CN117462836B - Functionalized ultrasonic controlled-release puncture dressing patch and preparation method thereof - Google Patents
Functionalized ultrasonic controlled-release puncture dressing patch and preparation method thereof Download PDFInfo
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- CN117462836B CN117462836B CN202311799034.7A CN202311799034A CN117462836B CN 117462836 B CN117462836 B CN 117462836B CN 202311799034 A CN202311799034 A CN 202311799034A CN 117462836 B CN117462836 B CN 117462836B
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- puncture
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Classifications
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- A61M37/0092—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin using ultrasonic, sonic or infrasonic vibrations, e.g. phonophoresis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F13/00—Bandages or dressings; Absorbent pads
- A61F2013/00361—Plasters
- A61F2013/00902—Plasters containing means
- A61F2013/00906—Plasters containing means for transcutaneous or transdermal drugs application
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F13/00—Bandages or dressings; Absorbent pads
- A61F2013/00361—Plasters
- A61F2013/00902—Plasters containing means
- A61F2013/0091—Plasters containing means with disinfecting or anaesthetics means, e.g. anti-mycrobic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F13/00—Bandages or dressings; Absorbent pads
- A61F13/02—Adhesive bandages or dressings
- A61F13/0276—Apparatus or processes for manufacturing adhesive dressings or bandages
- A61F2013/0296—Apparatus or processes for manufacturing adhesive dressings or bandages for making transdermal patches (chemical processes excluded)
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- Public Health (AREA)
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- Heart & Thoracic Surgery (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Vascular Medicine (AREA)
- Dermatology (AREA)
- Medical Informatics (AREA)
- Hematology (AREA)
- Anesthesiology (AREA)
- Manufacturing & Machinery (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a functional ultrasonic controlled-release puncture dressing patch and a preparation method thereof. The dressing plaster main body consists of a double-layer parallel structure and an annular cladding structure. The double-layer parallel structure is an energy conducting sheet and a visual drug storage and delivery system, and the structure combines an ultrasonic technology, can promote transdermal targeting high-permeability drug delivery, and realizes quantification and controllability of the drug; the energy conducting sheet is used for gathering, guiding and transmitting ultrasonic waves, so that the directional acting force of the energy conducting sheet on the medicine can be improved; the visual drug storage and delivery system can improve drug storage property and skin affinity, realize dual functions of drug quick release and slow release, reduce pain before and after puncture, promote vasodilation and improve puncture success rate; the annular cladding structure contains two kinds of indication windows, adopts the mould pressing technology preparation, can connect, fix and protect whole frame, realizes bacterial contamination monitoring and medicine release degree visualization, and helps medicine to stabilize and effectively play a role.
Description
Technical Field
The invention relates to the technical field of medical appliances, in particular to a functional ultrasonic controlled-release puncture dressing patch and a preparation method thereof.
Background
In the medical field, due to anesthesia and surgery, puncture operations, such as biopsy and catheterization, are often performed on patients.
However, since the puncture needle is long and thick, the patient feels pain during the puncture, and the patient is further frightened, stressed and anxious, so that the circulation function is changed, and the normal operation is affected, especially for patients who frequently need the puncture, such as patients with long-term transfusion, diabetes, renal dialysis and the like. Currently, clinicians will alleviate the pain of pre-operative punctures by injecting local anesthetic drugs. Although percutaneous injection provides analgesia, percutaneous injection itself can produce pain, and can also produce other side effects such as deformation of the operative site, stress atmosphere, etc., and continuous pain after puncture can also lead to patient's conflict.
Moreover, the failure rate of the first puncture operation is higher, especially for patients with smaller own vessel diameter and high puncture operation difficulty or easy tension, the repeated puncture failure can bring psychological burden to the patients and family members thereof, the risk of infection is increased, the recovery and treatment of the bodies of the patients are not facilitated, and the treatment scheme of medical workers is also not facilitated. In addition, the drugs in conventional patches cannot be effectively utilized, and the extent of drug release cannot be clearly known, affecting the course of treatment.
