Cyclodextrin-polyvinyl alcohol mechanical interlocking aerogel, preparation method and application of cyclodextrin-polyvinyl alcohol mechanical interlocking aerogel in controlled release of alkaloid

Abstract

The invention discloses cyclodextrin-polyvinyl alcohol mechanically-interlocked aerogel, a preparation method and application of the cyclodextrin-polyvinyl alcohol mechanically-interlocked aerogel in controlled release of alkaloid, and the preparation method comprises the following steps: adding a cross-linking agent solution and alkaloid into a solution containing polyvinyl alcohol and cyclodextrin under heating to obtain a reaction solution; stirring the reaction liquid under heating, and standing to form hydrogel; according to the preparation method disclosed by the invention, through the host-guest inclusion effect of cyclodextrin and the physical barrier of hierarchical pores of aerogel, the release time of alkaloid is greatly prolonged, meanwhile, the problem of poor stability of a material in the prior art is solved, and the whole components are non-toxic and environment-friendly. According to the invention, the pore distribution and specific surface area of the aerogel are optimized by regulating the interaction of cyclodextrin and polyvinyl alcohol, and effective controlled release of alkaloid is realized by combining the host-guest inclusion effect of cyclodextrin and the physical barrier of hierarchical pores of aerogel.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of aerogel materials, and particularly relates to a cyclodextrin-polyvinyl alcohol mechanically interlocked aerogel and a preparation method thereof and application thereof in alkaloid controlled release. BACKGROUND

[0002] Alkaloids are a class of nitrogen-containing organic compounds widely existing in nature, and have important applications in the fields of medicine and tobacco due to their significant physiological activity. How to accurately control the release rate of alkaloids and improve their bioavailability and action duration is one of the core challenges in the current technical field. Taking a mouth- containing tobacco product as an example, the core is to replace the traditional smoking behavior, and to make nicotine slowly dissolve and be absorbed in the oral environment through a carrier. However, the currently marketed products mostly use cellulose or other organic polymers as the nicotine carrier, and generally have problems such as fast release, short duration (about 0.5-1 hour to reach a 90% release rate), and easy dissolution of the substrate in a humid environment (such as the oral cavity).

[0003] To solve the above problems, one approach is to use the high porosity and large specific surface area of aerogels as a physical barrier to achieve slow release. However, traditional aerogels mostly use inorganic materials such as silicon dioxide as the skeleton, which has the defects of insufficient biocompatibility and difficulty in degradation, limiting its application in the biomedical field. Under this background, organic aerogels have become a more potential matrix material than traditional inorganic aerogels due to their excellent biocompatibility, degradability, and easy functionalization and regulation.

[0004] Another approach is to use host-guest chemistry. By incorporating cyclodextrin into the polymer matrix, the host-guest inclusion effect can be used to fix alkaloid molecules, thereby improving the release stability. However, simple physical blending or non-covalent fixation methods can cause free cyclodextrin to easily dissolve out of the matrix in a humid environment.

[0005] Some studies have attempted to use high molecular chains to pass through the cyclodextrin cavity to form a quasi-polyrotaxane structure in the form of a string of beads, thereby regulating the microstructure of the gel network. However, this strategy has two shortcomings: first, the cyclodextrin cavity occupied by the high molecular chain loses the core function of including alkaloids; second, for linear polymers lacking reactive groups (such as polyethylene glycol), cyclodextrin cannot be blocked on the chain through chemical crosslinking, and cyclodextrin will still slip off from the chain end. Therefore, this simple threading strategy cannot achieve effective functionalization and cannot form a truly stable and non-dissociable mechanically interlocked structure. SUMMARY

[0006] The present application aims to solve the problem of too fast release of existing alkaloid controlled release materials, and provides a cyclodextrin-polyvinyl alcohol mechanically interlocked aerogel with simple preparation method, environmental friendliness and precise control of alkaloid release, and a preparation method and application thereof in alkaloid controlled release.

[0007] To achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows:

[0008] A cyclodextrin-polyvinyl alcohol mechanically interlocked aerogel preparation method, comprising the following steps:

[0009] Under heating, a crosslinking agent solution and an alkaloid are added to a solution containing polyvinyl alcohol and cyclodextrin to obtain a reaction solution;

[0010] After stirring the reaction solution under heating, it is left to stand to form a hydrogel;

[0011] The hydrogel is dried to obtain a cyclodextrin-polyvinyl alcohol mechanically interlocked aerogel.

[0012] Further, the mass concentration of polyvinyl alcohol in the reaction solution is 5-20wt%.

[0013] Further, the mass of cyclodextrin is 10-30% of the mass of polyvinyl alcohol.

[0014] Further, the crosslinking agent is sodium citrate.

[0015] Further, the mass concentration of the crosslinking agent in the reaction solution is 5-20wt%.

[0016] Further, the alkaloid is nicotine bitartrate dihydrate, arecoline or berberine hydrochloride.

[0017] Further, the heating temperature is 70-100℃; and the drying is vacuum freeze drying.

