Pharmaceutical composition and application thereof in preparing medicine for treating EGFRIs (epidermal growth factor receptors)-induced skin toxicity

Abstract

The invention discloses a pharmaceutical composition, which comprises chlorogenic acid, ferulic acid and a zeolite imidazole framework material, the mass ratio of chlorogenic acid to ferulic acid is 4: 1-1: 4, and the zeolite imidazole framework material is a Zn-based zeolite imidazole framework material. In the composition, the compatibility of chlorogenic acid and ferulic acid can synergistically regulate the proliferation, migration and apoptosis of keratinocytes, and restore the physiological function imbalance of human skin keratinocytes caused by EGFRIs. The ZIF can efficiently carry chlorogenic acid and ferulic acid together, the nanoscale particle size of the ZIF is beneficial to permeation of the medicine into the skin, and hydroxyl on the surface of the ZIF and ceramide in the skin are subjected to hydrogen-bond interaction to retain the medicine at the focus position. The composition preparation disclosed by the invention is good in moisturizing performance and simple and convenient to use, and can be used for effectively treating skin toxic reactions such as pustule type rash, skin dryness and itching, perionychomycosis, abnormal hair regeneration and the like caused by EGFRIs.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicine, and particularly relates to a pharmaceutical composition for treating skin toxicity caused by EGFRIs, a preparation method thereof, and an application thereof in the preparation of a therapeutic drug for EGFRIs-induced skin toxicity. Background Art

[0002] In cancer treatment, epidermal growth factor receptor inhibitors (EGFRIs) are widely used in the clinical treatment of cancer patients with EGFR activating mutations, especially non-small cell lung cancer, breast cancer, colorectal cancer, etc. However, with the application of EGFRIs, patients have developed various adverse reactions, among which skin adverse reactions (including papulopustular rash, dry and itchy skin, paronychia, abnormal hair regrowth, etc.) are the most common adverse reactions, with an incidence rate as high as 79-88%. The initial appearance of skin toxicity reactions seriously affects the daily life and mood of patients. If the toxicity reactions cannot be treated in a timely and effective manner, they will gradually worsen with the continuous use of EGFRIs. Severe skin toxicity reactions will lead to a forced reduction or even discontinuation of the dose of EGFRIs, and the interruption of treatment will exacerbate the deterioration of cancer.

[0003] Currently, the expert consensus on the treatment of EGFRIs adverse reactions recommends the local use of antibiotics, steroids, and emollients, or oral antibiotics, immunomodulators, etc. for adjuvant treatment; however, the clinical efficacy is not good, it recurs frequently, and long-term use brings side effects, causing secondary harm to the physical and mental health of patients. Therefore, there is an urgent need to develop a pharmaceutical preparation with definite efficacy for EGFRIs-induced skin toxicity for clinical application.

[0004] The applicant has found through research (application number 202510176114X) that a pharmaceutical composition composed of chlorogenic acid, ferulic acid, and zinc salt has a good effect on treating EGFRIs adverse reactions, but the solubility, transdermal performance of the pharmaceutical composition vary greatly and the stability is poor. Simply administering the pharmaceutical composition cannot be retained in the skin basal layer for a long time, the drug utilization rate is not high, and there may be a risk of affecting the anti-tumor efficacy of EGFRIs. Summary of the Invention

[0005] In view of the deficiencies of the prior art, the first object of the present invention is to provide a pharmaceutical composition for treating skin toxicity caused by EGFRIs, its preparation method and its application in the preparation of therapeutic drugs for EGFRIs-induced skin toxicity. While using zeolitic imidazolate framework (ZIF) as a carrier material, the zinc element contained in ZIF is simultaneously used as a component of the therapeutic agent. This not only eliminates the need to add preservatives, reduces the introduction of risk substances, thereby reducing the risk of skin allergies, making it safer and more convenient for carrying and storage, but also can prolong the residence time of the drug in the skin, achieving better therapeutic effects.

[0006] To achieve the above object, the present invention adopts the following technical solutions: A pharmaceutical composition comprising chlorogenic acid, ferulic acid and zeolitic imidazolate framework (ZIF) material, wherein the mass ratio of chlorogenic acid to ferulic acid is 4:1 to 1:4, preferably 2:1 to 1:2, and most preferably 1.5:1. The zeolitic imidazolate framework material is a Zn-based zeolitic imidazolate framework material.

[0007] Preferably, the zeolitic imidazolate framework (ZIF) material is selected from ZIF91, ZIF90 or ZIF8. ZIF91 with a hydroxyl group on the surface is preferred.

[0008] Preferably, the mass ratio of the total amount of chlorogenic acid and ferulic acid to the Zn element in the zeolitic imidazolate framework (ZIF) material is 3:1 to 1:3, preferably 2:1 to 1:2, and most preferably 4:3.

[0009] Preferably, the ZIF91 is prepared by the following steps: (1) Reacting a zinc salt with an organic ligand in a mixed solution containing trioctylamine for 1 to 24 h to obtain an intermediate product; (2) Reacting the intermediate product in a methanol solution of sodium borohydride to obtain the ZIF91.

[0010] Preferably, the zinc salt in step (1) is any one of zinc acetate or zinc nitrate, and more preferably ZnCH 3 (COO) 2 ·2H 2 O.

[0011] Preferably, in the mixed solution in step (1), the volume fraction of trioctylamine is preferably 4 to 8%.

[0012] Preferably, the mass ratio of the zinc salt to the organic ligand in step (1) is (0.15 to 0.25):(0.1 to 0.2).

[0013] Preferably, the organic ligand in step (1) is imidazole-2-carbaldehyde.

[0014] Preferably, the temperature of the reaction in step (2) is 55-65°C, and the reaction time is 10-12 h.

[0015] Preferably, the concentration of sodium borohydride in step (2) is preferably 10-20 μg / mL.

[0016] Preferably, the pharmaceutical composition further comprises a matrix material. When the matrix material is a gel matrix and water, the pharmaceutical composition is a gel. When the matrix material is a spinning matrix, the pharmaceutical composition is a nanofiber membrane dressing.

[0017] Preferably, the gel matrix is one or a mixture of several of hyaluronic acid, carbomer, sodium alginate, xanthan gum or cellulose derivatives, and most preferably hyaluronic acid.

[0018] Preferably, the molecular weight of the hyaluronic acid is 10 k-1.2 million, and most preferably 10 k.

[0019] Preferably, in the gel, the mass fraction of the gel matrix is 1-12%, preferably 6-10%, and most preferably 8%.

[0020] Preferably, the total mass fraction of chlorogenic acid, ferulic acid and zeolitic imidazolate framework (ZIF) material in the gel is 0.5-2.0%.

[0021] Preferably, the spinning matrix is one or a mixture of several of hyaluronic acid, gelatin, silk fibroin, collagen, polyethylene glycol or polylactic acid, preferably a mixture of hyaluronic acid and gelatin, and more preferably, the mass ratio of hyaluronic acid to gelatin is 1:(4.8-7.2).

[0022] More preferably, in the nanofiber membrane dressing, the mass fraction of the spinning matrix material is 85-95%.

[0023] The second object of the present invention is to provide a preparation method of the pharmaceutical composition, comprising the following steps: Mix chlorogenic acid, ferulic acid and zeolitic imidazolate framework (ZIF) material in a methanol solution in the dark, and then perform solid-liquid separation to obtain drug particles.

[0024] Preferably, the mixing is stirring mixing.

[0025] Preferably, the mixing time is 6-24 h, and more preferably 10-12 h.

[0026] Preferably, the preparation method further comprises the steps of washing and freeze-drying after solid-liquid separation.

[0027] Preferably, the method for solid-liquid separation is centrifugation.

[0028] Preferably, when the pharmaceutical composition is a gel, the preparation method further comprises the following step A: Step A: Mix the gel matrix and water to allow the gel matrix to swell, and then add the remaining components and mix uniformly to obtain the gel.

[0029] Preferably, the swelling or uniform mixing step is carried out under stirring conditions, with a stirring speed of 1000 - 2000 rpm and a time of 0.5 - 5 h. Preferably, it is 1400 - 1600 rpm and 2 - 4 h.

[0030] Preferably, when the pharmaceutical composition is a nanofiber membrane dressing, the preparation method further comprises the following step B: Step B: Prepare a spinning solution from the spinning matrix and the drug particles, and then obtain the nanofiber membrane dressing by electrospinning the spinning solution.

[0031] Preferably, the spinning solution is prepared by the following method: Swell the spinning matrix in a spinning solvent, and then add the remaining components and mix uniformly to obtain the spinning solution.

[0032] Preferably, the spinning solvent is any one or a mixture of more than one of hexafluoroisopropanol, dichloromethane, chloroform, formic acid, or water. Preferably, it is a mixture of hexafluoroisopropanol and water, more preferably a mixture with a volume ratio of hexafluoroisopropanol to water of 6:4 - 8:2, and even more preferably a mixture with a volume ratio of hexafluoroisopropanol to water of 7:3.

[0033] Preferably, when the spinning matrix is a mixture of hyaluronic acid and gelatin, the mass concentration of hyaluronic acid in the spinning solution is 2.5 - 3.5%, and the mass concentration of gelatin is 12 - 18%. More preferably, the mass concentration of hyaluronic acid in the spinning solution is 2.8 - 3.2%, and the mass concentration of gelatin is 14 - 16%.

[0034] Preferably, the conditions for electrospinning are a voltage of 20 - 28 Kv, a feeding rate of 0.5 - 1.5 mL / h, and a receiving distance of 12 - 18 cm.

[0035] Preferably, the voltage is 24 - 26 Kv; the feeding rate is 0.8 - 1.2 mL / h; the receiving distance is 14 - 16 cm.

[0036] The third object of the present invention is to provide the use of the pharmaceutical composition in the preparation of a therapeutic drug for EGFRIs-induced skin toxicity.

[0037] Preferably, the EGFRIs include erlotinib, imatinib, nilotinib, sorafenib, rituximab, trastuzumab, cetuximab, bevacizumab or panitumumab.

[0038] The skin toxicity of the EGFRIs includes papulopustular rash, dry and itchy skin, desquamation, perionychial inflammation or abnormal hair regrowth.

[0039] The beneficial effects of the pharmaceutical compositions, preparations and applications of the present invention are manifested in the following aspects: The nano-scale size of ZIF is beneficial to the penetration of chlorogenic acid and ferulic acid into the skin. At the same time, it has unique drug-loading properties, can regulate the loading ratio of the two, and realizes the delivery of the two to the disease site according to the optimal ratio. The surface of ZIF-91 is rich in hydroxyl groups, which form hydrogen bonds with ceramide, increase the residence time to form a subcutaneous drug depot, effectively solve the problem of "only delivering drugs to the basal layer of the skin", and reduce the risk of affecting the anti-tumor effect of EGFRIs. In addition, ZIF-91 compensates for the zinc deficiency in the skin caused by EGFRIs and assists in the treatment of skin toxicity reactions induced by EGFRIs.

[0040] The present invention discovers that ferulic acid and chlorogenic acid have the effect of reversing the inhibition of the viability of human skin keratinocytes (HaCa-T cells) by EGFRIs, can reduce the apoptosis of HaCa-T cells caused by EGFRIs, restore the ability of EGFRIs to inhibit the migration of HaCa-T cells, and effectively treat skin toxicity reactions such as papulopustular rash, dry and itchy skin, desquamation, perionychial inflammation, and abnormal hair regrowth caused by EGFRIs. The effective rate is as high as 90%, providing a pharmaceutical composition for the clinical treatment of such skin toxicity reactions.

