Chitosan-based hydrogel contraceptive material as well as preparation method and application thereof

Abstract

The invention discloses a chitosan-based hydrogel contraceptive material as well as a preparation method and application thereof, and relates to the technical field of contraceptive materials. 3 to 10 weight percent of beta-sodium glycerophosphate; 0.5 to 3 wt% of polyacrylic acid; 0.1 to 5 wt% of a spermicide; 0.01 wt% to 0.1 wt% of silver nanoparticles; 0.1 to 1 wt% of chitosan oligosaccharide; a lactic acid bacteria metabolite: 0.05 to 0.5 wt%; the total percentage is 100%. The thermo-sensitive gelation mechanism is that chitosan is modified by a perfluoroalkyl chain, the perfluoroalkyl chain is a material with the lowest critical solution temperature (LCST), and the LCST of the perfluoroalkyl chain is 37 DEG C. The composite acting force of the spermicide and the gel matrix is intermolecular Van der Waals force and hydrogen bond.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of contraceptive materials, and particularly relates to a chitosan-based hydrogel contraceptive material, a preparation method and application thereof. BACKGROUND

[0002] The development of temperature-sensitive chitosan-based contraceptive hydrogel is derived from the exploration of injectable in-situ gel system, and its core relies on the temperature-sensitive synergistic effect of chitosan (CS) and β-glycerophosphate (β-GP). At low temperature (4-25℃), β-GP as a weak alkaline salt maintains the system pH≈7.0, so that chitosan remains in a dissolved state to form an injectable sol; when the temperature rises to physiological body temperature (37℃), the hydrophobic interaction between chitosan molecular chains is sharply enhanced, triggering the sol-gel transition, and a physical barrier is formed at the cervical port to block the penetration of sperm. To improve the contraceptive efficacy, the prior art further integrates chemical spermicides (such as nonoxynol-9 and benzalkonium chloride) to form a dual mechanism of “physical barrier + chemical killing”. The prior art further integrates chemical spermicides (such as nonoxynol-9 and benzalkonium chloride) to form a dual mechanism of “physical barrier + chemical killing”. For example, patent CN102895256A loads spermicides in chitosan / carbomer foam, but it relies on acetic acid solvent and propellant, which has a risk of biocompatibility; and CN101889974A attempts to use the positive charge characteristics of chitosan to adsorb sperm, but the spermicidal efficiency is insufficient (<80%), and an exogenous spermicide is still needed to supplement. Although such systems have initially achieved functional integration, they still have significant limitations in material safety, mechanical strength, and drug release, etc.

[0003] Existing thermosensitive chitosan-based gels face a triple contradiction: (1) The contradiction between gel functionality and mechanical properties restricts practical application. Due to insufficient hydrophobicity, natural chitosan generally results in low storage modulus of the gel, making it prone to structural collapse under the flushing of semen. Although polyvinyl alcohol (PVA) or hydroxybutyl chitosan (HBC) is introduced to enhance mechanical properties, the former delays gelation time, while the latter has a complex synthesis process and high cost. In addition, the gel has a short retention time on the vaginal mucosa, and even with the addition of carbomer thickener, frequent administration is still required due to the rapid dissolution rate, reducing the ease of use. (2) The contradiction between biosafety and solvent toxicity. More than 80% of the systems use acetic acid to dissolve chitosan, and residual acetic acid reduces the survival rate of vaginal mucosal epithelial cells to 82.1% and disrupts the pH balance of the vaginal microenvironment. At the same time, traditional spermicides such as nonyl alcohol ether damage the vaginal glycoprotein layer at high concentrations, increasing susceptibility to pathogens and creating a loophole in reproductive tract protection. (3) The contradiction between the demand for controlled drug release and the limitations of technology leads to functional imbalance. The compatibility between spermicides and thermosensitive components is insufficient. For example, nonoxynol ether will interfere with the gelation kinetics of chitosan / GP. At the same time, the encapsulation rate of traditional physical mixing drug loading methods is less than 70%, which triggers a burst release effect (more than 50% release in the first 2 hours), causing both early mucosal irritation and insufficient spermicide concentration in the later stage, making it difficult to achieve long-term protection.

[0004] In summary, the fundamental defect of current thermosensitive chitosan-based hydrogel contraceptive materials lies in the imbalance between material biocompatibility, mechanical stability, and functional continuity. Summary of the Invention

[0005] In view of the problems existing in the preparation methods and applications of chitosan-based hydrogel contraceptive materials, this invention is proposed.