[0018] A cyclodextrin-polyvinyl alcohol mechanically interlocked aerogel.

[0019] Application of a cyclodextrin-polyvinyl alcohol mechanically interlocked aerogel in alkaloid controlled release.

[0020] Compared with the prior art, the present application has the following beneficial effects:

[0021] 1. Mechanical interlocking structure regulated multi-level pore: The organic aerogel prepared by the present application uses organic materials with good biocompatibility and degradability as raw materials. The core innovation is that the present application actively utilizes and accurately regulates the mechanical interlocking structure formed between polyvinyl alcohol and cyclodextrin. This stable interlocking structure not only fundamentally avoids the slippage and loss of cyclodextrin, improving the overall structural stability of the material, but more importantly, it effectively regulates the formation process of the gel network, thereby obtaining a physical structure with ideal multi-level pore distribution.

[0022] 2. Dual-function synergistic controlled release of cyclodextrin: The present application ingeniously divides the role of cyclodextrin into two parts. The mechanical interlocking cyclodextrin as a structure regulating unit is responsible for building an efficient physical slow-release channel, while the covalently crosslinked cyclodextrin as a functional active site provides stable and persistent chemical binding force to load alkaloid molecules. The synergistic effect of physical barrier and chemical anchor greatly prolongs the release time of alkaloids (about 4-5 hours to reach 90% release rate) and improves the stability and predictability of the release process, solving the problem of poor controlled release effect caused by simply relying on physical channels or the dissolution of cyclodextrin from the matrix in the prior art.

[0023] 3. Application potential and preparation process: The raw materials used in the present application are all organic materials with excellent biocompatibility and degradability. The organic aerogel prepared has wide application prospects in the field of alkaloid controlled release, and is suitable as a nicotine controlled release carrier for oral tobacco products, and can also be expanded to other drug slow-release delivery systems. By introducing the mechanical interlocking structure during the gel formation stage, there is no need to rely on time-consuming and complex pretreatment steps such as repeated freeze-thaw cycles. The aerogel with excellent porous structure can be directly obtained by one-step freeze-drying, simplifying the preparation process. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1 is the morphology diagram of the aerogel of Example 1;

[0025] Figure 2 is the mechanism diagram of the aerogel;

[0026] Figure 3 is the time-absorbance diagram of the hydrogel of Comparative Examples 1-8;

[0027] Figure 4 is the infrared spectrum diagram of the aerogel of Comparative Examples 9-15;

[0028] Figure 5 is the SEM diagram of the aerogel of Comparative Example 12 and Comparative Example 15; wherein (a) is the SEM diagram of the aerogel of Comparative Example 12, (b) is a local enlarged view of Figure (a), (c) is the SEM diagram of the aerogel of Comparative Example 15, and (d) is a local enlarged view of Figure (c);

[0029] Figure 6 BJH pore size distribution of the aerogel of Comparative Example 14;

[0030] Figure 7 Pure water contact angle test images of the aerogels of Comparative Example 9, Comparative Example 14 and Comparative Example 15; wherein (a) is the image of Comparative Example 9 at the moment of droplet contact, (b) is the image of Comparative Example 9 after the droplet has been in contact for 30 s, (c) is the image of Comparative Example 14 at the moment of droplet contact, (d) is the image of Comparative Example 14 after the droplet has been in contact for 30 s, (e) is the image of Comparative Example 15 at the moment of droplet contact, (f) is the image of Comparative Example 15 after the droplet has been in contact for 30 s;

[0031] Figure 8 Nicotine time-release rate curves of the performance tests of Example 1 and a commercially available oral tobacco product;

[0032] Figure 9 D2O solution of β-CD and PVA 1 H- 1 H NOESY spectrum. DETAILED DESCRIPTION

[0033] In order to facilitate the understanding of the present application, the present application will be described in more detail below with reference to the relevant drawings. The preferred embodiments of the present application are shown in the drawings. However, the present application can be realized in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present application more thorough and comprehensive.

[0034] In view of the limitations of the prior art, a brand new design idea is still needed in the art, which divides the role of cyclodextrin in the organic polymer network into two parts and utilizes them synergistically. On the one hand, by forming a stable and non-dissociable mechanical interlocking structure, part of the cyclodextrin is fixed on the polymer chain. In this state, although the cavity of the cyclodextrin is occupied, it can effectively regulate the micro-arrangement of the gel network, thereby inducing the formation of an ideal multi-level pore physical structure. On the other hand, another part of the cyclodextrin is covalently cross-linked to the backbone of polyvinyl alcohol through the active hydroxyl group on its surface by using a cross-linking agent. The fixed cyclodextrin does not fall off, and its cavity remains open, which can be used as a stable active functional site for efficient inclusion of alkaloids to achieve long-acting sustained release at the chemical level.

[0035] Therefore, the present application provides an organic aerogel that can synergistically utilize the above-mentioned dual roles of cyclodextrin, and has excellent biocompatibility, complex porous structure and stable active functional site, which is of great significance for the development of an efficient, stable and biocompatible alkaloid controlled-release carrier.