[0041] The present invention preferably uses the ZIF91 nano-delivery carrier, which has a relatively uniform particle size, about 65 nm in size. The nano-scale size is beneficial to the penetration of chlorogenic acid and ferulic acid into the skin. The carrier can co-load chlorogenic acid and ferulic acid with large differences in solubility and transdermal performance. By controlling the input amount and ratio of ferulic acid and chlorogenic acid, the drug-loading ratio of ferulic acid and chlorogenic acid in ZIF91 can reach the optimal pharmacodynamic compatibility ratio of 1:1.5, and the total drug-loading amount is about 25%. The hydroxyl groups on its surface have hydrogen bond interactions with ceramide in the skin, retaining the drug in the target area of skin toxicity caused by EGFRIs, prolonging the residence time of the drug in the skin, increasing the retention amounts of ferulic acid and chlorogenic acid in the skin by 3 times and 13.5 times respectively, improving the drug utilization rate and reducing the dosage. In addition, the Zn element in the ZIF91 carrier has a regulatory effect on many physiological processes such as the proliferation, apoptosis and migration of keratinocytes, and can cooperate with chlorogenic acid and ferulic acid to play a role in treating skin toxicity.

[0042] The gelling agent of the present invention has good moisturizing effect, helps the skin lock in moisture, moisturizes dry skin, and is beneficial to relieve the symptoms of skin dryness and itching caused by EGFRIs. The gelling agent of the pharmaceutical composition has definite curative effect, is easy to apply, is convenient to use, has good patient compliance, and can better meet the clinical needs.

[0043] In the present invention, the drug-loaded ZIF91 nanoparticles are prepared into a nanofiber membrane dressing to form a "solid membrane" without adding preservatives, reducing the risk of skin allergy, being safer and convenient to carry and store. When the nanofiber membrane comes into contact with water, it immediately forms a film and adheres more closely to the skin. When hyaluronic acid is used as the material of the nanofiber membrane, its moisturizing effect is better, which is beneficial to relieve skin dryness, has good adhesiveness and is not easy to contaminate clothes, providing more choices to meet the needs of patients. Description of the Drawings

[0044] Figure 1 It is the particle size distribution and Zeta potential diagram of ZIF91 obtained in Example 1.

[0045] Figure 2 It is the SEM diagram of ZIF91 obtained in Example 1.

[0046] Figure 3 It is the inverted microscope photos of each group at 0 h and 24 h of the scratch in Example 4.

[0047] Figure 4 It is the scratch healing rate of each group in Example 4.

[0048] Figure 5 It is the comparison diagram of the amount of ferulic acid retained and permeated in the skin of each group in Example 5 (n = 3, X±SD).

[0049] Figure 6 It is the comparison diagram of the amount of chlorogenic acid retained and permeated in the skin of each group in Example 5 (n = 3, X±SD).

[0050] Figure 7 It is the comparison diagram of the DSC spectra of the skin of each group at different temperatures in Example 6.

[0051] Figure 8 It is the diagram of the alleviation of skin toxicity symptoms of each model mouse in Example 7.

[0052] Figure 9 It is the comparison diagram of the body weights of each group of model mice in Example 7 (n = 10, X±SD, * P <0.05, ** P <0.01).

[0053] Figure 10 It is the comparison diagram of the spleen indices of each group of model mice in Example 7 (n = 10, X±SD, *P < 0.05, ** P <0.01).

[0054] Figure 11 Comparison chart of liver indices of model mice in each group in Example 7 (n = 10, X ± SD, * P < 0.05, ** P <0.01).

[0055] Figure 12 Comparison chart of thymus indices of model mice in each group in Example 7.

[0056] Figure 13 Comparison chart of skin water content of model mice in each group in Example 7.

[0057] Figure 14 Results of HE and Oil Red staining of the skin of model mice in each group after treatment in Example 7 (scale bar in the figure is 100 μm). Detailed implementation manners

[0058] The sources of cells, animals, drugs, reagents, and instruments involved in the examples are as follows: Experimental cells: HaCa-T cells were purchased from the Shanghai Institute of Cell Biology, Chinese Academy of Sciences.

[0059] Experimental animals: SPF-grade BALB / c female mice were purchased from Jiangsu Jicui Yakang Biotechnology Co., Ltd., with the experimental animal license number (SCXK (Jiangsu) 2022 - 0009), and were raised in the Experimental Animal Center of Jiangsu Provincial Academy of Traditional Chinese Medicine under a light / dark cycle of (12 h / 12 h) and a temperature of (22 ± 3) °C, with free access to food and water, and the experimental animal use license (SYXK (Jiangsu) 2016 - 0018).

[0060] Experimental pig skin: Skin of Bama mini-pigs (Jingde Agricultural Products Sales Co., Ltd., Linxi County).

[0061] Drugs and reagents: Chlorogenic acid (HPLC ≥ 98%, Sichuan Pus Biotechnology Co., Ltd.); Ferulic acid (HPLC ≥ 98%, Sichuan Pus Biotechnology Co., Ltd.); Tween 80 (Biofroxx); Erlotinib hydrochloride (Aladdin); Zn(CH 3 COO) 2 ·2H 2O, imidazole-2-formaldehyde, dimethylformamide, trioctylamine (Rohn's reagent); methanol, ethanol, chloroform, chloroform, formic acid (Xilong Scientific); DMEM medium (Gibco); fetal bovine serum (Deary Tech); CCK8 (Tongren Chemical); DMSO (Rohn's reagent); (Xilong Scientific); gelatin, carbomer, sodium alginate, xanthan gum, carboxyethyl cellulose, silk fibroin, collagen, polyethylene glycol, polylactic acid, hexafluoroisopropanol (McLean).

[0062] Instruments: Mutiskan Go microplate reader, ST16R centrifuge, 311 CO 2 Incubator (Thermo Fisher); clean bench (Suantai Air Technology Co., Ltd.); cell counter (IC1000, Countstar); TriStar II3020 surface area and porosity analyzer (Micromeritics); ZEN3600 particle size analyzer (Malvern Instrument Co., Ltd.); MS205DU 1 / 100,000 electronic balance (Mettler Toledo); XMTD-8222 high temperature oven (Jinghong Instrument); OS20-Pro mechanical stirrer (SCILogex); ACQUITY ARC high performance liquid chromatograph (Waters, USA); freeze dryer (Shanghai Jingyan Technology Co., Ltd.); electrospinning instrument (high voltage power supply (Dalian Jeman Technology Co., Ltd.), micro propulsion pump (Yanhang Power Technology Co., Ltd.)).

[0063] All other sources are commercial unless otherwise specified.

[0064] Example 1: Preparation and characterization of physicochemical properties of chlorogenic acid-ferulic acid loaded nanoparticles Prescription 1: Take ZnCH 3 (COO) 2 ·2H 20.17 g of O, 0.15 g of imidazole-2-carboxaldehyde were dissolved in 10 mL of DMF, and magnetically stirred for 5 min. 0.6 mL of trioctylamine was added to the reaction solution, and the solution was continuously stirred for 12 h. The reactants were centrifuged at 12000 rpm for 0.5 h, the supernatant was discarded, the precipitate was washed with ethanol three times, centrifuged at 5500 rpm for 10 min, the precipitate was collected, and freeze-dried for 12 h to obtain the ZIF90 carrier. Take the ZIF90 carrier and place it in a methanol solution containing 15 μg / mL of sodium borohydride, stir in the dark for 24 h, and freeze-dry for 12 h to obtain the ZIF91 carrier. Take 0.2% chlorogenic acid, 0.2% ferulic acid, 0.1% ZIF91 carrier, and 10 mL of methanol. Dissolve chlorogenic acid and ferulic acid in methanol, add the ZIF91 carrier, stir in the dark for 12 h, then centrifuge at 5500 rpm for 10 min, take the precipitate, wash the precipitate with an appropriate amount of methanol, and freeze-dry for 12 h to obtain the ZIF co-loaded with chlorogenic acid (CA) and ferulic acid (FA), namely CA&FA-ZIF91.

[0065] Prescription 2: Take ZnCH 3 (COO) 2 ·2H 2 0.17 g of O, 0.15 g of imidazole-2-carboxaldehyde were dissolved in 10 mL of DMF, and magnetically stirred for 5 min. 0.6 mL of trioctylamine was added to the reaction solution, and the solution was continuously stirred for 12 h. The reactants were centrifuged at 12000 rpm for 0.5 h, the supernatant was discarded, the precipitate was washed with ethanol three times, centrifuged at 5500 rpm for 10 min, the precipitate was collected, and freeze-dried for 12 h to obtain the ZIF90 carrier. Take 0.2% chlorogenic acid, 0.2% ferulic acid, 0.1% ZIF90 carrier, and 10 mL of methanol. Dissolve chlorogenic acid and ferulic acid in methanol, add the ZIF90 carrier, stir in the dark for 12 h, then centrifuge at 5500 rpm for 10 min, take the precipitate, wash the precipitate with an appropriate amount of methanol, and freeze-dry for 12 h to obtain the ZIF co-loaded with chlorogenic acid (CA) and ferulic acid (FA), namely CA&FA-ZIF90.

[0066] Prescription 3: Take ZnCH 3 (COO) 2 ·2H 20.17 g of O, 0.15 g of imidazole-2-methyl are dissolved in 10 mL of DMF, magnetically stirred for 5 min, 0.6 mL of trioctylamine is added to the reaction solution, and the solution is continuously stirred for 12 h. The reactants are centrifuged at 12000 rpm for 0.5 h, the supernatant is discarded, the precipitate is washed with ethanol 3 times, centrifuged at 5500 rpm for 10 min, the precipitate is collected, and freeze-dried for 12 h to obtain the ZIF8 carrier. Take 0.2% chlorogenic acid, 0.2% ferulic acid, 0.1% ZIF8 carrier, and 10 mL of methanol. Dissolve chlorogenic acid and ferulic acid in methanol, add the ZIF8 carrier, stir in the dark for 12 h, centrifuge at 5500 rpm for 10 min, take the precipitate, wash the precipitate with an appropriate amount of methanol, and freeze-dry for 12 h to obtain the ZIF co-loaded with chlorogenic acid (CA) and ferulic acid (FA), namely CA&FA-ZIF8.

[0067] Prescription 4: Take Zn(NO 3 ) 2 ·6H 2 0.17 g of O, 0.15 g of imidazole-2-carboxaldehyde are dissolved in 10 mL of DMF, magnetically stirred for 5 min, 0.6 mL of trioctylamine is added to the reaction solution, and the solution is continuously stirred for 12 h. The reactants are centrifuged at 12000 rpm for 0.5 h, the supernatant is discarded, the precipitate is washed with ethanol 3 times, centrifuged at 5500 rpm for 10 min, the precipitate is collected, and freeze-dried for 12 h to obtain the ZIF90 carrier. Take 0.2% chlorogenic acid, 0.2% ferulic acid, 0.1% ZIF90 carrier, and 10 mL of methanol. Dissolve chlorogenic acid and ferulic acid in methanol, add the ZIF90 carrier, stir in the dark for 12 h, centrifuge at 5500 rpm for 10 min, take the precipitate, wash the precipitate with an appropriate amount of methanol, and freeze-dry for 12 h to obtain the ZIF co-loaded with chlorogenic acid (CA) and ferulic acid (FA), namely CA&FA-ZIF90.