[0006] Therefore, the problem to be solved by this invention is that the essential defect of current thermosensitive chitosan-based hydrogel contraceptive materials is the imbalance between material biocompatibility, mechanical stability and functional continuity.

[0007] To solve the above-mentioned technical problems, the present invention provides the following technical solution: In a first aspect, the present invention provides a chitosan-based hydrogel contraceptive material, comprising: Perfluoroalkyl chain modified chitosan: 1-5wt%; sodium β-glycerophosphate: 3-10wt%; polyacrylic acid: 0.5-3wt%; spermicide: 0.1-5wt%; silver nanoparticles: 0.01-0.1wt%; chitosan oligosaccharide: 0.1-1wt%; lactic acid bacteria metabolites: 0.05-0.5wt%; lactic acid aqueous solution: balance to 100%.

[0008] As a preferred embodiment of the chitosan-based hydrogel contraceptive material of the present invention, wherein the perfluoroalkyl chain of the chitosan modified with the perfluoroalkyl chain is a C4-C12 perfluoroalkyl chain.

[0009] The beneficial effects of this preferred technical solution are: the C4-C12 chain length range provides the best hydrophobic balance, which enhances the affinity with the vaginal mucosa while giving the material hydrophobicity.

[0010] As a preferred embodiment of the chitosan-based hydrogel contraceptive material of the present invention, the spermicide is selected from one or more of nonyl alcohol ether, benzalkonium chloride and chlorhexidine.

[0011] As a preferred embodiment of the chitosan-based hydrogel contraceptive material of the present invention, the silver nanoparticles have a particle size of 10-50 nm and a dispersibility index (PDI) ≤ 0.3.

[0012] The beneficial effects of this preferred technical solution are as follows: by adding 0.01-0.1wt% silver nanoparticles, the material is endowed with broad-spectrum antibacterial properties, effectively preventing vaginal infections and sexually transmitted diseases. At the same time, the controllable particle size (10-50nm) and dispersibility index (PDI≤0.3) of the silver nanoparticles ensure the stability and uniformity of the antibacterial effect.

[0013] As a preferred embodiment of the chitosan-based hydrogel contraceptive material of the present invention, wherein the molecular weight of the perfluoroalkyl chain modified chitosan is 2*10. 5 g / mol–8*10 5 Between g / mol, the degree of substitution is 5%–20%; Polyacrylic acid has a molecular weight of 5*10 3 g / mol⁻¹*10 6 Between g / mol, the degree of neutralization is 50%–90%.

[0014] The beneficial effects of this preferred technical solution are: the molecular weight of the perfluoroalkyl chain modified chitosan is controlled at 2*10. 5 g / mol–8*10 5 Within the g / mol range, it ensures sufficient molecular chain length to provide good film-forming properties and mechanical strength, while avoiding excessive viscosity and processing difficulties caused by excessively high molecular weight. The molecular weight of polyacrylic acid is 5*10. 3 g / mol⁻¹*10 6 g / mol optimized the electrostatic interaction strength with chitosan, ensuring sufficient adhesion to prolong residence time while avoiding excessive cross-linking that could affect drug release.

[0015] As a preferred embodiment of the chitosan-based hydrogel contraceptive material of the present invention, wherein the lactic acid bacteria metabolite is selected from one or more of lactobacillus, bacteriocins, and short-chain fatty acids.

[0016] Secondly, the present invention provides a method for preparing a chitosan-based hydrogel contraceptive material, comprising the following steps: Silver nanoparticles were dispersed in deionized water under ultrasonic conditions to obtain a silver nanoparticle dispersion. Perfluoroalkyl chain modified chitosan and chitosan oligosaccharide were added sequentially to a lactic acid aqueous solution and stirred until dissolved to a transparent state to obtain a chitosan mixed solution. Lactic acid bacteria metabolites were added to the chitosan mixed solution and stirred evenly in the dark to obtain a primary solution. A spermicide was added to the primary solution and stirred evenly in the dark to obtain a secondary solution. The silver nanoparticle dispersion was added to the secondary solution and stirred simultaneously to obtain a tertiary solution. β-glycerophosphate sodium was slowly added to the tertiary solution under ice bath conditions, followed by polyacrylic acid, and mixed evenly to obtain the chitosan-based hydrogel contraceptive material.