[0036] The aerogel of the present application takes biocompatible materials polyvinyl alcohol and cyclodextrin as the matrix, and obtains mechanical interlocking structure after chemical crosslinking by crosslinking agent, and obtains the aerogel by using the freeze-drying process. Experiments show that the aerogel can realize sustained and stable release of alkaloids in a simulated physiological environment, for example, the release time of nicotine is more than 6 times longer than that of traditional oral tobacco products. The present application applies organic aerogel to the alkaloid sustained-release carrier, and greatly prolongs the release time of alkaloids through the host-guest inclusion of cyclodextrin and the physical barrier of the multi-level pores of the aerogel, while solving the problem of poor material stability in the prior art, and the whole composition is non-toxic and environmentally friendly. The present application optimizes the pore distribution and specific surface area of the aerogel by regulating the interaction between cyclodextrin and polyvinyl alcohol, and realizes effective controlled release of alkaloids by combining the host-guest inclusion of cyclodextrin and the physical barrier of the multi-level pores of the aerogel.

[0037] The present application provides a preparation method of cyclodextrin-polyvinyl alcohol mechanically interlocked aerogel, which is characterized in that cyclodextrin is introduced into a polyvinyl alcohol solution, the cyclodextrin is penetrated by the polyvinyl alcohol molecules, and a polymer network with mechanical interlocking structure is formed after crosslinking by a crosslinking agent, so as to regulate and optimize the microstructure of the polyvinyl alcohol aerogel. At the same time, the controlled release of alkaloids is realized by the host-guest inclusion ability of cyclodextrin and the physical barrier effect of the unique multi-level pores of the aerogel. The present method only needs one step of freeze-drying to form the aerogel, which significantly simplifies the preparation process.

[0038] The preparation method of the cyclodextrin-polyvinyl alcohol mechanically interlocked aerogel of the present application comprises the following steps:

[0039] 1) Dissolve polyvinyl alcohol and cyclodextrin (β-CD) in ultrapure water, and stir at a stirring speed of 200-1000 rpm in a water bath at 70-100℃ for 0.5-3 hours to form a PVA-β-CD solution.

[0040] 2) At 70-100℃, add a crosslinking agent solution (for example, a sodium citrate solution) and alkaloids (for example, nicotine tartrate dihydrate, arecoline or berberine hydrochloride) to the PVA-β-CD solution to obtain a reaction solution;

[0041] In the reaction solution, the concentration of polyvinyl alcohol is 5-20wt%, the mass of cyclodextrin is 10-30% of the mass of polyvinyl alcohol, the concentration of the crosslinking agent is 5-20wt%, and the addition amount of the alkaloids is 1-10% of the mass of polyvinyl alcohol.

[0042] 3) After continuing to stir the reaction solution at a stirring speed of 200-1000 rpm for 0.5-3 hours, stand at room temperature of 10-30℃ for 12-72 hours, and wash with ultrapure water for 1-7 times to remove unreacted substances, a hydrogel is formed.

[0043] 4) Freeze-dry the hydrogel at -50℃ to -80℃, 5 to 20 Pa for 24 to 72 hours to obtain the cyclodextrin-polyvinyl alcohol mechanically interlocked aerogel.

[0044] The cyclodextrin-polyvinyl alcohol mechanically interlocked aerogel is crosslinked by polyvinyl alcohol and cyclodextrin through a crosslinking agent to form a complex polymer network with host-guest binding sites and mechanical interlocking structure, and load alkaloids. The aerogel has a multi-level pore structure and is used as an alkaloid controlled-release carrier, for example, for a smokeless tobacco product, to release alkaloids slowly.

[0045] The following is a specific example.

[0046] Example 1

[0047] 1) Dissolve 1 g of polyvinyl alcohol (PVA) and 0.2 g of β-cyclodextrin (β-CD) in 2.5 mL of ultrapure water, stir at 95℃, 600 rpm for 2 hours to obtain a PVA-β-CD solution.

[0048] 2) Add sodium citrate and nicotine tartrate dihydrate to water to obtain a sodium citrate-nicotine tartrate dihydrate mixed solution;

[0049] Stir the PVA-β-CD solution at 95℃, 600 rpm, and uniformly add 2.5 mL of the sodium citrate-nicotine tartrate dihydrate mixed solution in about 1 minute, continue to stir at 95℃, 600 rpm for 2 hours to obtain a reaction solution. The concentration of sodium citrate in the reaction solution is 9.2 wt%, and the mass of nicotine tartrate dihydrate is 2.5% of the mass of polyvinyl alcohol.

[0050] 3) Let the reaction solution stand at room temperature for 24 hours, and wash it with ultrapure water 3 times to obtain a hydrogel.

[0051] 4) Freeze-dry the hydrogel at -60℃, 10 Pa for 48 hours to obtain a nicotine-containing aerogel, i.e. a cyclodextrin-polyvinyl alcohol mechanically interlocked aerogel.