[0068] Prescription 5: Take ZnCH 3 (COO) 2 ·2H 20.15 g of O, 0.15 g of imidazole-2-carboxaldehyde were dissolved in 10 mL of DMF, and magnetically stirred for 5 min. 0.6 mL of trioctylamine was added to the reaction solution, and the solution was continuously stirred for 12 h. The reactants were centrifuged at 12000 rpm for 0.5 h, the supernatant was discarded, the precipitate was washed with ethanol three times, centrifuged at 5500 rpm for 10 min, the precipitate was collected, and freeze-dried for 12 h to obtain the ZIF90 carrier. The ZIF90 carrier was placed in a methanol solution containing 15 μg / mL of sodium borohydride, stirred in the dark for 24 h, and freeze-dried for 12 h to obtain the ZIF91 carrier. Take 0.2% chlorogenic acid, 0.2% ferulic acid, 0.1% ZIF90 carrier, and 10 mL of methanol. Chlorogenic acid and ferulic acid were dissolved in methanol, the ZIF90 carrier was added, stirred in the dark for 12 h, centrifuged at 5500 rpm for 10 min, the precipitate was taken, the precipitate was washed with an appropriate amount of methanol, and freeze-dried for 12 h to obtain the ZIF co-loaded with chlorogenic acid (CA) and ferulic acid (FA), namely CA&FA-ZIF91.

[0069] Prescription 6: Take ZnCH 3 (COO) 2 ·2H 2 0.2 g of O, 0.15 g of imidazole-2-carboxaldehyde were dissolved in 10 mL of DMF, and magnetically stirred for 5 min. 0.6 mL of trioctylamine was added to the reaction solution, and the solution was continuously stirred for 12 h. The reactants were centrifuged at 12000 rpm for 0.5 h, the supernatant was discarded, the precipitate was washed with ethanol three times, centrifuged at 5500 rpm for 10 min, the precipitate was collected, and freeze-dried for 12 h to obtain the ZIF90 carrier. The ZIF90 carrier was placed in a methanol solution containing 15 μg / mL of sodium borohydride, stirred in the dark for 24 h, and freeze-dried for 12 h to obtain the ZIF91 carrier. Take 0.2% chlorogenic acid, 0.2% ferulic acid, 0.1% ZIF90 carrier, and 10 mL of methanol. Chlorogenic acid and ferulic acid were dissolved in methanol, the ZIF90 carrier was added, stirred in the dark for 12 h, centrifuged at 5500 rpm for 10 min, the precipitate was taken, the precipitate was washed with an appropriate amount of methanol, and freeze-dried for 12 h to obtain the ZIF co-loaded with chlorogenic acid (CA) and ferulic acid (FA), namely CA&FA-ZIF91.

[0070] Prescription 7: Take ZnCH 3 (COO) 2 ·2H 20.25 g of O, 0.15 g of imidazole-2-carboxaldehyde were dissolved in 10 mL of DMF, and magnetically stirred for 5 min. 0.6 mL of trioctylamine was added to the reaction solution, and the solution was continuously stirred for 12 h. The reactants were centrifuged at 12000 rpm for 0.5 h, the supernatant was discarded, the precipitate was washed with ethanol three times, centrifuged at 5500 rpm for 10 min, the precipitate was collected, and freeze-dried for 12 h to obtain the ZIF90 carrier. The ZIF90 carrier was placed in a methanol solution containing 15 μg / mL of sodium borohydride, stirred in the dark for 24 h, and freeze-dried for 12 h to obtain the ZIF91 carrier. Take 0.2% chlorogenic acid, 0.2% ferulic acid, 0.1% ZIF91 carrier, and 10 mL of methanol. Chlorogenic acid and ferulic acid were dissolved in methanol, the ZIF90 carrier was added, stirred in the dark for 12 h, centrifuged at 5500 rpm for 10 min, the precipitate was taken, the precipitate was washed with an appropriate amount of methanol, and freeze-dried for 12 h to obtain the ZIF co-loaded with chlorogenic acid (CA) and ferulic acid (FA), namely CA&FA-ZIF91.

[0071] Prescription 8: Take ZnCH 3 (COO) 2 ·2H 2 0.17 g of O, 0.10 g of imidazole-2-carboxaldehyde were dissolved in 10 mL of DMF, and magnetically stirred for 5 min. 0.6 mL of trioctylamine was added to the reaction solution, and the solution was continuously stirred for 12 h. The reactants were centrifuged at 12000 rpm for 0.5 h, the supernatant was discarded, the precipitate was washed with ethanol three times, centrifuged at 5500 rpm for 10 min, the precipitate was collected, and freeze-dried for 12 h to obtain the ZIF90 carrier. The ZIF90 carrier was placed in a methanol solution containing 15 μg / mL of sodium borohydride, stirred in the dark for 24 h, and freeze-dried for 12 h to obtain the ZIF91 carrier. Take 0.2% chlorogenic acid, 0.2% ferulic acid, 0.1% ZIF90 carrier, and 10 mL of methanol. Chlorogenic acid and ferulic acid were dissolved in methanol, the ZIF91 carrier was added, stirred in the dark for 12 h, centrifuged at 5500 rpm for 10 min, the precipitate was taken, the precipitate was washed with an appropriate amount of methanol, and freeze-dried for 12 h to obtain the ZIF co-loaded with chlorogenic acid (CA) and ferulic acid (FA), namely CA&FA-ZIF91.

[0072] Prescription 9: Take ZnCH 3 (COO) 2 ·2H 20.17 g of O, 0.20 g of imidazole-2-carbaldehyde were dissolved in 10 mL of DMF, and magnetically stirred for 5 min. 0.6 mL of trioctylamine was added to the reaction solution, and the solution was continuously stirred for 12 h. The reactants were centrifuged at 12000 rpm for 0.5 h, the supernatant was discarded, the precipitate was washed with ethanol 3 times, centrifuged at 5500 rpm for 10 min, the precipitate was collected, and freeze-dried for 12 h to obtain the ZIF90 support. The ZIF90 support was placed in a methanol solution containing 15 μg / mL of sodium borohydride, stirred in the dark for 24 h, and freeze-dried for 12 h to obtain the ZIF91 support. Take 0.2% chlorogenic acid, 0.2% ferulic acid, 0.1% ZIF90 support, and 10 mL of methanol. Chlorogenic acid and ferulic acid were dissolved in methanol, the ZIF91 support was added, and after stirring in the dark for 12 h, the precipitate was taken after centrifugation at 5500 rpm for 10 min, the precipitate was washed with an appropriate amount of methanol, and freeze-dried for 12 h to obtain the ZIF co-loaded with chlorogenic acid (CA) and ferulic acid (FA), namely CA&FA-ZIF91.

[0073] Prescription 10: Take ZnCH 3 (COO) 2 ·2H 2 0.17 g of O, 0.15 g of imidazole-2-carbaldehyde were dissolved in 10 mL of DMF, and magnetically stirred for 5 min. 0.4 mL of trioctylamine was added to the reaction solution, and the solution was continuously stirred for 12 h. The reactants were centrifuged at 12000 rpm for 0.5 h, the supernatant was discarded, the precipitate was washed with ethanol 3 times, centrifuged at 5500 rpm for 10 min, the precipitate was collected, and freeze-dried for 12 h to obtain the ZIF90 support. The ZIF90 support was placed in a methanol solution containing 15 μg / mL of sodium borohydride, stirred in the dark for 24 h, and freeze-dried for 12 h to obtain the ZIF91 support. Take 0.2% chlorogenic acid, 0.2% ferulic acid, 0.1% ZIF90 support, and 10 mL of methanol. Chlorogenic acid and ferulic acid were dissolved in methanol, the ZIF91 support was added, and after stirring in the dark for 12 h, the precipitate was taken after centrifugation at 5500 rpm for 10 min, the precipitate was washed with an appropriate amount of methanol, and freeze-dried for 12 h to obtain the ZIF co-loaded with chlorogenic acid (CA) and ferulic acid (FA), namely CA&FA-ZIF91.

[0074] Prescription 11: Take ZnCH 3 (COO) 2 ·2H 20.17 g of O, 0.15 g of imidazole-2-carbaldehyde were dissolved in 10 mL of DMF, and magnetically stirred for 5 min. 0.8 mL of trioctylamine was added to the reaction solution, and the solution was continuously stirred for 12 h. The reactants were centrifuged at 12000 rpm for 0.5 h, the supernatant was discarded, the precipitate was washed with ethanol 3 times, centrifuged at 5500 rpm for 10 min, the precipitate was collected, and freeze-dried for 12 h to obtain the ZIF90 carrier. The ZIF90 carrier was placed in a methanol solution containing 15 μg / mL of sodium borohydride, stirred in the dark for 24 h, and freeze-dried for 12 h to obtain the ZIF91 carrier. Take 0.2% chlorogenic acid, 0.2% ferulic acid, 0.1% ZIF90 carrier, and 10 mL of methanol. Chlorogenic acid and ferulic acid were dissolved in methanol, the ZIF91 carrier was added, and after stirring in the dark for 12 h, the precipitate was taken after centrifugation at 5500 rpm for 10 min, the precipitate was washed with an appropriate amount of methanol, and freeze-dried for 12 h to obtain the ZIF co-loaded with chlorogenic acid (CA) and ferulic acid (FA), namely CA&FA-ZIF91.

[0075] Prescription 12: Take ZnCH 3 (COO) 2 ·2H 2 0.17 g of O, 0.15 g of imidazole-2-carbaldehyde were dissolved in 10 mL of DMF, and magnetically stirred for 5 min. 0.6 mL of trioctylamine was added to the reaction solution, and the solution was continuously stirred for 6 h. The reactants were centrifuged at 12000 rpm for 0.5 h, the supernatant was discarded, the precipitate was washed with ethanol 3 times, centrifuged at 5500 rpm for 10 min, the precipitate was collected, and freeze-dried for 12 h to obtain the ZIF90 carrier. The ZIF90 carrier was placed in a methanol solution containing 15 μg / mL of sodium borohydride, stirred in the dark for 24 h, and freeze-dried for 12 h to obtain the ZIF91 carrier. Take 0.2% chlorogenic acid, 0.2% ferulic acid, 0.1% ZIF90 carrier, and 10 mL of methanol. Chlorogenic acid and ferulic acid were dissolved in methanol, the ZIF91 carrier was added, and after stirring in the dark for 12 h, the precipitate was taken after centrifugation at 5500 rpm for 10 min, the precipitate was washed with an appropriate amount of methanol, and freeze-dried for 12 h to obtain the ZIF co-loaded with chlorogenic acid (CA) and ferulic acid (FA), namely CA&FA-ZIF91.

[0076] Prescription 13: Take ZnCH 3 (COO) 2 ·2H 20.17 g of O, 0.15 g of imidazole-2-carboxaldehyde were dissolved in 10 mL of DMF, and magnetically stirred for 5 min. 0.6 mL of trioctylamine was added to the reaction solution, and the solution was continuously stirred for 24 h. The reactants were centrifuged at 12000 rpm for 0.5 h, the supernatant was discarded, the precipitate was washed with ethanol three times, centrifuged at 5500 rpm for 10 min, the precipitate was collected, and freeze-dried for 12 h to obtain the ZIF90 carrier. The ZIF90 carrier was placed in a methanol solution containing 15 μg / mL of sodium borohydride, stirred in the dark for 24 h, and freeze-dried for 12 h to obtain the ZIF91 carrier. Take 0.2% chlorogenic acid, 0.2% ferulic acid, 0.1% ZIF90 carrier, and 10 mL of methanol. Chlorogenic acid and ferulic acid were dissolved in methanol, the ZIF91 carrier was added, and after stirring in the dark for 12 h, the precipitate was taken after centrifugation at 5500 rpm for 10 min, the precipitate was washed with an appropriate amount of methanol, and freeze-dried for 12 h to obtain the ZIF co-loaded with chlorogenic acid (CA) and ferulic acid (FA), namely CA&FA-ZIF91.

