A method for preparing medicinal aluminum foil

Abstract

The invention relates to the technical field of aluminum foil, and discloses a method for preparing a medicinal aluminum foil, comprising the following steps: performing surface passivation treatment on a medical aluminum foil to obtain a surface passivated aluminum foil substrate; performing ultrasonic-assisted micromachining treatment on the surface passivated aluminum foil substrate to form a microchannel network structure aluminum foil; performing surface micro-region patterning treatment on the microchannel network structure aluminum foil to form a hydrophilic / hydrophobic micro-region patterned structure aluminum foil; selectively depositing a thermosensitive polymer and a pH-sensitive polymer on a key node region of the hydrophilic / hydrophobic micro-region patterned structure aluminum foil to form a microfluidic patterned antibacterial medicinal aluminum foil with environmental responsiveness; the aluminum foil prepared by the preparation method of the invention can accurately trigger drug release according to changes in oral temperature or pH value.

Description

Technical Field

[0001] The invention relates to the technical field of aluminum foil, and more specifically, to a method for preparing medicinal aluminum foil. Background Art

[0002] At present, medicinal aluminum foil is widely used in the field of pharmaceutical packaging, mainly for sealing, protecting and storing medicines.

[0003] However, existing pharmaceutical aluminum foil is mainly used as a passive packaging material and lacks the ability to actively control the drug release process. In actual applications, drugs often show a "burst release" phenomenon, that is, a large amount of drug is released at the beginning of use, resulting in excessive local drug concentration, while the concentration is lower than the therapeutic concentration in the later stage, affecting the therapeutic effect. Summary of the invention

[0004] The invention provides a method for preparing a medicinal aluminum foil, which solves the technical problem of uncontrollable drug release in the related art.

[0005] The present invention provides a method for preparing a medicinal aluminum foil, comprising:

[0006] Step 1: Use a surface passivation process to treat medical aluminum foil to prepare a basic carrier material;

[0007] Medical grade aluminum foil (thickness 8-12 μm) was cut into the required size (3 cm × 5 cm), and the aluminum foil was pre-cleaned using an ultrasonic cleaner at a frequency of 40 kHz to remove surface impurities and obtain a clean aluminum foil substrate.

[0008] Sub-step 1.1: using a plasma surface activation instrument to treat a clean aluminum foil substrate to prepare an active enhanced aluminum foil;

[0009] A clean aluminum foil substrate is treated with a plasma surface activation instrument at a power of 80-100 W and an oxygen flow rate of 20-25 sccm for 60-90 seconds to obtain an aluminum foil material with enhanced surface activity.

[0010] Sub-step 1.2: Prepare a composite passivation solution using a sol-gel synthesis method to generate a silicon / titanium composite sol.

[0011] Sub-step 1.3: Use a precision spin coater to coat the silicon / titanium composite sol passivation solution to prepare a surface passivated aluminum foil substrate.

[0012] Step 2: Using ultrasonic assisted micromachining process to process the surface passivated aluminum foil substrate to prepare a microchannel network structure;

[0013] Sub-step 2.1: Use a precision spin coater to apply photoresist to prepare a photosensitive layer of aluminum foil.

[0014] Sub-step 2.2: Use a UV light exposure machine to expose the photoresist-coated aluminum foil to form a channel latent image pattern.

[0015] Sub-step 2.3: Process the channel latent image pattern using a developer tank to prepare a microfluidic channel pattern structure.

[0016] Sub-step 2.4: Use ultrasonic-assisted selective etching equipment to process the microfluidic channel pattern structure to prepare a microchannel network structure aluminum foil.

[0017] Step 3: using a surface micro-area patterning method to process the microchannel network structure aluminum foil to prepare a hydrophilic / hydrophobic region structure aluminum foil;

[0018] Sub-step 3.1: Process the microchannel network structure aluminum foil using a precision photolithography system to prepare a patterned mask aluminum foil.

[0019] Sub-step 3.2: Use a reactive ion etcher to process the patterned mask aluminum foil to prepare a regional hydrophilic microchannel structure.

[0020] Sub-step 3.3: Use a vapor deposition system to process the regional hydrophilic microchannel structure to prepare an aluminum foil with a hydrophilic / hydrophobic micro-region patterned structure.

[0021] Step 4: Using molecular imprinting method to treat the responsive polymer to prepare drug-loaded microdomain structure;

[0022] Sub-step 4.1: Using free radical polymerization technology to treat thermosensitive monomers to synthesize temperature-responsive polymers.

[0023] Sub-step 4.2: Treat chitosan using the carboxyl activation coupling method to synthesize a pH-sensitive polymer.

[0024] Sub-step 4.3: Use a microinjection system to process thermosensitive and pH-sensitive polymers to prepare a dual-responsive microdomain structure.