[0017] In a preferred embodiment of the preparation method of the chitosan-based hydrogel contraceptive material of the present invention, the preparation method of perfluoroalkyl chain modified chitosan includes: A1. Weigh chitosan into a three-necked flask, add N,N-dimethylformamide, and stir until the chitosan is completely dissolved; A2. Add potassium carbonate to the solution obtained in step A1, and continue stirring to mix evenly; A3. Add fluorinated haloalkanes dropwise to the solution obtained in step A2, heat to 60°C, and react for 48 hours to obtain a reaction solution; A4. After the reaction is complete, pour the reaction solution into methanol to precipitate, filter, and wash with methanol to obtain the final product; A5. Vacuum dry the final product for 6 hours to obtain the perfluoroalkyl chain modified chitosan.

[0018] The advantages of this preferred technical solution are as follows: using N,N-dimethylformamide as a reaction solvent can effectively dissolve chitosan and provide a good reaction environment; potassium carbonate as an alkaline catalyst promotes the nucleophilic substitution reaction; the reaction rate is controlled by adding fluorinated haloalkanes dropwise to avoid local overheating and side reactions; and the constant temperature reaction at 60°C for 48 hours ensures a full substitution reaction and obtains stable perfluoroalkyl linkages.

[0019] In a preferred embodiment of the preparation method of the chitosan-based hydrogel contraceptive material of the present invention, the molar ratio of sodium β-glycerophosphate to perfluoroalkyl chain modified chitosan is 2-4:1, and the crosslinking density is 0.1-0.5 mol / L.

[0020] The beneficial effects of this preferred technical solution are as follows: by limiting the molar ratio of sodium β-glycerophosphate to perfluoroalkyl chain modified chitosan and the crosslinking density, precise control of gelation time, mechanical strength and drug release behavior is achieved, ensuring rapid gelation and long-lasting protective performance of the material at body temperature.

[0021] Thirdly, the present invention provides an application of a chitosan-based hydrogel contraceptive material, wherein the chitosan-based hydrogel contraceptive material is used in contraceptive devices.

[0022] The beneficial effects of this invention are: The thermosensitive gelation mechanism of this invention involves perfluoroalkyl chain-modified chitosan, a material with a lowest critical solution temperature (LCST) of 37°C. The interaction between the spermicide and the gel matrix consists of intermolecular van der Waals forces and hydrogen bonds. In the MTT assay, AML12 (human hepatocytes) cell viability remained high, indicating that the chitosan / β-glycerophosphate material had some effect on the cells but did not cause serious damage. Live and dead cell staining showed almost no dead cells, further verifying a high proportion of live cells. Combined with the MTT data, this indicates that AML12 cells had a high survival rate under the experimental conditions, and cell death was minimal after chitosan / β-glycerophosphate treatment. Overall, the chitosan / β-glycerophosphate material had a relatively small impact on AML12 cells, and the cells maintained good activity after treatment with this material. Attached Figure Description

[0023] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0024] Figure 1 This invention provides a synthetic route for perfluoroalkyl chain modified chitosan in a chitosan-based hydrogel contraceptive material, as an embodiment of the present invention.

[0025] Figure 2 Photographs and flowability of a chitosan-based hydrogel contraceptive material provided in one embodiment of the present invention.

[0026] Figure 3 This is a schematic diagram illustrating the thermosensitive gelation behavior of a chitosan-based hydrogel contraceptive material according to an embodiment of the present invention.

[0027] Figure 4 This is a schematic diagram of a cytotoxicity test of a chitosan-based hydrogel contraceptive material provided in one embodiment of the present invention. Detailed Implementation

[0028] To make the above-mentioned objects, features, and advantages of the present invention more apparent and understandable, a detailed description is provided below in conjunction with specific embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the protection scope of the present invention.

[0029] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0030] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it a single or selective embodiment that is mutually exclusive with other embodiments.

[0031] In a first aspect, a chitosan-based hydrogel contraceptive material is provided, comprising: Perfluoroalkyl chain modified chitosan: 1-5 wt%; Sodium β-glycerophosphate: 3-10 wt% Polyacrylic acid: 0.5-3 wt%; Spermicide: 0.1-5 wt%; Silver nanoparticles: 0.01-0.1 wt%; Chitosan oligosaccharide: 0.1-1 wt%; Lactic acid bacteria metabolites: 0.05-0.5 wt%; Lactic acid aqueous solution: balance to 100%.

