Stimulus-responsive injectable composite drug-loaded hydrogel as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicine and hydrogel preparation, and particularly relates to stimuli-responsive injectable composite drug-loaded hydrogel as well as a preparation method and application of the stimuli-responsive injectable composite drug-loaded hydrogel. The structural formula of the stimuli-responsive injectable composite drug-loaded hydrogel is as shown in formula I in the specification. The preparation method is simple and easy to implement, the raw materials are simple, the cost is low, the prepared hydrogel has the soft property, meanwhile, the good tensile property and viscidity are achieved, the hydrogel can be continuously bonded with tissue along with pulling of the tissue, meanwhile, the rapid self-healing performance is achieved, and liquid leakage is prevented. The hydrogel wound dressing also has the characteristic of large drug loading capacity and can play a role according to different wound conditions, and the response type dressing based on the wound microenvironment can accurately release the drug at different times and places through different signals.

Description

Technical Field

[0001] The invention belongs to the technical field of medicine and hydrogel preparation, and specifically relates to a stimulus-responsive injectable composite drug-loaded hydrogel and a preparation method and application thereof. Background Art

[0002] The skin is the first barrier of the human body against interference and invasion of various external factors. It can prevent the invasion of foreign bacteria, viruses and other microorganisms, protect internal organs from external invasion, and prevent human infection. When the skin is severely damaged, external pollutants may enter the wound, causing bacterial infection in the wound. Wound dressings can play a temporary physical shielding role between the damaged skin and the outside world during the wound healing process, providing an environment conducive to creating a suitable wound healing. With the diversified clinical demand for wound dressings and the research and development of medical materials, traditional wound dressings such as gauze, bandages, and absorbent cotton have the disadvantages of single performance and lack of antibacterial properties. In addition, in surgical operations, traditional dressings are used in large quantities and frequently, and are easy to adhere to the wound surface. When replaced, they will face the problem of causing secondary trauma. Therefore, traditional dressings have certain limitations in solving such problems. Therefore, it is of great significance to design a simple and effective antibacterial dressing for wound healing.

[0003] Hydrogel is a gel material with water as the dispersion medium. Due to its rich pore structure and three-dimensional network structure, hydrogel can provide good permeability and mechanical support, absorb tissue exudate and maintain a moist environment, which is conducive to cell growth and migration. It can also serve as a barrier to prevent bacterial infection. Using hydrogel to load drugs, new hydrogel medical dressings with specific functions can be prepared, which also makes it have great application potential on wounds. There are two main ways for hydrogels to load drugs: one is physical binding, which is to embed and adsorb drugs through hydrophobic interactions, coordination, etc.; the other is chemical binding, which is to combine drugs with carrier hydrogels through chemical bonds that can be hydrolyzed or enzymatically hydrolyzed, and release drugs after the bonds are hydrolyzed or enzymatically hydrolyzed in the body. The drug release of physically bound gels mainly depends on mechanical destruction, gel erosion, or swelling behavior. It is difficult to control the release behavior of drugs, which may lead to explosive release of drugs. Excessive local concentration of drugs will also bring risks such as tissue damage. By combining drug molecules with hydrogels through chemical bonds and stimulating abnormal biochemical conditions at the lesion site, controlled release of loaded drugs and on-demand drug delivery for disease treatment can be achieved. The drug release method is more intelligent and has broad application prospects.