[0025] Step 5: Processing the active pharmaceutical ingredient using a drug microencapsulation method to prepare a drug-loaded microfluidic structure;

[0026] Sub-step 5.1: Use double emulsification method to process active drug and shell material to prepare drug microcapsules.

[0027] Sub-step 5.2: Treat drug microcapsules using electrostatic adsorption layer-by-layer self-assembly method to prepare surface-modified microcapsules.

[0028] Sub-step 5.3: Use microfluidic precision infusion method to process surface-modified microcapsules to prepare drug-loaded microfluidic structures.

[0029] Step 6: Use the microsystem packaging method to process the drug-loaded microfluidic structure to prepare a microfluidic patterned antibacterial aluminum foil that can accurately release drugs and is environmentally responsive;

[0030] Sub-step 6.1: Use laser micro-welding equipment to process drug-loaded microfluidic structures to prepare a sealed microfluidic system.

[0031] Sub-step 6.2: Use a focused ion beam etcher to process the sealed microfluidic system to prepare a controlled release window microfluidic system.

[0032] Sub-step 6.3: Use an atomic layer deposition device to process the controlled release window microfluidic system to prepare a microfluidic patterned antibacterial aluminum foil that can accurately release drugs and is environmentally responsive.

[0033] The beneficial effects of the present invention are as follows:

[0034] The aluminum foil prepared by the preparation method of the present invention can accurately trigger drug release according to changes in oral temperature (36-37°C) or pH value (normally about 6.8, which can be reduced to 5.5-6.0 in the inflammatory area). The spatial accuracy of drug release reaches ±15μm, and the time accuracy reaches ±4 minutes.

[0035] Through hydrophilic / hydrophobic micro-area patterning and ultrasound-assisted microfluidic channel construction technology, drugs can be released according to a predetermined path and sequence, achieving multi-point and multi-phase precise drug delivery, and the uniformity of drug release is improved by 65% ​​compared to traditional oral mucosal patches.

[0036] By using microencapsulation technology and microfluidic precise release window design, drug utilization has increased by about 40%, effectively reducing the risk of systemic adverse reactions. At the same time, through the use of environmentally responsive materials, the local concentration of drugs in the lesion site has increased by about 3 times.

[0037] The aluminum foil is designed to be thin and light (total thickness does not exceed 50μm), flexible (can be bent to an angle of >120° without damage), highly comfortable, and can customize drug release patterns according to individual treatment needs, greatly improving patients' treatment experience and compliance.

[0038] Through the capillary action of the microfluidic channel network and the sustained-release characteristics of drug microcapsules, the system can extend the sustained release time of drugs to 8-12 hours, which is about 2-3 times longer than traditional oral mucosal patches, significantly reducing the frequency of medication. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 is an example diagram of technical requirement parameters for a target application scenario in an application example of the present invention;

[0040] Figure 2This is an example diagram of surface passivation process parameters and results in an application example of the present invention;

[0041] Figure 3 is an example diagram of micro-machining process parameters and results in an application example of the present invention;

[0042] Figure 4 is an example diagram of surface micro-area patterning processing parameters and results in an application example of the present invention;

[0043] Figure 5 is an example diagram of the preparation parameters and results of the drug-loaded micro-region structure in the application example of the present invention;

[0044] Figure 6 is an example diagram of drug microcapsule encapsulation parameters and results in an application example of the present invention;

[0045] Figure 7 is an example diagram of system packaging parameters and results in an application example of the present invention;

[0046] Figure 8 is an example diagram of the environmental response performance test results in an application example of the present invention;

[0047] Fig. 9 is a line graph showing the relationship between the drug release rate and the pH value in the application example of the present invention;

[0048] Fig.10 is an example diagram of the drug release performance test results in the application example of the present invention;

[0049] Fig.11 is a comparison diagram of the cumulative release curve of minocycline in the application examples of the present invention;

[0050] Fig.12 is a line graph comparing the effect of maintaining local drug concentration in the application examples of the present invention;

[0051] Fig.13 This is an example diagram of the performance stability and safety test results in the application example of the present invention;

[0052] Fig.14 is a line chart of patch performance stability evaluation in an application example of the present invention;

[0053] Fig.15 is an example diagram of preliminary clinical evaluation results (n=20) in an application example of the present invention;

[0054] Fig.16 It is a line graph of the improvement trend of clinical gingival index in the application example of the present invention;

[0055] Fig.17 It is a multi-parameter clinical effect radar chart in the application example of the present invention. DETAILED DESCRIPTION

[0056] The subject matter described herein will now be discussed with reference to example implementations. It should be understood that the discussion of these implementations is only to enable those skilled in the art to better understand and implement the subject matter described herein, and the functions and arrangements of the elements discussed may be changed without departing from the scope of protection of the present specification. Various examples may omit, replace, or add various processes or components as needed. In addition, the features described in some examples may also be combined in other examples.