Therefore, to solve the above clinical problems, the following technical bottlenecks must be overcome:
(1) The puncture pretreatment must be a noninvasive design to avoid secondary skin wounds;
(2) The auxiliary device is aimed at medicaments for promoting vasodilation and is used before operation to improve the success rate of puncture;
(3) The auxiliary device is used before operation by aiming at the medicine for relieving the puncture pain, so that the pain in the puncture process is relieved by ensuring the rapid effect before the puncture, and the continuous pain relieving after the puncture is finished is ensured;
(4) The drug release should have certain targeting property, and can be effectively utilized by target vascular tissues to achieve the effective concentration of the drug, thereby avoiding excessive loss of the drug;
(5) The application of the medicine should be controllable, quantifiable and visual, and different dosages of the medicine can be selected according to different puncture positions or puncture depths or puncture types so as to meet various clinical requirements, and the degree of medicine release should be known.
The prior patent CN 106074849B provides a blood vessel dilating pain relieving and inflammation diminishing patch for arteriovenous puncture, which consists of an outer layer, a heating layer, a middle layer, a traditional Chinese medicine pain relieving and inflammation diminishing layer and an inner layer, wherein an isolation layer is arranged between the layers. The heating layer has the effects of increasing the temperature of the back of the hand, dilating blood vessels, relieving pain and diminishing inflammation, and the Chinese medicine pain relieving and diminishing inflammation layer has the effects of relieving pain and diminishing inflammation, and the painless anesthetic layer has the effects of local surface anesthesia and has a certain effect when being used in the process of arteriovenous injection and puncture. However, the ferrule type structural design can lead to the appearance of a response area corresponding to the patch functional area in the area to be punctured, so that the same skin cannot be subjected to anesthesia, pain relieving and heating effects at the same time, the quick effect of the medicine is not facilitated, the effect is unstable, the application range is small, and the inclusion is poor. Secondly, the medicine in the patch only passively and randomly enters the part to be punctured according to the molecular diffusion and similar compatibility principles, no targeting is achieved, the effective treatment concentration of the medicine cannot be ensured, the medicine release and absorption efficiency is slow, the utilization rate is low, and the medicine waste and the treatment effect are poor; finally, the patch cannot be controlled, quantified and visualized by changing the drug release rate, depth and extent, and in addition, the problem of postoperative pain at the puncture site cannot be solved.
In addition, CN 104367416A discloses a method for rapidly stopping pain by vascular puncture of children and an analgesic patch, which is a medical adhesive patch prepared in advance, namely, an analgesic patch, wherein one or more analgesic drugs are placed in the analgesic patch. Before puncturing blood vessel, the analgesic patch is covered on skin of puncture part to make analgesic absorbed by skin, so that no pain or pain is reduced during puncturing. However, the analgesic patch has only analgesic drugs, cannot dilate blood vessels, cannot evaluate whether the patch is infected by bacteria, cannot ensure rapid release and effective utilization of the drugs, cannot solve the problem of pain at a puncture site after operation, and cannot quantify and control drug release and visualize drug loading.
Disclosure of Invention
One of the purposes of the present invention is to provide a functionalized ultrasonic controlled release dressing patch for solving the above technical problems.
