A film pasting agent, and a preparation method and application thereof

Abstract

This invention relates to the field of medical devices, specifically to a patch application, its preparation method, and its application. The patch comprises an immediate-release layer, a cross-linking layer, and a sustained-release layer; the cross-linking layer is placed between the immediate-release and sustained-release layers, with the immediate-release layer in contact with the skin; the immediate-release layer comprises a first microsphere, which has a polyvinyl alcohol coating and an ibuprofen core; the cross-linking layer is a calcium ion cross-linked membrane obtained by cross-linking sodium alginate and calcium chloride; the sustained-release layer comprises a second microsphere, which has a polylactic acid-glycolic acid copolymer coating and a diclofenac sodium core. The patch application provided by this invention can rapidly reduce inflammation and pain through the anti-inflammatory and analgesic microspheres and maintain the surgical patch for a certain period of time, while also providing local physical cooling. Compared with traditional patches, it alleviates postoperative pain to a certain extent and accelerates wound healing.

Description

Technical Field

[0001] This invention relates to the field of medical devices, specifically to a patch agent, its preparation method, and its application. Background Technology

[0002] Pain is a normal phenomenon during the surgical wound healing process and usually lasts for 3 to 7 days. Commonly used postoperative pain management methods include oral analgesics and pain pumps. While both methods can alleviate pain to some extent, they have significant limitations: oral analgesics are distributed throughout the body, with only a small amount reaching the wound site precisely, resulting in poor pain relief. They may also cause unnecessary toxicity to other organs and tissues, and require multiple daily doses to maintain pain control during wound healing. Pain pumps are not only expensive but also require continuous use for several days after surgery, causing considerable inconvenience to daily activities and life.

[0003] Currently, there are already shell-type patches for postoperative wound analgesia, see [Uematsu M, Tamai K, Hyakutake H, et al. The Efficacy of Systemic Transdermal Diclofenac Patch for Postoperative Pain After Lumbar Spinal Surgery. Spine (Phila Pa 1976). 2025;50(3):201-206]. However, traditional patches do not have anti-inflammatory and analgesic effects. Existing technologies achieve their effects by loading drugs onto the patch in different scenarios, but most of them use a single layer to load drugs, see [Rocha Neto JBM, Lima GG, Fiamingo A, et al. Controlling antimicrobial activity and drug loading capacity of chitosan-based layer-by-layer films. Int J Biol Macromol. 2021;172:154-161]. A few use microspheres for controlled-release drug delivery, see [Sharma S, Pankaj, Kumar S, Sharma N, Verma S. Cutting-Edge Developments and Patent Trends in Microspheres Drug Delivery: A Comprehensive Overview. Recent Pat Nanotechnol. 2025;19(3):434-452]. Even with double-layer drug-loaded patches, there is still the problem of drug interpenetration within the double-layer patch, see [Chen L, Tang Y, Zhao K, et al. Sequential release of double drug (gradeddistribution) loaded gelatin microspheres / PMMA bone cement. J Mater Chem B. 2021;9(2):508-522].

[0004] For example, in the prior art, patent application CN112315965A discloses a method for preparing a composite mesh patch loaded with PLGA / triamcinolone microspheres. The composite mesh patch is used to prevent esophageal stenosis after ESD surgery. Specifically, firstly, PLGA is used to encapsulate triamcinolone to form microspheres, which are then loaded into a chitosan / collagen mesh patch cross-linked with genipin. Then, the in vitro long-acting release curve of triamcinolone in the composite patch is detected, and its inhibitory effect on fibroblast activation is confirmed by in vitro cell experiments. In a rat dermal defect model, the inhibitory effect of the composite patch on scar contraction is also preliminarily verified, indicating the potential significance of the composite mesh patch for the prevention of stenosis after ESD surgery.

[0005] Patent application CN200710060576.7 discloses a sterile patch for postoperative wound analgesia, comprising an anti-adhesive layer, a drug reservoir layer, and a backing layer. The drug reservoir layer consists of a matrix material and microspheres loaded with local anesthetic, wherein the matrix material is a film-forming polymer. This sterile patch, used for postoperative wound analgesia, can alleviate significant pain for patients during wound healing. However, the above solution only involves the direct film formation of sustained-release microspheres in a single-layer patch, resulting in slow onset of action, lack of physical cooling to reduce local swelling, and a limited range of drug types.