[0077] Prescription 14: Take ZnCH 3 (COO) 2 ·2H 2 0.17 g of O, 0.15 g of imidazole-2-carboxaldehyde were dissolved in 10 mL of DMF, and magnetically stirred for 5 min. 0.6 mL of trioctylamine was added to the reaction solution, and the solution was continuously stirred for 12 h. The reactants were centrifuged at 12000 rpm for 0.5 h, the supernatant was discarded, the precipitate was washed with ethanol three times, centrifuged at 5500 rpm for 10 min, the precipitate was collected, and freeze-dried for 12 h to obtain the ZIF90 carrier. The ZIF90 carrier was placed in a methanol solution containing 10 μg / mL of sodium borohydride, stirred in the dark for 24 h, and freeze-dried for 12 h to obtain the ZIF91 carrier. Take 0.2% chlorogenic acid, 0.2% ferulic acid, 0.1% ZIF90 carrier, and 10 mL of methanol. Chlorogenic acid and ferulic acid were dissolved in methanol, the ZIF91 carrier was added, and after stirring in the dark for 12 h, the precipitate was taken after centrifugation at 5500 rpm for 10 min, the precipitate was washed with an appropriate amount of methanol, and freeze-dried for 12 h to obtain the ZIF co-loaded with chlorogenic acid (CA) and ferulic acid (FA), namely CA&FA-ZIF91.

[0078] Prescription 15: Take ZnCH 3 (COO) 2 ·2H 20.17 g of O, 0.15 g of imidazole-2-carboxaldehyde were dissolved in 10 mL of DMF, and magnetically stirred for 5 min. 0.6 mL of trioctylamine was added to the reaction solution, and the solution was continuously stirred for 12 h. The reactants were centrifuged at 12000 rpm for 0.5 h, the supernatant was discarded, the precipitate was washed with ethanol three times, centrifuged at 5500 rpm for 10 min, the precipitate was collected, and freeze-dried for 12 h to obtain the ZIF90 carrier. The ZIF90 carrier was placed in a methanol solution containing 20 μg / mL of sodium borohydride, stirred in the dark for 24 h, and freeze-dried for 12 h to obtain the ZIF91 carrier. Take 0.2% chlorogenic acid, 0.2% ferulic acid, 0.1% ZIF90 carrier, and 10 mL of methanol. Chlorogenic acid and ferulic acid were dissolved in methanol, the ZIF91 carrier was added, and after stirring in the dark for 12 h, the precipitate was taken after centrifugation at 5500 rpm for 10 min, the precipitate was washed with an appropriate amount of methanol, and freeze-dried for 12 h to obtain the ZIF co-loaded with chlorogenic acid (CA) and ferulic acid (FA), namely CA&FA-ZIF91.

[0079] Prescription 16: Take ZnCH 3 (COO) 2 ·2H 2 0.17 g of O, 0.15 g of imidazole-2-carboxaldehyde were dissolved in 10 mL of DMF, and magnetically stirred for 5 min. 0.6 mL of trioctylamine was added to the reaction solution, and the solution was continuously stirred for 12 h. The reactants were centrifuged at 12000 rpm for 0.5 h, the supernatant was discarded, the precipitate was washed with ethanol three times, centrifuged at 5500 rpm for 10 min, the precipitate was collected, and freeze-dried for 12 h to obtain the ZIF90 carrier. The ZIF90 carrier was placed in a methanol solution containing 15 μg / mL of sodium borohydride, stirred in the dark for 24 h, and freeze-dried for 12 h to obtain the ZIF91 carrier. Take 0.1% chlorogenic acid, 0.1% ferulic acid, 0.1% ZIF91 carrier, and 10 mL of methanol. Chlorogenic acid and ferulic acid were dissolved in methanol, the ZIF91 carrier was added, and after stirring in the dark for 12 h, the precipitate was taken after centrifugation at 5500 rpm for 10 min, the precipitate was washed with an appropriate amount of methanol, and freeze-dried for 12 h to obtain the ZIF co-loaded with chlorogenic acid (CA) and ferulic acid (FA), namely CA&FA-ZIF91.

[0080] Prescription 17: Take ZnCH 3 (COO) 2 ·2H 20.17 g of O, 0.15 g of imidazole-2-carbaldehyde were dissolved in 10 mL of DMF, and magnetically stirred for 5 min. 0.6 mL of trioctylamine was added to the reaction solution, and the solution was continuously stirred for 12 h. The reactants were centrifuged at 12000 rpm for 0.5 h, the supernatant was discarded, the precipitate was washed with ethanol three times, centrifuged at 5500 rpm for 10 min, the precipitate was collected, and freeze-dried for 12 h to obtain the ZIF90 carrier. The ZIF90 carrier was placed in a methanol solution containing 15 μg / mL of sodium borohydride, stirred in the dark for 24 h, and freeze-dried for 12 h to obtain the ZIF91 carrier. Take 0.1% chlorogenic acid, 0.2% ferulic acid, 0.1% ZIF91 carrier, and 10 mL of methanol. Dissolve chlorogenic acid and ferulic acid in methanol, add the ZIF91 carrier, stir in the dark for 12 h, centrifuge at 5500 rpm for 10 min, take the precipitate, wash the precipitate with an appropriate amount of methanol, and freeze-dry for 12 h to obtain the ZIF co-loaded with chlorogenic acid (CA) and ferulic acid (FA), namely CA&FA-ZIF91.

[0081] Prescription 18: Take ZnCH 3 (COO) 2 ·2H 2 0.17 g of O, 0.15 g of imidazole-2-carbaldehyde were dissolved in 10 mL of DMF, and magnetically stirred for 5 min. 0.6 mL of trioctylamine was added to the reaction solution, and the solution was continuously stirred for 12 h. The reactants were centrifuged at 12000 rpm for 0.5 h, the supernatant was discarded, the precipitate was washed with ethanol three times, centrifuged at 5500 rpm for 10 min, the precipitate was collected, and freeze-dried for 12 h to obtain the ZIF90 carrier. The ZIF90 carrier was placed in a methanol solution containing 15 μg / mL of sodium borohydride, stirred in the dark for 24 h, and freeze-dried for 12 h to obtain the ZIF91 carrier. Take 0.2% chlorogenic acid, 0.3% ferulic acid, 0.1% ZIF91 carrier, and 10 mL of methanol. Dissolve chlorogenic acid and ferulic acid in methanol, add the ZIF91 carrier, stir in the dark for 12 h, centrifuge at 5500 rpm for 10 min, take the precipitate, wash the precipitate with an appropriate amount of methanol, and freeze-dry for 12 h to obtain the ZIF co-loaded with chlorogenic acid (CA) and ferulic acid (FA), namely CA&FA-ZIF91.

[0082] Prescription 19: Take ZnCH 3 (COO) 2 ·2H 20.17 g of O, 0.15 g of imidazole-2-carbaldehyde were dissolved in 10 mL of DMF, and magnetically stirred for 5 min. 0.6 mL of trioctylamine was added to the reaction solution, and the solution was continuously stirred for 12 h. The reactants were centrifuged at 12000 rpm for 0.5 h, the supernatant was discarded, the precipitate was washed with ethanol three times, centrifuged at 5500 rpm for 10 min, the precipitate was collected, and freeze-dried for 12 h to obtain the ZIF90 carrier. The ZIF90 carrier was placed in a methanol solution containing 15 μg / mL of sodium borohydride, stirred in the dark for 24 h, and freeze-dried for 12 h to obtain the ZIF91 carrier. Take 0.2% chlorogenic acid, 0.4% ferulic acid, 0.1% ZIF91 carrier, and 10 mL of methanol. The chlorogenic acid and ferulic acid were dissolved in methanol, the ZIF91 carrier was added, and after stirring in the dark for 12 h, the precipitate was taken after centrifugation at 5500 rpm for 10 min, the precipitate was washed with an appropriate amount of methanol, and freeze-dried for 12 h to obtain the ZIF co-loaded with chlorogenic acid (CA) and ferulic acid (FA), namely CA&FA-ZIF91.

[0083] Prescription 20: Take ZnCH 3 (COO) 2 ·2H 2 0.17 g of O, 0.15 g of imidazole-2-carbaldehyde were dissolved in 10 mL of DMF, and magnetically stirred for 5 min. 0.6 mL of trioctylamine was added to the reaction solution, and the solution was continuously stirred for 12 h. The reactants were centrifuged at 12000 rpm for 0.5 h, the supernatant was discarded, the precipitate was washed with ethanol three times, centrifuged at 5500 rpm for 10 min, the precipitate was collected, and freeze-dried for 12 h to obtain the ZIF90 carrier. The ZIF90 carrier was placed in a methanol solution containing 15 μg / mL of sodium borohydride, stirred in the dark for 24 h, and freeze-dried for 12 h to obtain the ZIF91 carrier. Take 0.2% chlorogenic acid, 0.5% ferulic acid, 0.1% ZIF91 carrier, and 10 mL of methanol. The chlorogenic acid and ferulic acid were dissolved in methanol, the ZIF91 carrier was added, and after stirring in the dark for 12 h, the precipitate was taken after centrifugation at 5500 rpm for 10 min, the precipitate was washed with an appropriate amount of methanol, and freeze-dried for 12 h to obtain the ZIF co-loaded with chlorogenic acid (CA) and ferulic acid (FA), namely CA&FA-ZIF91.

[0084] Prescription 21: Take ZnCH 3 (COO) 2 ·2H 20.17 g of O, 0.15 g of imidazole-2-carboxaldehyde were dissolved in 10 mL of DMF, and magnetically stirred for 5 min. 0.6 mL of trioctylamine was added to the reaction solution, and the solution was continuously stirred for 12 h. The reactants were centrifuged at 12000 rpm for 0.5 h, the supernatant was discarded, the precipitate was washed with ethanol three times, centrifuged at 5500 rpm for 10 min, the precipitate was collected, and freeze-dried for 12 h to obtain the ZIF90 support. The ZIF90 support was placed in a methanol solution containing 15 μg / mL of sodium borohydride, stirred in the dark for 24 h, and freeze-dried for 12 h to obtain the ZIF91 support. Take 0.2% chlorogenic acid, 0.6% ferulic acid, 0.1% ZIF91 support, and 10 mL of methanol. Dissolve chlorogenic acid and ferulic acid in methanol, add the ZIF91 support, stir in the dark for 12 h, centrifuge at 5500 rpm for 10 min, take the precipitate, wash the precipitate with an appropriate amount of methanol, and freeze-dry for 12 h to obtain the ZIF co-loaded with chlorogenic acid (CA) and ferulic acid (FA), namely CA&FA-ZIF91.

[0085] Prescription 22: Take ZnCH 3 (COO) 2 ·2H 2 0.17 g of O, 0.15 g of imidazole-2-carboxaldehyde were dissolved in 10 mL of DMF, and magnetically stirred for 5 min. 0.6 mL of trioctylamine was added to the reaction solution, and the solution was continuously stirred for 12 h. The reactants were centrifuged at 12000 rpm for 0.5 h, the supernatant was discarded, the precipitate was washed with ethanol three times, centrifuged at 5500 rpm for 10 min, the precipitate was collected, and freeze-dried for 12 h to obtain the ZIF90 support. The ZIF90 support was placed in a methanol solution containing 15 μg / mL of sodium borohydride, stirred in the dark for 24 h, and freeze-dried for 12 h to obtain the ZIF91 support. Take 0.2% chlorogenic acid, 0.4% ferulic acid, 0.1% ZIF91 support, and 10 mL of methanol. Dissolve chlorogenic acid and ferulic acid in methanol, add the ZIF91 support, stir in the dark for 12 h, centrifuge at 5500 rpm for 10 min, take the precipitate, wash the precipitate with an appropriate amount of methanol, and freeze-dry for 6 h to obtain the ZIF co-loaded with chlorogenic acid (CA) and ferulic acid (FA), namely CA&FA-ZIF91.