[0057] Example

[0058] In this embodiment, a method for preparing a medicinal aluminum foil is proposed, comprising:

[0059] Step 1: Use a surface passivation process to treat medical aluminum foil to prepare a basic carrier material;

[0060] Medical grade aluminum foil (thickness 8-12 μm) was cut into the required size (3 cm × 5 cm), and the aluminum foil was pre-cleaned using an ultrasonic cleaner at a frequency of 40 kHz to remove surface impurities and obtain a clean aluminum foil substrate.

[0061] Sub-step 1.1: using a plasma surface activation instrument to treat a clean aluminum foil substrate to prepare an active enhanced aluminum foil;

[0062] A clean aluminum foil substrate is treated with a plasma surface activation instrument at a power of 80-100 W and an oxygen flow rate of 20-25 sccm for 60-90 seconds to obtain an aluminum foil material with enhanced surface activity.

[0063] Sub-step 1.2: preparing a composite passivation solution by a sol-gel synthesis method to generate a silicon / titanium composite sol;

[0064] Chemical reagents were processed using a sol-gel synthesis method. Tetraethyl orthosilicate (TEOS), anhydrous ethanol, and deionized water were mixed in a molar ratio of 4:16:1, 0.1 mol / L hydrochloric acid was added as a catalyst, and the mixture was stirred in a stirrer for 4 hours. At the same time, butyl titanate and anhydrous ethanol were mixed in a volume ratio of 1:20, and a micro-injection pump was used to drop the mixture into the silica sol at a flow rate of 1 mL / min, and the mixture was stirred on a magnetic stirrer at 200 rpm for 2 hours to obtain a silicon / titanium composite sol passivation solution.

[0065] Sub-step 1.3: Use a precision spin coater to coat a silicon / titanium composite sol passivation solution to prepare a surface passivated aluminum foil substrate;

[0066] The aluminum foil material with enhanced surface activity and the silicon / titanium composite sol passivation solution were treated with a precision spin coater and spin coated at a speed of 2000 rpm for 30 seconds to obtain a uniformly coated aluminum foil; then dried at 60°C in a precision constant temperature drying oven for 1 hour, and then heat treated at 150°C in a muffle furnace for 30 minutes to obtain a surface passivated aluminum foil substrate.

[0067] Step 2: Using ultrasonic assisted micromachining process to process the surface passivated aluminum foil substrate to prepare a microchannel network structure;

[0068] Sub-step 2.1: Use a precision spin coater to apply photoresist to prepare a photosensitive layer aluminum foil;

[0069] Use a precision spin coater to process the surface passivated aluminum foil substrate obtained in step 1, add negative photoresist SU-82010 to the center of the aluminum foil surface (200 μL / cm²), spin coat at 3000 rpm for 60 seconds, soft bake at 65 °C for 2 minutes and bake at 95 °C for 5 minutes on a precision hot stage to obtain a uniform photoresist-coated aluminum foil.

[0070] Sub-step 2.2: using a UV exposure machine to expose the photoresist-coated aluminum foil to form a channel latent image pattern;

[0071] Use a UV exposure machine to process the uniform photoresist-coated aluminum foil, accurately align the designed microfluidic channel mask (the main channel width is designed to be 25μm, and the capillary channel width is designed to be 5μm) with the photoresist coating (alignment accuracy ±2μm), and expose it to UV light with a wavelength of 300-365nm and a power density of 15mW / cm² for 15 seconds to complete the cross-linking reaction of the photoresist and obtain the channel latent image pattern.

[0072] Sub-step 2.3: using a developing tank to process the channel latent image pattern to prepare a microfluidic channel pattern structure;

[0073] The channel latent image pattern was processed using a developing tank, and the exposed sample was immersed in SU-8 developer and developed at 25°C for 3 minutes. It was then rinsed with an isopropanol rinser at a flow rate of 30 mL / min for 30 seconds, and dried with a high-purity nitrogen blow-drying system at a pressure of 0.5 MPa to obtain a microfluidic channel pattern structure corresponding to the mask.

[0074] Sub-step 2.4: using an ultrasonic-assisted selective etching device to process the microfluidic channel pattern structure to prepare a microchannel network structure aluminum foil;

[0075] The microfluidic channel pattern structure was processed using ultrasonic-assisted selective etching equipment. The patterned sample was placed in an ultrasonic water bath at 30-45kHz and a power density of 0.5W / cm². A sodium hydroxide solution with a pH of 12.5 (concentration of 1.0mol / L) was used for selective etching. The etching temperature was controlled at 40±1°C for 5-8 minutes to obtain a microfluidic channel network with a main channel depth of 8-10μm. Subsequently, a deionized water washing system was used to wash the sample for 120 seconds at a flow rate of 50mL / min to obtain an aluminum foil with a microchannel network structure.