[0006] Patent application CN201110066217.9 discloses a medicated film for treating oral ulcers. The film comprises a matrix and the following raw materials: 15-25g of Gallnut, 5-10g of Indigo Naturalis, 10-15g of Atractylodes Rhizome, 10-15g of Lithospermum erythrorhizon, and 3-5g of Pearl Powder. This medicated film overcomes the shortcomings of existing powdered medications, such as long treatment time, short drug adhesion time, and inconvenient use. It can be applied to the affected area, is well absorbed, has a rapid onset of action, high drug utilization rate, and a low recurrence rate. Furthermore, the film is non-irritating, has a pleasant taste, is quickly absorbed, is convenient and hygienic to use, and has a simple preparation process, making it particularly suitable for hospital preparations and industrial production. It is an effective drug for treating oral ulcers worthy of promotion. However, this solution only involves adding the drug to the film and does not address drug sustained release.

[0007] Therefore, there is still room for improvement in the shell coating agents disclosed in the prior art. Summary of the Invention

[0008] The purpose of this invention is to provide a surgical patch, its preparation method, and its application. This patch can rapidly reduce inflammation and pain through anti-inflammatory and analgesic microspheres and maintain the effect for a certain period of time. It can also provide local physical cooling. Compared with traditional patches, this can alleviate postoperative pain for patients to a certain extent and accelerate wound healing.

[0009] To achieve the above objectives, the present invention has the following specific technical solutions:

[0010] In a first aspect, the present invention provides a patch, the patch comprising an immediate-release layer, a cross-linking layer, and a sustained-release layer; the cross-linking layer is disposed between the immediate-release layer and the sustained-release layer, the immediate-release layer being in contact with the skin; the immediate-release layer comprises a first microsphere, the first microsphere having a polyvinyl alcohol coating layer and an ibuprofen core; the cross-linking layer is a calcium ion cross-linking membrane, which is obtained by cross-linking sodium alginate and calcium chloride; the sustained-release layer comprises a second microsphere, the second microsphere having a polylactic acid-glycolic acid copolymer coating layer and a diclofenac sodium core.

[0011] In this invention, the immediate-release layer is composed of polyvinyl alcohol (PVA) microspheres, which rapidly dissolve and release ibuprofen upon contact with the skin, achieving rapid anti-inflammatory and analgesic effects. The cross-linked layer serves as an isolation layer and a physical cooling layer, not only isolating the immediate-release and sustained-release layers to prevent drug interpenetration but also providing a cooling effect to reduce local swelling. The sustained-release layer is composed of polylactic-co-glycolic acid (PLGA) microspheres containing diclofenac sodium, enabling sustained drug release over a long period and maintaining efficacy. The synergistic effect of these three layers structurally ensures that the product possesses both immediate-release and sustained-release functions, as well as unique physical cooling properties. This invention employs a layered drug loading method, with the immediate-release layer loaded with ibuprofen and the sustained-release layer loaded with diclofenac sodium, better meeting the needs of complex treatments.

[0012] In this invention, the first microsphere is a PVA microsphere, which is a fast-release drug carrier that dissolves in water within 3 minutes using polyvinyl alcohol as a carrier. The second microsphere is a PLGA microsphere, which is a tiny particle made of PLGA polymer and is commonly used in drug delivery systems. It can encapsulate drugs and release them into the body continuously over a long period of time through controlled release, reducing the frequency of drug administration.

[0013] In this invention, ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID), a small-molecule, fast-release drug used to relieve mild to moderate pain. Diclofenac sodium is a nonsteroidal anti-inflammatory drug (NSAID) with a longer duration of action.

[0014] In this invention, the calcium ion crosslinking membrane is an ion network isolation membrane formed by the reaction of sodium alginate and calcium chloride.

[0015] This invention discovers that the main reason for the slow onset of action of patch-based medications is that existing technologies only use a single-layer structure of sustained-release microspheres (such as PLGA microspheres), and the drug release is controlled by the sustained-release material, resulting in insufficient initial drug concentration and ultimately delayed onset of action. In contrast, this invention sets up a PVA fast-release microsphere layer (5μm~10μm small particle size) loaded with ibuprofen as the first layer that directly contacts the skin. Through the rapid solubility of PVA and the small size effect of the microspheres, combined with the selection of ibuprofen, specifically, the polyvinyl alcohol carrier can quickly dissolve after contact with skin tissue fluid, allowing high concentrations of ibuprofen to be rapidly released to the site of action, significantly shortening the onset time and solving the core defect of slow onset of action of patch-based medications.

[0016] This invention discovers that existing single-layer patch structures, lacking materials or designs with heat-absorbing and cooling functions, cannot provide a physical cooling effect to alleviate the local swelling and burning sensation associated with inflammatory responses. In contrast, this invention uses a hydrogel layer with sodium alginate-calcium ion crosslinking as the intermediate layer. This layer is rich in water, and its evaporative heat-absorbing properties and inherent thermal conductivity effectively reduce the local temperature at the application site. Furthermore, the ion network structure prevents the two drug layers from interpenetrating.