[0032] A new generation of thermosensitive chitosan-based hydrogel contraceptive materials focuses on hydrophobic modification and adhesion persistence to enhance gel performance. Chitosan is modified with perfluoroalkyl chains (e.g., -C6F13), utilizing the strong hydrophobic effect of the fluorocarbon segments to optimize the sol-gel transition temperature and crosslinking density, accelerating gelation time and enhancing gel storage modulus. Polyacrylic acid (PAA) is introduced to construct an electrostatic adhesion network; the ionic bonding between chitosan amino groups and PAA carboxyl groups improves mucosal peeling force and prolongs retention time. Simultaneously, lactic acid aqueous solution completely replaces acetic acid solvent to improve biocompatibility. Lactic acid bacteria metabolites, as natural metabolites in vivo, can regulate the system pH to the healthy vaginal range (3.8-4.5), reducing cytotoxicity.

[0033] In one embodiment of this application, the perfluoroalkyl chain modified chitosan has a C4-C12 perfluoroalkyl chain, and the molecular weight of the perfluoroalkyl chain modified chitosan is 2*10. 5 g / mol–8*10 5 The g / mol concentration ranges from 5% to 20% with a degree of substitution. The perfluoroalkyl chain length is predominantly C12. By controlling hydrophobicity, thermal stability, and biocompatibility, thermosensitivity and sustained-release drug delivery are achieved.

[0034] In one embodiment of this application, the spermicide is selected from one or more of nonoxynol-9, benzalkonium chloride, and chlorhexidine. Nonoxynol-9 is preferred; it is a nonionic surfactant with the chemical structure of polyoxyethylene nonylphenyl ether. The polyoxyethylene segment in its molecule is hydrophilic, and the nonylphenyl segment is lipophilic. This amphiphilicity allows it to disrupt the cell membrane structure of sperm, thereby exerting a spermicidal effect. Nonoxynol-9 can bind to the lipids and proteins of the sperm cell membrane, disrupting the membrane's integrity and rendering the sperm immobile and unable to fertilize, thus achieving a contraceptive effect.

[0035] In one embodiment of this application, the silver nanoparticles have a particle size of 10-50 nm and a dispersion index (PDI) ≤ 0.3. By adding 0.01-0.1 wt% of silver nanoparticles, the material is endowed with broad-spectrum antibacterial properties, effectively preventing vaginal infections and sexually transmitted diseases. At the same time, the controllable particle size (10-50 nm) and good dispersibility (PDI ≤ 0.3) of the silver nanoparticles ensure the stability and uniformity of the antibacterial effect.

[0036] In one embodiment of this application, the molecular weight of polyacrylic acid is 5*10. 3 g / mol⁻¹*10 6 Between g / mol, the degree of neutralization is 50%–90%.

[0037] In one embodiment of this application, the lactic acid bacteria metabolite is selected from one or more of lactobacillus, bacteriocins, and short-chain fatty acids.

[0038] Secondly, embodiments of this application provide a method for preparing a chitosan-based hydrogel contraceptive material, comprising the following steps: Silver nanoparticles were dispersed in deionized water under ultrasonic conditions to obtain a silver nanoparticle dispersion. Perfluoroalkyl chain modified chitosan and chitosan oligosaccharide were added sequentially to a lactic acid aqueous solution and stirred until dissolved to a transparent state to obtain a chitosan mixed solution. Lactic acid bacteria metabolites were added to the chitosan mixed solution, and the mixture was stirred and stirred evenly in the dark to obtain a primary solution. Add spermicide to the primary solution, stir and mix thoroughly in the dark to obtain the secondary solution; The silver nanoparticle dispersion was added to the secondary solution, and the mixture was stirred simultaneously to obtain a tertiary solution. Under ice bath conditions, sodium β-glycerophosphate was slowly added to the tertiary solution, followed by polyacrylic acid, and mixed thoroughly to obtain the chitosan-based hydrogel contraceptive material.

[0039] In this embodiment, the ice bath temperature is 0-4°C, the temperature is kept stable, and the ice is added slowly at a rate of 1-3 mL / min.

[0040] The molar ratio of sodium β-glycerophosphate to perfluoroalkyl chain modified chitosan is 2-4:1, and the crosslinking density is 0.1-0.5 mol / L when the sodium β-glycerophosphate solution is added dropwise.

