A nano film for relieving pain of bone injury and a preparation method thereof

Abstract

The application discloses a nano film for relieving bone injury pain and a preparation method thereof, relates to the technical field of medical films, and comprises an inner layer, a middle layer and an outer layer, wherein the three layers are prepared by mixing traditional Chinese medicine extracts and a base material and are prepared into the nano film through an electrostatic spinning process, the components of the layers are the same, but the proportions are different, and the base material is selected from a poly-caprolactone and polyvinyl alcohol blending system; the inner layer has high drug loading capacity and can quickly relieve symptoms, the middle layer can continuously release, the outer layer has low drug loading capacity, can reduce initial stimulation and increase stability, realizes the reduction of use frequency, prolongs the drug effect, and reduces adverse reactions; the "protection-slow release-fast release" function is realized only by adjusting the PCL / PVA proportion, and the production process is simplified.

Description

Technical Field

[0001] This invention relates to the field of medical thin film technology, and in particular to a nanofilm for relieving bone injury pain and its preparation method. Background Technology

[0002] Traditional Chinese medicine (TCM) external therapy involves applying TCM in various dosage forms to the body surface, directly targeting local lesions, or stimulating acupoints and meridians, as well as local physical stimulation, to achieve therapeutic effects. TCM external therapy has unique and effective advantages in treating local surgical lesions. With the rapid development of nanotechnology, its applications in the biomedical field are becoming increasingly widespread, particularly showing great potential in relieving orthopedic pain. Nanofilms, as innovative biomedical materials, exhibit unique advantages in relieving bone and joint pain due to their unique physical, chemical, and biological properties. Nanofilms are typically composed of nanoscale materials, which exhibit properties at the microscale that are drastically different from macroscopic materials. Nanofilms can possess extremely high specific surface areas, thereby increasing their ability to interact with other substances. In relieving bone and joint pain, nanofilms can exert their effects through multiple mechanisms, such as drug loading, promoting tissue regeneration, and inhibiting inflammatory responses.

[0003] For example, Chinese Patent Application No. CN202210739920.X discloses a method for preparing a traditional Chinese medicine micro / nanofiber film for treating psoriasis, and the prepared film, comprising the following steps: (1) preparing an electrospinning solution by mixing several polymers in a certain proportion; (2) adding the traditional Chinese medicine components for treating psoriasis to the electrospinning solution in step (1) to obtain the traditional Chinese medicine electrospinning solution; (3) transferring the traditional Chinese medicine electrospinning solution obtained in step (2) to the jet reservoir in the electrospinning device, and preparing a traditional Chinese medicine micro / nanofiber film with high diameter specific surface area, large porosity, and good air permeability for external application to treat psoriasis by setting the preparation scheme and preparation parameters. Its advantages are that it provides a low-cost, convenient, direct-acting, fast-acting, short-course, non-recurring, and non-toxic micro / nanofiber film for external application to treat psoriasis.

[0004] However, good breathability can easily lead to external bacteria or other contamination, and easy moisture absorption can reduce the mechanical properties of the membrane, ultimately resulting in uncontrollable drug release rate, inability to stabilize efficacy and difficulty in ensuring drug safety. Summary of the Invention

[0005] The embodiments of this application solve the problems of uncontrollable drug release rate and reduced drug safety in the prior art, and achieve a more stable membrane structure and a more uniform and stable drug release rate.

[0006] This application provides a nanofilm for relieving bone injury pain, comprising an inner layer, a middle layer, and an outer layer, all three layers being made of a mixture of traditional Chinese medicine extracts and a substrate, and the nanofilm is prepared by electrospinning process, wherein the substrate is a blend of polycaprolactone and polyvinyl alcohol.

[0007] Further, specific steps include:

[0008] S1. Preparation of Chinese herbal extracts: The preparation method is as follows: Mix Chinese herbs in proportion, pulverize them, and use ethanol-water (7:3) as solvent. Extract twice with ultrasonic assistance at 60℃ for 1 hour each time. Combine the extracts, concentrate under reduced pressure to extract paste, and freeze dry to obtain Chinese herbal extract powder.

[0009] S2. Preparation of layered electrospinning solution; the substrate is a blend of polycaprolactone and polyvinyl alcohol, and the solution is prepared in layers.

[0010] S3. Layered electrospinning process: A three-nozzle electrospinning device is used to draw the prepared electrospinning solution into a sterile syringe. The needle is installed, air bubbles are removed, and the voltage, solution injection speed, distance between the needle and the receiving device, spinning temperature and humidity are set. Spinning begins, and the solution is received by a flat plate or roller to obtain a micro-nano spun fiber membrane with good uniformity. After freeze-drying for 24-48 hours, it is ready for use.