[0086] Prescription 23: Take ZnCH 3 (COO) 2 ·2H 20.17 g of O, 0.15 g of imidazole-2-carboxaldehyde were dissolved in 10 mL of DMF, and magnetically stirred for 5 min. 0.6 mL of trioctylamine was added to the reaction solution, and the solution was continuously stirred for 12 h. The reactants were centrifuged at 12000 rpm for 0.5 h, the supernatant was discarded, the precipitate was washed with ethanol three times, centrifuged at 5500 rpm for 10 min, the precipitate was collected, and freeze-dried for 12 h to obtain the ZIF90 carrier. The ZIF90 carrier was placed in a methanol solution containing 15 μg / mL of sodium borohydride, stirred in the dark for 24 h, and freeze-dried for 12 h to obtain the ZIF91 carrier. Take 0.2% chlorogenic acid, 0.4% ferulic acid, 0.1% ZIF91 carrier, and 10 mL of methanol. Chlorogenic acid and ferulic acid were dissolved in methanol, the ZIF91 carrier was added, and after stirring in the dark for 10 h, the precipitate was taken after centrifugation at 5500 rpm for 10 min, the precipitate was washed with an appropriate amount of methanol, and freeze-dried for 6 h to obtain the ZIF co-loaded with chlorogenic acid (CA) and ferulic acid (FA), namely CA&FA-ZIF91.

[0087] Prescription 24: Take ZnCH 3 (COO) 2 ·2H 2 0.17 g of O, 0.15 g of imidazole-2-carboxaldehyde were dissolved in 10 mL of DMF, and magnetically stirred for 5 min. 0.6 mL of trioctylamine was added to the reaction solution, and the solution was continuously stirred for 12 h. The reactants were centrifuged at 12000 rpm for 0.5 h, the supernatant was discarded, the precipitate was washed with ethanol three times, centrifuged at 5500 rpm for 10 min, the precipitate was collected, and freeze-dried for 12 h to obtain the ZIF90 carrier. The ZIF90 carrier was placed in a methanol solution containing 15 μg / mL of sodium borohydride, stirred in the dark for 24 h, and freeze-dried for 12 h to obtain the ZIF91 carrier. Take 0.2% chlorogenic acid, 0.4% ferulic acid, 0.1% ZIF91 carrier, and 10 mL of methanol. Chlorogenic acid and ferulic acid were dissolved in methanol, the ZIF91 carrier was added, and after stirring in the dark for 10 h, the precipitate was taken after centrifugation at 5500 rpm for 10 min, the precipitate was washed with an appropriate amount of methanol, and freeze-dried for 6 h to obtain the ZIF co-loaded with chlorogenic acid (CA) and ferulic acid (FA), namely CA&FA-ZIF91.

[0088] Prescription 25: Take ZnCH 3 (COO) 2 ·2H 20.17 g of O, 0.15 g of imidazole-2-carboxaldehyde were dissolved in 10 mL of DMF, and magnetically stirred for 5 min. 0.6 mL of trioctylamine was added to the reaction solution, and the solution was continuously stirred for 12 h. The reactants were centrifuged at 12000 rpm for 0.5 h, the supernatant was discarded, the precipitate was washed with ethanol three times, centrifuged at 5500 rpm for 10 min, the precipitate was collected, and freeze-dried for 12 h to obtain the ZIF90 carrier. The ZIF90 carrier was placed in a methanol solution containing 15 μg / mL of sodium borohydride, stirred in the dark for 24 h, and freeze-dried for 12 h to obtain the ZIF91 carrier. Take 0.2% chlorogenic acid, 0.4% ferulic acid, 0.1% ZIF91 carrier, and 10 mL of ethanol. Chlorogenic acid and ferulic acid were dissolved in methanol, the ZIF91 carrier was added, and after stirring in the dark for 24 h, the precipitate was taken after centrifugation at 5500 rpm for 10 min, the precipitate was washed with an appropriate amount of methanol, and freeze-dried for 6 h to obtain ZIF co-loaded with chlorogenic acid (CA) and ferulic acid (FA), namely CA&FA-ZIF91.

[0089] Characterization of physical and chemical properties: Determination of drug loading: Take the supernatant after drug loading in Prescription 22 (M 2 ), centrifuge at 12000 rpm for 10 min, filter through a 0.22 μm filter membrane, take the filtrate, and inject for determination. Take the stock solutions of chlorogenic acid and ferulic acid reference substances, and prepare a series of chlorogenic acid and ferulic acid reference substance solutions with mass concentrations of 0.5 μg / mL, 1.0 μg / mL, 2.0 μg / mL, 4.0 μg / mL, and 8.0 μg / mL respectively with methanol. Treat them according to the above sample method. Determine the chlorogenic acid and ferulic acid reference substance solutions and the test solution according to the chromatographic conditions, record the peak areas, plot a graph with the concentrations of chlorogenic acid and ferulic acid reference substance solutions as the abscissa (X) and the peak areas (Y) as the ordinate, draw a standard curve, and calculate the contents of chlorogenic acid and ferulic acid using the standard curve. The chromatographic column is Agilent (4.6 mm × 250 mm, 5 μm), the mobile phase is acetonitrile and 0.1% phosphate solution, gradient elution, the flow rate is 1.0 mL / min, the column temperature is 35 °C, the injection volume is 10 μL, the detection wavelength is 327 nm, and the elution gradient is shown in Table 1.

[0090] Time (min) Acetonitrile (%) 0.1% Phosphate solution (%) 0→9 13→16 87→84 9→10 16→25 84→75 10→16 25→45 75→55 Calculate according to the following formula: Drug loading (%) = (M 1 - M 2 ) / M 3 × 100% Among them, M 1 is the dosage of the drug, M 2 is the remaining drug amount in the supernatant, and M 3 is the mass of CA / FA-ZIF91.

[0091] The loadings of chlorogenic acid and ferulic acid are approximately 14.95% and 10.56% respectively, and the total drug loading is approximately 25%. The particle size distribution, Zeta potential diagram and SEM image of the ZIF-91 nanoformulation are as Figure 1 , 2 shown. The particle size is relatively uniform, about 65 nm in size, and the Zeta potential is about -17 mV.

[0092] Example 2: Preparation process study of the gel (CA&FA-ZIF91 Gel) The fractions used in the formulation of this example are mass fractions, and the CA&FA-ZIF91 used is prepared according to Prescription 24 of Example 1.

[0093] Prescription 1: Take 6% hyaluronic acid (10k), add an appropriate amount of pure water, stir at 1500 rpm for 2 h to completely swell it, add 0.15% CA&FA-ZIF91 to the hyaluronic acid matrix, add pure water to 10 g, and continue to stir at 1500 rpm for 5 h to mix evenly, then it is obtained.

[0094] Prescription 2: Take 0.8% carbomer 940, add an appropriate amount of pure water to completely swell it, add 0.15% CA&FA-ZIF91 to the carbomer 940 matrix, add sodium hydroxide to adjust the pH value to 6.0, add pure water to 10 g, and continue to stir at 1500 rpm for 5 h to mix evenly, then it is obtained.

[0095] Prescription 3: Take 2% xanthan gum, add an appropriate amount of pure water to completely swell it, add 0.15% CA&FA-ZIF91 to the xanthan gum matrix, add pure water to 10 g, and continue to stir at 1500 rpm for 5 h to mix evenly, then it is obtained.

[0096] Prescription 4: Take 2% sodium alginate, add an appropriate amount of pure water to completely swell it, add 0.15% CA&FA-ZIF91 to the sodium alginate matrix, add pure water to 10 g, and continue to stir at 1500 rpm for 5 h to mix evenly, then it is obtained.

[0097] Prescription 5: Take 2% CMC-Na, add an appropriate amount of pure water to completely swell it, add 0.15% CA&FA-ZIF91 to the CMC-Na matrix, add pure water to 10 g, and continue to stir at 1500 rpm for 5 h to mix evenly, then it is obtained.

[0098] Prescription 6: Take 2% hyaluronic acid (40k), add appropriate amount of pure water, stir at 1500 rpm for 2 h to make it fully swell, add 0.15% CA&FA-ZIF91 to the hyaluronic acid matrix, add pure water to 10 g, continue to stir at 1500 rpm for 5 h, and mix evenly to obtain.

[0099] Prescription 7: Take 1.5% hyaluronic acid (80k), add appropriate amount of pure water, stir at 1500 rpm for 2 h to make it fully swell, add 0.15% CA&FA-ZIF91 to the hyaluronic acid matrix, add pure water to 10 g, continue to stir at 1500 rpm for 5 h, and mix evenly to obtain.

[0100] Prescription 8: Take 0.8% hyaluronic acid (120w), add appropriate amount of pure water, stir at 1500 rpm for 2 h to make it fully swell, add 0.15% CA&FA-ZIF91 to the hyaluronic acid matrix, add pure water to 10 g, continue to stir at 1500 rpm for 5 h, and mix evenly to obtain.

[0101] Prescription 9: Take 8% hyaluronic acid (10k), add appropriate amount of pure water, stir at 1000 rpm for 2 h to make it fully swell, add 0.15% CA&FA-ZIF91 to the hyaluronic acid matrix, add pure water to 10 g, continue to stir at 1000 rpm for 1 h, and mix evenly to obtain.

[0102] Prescription 10: Take 8% hyaluronic acid (10k), add appropriate amount of pure water, stir at 1500 rpm for 2 h to make it fully swell, add 0.15% CA&FA-ZIF91 to the hyaluronic acid matrix, add pure water to 10 g, continue to stir at 1500 rpm for 1 h, and mix evenly to obtain.

[0103] Prescription 11: Take 8% hyaluronic acid (10k), add appropriate amount of pure water, stir at 2000 rpm for 2 h to make it fully swell, add 0.15% CA&FA-ZIF91 to the hyaluronic acid matrix, add pure water to 10 g, continue to stir at 2000 rpm for 2 h, and mix evenly to obtain.

[0104] Prescription 12: Take 8% hyaluronic acid (10k), add appropriate amount of pure water, stir at 1500 rpm for 0.5 h to make it fully swell, add 0.15% CA&FA-ZIF91 to the hyaluronic acid matrix, add pure water to 10 g, continue to stir at 1500 rpm for 0.5 h, and mix evenly to obtain.

[0105] Prescription 13: Take 8% hyaluronic acid (10k), add an appropriate amount of pure water, stir at 1500 rpm for 1 h to make it fully swell, add 0.15% CA&FA-ZIF91 to the hyaluronic acid matrix, add pure water to 10 g, continue to stir at 1500 rpm for 1 h, and mix evenly to obtain.

[0106] Prescription 14: Take 8% hyaluronic acid (10k), add an appropriate amount of pure water, stir at 1500 rpm for 3 h to make it fully swell, add 0.15% CA&FA-ZIF91 to the hyaluronic acid matrix, add pure water to 10 g, continue to stir at 1500 rpm for 3 h, and mix evenly to obtain.

[0107] Prescription 15: Take 8% hyaluronic acid (10k), add an appropriate amount of pure water, stir at 1500 rpm for 5 h to make it fully swell, add 0.15% CA&FA-ZIF91 to the hyaluronic acid matrix, add pure water to 10 g, continue to stir at 1500 rpm for 5 h, and mix evenly to obtain.

