Preparation method of functionalized aerogel nano drug delivery system

Abstract

The invention belongs to the technical field of drug controlled release, and particularly discloses a preparation method of a functionalized aerogel nano drug delivery system, which comprises the following steps: ultrasonically dispersing silicon dioxide aerogel in a solvent A, stirring to obtain a transparent solution, adding glycerol into the solution, continuously stirring, then adding a silane coupling agent, stirring, and drying to obtain the functionalized aerogel nano drug delivery system. The aminated silicon dioxide aerogel is obtained, and the aminated silicon dioxide aerogel is NH2-PSI; dissolving the model drug in absolute ethyl alcohol in an ultrasonic manner, adding a carrier NH2-PSI, carrying out ultrasonic dissolving, stirring, carrying out drug loading, centrifuging, and drying, so as to obtain NH2-PSI loaded with the model drug; taking carboxymethyl chitosan, stirring and dissolving in water to obtain a CMCS solution, adding NH2-PSI loaded with the model drug into absolute ethyl alcohol for ultrasonic dissolution, adding the CMCS solution, stirring, centrifuging and drying to obtain the drug. According to the invention, a functional group CMCS is introduced to modify PSI, so that the functionalized aerogel nano drug delivery system with good pH controlled release is prepared, and the solubility, the targeting property and the bioavailability of the drug are remarkably improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug controlled release, and particularly relates to a preparation method of a functionalized aerogel nano drug delivery system. Background Art

[0002] At present, pharmacy is in a stage of continuous innovation and development, which is mainly reflected in the innovative research and development of new drug dosage forms. Since most oral drugs have defects such as poor adaptability, poor solubility, poor targeting, low bioavailability and adverse reactions, drug dosage forms are committed to research in the directions of improving stability, improving solubility (nano systems), and sustained release and controlled release, so as to better control the drug dosage, improve drug use safety and play an active and effective therapeutic effect. With the in-depth research on new drug delivery systems, developing drug carrier materials with drug release characteristics and targeting is one of the most critical steps.

[0003] According to the classification standard of the biopharmaceutics classification system: based on the solubility and intestinal permeability of drugs in vitro, oral drugs are divided into four categories: BCS type I drugs with high water solubility / high permeability, BCS type II drugs with low water solubility / high permeability, BCS type III drugs with high water solubility / low permeability, and BCS type IV drugs with low water solubility / low permeability. For BCS class II drugs, solubility is crucial because it changes the actual drug concentration in the solution over time. Therefore, in order to improve the bioavailability of such drugs, methods such as preparing nano drug delivery systems, preparing drug co-crystals, and preparing self-emulsifying drug delivery systems are usually used to solve their solubilization problems.

[0004] A nano drug delivery system uses nanotechnology to use various nanomaterials as drug carriers to encapsulate drugs, forming a nano-scale drug delivery system with a particle size within 1 - 1000 nm. Drug molecules can be encapsulated inside or adsorbed on the surface through physical interactions, or can be connected to the skeleton or matrix of the nano carrier through chemical bonds. The nano drug delivery system can enhance the solubility of poorly soluble drugs, enhance drug controlled release, improve drug utilization rate and reduce toxic and side effects. A number of studies have shown that compared with conventional chemotherapy, the nano drug delivery system has a targeting advantage in drug administration, can accumulate tumor drugs, reduce the drug dosage and inhibit tumors.

[0005] Aerogels are lightweight, have a porous network and an easily controllable structure, and are widely used in the medical field. Among them, SiO2 aerogels stand out and have been the most studied. Due to the characteristics of high porosity, high surface area, biodegradability and biocompatibility of SiO2 aerogels, their research in the biomedical field has attracted much attention, including drug delivery, tissue scaffolds, implant materials, bioimaging and biosensing, etc. They play their own advantages in the field of drug delivery: having many pores provides a place for drug attachment, and with further modification, it shows the potential to control drug release, but defects are also revealed: due to the inert structure of SiO2 aerogels themselves, they cannot recognize changes in external conditions and achieve responses; there is an easy burst release phenomenon during the drug delivery process, which restricts the application of SiO2 aerogels in the field of stimuli-responsive controlled-release materials. Therefore, aiming at the above deficiencies, it is found that the variable surface structure of SiO2 aerogels can be utilized to link with other specific structural groups through various physical and chemical means to synthesize composite materials and achieve the functionalization of aerogels. For example, by integrating signal molecules, drug-responsive release can be achieved through a certain stimulus, broadening its application in the field of drug controlled release.

[0006] Based on the above problems, the present invention provides a functionalized aerogel nano-drug delivery system, which should have the following advantages: (1) Increase solubility and dissolution rate: Applying nanotechnology can significantly reduce the particle size of drugs, increase the surface area, and thus improve the solubility of drugs. For poorly soluble drugs, their solubility is often the rate-limiting step of dissolution, and the improvement of solubility helps to improve the dissolution rate. Compared with traditional nano-drug carriers such as nanoparticles and nanoemulsions, inorganic carriers have advantages such as good physical stability, simple control of particle size and morphology, and easy surface functionalization. Among them, silicon-based aerogels have attracted great attention as drug carriers due to their large specific surface area, high porosity, good stability, and good biocompatibility. Smirnova et al. studied the dissolution of the drug substance and the drug delivery system loaded into SiO2 aerogel, and the results showed that the latter dissolved faster, indicating that this carrier can promote drug dissolution. (2) Improve bioavailability: After oral administration, the functionalized nano-drug delivery system can prolong the action time of drugs, reduce the drug dosage, enhance drug permeability, promote drug absorption, and improve bioavailability. (3) Increase drug stability: In the nano-drug delivery system, the carrier material has a protective effect on the encapsulated drug. Preparing the drug into nanoparticles can avoid drug oxidation and improve its stability. Li Cheng et al. prepared a molecular sieve with a high specific surface area and uniform pores loaded with quercetin. After TG testing, the results showed that compared with the quercetin drug substance, the weight loss rate was significantly slowed down, indicating that the molecular sieve loaded with quercetin can improve the thermal stability of quercetin. (4) Delay drug release: The nano-carrier can embed or encapsulate the drug in it. When the surface material degrades slowly, the drug inside the material can be gradually released, forming a good sustained-release effect. The results showed that the average particle size of the prepared quercetin-chitosan nanoparticles was 282 nm. Using 0.5% sodium dodecyl sulfate solution as the release medium, due to the lack of surface embedding, a sudden release occurred within the first two hours, and the release rate reached 20%. After that, the drug was slowly released from the inside of the nanoparticles, and reached 66.2% in 72 h. (5) Increase skin permeability: The transdermal drug delivery system has advantages such as good curative effect, few adverse reactions, no first-pass effect of the liver, constant effective blood drug concentration, and convenient clinical application. (6) Improve drug targeting: Improve the distribution of drugs in human tissues. Due to the diversity of the structure and composition of nanomaterials and their easy modification characteristics, therefore, according to some special physicochemical characteristics of the lesion site, stimuli-responsive nanomaterials can be designed and constructed to achieve the purpose of not releasing drugs before reaching the target site and releasing drugs as needed after reaching the target site. Summary of the Invention

[0007] The object of the present invention is to provide a preparation method of a functionalized aerogel nano-drug delivery system. By loading BCS class II drugs resveratrol and indomethacin with silica aerogel and modifying with amino groups to connect carboxymethyl chitosan with pH responsiveness on the surface of the aerogel, a functionalized aerogel nano-drug delivery system is prepared, significantly improving the solubility, targeting property and bioavailability of poorly soluble drugs.

[0008] In order to achieve the above object, the present invention provides the following technical solutions:

[0009] The present invention provides a preparation method of a functionalized aerogel nano-drug delivery system, comprising the following steps:

[0010] Step 1, preparation of the carrier: Weigh silica aerogel (PSI), ultrasonically disperse it in solvent A, stir to obtain a transparent solution, add glycerol to the above solution and continue stirring, then add a silane coupling agent, stir, and dry to obtain amino-functionalized silica aerogel, namely NH2-PSI;

[0011] Step 2, drug loading: Weigh the model drug, ultrasonically dissolve it in absolute ethanol, add the carrier NH2-PSI, ultrasonically dissolve, stir for drug loading, centrifuge, and dry to obtain NH2-PSI loaded with the model drug, and store it in the dark and dry;

[0012] Step 3, CMCS blocking: Weigh carboxymethyl chitosan (CMCS), add EDC and NHS, stir and dissolve in water to obtain a CMCS solution; ultrasonically dissolve NH2-PSI loaded with the model drug in absolute ethanol, add the CMCS solution, stir, centrifuge, and dry to obtain the aerogel nano-drug delivery system loaded with the model drug, namely the model drug-CMCS-PSI, and store it in the dark and dry.

[0013] Preferably, the solvent A is a mixed solution composed of absolute ethanol and water, and the volume ratio of absolute ethanol to water is 1-3:1.

[0014] Further, the volume ratio of absolute ethanol to water is 2:1.

[0015] Preferably, the silane coupling agent is 3-aminopropyltriethoxysilane.

[0016] Preferably, the glycerol is used as a drying control forming agent.

[0017] Preferably, the water is distilled water.

[0018] Preferably, based on mass fraction, the dosage of glycerol is 10-15% of silica aerogel (PSI), the dosage of silane coupling agent is 4.5-5.5% of silica aerogel (PSI), and the dosage of carboxymethyl chitosan (CMCS) is 15-25% of silica aerogel (PSI).

[0019] Further, based on mass fraction, the dosage of glycerol is 10% of silica aerogel (PSI), the dosage of silane coupling agent is 5% of silica aerogel (PSI), and the dosage of carboxymethyl chitosan (CMCS) is 20% of silica aerogel (PSI).

[0020] Preferably, the mass ratio of carboxymethyl chitosan (CMCS), EDC, and NHS is 1-4:0.5-2:0.5-2.

[0021] Further, the mass ratio of carboxymethyl chitosan (CMCS), EDC, and NHS is 2:1:1.

[0022] Preferably, the model drug is a BCS class II drug.

[0023] Further, the model drug is at least one of resveratrol (RES) and indomethacin (IMC).

[0024] Preferably, when the model drug is resveratrol (RES), the drug concentration of the model drug is 40-50 mg / mL, and the mass ratio of the drug to the carrier (drug-loading ratio) is 5-9:1.

[0025] Further, when the model drug is resveratrol (RES), the drug concentration of the model drug is 50 mg / mL, and the mass ratio of the drug to the carrier (drug-loading ratio) is 5:1.

[0026] Preferably, when the model drug is indomethacin (IMC), the drug concentration of the model drug is 40-50 mg / mL, and the mass ratio of the drug to the carrier (drug-loading ratio) is 5-9:1.

[0027] Further, when the model drug is indomethacin (IMC), the drug concentration of the model drug is 50 mg / mL, and the mass ratio of the drug to the carrier (drug-loading ratio) is 7:1.

[0028] Preferably, the time for ultrasonic dispersion in step one is 10-50 min.

[0029] Further, the time for ultrasonic dispersion in step one is 30 min.

[0030] Preferably, the temperature for carrier preparation in step one is 20-25 °C.

[0031] Furthermore, the temperature for preparing the carrier in Step 1 is 25°C.

[0032] Preferably, the stirring time after adding glycerol in Step 1 is 0.5 - 5 h.

[0033] Furthermore, the stirring time after adding glycerol in Step 1 is 2 h.

[0034] Preferably, the stirring time after adding the silane coupling agent in Step 1 is 24 - 36 h.

[0035] Furthermore, the stirring time after adding the silane coupling agent in Step 1 is 24 h.

[0036] Preferably, the ultrasonic dissolution time in Step 2 is 10 - 50 min.

[0037] Furthermore, the ultrasonic dissolution time in Step 2 is 30 min.

[0038] Preferably, the drug loading temperature in Step 2 is 20 - 30°C, and the drug loading time is 24 - 36 h.

[0039] Furthermore, the drug loading temperature in Step 2 is 25°C, and the drug loading time is 24 h.

[0040] Preferably, the ultrasonic dissolution time in Step 3 is 10 - 50 min.

[0041] Furthermore, the ultrasonic dissolution time in Step 3 is 30 min.

[0042] Preferably, the temperature for CMCS plugging in Step 3 is 20 - 25°C.

[0043] Furthermore, the temperature for CMCS plugging in Step 3 is 25°C.

[0044] Preferably, the stirring time after adding the CMCS solution in Step 3 is 24 - 36 h.

[0045] Furthermore, the stirring time after adding the CMCS solution in Step 3 is 24 h.

[0046] Preferably, the centrifugation speed is 3000 - 5000 r / min, and the centrifugation time is 10 - 30 min.

[0047] Furthermore, the centrifugation speed is 4000 r / min, and the centrifugation time is 20 min.

[0048] Preferably, the drying method is freeze-drying.

[0049] Preferably, the stirring is medium-speed stirring, and the stirring speed is 300 - 500 r / min.