[0076] Step 3: using a surface micro-area patterning method to process the microchannel network structure aluminum foil to prepare a hydrophilic / hydrophobic region structure aluminum foil;

[0077] Sub-step 3.1: Processing the microchannel network structure aluminum foil using a precision photolithography system to prepare a patterned mask aluminum foil;

[0078] The microchannel network structure aluminum foil obtained in step 2 was processed using a precision photolithography system, and positive photoresist AZ5214 was added to the surface of the aluminum foil (150 μL / cm²), and spin-coated at 2500 rpm for 45 seconds, and soft-baked on a precision hot stage at 100°C for 2 minutes to obtain a photoresist coating; a precision mask alignment exposure machine was used, and a second mask (pattern alignment accuracy of ±3 μm) was used to expose for 10 seconds under ultraviolet light with a wavelength of 365 nm and a power density of 12 mW / cm², and developed in AZ developer (concentration of 1:4) for 60 seconds to obtain a patterned mask aluminum foil with a specific area exposed.

[0079] Sub-step 3.2: using a reactive ion etcher to process the patterned mask aluminum foil to prepare a regional hydrophilic microchannel structure;

[0080] The patterned mask aluminum foil was processed using a reactive ion etcher, and the sample with the mask was placed in a reaction chamber and processed for 30 seconds under the conditions of a power of 60 W, an oxygen flow rate of 15 sccm, and a chamber pressure of 20 Pa. The exposed area was hydrophilized to obtain a microchannel structure with hydrophilization in a specific area.

[0081] Sub-step 3.3: using a vapor deposition system to process the regional hydrophilic microchannel structure to prepare an aluminum foil with a hydrophilic / hydrophobic micro-region patterned structure;

[0082] The hydrophilicized microchannel structure was processed using a vapor deposition system. First, an acetone solution (purity > 99.5%) was used to remove the residual photoresist. Then the sample was placed in a closed vacuum chamber containing heptadecafluorodecyltrichlorosilane (concentration of 0.1 mL / 100 mL volume) and vapor deposited at 50°C and 50 Pa for 4 hours to obtain a hydrophobic surface (contact angle > 145°) in the area not treated with hydrophilization, forming an aluminum foil with a hydrophilic / hydrophobic micro-region patterned structure.

[0083] Step 4: Using molecular imprinting method to treat the responsive polymer to prepare drug-loaded microdomain structure;

[0084] Sub-step 4.1: using free radical polymerization technology to treat the thermosensitive monomer to synthesize the temperature-responsive polymer;

[0085] Thermosensitive monomers were treated by free radical polymerization. N-isopropylacrylamide (NIPAM), N,N'-methylenebisacrylamide (MBA), and 2,2'-azobisisobutyronitrile (AIBN) were dissolved in anhydrous ethanol (concentration of 10% w / v) at a molar ratio of 100:2:1. The air in the reaction vessel was replaced by a nitrogen replacement system (flow rate of 30 mL / min) for 5 minutes. The reaction was carried out in an oil bath heating system at 65±0.5°C for 4 hours to obtain poly N-isopropylacrylamide (PNIPAM) thermosensitive polymer (average molecular weight of about 120,000 Daltons).

[0086] Sub-step 4.2: treating chitosan using a carboxyl activation coupling method to synthesize a pH-sensitive polymer;

[0087] The chitosan raw material was treated by the carboxyl activation coupling method. Chitosan (deacetylation degree>85%, molecular weight of about 50,000 Daltons) was dissolved in 1% acetic acid solution (concentration of 1% w / v), and quaternary ammonium salt compounds (concentration of 20 mmol / L) activated by N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) (concentration of 50 mmol / L) and N-hydroxysuccinimide (NHS) (concentration of 25 mmol / L) were added. The mixture was reacted at room temperature for 12 hours at 200 rpm on a magnetic stirrer, dialyzed for 48 hours using a dialysis device (molecular weight cutoff 3500 Da), and dried for 24 hours in a freeze dryer (temperature of -50°C, pressure of 10 Pa) to obtain a modified chitosan-quaternary ammonium salt complex (degree of substitution of about 40%).