[0011] Furthermore, the proportions of the Chinese herbs in step S1 are as follows: Tripterygium wilfordii 6.2%, Epimedium 9.7%, Angelica sinensis 6.5%, Rehmannia glutinosa 12.9%, Ligusticum chuanxiong 6.5%, Crocus sativus 3.1%, Eucommia ulmoides 12.9%, Boswellia carterii 6.5%, Commiphora myrrha 6.5%, Achyranthes bidentata 9.7%, Borneol 3.1%, Chaenomeles speciosa 3.5%, and Clematis chinensis 12.9%.

[0012] Furthermore, in step S2, the ratio of each layer is as follows: the outer layer substrate is PCL:PVA = 8:2; the middle layer substrate is PCL:PVA = 5:5; the inner layer substrate is PCL:PVA = 2:8; and the solvent is a mixture of hexafluoroisopropanol and ultrapure water in a ratio of 7:3.

[0013] Furthermore, the outer layer contains 20% of the outer layer's mass of traditional Chinese medicine extracts.

[0014] Furthermore, the intermediate layer contains 30% of the mass of traditional Chinese medicine extracts.

[0015] Furthermore, the outer layer contains traditional Chinese medicine extracts, which account for 40% of the mass of the inner layer.

[0016] Furthermore, 1% of nano-silica particles with a particle size of 10-50 nm are added to the outer layer of the film.

[0017] Furthermore, 2.5% of nano-silica particles with a particle size of 5-20 nm are also added to the intermediate layer of the film.

[0018] Furthermore, the intermediate layer contains a combination of nano-silica particles of different sizes, specifically: large particles: 20-50nm; small particles: 5-15nm; large particles: small particles = 3:1.

[0019] One or more technical solutions provided in the embodiments of this application have at least the following technical effects or advantages:

[0020] Firstly, the high drug loading in the inner layer rapidly relieves symptoms, the middle layer continuously releases the drug, and the low drug loading in the outer layer reduces initial irritation, thereby reducing the number of uses, prolonging the efficacy, and reducing adverse reactions; the "protection-slow release-rapid release" function is achieved simply by adjusting the PCL / PVA ratio, simplifying the production process.

[0021] Secondly, nano-silica possesses unique surface properties and a porous structure. Its small particle size, large specific surface area, and high surface energy give it a strong adsorption capacity. Furthermore, its abundant pore structure provides numerous adsorption sites, enhancing its water absorption performance. Adding nano-silica particles to the outer layer of the film allows these particles to adsorb moisture from the air, reducing moisture penetration into the intermediate and inner layers, thereby increasing the film's moisture resistance. Due to its large surface area, it bonds more strongly with the substrate in the outer layer, forming physical cross-linking points, improving tensile strength, and increasing the stability of the outer layer. The film's tear resistance is enhanced, allowing for repeated application. Nano-silica has high hardness and high wear resistance; its addition significantly improves the film's mechanical strength, making it more durable, enhancing its anti-aging properties and weather resistance, and extending its service life. Silica's good biocompatibility reduces the risk of irritation or allergic reactions in the human body.

[0022] Third, the nanoparticles in the outer and middle layers attract each other through physical interactions such as van der Waals forces, which affects their distribution and arrangement in the film. The particle size, shape, and surface properties of the nanoparticles all affect this physical interaction. Smaller particles are more likely to agglomerate near larger particles, forming a tighter packing structure at the junction of the outer and middle layers. This not only further prevents moisture from entering the middle and inner layers, but also increases the interfacial bonding strength and stability.

[0023] Fourth, the large and small particles form a denser network through geometric complementarity, enhancing the barrier properties of the film; the small particles have a high specific surface area and adsorb more drug molecules, delaying the initial burst release; the large particles extend the drug diffusion path and work synergistically with the small particles to achieve linear release, causing drug molecules to have to bypass the "maze-like" channels formed by the large and small particles, increasing the diffusion resistance; the initial burst release is reduced, and the mid-term sustained release is linearized. Detailed Implementation

[0024] 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 invention pertains; the terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to limit the invention; the term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0025] Example 1: A nanofilm for relieving bone injury pain, comprising: an inner layer, a middle layer, and an outer layer; specifically, the inner layer is an immediate-release layer, the middle layer is a sustained-release layer, and the outer layer is a protective layer. The materials used in each layer are the same, but the proportions are different.