[0004] On the other hand, although antibiotics were discovered after antibacterial metal preparations, they are undoubtedly the most commonly used and effective antibacterial agents. However, the drug resistance effect of bacteria has always been the biggest obstacle to the development and application of antibiotics. To overcome this, minimizing the dosage of conventional antibiotics is more promising and practical than exploring new antibiotics. Therefore, combining antibiotics with hydrogels in the form of chemical bonds and releasing them under stimulus-responsive conditions can achieve on-demand release of antibiotics, which not only reduces the dosage of antibiotics, but also avoids the toxicity caused by drug burst release. However, the hydrogels currently loaded with antibiotics often simply encapsulate the drugs in the porous structure of the hydrogel, which faces the risk of burst release during drug release. The use of covalent bonds with polymer carriers to load drugs will change the drug structure, reduce the efficacy, and face problems such as difficulty in drug release. Therefore, it is of great research significance to develop a new method for loading antibiotics to achieve controlled release of hydrogel-loaded antibiotics. Summary of the invention

[0005] Since antibiotics are directly encapsulated in hydrogels by physical bonding, there is a risk of explosive drug release. When antibiotics are combined with carriers by simple covalent bonds, there will be problems of reduced efficacy and difficulty in drug release. In view of the single problem of hydrogel-loaded antibiotics, the present invention provides a method for preparing and using a stimuli-responsive injectable antibiotic-loaded hydrogel, which specifically adopts the following technical solutions: In a first aspect of the present invention, a stimulus-responsive injectable composite drug-loaded hydrogel is provided, and the structural formula of the stimulus-responsive injectable composite drug-loaded hydrogel is as follows: .

[0006] Wherein R1-R6 are selected from one of hydrogen, amino, fluorine, methyl, ethyl, cyclopropyl, methoxy and 2,4-difluorophenyl respectively, and n is 1500-2400.

[0007] The second aspect of the present invention provides a method for preparing the above-mentioned stimuli-responsive injectable composite drug-loaded hydrogel, comprising the following steps: dissolving a quinolone antibiotic prodrug having a boronic acid group in an alkaline solution to obtain a prodrug solution; The quinolone antibiotic prodrug solution is mixed with an aqueous solution of polyvinyl alcohol to obtain a stimuli-responsive injectable composite drug-loaded hydrogel; The volume ratio of the quinolone antibiotic prodrug solution to the polyvinyl alcohol aqueous solution is 1:1.

[0008] In the present invention, the boron ester bond formed by the dihydroxy structure between polyvinyl alcohol (PVA) is used, and the quinolone antibiotic prodrug is used as a cross-linking agent to achieve cross-linking using dynamic covalent bonds and hydrogen bonds. It has the ability to self-heal. When cracks appear, it can recover to its initial strength and function. In addition, this self-healing hydrogel is also injectable. The injectability of the hydrogel makes it suitable for wounds of irregular shapes. This type of hydrogel wound dressing also has the characteristics of a large drug loading capacity, which can play a role in different wound conditions. The responsive dressing based on the wound microenvironment can accurately release drugs at different times and places through different signals.

[0009] Compared with the conventional antibiotic-loaded hydrogel, the present invention has the following advantages: (1) The prior art directly adsorbs the quinolone antibiotic raw drug into the voids of the hydrogel through weak interaction forces, which poses a risk of explosive release. The present invention modifies the quinolone antibiotic into a prodrug, thereby protecting the active part of the antibiotic and reducing the toxicity of the raw drug. At the same time, it enhances the modifiability of the drug and introduces a responsive functional group into the drug. (2) The prior art merely connects the antibiotic to the polymer by chemical bonds, which requires an additional cross-linking agent to achieve the gelation process. The present invention uses the prodrug itself as a cross-linking agent to directly gelate, without the need to add an additional cross-linking agent, thereby reducing the risk of introducing toxic monomers during the polymerization process. At the same time, the entire preparation process is simpler and more convenient. (3) The antibiotic prodrug cross-linking agent modified with boric acid can generate highly reactive oxygen species (ROS) at the site of wound infection, responsively break chemical bonds, and release the antibiotic raw drug on demand for treatment, thereby reducing the amount of antibiotics used. During this process, the hydrogel network is degraded and removed, thereby avoiding secondary damage to the wound.

