLA nanofibers in sodium alginate hydrogel, the network structure and physicochemical properties of the composite hydrogel are optimized, aiming to achieve a nanofiber hydrogel design that is injectable, degradable and has good piezoelectric properties. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 The present invention is a flow chart for preparing the injectable and degradable composite drug-loaded hydrogel.

[0039] Figure 2 This is a diagram of the piezoelectric nanofiber according to Example 1 of the present invention.

[0040] Figure 3 This is a before and after comparison of the hydrogel according to Embodiment 1 of the present invention.

[0041] Figure 4 This is the hydrogen nuclear magnetic resonance spectrum of Alg-PBA in Example 1 of the present invention.

[0042] Figure 5 This is a graph showing the release of the drug over time according to Example 1 of the present invention. DETAILED DESCRIPTION

[0043] The present invention is further described below in conjunction with specific embodiments, but the present invention is not limited in any way.

[0044] Example 1

[0045] 1. Raw materials and equipment: poly (L-lactic acid) (PLLA, molecular weight = 150000), sodium alginate (Alg), 3-aminophenylboronic acid, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, ropivacaine (Rop, MW = 370.51), triamcinolone acetonide (TA, MW = 434.504), all purchased from China Macklin Company. Equipment: electrospinning apparatus, magnetic stirrer, constant temperature shaker, freeze dryer, vacuum drying pump.

[0046] 2. Preparation of injectable and degradable composite drug-loaded hydrogel.

[0047] (1) Dissolve 1 g of PLLA in 10 ml of a mixed solution of chloroform and N,N-dimethylformamide (DMF) (chloroform:DMF=8:2) and stir for 12 h to obtain a PLLA solution. The PLLA solution was then transferred to a 5 mL syringe (with a 21 g stainless steel needle) for electrospinning.

[0048] (2) The PLLA solution was pumped at a rate of 1.08 mL / h to form a stable spinning jet under a 10 KV electrostatic field. The distance between the needle and the rotating collector (running at 3000 rpm) was 10 cm. The collected piezoelectric PLLA film was then annealed at 105 °C overnight, then slowly cooled to room temperature, and finally the annealing process was repeated at 160.1 °C to obtain a piezoelectric PLLA nanofiber membrane.

[0049] (3) The piezoelectric PLLA nanofiber membrane was wrapped in OCT gel and frozen, and then sliced ​​along the perpendicular fiber direction into short nanofibers with a length of 25 μm and a diameter of 100 to 800 nm. Finally, the slices were collected and washed with deionized water to obtain short piezoelectric nanofibers.

[0050] (4) Use ultrapure water to prepare an Alg-PBA solution with a mass fraction of 2.5%, and stir magnetically for 4 hours until the sodium alginate-phenylboric acid powder is completely dissolved. Add 10 mg / ml of ropivacaine and 2 mg / ml of triamcinolone acetonide to the Alg-PBA solution and continue stirring for 1 hour to prepare the first solution; use ultrapure water to prepare a PVA solution with a mass fraction of 4%, add the PVA powder into the ultrapure water, and stir magnetically at 90°C for 2 hours to prepare the second solution; use ultrapure water to prepare a calcium chloride solution with a concentration of 40 mM, add 90 mg / ml of piezoelectric nanofibers, and prepare the third mixed solution. Take 600 μL, 200 μl, and 100 μl of the first, second, and third solutions respectively into 2 ml centrifuge tubes. Mix thoroughly on a turbine oscillator to obtain the injectable and degradable composite drug-loaded hydrogel of this embodiment, such as Figure 1-Figure 4 shown.

[0051] Figure 5Prepare the drug release process of injectable composite hydrogel drug-carrying system for embodiment 1. Specifically, 1mL composite hydrogel (containing 10mg ropivacaine and 2mg triamcinolone acetonide) composite solution is transferred to dialysis bag (3500Da), then put into 20mL sample bottle containing PBS. Then incubate in oscillator at 40rpm. At predetermined time point (0, 1h, 2h, 4h, 6h, 8h, 16h, 24h, 48h, 72h), take out the sample of US+ group, place under ultrasonic intervention for five minutes, then take out the dialysis solution of 1ml of ultrasonic group and not ultrasonic group and replace with 1ml fresh PBS solution. Use ultraviolet-visible spectrophotometer to detect the concentration of ropivacaine and triamcinolone acetonide released into buffer solution at 263nm and 240nm respectively. The result shows that composite hydrogel can continuously release analgesic and anti-inflammatory drugs for 72h, and the release amount of ultrasonic group is higher than that of not ultrasonic group, which is most important for the controlled release of drug.