[0108] Prescription 16: Take 8% hyaluronic acid (10k), add an appropriate amount of pure water, stir at 1500 rpm for 2 h to make it fully swell, add 0.15% CA&FA-ZIF91 to the hyaluronic acid matrix, add pure water to 10 g, continue to stir at 1500 rpm for 1.5 h, and mix evenly to obtain.

[0109] Prescription 17: Take 8% hyaluronic acid (10k), add an appropriate amount of pure water, stir at 1500 rpm for 2 h to make it fully swell, add 0.15% CA&FA-ZIF91 to the hyaluronic acid matrix, add pure water to 10 g, continue to stir at 1500 rpm for 1 h, and mix evenly to obtain.

[0110] Example 3: Preparation of nanofiber membrane dressing (HA@CA&FA-ZIF91) The fractions used in the prescriptions of this example are mass fractions, and the CA&FA-ZIF91 used is the one prepared in Prescription 24 of Example 1.

[0111] Prescription 1: Add 3.0% hyaluronic acid and 15% gelatin to a 10 mL mixed solution of hexafluoroisopropanol and water (volume ratio 7:3) to swell, then add 0.10% CA&FA-ZIF91 to the above solution, mix well to obtain a uniform electrospinning solution; prepare it using an electrospinning instrument under the conditions of a voltage of 25 Kv, a feeding rate of 0.8 mL / h, and a receiving distance of 15 cm to obtain.

[0112] Prescription 2: Use 10 mL of formic acid with a mass fraction of 60% as the solvent to prepare a poly(ethylene glycol) solution with a mass fraction of 1%. Stir magnetically at room temperature for 24 h; then add 16% type I collagen peptide COP and 0.10% CA&FA-ZIF91, and stir magnetically at room temperature until evenly mixed to obtain the COP / PEG spinning solution. Obtain a uniform electrospinning solution; use an electrospinning instrument to prepare it under the conditions of a voltage of 25 Kv, a feeding rate of 0.8 mL / h, and a receiving distance of 15 cm, and that's it.

[0113] Prescription 3: Add 40% PVP and 0.10% CA&FA-ZIF91 to 6 mL of absolute ethanol, stir magnetically at room temperature for 8 h until completely dissolved, then perform ultrasonic degassing for 20 min to prepare a homogeneous PVP shell spinning solution containing the drug composition. Additionally, weigh an appropriate amount of PLA and dissolve it in an appropriate amount of chloroform-acetone (volume ratio 3:1) to prepare a 6% mixed solution. After stirring magnetically at room temperature for 15 h, perform ultrasonic degassing for 20 min to obtain the PLA core layer emulsion spinning solution; suck the core-shell layer spinning solutions into 2 10-mL syringes respectively, install them on a micro-injection pump, and connect the two interfaces of the coaxial needle. Use an electrospinning instrument to prepare it under the conditions of a voltage of 25 Kv, a feeding rate of 0.8 mL / h, and a receiving distance of 15 cm, and that's it.

[0114] Prescription 4: Swell 2.5% hyaluronic acid and 14% gelatin in 10 mL of a mixed solution of hexafluoroisopropanol and water (volume ratio 6:4), then add 0.10% CA&FA-ZIF91 to the above solution, mix well to obtain a uniform electrospinning solution; use an electrospinning instrument to prepare it under the conditions of a voltage of 25 Kv, a feeding rate of 0.8 mL / h, and a receiving distance of 15 cm, and that's it.

[0115] Prescription 5: Swell 2.5% hyaluronic acid and 16% gelatin in 10 mL of a mixed solution of hexafluoroisopropanol and water (volume ratio 7:3), then add 0.10% CA&FA-ZIF91 to the above solution, mix well to obtain a uniform electrospinning solution; use an electrospinning instrument to prepare it under the conditions of a voltage of 25 Kv, a feeding rate of 0.8 mL / h, and a receiving distance of 15 cm, and that's it.

[0116] Prescription 6: Swell 2.5% hyaluronic acid and 18% gelatin in 10 mL of a mixed solution of hexafluoroisopropanol and water (volume ratio 8:2), then add 0.10% CA&FA-ZIF91 to the above solution, mix well to obtain a uniform electrospinning solution; use an electrospinning instrument to prepare it under the conditions of a voltage of 25 Kv, a feeding rate of 0.8 mL / h, and a receiving distance of 15 cm, and that's it.

[0117] Prescription 7: 3.0% hyaluronic acid and 14% gelatin were added to a 10 mL mixed solution of hexafluoroisopropanol and water (volume ratio 7:3) for swelling, and then 0.10% CA&FA-ZIF91 was added to the above solution and mixed evenly to obtain a uniform electrospinning solution; it was prepared using an electrospinning instrument under the conditions of a voltage of 25 Kv, a feeding speed of 0.8 mL / h, and a receiving distance of 15 cm, and that's it.

[0118] Prescription 8: 3.0% hyaluronic acid and 16% gelatin were added to a 10 mL mixed solution of hexafluoroisopropanol and water (volume ratio 8:2) for swelling, and then 0.10% CA&FA-ZIF91 was added to the above solution and mixed evenly to obtain a uniform electrospinning solution; it was prepared using an electrospinning instrument under the conditions of a voltage of 25 Kv, a feeding speed of 0.8 mL / h, and a receiving distance of 15 cm, and that's it.

[0119] Prescription 9: 3.0% hyaluronic acid and 18% gelatin were added to a 10 mL mixed solution of hexafluoroisopropanol and water (volume ratio 6:4) for swelling, and then 0.10% green CA&FA-ZIF91 was added to the above solution and mixed evenly to obtain a uniform electrospinning solution; it was prepared using an electrospinning instrument under the conditions of a voltage of 25 Kv, a feeding speed of 0.8 mL / h, and a receiving distance of 15 cm, and that's it.

[0120] Prescription 10: 3.5% hyaluronic acid and 14% gelatin were added to a 10 mL mixed solution of hexafluoroisopropanol and water (volume ratio 8:2) for swelling, and then 0.10% CA&FA-ZIF91 was added to the above solution and mixed evenly to obtain a uniform electrospinning solution; it was prepared using an electrospinning instrument under the conditions of a voltage of 25 Kv, a feeding speed of 0.8 mL / h, and a receiving distance of 15 cm, and that's it.

[0121] Prescription 11: 3.5% hyaluronic acid and 16% gelatin were added to a 10 mL mixed solution of hexafluoroisopropanol and water (volume ratio 6:4) for swelling, and then 0.10% CA&FA-ZIF91 was added to the above solution and mixed evenly to obtain a uniform electrospinning solution; it was prepared using an electrospinning instrument under the conditions of a voltage of 25 Kv, a feeding speed of 0.8 mL / h, and a receiving distance of 15 cm, and that's it.

[0122] Prescription 12: 3.5% hyaluronic acid and 18% gelatin were added to a 10 mL mixed solution of hexafluoroisopropanol and water (volume ratio 7:3) for swelling, and then 0.10% CA&FA-ZIF91 was added to the above solution and mixed evenly to obtain a uniform electrospinning solution; it was prepared using an electrospinning instrument under the conditions of a voltage of 25 Kv, a feeding speed of 0.8 mL / h, and a receiving distance of 15 cm, and that's it.

[0123] Prescription 13: 2.8% hyaluronic acid and 15% gelatin were added to 10 mL of a mixed solution of hexafluoroisopropanol and water (volume ratio 7:3) for swelling, and then 0.10% CA&FA-ZIF91 was added to the above solution and mixed evenly to obtain a uniform electrospinning solution; it was prepared using an electrospinning instrument under the conditions of a voltage of 25 Kv, a feeding speed of 0.8 mL / h, and a receiving distance of 15 cm, and that's it.

[0124] Prescription 14: 3.2% hyaluronic acid and 15% gelatin were added to 10 mL of a mixed solution of hexafluoroisopropanol and water (volume ratio 7:3) for swelling, and then 0.10% CA&FA-ZIF91 was added to the above solution and mixed evenly to obtain a uniform electrospinning solution; it was prepared using an electrospinning instrument under the conditions of a voltage of 25 Kv, a feeding speed of 0.8 mL / h, and a receiving distance of 15 cm, and that's it.

[0125] Prescription 15: 3.0% hyaluronic acid and 15% gelatin were added to 10 mL of a mixed solution of hexafluoroisopropanol and water (volume ratio 7:3) for swelling, and then 0.05% CA&FA-ZIF91 was added to the above solution and mixed evenly to obtain a uniform electrospinning solution; it was prepared using an electrospinning instrument under the conditions of a voltage of 25 Kv, a feeding speed of 1.0 mL / h, and a receiving distance of 15 cm, and that's it.

[0126] Prescription 16: 3.0% hyaluronic acid and 15% gelatin were added to 10 mL of a mixed solution of hexafluoroisopropanol and water (volume ratio 7:3) for swelling, and then 0.15% CA&FA-ZIF91 was added to the above solution and mixed evenly to obtain a uniform electrospinning solution; it was prepared using an electrospinning instrument under the conditions of a voltage of 25 Kv, a feeding speed of 1.0 mL / h, and a receiving distance of 15 cm, and that's it.

[0127] Prescription 17: 3.0% hyaluronic acid and 15% gelatin were added to 10 mL of a mixed solution of hexafluoroisopropanol and water (volume ratio 7:3) for swelling, and then 0.20% CA&FA-ZIF91 was added to the above solution and mixed evenly to obtain a uniform electrospinning solution; it was prepared using an electrospinning instrument under the conditions of a voltage of 25 Kv, a feeding speed of 1.0 mL / h, and a receiving distance of 15 cm, and that's it.

[0128] Prescription 18: 3.0% hyaluronic acid and 12% gelatin were added to 10 mL of a mixed solution of hexafluoroisopropanol and water (volume ratio 7:3) for swelling, and then 0.10% CA&FA-ZIF91 was added to the above solution and mixed evenly to obtain a uniform electrospinning solution; it was prepared using an electrospinning instrument under the conditions of a voltage of 25 Kv, a feeding speed of 0.8 mL / h, and a receiving distance of 15 cm, and that's it.

[0129] Prescription 19: 3.0% hyaluronic acid and 15% gelatin were added to 10 mL of a mixed solution of hexafluoroisopropanol and water (volume ratio 7:3) for swelling, and then 0.10% CA&FA-ZIF91 was added to the above solution and mixed evenly to obtain a uniform electrospinning solution; it was prepared using an electrospinning instrument under the conditions of a voltage of 20 Kv, a feeding rate of 0.5 mL / h, and a receiving distance of 12 cm, and that's it.

[0130] Prescription 20: 3.0% hyaluronic acid and 15% gelatin were added to 10 mL of a mixed solution of hexafluoroisopropanol and water (volume ratio 7:3) for swelling, and then 0.10% CA&FA-ZIF91 was added to the above solution and mixed evenly to obtain a uniform electrospinning solution; it was prepared using an electrospinning instrument under the conditions of a voltage of 20 Kv, a feeding rate of 1.0 mL / h, and a receiving distance of 15 cm, and that's it.

[0131] Prescription 21: 3.0% hyaluronic acid and 15% gelatin were added to 10 mL of a mixed solution of hexafluoroisopropanol and water (volume ratio 7:3) for swelling, and then 0.10% CA&FA-ZIF91 was added to the above solution and mixed evenly to obtain a uniform electrospinning solution; it was prepared using an electrospinning instrument under the conditions of a voltage of 20 Kv, a feeding rate of 1.5 mL / h, and a receiving distance of 18 cm, and that's it.

[0132] Prescription 22: 3.0% hyaluronic acid and 15% gelatin were added to 10 mL of a mixed solution of hexafluoroisopropanol and water (volume ratio 7:3) for swelling, and then 0.10% CA&FA-ZIF91 was added to the above solution and mixed evenly to obtain a uniform electrospinning solution; it was prepared using an electrospinning instrument under the conditions of a voltage of 24 Kv, a feeding rate of 0.5 mL / h, and a receiving distance of 15 cm, and that's it.