[0010] As a further preferred embodiment, the above-mentioned quinolone antibiotic prodrug with a boronic acid group is obtained by the following process: Potassium carbonate is dissolved in a mixed solution of water and N,N-dimethylformamide to obtain a potassium carbonate solution; then the quinolone original drug is added, ultrasonicated, and after it is completely dissolved, borate is added to react, and after the reaction is completed, the pH is adjusted to weak acidity with hydrochloric acid to precipitate the product, which is then filtered, washed, and dried to obtain a quinolone prodrug with a boronic acid group.

[0011] As a further preferred embodiment, the structural formula of the quinolone prodrug with a boronic acid group is as follows: .

[0012] Wherein R1-R6 are selected from one of hydrogen, amino, fluorine, methyl, ethyl, cyclopropyl, methoxy and 2,4-difluorophenyl respectively, and n is 1500-2400.

[0013] As a further preferred embodiment, the borate is 4-bromomethylphenylboronic acid; the molar ratio of 4-bromomethylphenylboronic acid to quinolone is 0.8-1.5. If the ratio is too high or too low during the preparation process, the raw material reaction will be incomplete, and the subsequent product purification will be difficult. The present invention uses 4-bromomethylphenylboronic acid to react with the quinolone original drug to generate a quaternary ammonium salt, and the boric acid group contained in the quaternary ammonium salt will break when stimulated by active oxygen in the wound microenvironment, thereby releasing the quinolone antibiotic original drug.

[0014] As a further preferred embodiment, the alkaline solution is a 0.1 M sodium hydroxide solution.

[0015] As a further preferred embodiment, the concentration of the quinolone prodrug solution is 1.5%-3.0%; the concentration of the polyvinyl alcohol solution is 5%-13%.

[0016] As a further preferred embodiment, the mixing temperature is 90°C-100°C, and the mixing time is 3s-10s.

[0017] The third aspect of the present invention also provides the use of the above-mentioned stimulus-responsive injectable composite drug-loaded hydrogel in the preparation of medical wound dressings.

[0018] The hydrogel wound dressing prepared by the present invention has the advantages of good biocompatibility and multifunctionality, strong drug loading capacity, and good drug controlled release effect. This new hydrogel wound dressing has the characteristics of injectability and self-healing, can treat wounds of various types and different stages, respond to changes in the microenvironment in the body, and achieve drug release to improve the treatment effect. These advantages provide a strong impetus for the development of hydrogel wound dressings, making the hydrogel dressing an "ideal dressing" with great application prospects in the biomedical field.

[0019] The beneficial effects of the present invention are: (1) The preparation method of the present invention is simple and easy, with simple raw materials and low cost. The prepared hydrogel has soft properties and good tensile properties and viscosity. It can continuously adhere to tissues as the tissues are pulled, and at the same time has rapid self-healing properties to prevent liquid leakage.

[0020] (2) The present invention uses antibiotic prodrugs as crosslinkers, and uses dynamic covalent bonds and hydrogen bonds to achieve crosslinking, which can responsively release drugs on demand and prevent explosive release of drugs. Since the prodrug itself is used as a crosslinker, after the prodrug responsively releases the original drug, the corresponding hydrogel network structure breaks, the hydrogel degrades and does not adhere to the wound, and is easy to remove, thereby avoiding secondary damage to the wound.

[0021] (3) Antibiotic prodrugs are used as cross-linking agents, eliminating the need for additional cross-linking agents, reducing the risk of introducing toxic monomers, making the preparation process simpler and more convenient, and facilitating industrial production.