[0052] 6) Divide the nicotine-containing aerogel into blocks with the same mass as commercially available products (smokeless tobacco products (VELO Beauty Edition - Purple Grape - 10 mg, recorded as VE)) and place them in 9 cm petri dishes lined with 4 mL of ultrapure water moistened 9 cm filter paper, wait for 0 to 512 minutes, and sample at the preset time points.

[0053] 7) Move the aerogel block taken out each time to a new 15 mL of ultrapure water, while supplementing 16 mL of ultrapure water to the original petri dish, and stand for 24 hours to ensure complete release.

[0054] 8) The UV absorbance of the dissolution liquid and the petri dish liquid was detected at 260 nm using a UV-Vis spectrometer, and the nicotine concentration was measured according to a standard curve. The residual nicotine mass of the aerogel and the nicotine release mass of the aerogel were calculated respectively, so as to calculate the cumulative release rate of nicotine of the aerogel in the simulated oral environment.

[0055] The cyclodextrin-polyvinyl alcohol mechanically interlocked aerogel in Example 1 was verified by in vitro release experiment, which was divided into blocks and placed in a simulated oral environment. The results showed that the release time of 90% release rate of alkaloids (such as nicotine) could reach 4-5 hours, which was more than 6 times longer than traditional carriers (such as commercially available oral smoke products), showing excellent sustained-release performance.

[0056] Example 2

[0057] Different from Example 1, the used alkaloid was arecoline.

[0058] Example 3

[0059] Different from Example 1, the used alkaloid was berberine hydrochloride.

[0060] Example 4

[0061] 1) 0.3 g of PVA and 0.03 g of β-CD were dissolved in 2.5 mL of ultrapure water, and stirred at 70°C and 1000 rpm for 3 hours to obtain a PVA-β-CD solution.

[0062] 2) The PVA-β-CD solution was stirred at 70°C and 1000 rpm, and the sodium citrate solution and berberine hydrochloride were added at a uniform speed within about 1 minute. The reaction liquid was obtained by continuing to stir at 70°C and 1000 rpm for 3 hours.

[0063] In the reaction liquid, the PVA concentration was 5wt%, the mass of β-CD was 10% of the mass of PVA, the sodium citrate concentration was 5wt%, and the mass of berberine hydrochloride was 1% of the mass of PVA.

[0064] 3) The reaction liquid was placed at room temperature of 10°C for 72 hours, and washed once with ultrapure water to obtain a hydrogel.

[0065] 4) The hydrogel was freeze-dried at -80°C and 5 Pa for 24 hours to obtain an aerogel containing berberine hydrochloride, i.e. a cyclodextrin-polyvinyl alcohol mechanically interlocked aerogel.

[0066] Example 5

[0067] 1) 0.7 g of PVA and 0.1 g of β-CD were dissolved in 2.5 mL of ultrapure water, and stirred at 80°C and 800 rpm for 1.5 hours to obtain a PVA-β-CD solution.

[0068] 2) The PVA-β-CD solution was stirred at 80°C and 800 rpm, and the sodium citrate solution and berberine hydrochloride were added at a uniform speed within about 1 minute. The stirring was continued at 80°C and 800 rpm for 1.5 hours to obtain a reaction solution.

[0069] In the reaction solution, the PVA concentration was 11wt%, the mass of β-CD was 14.3% of the mass of PVA, the sodium citrate concentration was 8wt%, and the mass of berberine hydrochloride was 3% of the mass of PVA.

[0070] 3) The reaction solution was placed at room temperature for 60 hours, and was washed with ultrapure water for 2 times to obtain a hydrogel.

[0071] 4) The hydrogel was freeze-dried at -70°C and 10 Pa for 24 hours to obtain an aerogel containing berberine hydrochloride, i.e., a cyclodextrin-polyvinyl alcohol mechanically interlocked aerogel.

[0072] Example 6

[0073] 1) 2g of polyvinyl alcohol (PVA) and 0.6g of β-cyclodextrin (β-CD) were dissolved in 2.5mL of ultrapure water, and were stirred at 100°C and 200 rpm for 0.5 hours to obtain a PVA-β-CD solution.

[0074] 2) The PVA-β-CD solution was stirred at 100°C and 200 rpm, and the sodium citrate solution and arecoline were added at a uniform speed within about 1 minute. The stirring was continued at 100°C and 200 rpm for 0.5 hours to obtain a reaction solution.

[0075] In the reaction solution, the PVA concentration was 20wt%, the mass of β-CD was 30% of the mass of PVA, the sodium citrate concentration was 20wt%, and the mass of arecoline was 10% of the mass of polyvinyl alcohol.

[0076] 3) The reaction solution was placed at room temperature for 12 hours, and was washed with ultrapure water for 7 times to obtain a hydrogel.

[0077] 4) The hydrogel was freeze-dried at -50°C and 20 Pa for 72 hours to obtain an aerogel containing arecoline, i.e., a cyclodextrin-polyvinyl alcohol mechanically interlocked aerogel.