[0026] The film is prepared by electrospinning in layers after mixing a substrate with a traditional Chinese medicine extract. The preparation method is as follows:

[0027] S1. Preparation of Chinese herbal extracts: The preparation method is as follows: Mix Chinese herbs in proportion, pulverize them, and use ethanol-water (7:3) as solvent. Extract twice with ultrasonic assistance at 60℃ for 1 hour each time. Combine the extracts, concentrate under reduced pressure to extract paste, and freeze dry to obtain Chinese herbal extract powder.

[0028] The herbal formula is as follows: Clematis chinensis 12.9%, Angelica sinensis 6.5%, Rehmannia glutinosa 12.9%, Ligusticum chuanxiong 6.5%, Saffron 3.1%, Eucommia ulmoides 12.9%, Boswellia carterii 6.5%, Epimedium brevicornu 9.7%, Commiphora myrrha 6.5%, Achyranthes bidentata 9.7%, Borneol 3.1%, Chaenomeles speciosa 3.5%, Tripterygium wilfordii 6.2%;

[0029] S2. Preparation of layered electrospinning solution; the substrate is a blend of polycaprolactone (PCL) and polyvinyl alcohol (PVA), and the solution is prepared in layers as follows:

[0030] The outer layer is composed of PCL:PVA = 8:2 + traditional Chinese medicine extract (20%).

[0031] The intermediate layer consists of PCL:PVA = 5:5 + traditional Chinese medicine extract (30%).

[0032] The inner layer is composed of PCL:PVA = 2:8 + traditional Chinese medicine extract (40%).

[0033] The solvent is a mixture of hexafluoroisopropanol and ultrapure water in a 7:3 ratio;

[0034] S3. Layered electrospinning process: Using a three-nozzle electrospinning device, the prepared electrospinning solution is drawn into a sterile syringe, the needle is installed, air bubbles are removed, the voltage, solution pushing speed, distance between the needle spray and the receiving device, spinning temperature and humidity are set, spinning begins, and the solution is received using a flat plate or roller to obtain a micro-nano spun fiber membrane with good uniformity. After freeze-drying for 24-48 hours, it is ready for use.

[0035] The process parameters are shown in Table 1:

[0036]

[0037] The technical solutions described in the embodiments of this application have at least the following technical effects or advantages:

[0038] Through a layered structural design, the outer layer uses a high PCL ratio to form a hydrophobic and dense network, increasing stability. High voltage and low pushing speed create a microporous structure (porosity 50%-60%, pore size 0.5-1μm), providing good air permeability (WVTR ≥ 700 g / m²·24h). The middle layer uses a blend of PCL and PVA to balance hydrophobicity and hydrophilicity, allowing for synergistic sustained drug release through PVA swelling and PCL degradation (60% drug release within 72 hours). The inner layer uses a high PVA ratio for rapid water absorption and swelling, releasing 50% of the drug within 1 hour, resulting in rapid onset of action after skin contact.

[0039] The inner layer has a high drug loading capacity to quickly relieve symptoms, the middle layer releases drugs continuously, and the outer layer has a low drug loading capacity to reduce initial stimulation, thereby reducing the number of times it can be used, prolonging the efficacy, and reducing adverse reactions.

[0040] The "protection-slow release-rapid release" function can be achieved simply by adjusting the PCL / PVA ratio, simplifying the production process;

[0041] The Chinese herbal ingredients achieve a synergistic effect of anti-inflammation and repair. Clematis chinensis, Tripterygium wilfordii, and Epimedium brevicornu inhibit inflammatory factors and enhance immunity; frankincense and myrrh promote wound healing; borneol and saffron act as transdermal penetration enhancers to improve drug penetration efficiency.

[0042] The average fiber diameter was measured using a microscope, porosity was calculated using nitrogen gas adsorption, drug release was tested in physiological saline, and transdermal absorption rate was tested using simulated pig skin at 37℃ and 80% humidity. Tensile strength was tested according to GB / T 1040.3-2006. The films of different layers were tested separately, and the results are shown in Table 2.

[0043]

[0044] Example 2: The above example achieves the "protection-slow release-rapid release" function by adjusting the PCL / PVA ratio, simplifying the production process. However, in actual use, it was found that the increased pores in the outer layer, while increasing air permeability, also increased moisture absorption. Although the outer layer has high stability, the middle and inner layers will expand and the efficacy will decrease due to moisture in the air, ultimately leading to reduced efficacy and film life. Further improvements were made based on Example 1 to increase moisture resistance.

[0045] The outer layer of the film also contains 1% nano-silica particles with a particle size of 10-50 nm.