[0022] (4) The antibiotic-loaded hydrogel of the present invention is injectable and can be adapted to treat various complex wound conditions. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 Shown is the H-NMR spectrum of ciprofloxacin prodrug (Cip-PBA Gels) hydrogel; Figure 2 Shown is the preparation of ciprofloxacin prodrug / polyvinyl alcohol (Cip-PBA / PVA Gels) hydrogel and its infrared spectrum; Figure 3 Shown is the scanning electron micrograph of ciprofloxacin prodrug / polyvinyl alcohol (Cip-PBA / PVA Gels) hydrogel after freeze-drying; Figure 4 Shown is the amplitude scanning rheological behavior diagram of the hydrogel of each embodiment; Figure 5 Shown is the strain scanning rheological behavior diagram of the hydrogel of each embodiment; Figure 6 Shown is the alternating strain behavior graph of ciprofloxacin prodrug / polyvinyl alcohol (Cip-PBA / PVA Gels) hydrogel; Figure 7 Shown is the viscosity-shear rate curve of ciprofloxacin prodrug / polyvinyl alcohol (Cip-PBA / PVA Gels) hydrogel; Figure 8 Shown is a self-healing test image of ciprofloxacin prodrug / polyvinyl alcohol (Cip-PBA / PVA Gels) hydrogel; Fig. 9 Shown is the injectable characterization of ciprofloxacin prodrug / polyvinyl alcohol (Cip-PBA / PVA Gels) hydrogel; Fig.10 Shown is an electron photo of ciprofloxacin prodrug / polyvinyl alcohol (Cip-PBA / PVA Gels) hydrogel adhered to pig skin; Fig.11 Shown is the drug release profile of ciprofloxacin prodrug / polyvinyl alcohol (Cip-PBA / PVA Gels) hydrogel. DETAILED DESCRIPTION

[0024] The following will be combined with the embodiments and drawings to clearly and completely describe the concept, specific structure and technical effects of the present invention, so as to fully understand the purpose, scheme and effect of the present invention. It should be noted that the embodiments and features in the embodiments of this application can be combined with each other without conflict.

[0025] The preparation method of the stimulus-responsive injectable composite drug-loaded hydrogel in the present invention has the following preparation route: Wherein, R1-R6 are selected from one of hydrogen, amino, fluorine, methyl, ethyl, cyclopropyl, methoxy, and 2,4-difluorophenyl, respectively, and n is 1500-2400.

[0026] Example 1 The preparation method of the stimuli-responsive injectable composite drug-loaded hydrogel, the specific preparation process is as follows: ; (1) Preparation of ciprofloxacin prodrug with boronic acid group (Cip-PBA) Weigh 0.96 g of potassium carbonate and dissolve it in 6 mL of water and 12 mL of N,N-dimethylformamide to obtain a potassium carbonate solution; add 0.75 g of ciprofloxacin and sonicate until the supernatant is completely dissolved; then add 0.6 g of 4-bromomethylphenylboronic acid and stir overnight, and monitor the progress of the reaction by thin layer chromatography. After the reaction is completed, adjust the pH to weak acidity with hydrochloric acid to precipitate the product, filter it with a suction funnel, wash it three times and dry it to obtain 0.63 g of a white solid, namely, ciprofloxacin prodrug (Cip-PBA) (its nuclear magnetic hydrogen spectrum is shown in Figure 1 As shown), the yield is 58%; Its NMR data are 1 H NMR (400 MHz, DMSO-d6) δ 15.21 (s, 1H), 8.65 (s, 1H), 8.00 (s, 2H), 7.90 (d, J = 13.2 Hz, 1H), 7.76 (d, J = 7.6 Hz, 2H), 7.56 (d, J= 7.4 Hz, 1H), 7.31 (d, J = 7.6 Hz, 2H), 3.81 (d, J = 7.2 Hz, 1H), 3.15 –3.20 (m, 8H), 2.73 – 2.55 (m, 4H), 1.31 (d, J = 7.0 Hz, 2H), 1.17 (s, 2H).