[0078] Example 7

[0079] 1) 1.3g of polyvinyl alcohol (PVA) and 0.25g of β-cyclodextrin (β-CD) were dissolved in 2.5mL of ultrapure water, and were stirred at 90°C and 300 rpm for 1 hour to obtain a PVA-β-CD solution.

[0080] 2) The PVA-β-CD solution was stirred at 90°C and 300 rpm, and the sodium citrate solution and arecoline were added at a uniform speed within about 1 minute, and then the stirring was continued at 90°C and 300 rpm for 1 hour to obtain a reaction solution.

[0081] In the reaction solution, the PVA concentration was 15wt%, the mass of β-CD was 19.2% of the mass of PVA, the sodium citrate concentration was 10wt%, and the mass of arecoline was 8% of the mass of polyvinyl alcohol.

[0082] 3) The reaction solution was placed at room temperature for 36 hours, and then washed with ultrapure water for 5 times to obtain a hydrogel.

[0083] 4) The hydrogel was freeze-dried at -55°C and 15 Pa for 60 hours to obtain an aerogel containing arecoline, i.e., a cyclodextrin-polyvinyl alcohol mechanically interlocked aerogel.

[0084] Comparative Example 1

[0085] 1) 1 g of PVA and 0 g of β-CD were dissolved in ultrapure water, and then stirred at 80°C and 500 rpm for 2 hours to obtain a PVA mixed solution.

[0086] 2) A sodium citrate solution with a concentration of 0.2 g / mL was prepared.

[0087] 3) The PVA mixed solution was stirred at 80°C and 500 rpm, and an equal volume of the sodium citrate solution was added at a uniform speed within about 1 minute. After the stirring was continued at 80°C and 500 rpm for 2 hours, a hydrogel was obtained.

[0088] 4) The hydrogel was placed in a sample bottle, and the ultraviolet-visible absorbance of the hydrogel at 433 nm was measured at intervals to quantify the progress of the cross-linking reaction, and a gel was obtained, which was recorded as β-CD-0.

[0089] Comparative Example 2

[0090] 1) 1 g of PVA and 1 g of fructose were dissolved in ultrapure water, and then stirred at 80°C and 500 rpm for 2 hours to obtain a PVA solution.

[0091] 2) A sodium citrate solution with a concentration of 0.2 g / mL was prepared.

[0092] 3) The PVA mixed solution was stirred at 80°C and 500 rpm, and an equal volume of the sodium citrate solution was added at a uniform speed within about 1 minute. After the stirring was continued at 80°C and 500 rpm for 2 hours, a hydrogel was obtained.

[0093] 4) The hydrogel was placed in a sample bottle, and the ultraviolet-visible absorbance of the hydrogel at 433 nm was measured at intervals to quantify the progress of the cross-linking reaction, and a gel was obtained, which was recorded as fructose-1.

[0094] Comparative Example 3

[0095] 1) Dissolve 1 g of PVA and 1 g of soluble starch in equal amount of ultrapure water, 80 °C, 500 rpm stirring for 2 hours, to obtain PVA solution.

[0096] 2) Prepare a sodium citrate solution with a concentration of 0.2 g / mL.

[0097] 3) Stir the PVA mixed solution at 80 °C, 500 rpm, and add an equal volume of sodium citrate solution at a uniform speed within about 1 minute. Continue to stir at 80 °C, 500 rpm for 2 hours to obtain a hydrogel.

[0098] 4) The hydrogel is placed in a sample bottle, and the ultraviolet-visible absorbance of the hydrogel at 433 nm is measured at regular intervals to quantify the progress of the crosslinking reaction, and a gel is obtained, which is designated as starch-1.

[0099] Comparative Example 4

[0100] The difference from Comparative Example 1 is that the mass of β-CD is 0.2 g, and a gel is obtained, which is designated as β-CD-0.2.

[0101] Comparative Example 5

[0102] The difference from Comparative Example 1 is that the mass of β-CD is 0.4 g, and a gel is obtained, which is designated as β-CD-0.4.

[0103] Comparative Example 6

[0104] The difference from Comparative Example 1 is that the mass of β-CD is 0.6 g, and a gel is obtained, which is designated as β-CD-0.6.

[0105] Comparative Example 7

[0106] The difference from Comparative Example 1 is that the mass of β-CD is 0.8 g, and a gel is obtained, which is designated as β-CD-0.8.

[0107] Comparative Example 8

[0108] The difference from Comparative Example 1 is that the mass of β-CD is 1 g, and a gel is obtained, which is designated as β-CD-1.

[0109] Comparative Example 9

[0110] 1) Dissolve PVA and 0 g of β-CD (designated as β-CD-0) in ultrapure water, 80 °C, 500 rpm stirring for 2 hours, to obtain PVA-β-CD solution.

[0111] 2) Prepare a sodium citrate solution with a concentration of 0.2 g / mL.

[0112] 3) The PVA-β-CD solution was stirred at 80 °C, 500 rpm, and an equal volume of sodium citrate solution was added at a uniform rate within about 1 minute. Stirring was continued at 80 °C, 500 rpm, for 2 hours.