[0041] In this application embodiment, the preparation method of perfluoroalkyl chain modified chitosan includes: A1. Weigh chitosan into a three-necked flask, add N,N-dimethylformamide, and stir until the chitosan is completely dissolved. A2. Add potassium carbonate to the solution obtained in step A1 and continue stirring to mix evenly; A3. Add fluorinated haloalkanes dropwise to the solution obtained in step A2, heat to 60°C, and react for 48 hours to obtain the reaction solution; A4. After the reaction is complete, pour the reaction solution into methanol to precipitate, filter and wash with methanol to obtain the final product. A5. The final product is vacuum dried for 6 hours to obtain the perfluoroalkyl chain modified chitosan.

[0042] By controlling the cross-linking network of chitosan and polyacrylic acid through the polyacrylic acid content, the sustained-release properties of the polyelectrolyte are modulated, achieving linear release of the spermicide. The process of adding sodium β-glycerophosphate (ice bath slow addition) is optimized to avoid interference with the temperature-sensitive gelation process by the spermicide, thus optimizing the gelation time. This technical approach ultimately points to a synergistic mechanism of "immediate formation of physical barrier - long-term maintenance of chemical spermicide effect."

[0043] Thirdly, embodiments of this application provide an application of a chitosan-based hydrogel contraceptive material, which is used in contraceptive devices.

[0044] Example 1: This example provides a chitosan-based hydrogel contraceptive material, comprising: Perfluoroalkyl chain modified chitosan: 1 wt% Sodium β-glycerophosphate: 3wt% Polyacrylic acid: 0.5 wt% Spermicide: 0.1 wt%; Silver nanoparticles: 0.01 wt% Chitosan oligosaccharide: 0.1 wt%; Lactic acid bacteria metabolites: 0.05 wt%; Lactic acid aqueous solution: balance to 100%.

[0045] The perfluoroalkyl chain of the chitosan modified with perfluoroalkyl chain is a C4 perfluoroalkyl chain.

[0046] The spermicide is selected from nonylbenzene alcohol ether.

[0047] The silver nanoparticles have a particle size of 10 nm and a dispersion index (PDI) ≤ 0.3.

[0048] The molecular weight of perfluoroalkyl chain modified chitosan is 2*10. 5 g / mol–4*10 5 Between g / mol, the degree of substitution is 5%–10%; Polyacrylic acid has a molecular weight of 5*10 3 g / mol⁻⁷*10 3 Between g / mol, the degree of neutralization is 50%–65%.

[0049] Example 2: This example provides a chitosan-based hydrogel contraceptive material, comprising: Perfluoroalkyl chain modified chitosan: 3wt%; Sodium β-glycerophosphate: 6wt% Polyacrylic acid: 1.5 wt% Spermicide: 3 wt% Silver nanoparticles: 0.05 wt% Chitosan oligosaccharide: 0.5 wt%; Lactic acid bacteria metabolites: 0.2 wt%; Lactic acid aqueous solution: balance to 100%.

[0050] The perfluoroalkyl chain of the chitosan modified with perfluoroalkyl chain is a C8 perfluoroalkyl chain.

[0051] The spermicide is selected from benzalkonium chloride.

[0052] The silver nanoparticles have a particle size of 25 nm and a dispersion index (PDI) ≤ 0.3.

[0053] The molecular weight of perfluoroalkyl chain modified chitosan is 4*10. 5 g / mol–6*10 5 Between g / mol, the degree of substitution is 10%–15%; The molecular weight of polyacrylic acid is 7*10. 3 g / mol⁻¹*10 4 Between g / mol, the degree of neutralization is 65%–75%.

[0054] Example 3: This example provides a chitosan-based hydrogel contraceptive material, comprising: Perfluoroalkyl chain modified chitosan: 5 wt% Sodium β-glycerophosphate: 10 wt% Polyacrylic acid: 3wt% Spermicide: 5 wt% Silver nanoparticles: 0.1 wt% Chitosan oligosaccharide: 1 wt% Lactic acid bacteria metabolites: 0.5 wt%; Lactic acid aqueous solution: balance to 100%.

[0055] The perfluoroalkyl chain of the chitosan modified with perfluoroalkyl chain is a C12 perfluoroalkyl chain.

[0056] The spermicide is chlorhexidine.

[0057] The silver nanoparticles have a particle size of 50 nm and a dispersion index (PDI) ≤ 0.3.

[0058] The molecular weight of perfluoroalkyl chain modified chitosan is 6*10. 5 g / mol–8*10 5 Between g / mol, the degree of substitution is 15%–20%; The molecular weight of polyacrylic acid is 1*10. 4 g / mol⁻¹*10 6 Between g / mol, the degree of neutralization is 75%–90%.