[0050] BCS class II drugs have extremely low solubility and little accumulation at the medicinal site, which limits the absorption rate and extent of drugs at the administration site, resulting in extremely low bioavailability. Most oral drugs have defects such as poor adaptability, poor water solubility, poor targeting, low bioavailability, and adverse reactions. Therefore, poorly soluble drugs are committed to research in the directions of improving stability, improving solubility (nano-system), and sustained and controlled release in order to better control the drug dosage, improve medication safety while exerting positive and effective therapeutic effects. Therefore, to solve the problem of low drug bioavailability, it is necessary to start from improving the solubility and dissolution rate of drugs and achieving controlled drug release.

[0051] In this study, poorly soluble drugs RES and IMC were selected as model drugs, both of which belong to BCS class II drugs with low solubility and low bioavailability. RES and IMC both belong to antibacterial and anti-inflammatory drugs. Among them, RES is a non-flavonoid polyphenol compound, and IMC is an arylalkanoic acid compound. The relative molecular weights of RES and IMC are 228.25 and 357.79 respectively, the ionization constants pKa are 9.22 and 4.5 respectively, and the lipophilicity-hydrophilicity partition coefficients lgP are 3.14 and 3.80 respectively. There are differences in their relative molecular weights, lipophilicity, and charge properties, and the coverage range is relatively wide, which can represent different poorly soluble drugs of anti-inflammatory drugs to a certain extent.

[0052] PSI nano-carrier materials have extremely wide applications in the biomedical field due to their advantages such as large specific surface area, high porosity, and low density. In addition, the easily modified surface determines that PSI can be functionalized. Regarding the problem of drug controlled release in the SiO2 aerogel nano-drug delivery system, it is designed to use "gatekeeper molecules" to coat the pores and surface of SiO2 aerogel. The functionalized SiO2 aerogel can not only reduce the loss of drugs during the process of reaching the target, but also control its release rate. In addition, ideal "gatekeeper molecules" can also respond to changes in environmental temperature, acidity and alkalinity, etc. and release. The selection and preparation of "gatekeeper molecules" are particularly important for functionalized composite materials. It should not only have groups that can be linked to the aerogel, but also meet biocompatibility and biodegradability. CMCS, due to its good biocompatibility, can not only enhance the overall membrane penetration ability and bioadhesion of nanoparticles in the drug delivery system. CMCS is non-toxic and can be biodegradable later, and can also promote drug absorption and the degradation of aerogel. The structure of CMCS also meets the conditions for connecting with SiO2 aerogel. In addition, CMCS structure contains both -NH2 and -COOH. -NH2 and -COOH belong to basic group and acidic group respectively, and can be protonated under certain pH conditions, so it shows pH-responsive characteristics. These characteristics all make it meet the conditions as a "gatekeeper molecule" to modify SiO2 aerogel to make it functionalized, which can be used as a drug carrier material to achieve the goal of targeted drug release.

[0053] Modifying PSI with CMCS can make the drug delivery system non-toxic, antibacterial, and pH-responsive, giving the aerogel functionalization and further improving the application value of aerogel in the field of biomedicine. Using SiO2 aerogel as a carrier, in order to avoid drug leakage and prolong the drug action time, CMCS is used to modify PSI to prepare a functional nano drug delivery system. Oral administration can prevent the drug from being destroyed by gastric acid and transport the drug to the appropriate location to exert its efficacy. According to the pH changes of the gastrointestinal digestive fluid, the drug is released in a controlled manner, achieving the purpose of controlling drug release and improving its bioavailability.

[0054] To ensure controlled drug release, this study loaded RES and IMC into SiO2 aerogel, blocked the surface of the carrier material with CMCS, and analyzed the feasibility of RES-CMCS-PSI and IMC-CMCS-PSI. The drug release of the drug delivery system in vivo and in vitro was observed to analyze whether the controlled drug release was achieved. By preparing a drug delivery system, the shortcomings of traditional chemotherapy and anti-inflammatory drugs can be improved to maximize the utilization of drugs. At the same time, the scope of use of SiO2 aerogel nanocarriers in the medical field can be further expanded, providing the latest theoretical basis and practical experience for the preparation of nanoformulations.

[0055] The present invention also provides a functionalized aerogel nano drug delivery system, which is prepared by the above method.

[0056] The present invention also provides a quality evaluation method for the above-mentioned functionalized aerogel nano-drug delivery system, including but not limited to quality evaluation through scanning electron microscopy (SEM) analysis, transmission electron microscopy (TEM) analysis, infrared spectroscopy (FT-IR) analysis, N2 adsorption-desorption analysis, X-ray diffraction (XRD) analysis and thermogravimetric (TG) analysis, in vitro drug release assay, gastrointestinal stability assay, and pharmacokinetic analysis.

[0057] Based on the solution idea of ​​improving the solubility of poorly soluble drugs, controlling the drug release rate, improving the targeting of drugs, and improving the bioavailability of oral administration, the present invention focuses on the preparation of CMCS-PSI and its application in drug delivery: the prepared CMCS-PSI is evaluated accordingly; the drug release of CMCS-PSI under different pH environments is studied; the thermal stability, light stability and the conditions in the stomach, small intestine and large intestine contents of isolated rats of CMCS-PSI are investigated respectively, and the stability of CMCS-PSI is studied; and a preliminary pharmacokinetics study of CMCS-PSI is conducted.

[0058] The present invention also provides the use of the functionalized aerogel nano drug delivery system in improving drug solubility, targeting and bioavailability.

[0059] Compared with the prior art, the advantages and beneficial effects of the present invention are as follows:

[0060] (1) The present invention provides a preparation method of a functionalized aerogel nano-drug delivery system. Using two poorly soluble BCS class II drugs RES and IMC as model drugs, RES-CMCS-PSI and IMC-CMCS-PSI are prepared by the centrifugal impregnation method. In the first step, PSI is aminated to obtain NH2-PSI; in the second step, the model drugs are loaded into NH2-PSI to obtain RES-NH2-PSI and IMC-NH2-PSI respectively; finally, they are modified with CMCS to obtain RES-CMCS-PSI and IMC-CMCS-PSI. Through single-factor investigation, the present invention selects the optimal synthesis conditions and formulation process. The drug loading amounts of RES-CMCS-PSI and IMC-CMCS-PSI prepared under the optimal conditions are 42.26% and 44.38% respectively; the entrapment efficiencies are 85.56% and 88.28% respectively.

[0061] (2) The present invention evaluates the morphology, molecular structure, thermal stability and pore size change of the drug delivery system by means of SEM, TEM, FT-IR, N2 adsorption-desorption, XRD and thermogravimetric analysis. The results show that PSI is a porous network structure, the drugs are successfully loaded into the aerogel pores, the pore size decreases, shadows appear on the surface, and a small amount of drugs adheres to the surface; the FT-IR spectrum shows that RES is physically adsorbed in the pores or on the surface of the aerogel, while IMC and PIR are loaded into the aerogel pores or on the surface through the combined action of physical adsorption and chemical bonding, and the aerogel structure remains intact after loading; the N2 adsorption-desorption experimental data shows that the pore volume and specific surface area of the synthesized drug delivery system decrease, indicating that the drugs are successfully loaded; the aerogel drug delivery system has a broad diffraction peak identical to that of PSI, which is amorphous and does not change the PSI backbone structure; the TG results show that, compared with the raw drug, the thermal stability of CMCS-PSI is improved; through the above evaluation methods, it is proved that CMCS-PSI provides favorable conditions for drug loading and can meet the requirements as a drug carrier.

[0062] (3) Through in vitro drug release determination methods, the present invention examines the pH-sensitive properties of the model drugs RES and IMC, as well as the aerogel drug delivery systems RES-CMCS-PSI and IMC-CMCS-PSI loaded with drugs respectively, in pH 1.2 hydrochloric acid solution, pH 4.5 PBS, pH 6.8 PBS and pH 7.4 PBS. The results show that, compared with the raw drug, the release rates of RES-CMCS-PSI and IMC-CMCS-PSI in pH 1.2, pH 4.5 and pH 7.4 PBS buffer solutions all decrease, and the release amounts within the same time decrease, while in pH 6.8 PBS buffer solution, the release rates are significantly increased, realizing the pH-controlled release of the drugs.

[0063] (4) The stability of the drug-loading system of the present invention was investigated under high temperature, high humidity, and light conditions. The results showed that it was relatively stable under high temperature conditions, and its stability was slightly worse under high humidity and light conditions. It should be stored in a sealed, dry, and light-proof manner. An HPLC analysis method for RES and IMC in gastrointestinal contents was established, and the specificity, precision, and recovery rate of the methodology investigation met the requirements. The stability of RES, IMC, RES-CMCS-PSI, and IMC-CMCS-PSI in the gastric, small intestine, and large intestine contents of isolated rats was studied. The results showed that the gastrointestinal stability of the drugs was enhanced after loading, and a responsive release was exhibited in the small intestine environment.

[0064] (5) The pharmacokinetics of the aerogel nano drug-loading system loaded with RES and IMC after intragastric administration in rats was preliminarily studied by HPLC. The blood drug concentrations of RES, IMC, RES-CMCS-PSI, and IMC-CMCS-PSI in rat plasma were measured for 24 hours respectively; finally, various pharmacokinetic parameters were calculated and analyzed. The experimental results showed that compared with the raw drug, after rats were intragastric administrated with RES-CMCS-PSI and IMC-CMCS-PSI, C max increased, t 1 / 2 prolonged, and the AUC 0-t of the drug-loading system was 2-4 times that of the raw drug group; it indicated that after modifying PSI with CMCS for drug loading, the action time of the drug was prolonged and the bioavailability was significantly increased.

[0065] (6) In summary, the present invention prepared a PSI nano drug-loading system modified with CMCS, and analyzed and evaluated its morphology, pore volume, thermal stability, and structure. The results showed that the prepared aerogel carrier met the drug loading requirements, and was blocked by CMCS to prevent drug leakage, while enhancing the thermal stability of the drug; through the in vitro drug release analysis of the drug-loading system, the results showed that the release rate increased significantly at pH 6.8, realizing the pH-responsive controlled release of the drug, providing materials for the preparation of drug controlled-release preparations; the gastrointestinal stability was significantly improved compared with the raw drug, and the release amount was large in the small intestine, which once again proved that the drug-loading system achieved pH responsiveness, echoing the in vitro drug release results; through the preliminary study of the pharmacokinetics of the aerogel drug-loading system in rats, the results showed that the drug-loading system prolonged the action time of the drug and improved the bioavailability of poorly soluble drugs; finally, it was proved that there was a certain correlation in vivo and in vitro, and the in vivo absorption behavior could be predicted through the in vitro release data, providing a reference for in vivo test research and reducing the cost of new drug research and development of the drug delivery system. Description of the Drawings

[0066] Figure 1 It is the synthesis principle and drug release principle of the functionalized aerogel nano drug-loading system CMCS-PSI;

[0067] Figure 2 It is the preparation flow chart of the functionalized aerogel nano-drug delivery system CMCS-PSI;

[0068] Figure 3 It is the dosage optimization of glycerol, the drying control forming agent of CMCS-PSI;

[0069] Figure 4 It is the dosage optimization of the silane coupling agent of CMCS-PSI;

[0070] Figure 5 It is the dosage optimization of CMCS of CMCS-PSI;

[0071] Figure 6 It is the selection of the RES drug loading ratio;

[0072] Figure 7 It is the selection of the IMC drug loading ratio;

[0073] Figure 8 It is the selection of the preparation temperature of the NH2-PSI carrier;

[0074] Figure 9 It is the selection of the drug loading time;

[0075] Figure 10 It is the selection of the drug loading temperature;

[0076] Figure 11 It is the ultraviolet scanning spectrum of the model drug solution;

[0077] Figure 12 It is the standard curve of RES determined by ultraviolet absorption photometry;

[0078] Figure 13 It is the standard curve of IMC determined by ultraviolet absorption photometry;

[0079] Figure 14 It is the SEM image of RES-CMCS-PSI;

[0080] Figure 15 It is the SEM image of IMC-CMCS-PSI;

[0081] Figure 16 It is the TEM image of RES-CMCS-PSI;

[0082] Figure 17 It is the TEM image of IMC-CMCS-PSI;

[0083] Figure 18 It is the XRD spectrum of RES-CMCS-PSI;

[0084] Figure 19XRD pattern of IMC-CMCS-PSI;

[0085] Figure 20 N2 adsorption-desorption isotherms (a) and pore size distribution curves (b) of the drug-loading system before and after loading RES;

[0086] Figure 21 N2 adsorption-desorption isotherms (a) and pore size distribution curves (b) of the drug-loading system before and after loading IMC;

[0087] Figure 22 FT-IR spectrum of CMCS-PSI;

[0088] Figure 23 FT-IR spectrum of RES-CMCS-PSI;

[0089] Figure 24 FT-IR spectrum of IMC-CMCS-PSI;

[0090] Figure 25 TG curve of CMCS-PSI;

[0091] Figure 26 TG curve of RES-CMCS-PSI;

[0092] Figure 27 TG curve of IMC-CMCS-PSI;

[0093] Figure 28 Release curves of RES and RES-CMCS-PSI in different solutions (a) pH1.2, (b) pH4.5, (c) pH6.8, (d) pH7.4;

[0094] Figure 29 Release curves of IMC and IMC-CMCS-PSI in different solutions (a) pH1.2, (b) pH4.5, (c) pH6.8, (d) pH7.4;

[0095] Figure 30 Fitting graphs of the drug release kinetic models of RES and RES-CMCS-PSI, (a) first-order kinetic model, (b) Korsmeyer-Peppas model, (c) Higuchi model;

[0096] Figure 31 Fitting graphs of the drug release kinetic models of IMC and IMC-CMCS-PSI, (a) first-order kinetic model, (b) Korsmeyer-Peppas model, (c) Higuchi model;

[0097] Figure 32For the average residual rate curves of RES, RES-CMCS-PSI (a) gastric contents, (b) small intestine contents, (c) large intestine contents;

[0098] Figure 33 For the average residual rate curves of IMC, IMC-CMCS-PSI (a) gastric contents, (b) small intestine contents, (c) large intestine contents;

[0099] Figure 34 For the blood concentration-time curves of RES, RES-CMCS-PSI;

[0100] Figure 35 For the blood concentration-time curves of IMC, IMC-CMCS-PSI;

[0101] Figure 36 For the in vitro-in vivo absorption correlation curves of RES, RES-CMCS-PSI, IMC, IMC-CMCS-PSI. Detailed implementation mode

[0102] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0103] Indomethacin raw material medicine (purity ≥ 98%): Purchased from Shanghai Yuanye Bio-Technology Co., Ltd., batch number: AA18279.