[0113] 4) After stirring was completed, the hydrogel was obtained by standing at room temperature for 24 hours, and washed 4 times with ultrapure water.

[0114] 5) The hydrogel was freeze-dried at -60 °C, 10 Pa, for 48 hours to obtain an aerogel, which was recorded as NaOH-0.

[0115] Comparative Example 10

[0116] 1) 1 g of PVA was dissolved in ultrapure water, stirred at 80 °C, 500 rpm, for 2 hours to obtain a PVA solution.

[0117] 2) A citric acid (CA) solution with a concentration of 0.2 g / mL was prepared.

[0118] 3) The PVA-β-CD solution was stirred at 80 °C, 500 rpm, and an equal volume of CA solution was added at a uniform rate within about 1 minute. Stirring was continued at 80 °C, 500 rpm, for 2 hours.

[0119] 4) After stirring was completed, the hydrogel was obtained by standing at room temperature for 24 hours, and washed 4 times with ultrapure water.

[0120] 5) The hydrogel was freeze-dried at -60 °C, 10 Pa, for 48 hours to obtain an aerogel, which was recorded as CA-0.

[0121] Comparative Example 11

[0122] 1) PVA was dissolved in ultrapure water, stirred at 80 °C, 500 rpm, for 2 hours to obtain a PVA solution.

[0123] 2) A NaOH solution with a concentration of 0.2 g / mL was prepared.

[0124] 3) The PVA-β-CD solution was stirred at 80 °C, 500 rpm, and an equal volume of NaOH solution was added at a uniform rate within about 1 minute. Stirring was continued at 80 °C, 500 rpm, for 2 hours.

[0125] 4) After stirring was completed, the hydrogel was obtained by standing at room temperature for 24 hours, and washed 4 times with ultrapure water.

[0126] 5) The hydrogel was freeze-dried at -60 °C, 10 Pa, for 48 hours to obtain an aerogel, which was recorded as CA-0.

[0127] Comparative Example 12

[0128] The difference between Comparative Example 9 and Example 1 is that the mass of β-CD is 0.1 g, and an aerogel is obtained, which is denoted as β-CD-0.1.

[0129] Comparative Example 13

[0130] The difference between Comparative Example 9 and Example 1 is that the mass of β-CD is 0.2 g, and an aerogel is obtained, which is denoted as β-CD-0.2.

[0131] Comparative Example 14

[0132] The difference between Comparative Example 9 and Example 1 is that the mass of β-CD is 0.3 g, and an aerogel is obtained, which is denoted as β-CD-0.3.

[0133] Comparative Example 15

[0134] The difference between Comparative Example 9 and Example 1 is that the mass of β-CD is 0.4 g, and an aerogel is obtained, which is denoted as β-CD-0.4.

[0135] Performance test:

[0136] 1) Place a 9 cm filter paper in a 9 cm petri dish, and wet it with 4 mL of ultrapure water to simulate an oral environment.

[0137] 2) Place a commercially available oral tobacco product (VELO Beauty Edition- purple grape- 10 mg, denoted as VE; SUPEROUSE-grape-10 mg, denoted as SP) on the filter paper, and take it out after a certain period of time.

[0138] 3) Move the product taken out to a new 15 mL ultrapure water, and supplement 16 mL of ultrapure water to the original petri dish, and stand for 24 hours to ensure complete release.

[0139] 4) Use an ultraviolet-visible spectrometer to detect the ultraviolet absorbance of the dissolution liquid and the petri dish liquid at 260 nm, and measure the nicotine concentration according to the standard curve. Calculate the residual nicotine mass of the product and the nicotine mass released by the product, respectively, so as to calculate the cumulative release rate of nicotine of the product in the simulated oral environment.

[0140] Figure 1 The morphology of the aerogel sample prepared in Example 1 is shown, and it can be seen that the prepared aerogel is a white light-weight block-shaped solid.

[0141] Figure 2 The schematic diagram of the mechanism of the mechanical interlocking structure of the aerogel and the host-guest binding site, part of the β-CD is worn on the PVA, and after being capped by the CA, a mechanical interlocking structure is formed, so that it cannot fall off, and plays a role in regulating the microstructure of the aerogel; Another part of the β-CD is crosslinked with the PVA through the crosslinking agent CA, and the cavity structure as the host-guest binding site is reserved, which can be used as an active site for loading alkaloid molecules.

[0142] Figure 3 The time-absorbance graph of the hydrogel of Comparative Example 1-Comparative Example 8. The results show that the crosslinking reaction rate of the hydrogel gradually decreases with the addition of β-CD. As can be seen from the graph, the amount of β-CD added should be less than 40% of the mass of PVA, otherwise the crosslinking reaction will be significantly inhibited. Fructose and soluble starch as controls do not have as strong a crosslinking reaction inhibition effect as β-CD. This phenomenon is attributed to the fact that β-CD is threaded on the PVA molecular chain, thereby shielding part of the hydroxyl sites on the PVA molecular chain, hindering the esterification crosslinking reaction of CA with the hydroxyl groups on PVA. At the same time, due to the presence of intramolecular hydrogen bonds in β-CD, the hydroxyl groups have weak reactivity, and the crosslinking reaction rate of β-CD with CA is significantly lower than that of PVA with CA. Therefore, with the addition of β-CD, the crosslinking reaction rate of the hydrogel gradually decreases.