[0088] Sub-step 4.3: Using a microinjection system to process the thermosensitive and pH-sensitive polymers to prepare a dual-responsive microdomain structure;

[0089] The hydrophilic / hydrophobic micro-domain patterned aluminum foil obtained in step 3, the poly (N-isopropylacrylamide) thermosensitive polymer obtained in sub-step 4.1, and the modified chitosan-quaternary ammonium salt complex obtained in sub-step 4.2 were processed using a microinjection system. A microinjection pump was used at a flow rate of 0.5 μL / min and a needle tip diameter of 10 μm to selectively deposit a thermosensitive polymer solution (at a concentration of 5 mg / mL) and a pH-sensitive polymer solution (at a concentration of 5 mg / mL) at predetermined key node areas of the microfluidic channel (i.e., the intersection of the main channel and the capillary channel, with a point spacing of 100 μm). The microinjection pump was then heat treated and cured (60°C, 10 minutes) to obtain a dual-responsive micro-domain structure with thermosensitive and pH-sensitive areas.

[0090] Step 5: Processing the active pharmaceutical ingredient using a drug microencapsulation method to prepare a drug-loaded microfluidic structure;

[0091] Sub-step 5.1: using a double emulsification method to treat the active drug and the shell material to prepare drug microcapsules;

[0092] The active pharmaceutical ingredients and encapsulation materials were processed using a double emulsification method. The active pharmaceutical ingredients (such as chlorhexidine digluconate, with a concentration of 2% w / v or minocycline hydrochloride, with a concentration of 1% w / v) were dissolved in an inner aqueous phase (pH 7.4 phosphate buffer, 5 mL), mixed with an oil phase (dichloromethane, 20 mL) containing an emulsifier (Span 80, with a concentration of 2% w / v), and emulsified at a speed of 10,000 rpm using a high-speed shear homogenizer for 5 minutes to form colostrum (W / O emulsion); the colostrum was added to a chitosan aqueous solution (with a concentration of 1% w / v, 50 mL) containing a cross-linking agent (sodium tripolyphosphate, with a concentration of 5 mg / mL), emulsified at 400 rpm on a stirrer for 30 minutes, and the precipitate was collected using a centrifuge (5000 rpm, 10 minutes), washed 3 times, and drug microcapsules (particle size 2-5 μm, drug encapsulation efficiency> 80%) were obtained.

[0093] Sub-step 5.2: treating drug microcapsules using an electrostatic adsorption layer-by-layer self-assembly method to prepare surface-modified microcapsules;

[0094] The drug microcapsules were treated by electrostatic adsorption layer-by-layer self-assembly method. The drug microcapsule suspension (concentration of 10 mg / mL) obtained in sub-step 5.1 was sequentially immersed in polyelectrolyte solutions (sodium polyacrylate and polylysine, concentration of 2 mg / mL). An automatic dipping device was used to control the adsorption time for each time to be 10 minutes. Between two adsorptions, the solution was washed with pH 7.4 phosphate buffer (concentration of 10 mmol / L) for 90 seconds. The operation was repeated to form 5 layers of polyelectrolyte film (total thickness of about 15 nm) to obtain surface-modified drug microcapsules.

[0095] Sub-step 5.3: using a microfluidic precision infusion method to process the surface-modified microcapsules to prepare a drug-loaded microfluidic structure;

[0096] The surface-modified drug microcapsules and dual-responsive microdomain structures were processed using the microfluidic precision perfusion method. The dual-responsive microdomain structure obtained in sub-step 4.3 was used. A microinjection pump was used to inject the surface-modified drug microcapsule suspension (concentration of 5 mg / mL) from sub-step 5.2 into the microfluidic channel network at a flow rate of 0.3 μL / min and a pressure of 20 kPa. The microcapsules were evenly distributed in the channel through capillary force (the contact angle between the liquid and the channel wall was <30°). The microcapsules were then dried at room temperature for 2 hours to obtain a drug-loaded microfluidic structure.

[0097] Step 6: Use the microsystem packaging method to process the drug-loaded microfluidic structure to prepare a microfluidic patterned antibacterial aluminum foil that can accurately release drugs and is environmentally responsive;

[0098] Sub-step 6.1: Processing drug-loaded microfluidic structures using laser micro-welding equipment to prepare a sealed microfluidic system;

[0099] The drug-loaded microfluidic structure obtained in step 5 was processed using a laser micro-welding device. The drug-loaded microfluidic structure was aligned with the pre-treated transparent medical polymer film (such as polylactic acid, with a thickness of 20 μm) using a precision alignment platform (alignment accuracy of ±5 μm). A laser with a wavelength of 1064 nm, a power of 5 W, and a spot diameter of 50 μm was used to perform spot welding along the edge of the microfluidic channel. The weld spacing was 500 μm and the scanning speed was 2 mm / s to obtain an edge-sealed microfluidic system.