[0104] Resveratrol raw material medicine (purity ≥ 98%): Purchased from Hubei Xingyinhe Pharmaceutical Co., Ltd., batch number: 20181127.

[0105] Carboxymethyl chitosan: Purchased from Shanghai Macklin Biochemical Co., Ltd.

[0106] Silica aerogel: Purchased from Henan Fanrui Composite Materials Research Institute Co., Ltd.

[0107] Silane coupling agent (KH550): 3-aminopropyltriethoxysilane (APTES), purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.

[0108] EDC: Full name: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, purchased from Shanghai Macklin Biochemical Co., Ltd.

[0109] NHS: Full name: N-hydroxysuccinimide, purchased from Shanghai Macklin Biochemical Co., Ltd.

[0110] Hydrochloric acid (analytical reagent grade): Purchased from Xilong Science Co., Ltd., batch number: 191102.

[0111] Absolute ethanol (analytical reagent grade): Purchased from Tianjin Tianli Chemical Reagent Co., Ltd.

[0112] Methanol (analytical reagent grade): Purchased from Tianjin Tianli Chemical Reagent Co., Ltd.

[0113] Glycerol: Purchased from Tianjin Fuyu Fine Chemical Co., Ltd.

[0114] Potassium bromide (spectral pure): Purchased from Tianjin Guangfu Fine Chemical Research Institute.

[0115] Distilled water: Purchased from Harbin Wenjing Distilled Water Factory.

[0116] Example 1

[0117] This example provides a preparation method of a functionalized aerogel nano-drug delivery system, including the following steps:

[0118] Step 1. Amino modification of PSI:

[0119] Weigh an appropriate amount of silica aerogel (PSI) and ultrasonically disperse it in a mixed solution composed of absolute ethanol and distilled water (the volume ratio of the absolute ethanol to the distilled water is 2:1). Stir at 25 °C until it becomes transparent to obtain a transparent solution. Dropwise add glycerol to the above solution and continue stirring for 2 h. Then add the silane coupling agent 3-aminopropyltriethoxysilane and stir at room temperature for 24 h. Dry to obtain amino-functionalized silica aerogel, namely NH2-PSI; among them, the ultrasonic dispersion time is 30 min;

[0120] Step 2. Loading of the model drug on NH2-PSI:

[0121] Weigh an appropriate amount of the model drug and ultrasonically dissolve it in absolute ethanol. Add an appropriate proportion of the carrier NH2-PSI and ultrasonically dissolve it. Then stir at 25 °C for 24 h. Centrifuge (4000 r / min, 20 min) and dry to obtain NH2-PSI loaded with the model drug, and store it in the dark and dry; among them, the ultrasonic dissolution time is 30 min;

[0122] Step 3. Sealing of NH2-PSI loaded with the model drug with CMCS:

[0123] Weigh an appropriate amount of carboxymethyl chitosan (CMCS), add an appropriate amount of EDC and NHS, stir to dissolve them in distilled water, activate carboxymethyl to obtain a CMCS solution; add the NH2-PSI loaded with the model drug to anhydrous ethanol, ultrasonically dissolve it, add the CMCS solution, continuously stir at room temperature for 24 h, centrifuge (4000 r / min, 20 min), and dry to obtain an aerogel nano-drug delivery system loaded with the model drug, which is the model drug-CMCS-PSI, and store it in the dark and dry. Among them, the ultrasonic dissolution time is 30 min.

[0124] Among them, in terms of mass fraction, the dosage of glycerol is 10% of silica aerogel (PSI), the dosage of silane coupling agent is 5% of silica aerogel (PSI), and the dosage of CMCS is 20% of silica aerogel (PSI);

[0125] The mass ratio of the carboxymethyl chitosan (CMCS), EDC and NHS is 2:1:1;

[0126] The model drug is a BCS class II drug, specifically resveratrol (RES) and indomethacin (IMC);

[0127] When the model drug is RES, the drug concentration of the model drug is 50 mg / mL, and the mass ratio of the drug to the carrier (drug loading ratio) is 5:1;

[0128] When the model drug is IMC, the drug concentration of the model drug is 50 mg / mL, and the mass ratio of the drug to the carrier (drug loading ratio) is 7:1;

[0129] The drying method is freeze-drying;

[0130] The temperature for preparing the carrier in step one is 25 °C;

[0131] The drug loading temperature in step two is 25 °C, and the drug loading time is 24 h;

[0132] The stirring is medium-speed stirring, and the stirring speed is 300 - 500 r / min.

[0133] Example 2

[0134] Optimization of CMCS-PSI drug loading prescription factors

[0135] Investigate factors such as the solvent for preparing the carrier, the organic solvent for drug loading, the dosage of glycerol, the dosage of silane coupling agent, the dosage of CMCS, the drug concentration and the drug loading ratio, and select the best prescription factors with the drug loading amount as the index.

[0136] (1) Selection of the solvent for preparing the carrier

[0137] The dissolution process of CMCS, silane coupling agent and PSI is crucial. Only when the dissolution is complete can the chemical groups be fully combined. In this experiment, distilled water and 0.5 vol% acetic acid solution were used as solvents for CMCS, and a mixture of distilled water, absolute ethanol and distilled water was used as solvents for PSI and silane coupling agent to observe the dissolution effects of each part.

[0138] The results showed that CMCS was completely dissolved in distilled water but not completely dissolved in 0.5 vol% acetic acid solution. Therefore, distilled water was selected as its solvent. In distilled water, the PSI powder was not completely dissolved and there was precipitation at the bottom. Using absolute ethanol and distilled water as solvents for the silane coupling agent and PSI powder, by observing the dissolution situation, the solution was clear and transparent without residue. Therefore, in this experiment, a mixed solution of absolute ethanol and distilled water (volume ratio 2:1) was selected as the solvent for the silane coupling agent and PSI powder.

[0139] (2) Selection of organic solvents for drug loading

[0140] When using the centrifugal impregnation method to load drugs into the carrier, to achieve a good drug loading effect (high drug loading amount) for the drug loading system, a suitable solvent needs to be selected to dissolve the drug. Therefore, the organic solvent for drug loading should meet the following conditions: the drug is easily soluble in this organic solvent; it is non-toxic or has low toxicity; it is inexpensive and easily available.

[0141] It can be seen from the second part of the Chinese Pharmacopoeia 2020 Edition that RES is easily soluble in organic solvents such as methanol, ethanol, acetone, and ethyl acetate; IMC is soluble in ethanol, ether, and acetone. In this experiment, absolute ethanol was selected as the solvent for RES and IMC.

[0142] (3) Dosage of glycerol as a drying control molding agent

[0143] In this experiment, absolute ethanol and distilled water were used as solvents, which are strong polar solvents. When in a dry state, they are volatile and generate surface tension, affecting the structure of CMCS - PSI. Therefore, a drying control agent with less polarity needs to be selected to protect the structure of the carrier. In this experiment, glycerol was selected as the drying control molding agent, and the dosage of glycerol: 0%, 5%, 10%, 15%, 20% was investigated for its effect on the drug loading amount of the synthesized carrier. The results are shown in Table 1. Figure 3 。

[0144] Table 1: Dosage of drying control molding agent (n = 6)

[0145]

[0146] From Figure 3It can be seen from the figure that when the process parameters of reaction temperature, drying method, dosage of silane coupling agent and dosage of CMCS are the same, with the increase of the dosage of drying control molding agent, the drug loading amount of CMCS-PSI for the model drug shows a trend of increasing first and then decreasing. When the dosage of the drying control molding agent is 10% of CMCS-PSI, the drug loading amount is 42.34%, which is higher than that prepared under other dosages. Therefore, 10% is selected as the dosage of the drying control molding agent.

[0147] (4) Dosage of silane coupling agent

[0148] As an amino-functionalized modifier for aerogel, the silane coupling agent can interact with both the hydroxyl groups in PSI and the long molecular chains in CMCS, combining two materials with different properties, namely CMCS and PSI. The dosage of the silane coupling agent has an important influence on whether the combination of CMCS and PSI is sufficient. In this experiment, the effects of the dosages of the silane coupling agent of 3%, 4%, 5%, 6% and 7% on the synthesized drug delivery system were investigated, the drug loading amounts of the five groups of carriers for the model drug were compared, and the five groups of carrier materials were evaluated. The results are shown in Table 2. Figure 4 。

[0149] Table 2: Dosage of silane coupling agent in CMCS-PSI (n = 6)

[0150]

[0151] From Figure 4 It can be seen from the figure that when the process parameters of reaction temperature, dosage of CMCS and drying method are the same, with the increase of the dosage of the silane coupling agent, the drug loading amount of CMCS-PSI for the model drug shows a trend of increasing first and then decreasing. When the dosage of the silane coupling agent is 5% of CMCS-PSI, the drug loading amount is 41.53%, which is higher than that of the carriers prepared under other dosages. Therefore, the mass fraction of 5% is selected as the dosage of the silane coupling agent.

[0152] (5) Dosage of CMCS

[0153] As a plugging material, CMCS can avoid the waste caused by the leakage of drugs midway. The carboxyl groups contained in the CMCS molecular chain can be connected to PSI through the silane coupling agent, effectively preventing the leakage of drugs. However, continuously increasing the CMCS content will cause uneven voids in PSI and occupy the pore space. Therefore, the dosage of CMCS has a certain influence on the drug loading amount of aerogel nanoparticles. In this experiment, the effects of the dosages of CMCS of 10%, 15%, 20%, 25% and 30% on the synthesized drug delivery system were investigated, the drug loading amounts of the five groups of carriers for the model drug were compared, and the five groups of carrier materials were evaluated. The results are shown in Table 3. Figure 5 。

[0154] Table 3: Dosage of CMCS in CMCS-PSI (n = 6)

[0155]

[0156] from Figure 5 It can be seen that when the reaction temperature, silane coupling agent dosage, propylene glycol dosage and drying method process parameters are the same, with the increase of CMCS dosage, the drug loading of CMCS-PSI for the model drug shows a trend of first increasing and then decreasing, because CMCS can form a coating layer on the surface of PSI and block the pores, which increases the encapsulation rate and loading amount of the drug to a certain extent. However, when the dosage of CMCS is too much, it occupies the adsorption sites on the surface of PSI and competes with the drug for adsorption. A part of the drug adsorbed inside the pores is replaced by CMCS because the adsorbed active sites are desorbed from the pores and free outside the PSI pores, so the encapsulation rate and drug loading show a downward trend. It can be seen from the figure that when the dosage of CMCS is 20% of CMCS-PSI, the drug loading of the prepared carrier is 42.37%, which is higher than the drug loading of the carrier prepared at other dosages, so 20% is selected as the dosage of CMCS.

[0157] (6) Drug concentration

[0158] During the drug loading process, changes in drug concentration will cause changes in the drug loading amount of the aerogel nano drug loading system. When the amount of carrier, solvent, propylene glycol, silane coupling agent and CMCS is the same, the drug loading amount of the aerogel nano drug loading system is investigated when the RES and IMC model drug concentrations are 10, 20, 30, 40, and 50 mg / mL. The results are shown in Table 4.