[0046] The technical solutions described in the embodiments of this application have at least the following technical effects or advantages:

[0047] Nano-silica possesses unique surface properties and a porous structure. Its small particle size, large specific surface area, and high surface energy give it strong adsorption capacity. Furthermore, its abundant porous structure provides numerous adsorption sites, enhancing its water absorption performance. Adding nano-silica particles to the outer layer of a film allows these particles to adsorb moisture from the air, reducing moisture penetration into the intermediate and inner layers, thereby increasing the film's moisture resistance (contact angle increased from 112° to 127°). Additionally, due to its large surface area, it exhibits a higher degree of bonding with the substrate in the outer layer, forming physical cross-linking points and increasing tensile strength (from 4.2 MPa to 5.5 MPa), thus enhancing the stability of the outer layer. The film's tear resistance is also enhanced, allowing for repeated application.

[0048] Nano-silica has high hardness and high wear resistance. When added, it can significantly improve the mechanical strength of the film, making it more durable, enhancing its anti-aging properties and weather resistance, and extending its service life. Silica also has good biocompatibility, which can reduce irritation or allergic reactions to the human body.

[0049] Example 3: Example 2 improved moisture resistance by adding nano-silica to the outer layer. To further improve the interlayer bonding, nano-silica was also added to the middle layer based on Example 2.

[0050] The intermediate layer of the film also contains 2.5% nano-silica particles with a particle size of 5-20 nm;

[0051] The technical solutions described in the embodiments of this application have at least the following technical effects or advantages:

[0052] Small-particle-size nano-silica forms microchannels in the PCL / PVA matrix, adsorbing drug molecules on the surface through adsorption-desorption effects, delaying the initial burst release, hindering the diffusion path of drug molecules, achieving linear release, and making the sustained release more stable; it also further improves the moisture resistance, with an expansion rate of 9.7% in 1 hour under 85% humidity.

[0053] The intermediate layer nanoparticles form hydrogen bonds / van der Waals forces with the inner and outer layer materials, increasing the interfacial bonding strength by 20%.

[0054] Furthermore, the surface modification of nano-silica with hydroxyl groups disrupts bacterial cell membranes (inhibition rate against Staphylococcus aureus ≥70%); it can also inhibit polymer chain segment movement, increasing the film thermal decomposition temperature from 220℃ to 250℃;

[0055] The nanoparticles in the outer and middle layers attract each other through physical interactions such as van der Waals forces, which affects their distribution and arrangement in the film. The particle size, shape, and surface properties of the nanoparticles all affect this physical interaction. Smaller particles are more likely to agglomerate near larger particles, forming a tighter packing structure at the junction of the outer and middle layers. This not only further prevents moisture from entering the middle and inner layers, but also increases the interfacial bonding strength and stability.

[0056] The tensile strength and drug release capacity of the film were tested, and the results are shown in Table 3.

[0057]

[0058] Example 4: Example 3 not only enhanced the moisture resistance by adding nanoparticles to the intermediate layer, but also further optimized the sustained-release capability. To further optimize the particle distribution, further improvements were made based on Example 3.

[0059] The intermediate layer contains a combination of nano-silica particles of different sizes, specifically: large particles: 20-50nm; small particles: 5-15nm; large particles: small particles = 3:1 (mass ratio).

[0060] The technical solutions described in the embodiments of this application have at least the following technical effects or advantages:

[0061] The large particles in the middle layer act as a framework to support the structure, forming the main body; the small particles fill the gaps between the large particles, reducing the porosity (down to 35%) and complicating the water infiltration path.

[0062] Large and small particles complement each other to form a denser network, enhancing the barrier properties of the film; small particles, with their high specific surface area, adsorb more drug molecules, delaying the initial burst release; large particles extend the drug diffusion path and work synergistically with small particles to achieve linear release (the 72-hour release rate is optimized from 53% to a more stable 50%), requiring drug molecules to navigate around the "maze-like" channels formed by large and small particles, increasing diffusion resistance; the initial burst release is reduced (the release rate of the inner layer in 1 hour is reduced from 50% to 40%), and the mid-term sustained release is linearized (the release rate of the middle layer in 24 hours is reduced from 29% to 26%).

[0063] Large particles disperse stress and improve tear resistance; small particles fill defect sites and improve tensile strength. The large and small particles form a "rigid-flexible" structure through physical cross-linking, which improves strength and increases tear resistance.

[0064] The intermediate layer mixed particles form a gradient interface with the inner layer (high PVA) and the outer layer (high PCL + large particles) through van der Waals forces and hydrogen bonds; the large particles in the outer layer are interlocked with the large particles in the intermediate layer, and the small particles in the intermediate layer can penetrate into the inner PVA network; thus, the outer and intermediate layers are interlocked, and the small particles in the inner layer are attracted by the large particles in the intermediate layer, thereby strengthening the three-layer structure and enhancing the interfacial bonding force.