[0100] Sub-step 6.2: Processing the sealed microfluidic system using a focused ion beam etcher to prepare a controlled release window microfluidic system;

[0101] The sealed microfluidic system was processed using a focused ion beam etcher, with a gallium ion beam current of 50pA and an acceleration voltage of 30kV. Micropore arrays with a diameter of 10-15μm (each array contained 25 micropores with a pore spacing of 30μm) were etched at 10 predetermined specific locations of the sealed system (usually drug microcapsule-enriched areas, areas with drug microcapsule density >100 / mm²) as drug release windows to obtain a windowed microfluidic system with controllable release capability.

[0102] Sub-step 6.3: Using an atomic layer deposition device to process a controlled release window microfluidic system to prepare a microfluidic patterned antibacterial aluminum foil that can accurately release drugs and is environmentally responsive;

[0103] The controlled release window microfluidic system was processed using an atomic layer deposition device. Titanium tetrachloride was used as a precursor and water as an oxidant. The deposition was repeated for 100 cycles at 80°C and a pressure of 100 Pa. A 5-10 nm thick titanium dioxide biocompatible coating (uniformity > 95%) was deposited on the surface of the controlled release window microfluidic system obtained in sub-step 6.2 to obtain a microfluidic patterned antibacterial aluminum foil that can precisely release drugs and is environmentally responsive.

[0104] Application Examples

[0105] The following is the case data and implementation verification of the application of medicinal aluminum foil in the precise drug release system of oral mucosal patches.

[0106] 1. Application scenario description

[0107] This application example aims to develop an oral mucosal patch system that can accurately deliver minocycline in the gingival pocket to meet the oral topical medication needs of periodontitis patients. Periodontitis is a common oral disease. Traditional treatment methods have problems such as the inability to maintain effective drug concentrations, large side effects of systemic administration, and low accuracy of local administration.

[0108] Figure 1 : Technical requirement parameters for the target application scenario.

[0109] 2. Steps to implement examples

[0110] This application example is carried out strictly in accordance with the process flow in the above embodiment, and detailed process parameters and intermediate product data are collected at key steps. The following are the implementation details of each step:

[0111] Step 1 implementation data: surface passivation process treatment;

[0112] Figure 2 : Surface passivation process parameters and results.

[0113] Step 2 implementation data: ultrasonic assisted micromachining process;

[0114] Figure 3 : Micromachining process parameters and results.

[0115] Step 3: Implementation data: surface micro-area patterning;

[0116] Figure 4 : Surface micro-area patterning processing parameters and results.

[0117] Step 4 implementation data: preparation of drug-loaded microdomain structures;

[0118] Figure 5 : Preparation parameters and results of drug-loaded microdomain structures.

[0119] Step 5 implementation data: drug microencapsulation;

[0120] Figure 6 : Drug microencapsulation parameters and results.

[0121] Step 6 Implementation data: Oral mucosal patch system packaging;

[0122] Figure 7 : System packaging parameters and results.

[0123] 3. Technical Effect Verification

[0124] In order to verify the effect of this embodiment in practical application, the prepared oral mucosal patch precision drug release system was fully tested using in vitro models and preliminary clinical evaluation. The following is the verification data of the key technical effects:

[0125] 1. Environmental response performance verification

[0126] Figure 8 : Environmental response performance test results;

[0127] Fig. 9 : The relationship between drug release rate and pH value.

[0128] Fig. 9 The relationship between drug release rate and environmental pH is shown. The release rate of the traditional patch (dashed line) does not change significantly when the pH changes, while the release rate of the microfluidic patch (solid line) of this technology rises sharply when the pH is below 6.2, showing precise pH response characteristics. This feature enables the patch to increase drug release in an inflammatory environment (usually with a low pH) in a targeted manner, while maintaining a low basal release rate in a normal physiological environment, achieving "smart" drug delivery.

[0129] 2. Drug release performance verification

[0130] Fig.10 : Drug release performance test results;

[0131] Fig.11 : Comparison of cumulative release profiles of minocycline.

[0132] Fig.11The cumulative release curves of minocycline from two patches in a simulated in vitro environment within 24 hours are shown. The traditional patch (dashed line) released about 60% of the drug in the first 2 hours, and then the release rate decreased rapidly, and a small amount of drug was still not released after 24 hours. In contrast, the microfluidic patterned patch (solid line) showed a more ideal release behavior: about 28% of the drug was released in the first 2 hours, and then a stable release rate was maintained within 12 hours, releasing about 62% of the drug, and the remaining drug was slowly released in the last 10 hours. This release pattern avoids the initial "dose burst" and prolongs the effective action time.

[0133] 3. Comparison of the effect of maintaining local drug concentration

[0134] Fig.12 : Comparison of the effects of maintaining local drug concentration.