The second object of the invention is to provide a preparation method of the functionalized ultrasonic controlled release puncture dressing, which comprises the following operation steps:
(1) Preparation of drug-loaded ethosome: weighing egg yolk lecithin, cholesterol, a vasodilator and a pain relieving medicine according to a formula, stirring and dissolving the egg yolk lecithin, the cholesterol, the vasodilator and the pain relieving medicine in absolute ethyl alcohol at 30 ℃; injecting ultrapure water into the absolute ethyl alcohol at the flow rate of 200 mu L/min, stirring for 30 min, performing ice water bath ultrasonic treatment, and filtering with a 0.22 mu m filter membrane to obtain a drug-carrying ethosome;
To better practice the invention, further, the formulation: 100-300 mg of egg yolk lecithin, 30-100 mg of cholesterol, 30-70 mg of vasodilator, 30-70 mg of pain relieving medicine and 1-5 mL of ultrapure water;
In order to better realize the invention, the vasodilator is one of nitroglycerin and phentolamine;
in order to better realize the invention, the pain relieving medicine is one of lidocaine and tetracaine hydrochloride;
In order to better realize the invention, further, the ultrasonic treatment is carried out with parameters of ultrasonic power of 100-110 w and ultrasonic time of 1-9 min;
(2) Preparation of drug-loaded liposome: weighing egg yolk lecithin, cholesterol and a pain relieving medicine according to a formula, fixing the volume to 10 mL by using a composite organic solvent, stirring, mixing and dissolving, decompressing and evaporating under a water bath at 30 ℃ until a lipid film layer is formed, injecting nitrogen, then adding sodium cholate solution, removing the organic solvent by rotary evaporation until liposome suspension is formed, injecting nitrogen again, carrying out ultrasonic treatment, and filtering by using a 0.22 mu m filter membrane to obtain the drug-loaded liposome;
To better practice the invention, further, the formulation: 100-300 mg of egg yolk lecithin, 30-100 mg of cholesterol and 30-70 mg of pain relieving drugs;
In order to better realize the invention, the compound organic solvent is further prepared by mixing chloroform and methanol according to the volume ratio of 1:1;
in order to better realize the invention, the pain relieving medicine is one of lidocaine and tetracaine hydrochloride;
In order to better realize the invention, the concentration of the sodium cholate solution is 1-5%, and the addition amount is 7-13 mL;
In order to better realize the invention, further, the ultrasonic treatment is carried out with parameters of ultrasonic power of 100-110 w and ultrasonic time of 1-9 min;
(3) Preparing an annular cladding structure: injecting ABS into a mold cavity, and performing a mold pressing process to obtain an annular coating structure containing a bacterial contamination indication window and a drug release indication window;
To better implement the invention, further, the molding process parameters are as follows: the temperature of the die is 60-65 ℃, the die pressing time is 180-700 s, and the die pressing pressure is 1-9 bar;
(4) Preparation of magnetic hydrogel prepolymerization solution: uniformly mixing an acetone solution containing ferrocene with 30% H 2O2, reacting at 180 ℃ for 70: 70H, cooling, and washing and redispersing to obtain a magnetic nanoparticle dispersion liquid; uniformly mixing N-isopropyl acrylamide, acrylic acid and N, N' -methylene bisacrylamide into an ethanol and ethylene glycol mixed solution, and then adding a photoinitiator for light-shielding and uniformly mixing to obtain a hydrogel prepolymerization solution; uniformly mixing the hydrogel prepolymerization solution, the magnetic nanoparticle dispersion liquid and the collagen according to a proportion in a dark place to obtain a magnetic hydrogel prepolymerization solution;
In order to better realize the invention, the concentration of the acetone solution containing ferrocene is 0.9-1.1%, and the adding amount of 30% H 2O2 is 2.0-3.0%; the redispersion refers to redispersing magnetic nano particles with certain mass into glycol solution, so that the concentration of the magnetic nano particles in the solution is 30 mg/mL;
In order to better realize the invention, the concentrations of the N-isopropyl acrylamide, the acrylic acid and the N, N' -methylene bisacrylamide in the ethanol and ethylene glycol mixed solution are respectively 0.55-0.75 g/mL, 5.5-7.5% and 18-22 mg/mL;
in order to better realize the invention, the weight ratio of the ethanol to the glycol in the ethanol and glycol mixed solution is (0.9-1.1): 1;
In order to better realize the invention, the photoinitiator is one of 2,4, 6-trimethylbenzoyl diphenyl phosphine oxide and 2,4, 6-trimethylbenzoyl phenyl phosphonic acid ethyl ester, and the addition amount of the photoinitiator is 1.25-1.45%;
In order to better realize the invention, the ratio of the hydrogel prepolymerization solution, the magnetic nanoparticle dispersion liquid and the collagen is (25-35) 10:1;
(5) Visual drug storage delivery system preparation: placing a glass mold containing the magnetic hydrogel prepolymerization solution in a magnetic field of 0.2T and an ultraviolet light environment of 356. 356 nm for polymerization reaction to obtain magnetic hydrogel; placing the magnetic hydrogel in a suspension of drug-carrying liposome and drug-carrying ethosome, and soaking at 25 ℃ for 72 h to obtain a visual drug storage and delivery system;