[0159] Table 4: Drug concentration selection (n=6)

[0160]

[0161] As shown in Table 4, within the drug dissolution concentration range, as the concentration increases, the drug loading of RES-CMCS-PSI and IMC-CMCS-PSI increases to varying degrees. The drug loading of RES-CMCS-PSI and IMC-CMCS-PSI increases evenly in the range of 10-40 mg / mL, and the drug loading increases by about 7.4% and 8.6% for every 10 mg / mL increase in concentration. In the range of 40-50 mg / mL, the drug loading increases slowly, and the drug loading increases by about 5.0%. The saturated solubility of RES and IMC in anhydrous ethanol is 50 mg / mL, so the drug concentration is selected to be 50 mg / mL. Therefore, the drug concentration of RES and IMC is selected to be 50 mg / mL, and the drug loading is approximately 42.82% and 43.82%, respectively.

[0162] (7) Mass ratio of drug to carrier

[0163] Drugs require a certain amount of attachment space. To avoid some drugs being free in the solvent due to insufficient carrier space, it is necessary to screen the appropriate mass ratio of the drug to the carrier. Under the condition that other conditions remain unchanged, the influence of different drug-loading ratios on the drug-loading capacity is compared.

[0164] RES: Keep a certain drug concentration unchanged, change the concentration of the carrier material PSI within a certain range. When the amounts of glycerol, silane coupling agent, and CMCS are the same, select different RES:PSI ratios (1:1, 3:1, 5:1, 7:1, 9:1, 11:1) for screening, and analyze the drug-loading capacity of RES-CMCS-PSI.

[0165] IMC: Keep a certain drug concentration unchanged, change the concentration of the carrier material PSI within a certain range. When the amounts of glycerol, silane coupling agent, and CMCS are the same, select different IMC:PSI ratios (1:1, 3:1, 5:1, 7:1, 9:1, 11:1) for screening, and analyze the drug-loading capacity of IMC-CMCS-PSI. The results are shown in Table 5 and Table 6. Figure 6 、 Figure 7 。

[0166] Table 5: Selection of RES drug-loading ratio (n = 6)

[0167]

[0168] Table 6: Selection of IMC drug-loading ratio (n = 6)

[0169]

[0170] It can be seen from the charts that the drug-loading capacity of RES-CMCS-PSI gradually increases in the range of 1:1 - 5:1 of the drug-loading ratio. When the drug-loading ratio is 7:1, the drug-loading capacity is slightly higher than that at 5:1, but it is found that there are drugs existing alone around the drug-loading system. In the range of 7:1 - 9:1, the drug-loading capacity gradually decreases. It is possible that the drug adsorption is oversaturated. Therefore, considering comprehensively, 5:1 is selected as the best drug-loading ratio for RES; for IMC-CMCS-PSI, the drug-loading capacity gradually increases in the range of 1:1 - 7:1 of the drug-loading ratio. When the drug-loading ratios are 9:1 and 11:1, the drug-loading capacity shows a gradually decreasing trend. Considering comprehensively, 7:1 is selected as the best drug-loading ratio for IMC; therefore, the drug-loading ratios of RES and IMC are selected as 5:1 and 7:1 respectively.

[0171] Example 3

[0172] Optimization of the preparation process factors of CMCS-PSI:

[0173] Investigate factors such as the drying method, carrier preparation temperature, drug-loading time, drug-loading temperature, stirring speed, etc., and screen the best prescription factors with the drug-loading capacity as the index.

[0174] (1) Drying method

[0175] The drying process is a key step in the preparation of CMCS-PSI, and the shape and structure of the obtained finished product are greatly affected by the drying method. The effects of freeze-drying and atmospheric drying on the synthesis of CMCS-PSI were selected and compared, and the drug loading was analyzed to evaluate it. The results are shown in Table 7.

[0176] Table 7: Selection of drying methods for CMCS-PSI (n = 6)

[0177]

[0178] It can be seen from Table 7 that when the process parameters of the amount of silane coupling agent, the amount of CMCS, the amount of glycerol, and the reaction temperature are the same, the drug loading of CMCS-PSI prepared by freeze-drying is higher than that of the carrier prepared by atmospheric drying. Since the freeze-drying method can evenly disperse the initial components in the initial suspension or solution, and differential separation usually does not occur during the freezing process, the phase distribution in the final composite material is uniform, which is very important for the uniformity of the multifunctional material. Therefore, freeze-drying was selected as the drying method for the gel.

[0179] (2) Carrier preparation temperature

[0180] The hydrolysis polymerization reaction temperature of PSI powder, CMCS, and silane coupling agent affects the effect of the sol and the structure of the finally prepared CMCS-PSI. In this experiment, 20 °C, 25 °C, 30 °C, 35 °C, and 40 °C were respectively investigated as the reaction temperature to study its influence on the gel, and the drug loadings of five groups of carriers for the model drug were compared to evaluate the five groups of carrier materials. The results are shown in Table 8. Figure 8 .

[0181] Table 8: Selection of preparation temperature of NH2-PSI (n = 6)

[0182]

[0183]

[0184] From Figure 8 it can be seen that when the process parameters of the amount of silane coupling agent, the amount of CMCS, the amount of glycerol, and the drying method are the same, with the increase of temperature, the drug loading of CMCS-PSI for the model drug shows a trend of first increasing and then decreasing. When the temperature is 25 °C, the drug loading of the prepared carrier is 40.65%, which is higher than that of the carriers prepared at other temperatures. Therefore, 25 °C was selected as the reaction temperature.

[0185] (3) Drug loading time

[0186] The length of the drug loading time affects the amount of drug entering the pores of the carrier or attaching to the surface of the carrier, which involves the adsorption equilibrium problem. When the amounts of glycerol, silane coupling agent, and CMCS are the same, the drug loading times of the model drug RES are respectively investigated for 6 h, 12 h, 24 h, 36 h, and 48 h, and the effect of the drug loading time on the drug loading amount is analyzed. The results are shown in Table 9. Figure 9 。

[0187] Table 9: Selection of drug loading time (n = 6)

[0188]

[0189] The drug needs sufficient time to enter the pores of the carrier. The drug loading time affects the effect of drug loading into the carrier, which is related to whether adsorption equilibrium is achieved between the two. The RES raw material drug is a pale yellow crystalline powder, which is Figure 9 It can be seen that the drug loading amount at a drug loading time of 6 h is 32.49%, and the drug loading amount at 12 h is 38.09%. After drug loading, the color of the sample deepens and there is caking. It is speculated that the reason may be that there is drug attachment on the outside and it is not completely adsorbed into the pores by the carrier, resulting in caking on the surface after drying; when the drug loading time ≥ 24 h, the drug loading amount decreases. The drug loading amounts at 24 h, 36 h, and 48 h are 44.92%, 40.57%, and 37.39% respectively. It is speculated that due to the too long stirring time, the structure of the carrier is damaged and the drug leaks. Therefore, the drug loading time of 24 h is selected.

[0190] (4) Drug loading temperature

[0191] The solubility of the drug is related to the temperature during drug loading. Therefore, under the condition of ensuring the same other drug loading conditions, the drug loading conditions at drug loading temperatures of 20 °C, 25 °C, 30 °C, 35 °C, and 40 °C are respectively investigated, and the changes in the drug loading amount at different temperatures are analyzed. The results are shown in Table 10. Figure 10 。

[0192] Table 10: Selection of drug loading temperature (n = 6)

[0193] Drug-loading temperature (°C) Drug-loading amount (%) 20 42.09±0.56 25 42.68±0.64 30 42.24±0.87 35 41.81±0.44 40 41.73±1.20

[0194] From Figure 10 it can be seen that in the range of 20 - 30 °C of the drug loading temperature, as the temperature increases, the drug loading amount gradually increases. In the range of 30 °C - 40 °C, the drug loading amount decreases as the temperature increases; when the drug loading temperatures are 25 °C and 30 °C, the drug loading amounts of CMCS-PSI are not significantly different, which are 42.68% and 42.24% respectively. Therefore, 25 °C is selected as the drug loading temperature.

[0195] (5) Stirring speed

[0196] The stirring speed affects the distribution of the drug inside or on the surface of the carrier. Therefore, under the condition of ensuring the same other drug-loading conditions, the drug-loading conditions at low speed (100 - 200 r / min), medium speed (300 - 500 r / min), and high speed (600 - 900 r / min) were investigated, and the relationship between the drug-loading amount and the stirring speed was analyzed. The results are shown in Table 11.

[0197] Table 11: Stirring speed selection (n = 6)

[0198]

[0199]

[0200] As can be seen from Table 11, the drug-loading amounts of the drug at different stirring speeds are different, medium speed (43.37%) > low speed (42.28%) > high speed (41.56%). The stirring speed affects the amount and speed of the drug entering the carrier. If the stirring speed is too slow, the drug lacks power, and the carrier is likely to stay at the bottom of the container, resulting in the inability to disperse evenly in the solution, thus failing to achieve a high drug-loading amount; if the stirring speed is too fast, the solution will splash out of the container, causing losses and resulting in a decrease in the drug content. To sum up, the solution should be stirred at medium speed, which can not only make the drug and the carrier mix and contact evenly, but also ensure the drug content.

[0201] Test example

[0202] I. Determination of drug content by ultraviolet spectrophotometry

[0203] (1) Determination of detection wavelength

[0204] Weigh a certain amount of two model drugs, RES and IMC, respectively. RES and IMC are dissolved and diluted with absolute ethanol to prepare RES absolute ethanol solution and IMC absolute ethanol solution with a certain concentration; weigh an appropriate amount of NH2-PSI and CMCS-PSI and dissolve them in absolute ethanol, and filter through a 0.45 μm filter membrane. Using the solvents of each model drug as blank controls, the above solutions were respectively scanned for ultraviolet wavelengths in the range of 200 - 400 nm according to the ultraviolet spectrophotometry. As Figure 11 shown.

[0205] From Figure 11 it can be seen that the ultraviolet scanning wavelengths of RES and IMC are 306 nm and 320 nm respectively, and within this range, no absorption wavelength of the carrier aerogel is detected, indicating that the aerogel does not affect the determination of RES and IMC. Therefore, 306 nm and 320 nm are respectively used as the optimal wavelengths for RES and IMC.

[0206] (2) Establishment of standard curve

[0207] a. Preparation of RES standard curve: Weigh 10.2 mg of RES reference substance into a 100-ml volumetric flask, dissolve it with absolute ethanol and make up to the mark to prepare a stock solution with a concentration of 102 μg / mL. Pipette 0.1, 0.2, 0.3, 0.4, 0.5, and 0.6 mL from it into 10-ml brown volumetric flasks, dilute with absolute ethanol and make up to the mark to prepare control solutions with different concentrations of 1.02, 2.04, 3.06, 4.08, 5.10, and 6.12 μg / mL. Measure the absorbance A at the maximum detection wavelength. Using the concentration C as the abscissa and the absorbance A as the ordinate, establish a standard curve. The results are shown in Table 12.

[0208] b. Preparation of IMC standard curve: Weigh 40.0 mg of IMC reference substance into a 100-ml volumetric flask, dissolve it with absolute ethanol and make up to the mark to prepare a stock solution with a concentration of 400 μg / mL. Pipette 0.1, 0.3, 0.5, 0.7, 0.9, and 1.0 mL from it into 10-ml brown volumetric flasks, dilute with absolute ethanol and make up to the mark to prepare a series of control solutions with concentrations of 4, 12, 20, 28, 36, and 40 μg / mL. Measure the absorbance A at the maximum detection wavelength. Using the concentration C as the abscissa and the absorbance A as the ordinate, establish a standard curve. The results are shown in Table 12.

[0209] Table 12: Test results of establishing standard curves for RES and IMC (n = 6)

[0210]

[0211] Establishment of RES standard curve: The test results show that RES has a good linear relationship in the range of 1.20 - 7.20 μg / mL, and the regression equation is A = 0.1218C + 0.0435 (R 2 = 0.9998). The results are shown in Figure 12 .

[0212] Establishment of IMC standard curve: The test results show that IMC has a good linear relationship in the range of 4.0 - 40.0 μg / mL, and the regression equation is A = 0.0146C + 0.0355 (R 2 = 0.9999). The results are shown in Figure 13 .

[0213] (3) Reproducibility investigation

[0214] First, weigh appropriate amounts of the two model drug reference substances respectively to prepare RES absolute ethanol solution and IMC absolute ethanol solution. Continuously measure 6 times using a UV spectrophotometer under the same conditions, record the absorbance A, and investigate the reproducibility of the sample solution. Calculate the RSD value and analyze the reproducibility of the model drug solution. The results are shown in Table 13.

[0215] Table 13: Results of Repeatability Investigation of RES and IMC (n = 6)

[0216]

[0217] The results showed that the RSD values of the repeatability of RES and IMC solutions were both less than 2.0%, indicating good repeatability.

[0218] (4) Stability Investigation

[0219] According to reports, both RES and IMC, the two model drugs, are photosensitive. Therefore, the stability of the model drugs was investigated under two different conditions: protected from light and unprotected from light. Appropriate amounts of the RES and IMC model drug standards were weighed and divided into two equal parts on average. One part was placed in a brown volumetric flask, and the other part was placed in a transparent volumetric flask. Solutions with a certain concentration were prepared, and the absorbance of the samples was measured at 0, 1, 3, 5, 7, and 9 h. The results are shown in Table 14 and Table 15.