[0133] Prescription 23: 3.0% hyaluronic acid and 15% gelatin were added to 10 mL of a mixed solution of hexafluoroisopropanol and water (volume ratio 7:3) for swelling, and then 0.10% CA&FA-ZIF91 was added to the above solution and mixed evenly to obtain a uniform electrospinning solution; it was prepared using an electrospinning instrument under the conditions of a voltage of 24 Kv, a feeding rate of 1.0 mL / h, and a receiving distance of 18 cm, and that's it.

[0134] Prescription 24: 3.0% hyaluronic acid and 15% gelatin were added to 10 mL of a mixed solution of hexafluoroisopropanol and water (volume ratio 7:3) for swelling, and then 0.10% CA&FA-ZIF91 was added to the above solution and mixed evenly to obtain a uniform electrospinning solution; it was prepared using an electrospinning instrument under the conditions of a voltage of 24 Kv, a feeding rate of 1.5 mL / h, and a receiving distance of 12 cm, and that's it.

[0135] Prescription 25: 3.0% hyaluronic acid and 15% gelatin were added to 10 mL of a mixed solution of hexafluoroisopropanol and water (volume ratio 7:3) for swelling, and then 0.10% CA&FA-ZIF91 was added to the above solution and mixed evenly to obtain a uniform electrospinning solution; it was prepared using an electrospinning instrument under the conditions of a voltage of 28 Kv, a feeding speed of 0.5 mL / h, and a receiving distance of 18 cm, and thus obtained.

[0136] Prescription 26: 3.0% hyaluronic acid and 15% gelatin were added to 10 mL of a mixed solution of hexafluoroisopropanol and water (volume ratio 7:3) for swelling, and then 0.10% CA&FA-ZIF91 was added to the above solution and mixed evenly to obtain a uniform electrospinning solution; it was prepared using an electrospinning instrument under the conditions of a voltage of 28 Kv, a feeding speed of 1.0 mL / h, and a receiving distance of 12 cm, and thus obtained.

[0137] Prescription 27: 3.0% hyaluronic acid and 15% gelatin were added to 10 mL of a mixed solution of hexafluoroisopropanol and water (volume ratio 7:3) for swelling, and then 0.10% CA&FA-ZIF91 was added to the above solution and mixed evenly to obtain a uniform electrospinning solution; it was prepared using an electrospinning instrument under the conditions of a voltage of 28 Kv, a feeding speed of 1.5 mL / h, and a receiving distance of 15 cm, and thus obtained.

[0138] Prescription 28: 3.0% hyaluronic acid and 15% gelatin were added to 10 mL of a mixed solution of hexafluoroisopropanol and water (volume ratio 7:3) for swelling, and then 0.10% CA&FA-ZIF91 was added to the above solution and mixed evenly to obtain a uniform electrospinning solution; it was prepared using an electrospinning instrument under the conditions of a voltage of 25 Kv, a feeding speed of 1.0 mL / h, and a receiving distance of 15 cm, and thus obtained.

[0139] Prescription 29: 3.0% hyaluronic acid and 15% gelatin were added to 10 mL of a mixed solution of hexafluoroisopropanol and water (volume ratio 7:3) for swelling, and then 0.10% CA&FA-ZIF91 was added to the above solution and mixed evenly to obtain a uniform electrospinning solution; it was prepared using an electrospinning instrument under the conditions of a voltage of 26 Kv, a feeding speed of 1.0 mL / h, and a receiving distance of 15 cm, and thus obtained.

[0140] Prescription 30: 3.0% hyaluronic acid and 15% gelatin were added to 10 mL of a mixed solution of hexafluoroisopropanol and water (volume ratio 7:3) for swelling, and then 0.10% CA&FA-ZIF91 was added to the above solution and mixed evenly to obtain a uniform electrospinning solution; it was prepared using an electrospinning instrument under the conditions of a voltage of 24 Kv, a feeding speed of 0.8 mL / h, and a receiving distance of 15 cm, and thus obtained.

[0141] Prescription 31: 3.0% hyaluronic acid and 15% gelatin were added to a 10 mL mixed solution of hexafluoroisopropanol and water (volume ratio 7:3) for swelling, and then 0.10% CA&FA-ZIF91 was added to the above solution and mixed evenly to obtain a uniform electrospinning solution; it was prepared using an electrospinning instrument under the conditions of a voltage of 24 Kv, a feeding rate of 1.2 mL / h, and a receiving distance of 15 cm, and thus obtained.

[0142] Prescription 32: 3.0% hyaluronic acid and 15% gelatin were added to a 10 mL mixed solution of hexafluoroisopropanol and water (volume ratio 7:3) for swelling, and then 0.10% CA&FA-ZIF91 was added to the above solution and mixed evenly to obtain a uniform electrospinning solution; it was prepared using an electrospinning instrument under the conditions of a voltage of 24 Kv, a feeding rate of 1.0 mL / h, and a receiving distance of 14 cm, and thus obtained.

[0143] Prescription 33: 3.0% hyaluronic acid and 15% gelatin were added to a 10 mL mixed solution of hexafluoroisopropanol and water (volume ratio 7:3) for swelling, and then 0.10% CA&FA-ZIF91 was added to the above solution and mixed evenly to obtain a uniform electrospinning solution; it was prepared using an electrospinning instrument under the conditions of a voltage of 24 Kv, a feeding rate of 1.0 mL / h, and a receiving distance of 16 cm, and thus obtained.

[0144] Prescription 34: 3.0% hyaluronic acid and 15% gelatin were added to a 10 mL mixed solution of hexafluoroisopropanol and water (volume ratio 7:3) for swelling, and then 0.10% CA&FA-ZIF91 was added to the above solution and mixed evenly to obtain a uniform electrospinning solution; it was prepared using an electrospinning instrument under the conditions of a voltage of 25 Kv, a feeding rate of 1.0 mL / h, and a receiving distance of 15 cm, and thus obtained.

[0145] Example 4: Effect of HA@CA&FA-ZIF91 on the migration of HaCa-T cells HaCa-T cells in the logarithmic growth phase were taken, digested, and the cell density was adjusted to 4×10 5 cells / mL. The above cell suspension was added to a 6-well plate, with a volume of 2 mL per well, and placed in an incubator at 37°C and 5% CO 2The incubator was used for continuous culturing. The cells were observed until they reached a confluent state, and then a scratch was made. A 10 μL sterile pipette tip was used to make a scratch in a direction perpendicular to the previously positioned horizontal line. The pipette tip was placed perpendicular to the six-well plate to ensure a consistent scratch width. After making the scratch, the culture medium was slowly aspirated with a pipette, and an appropriate amount of PBS was added to wash the cells three times to remove cell debris. The PBS was discarded, and complete medium was added to each well. Erlotinib hydrochloride (16 μM, model group), Erlotinib hydrochloride (16 μM) and CA&FA (mass ratio 1.5:1, CA&FA group), Erlotinib hydrochloride (16 μM) and HA@ZIF91 (HA@ZIF91 group, without adding CA&FA, prepared by the method of Prescription 24 in Example 1 and Prescription 1 in Example 3), Erlotinib hydrochloride (16 μM) and HA@CA&FA-ZIF91 (HA@CA&FA-ZIF91 group, Prescription 1 in Example 3) were added respectively. The addition amounts in the groups containing CA and FA were kept consistent (CA: 0.02 μg / mL, FA: 0.014 μg / mL). There were 3 replicate wells for each concentration, and an equal volume of complete medium was added as the blank group. At different time points of the scratch (0, 24 h), the six-well plate was placed under an inverted microscope for photographing to observe the degree of scratch healing before and after modeling and compared with the model group. The healing rate was calculated according to the following formula: Healing rate = (width at 0 h - width at 24 h) / width at 0 h × 100%.

[0146] The results are as Figure 3 、 4 shown: Compared with the model group, the CA&FA, HA@ZIF91, and HA@CA&FA-ZIF91 groups could significantly restore the migration ability of HaCa-T cells. It was shown that HA@CA&FA-ZIF91 had the effect of restoring the ability of erlotinib hydrochloride to inhibit the migration of HaCa-T cells.

[0147] Example 5: Retention of CA&FA, CA&FA-ZIF91 and HA@CA&FA-ZIF91 in the skin A Franz vertical diffusion cell with an effective diffusion area of 3.14 cm 2, the volume of the receiving pool is 8 mL. The instrument settings are as follows: rotation speed 400 r / min, temperature 32 °C. Using porcine dorsal skin as a model, hair is removed physically to ensure the integrity of the skin stratum corneum and no damage to the skin surface. It is stored at -80 °C, thawed at room temperature before the experiment, washed thoroughly with physiological saline, and cut into squares with a side length of 3 cm for standby. The receiving solution is PBS buffer (pH 7.4) containing 1% polyethylene glycol-400 and 0.1% gentamicin (to prevent bacterial fermentation of the skin and affect drug penetration and retention). 1 mL of CA&FA 20% ethanol solution (CA&FA group), CA&FA-ZIF91 solution (disperse the prescription 24 of Example 1 in an appropriate amount of water), and HA@CA&FA-ZIF91 dressing (apply the prescription 1 of Example 3 on porcine dorsal skin and spray an appropriate amount of water to make it permeable) are added to the supply pool respectively. All test preparations contain 1 mg of ferulic acid and 1.5 mg / mL of chlorogenic acid. After 24 h, 2 mL of the sample is taken from the receiving pool to detect the skin permeation amount of the drug.

[0148] Skin retention amount: After 24 h, the skin is taken out from the diffusion cell, and the residual drug on the surface of the porcine skin is washed with PBS buffer (pH 7.4) containing 1% (w / %) polyethylene glycol-400. The skin is air-dried, cut into small pieces with scissors, ground, and ultrasonically extracted with 1 mL of methanol. The obtained mixture is centrifuged at 12000 r / min for 15 min, and then passed through a 0.22 μm filter membrane. The filtrate is analyzed by HPLC. The content determination method of CA&FA is the same as that in Example 4.

[0149] The results are as Figure 5 , 6 shown: The retention amounts of ferulic acid in the skin of the CA&FA solution, CA&FA-ZIF91, and HA@CA&FA-ZIF91 are 22.11 ± 0.96, 58.8 ± 6.03, and 60.12 ± 2.29 μg / cm 2 , respectively, and there is no significant difference among the groups. The retention amounts of chlorogenic acid in the skin of the CA&FA solution, CA&FA-ZIF91, and HA@CA&FA-ZIF91 are 13.33 ± 0.56, 93.90 ± 4.26, and 95.51 ± 4.15 μg / cm 2 , respectively. Compared with the CA&FA group, the retention of chlorogenic acid in the skin of CA&FA-ZIF91 and HA@CA&FA-ZIF91 increases significantly. It indicates that ZIF91 can significantly increase the retention of drugs in the skin.