[0027] (2) Preparation of stimuli-responsive injectable composite drug-loaded (ciprofloxacin prodrug / polyvinyl alcohol) hydrogel A 9% w / v polyvinyl alcohol solution (9 g of polyvinyl alcohol is contained in 100 mL of polyvinyl alcohol solution) (the polyvinyl alcohol solution is prepared by dissolving at 95°C) and a 1.5% w / v ciprofloxacin prodrug solution (1.5 g of ciprofloxacin prodrug is contained in 100 mL of solution) were prepared with deionized water respectively; equal volumes of the two solutions were mixed and reacted at a mixing temperature of 95°C and a mixing time of 10 s to obtain a responsive injectable composite drug-loaded hydrogel (ciprofloxacin prodrug / polyvinyl alcohol hydrogel).

[0028] The ciprofloxacin prodrug / polyvinyl alcohol (Cip-PBA / PVAGels) hydrogel prepared above was analyzed by hydrogen nuclear magnetic resonance spectroscopy, and the results were as follows: Figure 1 As shown, the characteristic peak of ciprofloxacin prodrug appeared between 7.0 and 9.0 ppm in the ciprofloxacin prodrug / polyvinyl alcohol (Cip-PBA / PVAGels) hydrogel (part A), and the chemical shift of the aromatic region moved to the high field due to the formation of the boronate bond, while the characteristic peak of polyvinyl alcohol (PVA) was retained in the high field region (region B).

[0029] The samples were analyzed by Fourier transform infrared spectroscopy (FT-IR) at 25 °C in the range of 500 to 4000 cm -1 The infrared spectrum obtained is as follows: Figure 2 As shown in Figure 2, by comparison, it can be found that the 1300 cm -1 The boric acid characteristic was found at 1300 cm -1 The characteristic peak of boric acid basically disappeared, and at the same time, the peak at 1080cm -1 The characteristic peak of boronate bond appeared at 140°, indicating that the ciprofloxacin prodrug / polyvinyl alcohol (Cip-PBA / PVA) hydrogel was successfully constructed. The ciprofloxacin prodrug / polyvinyl alcohol (Cip-PBA / PVA Gels) hydrogel was freeze-dried and then obtained by field emission scanning electron microscopy. Figure 3 . Figure 3 This is a scanning electron micrograph of ciprofloxacin prodrug / polyvinyl alcohol (Cip-PBA / PVA Gels) hydrogel after freeze-drying. Figure 3 It was found that the hydrogel exhibited a uniform porous and dense structure.

[0030] Example 2 The preparation method of the stimuli-responsive injectable composite drug-loaded hydrogel, the specific preparation process is as follows: ; (1) Preparation of norfloxacin prodrug with boronic acid group (Nor-PBA) Weigh 0.96 g of potassium carbonate and dissolve it in 6 mL of water and 12 mL of N,N-dimethylformamide to obtain a potassium carbonate solution; add 0.72 g of norfloxacin and sonicate until the supernatant is completely dissolved; then add 0.6 g of 4-bromomethylphenylboronic acid and stir overnight, and monitor the progress of the reaction by thin layer chromatography. After the reaction is completed, adjust the pH to weak acidity with hydrochloric acid to precipitate the product, filter it with a suction funnel, wash it three times and dry it to obtain 0.55 g of a white solid, i.e., norfloxacin prodrug (Nor-PBA), with a yield of 54%; Its NMR data are 1 H NMR (400 MHz, DMSO-d6) δ 15.33 (s, 1H), 8.94 (s, 1H), 7.99 (s, 2H), 7.89 (d, J = 13.3 Hz, 1H), 7.77 (d, J = 7.5 Hz, 2H), 7.31 (d, J = 7.5Hz, 2H), 7.17 (d, J = 7.2 Hz, 1H), 4.57 (q, J = 7.2 Hz, 2H), 3.57 (s, 2H), 3.31 –3.36 (m, 4H), 2.54 – 2.60 (m, 4H), 1.41 (t, J = 7.1 Hz, 3H).