[0052] Example 2

[0053] The raw materials and equipment of this embodiment are the same as those of embodiment 1. The specific preparation steps of the injectable and degradable composite drug-loaded hydrogel of this embodiment are as follows:

[0054] (1) Dissolve 1 g of PLLA in 10 ml of a mixed solution of chloroform and DMF (chloroform:DMF=8:2) and stir for 12 h to obtain a PLLA solution. Then transfer the mixed solution to a 5 mL syringe (with a 21 g stainless steel needle) for electrospinning.

[0055] (2) The solution was pumped at a rate of 1.08 mL / h to form a stable spinning jet under a 12 KV electrostatic field. The distance between the needle and the rotating collector (running at 100 rpm) was 10 cm. The collected piezoelectric PLLA film was then annealed at 105 °C overnight, then slowly cooled to room temperature, and finally the annealing process was repeated at 160.1 °C to obtain a piezoelectric PLLA nanofiber membrane.

[0056] (3) The piezoelectric PLLA nanofiber membrane was wrapped in OCT gel and frozen, and then sliced ​​along the perpendicular fiber direction into short nanofibers with a length of 25 μm and a diameter of 100 to 800 nm. Finally, the slices were collected and washed with deionized water to obtain piezoelectric nanofibers.

[0057] (4) Prepare an Alg-PBA solution with a mass fraction of 2.5% with ultrapure water, and stir magnetically for 4 hours until the sodium alginate powder is completely dissolved. Add 10 mg / ml of ropivacaine and 2 mg / ml of triamcinolone acetonide to the Alg-PBA solution and continue stirring for 1 hour to obtain the first solution; prepare a calcium chloride solution with a concentration of 40 mM with ultrapure water, add 120 mg / ml of left-handed polylactic acid nanofibers, and obtain the second mixed solution. Take 500 μL, 200 μl and 100 μl of the first, second and third solutions respectively into 2 ml centrifuge tubes. Mix thoroughly in a turbine oscillator to obtain the injectable and degradable composite drug-loaded hydrogel of this embodiment.

[0058] The effect of this embodiment is the same as that of embodiment 1.

[0059] Example 3

[0060] The raw materials and equipment of this embodiment are the same as those of embodiment 1. The specific preparation steps of the injectable and degradable composite drug-loaded hydrogel of this embodiment are as follows:

[0061] (1) Dissolve 1 g of PLLA in 10 ml of a mixed solution of chloroform and DMF (chloroform:DMF=8:2) and stir for 12 h to obtain a PLLA solution. Then transfer the mixed solution to a 5 mL syringe (with a 21 g stainless steel needle) for electrospinning.

[0062] (2) The solution was pumped at a rate of 1.08 mL / h to form a stable spinning jet under a 12 KV electrostatic field. The distance between the needle and the rotating collector (running at 100 rpm) was 10 cm. The collected piezoelectric PLLA film was then annealed at 105 °C overnight, then slowly cooled to room temperature, and finally the annealing process was repeated at 160.1 °C to obtain a piezoelectric PLLA nanofiber membrane.

[0063] (3) The piezoelectric PLLA nanofiber membrane was wrapped in OCT gel and frozen, and then sliced ​​along the perpendicular fiber direction into short nanofibers with a length of 25 μm and a diameter of 100 to 800 nm. Finally, the slices were collected and washed with deionized water to obtain piezoelectric nanofibers.

[0064] (4) Prepare a 2.5% Alg-PBA solution with ultrapure water, and stir magnetically for 4 hours until the sodium alginate powder is completely dissolved. Add 10 mg / ml of ropivacaine and 2 mg / ml of triamcinolone acetonide to the SA solution and continue stirring for 1 hour to prepare the first solution; prepare a 40 mM calcium chloride solution with ultrapure water, add 200 mg / ml of left-handed polylactic acid nanofibers, and prepare the second mixed solution. Take 600 μL, 300 and 150 μL of the first, second and third solutions respectively into 2 ml centrifuge tubes, mix them thoroughly in a turbine oscillator, and obtain the injectable and degradable composite drug-loaded hydrogel of this embodiment.

[0065] The effect of this embodiment is the same as that of embodiment 1.

[0066] In summary, in view of the problems that the traditional drug delivery system cannot control the drug delivery according to the patient's needs, and the injectable, degradable and degradable piezoelectric biomaterials are difficult to prepare, the present invention provides an injectable, degradable composite drug-loaded hydrogel, whose porous spatial three-dimensional structure can evenly encapsulate drugs and piezoelectric nanofibers. Under the action of ultrasound, the internal structure of the hydrogel achieves a reversible phase change, thereby achieving controllable and long-term release of drugs, improving the analgesic effect, reducing the number of medications and medical expenses. At the same time, the piezoelectric effect stimulated by ultrasound can effectively repair damaged nerves and avoid recurrence of the disease. In addition, the injectable, degradable composite drug-loaded hydrogel is made of degradable biomaterials, which can be degraded over time after being injected into the body, and does not need to be removed by secondary surgery, reducing the risk of complications.