In order to better realize the invention, the size of the glass mold is consistent with that of the annular cladding structure, and the polymerization reaction time is 2-4 min;
In order to better realize the invention, further, the solute of the suspension is a mixture of the drug-loaded liposome and the drug-loaded ethosome according to the mass ratio of 1:1, and the concentration of the mixture in the suspension is 70-90%;
(6) The preparation of the coating for the bacterial contamination indicator window comprises the following steps: stirring sucrose fatty acid ester and dissolving in water to obtain an emulsifier; uniformly mixing maltodextrin and gum arabic according to a proportion, and dissolving the mixture in water to obtain a wall material solution; adding an emulsifying agent and PNPG into the wall material solution, emulsifying, adding methylene blue and tetrabromo sodium fluorescein, and uniformly mixing again; ultrasonic embedding is carried out for 30 min times after uniform mixing, then 30 MPa is homogenized for 5 times, 1 min each time; homogenizing, and then spray drying to obtain microcapsules; adding the microcapsule, the carboxymethyl cellulose and the starch into the purified water according to the formula, and stirring and uniformly mixing to prepare the coating for the bacterial contamination indicator window;
in order to better realize the invention, the concentration of the emulsifier is 0.1-1.0%;
in order to better realize the invention, the even mixing proportion of the maltodextrin and the gum arabic is (1-5): 1;
in order to better realize the invention, the wall material concentration is 33-47%;
in order to better realize the invention, further, the emulsifier, PNPG, methylene blue and tetrabromo sodium are added into the wall material solution, wherein the concentrations of the emulsifier, PNPG, methylene blue and tetrabromo sodium are respectively 1-3%, 15-25% and 15-25%;
To better practice the invention, further, the spray drying parameters are: the air inlet temperature is 140-160 ℃, the feeding flow is 15-20 mL/min -1, and the air outlet temperature is 70-80 ℃;
In order to better realize the invention, the formula of the coating for the bacterial contamination indicator window comprises 25-65% of microcapsules, 2-10% of carboxymethyl cellulose and 2-10% of starch;
(7) Preparation of a functional ultrasonic controlled-release puncture dressing patch: inverting the annular coating structure, firstly placing an energy conducting sheet, then coating a bacterial contamination indication window coating on the bacterial contamination indication window of the annular coating structure, then attaching a visual drug storage and delivery system on the energy conducting sheet and completely covering the bacterial contamination indication window coating, and then compounding a tearable anti-sticking layer to obtain a functional ultrasonic controlled release puncture dressing;
in order to better realize the invention, further, the ultrasonic transmission material used by the energy conducting sheet is one of metal, ceramic and plastic;
in order to better realize the invention, the tearable anti-adhesive layer is one of a polystyrene film, an aluminum foil, a siliconized polyvinyl chloride film and a polycarbonate film.
The components used in the present invention are all commercially available products, the structure and composition of which are known to those skilled in the art.
The invention has the beneficial effects that:
1. The functional ultrasonic controlled-release puncture dressing patch provided by the invention can avoid secondary injury to skin. The medicine can directly reach the puncture part through skin and biomembrane to form high-concentration medicine aggregation, achieves the effect of needleless injection transdermal administration, and belongs to a green, safe and effective administration mode.
2. According to the functional ultrasonic controlled-release puncture dressing patch provided by the invention, the annular coating structure is provided with the medicine real-time monitoring window, and the medicine release degree can be directly judged through the color change of the window, so that a prompt is given to medical workers, and the visualization of the medicine release degree is realized. The change in color of the window is from a visual change in color of the drug storage delivery system, i.e., the system appears red when it is full of drug, and the system color changes gradually from red to blue as the drug is released.
3. The annular coating structure of the functional ultrasonic controlled-release puncture dressing patch provided by the invention is provided with the bacterial infection prompt window for daily monitoring whether the functional ultrasonic controlled-release puncture dressing patch is polluted by bacteria, so that the aim of helping medical workers judge whether the functional ultrasonic controlled-release puncture dressing patch can be applied to clinic as a qualified product or not is achieved, and skin infection of patients is avoided. In addition, the annular cladding structure is also used for connecting, fixing and protecting the integral frame, and assisting the sustained release of the medicine.