[0220] Table 14: Results of Stability Investigation of RES within 9 h (n = 6)

[0221]

[0222] Table 15: Results of Stability Investigation of IMC within 9 h (n = 6)

[0223]

[0224]

[0225] The results showed that the RSD values of RES and IMC were both < 2.0% after being placed for 9 h under light protection conditions, indicating relatively good stability; under light exposure conditions, the absorbance of the RES absolute ethanol solution and the IMC absolute ethanol solution showed a significant downward trend within 9 h, indicating that the stability of the drug decreased upon light stimulation, the structure changed, and the drug content decreased. Therefore, it is necessary to create a light-protected condition during the experiment, and the drug should also be stored in the dark usually.

[0226] (5) Precision Investigation

[0227] RES: Five portions of RES absolute ethanol solutions with concentrations of 1.40, 3.60, and 6.65 μg / mL were prepared respectively, and repeated measurements were carried out 5 times within one day to investigate the within-day precision; measurements were carried out continuously for 5 days to investigate the between-day precision. The results are shown in Table 16.

[0228] IMC: Five portions of IMC absolute ethanol solutions with concentrations of 9.48, 20.05, and 38.50 μg / mL were prepared respectively, and repeated measurements were carried out 5 times within one day to investigate the within-day precision; measurements were carried out continuously for 5 days to investigate the between-day precision. The results are shown in Table 16.

[0229] Table 16: Intra-day and inter-day precision results of RES, IMC and PIR (n = 5)

[0230]

[0231]

[0232]

[0233] The results showed that after calculating the precision of the two model drugs, the intra-day and inter-day precision RSD values of RES and IMC were both less than 2.0%, meeting the methodological requirements.

[0234] (6) Recovery rate investigation

[0235] RES absolute ethanol solutions and IMC absolute ethanol solutions with three different concentrations of low, medium and high were prepared respectively, the contents of the three model drugs were determined, and the recovery rates were calculated respectively. The results are shown in Table 17.

[0236] Table 17: Recovery rate investigation results of RES and IMC (n = 5)

[0237]

[0238]

[0239] The recovery rates of the two model drugs were obtained through experiments, and the results all met the methodological requirements.

[0240] (7) Determination of drug content

[0241] RES-PSI, IMC-PSI, RES-CMCS-PSI and IMC-CMCS-PSI were prepared by using the raw material ratio and process conditions of Example 1. Appropriate amounts of RES-PSI and IMC-PSI were weighed respectively, and appropriate amounts of absolute ethanol were added to RES-CMCS-PSI and IMC-CMCS-PSI, and ultrasonicated for 30 min to prepare model drug solutions. After waiting for the temperature to drop to room temperature, the absorbance A was measured by using an ultraviolet spectrophotometer. After substituting into the standard curves of each drug and obtaining each concentration, the drug loading and encapsulation efficiency were calculated. The results are shown in Table 18.

[0242] The calculation formulas for drug loading and encapsulation efficiency are as follows:

[0243] Drug loading (%) = (W / W 总 ) × 100%; Encapsulation efficiency (%) = (W / W0) × 100%.

[0244] Among them, W: the mass of the drug loaded in the drug-loading system, W0: the total amount of drug input, W 总 : the total mass of the drug-loading system.

[0245] Table 18: Drug loading and encapsulation efficiency test results of drug delivery system (n=6)

[0246]

[0247] According to the drug loading capacity and encapsulation efficiency formulas, the drug loading capacity and encapsulation efficiency of RES-PSI, IMC-PSI, RES-CMCS-PSI and IMC-CMCS-PSI were calculated respectively, and a comparative analysis was performed. It was found that the drug loading capacity and encapsulation efficiency of the drug delivery system were improved to varying degrees after PSI was modified with CMCS after amination. This is because the introduction of -NH2 can form electrostatic interactions with the phenolic hydroxyl and carboxyl groups contained in the drug, thereby enhancing the interaction between the carrier and the drug. In addition, CMCS is blocked to prevent drug leakage, thereby increasing the drug loading capacity and encapsulation efficiency.

[0248] 2. Characterization of CMCS-PSI

[0249] (1) Morphological analysis of CMCS-PSI

[0250] (1.1) SEM analysis

[0251] The particle size and morphology of PSI, NH2-PSI, RES-NH2-PSI, IMC-NH2-PSI, RES-CMCS-PSI, and IMC-CMCS-PSI were observed using a scanning electron microscope. Appropriate amounts of the above samples were sprayed with gold on the surface and photographed using an electron microscope at 4000 times magnification to observe and compare the structural morphology and particle size of the aerogel materials before and after drug loading. The results are shown in Figure 14 , Figure 15 .

[0252] Depend on Figure 14 It can be seen that the surface of the PSI aerogel before drug loading presents an irregular spherical structure; the spherical morphology of the aerogel surface becomes compact and some protrusions appear after amino treatment; the surface of the aerogel nano-drug delivery system appears agglomerated after loading with RES; the surface of the aerogel nano-drug delivery system after CMCS modification becomes compact and obvious flocs are present.

[0253] Depend on Figure 15 It can be seen that the surface of the PSI aerogel before drug loading presents an irregular spherical structure; the spherical morphology of the aerogel surface becomes compact and some protrusions appear after amino treatment; the surface of the aerogel nano-drug delivery system appears agglomerated after loading with IMC; the surface of the aerogel nano-drug delivery system after CMCS modification becomes compact and has obvious flocs.

[0254] (1.2) TEM analysis

[0255] The microscopic and pore morphologies of PSI, NH2-PSI, RES-NH2-PSI, IMC-NH2-PSI, RES-CMCS-PSI, and IMC-CMCS-PSI were observed using a transmission electron microscope. The conditions were set as follows: acceleration voltage 220 V, magnification 2000 times, and resolution 20 - 500 nm. The results are shown in Figure 16 and Figure 17 .

[0256] It can be seen from Figure 16 that the aerogel nano-drug delivery system has a porous network structure. Before drug loading, it resembles a loose sponge with well-developed pores and irregular channels; after drug loading, the pore size becomes smaller, the structure is compact and the surface is uneven; after CMCS modification, there are shadows on the surface, and it is speculated that CMCS blocks the pores of the aerogel.

[0257] It can be seen from Figure 17 that the aerogel nano-drug delivery system has a porous network structure. Before drug loading, it resembles a loose sponge with well-developed pores and irregular channels; after drug loading, the pore size becomes smaller, the structure is compact and the surface is uneven; after CMCS modification, there are shadows on the surface, and CMCS may block the pores of the aerogel.

[0258] (2) Phase analysis of CMCS-PSI

[0259] The morphologies of RES, IMC, PSI, NH2-PSI, RES-NH2-PSI, IMC-NH2-PSI, RES-CMCS-PSI, and IMC-CMCS-PSI were analyzed using an X-ray diffractometer. The 2θ angle range was 0.5 - 20°, Cu target Kα radiation was used, the voltage was 40 kV, the current was 40 mA, and the scanning speed was 0.02° / s. The results are shown in Figure 18 and Figure 19 .

[0260] It can be seen from Figure 18 and Figure 19As shown, a represents the characteristic peaks of RES and IMC respectively, indicating that the drugs are in crystal state; b represents NH2-PSI, and a relatively wide diffraction peak at 2θ = 22.5° appears, which is its amorphous diffraction peak and is the same as the characteristic diffraction peak of PSI, indicating that the original crystal structure has not changed after amino modification; c represents RES-NH2-PSI and IMC-NH2-PSI. The main peak of the aerogel at 2θ = 22.5° remains unchanged after drug loading, and weak drug characteristic peaks appear. This is because after the drug is loaded into the aerogel, hydrogen bonds are formed with silanol groups, converting from the crystalline state to the amorphous state, but there is a little drug attached to the surface; d represents RES-CMCS-PSI and IMC-CMCS-PSI, indicating that the diffraction peak of PSI remains unchanged after CMCS modification and there is no obvious change, which has no effect on the skeleton structure of the carrier. The drug crystal diffraction peak disappears. It is speculated that after CMCS modification, the drug is blocked in the aerogel material and the drug diffraction peak is covered up.

[0261] (3) Specific surface area and pore size analysis of CMCS-PSI

[0262] Weigh an appropriate amount of PSI, NH2-PSI, RES-NH2-PSI, IMC-NH2-PSI, RES-CMCS-PSI, and IMC-CMCS-PSI. Under the condition that the test temperature is 77K, use a specific surface area and porosity analyzer to conduct N2 adsorption-desorption experiments on them. Make an isothermal curve graph and a pore size distribution graph through the experimental data, and then calculate the pore size and pore volume by the BJH (Barrett-Joyner-Halenda) method; calculate the specific surface area by BET (Brunauer-Emmett-Teller) and analyze the drug loading situation. The results are shown in Figure 20 、 Figure 21 。

[0263] Figure 20 、 Figure 21N2 adsorption - desorption isotherm curves (a) and pore size distribution curves (b) of aerogel before and after loading RES and IMC model drugs respectively. As can be seen from the figure, when the relative pressure changes from low to high before and after drug loading, the adsorption gradually rises from gentle, then tends to be gentle again. The adsorption form also changes from monolayer adsorption to multi - layer adsorption. When the relative pressure drops to 0.6P / P0, the curves coincide again. By observation, it is found that the adsorption isotherm conforms to the aerogel and is a type Ⅳ isotherm curve with a hysteresis loop. The hysteresis loop of the drug - loaded system is between H1 and H2 types, and the pore type of the carrier is irregular. The hysteresis loop changes before and after drug loading, and the nitrogen adsorption amount decreases significantly. The specific surface area decreases after drug loading, which is due to the occupation of space by drug loading; from the pore size distribution diagram, the center of the pore size distribution peak of the aerogel before drug loading is located at 22.50 nm. After drug loading, the peak center values of RES - NH2 - PSI, IMC - NH2 - PSI, RES - CMCS - PSI, and IMC - CMCS - PSI generally increase. This is because the drug loading squeezes the aerogel and causes elastic deformation. To sum up, it shows that RES and IMC are successfully loaded into the aerogel.

[0264] The specific surface area, pore size and pore volume of NH2 - PSI, RES - NH2 - PSI, IMC - NH2 - PSI, RES - CMCS - PSI, and IMC - CMCS - PSI were calculated by BET method and BJH method respectively to observe whether the drugs were successfully loaded. The results are shown in Table 19.

[0265] Table 19: N2 adsorption - desorption analysis results of NH2 - PSI and CMCS - PSI

[0266]

[0267] As can be seen from Table 19, the pore volume and specific surface area of the aerogel after loading drugs are smaller than those before drug loading. The pore volumes decreased by 82.73% and 85.59% respectively, and the specific surface areas decreased by 84.83% and 84.36% respectively, indicating that the drugs were successfully loaded into the aerogel; while the average pore size increased compared with that before drug loading. The reason may be that the mechanical properties of the aerogel are poor. When the drugs enter the pores, the pore size of the aerogel is elastically deformed and increased due to the internal drug filling and extrusion, but the structure has not changed.

[0268] (4) FT - IR spectral analysis of CMCS - PSI

[0269] Take a small amount of PSI, NH2 - PSI, RES - NH2 - PSI, IMC - NH2 - PSI, RES - CMCS - PSI, IMC - CMCS - PSI, as well as the powder of the mixture of each drug and carrier and potassium bromide respectively, irradiate them under an infrared lamp for a period of time to dry them, grind them into fine powder in a mortar in a certain proportion, and then press tablets. Set the conditions: the wavelength range is 4000 - 400 cm -1, the number of scans was 16 times, and the resolution was 2 cm -1 , it was analyzed by Fourier transform infrared spectrometer to obtain its infrared spectrum and analyze the change of molecular structure. The results are shown in Figure 22 , Figure 23 , Figure 24 .

[0270] Among them, the infrared spectra of CMCS, PSI, NH2-PSI and CMCS-PSI are as shown in Figure 22 . In the CMCS spectrum, the absorption peaks around 1604 cm -1 and around 1418 cm -1 prove the existence of carboxyl groups. 1604 cm -1 is the asymmetric stretching vibration absorption peak of carboxyl groups, 1418 cm -1 is its symmetric stretching vibration absorption peak, and the absorption peak around 1062 cm -1 is the stretching vibration absorption peak of the ether bond (C-O) formed by primary alcohol, indicating that the carboxymethylation reaction mainly occurs at the C6 position. The absorption peaks around 2918 cm -1 and around 1327 cm -1 are the stretching vibration and bending vibration absorption peaks of C-H bonds respectively, and the strong and broad absorption peak around 3408 cm -1 is the stretching vibration absorption peak of O-H and N-H. The unique characteristic peaks of PSI are Si-O (1065 cm -1 ), Si-CH3 (853 cm -1 ), Si-OH (956 cm -1 ), and Si-O-Si (1060 cm -1 , 465 cm -1 ). After PSI was modified by silane coupling agent, the surface hydroxyl groups were significantly reduced because it can be seen from the figure that the bending vibration absorption peak (1635 cm -1 ) and stretching vibration absorption peak (3450 cm -1 ) of silanol groups were significantly weakened. The weak absorption peak at 2920 cm -1 should be due to the vibration of C-H of -N-CH2- of KH-550. The weak and broad absorption peak at 1435 cm -1 should be caused by the stretching vibration of -NH2 of KH-550, proving that -NH2 was successfully connected to the surface of PSI. After being modified by CMCS, the characteristic peak of CMCS at 1310 cm -1 appeared in CMCS-PSI, and an obvious characteristic peak of amide bond appeared at 1623 cm -1 , indicating that the amino group of NH2-PSI and the carboxyl group of CMCS have successfully reacted to form an amide bond, and the CMCS-PSI drug delivery system has been successfully prepared.