[0031] (2) Preparation of stimuli-responsive injectable composite drug-loaded (norfloxacin prodrug / polyvinyl alcohol) hydrogel A 9% w / v polyvinyl alcohol solution (9 g of polyvinyl alcohol is contained in 100 mL of polyvinyl alcohol solution) (the polyvinyl alcohol solution is prepared by dissolving at 95°C) and a 1.5% w / v norfloxacin prodrug solution (1.5 g of norfloxacin prodrug is contained in 100 mL of solution) were prepared with deionized water respectively; equal volumes of the two solutions were mixed and reacted at a mixing temperature of 95°C and a mixing time of 10 s to obtain a responsive injectable composite drug-loaded hydrogel (norfloxacin prodrug / polyvinyl alcohol hydrogel).

[0032] Example 3 The preparation method of the stimuli-responsive injectable composite drug-loaded hydrogel, the specific preparation process is as follows: ; (1) Preparation of gatifloxacin prodrug with boronic acid group (Gat-PBA) Weigh 0.96 g of potassium carbonate and dissolve it in 6 mL of water and 12 mL of N,N-dimethylformamide to obtain a potassium carbonate solution; add 0.84 g of gatifloxacin and sonicate until the supernatant is completely dissolved; then add 0.6 g of 4-bromomethylphenylboronic acid and stir overnight, and monitor the progress of the reaction by thin layer chromatography. After the reaction is completed, adjust the pH to weak acidity with hydrochloric acid to precipitate the product, filter it with a suction funnel, wash it three times and dry it to obtain 0.69 g of white solid, i.e., gatifloxacin prodrug (Gat-PBA), with a yield of 60%.

[0033] Its NMR data are 1 H NMR (400 MHz, DMSO-d6) δ 14.94 (s, 1H), 8.69 (s, 1H), 8.04 (s, 2H), 7.70 – 7.77 (m, 3H), 7.30 – 7.35 (m, 2H), 4.02 – 4.12 (m, 2H),3.74 (s, 3H), 3.20 – 3.31 (m, 2H), 3.07 (t, J = 10.3 Hz, 1H), 2.84 – 2.56 (m,2H), 2.29 (s, 1H), 1.16 (t, J = 6.1 Hz, 3H), 1.10 – 1.13 (m, 2H), 1.06 – 0.97 (m, 2H).

[0034] (2) Preparation of stimuli-responsive injectable composite drug-loaded (gatifloxacin prodrug / polyvinyl alcohol) hydrogel A 9% w / v polyvinyl alcohol solution (9 g of polyvinyl alcohol is contained in 100 mL of polyvinyl alcohol solution) (the polyvinyl alcohol solution is prepared by dissolving at 95°C) and a 1.5% w / v gatifloxacin prodrug solution (1.5 g of gatifloxacin prodrug is contained in 100 mL of solution) were prepared with deionized water respectively; equal volumes of the two solutions were mixed and reacted at a mixing temperature of 95°C and a mixing time of 10 s to obtain a responsive injectable composite drug-loaded hydrogel (gatifloxacin prodrug / polyvinyl alcohol hydrogel).

[0035] Example 4 Hydrogel rheology testing The hydrogel prepared in Example 1-3 was made into a disc with a diameter of 40 mm and a height of 1 mm, and placed on the disc carrier of the rotational rheometer. In the frequency scanning experiment, the shear strain was 1%, and the angular frequency range was set to 0.1-100 rad / s, and the storage modulus and loss modulus of the sample were recorded as the frequency curve. The amplitude scanning was performed with an angular frequency of 10 rad / s and a strain range of 0.1%~1000% to obtain the law of the storage modulus and loss modulus of the hydrogel material changing with strain. In the alternating strain experiment, the hydrogel was scanned alternately for 600 s under the strain conditions of 1% and 600%, that is, low shear was performed for 120 s under 1% strain, and high shear was performed for 120 s under 600% strain, for a total of 2.5 cycles, and a low shear measurement of 1% strain was performed again for 120 s after the cycle was completed once. The frequency of the whole process kept the angular frequency of 10 rad / s unchanged. The shear rate range was set to 0.1-11 / s, and the relationship curve between the viscosity of the sample and the shear rate was recorded.