[0017] In some embodiments, the particle size of the first microsphere is 5 μm to 10 μm. Exemplarily, the particle size of the first microsphere can be 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10 μm, or a value within a range of any two of these.

[0018] In some embodiments, the particle size of the second microsphere is 20 μm to 50 μm. Exemplarily, the particle size of the second microsphere can be 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50 μm, or a value within a range of any two of these.

[0019] In this invention, the first microsphere has a particle size of 5μm to 10μm, and the second microsphere has a particle size of 20μm to 50μm. Specific particle sizes contribute to the drug release performance and the overall performance of the patch. While the first microsphere meets the requirement of "immediate onset of action," the specific surface area is controlled by adjusting the particle size of the first microsphere in the immediate-release layer, thereby regulating the dissolution rate of ibuprofen. This ensures rapid drug release within 5 minutes of contact with the affected area, achieving immediate analgesia and avoiding delayed dissolution or local irritation. Simultaneously, by synergistically controlling the particle size of the second microsphere in the sustained-release layer, the larger particle size of the second microsphere, as part of the sustained-release layer, provides higher mechanical strength, supporting the overall structural stability of the patch. It also reduces the direct contact area with the immediate-release layer, lowering the risk of premature drug cross-penetration. Furthermore, the above configuration, combined with the aforementioned cross-linking layer, further enhances the isolation effect.

[0020] In some embodiments, the porosity of the crosslinked layer is 60% to 85%. Exemplarily, the porosity of the crosslinked layer can be 60%, 62%, 64%, 66%, 68%, 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 85%, or a value within a range of any two of these.

[0021] This invention balances the cooling effect of moisture evaporation with the drug barrier function by controlling the porosity of the cross-linked layer, effectively preventing interpenetration between the immediate-release and sustained-release drugs. Specifically, the density of the calcium ion cross-linked layer is precisely controlled by the sodium alginate concentration and calcium chloride cross-linking time to balance mechanical strength with the cooling effect caused by moisture evaporation. This structural design achieves an organic combination of physical cooling and gradient drug release, significantly improving postoperative wound recovery efficiency.

[0022] In some embodiments, the first microspheres are prepared from a first aqueous phase raw material and a first oil phase raw material, wherein the first aqueous phase raw material includes an aqueous solution of polyvinyl alcohol and the first oil phase raw material includes an ethyl acetate solution of ibuprofen.

[0023] In some embodiments, the volume ratio of the first aqueous phase feedstock to the first oil phase feedstock is (2~5):1. Exemplarily, the volume ratio of the first aqueous phase feedstock to the first oil phase feedstock can be 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1, or a numerical ratio between any two of these ranges.

[0024] In some embodiments, the concentration of the polyvinyl alcohol aqueous solution is 1% to 5%. Exemplarily, the concentration of the polyvinyl alcohol aqueous solution can be 1%, 2%, 3%, 4%, 5%, or a value between any two of these.

[0025] In some embodiments, the concentration of the ibuprofen ethyl acetate solution is 5% to 15%. Exemplarily, the concentration of the ibuprofen ethyl acetate solution can be 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or a value within a range of any two of these.

[0026] In some embodiments, the second microspheres are prepared from a second aqueous phase raw material and a second oil phase raw material, wherein the second aqueous phase raw material includes an aqueous solution of polyvinyl alcohol, and the second oil phase raw material is obtained by dissolving polylactic acid-glycolic acid copolymer and diclofenac sodium in ethyl acetate.

[0027] In some embodiments, the volume ratio of the second aqueous phase feedstock to the second oil phase feedstock is (3~6):1. Exemplarily, the volume ratio of the second aqueous phase feedstock to the second oil phase feedstock can be 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1, or a numerical ratio between any two of these ranges.

[0028] In some embodiments, the concentration of the polyvinyl alcohol aqueous solution is 1% to 3%. Exemplarily, the concentration of the polyvinyl alcohol aqueous solution can be 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, or a value within a range of any two of these.

[0029] In some embodiments, the mass ratio of the polylactic acid-glycolic acid copolymer to diclofenac sodium in the second oil phase raw material is (2~5):1, which can be, for example, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1, or any range thereof; the total concentration of the polylactic acid-glycolic acid copolymer and diclofenac sodium is 10%~25%, which can be, for example, 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 25%, or any range thereof.