4. The functional ultrasonic controlled-release puncture dressing patch provided by the invention can be combined with an ultrasonic technology to realize targeted drug delivery, biological pore making and pressure driving. The method can adjust the release, absorption and utilization efficiency of the drug by changing the frequency, intensity, continuous or pulse mode and the like of ultrasonic waves, and can target the drug to the target tissue at the same time, thereby realizing the quantifiable drug delivery and controllable release. In addition, the ultrasound conducting layer can be used for both ultrasound collection and conduction and for the gel backing layer, in one instance.
5. The functional ultrasonic controlled-release puncture dressing patch provided by the invention contains a visual drug storage and delivery system, and the system has the following advantages:
First, the system contains pain-relieving medications that can improve patient comfort and acceptance; meanwhile, the puncture needle contains the medicine for dilating blood vessels, so that the blood circulation is promoted, the diameter of the blood vessels is increased, the puncture operation is easier to carry out, and the puncture accuracy and efficiency are improved;
Secondly, the medicine is wrapped by the ethosome and the liposome, so that the storage resistance of the medicine can be improved, and the denaturation and failure of the medicine are avoided; most importantly, the ethosome has small particle size, strong transdermal performance and good skin tolerance performance, effectively enhances the transdermal permeability of the medicine, can rapidly take effect, and the liposome can form a medicine reservoir in epidermis dermis, so that the medicine is slowly released, and the local pain relieving effect can be permanently exerted. The system combines the advantages of the ethosome and the liposome to realize the slow release and quick release dual-functionalization of the medicine, thereby relieving pain before and after puncture, simultaneously promoting vasodilation, improving the success rate of puncture and relieving pain of patients;
Finally, the system is embedded with various components such as collagen, and the like, so that the transdermal property, skin-friendly property, softness and comfortableness of the patch can be enhanced, skin discomfort is avoided, the patch can be better attached to the skin, and the transdermal release of nano drug carrier particles is cooperated.
Drawings
Fig. 1 is a three-dimensional structure diagram of a functionalized ultrasonic controlled release puncture dressing patch
FIG. 2 is a view showing the structure of the longitudinal section of the functionalized ultrasonic controlled release puncture dressing patch
FIG. 3 is a top plan view of a functionalized ultrasonic controlled release puncture dressing patch
FIG. 4 is a diagram of the internal microstructure of a visualized drug storage delivery system
FIG. 5 is a schematic view of a longitudinal section of a functionalized ultrasound controlled release puncture dressing patch in ultrasound guided clinical application
FIG. 6 is a graph showing the results of in vitro drug release tests in the functionalized ultrasonic controlled release puncture dressing drug-loaded ethosome
FIG. 7 is a graph showing the results of in vitro drug release test in functionalized ultrasonic controlled release puncture dressing drug-loaded liposome
Reference numerals: 1. the medical ultrasonic puncture device comprises an annular coating structure, 2, an energy conducting sheet, 3, a visual drug storage and delivery system, 4, a tearable anti-adhesive layer, 5, a bacterial contamination indication window, 6, a drug release indication window, 7, a three-dimensional cross-linked network, 8, magnetic nano particles, 9, a drug carrying ethosome, 10, a drug carrying liposome, 11, a chain photon crystal structure, 12, a handheld medical ultrasonic instrument, 13, a functional ultrasonic controlled release puncture dressing patch, 14, skin to be punctured, 15, a percutaneous puncture site, 16, a blood vessel to be punctured subcutaneously, 17 and an ultrasonic propagation simulation track.
Detailed Description
The technical scheme of the present invention will be described in further detail with reference to examples and comparative examples, but the present invention is not limited by these specific examples.
The following are examples and comparative examples.