[0059] Comparative Example 1 (Traditional Unmodified Chitosan): Chitosan (unmodified): 1 wt% Sodium β-glycerophosphate: 3wt% Polyacrylic acid: 0.5 wt% Spermicide (nonoxynol-9): 0.1 wt%; Silver nanoparticles: 0.01 wt% Chitosan oligosaccharide: 0.1 wt%; Lactic acid bacteria metabolites: 0.05 wt%; Lactic acid aqueous solution: balance to 100%.

[0060] Comparative Example 2 (Hydroxybutyl chitosan modification): Hydroxybutyl chitosan: 1 wt% Sodium β-glycerophosphate: 3wt% Polyacrylic acid: 0.5 wt% Spermicide (nonoxynol-9): 0.1 wt%; Silver nanoparticles: 0.01 wt% Chitosan oligosaccharide: 0.1 wt%; Lactic acid bacteria metabolites: 0.05 wt%; Lactic acid aqueous solution: balance to 100%.

[0061] Performance comparison experiment results table:

[0062] The gelation time test employed the inverted test tube method. A 5 mL sample solution was placed in a test tube and heated in a 37°C constant temperature water bath. The test tube was inverted every 30 seconds to observe the flowability, and the point at which the solution completely stopped flowing was recorded. In the gelation time test at 37°C, reference was made to… Figure 3 As shown, Example 1 required only 4.2 ± 0.3 minutes to complete gelation, while Comparative Example 1 required 12.5 ± 1.2 minutes and Comparative Example 2 required 8.7 ± 0.8 minutes. This difference stems from the superhydrophobicity of the perfluoroalkyl chains. When the temperature reaches 37°C, the hydrophobic interactions between the perfluoro segments intensify, triggering a rapid phase separation process. In contrast, unmodified chitosan lacks sufficient hydrophobic driving force, and while hydroxybutyl modification provides some hydrophobicity, its hydrophobic strength is far less than that of the perfluoro segments, thus the gelation speed remains relatively slow.

[0063] The gel strength test was performed using a rotational rheometer at 37°C to determine the storage modulus. A parallel plate geometry with a diameter of 25 mm and a gap of 1 mm was used, and the test was conducted under conditions of 1% shear strain and 1 Hz frequency. The gel strength test showed that Example 1 achieved 1850 ± 120 Pa, which is superior to Comparative Example 1's 680 ± 50 Pa and Comparative Example 2's 1100 ± 80 Pa. Perfluoroalkyl chain modified chitosan can form a denser and more ordered cross-linked network structure. This is because the strong hydrophobic aggregation of the perfluoro segments provides more effective cross-linking sites for the cross-linking of sodium β-glycerophosphate. Simultaneously, the interaction forces between perfluoro segments are stronger than those of ordinary hydrophobic groups, thus constructing a three-dimensional network with higher mechanical strength. Traditional chitosan has a low cross-linking density due to insufficient hydrophobicity, and while hydroxybutyl modification improves this somewhat, it still cannot achieve the effect of perfluoro modification.

[0064] Hydrophobicity testing was performed using a contact angle meter. The gel sample was prepared with a smooth surface, and the static contact angle was measured at room temperature using a 2 μL droplet of deionized water. The contact angle results showed that the hydrophobicity of Example 1 was 78.5 ± 2.1°, higher than that of Comparative Example 1 (45.2 ± 3.1°) and Comparative Example 2 (52.8 ± 2.8°). The fluorine atoms in the perfluoroalkyl chain have extremely strong electronegativity, making it almost impossible for the CF bond to form hydrogen bonds with water molecules, thus endowing the material with excellent hydrophobic properties. This enhanced hydrophobicity not only benefits thermosensitive transitions but also improves the stability and erosion resistance of the gel in physiological environments. Traditional chitosan, due to its large number of hydroxyl and amino groups, exhibits strong hydrophilicity, while hydroxybutyl modification only provides limited improvement in hydrophobicity.

[0065] Reference Figure 2 The image shows a photograph and flowability demonstration of the chitosan-based hydrogel contraceptive material prepared according to this invention. Viscosity testing at 25°C was performed using a Brookfield viscometer with an S61 rotor at 60 rpm. The viscosity of Example 1 is 850±45, lower than Comparative Example 1's 1250±80, and slightly lower than Comparative Example 2's 980±65. Perfluoroalkyl chain modification maintains the material's temperature sensitivity while improving low-temperature flowability by reducing intermolecular hydrogen bonding, resulting in better operability when stored and used at room temperature. Unmodified chitosan has a higher viscosity due to more intermolecular hydrogen bonds, affecting ease of use; however, perfluoro modification effectively balances this problem by introducing hydrophobic groups.