[0143] Figure 4 The infrared spectrum of the aerogel of Comparative Example 9-Comparative Example 15. The infrared spectrum results show that β-CD can inhibit the crosslinking of CA and PVA. At the same time, β-CD is threaded through the PVA molecular chain, thereby inhibiting the skeleton vibration of PVA. Among them, the characteristic peaks of β-CD-0.4 are significantly weakened, and the gel skeleton strength is greatly weakened. Therefore, the amount of β-CD added should be less than 40% of the mass of PVA.

[0144] Figure 5 Figures (a)-(d) are SEM images of the aerogel of Comparative Example 12 and Comparative Example 15. For the β-CD-0.1 aerogel, the surface presents a hierarchical pore structure, including macroscopic pores of 1-5 μm and mesopores of about 50 nm, indicating that the introduction of an appropriate amount of β-CD can effectively regulate the formation of pores. Therefore, the amount of β-CD added should be greater than or equal to 10% of the mass of PVA. For the β-CD-0.4 aerogel, the surface has no large pore structure, and a large number of rod-like clusters can be seen. This is mainly due to the fact that an excessive amount of β-CD inhibits the crosslinking reaction, causing the uncompletely crosslinked gel network to collapse during the freeze-drying process. Therefore, the amount of β-CD added should be less than 40% of the mass of PVA.

[0145] Figure 6 The BJH pore size distribution graph of the aerogel of Comparative Example 14. It can be seen that the sample has a large number of 72-144 nm macropores, part of the 4 nm mesopores, and part of the 1.8-1.9 nm micropores. It can be seen that the aerogel with 30% of the mass of PVA added has a complex hierarchical pore structure, which will be beneficial to the slow release of alkaloids. At the same time, for the three aerogel samples of β-CD-0, β-CD-0.3, and β-CD-0.4, their BET specific surface areas are 1.9331, 32.2663, and 2.0131 m 2g, which indicates that the introduction of an appropriate amount of β-CD can increase the specific surface area of the aerogel, so it is necessary to add β-CD to the aerogel to increase the specific surface area of the aerogel, and an excessive amount of β-CD can cause the network structure of the aerogel to be insufficient in strength and collapse during freeze-drying, greatly reducing the specific surface area of the aerogel, therefore, the amount of β-CD added should be less than 40% of the mass of PVA.

[0146] Figure 7 Figures (a)-(f) are pure water contact angle test images of the three aerogel samples β-CD-0, β-CD-0.3, and β-CD-0.4 prepared in Comparative Example 9, Comparative Example 14, and Comparative Example 15, in which the left side is an image at the moment of contact of the liquid drop, and the right side is an image after the liquid drop has been in contact for 30 s. The static contact angle of the β-CD-0.3 aerogel is the largest, and is significantly improved compared to β-CD-0 and β-CD-0.4, which is attributed to the rough surface of the hierarchical porous structure thereof, and the increased hydrophobicity thereof can slow down the diffusion of water, thereby slowing down the release process of the alkaloid, so the aerogel with 30% of the mass of PVA of β-CD is superior to the aerogels without β-CD and with 40% of the mass of PVA of β-CD in terms of hydrophobicity. The dynamic wetting behavior shows that the liquid drop on the surface of the β-CD-0.3 and β-CD-0.4 aerogels collapses within 30 s, while the liquid drop on the surface of the β-CD-0 aerogel remains stable and basically does not undergo a water diffusion process, which will make the alkaloid unable to be effectively dissolved and released. This is because the introduction of β-CD increases the intermolecular distance of PVA by forming mechanical interlocking molecules with PVA, forming pores, and allowing water molecules to quickly penetrate by capillary action. Although the β-CD-0.4 aerogel has a low specific surface area due to the collapse of the pores caused by insufficient crosslinking, the loose skeleton thereof is still superior to the compact structure of the β-CD-0 aerogel, allowing water diffusion.

[0147] Figure 8 Figure 1 is a nicotine time-release rate curve of the aerogel prepared in Example 1 and a commercially available oral tobacco product. In order to quantitatively compare the release behavior, the release curve is fitted using a first-order kinetic equation:

[0148]

[0149] In the formula, t is the release time (min); x is the cumulative release rate at time t (%); x0 is the equilibrium release rate, i.e., the maximum percentage of the total load that can be released theoretically when the time tends to infinity, which reflects the maximum release capacity of the carrier; τ is the release time constant (min), which is the core parameter characterizing the release rate, and the larger the value, the slower and more persistent the release process is; R 2 R is the correlation coefficient, and the closer the value is to 1, the more stable the release process is, and the more consistent the release process is with the kinetic model.