[0135] Fig.12 The time-varying curves of local drug concentrations of microfluidic patterned patches and traditional patches in the gingival pocket model are shown. The traditional patch (dashed line) reaches a higher concentration at the beginning, but the drug concentration quickly drops below the minimum inhibitory concentration (MIC, about 5 μg / mL) after 12 hours. Although the concentration of the microfluidic patterned patch (solid line) is slightly lower at the beginning, it can maintain a stable drug concentration, which remains above the MIC after 48 hours and does not drop below the MIC until 72 hours, effectively prolonging the duration of the therapeutic effect. The horizontal dotted line represents the minimum inhibitory concentration of minocycline against major periodontal pathogens.

[0136] 4. Performance stability and safety verification

[0137] Fig.13 : Performance stability and safety test results;

[0138] Fig.14 :Patch performance stability evaluation.

[0139] Fig.14 The function retention rate of the two patches under accelerated aging test conditions (25°C, 60% relative humidity) is shown. The function retention rate of the traditional patch (dashed line) has a short-term increase at 2-3 months, which may be related to the change of physical properties during the degradation of the material, but it shows an overall downward trend, falling below 60% at 6 months. The microfluidic patterned patch (solid line) shows excellent stability, and the function retention rate remains above 95% during the entire test period, indicating that it has good storage stability and reliability in use.

[0140] 5. Preliminary clinical evaluation data

[0141] Fig.15 : Preliminary clinical evaluation results (n=20);

[0142] Fig.16 : Improvement trend of clinical gingival index.

[0143] Fig.16 The trend of gingival index (GI) over time in 20 periodontitis patients using microfluidic patterned patches and traditional treatment (SRP + antibiotic patch) is shown. GI is an important indicator to measure the severity of gingival inflammation. The GI values ​​of the two groups of patients were similar before treatment (about 2.3). After the start of treatment, the GI value of the microfluidic patch group (solid line) dropped rapidly within 3 days, reaching a stable value of about 0.8 on the 7th day. The traditional treatment group (dashed line) also showed significant improvement in the first 3 days, but the improvement rate slowed down afterwards, and the GI value was about 1.5 on the 7th day. Both treatment methods maintained relatively stable treatment effects within 21 days, but the inflammation control effect of the microfluidic patch group was significantly better than that of the traditional treatment group.

[0144] Fig.17 : Multi-parameter clinical effect radar chart.

[0145] Fig.17 The radar chart comprehensively shows the performance of the two treatment methods in four key clinical indicators: efficacy (GI improvement rate), stability (7-day fitting rate), comfort (VAS score) and incidence of adverse reactions (reverse index). The microfluidic patterned patch (solid line) is superior to the traditional patch (dashed line) in all four dimensions, especially in comfort and stability. This radar chart intuitively shows the comprehensive advantages of the microfluidic patterned patch in actual clinical applications.

[0146] Comprehensive verification results show that the oral mucosal patch precision drug release system is significantly superior to traditional drug delivery methods in terms of drug release control accuracy, sustained release time, local drug concentration maintenance, and therapeutic effect. In particular, breakthrough progress has been made in environmental response accuracy, drug utilization, and patient compliance, providing a new option for efficient and precise treatment of periodontal diseases.

[0147] The above describes an embodiment of the present invention, but this embodiment is not limited to the above-mentioned specific implementation mode. The above-mentioned specific implementation mode is merely illustrative and not restrictive. Under the guidance of this embodiment, ordinary technicians in this field can also make more forms of equivalent embodiments, all of which are within the protection of this embodiment.

Claims

1. A method for preparing medicinal aluminum foil, characterized in that: The following steps are involved: Performing surface passivation treatment on the medical aluminum foil to obtain a surface passivated aluminum foil substrate; The surface-passivated aluminum foil substrate is subjected to ultrasonic-assisted micromachining to form an aluminum foil with a microchannel network structure; Performing surface micro-region patterning treatment on the microchannel network structure aluminum foil to form a hydrophilic / hydrophobic micro-region patterned structure aluminum foil; Thermosensitive polymers and pH-sensitive polymers are selectively deposited on key node areas of the hydrophilic / hydrophobic micro-region patterned structure aluminum foil to form a microfluidic patterned antibacterial medicinal aluminum foil with environmental responsiveness.

2. The method for preparing a medicinal aluminum foil according to claim 1, characterized in that: The surface passivation treatment comprises the following steps: pre-cleaning the medical aluminum foil with an ultrasonic cleaning machine to obtain a clean aluminum foil substrate; treating the clean aluminum foil substrate with a plasma surface activation instrument to obtain an aluminum foil material with enhanced surface activity; preparing a silicon / titanium composite sol passivation solution with a sol-gel synthesis method; coating the silicon / titanium composite sol passivation solution on the aluminum foil material with enhanced surface activity with a precision spin coater, and obtaining a surface passivated aluminum foil substrate after drying and heat treatment.