[0066] The mucosal retention time was tested using an in vitro simulation experiment with porcine vaginal mucosal tissue in a simulated vaginal fluid environment at 37°C and pH 4.2. The retention time in Example 1 reached 10.5 ± 0.8 hours, longer than that of Comparative Example 1 (3.8 ± 0.4 hours) and Comparative Example 2 (6.2 ± 0.6 hours). The electrostatic adhesion network formed by perfluoroalkyl chain-modified chitosan and polyacrylic acid exhibited stronger mucosal binding force. This is because the modified chitosan, while undergoing hydrophobic modification, still retained sufficient amino groups to form ionic bonds with the carboxyl groups of polyacrylic acid. Simultaneously, the presence of hydrophobic segments enhanced the hydrophobic interaction with the mucosal tissue, thus significantly prolonging the retention time.

[0067] The duration of spermicidal effect was evaluated using sperm motility testing. The gel sample was mixed with human semen at a 1:10 ratio, incubated at 37°C, and sperm motility was monitored periodically. The duration of effect in Example 1 was 8.2 ± 0.4 hours, significantly longer than the 3.2 ± 0.3 hours in Comparative Example 1 and the 5.1 ± 0.4 hours in Comparative Example 2. The gel network formed by perfluoroalkyl chain modification exhibits better controlled drug release characteristics. The interaction between the hydrophobic segments and the spermicidal molecules delays the burst release of the drug, resulting in a more stable drug release profile. Traditional chitosan gels are prone to burst release due to insufficient cross-linking density, and while hydroxybutyl modification improves this, its effect is still inferior to perfluoro modification.

[0068] Example 4: This example provides a method for preparing a chitosan-based hydrogel contraceptive material, including the following steps: Silver nanoparticles were dispersed in deionized water under ultrasonic conditions to obtain a silver nanoparticle dispersion. Perfluoroalkyl chain modified chitosan and chitosan oligosaccharide were added sequentially to a lactic acid aqueous solution and stirred until dissolved to a transparent state to obtain a chitosan mixed solution. Lactic acid bacteria metabolites were added to the chitosan mixed solution, and the mixture was stirred and stirred evenly in the dark to obtain a primary solution. Add spermicide to the primary solution, stir and mix thoroughly in the dark to obtain the secondary solution; The silver nanoparticle dispersion was added to the secondary solution, and the mixture was stirred simultaneously to obtain a tertiary solution. Under ice bath conditions, sodium β-glycerophosphate was slowly added to the tertiary solution, followed by polyacrylic acid, and mixed thoroughly to obtain the chitosan-based hydrogel contraceptive material.

[0069] The molar ratio of sodium β-glycerophosphate to perfluoroalkyl chain modified chitosan is 2:1, and the crosslinking density is 0.1 mol / L.

[0070] Reference Figure 1 As shown, the preparation method of perfluoroalkyl chain modified chitosan includes: A1. Weigh chitosan into a three-necked flask, add N,N-dimethylformamide, and stir until the chitosan is completely dissolved. A2. Add potassium carbonate to the solution obtained in step A1 and continue stirring to mix evenly; A3. Add fluorinated haloalkanes dropwise to the solution obtained in step A2, heat to 60°C, and react for 48 hours to obtain the reaction solution; A4. After the reaction is complete, pour the reaction solution into methanol to precipitate, filter and wash with methanol to obtain the final product. A5. The final product is vacuum dried for 6 hours to obtain the perfluoroalkyl chain modified chitosan.

[0071] The cytotoxicity of chitosan-based hydrogel contraceptive materials was tested, referring to... Figure 4 As shown in the figure. The results showed that in the MTT assay, the cell viability of the control group was approximately 100%, while that of the experimental group was approximately 90%. Figure 4 As shown in Figure a, the viability of AML12 (human hepatocytes) cells decreased to some extent but remained at a high level, indicating that the chitosan / β-glycerophosphate material had some effect on the cells but did not cause serious damage. Fluorescence staining images: Live and dead cell staining AM (Calcein-AM): stains live cells, emitting green fluorescence. The green fluorescent areas in the image represent live AML12 cells, showing cell morphology and distribution. PI (Propidium Iodide): stains dead cells, emitting red fluorescence. No obvious red fluorescence is observed in this image, indicating almost no dead cells. Merge image: AM and PI staining are superimposed, further verifying the high proportion of live cells. Combined with MTT experimental data, this indicates that AML12 cells had a high survival rate under experimental conditions, and cell death was minimal after CS / β-GP treatment. Figure 4 As shown in b. Overall, the CS / β-GP material had little impact on AML12 cells, and the cells maintained good viability after treatment with this material.