[0030] The particle size of PLGA microspheres in the sustained-release layer is synergistically adjusted with the copolymer ratio to control their specific surface area and membrane pore diffusion pathways, thereby precisely regulating the release kinetics of diclofenac sodium and ensuring its continuous release over 24 hours, maintaining an effective blood drug concentration. Simultaneously, the adjustable ratio of lactic acid to glycolic acid in the PLGA copolymer further optimizes the degradation rate and drug release behavior, achieving long-lasting anti-inflammatory effects.

[0031] Secondly, the present invention provides a method for preparing the above-mentioned adhesive film, the method comprising:

[0032] Step 1:

[0033] S1: Preparation of the first microspheres:

[0034] S1-1: Polyvinyl alcohol is dissolved in water to obtain an aqueous solution of polyvinyl alcohol, which is the first aqueous phase raw material; ibuprofen is dissolved in ethyl acetate to obtain an ethyl acetate solution of ibuprofen, which is the first oil phase raw material.

[0035] S1-2: The first aqueous phase raw material and the first oil phase raw material are mixed and homogenized to obtain the first emulsion;

[0036] S1-3: The first emulsion is atomized through a nozzle and then dried to obtain a microsphere suspension. The suspension is centrifuged, the supernatant is discarded, and the first microspheres with a particle size of 5μm~10μm are collected.

[0037] S2: Preparation of the second microspheres:

[0038] S2-1: Polyvinyl alcohol is dissolved in water to obtain an aqueous solution of polyvinyl alcohol, which is the second aqueous phase raw material; polylactic acid-glycolic acid copolymer and diclofenac sodium are dissolved in ethyl acetate to obtain the second oil phase raw material;

[0039] S2-2: Microfluidic emulsification of the second aqueous phase raw material and the second oil phase raw material is performed to obtain the second emulsion;

[0040] S2-3: The emulsion is subjected to solvent removal treatment, then freeze-dried, and the second microspheres of 20μm~50μm are sieved.

[0041] S3: Preparation of cross-linking layer raw materials:

[0042] Sodium alginate was dissolved in water to obtain an aqueous solution of sodium alginate, and calcium chloride was added to the aqueous solution of sodium alginate for crosslinking.

[0043] Step 2:

[0044] The first microspheres were dissolved in PBS buffer to obtain the immediate-release layer material; the second microspheres were dissolved in 1%~10% (w / v) PLGA solution to obtain the sustained-release layer material; the immediate-release layer material, the sustained-release layer material and the crosslinking layer material were simultaneously extruded to obtain a composite film; and the composite film was UV cured.

[0045] In some embodiments, during the homogenization process in step 1, primary emulsification is performed at 30 MPa to 50 MPa, followed by secondary emulsification at 80 MPa to 120 MPa. During microfluidic emulsification, the microchannel width is 100 μm to 300 μm, the flow rate of the second oil phase feedstock is 0.1 ml / min to 0.3 ml / min, and the flow rate of the second aqueous phase feedstock is 0.8 ml / min to 1.2 ml / min.

[0046] In some embodiments, in step 2, the immediate-release layer material, the sustained-release layer material, and the crosslinking layer material are simultaneously extruded at 45°C to 55°C and 0.5MPa to 1.0MPa to form a composite film with a total thickness of 250μm to 350μm.

[0047] In this invention, the patch product simultaneously achieves a drug release mode combining immediate and sustained release. The immediate-release ibuprofen layer provides rapid pain relief, while the sustained-release diclofenac sodium layer provides sustained anti-inflammatory and analgesic effects over a longer period, meeting the treatment needs at different stages. This rational drug release design prolongs the duration of drug action, reduces the frequency of administration, and improves therapeutic efficacy.

[0048] Thirdly, the present invention also provides the use of the above-described adhesive film or the adhesive film prepared by the above-described preparation method in the preparation of products for postoperative wound healing.

[0049] In this invention, the patch is designed to address the shortcomings of traditional patches by achieving rapid and sustained anti-inflammatory and analgesic effects through anti-inflammatory and analgesic microspheres, while also providing local physical cooling. These effects alleviate postoperative pain, accelerate wound healing, and reduce inflammatory responses, demonstrating significant application value in the surgical field.

[0050] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0051] The patch agent, its preparation method, and its application provided by this invention can rapidly reduce inflammation and pain through anti-inflammatory and analgesic microspheres and maintain the surgical patch for a certain period of time. At the same time, it can also provide local physical cooling. Compared with traditional patches, it can alleviate postoperative pain for patients to a certain extent and accelerate wound healing.