3. The method for preparing a medicinal aluminum foil according to claim 2, characterized in that: The plasma surface activation treatment is carried out for 60-90 seconds under the conditions of a power of 80-100W and an oxygen flow rate of 20-25sccm; the silicon / titanium composite sol passivation solution is prepared by mixing ethyl orthosilicate, anhydrous ethanol, and deionized water in a molar ratio of 4:16:1, adding 0.1 mol / L hydrochloric acid as a catalyst, stirring for 4 hours, and then adding butyl titanate and anhydrous ethanol in a volume ratio of 1:20 and stirring for 2 hours; the spin coating is carried out at a rotation speed of 2000rpm for 30 seconds, followed by drying at 60°C for 1 hour, and then heat treating at 150°C for 30 minutes.

4. The method for preparing a medicinal aluminum foil according to claim 1, characterized in that: The ultrasonic-assisted micromachining process comprises the following steps: using a precision spin coater to coat the surface-passivated aluminum foil substrate with a negative photoresist to obtain a uniform photoresist-coated aluminum foil; using an ultraviolet light exposure machine to expose the uniform photoresist-coated aluminum foil to form a channel latent image pattern; using a developing tank to develop the channel latent image pattern to obtain a microfluidic channel pattern structure; using an ultrasonic-assisted selective etching device to etch the microfluidic channel pattern structure to form a microchannel network structure aluminum foil.

5. The method for preparing a medicinal aluminum foil according to claim 4, characterized in that: The negative photoresist is SU-82010, the spin coating speed is 3000rpm, the time is 60 seconds, soft baking is carried out at 65℃ for 2 minutes, and baking is carried out at 95℃ for 5 minutes; the ultraviolet light exposure is carried out for 15 seconds at a wavelength of 300-365nm and a power density of 15mW / cm²; the ultrasonic assisted selective etching is carried out at 30-45kHz, a power density of 0.5W / cm² in an ultrasonic water bath, using a sodium hydroxide solution with a pH value of 12.5 at 40±1℃ for 5-8 minutes.

6. The method for preparing a medicinal aluminum foil according to claim 1, characterized in that: The surface micro-region patterning treatment includes the following steps: using a precision photolithography system to perform secondary photolithography on the microchannel network structure aluminum foil to obtain a patterned mask aluminum foil; using a reactive ion etcher to perform hydrophilization treatment on the patterned mask aluminum foil to obtain a regional hydrophilic microchannel structure; using a vapor deposition system to perform hydrophobic treatment on the regional hydrophilic microchannel structure to form a hydrophilic / hydrophobic micro-region patterned structure aluminum foil.

7. The method for preparing a medicinal aluminum foil according to claim 6, characterized in that: The secondary photolithography uses positive photoresist, the spin coating speed is 2500rpm, the time is 45 seconds, and the soft baking is performed at 100°C for 2 minutes; it is exposed to ultraviolet light with a wavelength of 365nm and a power density of 12mW / cm² for 10 seconds, and developed in AZ developer for 60 seconds; the hydrophilization treatment is performed for 30 seconds at a power of 60W, an oxygen flow rate of 15sccm, and a chamber pressure of 20Pa; the hydrophobicization treatment uses heptadecafluorodecyltrichlorosilane for vapor deposition at 50°C and a pressure of 50Pa for 4 hours.

8. The method for preparing a medicinal aluminum foil according to claim 1, characterized in that: The preparation method of the thermosensitive polymer is as follows: using free radical polymerization technology to dissolve N-isopropylacrylamide, N,N'-methylenebisacrylamide, and 2,2'-azobisisobutyronitrile in anhydrous ethanol at a molar ratio of 100:2:1, and reacting at 65±0.5° C. for 4 hours under nitrogen protection to obtain a poly N-isopropylacrylamide thermosensitive polymer.

9. The method for preparing a medicinal aluminum foil according to claim 1, characterized in that: The preparation method of the pH sensitive polymer is as follows: chitosan is dissolved in 1% acetic acid solution using carboxyl activation coupling technology, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and a quaternary ammonium salt compound activated by N-hydroxysuccinimide are added, reacted at room temperature for 12 hours, dialyzed for 48 hours, and freeze-dried to obtain a modified chitosan-quaternary ammonium salt complex.

10. The method for preparing a medicinal aluminum foil according to claim 1, characterized in that: The selective deposition adopts a microinjection system, and uses a microinjection pump to deposit the temperature-sensitive polymer solution and the pH-sensitive polymer solution in the predetermined key node area of ​​the microfluidic channel at a flow rate of 0.5 μL / min and a needle tip diameter of 10 μm, and then performs heat treatment to solidify.

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