[0271] The infrared spectra of the aerogel before and after loading RES are shown as Figure 23 follows. Structural characteristics of RES: There is an absorption peak of phenolic hydroxyl at 3250 cm -1 , benzene ring absorption peaks at 1602 cm -1 and 1540 cm -1 , characteristic absorptions of trans- and cis-C═C- at 965 cm -1 and 700 cm -1 respectively; characteristic peaks of NH2-PSI at 1635 cm -1 and 3450 cm -1 , a weak absorption peak at 2920 cm -1 caused by the C-H vibration of -N-CH2-, and a weak and broad absorption peak at 1435 cm -1 caused by the stretching vibration of -NH2, proving that -NH2 has been successfully grafted onto the surface of PSI; in the infrared spectrum of RES-NH2-PSI, in addition to the characteristic peaks of NH2-PSI, there are also weak characteristic peaks of RES appearing, indicating that the NH2-PSI skeleton after drug loading is still intact, and there are no other obvious characteristic peaks, indicating that RES is loaded into the aerogel in the form of physical adsorption, proving that RES is successfully loaded into NH2-PSI; the chromatographic peaks of RES, NH2-PSI and CMCS in the physical mixture are clearly distinguishable, while in the drug delivery system, the characteristic peaks at 1623 cm -1 of the amide bond formed by the connection of -NH2 and -COOH and at 1310 cm -1 are obvious. The infrared spectrum of PSI modified with CMCS to load RES shows that the CMCS characteristic peaks are obvious and the RES characteristic peaks are weak, preliminarily indicating that CMCS has successfully modified PSI loaded with RES.

[0272] The infrared spectra of the aerogel before and after loading IMC are shown as Figure 24 follows. As shown in the infrared spectrum of IMC, there are obvious absorption vibration peaks of the terminal carboxyl group of IMC at 1717 cm -1 and 1691 cm -1 , two characteristic absorption peaks on the main chain of IMC at 1638 cm -1 and 1556 cm -1 , the bending vibration peak of CH-CH3 at 1358 cm -1 , and in addition, there are other obvious characteristic peaks (1479 cm -1 , 1233 cm -1 , 1222 cm -1 , 748 cm -1 ). Characteristic peaks of NH2-PSI at 1635 cm -1 and 3450 cm -1, the weak absorption peak at 2920 cm caused by the C-H vibration of -N-CH2- -1 , the weak and broad absorption peak at 1435 cm caused by the stretching vibration of -NH2 -1 , indicating that -NH2 has been successfully grafted onto the surface of PSI; in the infrared spectrum of IMC-NH2-PSI, in addition to the characteristic peaks of NH2-PSI, there are also weak characteristic peaks of IMC, indicating that the NH2-PSI skeleton is still intact after drug loading. Compared with blank NH2-PSI, after the drug is loaded into the aerogel, the -OH absorption peak at 3500 cm -1 shifts to lower wavenumbers, the carbonyl peak at 1623 cm -1 becomes wider, and the C-O absorption peak at 1310 cm -1 is enhanced, indicating that there are hydrogen bonds and dipole-dipole interactions between IMC and the aerogel. This can also be seen from the chemical structural formula of IMC. There is a hydrogen bond interaction between the -OH functional group in PSI and the -COOH functional group in IMC, which plays a certain role in the prolonged release of the drug; the chromatographic peaks of IMC, NH2-PSI, and CMCS physical mixture are clearly distinguishable, while in the drug delivery system, the amide bond formed by the connection of -NH2 and -COOH of CMCS-PSI at 1623 cm -1 and the characteristic peak at 1310 cm -1 are obvious; the infrared spectrum of CMCS-modified PSI loaded with IMC shows that the CMCS characteristic peak is obvious and the IMC characteristic peak is weak, preliminarily indicating that CMCS has successfully modified PSI loaded with IMC.

[0273] (5) Thermal stability analysis of CMCS-PSI

[0274] The thermal stability of RES, IMC, PSI, NH2-PSI, RES-NH2-PSI, IMC-NH2-PSI, RES-CMCS-PSI, and IMC-CMCS-PSI was analyzed using a thermogravimetric analyzer. The atmosphere used was N2, the temperature range was from room temperature to 600 °C, the heating rate was 10 °C / min, and the flow rate was 30 mL / min. The thermogravimetric curves of the samples were obtained and their thermal stability was analyzed. The results are shown in Figure 25 , Figure 26 , Figure 27 .

[0275] The thermogravimetric curve of PSI is as shown in Figure 25As shown by Curve A, as the temperature rises to 600 °C, PSI has a slight weight loss, and the weight loss rate is about 15%. Obvious weight loss occurs from room temperature to 100 °C, because the internal moisture of PSI volatilizes. The thermogravimetric curve of NH2-PSI is shown in Figure B. It can be seen that NH2-PSI has three obvious weight losses during the process from room temperature to 600 °C. The first occurs from room temperature to 100 °C, and the weight loss rate is about 10%. This stage is mainly caused by the volatilization of water molecules and residual solvent (ethanol); the second is between about 100 - 300 °C, and the weight loss rate is about 15%, which is caused by the desorption of amino bonds in the structure; the third is between about 300 - 600 °C, and the weight loss rate is about 10%, which is caused by the decomposition of silane coupling agent KH550; the thermogravimetric curve of CMCS-PSI is shown in Figure C. It can be seen that CMCS-PSI has two obvious weight losses during the process from room temperature to 600 °C. The first occurs from room temperature to 100 °C, and the weight loss rate is about 15%. It is mainly caused by the volatilization of water molecules on the surface and inside of CMCS-PSI and the volatilization of residual solvent (ethanol); the second is between about 100 - 600 °C, and the weight loss rate is about 25%, which is caused by the decomposition of CMCS in the structure and the desorption of amide bonds formed by CMCS and amino-functionalized PSI; the above results show that the carrier material can meet the requirements of being a drug carrier in terms of thermal stability.

[0276] As Figure 26 shown, where A is the TG curve of RES API; B is the TG curve of NH2-PSI; C is the TG curve of CMCS-PSI loaded with RES API. It can be seen from the figure that the TG curve of RES API drops sharply at 250 °C. It is inferred that the weight loss may be caused by the breakage of the C2-C7 chemical bond in the RES molecule, and the drug turns into ashes when the experiment is completed; NH2-PSI has three obvious weight losses during the process from room temperature to 600 °C. The first occurs from room temperature to 100 °C, and the weight loss rate is about 10%. This stage is mainly caused by the volatilization of water molecules and residual solvent (ethanol); the second is between about 100 - 300 °C, and the weight loss rate is about 15%, which is caused by the desorption of amino bonds in the structure; the third is between about 300 - 600 °C, and the weight loss rate is about 10%, which is caused by the decomposition of silane coupling agent KH550; RES-CMCS-PSI has the first weight loss during the process from room temperature to 100 °C, and the weight loss rate is about 10%. The second weight loss occurs in the temperature range of 100 °C - 600 °C, and the weight loss rate is about 40%, which is caused by the decomposition of amide bonds and the drug. Due to the hydrogen bond interaction between the drug and the carrier, the disappearance of the hydrogen bond force requires energy, which indirectly increases the drug decomposition temperature. Therefore, compared with RES API, the weight loss rate of RES-CMCS-PSI decreases, improving the thermal stability of the drug.

[0277] As Figure 27As shown in the figure, where A is the TG curve of the IMC raw material drug; B is the TG curve of NH2-PSI; C is the TG curve of CMCS-PSI loaded with the IMC raw material drug. It can be seen from the figure that the IMC raw material drug begins to decompose rapidly at 220 °C, and by 300 °C, the weight loss rate is about 74%; NH2-PSI has three obvious weight losses during the process from room temperature to 600 °C. The first occurs from room temperature to 100 °C, and the weight loss rate is about 10%. This stage is mainly due to the volatilization of water molecules and residual solvents (ethanol); the second is approximately between 100 - 300 °C, and the weight loss rate is about 15%, which is caused by the desorption of amino bonds in the structure; the third is approximately between 300 - 600 °C, and the weight loss rate is about 10%, which is due to the decomposition of the silane coupling agent KH550; IMC-CMCS-PSI has the first weight loss during the process from room temperature to 100 °C, and the weight loss rate is about 10%. The second weight loss occurs in the temperature range of 100 °C - 220 °C, and the weight loss rate is about 15%. The reason may be the breaking of amino bonds. The third weight loss occurs in the temperature range of 220 °C - 600 °C, and the weight loss rate is about 40%. It may be caused by the decomposition of CMCS and the IMC raw material drug. Due to the existence of hydrogen bonds and chemical bond interactions between the drug and the carrier, the disappearance of hydrogen bond forces and the breaking of chemical bonds require energy, indirectly increasing the drug decomposition temperature. Therefore, compared with the IMC raw material drug, the weight loss rate of IMC-CMCS-PSI decreases, improving the thermal stability of the drug.

[0278] III. In vitro drug release performance of CMCS-PSI

[0279] The in vitro dissolution of RES, IMC, RES-CMCS-PSI, and IMC-CMCS-PSI was measured respectively with reference to the dissolution determination method (Appendix XC, Method 2, Volume IV of the Chinese Pharmacopoeia 2020 Edition), and the cumulative dissolution percentage was calculated to plot the cumulative drug release curve.

[0280] Method for measuring the in vitro dissolution of RES: Weigh a certain amount of RES raw material drug and RES-CMCS-PSI samples in two groups respectively, with four parallels in each group, and each portion is approximately equivalent to 20 mg of RES. Dissolution medium: 900 mL of PBS with pH 1.2, pH 4.5, pH 6.8, and pH 7.4, temperature: 37 ± 0.5 °C, rotation speed: 50 r / min. Samples were taken at regular intervals. 5 mL of PBS from each group was taken at 5, 15, 30, 60, 105, 165, 255, 375, 460, 640, and 720 min, and at the same time, an equal volume of dissolution medium at the same temperature was quickly added. After filtration through a 0.45 μm microporous membrane, the absorbance was measured using an ultraviolet spectrophotometer, substituted into the standard curve, and the cumulative dissolution was calculated.

[0281] In vitro dissolution determination method of IMC: Weigh a certain amount of IMC raw material drug and two groups of samples of IMC-CMCS-PSI respectively, with four parallels in each group, and each portion is approximately equivalent to 20 mg of IMC. Dissolution medium: 900 mL of PBS with pH 1.2, pH 4.5, pH 6.8, and pH 7.4, temperature: 37 ± 0.5 °C, rotation speed: 100 r / min. 5 mL of PBS in each group is sampled at 5, 15, 30, 60, 105, 165, 255, 375, 460, 640, and 720 min respectively, and at the same time, the same volume of dissolution medium at the same temperature is quickly replenished. After filtration through a 0.45 μm microporous membrane, the absorbance is measured using an ultraviolet spectrophotometer, substituted into the standard curve, and the cumulative dissolution is calculated.

[0282] The cumulative drug release curves of RES and RES-CMCS-PSI at different pH values are shown in Figure 28 ; The cumulative drug release curves of IMC and IMC-CMCS-PSI at different pH values are shown in Figure 29 .

[0283] As Figure 28 shown, the cumulative release rates of RES raw material drug in four different PBS buffer solutions with pH 1.2, pH 4.5, pH 6.8, and pH 7.4 within 12 h are 72.12 ± 1.63%, 60.33 ± 1.68%, 44.23 ± 2.12%, and 42.65 ± 2.76% respectively, while the cumulative release amounts of RES-CMCS-PSI in different PBS buffer solutions within 12 h are 34.73 ± 1.89%, 42.20 ± 2.45%, 77.32 ± 3.22%, and 37.65 ± 2.91% respectively. The release of RES raw material drug is faster under acidic (pH 1.2, pH 4.5) conditions, and the release amount gradually decreases with the increase of pH. The release amount of RES-CMCS-PSI decreases and the release rate slows down in PBS buffer solutions with pH 1.2, pH 4.5, and pH 7.4, while the cumulative release rate increases significantly and the release rate accelerates in PBS solution with pH 6.8. It is speculated that the drug release in RES-CMCS-PSI depends on the combined action of PSI and CMCS. When the environment is strongly acidic (such as 1.2 and 4.5), H +Excessive amounts will cause molecular curling of the external CMCS, reduce its swelling ability, prevent the release of RES, result in slow release and reduced release amount; under acidic conditions (pH 6.8); in a pH 7.4 dissolution medium, since the amide bond connecting CMCS and PSI is not broken, the drug is blocked in the carrier, and the -NH2 of CMCS has a same-sex repulsion with the basic groups in the solution, hindering the release of RES and reducing the release amount of the drug. Therefore, when the pH value of the release medium is 6.8, the release amount of RES is the largest. The above experimental results prove that RES-CMCS-PSI has pH sensitivity and can provide a reference for the research and development of enteric-soluble sustained and controlled release drugs and tumor preparations.