[0036] In the frequency sweep experiment ( Figure 4 ), the storage modulus of the hydrogel is greater than the loss modulus, indicating that the ciprofloxacin prodrug / polyvinyl alcohol (Cip-PBA / PVA Gels) hydrogel has the characteristics of a viscoelastic solid. In the amplitude sweep experiment, Figure 5 As shown in the figure, stress rates above 500% can destroy most of the crosslinks of the ciprofloxacin prodrug / polyvinyl alcohol (Cip-PBA / PVA Gels) hydrogel. Therefore, the hydrogel is completely broken under the condition of a strain rate of 600%. The two strain rates of 1% and 600% were selected for alternating strain tests. Figure 6 The alternating strain test showed that the hydrogel repeatedly broke at a strain rate of 600% and recovered at a strain rate of 1%, indicating that the hydrogel has self-healing ability. Figure 7 It can be seen that the viscosity of the hydrogel decreases with the increase of shear rate, indicating that the hydrogel has a shear thinning effect and thus has injectability.

[0037] Example 5 Experimental verification of the self-healing, injectability and tissue adhesion effects of ciprofloxacin prodrug / polyvinyl alcohol (Cip-PBA / PVA Gels) hydrogels The self-healing, injectability and adhesion properties of the hydrogels were determined by macroscopic experiments. To test the self-healing properties of the hydrogels, two circular hydrogels were stained with methylene blue and rhodamine B, respectively. These behaviors of the hydrogels were monitored by digital photos taken at specific time intervals. In the injection behavior test, the stained hydrogels were injected through a single / double-hole syringe. The adhesion of the hydrogels was tested using purchased pig skin.

[0038] exist Figure 8 In the self-healing macroscopic photograph, the blue and pink hydrogels contacted each other and formed a whole after 3 minutes. The color of the contact interface between the two hydrogels became blurred, and there were no scratches at the healing site, indicating that the hydrogel has excellent self-healing properties. This is due to the formation of dynamic reversible boron ester bonds between the hydroxyl groups on polyvinyl alcohol (PVA) and the boric acid on the ciprofloxacin prodrug (Cip-PBA). Fig. 9 The injectable behavior of the prepared injectable hydrogel is shown in the figure. It can be easily injected from a syringe with a diameter of 0.6 mm to present any shape, with excellent injectability. In addition, the hydrogel has strong tissue adhesion to pig skin and can maintain adhesion even under continuous folding and twisting ( Fig.10 ), indicating that after the ciprofloxacin prodrug (Cip-PBA Gels) hydrogel covers the wound skin, it can adhere tightly to the wound surface. At the same time, the hydrogel can be easily peeled off from the pig skin without leaving any traces, that is, the hydrogel patch can be replaced at any time without residue.

[0039] Example 6 In vitro drug release study of ciprofloxacin prodrug / polyvinyl alcohol (Cip-PBA / PVA Gels) hydrogels The prepared ciprofloxacin prodrug / polyvinyl alcohol (Cip-PBA / PVA Gels) hydrogel was placed in 8 mL of phosphate buffer solution (pH 7.4) and phosphate buffer solution containing 1 mM H2O2 and incubated at room temperature. The supernatant of the phosphate buffer solution was collected at each time point and the Cip content was detected by UV-visible spectrophotometer to calculate the cumulative release rate. The results are shown in Figure 2. Fig.10 shown.

[0040] from Fig.11 It can be seen that the ciprofloxacin prodrug / polyvinyl alcohol (Cip-PBA / PVA Gels) hydrogel has an active oxygen response and releases the ciprofloxacin original drug when it encounters H2O2 stimulation response. Through the above in vitro release test and the calculation formula of the drug loading rate, it is calculated that the drug loading of the ciprofloxacin prodrug / polyvinyl alcohol (Cip-PBA / PVA Gels) hydrogel prepared in Example 1 is 1.4%.