Example 1
Weighing egg yolk lecithin 200 mg, cholesterol 65 mg, vasodilator 50 mg and pain relieving 50 mg, stirring at 30deg.C to dissolve in absolute ethanol; measuring 3 mL of ultrapure water, injecting the mixture into the absolute ethyl alcohol at a flow rate of 200 mu L/min, stirring for 30 min, performing ultrasonic treatment on the mixture by 105 w for 5 min (in an ice-water bath), and filtering the mixture by a filter membrane with the thickness of 0.22 mu m to obtain a drug-loaded ethosome 9. Weighing 200 mg of egg yolk lecithin, 65 mg of cholesterol and 50 mg of pain relieving medicine, fixing the volume to 10 mL by using a compound organic solvent, stirring for dissolution, evaporating under reduced pressure at 30 ℃ in water bath until a lipid film layer is formed, injecting nitrogen, adding 10 mL of 3% sodium cholate solution, steaming until liposome suspension is formed, injecting nitrogen, performing ultrasonic treatment of 105 w for 5 min, and filtering by using a 0.22 mu m filter membrane to obtain the drug-loaded liposome 10. The ABS was injected into the mold cavity and molded 440 s at 62.5 ℃ and 5 bar ℃ to produce the annular cladding structure 1. Mixing 30 mL of acetone solution containing 1.0% of ferrocene with 0.75 mL of 30% H 2O2 uniformly, reacting at 180 ℃ for 70H, cooling, washing, and re-dispersing into ethylene glycol (30 mg/mL) to obtain a dispersion liquid of magnetic nano particles 8; uniformly mixing 1.0 g N-isopropyl acrylamide, 0.1 mL acrylic acid and 30 mg of N, N' -methylene bisacrylamide, dissolving in a mixed solution of 1.5 mL ethanol and ethylene glycol (weight ratio of 1:1), and then adding 20 mu L of photoinitiator, and uniformly mixing in a dark place to obtain a hydrogel prepolymer solution; and then uniformly mixing the hydrogel prepolymerization solution, the dispersion liquid of the magnetic nano particles 8 and the collagen in a ratio of 30:10:1 in a dark place to obtain the magnetic hydrogel prepolymerization solution. Placing a glass mold containing the magnetic hydrogel prepolymerization solution in a 0.2T magnetic field and 356 nm ultraviolet light environment for polymerization reaction of 3 min to obtain magnetic hydrogel; the magnetic hydrogel is placed in a suspension of 80% drug-loaded liposome 10 and drug-loaded ethosome 9, and soaked at 25 ℃ for 72 h, so as to obtain the visualized drug storage and delivery system 3. Dissolving sucrose fatty acid ester in water to obtain 0.5% of emulsifier; dissolving maltodextrin and gum arabic in water according to a ratio of 3:1 to obtain a 40% wall material solution; adding 2% of emulsifying agent, 20% of PNPG, 20% of methylene blue and 20% of tetrabromofluorescein sodium into the wall material solution, and uniformly mixing; ultrasonic embedding for 30 min, homogenizing under 30 MPa for 5 times, each time 1 min; spray drying (inlet air temperature 150 deg.C, feed flow rate 17 mL/min -1, outlet air temperature 75 deg.C) to obtain microcapsule; adding 45% microcapsule, 6% carboxymethyl cellulose and 6% starch into purified water, stirring and mixing uniformly to obtain the bacterial contamination indicator window coating. The annular coating structure 1 is inverted, the energy conducting sheet 2 is firstly placed, then the bacterial contamination indicating window coating is coated on the bacterial contamination indicating window 5 of the annular coating structure 1, the visual drug storage and delivery system 3 is attached to the energy conducting sheet 2 and completely covers the bacterial contamination indicating window coating, and then the tearable anti-sticking layer 4 is compounded, so that the functional ultrasonic controlled release puncture dressing 13 is obtained.