[0065] The dense structure of the intermediate layer reduces the reverse permeation of moisture into the outer layer, delaying the hydrolysis of the outer PCL; the particle gradient distribution (large particles in the outer layer → mixed particles in the intermediate layer → a small number of permeated small particles in the inner layer) forms a continuous barrier, improving moisture resistance (film expansion rate <5% at 85% humidity); the densification of the intermediate layer reduces the moisture absorption and expansion of the inner layer, maintaining the high porosity of the inner layer (64%→62%), ensuring that the rapid release function is not affected by deliquescence.

[0066] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. For those skilled in the art, the present invention can have various modifications and variations. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A nanofilm for relieving bone injury pain, characterized in that, The three layers, including the inner layer, middle layer, and outer layer, all contain Chinese herbal extracts and a substrate. The nanofilm is prepared by electrospinning, and the substrate is a blend of polycaprolactone (PCL) and polyvinyl alcohol (PVA). The specific ratios of each layer are as follows: outer layer substrate is PCL:PVA = 8:2; middle layer substrate is PCL:PVA = 5:5; inner layer substrate is PCL:PVA = 2:

8. The outer layer contains 20% Chinese herbal extracts by mass, the middle layer contains 30% Chinese herbal extracts by mass, and the inner layer contains 40% Chinese herbal extracts by mass. The outer layer contains 1% nano-silica particles with a particle size of 10-50 nm. The intermediate layer contains 2.5% nano-silica particles, including large particles (20-50nm) and small particles (5-15nm); the mass ratio of large particles to small particles is 3:

1.

2. A method for preparing a nanofilm for relieving bone injury pain as described in claim 1, characterized in that, The specific steps include: S1. Preparation of Chinese herbal extract: The preparation method is as follows: Mix Chinese herbs in a certain proportion, pulverize them, and extract them twice with ultrasonic assistance at 60℃ for 1 hour each time using ethanol-water 7:3 as solvent. Combine the extracts, concentrate them under reduced pressure to obtain an extract, and freeze-dry them to obtain Chinese herbal extract powder. S2. The layered electrospinning solution is prepared by using a blend of polycaprolactone and polyvinyl alcohol as the base material and then layering the solution. S3. Layered electrospinning process: A three-nozzle electrospinning device is used. The prepared electrospinning solution is drawn into a sterile syringe, a needle is installed, air bubbles are removed, and the voltage, solution injection rate, distance between the needle and the receiving device, spinning temperature, and humidity are set. Spinning begins, and the solution is received using a flat plate or roller to obtain a uniform nanofiber membrane. After freeze-drying for 24-48 hours, it is ready for use. The process parameters are as follows: Outer layer: Voltage 20KV, pushing speed 0.05mm / min, receiving distance 18cm, 25℃, 30% humidity; Intermediate layer: voltage 15KV, pushing speed 0.1mm / min, receiving distance 15cm, 25℃, 40% humidity; Inner layer: voltage 10KV, pushing speed 0.2mm / min, receiving distance 12cm, 25℃, 50% humidity.

3. The method for preparing a nanofilm for relieving bone injury pain as described in claim 2, characterized in that, The proportions of Chinese herbs in step S1 are as follows: Tripterygium wilfordii 6.2%, Epimedium brevicornu 9.7%, Angelica sinensis 6.5%, Rehmannia glutinosa 12.9%, Ligusticum chuanxiong 6.5%, Crocus sativus 3.1%, Eucommia ulmoides 12.9%, Boswellia carterii 6.5%, Commiphora myrrha 6.5%, Achyranthes bidentata 9.7%, Borneol 3.1%, Chaenomeles speciosa 3.5%, and Clematis chinensis 12.9%.

4. The method for preparing a nanofilm for relieving bone injury pain as described in claim 2, characterized in that, In step S2, the ratio of each layer is as follows: the outer layer substrate is PCL:PVA = 8:2; the middle layer substrate is PCL:PVA = 5:5; the inner layer substrate is PCL:PVA = 2:8; and the solvent is a mixture of hexafluoroisopropanol and ultrapure water in a ratio of 7:

3.

5. The method for preparing a nanofilm for relieving bone injury pain as described in claim 4, characterized in that, The outer layer of the film contains 1% nano-silica particles with a particle size of 10-50 nm.

6. The method for preparing a nanofilm for relieving bone injury pain as described in claim 4, characterized in that, The intermediate layer contains a combination of nano-silica particles of different sizes, specifically: large particles: 20-50nm; small particles: 5-15nm; and a mass ratio of large particles to small particles of 3:1.

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