[0067] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent application. It should be pointed out that, for a person of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. An injectable and degradable composite drug-loaded hydrogel, characterized in that: The injectable and degradable composite drug-loaded hydrogel comprises a sodium alginate hydrogel and piezoelectric nanofibers and triamcinolone acetonide and / or ropivacaine loaded on the sodium alginate hydrogel; The piezoelectric nanofiber is left-handed polylactic acid nanofiber.

2. The injectable and degradable composite drug-loaded hydrogel according to claim 1, characterized in that: The length of the L-polylactic acid nanofiber is 20 μm to 25 μm, and the diameter is 100 nm to 800 nm; The loading amount of triamcinolone acetonide in the injectable and degradable composite drug-loaded hydrogel is 0.2wt% to 0.5wt%; The loading amount of ropivacaine in the injectable and degradable composite drug-loaded hydrogel is 0.5wt% to 1wt%; The loading amount of the piezoelectric nanofibers in the injectable and degradable composite drug-loaded hydrogel is 1wt% to 3wt%; The mass ratio of the ropivacaine to the triamcinolone acetonide is (5-10):(2-5).

3. A method for preparing the injectable and degradable composite drug-loaded hydrogel according to any one of claims 1 to 2, characterized in that: The following steps are involved: (1) dissolving L-polylactic acid in an organic solvent to obtain a L-polylactic acid solution; (2) using the L-polylactic acid solution to perform electrospinning to obtain the L-polylactic acid nanofiber membrane; (3) freeze-drying the left-handed polylactic acid nanofiber membrane and then slicing it along a direction perpendicular to the fiber to obtain the piezoelectric nanofiber; (4) adding the piezoelectric nanofibers into a calcium chloride solution and mixing to obtain a first mixed solution; (5) adding polyvinyl alcohol to ultrapure water and mixing to obtain a second mixed solution; (6) mixing sodium alginate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 3-aminophenylboronic acid with water, reacting and dialyzing in sequence, and mixing the obtained sodium alginate-phenylboronic acid hydrogel precursor with ropivacaine and / or triamcinolone acetonide to obtain a pre-gel solution; (7) Mixing the first mixed solution, the second mixed solution and the pre-gel solution to obtain the injectable and degradable composite drug-loaded hydrogel.

4. The preparation method according to claim 3, characterized in that: In step (1), the mass fraction of the poly(L-lactic acid) in the poly(L-lactic acid) solution is 8% to 12%; the organic solvent comprises one or both of chloroform and N,N-dimethylformamide; In step (2), the electrospinning is specifically as follows: collecting by a rotary collector, applying a DC voltage of 10 kV to 15 kV, rotating the collecting drum at a speed of 100 rpm to 3000 rpm, the distance between the syringe needle and the collecting drum being 8 cm to 12 cm, the feeding speed being 1 mL / h to 1.5 mL / h, the ambient temperature being 20° C. to 35° C., and the humidity being 25% to 40%; In step (4), the concentration of the calcium chloride solution is 20 mM to 80 mM; the concentration of the piezoelectric nanofibers in the first mixed solution is 80 mg / mL to 220 mg / mL.

5. The preparation method according to claim 3, characterized in that: In step (5), the mixing temperature is 80° C. to 100° C.; and the mass concentration of polyvinyl alcohol in the second mixed solution is 4% to 8%.

6. The preparation method according to claim 3, characterized in that: In step (6), the mass volume ratio of the sodium alginate, water, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 3-aminophenylboronic acid is (50 mg to 100 mg): (5 ml to 10 ml): (45 mg to 90 mg): (40 mg to 85 mg); the molecular weight cutoff of the dialysis bag used for dialysis is 3500 KDa to 8000 KDa, and the dialysis time is 5 to 7 days.

7. The preparation method according to claim 3, characterized in that: In step (6), the mass ratio of the sodium alginate-phenylboric acid hydrogel precursor to ropivacaine is (100-200):1; the mass ratio of the sodium alginate-phenylboric acid hydrogel precursor to triamcinolone acetonide is (200-500):

1.

8. The preparation method according to claim 3, characterized in that: In step (7), the first mixed solution, the second mixed solution and the pre-gel solution are mixed in a volume ratio of (100-200): (200-300): (400-600) to obtain the injectable and degradable composite drug-loaded hydrogel.

9. Use of the injectable and degradable composite drug-loaded hydrogel as claimed in any one of claims 1 to 2, or the injectable and degradable composite drug-loaded hydrogel prepared by the preparation method as claimed in any one of claims 3 to 8 in a drug delivery system.

10. Use of the injectable and degradable composite drug-loaded hydrogel as claimed in any one of claims 1 to 2, or the injectable and degradable composite drug-loaded hydrogel prepared by the preparation method as claimed in any one of claims 3 to 8 in an injection drug delivery system.

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