Example 2
Weighing egg yolk lecithin 100 mg, cholesterol 30 mg, vasodilator 30 mg and pain relieving 30 mg, stirring at 30deg.C to dissolve in absolute ethanol; measuring 1 mL of ultrapure water, injecting the mixture into the absolute ethyl alcohol at a flow rate of 200 mu L/min, stirring for 30 min, performing ultrasonic treatment on the mixture at 100 w for 1 min (in an ice-water bath), and filtering the mixture by using a 0.22 mu m filter membrane to obtain a drug-loaded ethosome 9. Weighing egg yolk lecithin 100 mg, cholesterol 30 mg and pain relieving medicine 30 mg, fixing the volume to 10 mL by using a compound organic solvent, stirring for dissolution, evaporating under reduced pressure at 30 ℃ in a water bath until a lipid film layer is formed, injecting nitrogen, adding 1% sodium cholate solution 7 mL, steaming until liposome suspension is formed, injecting nitrogen, performing ultrasonic treatment on 100 w for 1 min, and filtering by using a 0.22 mu m filter membrane to obtain the drug-loaded liposome 10. The ABS was injected into a mold cavity and molded 180, 180 s at 60 c, 1 bar c to produce an annular cladding structure 1. Mixing 30 mL of acetone solution containing 0.9% ferrocene with 0.6 mL of 30% H 2O2 uniformly, reacting at 180 ℃ for 70H, cooling, washing, and re-dispersing into ethylene glycol (30 mg/mL) to obtain a dispersion liquid of magnetic nano particles 8; uniformly mixing 0.83 g N-isopropyl acrylamide, 0.083 mL acrylic acid and 27 mg of N, N' -methylene bisacrylamide, dissolving in a mixed solution of 1.5 mL ethanol and ethylene glycol (weight ratio of 0.9:1), and then adding 18 mu L of photoinitiator, and uniformly mixing in a dark place to obtain a hydrogel prepolymer solution; and then uniformly mixing the hydrogel prepolymerization solution, the dispersion liquid of the magnetic nano particles 8 and collagen in a proportion of 25:10:1 in a dark place to obtain the magnetic hydrogel prepolymerization solution. Placing a glass mold containing the magnetic hydrogel prepolymerization solution in a 0.2T magnetic field and 356 nm ultraviolet light environment for polymerization reaction 4 min to obtain magnetic hydrogel; the magnetic hydrogel is placed in a suspension of 70% drug-loaded liposome 10 and drug-loaded ethosome 9, and soaked at 25 ℃ for 72 h, so as to obtain the visualized drug storage and delivery system 3. Dissolving sucrose fatty acid ester in water to obtain 0.1% emulsifier; dissolving maltodextrin and gum arabic in water according to a ratio of 1:1 to obtain 33% wall material solution; adding 1% of emulsifying agent, 15% of PNPG, 15% of methylene blue and 15% of tetrabromo sodium into the wall material solution, and uniformly mixing; ultrasonic embedding for 30 min, homogenizing under 30 MPa for 5 times, each time 1 min; spray drying (inlet air temperature 140 deg.C, feed flow 15 mL/min -1, outlet air temperature 70 deg.C) to obtain microcapsule; and adding 25% of microcapsules, 2% of carboxymethyl cellulose and 2% of starch into the purified water, and stirring and uniformly mixing to prepare the bacterial contamination indicating window coating. The annular coating structure 1 is inverted, the energy conducting sheet 2 is firstly placed, then the bacterial contamination indicating window coating is coated on the bacterial contamination indicating window 5 of the annular coating structure 1, the visual drug storage and delivery system 3 is attached to the energy conducting sheet 2 and completely covers the bacterial contamination indicating window coating, and then the tearable anti-sticking layer 4 is compounded, so that the functional ultrasonic controlled release puncture dressing 13 is obtained.