[0284] As Figure 29 shown, the cumulative release rates of the IMC raw material drug in four different PBS buffer solutions with pH 1.2, pH 4.5, pH 6.8, and pH 7.4 within 12 h were 36.36 ± 2.68%, 43.65 ± 3.16%, 64.23 ± 2.89%, and 78.52 ± 1.47% respectively. Since IMC is a weakly acidic drug, as the pH of the dissolution medium increases, the cumulative release rate of the raw material drug within 12 h gradually increases. The cumulative release amounts of IMC-CMCS-PSI in different PBS buffer solutions within 12 h were 22.81 ± 1.85%, 32.74 ± 2.57%, 75.84 ± 3.56%, and 12.37 ± 1.43% respectively. The release amount decreased and the release rate slowed down in the pH 1.2, pH 4.5, and pH 7.4 PBS buffer solutions, while the cumulative release rate increased significantly and the release rate accelerated in the pH 6.8 PBS solution. The speculated reason may be that the release of the drug in IMC-CMCS-PSI depends on the combined action of both PSI and CMCS. When the environment is strongly acidic (such as 1.2 and 4.5), H + in the solution is excessive, which will cause molecular curling of the external CMCS, reduce its swelling ability, prevent the release of IMC, result in slow release and reduced release amount; under slightly acidic conditions (pH 6.8), H + in the solution decreases, the swelling ability of CMCS increases, the amide bond connecting CMCS and PSI breaks, releasing the drug, and the cumulative release amount of IMC increases; in a pH 7.4 PBS dissolution medium, since the amide bond connecting CMCS and PSI is not broken, the drug is blocked in the carrier, and the -NH2 of CMCS has a same-sex repulsion with the basic groups in the solution, hindering the release of IMC and reducing the release amount of the drug. Therefore, when the pH value of the dissolution medium is 6.8, the release amount of IMC is the largest. The above experimental results prove that IMC-CMCS-PSI has pH sensitivity and can provide a reference for the research and development of enteric-soluble controlled release drugs and tumor preparations.

[0285] In summary, by analyzing the in vitro release profiles of RES and IMC APIs, it was found that the release profiles of the model drugs were highly similar. This is because both belong to non-steroidal drugs with similar physicochemical properties and the same binding mode to PSI (chemical bonding).

[0286] After loading the poorly soluble drugs RES and IMC into CMCS-modified PSI, the drug release rates changed to varying degrees. From the overall experimental data, it can be seen that the release rates decreased in PBS buffer solutions at pH 1.2, pH 4.5, and pH 7.4, while the release rates of the three drugs increased significantly in the PBS buffer solution at pH 6.8, achieving pH-controlled drug release. The above results indicate that the drug release amounts in RES-CMCS-PSI and IMC-CMCS-PSI are closely related to the environmental pH value and show obvious pH dependence. Therefore, the drug release in the drug delivery system can be regulated by controlling the environmental pH value. Compared with normal tissues, the intestinal environment and tumor cells usually have weak acidity (pH value is about 6.8). Therefore, RES-CMCS-PSI and IMC-CMCS-PSI can provide references for the research of enteric-coated preparations and tumor preparations.

[0287] IV. Drug Release Kinetics of CMCS-PSI

[0288] To deeply understand the drug release behaviors of RES-CMCS-PSI and IMC-CMCS-PSI in simulated body fluids (pH 1.2, 4.5, 7.4) and cancer cell body fluid (pH 6.8), the drug release kinetic model equations (first-order kinetic model, Korsmeyer-Peppas model, and Higuchi model) were used to fit the cumulative release curves of the drugs, analyze the drug release mechanisms, and explore the drug release kinetics of the drug delivery system. F: Cumulative release rate; K: Rate constant; M t : Drug release amount at time t; t n : Drug half-life.

[0289] First-order kinetic model: F = ln(1 - M t / M) = -Kt;

[0290] Korsmeyer-Peppas model: F = M t / M = Kt n ;

[0291] Higuchi model: F = M t / M = Kt 1 / 2 .

[0292] By fitting the first-order kinetic equation, Korsmeyer-Peppas model, and Higuchi model, the in vitro drug release process of the drug delivery system was further studied. The results are shown in Figure 30 、 Figure 31 and Tables 20 and 21.

[0293] Table 20: Related parameters of RES drug release kinetics

[0294]

[0295] Table 21: Related parameters of IMC drug release kinetics

[0296]

[0297]

[0298] Figure 30 They are the fittings of the first-order kinetic model, Korsmeyer-Peppas model, and Higuchi model for the release of RES in four pH buffer solutions by RES and RES-CMCS-PSI, respectively. By comparing the R2 values of various model fittings, it was found that the fitting degree of the RES raw material drug for the first-order kinetic release model was higher than that of the Korsmeyer-Peppas model and Higuchi model, indicating that the RES raw material drug was released by pseudo-first-order kinetics; while the fitting effect of RES-CMCS-PSI for the Korsmeyer-Peppas model was better than that of the other two models. As shown in the data in Table 4-16, the linear correlation coefficient of the Korsmeyer-Peppas model fitting of RES-CMCS-PSI at different pH values was the largest, and the n values of the Korsmeyer-Peppas model fitting of RES-CMCS-PSI at different pH values were 0.52, 0.46, 0.63, and 0.72, respectively, which were between 0.45 and 0.9. At this time, the release of RES by the drug delivery system satisfied the law of erosion and diffusion.

[0299] Figure 31The first-order kinetic model, Korsmeyer-Peppas model, and Higuchi model fittings of IMC and IMC-CMCS-PSI in four pH buffer solutions were carried out respectively. By comparing the R2 values of various model fittings, it was found that the fitting degree of the IMC raw material drug to the first-order kinetic release model was higher than that of the Korsmeyer-Peppas model and the Higuchi model, indicating that the IMC raw material drug conforms to the first-order kinetic release; while the fitting effect of IMC-CMCS-PSI to the Korsmeyer-Peppas model was better than the other two models. As shown in the data of Table 4-17, the linear correlation coefficient of the Korsmeyer-Peppas model fitting of IMC-CMCS-PSI at different pH values was the largest. And the n values of the Korsmeyer-Peppas model fitting of IMC-CMCS-PSI at different pH values were 0.42, 0.35, 0.38, and 0.46 respectively, indicating that the release of IMC by IMC-CMCS-PSI in pH 1.2, 4.5, and 6.8 buffer solutions satisfied the law of erosion-diffusion (n < 0.45); the release of IMC in pH 7.4 buffer solution satisfied the law of erosion-diffusion (n between 0.45 - 0.9), and at this time the release of IMC by IMC-CMCS-PSI conforms to the law of Fick diffusion.

[0300] In summary, by simulating the three models, it was obtained that the in vitro release of the raw material drug conforms to the characteristics of first-order kinetic release, while the drug release of the drug delivery system conforms more to the characteristics of the Korsmeyer-Peppas model release, indicating that after the drug is loaded by PSI blocked by CMCS, the drug release form changes, conforms to the law of swelling-erosion diffusion, and makes the drug release controllable. It provides research materials for the research and development of new drug sustained-release and controlled-release preparations.

[0301] V. Stability test of CMCS-PSI

[0302] (1) Influence factor stability test of CMCS-PSI

[0303] Since the drug is prone to moisture absorption, decomposes upon exposure to light, and is unstable, it needs to be stored in a dry and light-protected manner. By loading the drug with a carrier material, its stability can be improved. In this experiment, referring to the guiding principle of the stability test of raw material drugs and preparations in Part IV of the Chinese Pharmacopoeia 2020 Edition, high temperature, high humidity, and light were selected as the influencing factor variables to investigate the influencing factors of the stability of the drug delivery system.

[0304] High temperature: RES-CMCS-PSI and IMC-CMCS-PSI were placed in an oven at a constant temperature of 60 °C. Samples were taken and measured on the 0th, 5th, and 10th days respectively to investigate the high-temperature stability of RES-CMCS-PSI and IMC-CMCS-PSI, and the changes in the drug loading of the drug delivery system were recorded. The results are shown in Table 22.

[0305] High humidity: RES-CMCS-PSI and IMC-CMCS-PSI were placed in a desiccator. A supersaturated potassium nitrate solution (RH 92.5%) was prepared and placed at the bottom of the desiccator. They were placed for 10 days at 25 °C and RH 92.5%. Samples were taken and measured on the 0th, 5th, and 10th days respectively to investigate the high-humidity stability of RES-CMCS-PSI and IMC-CMCS-PSI, and the changes in the drug loading of the drug delivery system were recorded. The results are shown in Table 23.

[0306] Light: RES-CMCS-PSI and IMC-CMCS-PSI were placed in suitable clean containers and placed at room temperature under light of 4500 lx ± 500 lx for 10 days. Samples were taken on the 0th, 5th, and 10th days respectively to investigate the light stability of RES-CMCS-PSI and IMC-CMCS-PSI, and the changes in the drug loading of the drug delivery system were recorded. The results are shown in Table 24.

[0307] Table 22: High-temperature test results of RES-CMCS-PSI and IMC-CMCS-PSI (n = 6)

[0308] Time (d) Drug-loading amount of RES-CMCS-PSI (%) Drug-loading amount of IMC-CMCS-PSI (%) 0 43.57±0.78 46.16±0.85 5 42.90±0.81 45.88±1.03 10 42.61±0.68 45.34±0.87

[0309] The high-temperature test results are shown in Table 22. The results show that the drug loading of RES-CMCS-PSI decreased by 0.96% after being placed at high temperature for 10 days compared with the 0th day, and the drug loading of IMC-CMCS-PSI decreased by 0.82% after being placed at high temperature for 10 days compared with the 0th day. The decline of both was small, indicating that the drug delivery system was stable under high-temperature conditions.

[0310] Table 23: High-humidity test results of RES-CMCS-PSI and IMC-CMCS-PSI (n = 6)

[0311]

[0312]

[0313] The results of the high humidity test are shown in Table 23. The data show that after 10 days of storage at 25°C and RH 92.5%, the drug loading of RES-CMCS-PSI decreased by 2.49% compared with that on day 0, and the drug loading of IMC-CMCS-PSI decreased by 2.57% compared with that on day 0 under the same conditions. This indicates that the drug delivery system should be stored under sealed and dry conditions.

[0314] Table 24: Results of the light exposure test of RES-CMCS-PSI and IMC-CMCS-PSI (n = 6)

[0315] Time (d) Drug-loading amount of RES-CMCS-PSI (%) Drug-loading amount of IMC-CMCS-PSI (%) 0 43.18±1.21 45.23±1.33 5 42.88±1.12 44.86±1.45 10 42.26±1.36 44.32±1.27

[0316] The results of the strong light exposure test are shown in Table 24. It can be seen from the experimental data that after 10 days of strong light exposure, the drug loadings of RES-CMCS-PSI and IMC-CMCS-PSI decreased by 0.92%, 0.91% and 0.54% respectively compared with that on day 0. The decrease amplitudes are all relatively small, indicating that the light stability of the drug delivery system is better than that of the raw drug, improving the light stability of the raw drug.

[0317] (2) Stability study of CMCS-PSI in gastrointestinal contents

[0318] Experimental animals: SD rats (SPF grade, Changchun Yisi Experimental Animal Technology Co., Ltd.), male, 250 ± 20 g, license number: SCXK(Ji)2018-0007. This experiment was approved by the Experimental Animal Ethics Committee of our unit.

[0319] Ⅰ. Preparation of solutions

[0320] (A) Preparation of buffer solutions: (1) pH 1.2 hydrochloric acid solution: Mix 0.7 mL of hydrochloric acid with an appropriate volume of distilled water; (2) pH 6.8 PBS: Dissolve an appropriate amount of potassium dihydrogen phosphate in distilled water and adjust the pH of the solution to 6.8 with 0.1 mol / L sodium hydroxide; (3) pH 7.4 PBS: Dissolve an appropriate amount of potassium dihydrogen phosphate in an appropriate amount of distilled water and adjust the pH of the solution to 7.4 with 0.1 mol / L sodium hydroxide. Store in a refrigerator at 4°C.