[0052] In this invention, the descriptions in the specification are merely exemplary and explanatory, and do not limit the scope of protection of this invention. Attached Figure Description

[0053] To more clearly illustrate the technical solutions in this invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of this invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0054] Figure 1 This is a scanning electron microscope image of the quick-release layer microspheres of the adhesive film provided in Example 1 of the present invention.

[0055] Figure 2 This is one of the scanning electron microscope images of the sustained-release layer microspheres of the adhesive film provided in Example 1 of the present invention.

[0056] Figure 3 This is the second scanning electron microscope image of the sustained-release layer microspheres of the film-forming agent provided in Example 1 of the present invention.

[0057] Figure 4 This is a cross-sectional scanning electron microscope image of the composite film of the adhesive agent in Example 1 of the present invention.

[0058] Figure 5 This is the release curve of the immediate-release layer microspheres of Example 1 provided by the present invention.

[0059] Figure 6 This is the release curve of the sustained-release layer microspheres of Example 1 provided by the present invention. Detailed Implementation

[0060] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of this invention, not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention. In the embodiments provided in this specification, unless specific techniques or conditions are specified, they should be performed according to the techniques or conditions described in the literature in this field, or according to the product instructions. Reagents or instruments used without specified manufacturers are all conventional products that can be purchased through legitimate channels. In the following embodiments, "parts" refers to parts by weight, and the specific unit can be g or kg, etc.

[0061] In the following embodiments, unless otherwise specified, "%" refers to mass-volume percentage, i.e., "w / v".

[0062] Example 1

[0063] This embodiment provides a film-forming agent, the preparation method of which includes the following steps:

[0064] (1) Preparation of immediate-release layer microspheres (first microspheres)

[0065] S1-1: Dissolve polyvinyl alcohol (PVA) in pure water, heat in a water bath at 70°C, and stir until PVA is completely dissolved. After dissolution, cool to room temperature to obtain the first aqueous phase raw material (3% PVA aqueous solution); dissolve ibuprofen in the organic solvent ethyl acetate to obtain the first oil phase raw material with a concentration of 10%.

[0066] S1-2: The prepared first oil phase raw material is slowly added dropwise to the first aqueous phase raw material, and the mixture is continuously stirred and homogenized under high pressure at 40 MPa and 10000 rpm for 10 min to obtain the primary emulsion (oil-in-water O / W); the primary emulsion is homogenized under high pressure at 100 MPa and 15000 rpm for 5 min to undergo secondary emulsification to obtain the first emulsion; wherein the volume ratio of the first aqueous phase raw material to the first oil phase raw material is 4:1.

[0067] S1-3: The first emulsion is pumped into a centrifugal spray drying tower (inlet temperature 80℃, outlet temperature 40℃), atomized through nozzles, and enters the drying chamber. The solvent evaporates to form solid microspheres. The solid microspheres are redispersed in water to obtain a PVA-stabilized ibuprofen microsphere suspension. The suspension is poured into centrifuge tubes and centrifuged at 5000 rpm to settle the microspheres. The supernatant is discarded, and the immediate-release microspheres with a particle size of 5μm~10μm are collected. To remove residual PVA, solvent, and surface-adsorbed drug, the microsphere precipitate obtained by centrifugation is resuspended in pure water, centrifuged again, and the supernatant is discarded. This process is repeated 4 times to obtain the first microsphere.

[0068] The scanning electron microscope image of the first microsphere can be found here. Figure 1 .

[0069] (2) Preparation of sustained-release layer microspheres (second microspheres)

[0070] S2-1: Dissolve 2g PLGA and 0.5g diclofenac sodium in 20mL ethyl acetate to obtain the second oil phase feedstock;

[0071] S2-2: Dissolve polyvinyl alcohol (PVA) in pure water, heat in a water bath at 70°C, and stir until PVA is completely dissolved. After dissolution, cool to room temperature to obtain the second aqueous phase raw material (2% PVA solution).

[0072] S2-3: The second oil phase raw material and the second aqueous phase raw material are mixed in a microfluidic emulsification device with a channel width of 200μm, and a second emulsion (water-in-oil-in-water, W / O / W) is generated at a flow rate of 0.2ml / min for the oil phase and 1ml / min for the aqueous phase.

[0073] S2-4: The second emulsion is transferred to a magnetic stirring reactor and stirred for 4 hours to evaporate the solvent. Then it is cured in a freeze dryer at -40℃ for 24 hours, and the second microspheres of 20μm~50μm are sieved.

[0074] The scanning electron microscope image of the second microsphere can be found here. Figure 2 and Figure 3 .