[0150] The time constant τ (121.95 min) of the aerogel of the present application is significantly higher than that of the commercial products VE (17.13 min) and SP (24.96 min), which clearly indicates that the aerogel of the present application has the most durable sustained-release effect, and can extend the effective release time of nicotine by about 5 to 7 times. In addition, the fitting correlation coefficient R 2 (0.980) of the aerogel of the present application is higher than that of the commercial products VE (0.957) and SP (0.942), indicating that the release process of the aerogel of the present application is more stable and predictable. In addition, the equilibrium release rate x0 (0.5577) of the aerogel of the present application is at the same level as that of the commercial products VE (0.4516) and SP (0.6442), indicating that the aerogel of the present application does not sacrifice its effective drug loading and release capacity while greatly extending the release time.

[0151] Figure 9 The D2O solution of β-CD and PVA 1 H- 1 H NOESY spectrum, it can be seen that there is a cross peak between PVA and β-CD, further proving that β-CD is penetrated by PVA molecules.

[0152] From the above results, it can be seen that in the prepared aerogel, β-CD should be added to increase the specific surface area and hydrophobic property of the aerogel, and β-CD should not be added more than 40% of the mass of PVA to avoid the collapse of the aerogel structure, therefore, in Example 1, the amount of β-CD added is 20% of the mass of PVA.

[0153] This excellent controlled release performance is mainly due to two synergies: on the one hand, the cavity structure of cyclodextrin can effectively fix alkaloid molecules (such as nicotine) through host-guest inclusion, delaying their diffusion; on the other hand, the unique multi-level pore structure of the aerogel provides a physical barrier, further reducing the release rate of alkaloids.

[0154] Organic aerogels, especially aerogels based on biocompatible polyvinyl alcohol, provide a new way for drug controlled release. However, the existing preparation methods of polyvinyl alcohol aerogels, such as repeated freeze-thaw cycles to construct porous structures, have complex process flow and long time-consuming, increasing the difficulty of industrial production. The preparation method of the aerogel of the present application only needs one step of freeze-drying, which has the advantages of short time and easy industrial production.

[0155] The aerogel prepared by the present application has specific binding sites for alkaloid molecules, stable and controllable multi-level pore physical structure, excellent biocompatibility and material stability, and the preparation method is simple, environmentally friendly and low cost. The aerogel prepared by the present application can combine host-guest interaction with the physical barrier of the aerogel, thereby achieving long-acting, stable and precise controlled release of alkaloids.

[0156] The above description only illustrates the best mode of the present application and cannot be understood as a limitation to the claims. The present application is not limited to the above embodiments and the specific construction allows variations. Any variations made within the scope of the independent claims are within the scope of the present application.

[0157] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in the description of the application herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

Claims

1. A method of preparing a cyclodextrin-polyvinyl alcohol mechanically interlocked aerogel, characterized by, The method comprises the following steps: adding a crosslinking agent solution and an alkaloid into a solution containing polyvinyl alcohol and cyclodextrin under heating to obtain a reaction solution; stirring the reaction solution under heating and then standing to form a hydrogel; drying the hydrogel to obtain a cyclodextrin-polyvinyl alcohol mechanically interlocked aerogel.

2. The process for preparing a cyclodextrin-polyvinyl alcohol mechanically interlocked aerogel according to claim 1, characterized in that, The mass concentration of polyvinyl alcohol in the reaction solution is 5-20wt%.

3. The process for preparing a cyclodextrin-polyvinyl alcohol mechanically interlocked aerogel of claim 1, wherein, The mass of cyclodextrin is 10-30% of the mass of polyvinyl alcohol.

4. The process for preparing a cyclodextrin-polyvinyl alcohol mechanically interlocked aerogel of claim 1, wherein, The crosslinking agent is sodium citrate.

5. The cyclodextrin-polyvinyl alcohol mechanically interlocked aerogel preparation method of claim 1, wherein, The mass concentration of the crosslinking agent in the reaction solution is 5-20wt%.

6. The process for preparing a cyclodextrin-polyvinyl alcohol mechanically interlocked aerogel of claim 1, wherein, The alkaloid is nicotine bitartrate dihydrate, arecoline or berberine hydrochloride.

7. The process for preparing a cyclodextrin-polyvinyl alcohol mechanically interlocked aerogel of claim 1, wherein, The added amount of the alkaloid is 1-10% of the mass of polyvinyl alcohol.

8. The process for preparing a cyclodextrin-polyvinyl alcohol mechanically interlocked aerogel of claim 1, wherein, The heating temperature is 70-100℃; and the drying is vacuum freeze drying.

9. A cyclodextrin-polyvinyl alcohol mechanically interlocked aerogel prepared by the method according to any one of claims 1-8.

10. Application of a cyclodextrin-polyvinyl alcohol mechanically interlocked aerogel prepared by the method according to any one of claims 1-8 in alkaloid controlled release.

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