[0150] Example 6: Interaction between CA&FA-ZIF91 and ceramide in the skin Using a Franz vertical diffusion cell, the effective diffusion area is 3.14 cm2 , the volume of the receiving pool was 8 mL. The instrument settings were as follows: rotation speed 400 r / min, temperature 32 °C. Using porcine back skin as the model, hair was removed physically to ensure the integrity of the skin stratum corneum and no damage to the skin surface. It was stored at -80 °C, thawed at room temperature before the experiment, washed clean with normal saline, and cut into squares with a side length of 3 cm for standby. The release medium was PBS buffer (pH 7.4) containing 1% (w / %) polyethylene glycol - 400 and 0.1% gentamicin (to prevent bacterial fermentation of the skin and affect drug penetration and retention). A blank group, a ZIF91 group (without adding CA&FA, prepared by the method of Prescription 24 in Example 1, dispersed with an appropriate amount of water), a CA&FA group (in 20% ethanol solution), and a CA&FA-ZIF91 group (Prescription 24 in Example 1, dispersed with an appropriate amount of water) were set up. All the test preparations contained 1 mg / mL ferulic acid and 1.5 mg / mL chlorogenic acid. After 24 h, the skin was removed, the drug administration site was cut off, rinsed clean with normal saline, and freeze-dried. An appropriate amount of skin samples was taken for DSC analysis of the interaction between CA&FA-ZIF91 and ceramide in the skin. The detection conditions were as follows: heating rate 10 °C / min, heating range 30 - 200 °C, nitrogen flow rate 50 mL / min.

[0151] The results are as Figure 7 shown: The wavenumber changes of the DSC spectra of porcine back skin treated with CA&FA were similar to those of the blank group skin. The phase transition temperature and enthalpy change value of porcine back skin treated with ZIF91 and CA&FA-ZIF91 increased significantly, indicating that ZIF91 formed hydrogen bond forces with ceramide in the skin, enabling the drug to be retained in the skin and facilitating the drug to exert its efficacy at the target area where EGFRIs-induced skin toxicity occurred.

[0152] Example 7: Pharmacodynamic evaluation of the drug composition in treating EGFRIs-induced skin toxicity BALB / c mice (about 20 g) were randomly grouped according to body weight after being raised for 3 days to adapt to the environment, with a total of 2 groups. They were randomly divided into a blank group and an erlotinib hydrochloride group, with 10 mice in the blank group and 50 mice in the erlotinib hydrochloride group. One day before drug administration, the back hair of BALB / c mice was removed, and they were given an erlotinib hydrochloride solution by gavage at a dose of 150 mg / kg (i.e., 0.015 mL / g), once a day, and continuously administered until skin toxicity appeared (about 48 d).

[0153] After establishing an animal model of skin toxicity caused by EGFRIs, the rats in the erlotinib hydrochloride group were re-grouped and randomly divided into 10 rats in the erlotinib hydrochloride group (model group), 10 rats in the erlotinib hydrochloride + drug solution group (CA&FA), 10 rats in the erlotinib hydrochloride + blank matrix group (HA@ZIF91), 10 rats in the erlotinib hydrochloride + nanofiber membrane dressing of drug composition group (HA@CA&FA-ZIF91), and 10 rats in the erlotinib hydrochloride + gel of drug composition group (CA&FA-ZIF91 Gel). Each group of mice continued to be gavaged with erlotinib hydrochloride at 150 mg / kg once a day. On this basis, the corresponding preparations were topically applied to the administration groups (the method for obtaining each preparation was the same as in Example 5), with a dose of 125 mg / kg, and normal saline was topically applied to the model group once a day; continuous administration was carried out for 14 days.

[0154] After the animal experiment, the skin toxicity of each group of mice was observed and the severity of skin toxicity was scored ( Figure 8 ), the body weight change curves of each group of mice were statistically analyzed ( Figure 9 ), the thymus, spleen and liver of mice in different groups were weighed, the organ indices were calculated, and the differences between groups were compared ( Figures 10 - 12 , the water content of a part of the back skin of the mice was measured ( Figure 13 ), and the curative effect of the drug composition was observed by HE and Oil Red staining pathological sections of the skin ( Figure 14 ).

[0155] The results are shown in Tables 2 to 4: It can be seen from the severity of skin dryness, desquamation, redness, swelling, herpes and rash in mice that in the model group, the hair around the eyes, on the shoulders, neck and back of the mice fell off, and there were phenomena of skin dryness, desquamation, chapping and herpes around the mouth and on the limbs, and the activity state became worse; the CA&FA group, HA@ZIF91 group, HA@CA&FA-ZIF91 group and CA&FA-ZIF91 Gel group all had different degrees of therapeutic effects on skin toxicity. The HA@CA&FA-ZIF91 group and CA&FA-ZIF91 Gel group had better curative effects, significantly reducing the incidence of skin redness, swelling, herpes and rash in mice. The hair of the mice recovered growth, the symptoms disappeared significantly, effectively treating the skin toxicity reaction, and the effective rate reached 90%.

[0156] Group Number None Mild Moderate Severe Incidence Blank group 10 10 - - - - Model group 10 - - 7 3 100% CA&FA 10 5 4 1 - 50% HA@ZIF91 10 1 5 3 1 90% HA@CA&FA - ZIF91 10 9 1 - - 10% CA&FAZIF91 Gel 10 9 1 - - 10%

[0157] Group Number None Mild Moderate Severe Incidence Blank group 10 10 - - - - Model group 10 5 2 3 - 50% CA&FA 10 8 1 1 - 20% HA@ZIF91 10 6 3 1 - 40% HA@CA&FA - ZIF91 10 10 - - - - CA&FA - ZIF91 Gel 10 10 - - - -

[0158] Group Number None Mild Moderate Severe Incidence Blank group 10 10 - - - - Model group 10 - 2 5 3 100% CA&FA 10 8 2 - - 20% HA@ZIF91 10 6 4 - - 40% HA@CA&FA - ZIF91 10 10 - - - - CA&FA - ZIF91 Gel 10 10 - - - - During the process of therapeutic administration, the body weights of the mice in the model group did not change significantly, while the body weights of the mice in the CA&FA group, HA@ZIF91 group, HA@CA&FA-ZIF91 group, and CA&FA-ZIF91 Gel group increased, indicating that the quality of life of the mice could be improved after administration. The liver index and spleen index of the mice in the model group were significantly increased and the thymus index was decreased, indicating that erlotinib hydrochloride had serious damage to the immune system of the mice; after administration of CA&FA, HA@ZIF91, HA@CA&FA-ZIF91, and CA&FA-ZIF91 Gel, it could be restored to varying degrees, indicating that the drugs had a certain reversing and protective effect on the organ damage caused by erlotinib hydrochloride, and the HA@CA&FA-ZIF91 group and CA&FA-ZIF91 Gel group were more significant.

[0159] From the analysis of the skin water content results, compared with the blank group, the water content of the mice in the model group was significantly decreased, indicating that erlotinib hydrochloride had serious damage to the skin barrier of the mice and affected its moisturizing function; after administration of CA&FA, HA@ZIF91, HA@CA&FA-ZIF91, and CA&FA-ZIF91 Gel, the skin water content increased significantly; indicating that topical application of the drug composition gel could have a certain repairing effect on the skin barrier.

[0160] From the HE results, it can be seen that: compared with the blank group, the characteristics of skin inflammation were observed in the mice in the model group, namely parakeratosis (retention of the nuclei of the stratum corneum), significant thickening of the stratum corneum of the skin, and changes in the skin structure. After administration of CA&FA, HA@ZIF91, HA@CA&FA-ZIF91, and CA&FA-ZIF91 Gel, the skin toxicity reaction of the mice was improved, and the HA@CA&FA-ZIF91 group and CA&FA-ZIF91 Gel group were more significantly improved. The oil red staining results showed that: compared with the blank group, the sebaceous gland inhibition and significantly reduced swollen follicles in the model group were stained with oil red. Compared with the model group, after administration of CA&FA, HA@ZIF91, HA@CA&FA-ZIF91, and CA&FA-ZIF91 Gel, the number of swollen follicles in the skin of the mice increased significantly, indicating that the drug composition could effectively restore the inhibition of sebum secretion by erlotinib hydrochloride.

Claims

1. A pharmaceutical composition, characterized in that The invention comprises chlorogenic acid, ferulic acid and a zeolite imidazole framework material, wherein the mass ratio of the chlorogenic acid to the ferulic acid is 4:1 to 1:4, preferably 2:1 to 1:2, and most preferably 1.5:

1. The zeolite imidazole framework material is a Zn-based zeolite imidazole framework material.

2. The pharmaceutical composition according to claim 1, characterized in that The zeolite imidazole framework material is selected from ZIF91, ZIF90 or ZIF8.

3. The pharmaceutical composition according to claim 1, characterized in that The mass ratio of the total amount of chlorogenic acid and ferulic acid to the Zn element in the zeolite imidazole framework material is 3:1-1:3, preferably 2:1-1:2, and most preferably 4:

3.

4. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition further comprises a matrix material, When the matrix material is a gel matrix and water, the pharmaceutical composition is a gel; When the matrix material is a spinning matrix, the pharmaceutical composition is a nanofiber membrane dressing.

5. The pharmaceutical composition according to claim 4, characterized in that The gel matrix is ​​one or a mixture of hyaluronic acid, carbomer, sodium alginate, xanthan gum or cellulose derivatives; The spinning matrix is ​​a mixture of one or more of hyaluronic acid, gelatin, silk fibroin, collagen, polyethylene glycol or polylactic acid, preferably a mixture of hyaluronic acid and gelatin, and more preferably, the mass ratio of hyaluronic acid to gelatin is 1:(4.8~7.2).

6. The pharmaceutical composition according to claim 4, characterized in that In the gel, the mass fraction of the gel matrix is ​​1-12%, preferably 6-10%, and most preferably 8%; the mass fraction of the total amount of chlorogenic acid, ferulic acid and zeolite imidazole framework material in the gel is 0.5-2.0%; In the nanofiber membrane dressing, the mass fraction of the spinning matrix material is 85-95%.

7. The method for preparing the pharmaceutical composition according to any one of claims 1 to 6, characterized in that: The steps include: Chlorogenic acid, ferulic acid and zeolite imidazole framework material are mixed in a methanol or ethanol solution in the dark, followed by solid-liquid separation to obtain drug particles.

8. The preparation method according to claim 7, characterized in that: When the pharmaceutical composition is a gel, the preparation method further comprises the following step A; when the pharmaceutical composition is a nanofiber membrane dressing, the preparation method further comprises the following step B; Step A: mixing the gel matrix and water to make the gel matrix swell, then adding the drug particles and mixing them evenly to obtain the gel; Step B: preparing the spinning matrix and the drug particles into a spinning solution, and then subjecting the spinning solution to an electrospinning method to obtain the nanofiber membrane dressing; preferably, the electrospinning conditions are a voltage of 20 to 28 kV, preferably 24 to 26 kV, a propulsion speed of 0.5 to 1.5 mL / h, preferably 0.8 to 1.2 mL / h, and a receiving distance of 12 to 18 cm, preferably 14 to 16 cm.

9. The preparation method according to claim 8, characterized in that: The spinning solution is prepared by the following method: The spinning matrix is ​​swollen in a spinning solvent, and then the drug particles are added and uniformly mixed to obtain the spinning solution; Preferably, the spinning solvent is a mixture of any one or more of hexafluoroisopropanol, dichloromethane, chloroform, formic acid or water, preferably a mixture of hexafluoroisopropanol and water, more preferably a mixture of hexafluoroisopropanol and water in a volume ratio of 6:4 to 8:2, more preferably a mixture of hexafluoroisopropanol and water in a volume ratio of 7:3; Preferably, when the spinning matrix is ​​a mixture of hyaluronic acid and gelatin, the mass concentration of hyaluronic acid in the spinning solution is 2.5-3.5%, and the mass concentration of gelatin is 12-18%. More preferably, the mass concentration of hyaluronic acid in the spinning solution is 2.8-3.2%, and the mass concentration of gelatin is 14-16%.

10. Use of the pharmaceutical composition according to any one of claims 1 to 6 in the preparation of a therapeutic drug for EGFRIs-induced skin toxicity.

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