[0075] (3) Preparation of cross-linking layer raw materials:

[0076] Sodium alginate was dissolved in pure water to obtain a 2wt% sodium alginate aqueous solution; 5ml of 10% calcium chloride was added to 10ml of sodium alginate aqueous solution to crosslink into a hydrogel.

[0077] (4) Preparation of composite membrane:

[0078] 0.5g of immediate-release microspheres were suspended in 5ml of PBS buffer to obtain the immediate-release layer material; 0.8g of sustained-release microspheres were mixed with 5ml of 5% PLGA solution to obtain the sustained-release layer material; the microspheres were simultaneously extruded using a three-channel co-extrusion die (Collin Teach-Line™, Germany) at a constant temperature of 50℃ and a pressure of 0.8MPa to form a composite film with a total thickness of 300μm.

[0079] The composite film is immediately inserted into a UV curing tunnel (365nm, intensity 80mW / cm², exposure for 10 seconds) to achieve instantaneous interlayer bonding.

[0080] Cross-sectional scanning electron microscope images of the composite membrane are shown below. Figure 4 , Figure 4The upper layer consists of rapidly releasing microspheres with smaller particle sizes, the middle layer is a hydrogel to prevent interpenetration, and the lower layer is a sustained-release microsphere with larger particle sizes. The porosity of the cross-linked layer is 75%.

[0081] Example 2

[0082] The only difference between the film-forming agent provided in this embodiment and that in Example 1 is that the primary emulsion is not subjected to secondary emulsification, and the first microspheres with a particle size of 20μm~50μm are collected after centrifugation.

[0083] Example 3

[0084] The difference between the film-forming agent provided in this embodiment and that in Example 1 is only that: the microfluidic emulsification device has a channel width of 100μm, the emulsion is transferred into a magnetically stirred reactor (4 hours) to evaporate the solvent, and then it is cured by a freeze dryer (-40℃, 24h) and the second microspheres of 10μm~20μm are sieved.

[0085] Comparative Example 1

[0086] The only difference between the adhesive film provided in this embodiment and that in Example 1 is that it does not contain a crosslinking layer.

[0087] Comparative Example 2

[0088] The only difference between the film agent provided in this embodiment and that in Example 1 is that it does not contain a cross-linking layer and a sustained-release layer.

[0089] Test case

[0090] 1. Immediate-release layer release curve

[0091] Test method: Immediate-release microspheres (PVA-ibuprofen) were placed in simulated tissue fluid (PBS, pH 7.4) and stirred at 37°C. Samples were taken at different time points (0.5 min, 1 min, 2 min, 3 min, 5 min, 10 min) to determine the cumulative release rate of ibuprofen. The cumulative release rates of the immediate-release microspheres of Examples 1-3 and Comparative Examples 1-2 within 3 min are shown in Table 1.

[0092] Test results: The release curve results of the immediate-release layer in Example 1 are shown below. Figure 5 ,according to Figure 5 It can be seen that the immediate-release microspheres release more than 80% of the drug within 3 minutes.

[0093] Table 1

[0094] Cumulative release rate within 3 minutes Example 1 80% Example 2 30% Example 3 80% Comparative Example 1 79% Comparative Example 2 80%

[0095] 2. Release curve of the sustained-release layer

[0096] Test method: The sustained-release microspheres (PLGA-diclofenac sodium) of Examples 1-3 and Comparative Example 1 were placed in simulated tissue fluid and stirred at 37°C. Samples were taken at different time points (2h, 4h, 8h, 12h, 24h) to determine the cumulative release rate of diclofenac sodium.

[0097] Test results: The results for the sustained-release microspheres in Example 1 are shown in [the table below]. Figure 6 ,according to Figure 6 It can be seen that the release curve conforms to the characteristics of sustained release, with about 50% released after 12 hours and more than 60% released after 24 hours.

[0098] Table 2

[0099] Cumulative release rate within 12 hours Cumulative release rate within 24 hours Example 1 More than 50% More than 60% Example 2 More than 50% More than 60% Example 3 More than 60% More than 80% Comparative Example 1 More than 50% More than 60%

[0100] 3. Cooling effect experiment

[0101] Test method: The temperature change of the film agents of Examples 1-3 and Comparative Examples 1-2 applied to simulated heat-generating skin models (pigskin heated to 38°C) was measured using a thermal imager, and the temperature was recorded at 0 min, 5 min, 10 min, 30 min and 60 min.