[0041] Drug loading rate (%) = actual mass of ciprofloxacin loaded into the hydrogel / mass of the hydrogel × 100 In the release experiment, the control group released only 24% of ciprofloxacin within 13 h, and it was completely released after 33.5 h. In contrast, the H2O2 group released faster at 13 h, with a release rate of 76%, and it was completely released after 21.5 h, indicating that the hydrogel can prolong the release of drugs and that the ciprofloxacin prodrug / polyvinyl alcohol (Cip-PBA / PVA Gels) hydrogel is responsive to reactive oxygen species (ROS).

[0042] Although the description of the present invention has been quite detailed and specifically describes several described embodiments, it is not intended to be limited to any of these details or embodiments or any particular embodiment, but should be regarded as providing a broad possible interpretation of these claims in view of the prior art by reference to the appended claims, thereby effectively covering the intended scope of the present invention. In addition, the above description of the present invention is based on the embodiments foreseeable by the inventor, and its purpose is to provide a useful description, and those non-substantial changes to the present invention that have not yet been foreseen may still represent equivalent changes to the present invention.

Claims

1. A stimulus-responsive injectable composite drug-loaded hydrogel, characterized in that: The structural formula of the stimulus-responsive injectable composite drug-loaded hydrogel is shown in Formula I: Formula I. Wherein R1-R6 are selected from one of hydrogen, amino, fluorine, methyl, ethyl, cyclopropyl, methoxy and 2,4-difluorophenyl respectively, and n is 1500-2400.

2. A method for preparing the stimulus-responsive injectable composite drug-loaded hydrogel according to claim 1, characterized in that: The following steps are involved: dissolving a quinolone antibiotic prodrug having a boronic acid group in an alkaline solution to obtain a prodrug solution; The quinolone antibiotic prodrug solution is mixed with an aqueous solution of polyvinyl alcohol to obtain a stimuli-responsive injectable composite drug-loaded hydrogel; The volume ratio of the quinolone antibiotic prodrug solution to the polyvinyl alcohol aqueous solution is 1:

1.

3. The preparation method according to claim 2, characterized in that: The quinolone antibiotic prodrug with a boronic acid group is obtained by the following process: Potassium carbonate is dissolved in a mixed solution of water and N,N-dimethylformamide to obtain a potassium carbonate solution; then, a quinolone antibiotic is added, ultrasonicated, and after complete dissolution, a borate is added to react, and after the reaction is completed, the pH is adjusted to a weakly acidic state using hydrochloric acid to precipitate the product, which is then filtered, washed, and dried to obtain a quinolone antibiotic prodrug with a boronic acid group.

4. The preparation method according to claim 3, characterized in that: The structural formula of the quinolone antibiotic prodrug with a boronic acid group is shown below: 。 Wherein R1-R6 are selected from one of hydrogen, amino, fluorine, methyl, ethyl, cyclopropyl, methoxy and 2,4-difluorophenyl respectively, and n is 1500-2400.

5. The preparation method according to claim 3, characterized in that: The borate is 4-bromomethylphenylboronic acid; the molar ratio of 4-bromomethylphenylboronic acid to quinolone antibiotics is 0.8-1.

5.

6. The preparation method according to claim 2, characterized in that: The alkaline solution is 0.1 M sodium hydroxide solution.

7. The preparation method according to claim 2, characterized in that: The concentration of the quinolone antibiotic prodrug solution is 1.5%-3.0%.

8. The preparation method according to claim 2, characterized in that: The concentration of the polyvinyl alcohol solution is 5%-13%.

9. The preparation method according to claim 2, characterized in that: The mixing temperature is 90°C-100°C, and the mixing time is 3 s-10 s.

10. Use of the stimulus-responsive injectable composite drug-loaded hydrogel according to claim 1 in the preparation of medical wound dressings.

Images