[0321] (B) Preparation of gastrointestinal content solutions: Take 12 SD rats, fast for 24 h, allow free access to water, and immediately open the abdomen after sacrifice. Remove the stomach, small intestine and large intestine of the rats, and rinse the contents of the stomach, small intestine and large intestine with 6 mL of pre-cooled pH 1.2 hydrochloric acid solution, pH 6.8 PBS and pH 7.4 PBS solution respectively. Vortex mix the rinsing solutions evenly, then centrifuge at 5000 r / min for 10 min, and take the supernatant as the gastrointestinal content solution. Store in a refrigerator at 4°C.

[0322] (C) Preparation of sample suspension: Add 10 mg of RES and 10 mg of IMC into a 10 mL volumetric flask respectively, make up the volume with normal saline, and perform magnetic stirring at 37 °C for 15 min to prepare RES suspension and IMC suspension; Take appropriate amounts of RES-CMCS-PSI and IMC-CMCS-PSI, add normal saline, and perform magnetic stirring at 37 °C for 15 min to prepare RES-CMCS-PSI suspension and IMC-CMCS-PSI suspension, ensuring that the drug content is 1 mg / mL.

[0323] Ⅱ. Stability test

[0324] By comparing the digestion of the drug-loading systems of RES-CMCS-PSI and IMC-CMCS-PSI and the raw materials of RES and IMC by the isolated stomach and intestine of rats, the gastrointestinal stability of the prepared drug-loading systems was investigated. To ensure the activity of digestive enzymes and flora in gastrointestinal contents, the sampling times were set at 0, 0.5 h, 1 h, 1.5 h, 2 h, 3 h, and 4 h. Specifically: Add RES, IMC, RES-CMCS-PSI, and IMC-CMCS-PSI into the gastric, small intestinal, and large intestinal contents respectively, mix well to make the concentrations of RES, IMC, RES-CMCS-PSI, and IMC-CMCS-PSI 50.0 μg / mL, incubate in a water bath shaker at 37 °C (100 r / min), take 400 μL of samples at 0, 0.5, 1.0, 1.5, 2.0, 3.0, and 4.0 h respectively, take 300 μL of the samples, quickly add 400 μL of ice acetonitrile to stop the reaction, vortex and mix for 1 min, centrifuge (5000 r / min) for 15 min, filter through a 0.45 μm filter membrane, and inject and determine by high performance liquid chromatography, record the peak area, and calculate the remaining percentage of the drug. The results are shown in Figure 32 , Figure 33 .

[0325] As Figure 32 shown, the stability of RES in gastrointestinal contents is poor, and the remaining drug content could not be detected in the gastric, small intestinal, and large intestinal contents after 3 h; The drug remaining rates of RES-CMCS-PSI in the gastric, small intestinal, and large intestinal contents at 4 h were 45.65%, 27.20%, and 41.77% respectively. It can be seen that the drug-loading system was largely decomposed in the small intestinal part, which was due to the pH response of the drug-loading system in the small intestinal environment (about pH 6.8). The data indicate that after RES was loaded by CMCS-modified PSI, its gastrointestinal stability was significantly enhanced.

[0326] As Figure 33As shown in the figure, after 2 hours of digestion by the contents of the stomach, small intestine, and large intestine, the remaining content of the drug could not be detected in IMC, indicating that IMC is more easily degraded by the active ingredients in the stomach, small intestine, and large intestine than RES; after being loaded into the drug delivery system, the drug remaining rates of IMC-CMCS-PSI in the contents of the stomach, small intestine, and large intestine for 4 hours were 47.32%, 25.42%, and 42.38% respectively. Similarly, the drug delivery system was more sensitive to the contents of the small intestine, promoting the decomposition of the drug. The data show that after the drug is loaded onto the carrier, its gastrointestinal stability is significantly enhanced.

[0327] The various active ingredients in the gastrointestinal environment of rats affect the stability of drugs in the gastrointestinal tract. The experimental data results show that the stability of RES and IMC raw materials in gastrointestinal contents is generally poor, and the degradation rate is relatively fast. It may be that the digestive enzymes and flora in the gastrointestinal tract of rats affect the degradation of drugs. After being loaded with CMCS-PSI, the gastrointestinal stability of drugs has been improved to varying degrees, and at the same time, it shows pH responsiveness to the contents of the small intestine. It can be seen that the drug delivery system prepared in this study can not only protect the loaded drugs, improve the stability of drugs in gastrointestinal contents, but also achieve pH-responsive release of drugs, thus better exerting the drug effect.

[0328] VI. Pharmacokinetic study of CMCS-PSI

[0329] (1) In vivo pharmacokinetic study method

[0330] Experimental animals: SD rats (SPF grade, Changchun Yisi Experimental Animal Technology Co., Ltd.), male, 250±20 g, license number: SCXK(Ji)2018-0007. This experiment was approved by the Experimental Animal Ethics Committee of our unit.

[0331] Take 24 SD rats, first fast them for 12 hours and provide normal drinking water. Then randomly divide them into 4 groups, namely the experimental groups (RES-CMCS-PSI, IMC-CMCS-PSI) and the control groups (RES, IMC). All rats were administered by gavage. The dosage was RES: 30 mg / kg, IMC: 30 mg / kg. After administration, about 0.5 mL of blood was taken from the fundus venous plexus at 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, and 24 h and placed in a centrifuge tube pre-coated with heparin. Gently shake to mix the sodium heparin with the plasma to prevent blood clotting. Centrifuge (10000 r / min, 10 min). After centrifugation, the upper yellow transparent plasma was stored at -80 °C for later detection. Subsequently, high performance liquid chromatography (HPLC) was used to detect the drug concentration in the plasma. The results are shown in Tables 25 and 26. Figure 34 、 Figure 35 。

[0332] Table 25: Main pharmacokinetic parameters of RES (n = 6)

[0333]

[0334] Table 26: Main pharmacokinetic parameters of IMC (n = 6)

[0335]

[0336] From Figure 34 and Table 25, it can be seen that after intragastric administration of RES and RES-CMCS-PSI to rats, the drugs reached the peak blood drug concentration at about 1.47 h and 4.04 h respectively. The C max of the RES group was 416.85 ng·mL -1 , and the C max of the RES-CMCS-PSI group was 1227.41 ng·mL -1 . Comparing the two groups, the C max of the RES-CMCS-PSI group was significantly higher than that of the RES group, indicating that the blood drug concentration of the drug increased significantly after being loaded with aerogel; the t max and t 1 / 2 of the RES-CMCS-PSI group were significantly longer than those of the RES group, indicating that the drug delivery system prolonged the drug action time for RES; and the AUC 0-t of the RES-CMCS-PSI group was 3.92 times that of the RES group, indicating that the drug delivery system significantly improved the bioavailability of RES. The reason for the improvement of the drug bioavailability by this drug delivery system may be that the CMCS structure contains amino - NH2, and the gastrointestinal environment is dilute acid with H + , which causes its amino group to be protonated to form NH 3+ . After protonation, the positive charges repel each other, making its molecular chain in a stretched state, increasing the viscosity, forming a protective layer on the surface of PSI, delaying drug release, prolonging the residence time of the drug in the gastrointestinal tract, and thus increasing the drug bioavailability.

[0337] From Figure 35 and Table 26, it can be seen that after intragastric administration of IMC and IMC-CMCS-PSI to rats, the drugs reached the peak blood drug concentration at about 3.97 h and 5.84 h respectively. The C max of the IMC group was 1834.29 ng·mL -1 , and the C max of the IMC-CMCS-PSI group was 3216.99 ng·mL -1 . Comparing the two groups, the C max of the IMC-CMCS-PSI group was significantly higher than that of the IMC group, indicating that the blood drug concentration of the drug increased significantly after being loaded with aerogel; the t max of IMC and IMC-CMCS-PSI were 3.97 h and 5.84 h respectively, and the t1 / 2 were 4.24 h and 7.45 h respectively. In the IMC-CMCS-PSI group, the t max and t 1 / 2 were significantly longer than those in the IMC group, indicating that the drug-loading system prolonged the action time of IMC; and the AUC of the IMC-CMCS-PSI group 0-t was 1.77 times that of the IMC group, indicating that the drug-loading system significantly improved the bioavailability of IMC. The reason for the improvement of the drug bioavailability by this drug-loading system may be that the CMCS structure contains amino group -NH2, and the gastrointestinal environment belongs to dilute acid with H + , which protonates its amino group to form NH 3+ . After protonation, the positive charges repel each other, making its molecular chain in a stretched state, increasing the viscosity, forming a protective layer on the surface of PSI, delaying drug release, prolonging the residence time of the drug in the gastrointestinal tract, and thus increasing the drug bioavailability.

[0338] (2) Evaluation of in vivo-in vitro absorption correlation

[0339] In vivo-in vitro absorption correlation (IVIVC) refers to a predictive mathematical model of the correlation between the in vitro cumulative drug release percentage and the amount of drug absorbed in vivo for sustained-release and controlled-release preparations. The parameters of in vivo-in vitro absorption correlation are used to objectively evaluate whether the quality of the preparation is reasonable. According to the in vivo and in vitro drug release data obtained from the experiment, a standard curve is made with the in vivo absorption percentage (Fa) and the in vitro cumulative release degree (Fd) as the horizontal and vertical coordinates respectively, and the correlation between the two is calculated and analyzed. The results are shown in Figure 36 .

[0340] According to the experimental data, linear regression is performed with the in vivo absorption percentage (Fa) as the horizontal coordinate and the in vitro cumulative release degree (Fd) as the vertical coordinate as Figure 36 shown. The regression equations of RES and RES-CMCS-PSI are y = 0.8844x + 8.2838 and y = 0.9759x + 33.2373 respectively; the regression equations of IMC and IMC-CMCS-PSI are y = 0.6925x + 34.2306 and y = 0.9543x + 6.4979 respectively, and the R2 values are all greater than 0.9. From the linear equations and R2 values, it can be preliminarily judged that there is a good correlation between the in vivo absorption percentage and the in vitro cumulative release percentage.

[0341] The above is the preferred implementation mode of the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the principle described in the present invention, several improvements and refinements can still be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A preparation method of a functionalized aerogel nano-drug delivery system, characterized in that, It includes the following steps: Step 1, carrier preparation: Weigh silica aerogel and ultrasonically disperse it in solvent A, stir to obtain a transparent solution, add glycerol to the above solution and continue stirring, then add a silane coupling agent, stir, and dry to obtain amino-functionalized silica aerogel, namely NH2-PSI; Step 2, drug loading: Weigh the model drug and ultrasonically dissolve it in absolute ethanol, add the carrier NH2-PSI, ultrasonically dissolve, stir for drug loading, centrifuge, and dry to obtain NH2-PSI loaded with the model drug; Step 3, CMCS blocking: Weigh carboxymethyl chitosan, add EDC and NHS and stir to dissolve in water to obtain a CMCS solution. Ultrasonically dissolve the NH2-PSI loaded with the model drug in absolute ethanol, add the CMCS solution, stir, centrifuge, and dry to obtain an aerogel nano-drug delivery system loaded with the model drug.

2. The preparation method of the functionalized aerogel nano drug delivery system according to claim 1, characterized in that, By mass fraction, the dosage of glycerol is 10-15% of silica aerogel, the dosage of the silane coupling agent is 4.5-5.5% of silica aerogel, and the dosage of carboxymethyl chitosan is 15-25% of silica aerogel.

3. The preparation method of the functionalized aerogel nano drug delivery system according to claim 1, wherein The solvent A is a mixed solution composed of absolute ethanol and water, and the volume ratio of absolute ethanol to water is 1-3:1; the silane coupling agent is 3-aminopropyltriethoxysilane.

4. The preparation method of the functionalized aerogel nano drug delivery system according to claim 1, characterized in that, The mass ratio of carboxymethyl chitosan, EDC and NHS is 1-4:0.5-2:0.5-2.

5. The preparation method of the functionalized aerogel nano drug delivery system according to claim 1, wherein The model drug is a BCS class II drug, and the model drug is at least one of resveratrol and indomethacin; the drug concentration of the model drug is 40-50 mg / mL, and the mass ratio of the drug to the carrier is 5-9:

1.

6. The preparation method of the functionalized aerogel nano drug delivery system according to claim 1, wherein, The temperature for carrier preparation in Step 1 is 20-25 °C; the drug loading temperature in Step 2 is 20-30 °C, and the drug loading time is 24-36 h.

7. The preparation method of the functionalized aerogel nano-drug delivery system according to claim 1, characterized in that, The drying method is freeze-drying; the stirring is medium-speed stirring, and the stirring speed is 300-500 r / min.

8. A functionalized aerogel nano-drug delivery system, characterized in that, Prepared according to the method described in any one of claims 1-7.

9. The quality evaluation method of the functionalized aerogel nano-drug delivery system according to claim 8, characterized in that, It includes at least one of scanning electron microscope analysis, transmission electron microscope analysis, infrared spectroscopy analysis, N2 adsorption-desorption analysis, X-ray diffraction analysis, thermogravimetric analysis, in vitro drug release determination of the drug, gastrointestinal stability determination, and pharmacokinetic analysis.

10. Application of the functionalized aerogel nano-drug delivery system according to claim 8 in improving drug solubility, targeting property and bioavailability.

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