[0102] Table 3

[0103] Test Results Example 1 The local temperature decreases by approximately 2°C to 3°C within 10 minutes of application. Example 2 The local temperature decreases by approximately 2°C to 3°C within 30 minutes of application. Example 3 Within 10 minutes of application, the local temperature will decrease by approximately 1.5℃~2.5℃. Comparative Example 1 Within 10 minutes of application, the local temperature will decrease by approximately 0.2~0.5℃. Comparative Example 2 Within 10 minutes of application, the local temperature will decrease by approximately 0.2℃~0.3℃.

[0104] 4. Dosing frequency experiment

[0105] The dosing frequency of the patches from Examples 1-3 and Comparative Examples 1-2 was tested as follows: Ten healthy adult volunteers were randomly divided into five groups of two. Patches from Examples 1-3 and Comparative Examples 1-2 were applied to the inner forearm of each volunteer. Venous blood (3-5 mL) was collected from each subject every 12 hours to assess the maintenance of effective drug concentrations. Monitoring continued for 48 hours. The concentrations of ibuprofen and diclofenac sodium in plasma were determined using high-performance liquid chromatography-mass spectrometry (HPLC-MS / MS). The specific detection methods are as follows:

[0106] (1) Ibuprofen detection: Diclofenac sodium was used as an internal standard. After protein precipitation in acetonitrile, the supernatant of the plasma sample was injected for analysis. A C18 column (250 mm × 4.6 mm, 5 μm) was used. The mobile phase was methanol-0.1% formic acid aqueous solution (75:25, v / v), the flow rate was 1.0 mL / min, and the detection wavelength was 220 nm.

[0107] (2) Detection of diclofenac sodium: Ibuprofen was used as an internal standard. Plasma samples were analyzed after liquid-liquid extraction. Chromatographic conditions were the same as above, and the detection wavelength was 275 nm.

[0108] The results are shown in Table 4. In Example 1, the effective blood drug concentration was maintained for 24 hours within 48 hours. Repeated administration every 24 hours was required to achieve the same therapeutic effect, and the dosing frequency was significantly lower than that of Examples 2-3 and Comparative Examples 1-2. This demonstrates that the synergistic effect of the cross-linking layer and the sustained-release layer not only significantly improves the controllability of drug release but also effectively prolongs the duration of efficacy, meeting the "long-acting, stable, and safe" quality requirements for transdermal drug delivery systems stipulated in the Chinese Pharmacopoeia.

[0109] Test results:

[0110] Table 4

[0111] Dosage frequency Example 1 Change it approximately every 24 hours. Example 2 Change it approximately every 24 hours. Example 3 Change every 10-12 hours. Comparative Example 1 Change every 5-7 hours. Comparative Example 2 Change every 3-4 hours.

[0112] The results showed that the three-layer co-extruded film of Example 1 could be replaced every 24 hours. This was because the immediate-release layer (PVA microspheres) rapidly released ibuprofen within 3 minutes of contact with the skin, achieving rapid onset of action, while the sustained-release layer (PLGA microspheres) maintained a stable blood drug concentration for 24 hours by controlling the release of diclofenac sodium.

[0113] The three-layer structure of Example 2 has a certain sustained-release capacity, and theoretically the dosing interval is not much different from that of Example 1. However, due to the large particle size of the first microparticle in the immediate-release layer, it is difficult to meet the requirement of immediate effect, so the patient experience is poor in actual application. Although the three-layer structure of Example 3 has a certain sustained-release capacity, the small particle size of the second microparticle in the sustained-release layer leads to a significantly faster drug release, so the replacement frequency is more frequent than that of Example 1.

[0114] Comparative Example 1, lacking a cross-linking layer for protection, experienced severe drug burst release, resulting in a short duration of effective blood drug concentration and a significantly shortened dosing interval.

[0115] In contrast, the conventional single-layer patch in Comparative Example 2 lacks a sustained-release mechanism, causing the drug to be released rapidly within a short period of time, resulting in a rapid drop in blood drug concentration. Frequent replacement is required to continuously relieve pain and inflammation.

[0116] The above differences further validate the synergistic advantages of the three-layer structure design in controlling the release rate and prolonging the duration of action.

[0117] The above are merely embodiments of the present invention and are not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principle of the present invention should be included within the scope of the claims of the present invention.

Claims

1. A film-forming agent, wherein, The film includes an immediate-release layer, a cross-linking layer, and a sustained-release layer; the cross-linking layer is placed between the immediate-release layer and the sustained-release layer, and the immediate-release layer is in contact with the skin; The immediate-release layer includes a first microsphere, which has a polyvinyl alcohol coating and an ibuprofen core. The cross-linked layer is a calcium ion cross-linked membrane, which is obtained by cross-linking sodium alginate and calcium chloride. The sustained-release layer includes a second microsphere, which has a polylactic acid-glycolic acid copolymer as a coating layer and diclofenac sodium as a core.