[0072] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the present invention.

Claims

1. A chitosan-based hydrogel contraceptive material, characterized in that, include: Perfluoroalkyl chain modified chitosan: 1-5 wt%; Sodium β-glycerophosphate: 3-10 wt% Polyacrylic acid: 0.5-3 wt%; Spermicide: 0.1-5 wt%; Silver nanoparticles: 0.01-0.1 wt%; Chitosan oligosaccharide: 0.1-1 wt%; Lactic acid bacteria metabolites: 0.05-0.5 wt%; Lactic acid aqueous solution: balance to 100%.

2. The chitosan-based hydrogel contraceptive material as described in claim 1, characterized in that, The perfluoroalkyl chain modified chitosan has a C4-C12 perfluoroalkyl chain.

3. The chitosan-based hydrogel contraceptive material as described in claim 2, characterized in that, The spermicide is selected from one or more of nonyl alcohol ether, benzalkonium chloride, and chlorhexidine.

4. The chitosan-based hydrogel contraceptive material as described in claim 3, characterized in that, The silver nanoparticles have a particle size of 10-50 nm and a dispersion index (PDI) ≤ 0.

3.

5. The chitosan-based hydrogel contraceptive material as described in claim 4, characterized in that, The molecular weight of the perfluoroalkyl chain modified chitosan is 2*10. 5 g / mol–8*10 5 Between g / mol, the degree of substitution is 5%–20%; Polyacrylic acid has a molecular weight of 5*10 3 g / mol⁻¹*10 6 Between g / mol, the degree of neutralization is 50%–90%.

6. The chitosan-based hydrogel contraceptive material as described in claim 5, characterized in that, The lactic acid bacteria metabolites are selected from one or more of lactobacillus, bacteriocins, and short-chain fatty acids.

7. A method for preparing a chitosan-based hydrogel contraceptive material, characterized in that, Includes the following steps: Silver nanoparticles were dispersed in deionized water under ultrasonic conditions to obtain a silver nanoparticle dispersion. Perfluoroalkyl chain modified chitosan and chitosan oligosaccharide were added sequentially to a lactic acid aqueous solution and stirred until dissolved to a transparent state to obtain a chitosan mixed solution. Lactic acid bacteria metabolites were added to the chitosan mixed solution, and the mixture was stirred and stirred evenly in the dark to obtain a primary solution. Add spermicide to the primary solution, stir and mix thoroughly in the dark to obtain the secondary solution; The silver nanoparticle dispersion was added to the secondary solution, and the mixture was stirred simultaneously to obtain a tertiary solution. Under ice bath conditions, sodium β-glycerophosphate was slowly added to the tertiary solution, followed by polyacrylic acid, and mixed thoroughly to obtain the chitosan-based hydrogel contraceptive material.

8. The method for preparing the chitosan-based hydrogel contraceptive material as described in claim 7, characterized in that, The preparation method of the perfluoroalkyl chain modified chitosan includes: A1. Weigh chitosan into a three-necked flask, add N,N-dimethylformamide, and stir until the chitosan is completely dissolved. A2. Add potassium carbonate to the solution obtained in step A1 and continue stirring to mix evenly; A3. Add fluorinated haloalkanes dropwise to the solution obtained in step A2, heat to 60°C, and react for 48 hours to obtain the reaction solution; A4. After the reaction is complete, pour the reaction solution into methanol to precipitate, filter and wash with methanol to obtain the final product. A5. The final product is vacuum dried for 6 hours to obtain the perfluoroalkyl chain modified chitosan.

9. The method for preparing the chitosan-based hydrogel contraceptive material as described in claim 8, characterized in that, The molar ratio of sodium β-glycerophosphate to perfluoroalkyl chain modified chitosan is 2-4:1, and the crosslinking density is 0.1-0.5 mol / L.

10. An application of a chitosan-based hydrogel contraceptive material, characterized in that, The chitosan-based hydrogel contraceptive material is the chitosan-based hydrogel contraceptive material according to any one of claims 1 to 6, and the chitosan-based hydrogel contraceptive material is used in contraceptive devices.

Images