2. The adhesive film according to claim 1, wherein, The first microsphere has a particle size of 5 μm to 10 μm, and / or the second microsphere has a particle size of 20 μm to 50 μm.

3. The adhesive film according to claim 1 or 2, wherein, The porosity of the cross-linked layer is 60%~85%.

4. The adhesive film according to any one of claims 1 to 3, wherein, The first microsphere is prepared from a first aqueous phase raw material and a first oil phase raw material. The first aqueous phase raw material includes an aqueous solution of polyvinyl alcohol, and the first oil phase raw material includes an ethyl acetate solution of ibuprofen.

5. The adhesive film according to claim 4, wherein, The volume ratio of the first aqueous phase feedstock to the first oil phase feedstock is (2~5):1; and / or, The concentration of the polyvinyl alcohol aqueous solution is 1% to 5%; and / or, The concentration of the ibuprofen ethyl acetate solution is 5% to 15%.

6. The adhesive film according to any one of claims 1 to 5, wherein, The second microsphere is prepared from a second aqueous phase raw material and a second oil phase raw material. The second aqueous phase raw material includes an aqueous solution of polyvinyl alcohol, and the second oil phase raw material is obtained by dissolving polylactic acid-glycolic acid copolymer and diclofenac sodium in ethyl acetate.

7. The adhesive film according to claim 6, wherein, The volume ratio of the second aqueous phase feedstock to the second oil phase feedstock is (3~6):1; and / or, The concentration of the polyvinyl alcohol aqueous solution is 1% to 3%; and / or, The mass ratio of the polylactic acid-glycolic acid copolymer to diclofenac sodium is (2~5):1, and the total concentration of the polylactic acid-glycolic acid copolymer and diclofenac sodium is 10%~25%.

8. The method for preparing the adhesive film according to any one of claims 1 to 7, wherein, The preparation method includes: Step 1: S1: Preparation of the first microspheres: S1-1: Polyvinyl alcohol is dissolved in water to obtain an aqueous solution of polyvinyl alcohol, which is the first aqueous phase raw material; ibuprofen is dissolved in ethyl acetate to obtain an ethyl acetate solution of ibuprofen, which is the first oil phase raw material. S1-2: The first aqueous phase raw material and the first oil phase raw material are mixed and homogenized to obtain the first emulsion; S1-3: The first emulsion is atomized through a nozzle and then dried. The treated microsphere powder is then redispersed in water to obtain a microsphere suspension. The suspension is centrifuged, the supernatant is discarded, and the first microspheres with a particle size of 5μm~10μm are collected. S2: Preparation of the second microspheres: S2-1: Polyvinyl alcohol is dissolved in water to obtain an aqueous solution of polyvinyl alcohol, which is the second aqueous phase raw material; polylactic acid-glycolic acid copolymer and diclofenac sodium are dissolved in ethyl acetate to obtain the second oil phase raw material; S2-2: Microfluidic emulsification of the second aqueous phase raw material and the second oil phase raw material is performed to obtain the second emulsion; S2-3: The emulsion is subjected to solvent removal treatment, then freeze-dried, and the second microspheres of 20μm~50μm are sieved. S3: Preparation of cross-linking layer raw materials: Sodium alginate was dissolved in water to obtain an aqueous solution of sodium alginate, and calcium chloride was added to the aqueous solution of sodium alginate for crosslinking. Step 2: The first microspheres were dissolved in PBS buffer to obtain the immediate release layer material; The second microspheres were dissolved in PLGA solution to obtain the sustained-release layer material; The immediate-release layer material, the sustained-release layer material, and the crosslinking layer material are extruded simultaneously to obtain a composite film, which is then UV-cured.

9. The method for preparing the adhesive film according to claim 8, wherein, In step 1, during the homogenization process, primary emulsification is performed at 30 MPa to 50 MPa, followed by secondary emulsification at 80 MPa to 120 MPa; during microfluidic emulsification, the microchannel width is 100 μm to 300 μm, the flow rate of the second oil phase feedstock is 0.1 to 0.3 ml / min, and the flow rate of the second aqueous phase feedstock is 0.8 ml / min to 1.2 ml / min; and / or, In step 2, the immediate-release layer material, the sustained-release layer material, and the crosslinking layer material are simultaneously extruded at 45℃~55℃ and 0.5MPa~1.0MPa to form a composite film with a total thickness of 250μm~350μm.

10. The use of the patch agent according to any one of claims 1 to 7 or the patch agent prepared by the preparation method according to claims 8 to 9 in the preparation of products for postoperative wound healing.

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