Example 3
Weighing egg yolk lecithin 300 mg, cholesterol 100 mg, vasodilator 70 mg and pain relieving 70 mg, stirring at 30deg.C to dissolve in absolute ethanol; measuring 5 mL% of ultrapure water, injecting into the absolute ethyl alcohol at a flow rate of 200 mu L/min, stirring for 30 min, performing 110 w ultrasonic treatment on the mixture 9 min (in an ice-water bath), and filtering the mixture with a 0.22 mu m filter membrane to obtain a drug-loaded ethosome 9. Weighing egg yolk lecithin 300 mg, cholesterol 100 mg and pain relieving medicine 70 mg, fixing the volume to 10 mL by using a compound organic solvent, stirring and dissolving, evaporating under reduced pressure at 30 ℃ in water bath until a lipid film layer is formed, injecting nitrogen, adding 5% sodium cholate solution 13 mL, steaming until liposome suspension is formed, injecting nitrogen, performing ultrasonic treatment on the mixture of the liposome and the nitrogen at 110 w to 9 min, and filtering by using a 0.22 mu m filter membrane to obtain the drug-loaded liposome 10. The ABS was injected into the mold cavity and molded 700 s at 65 ℃ and 9 bar to produce the annular cladding structure 1. Mixing 30 mL of acetone solution containing 1.1% of ferrocene with 0.9 mL of 30% H 2O2 uniformly, reacting at 180 ℃ for 70H, cooling, washing, and re-dispersing into ethylene glycol (30 mg/mL) to obtain a dispersion liquid of magnetic nano particles 8; 1.13 g N-isopropyl acrylamide, 0.113 mL acrylic acid and 33 mg of N, N' -methylene bisacrylamide are uniformly mixed and dissolved in a mixed solution of 1.5-mL ethanol and ethylene glycol (weight ratio of 1.1:1), and then 22 mu L of photoinitiator is added and uniformly mixed in a dark place, so that a hydrogel prepolymer solution is obtained; and then uniformly mixing the hydrogel prepolymerization solution, the dispersion liquid of the magnetic nano particles 8 and the collagen in a ratio of 35:10:1 in a dark place to obtain the magnetic hydrogel prepolymerization solution. Placing a glass mold containing a magnetic hydrogel prepolymerization solution in a 0.2T magnetic field and 356 nm ultraviolet light environment for polymerization reaction 2 min to obtain magnetic hydrogel; the magnetic hydrogel is placed in a suspension of 90% drug-loaded liposome 10 and drug-loaded ethosome 9, and soaked at 25 ℃ for 72 h, so as to obtain the visualized drug storage and delivery system 3. Dissolving sucrose fatty acid ester in water to obtain 1.0% of emulsifier; dissolving maltodextrin and gum arabic in water according to a ratio of 5:1 to obtain a 47% wall material solution; adding 3% of emulsifying agent, 25% of PNPG, 25% of methylene blue and 25% of tetrabromo sodium into the wall material solution, and uniformly mixing; ultrasonic embedding for 30 min, homogenizing under 30 MPa for 5 times, each time 1 min; spray drying (inlet air temperature 160 deg.C, feed flow 20 mL/min -1, outlet air temperature 80 deg.C) to obtain microcapsule; adding 65% of microcapsule, 10% of carboxymethyl cellulose and 10% of starch into purified water, and stirring and uniformly mixing to obtain the bacterial contamination indicator window coating. The annular coating structure 1 is inverted, the energy conducting sheet 2 is firstly placed, then the bacterial contamination indicating window coating is coated on the bacterial contamination indicating window 5 of the annular coating structure 1, the visual drug storage and delivery system 3 is attached to the energy conducting sheet 2 and completely covers the bacterial contamination indicating window coating, and then the tearable anti-sticking layer 4 is compounded, so that the functional ultrasonic controlled release puncture dressing 13 is obtained.
Example 4
Weighing egg yolk lecithin 200 mg, cholesterol 65 mg, vasodilator 50 mg and pain relieving 50 mg, stirring at 30deg.C to dissolve in absolute ethanol; measuring 1 mL of ultrapure water, injecting the mixture into the absolute ethyl alcohol at a flow rate of 200 mu L/min, stirring for 30 min, performing ultrasonic treatment on the mixture at 100 w for 1 min (in an ice-water bath), and filtering the mixture by using a 0.22 mu m filter membrane to obtain a drug-loaded ethosome 9. Weighing egg yolk lecithin 300 mg, cholesterol 100 mg and pain relieving medicine 70 mg, fixing the volume to 10 mL by using a compound organic solvent, stirring and dissolving, evaporating under reduced pressure at 30 ℃ in water bath until a lipid film layer is formed, injecting nitrogen, adding 5% sodium cholate solution 13 mL, steaming until liposome suspension is formed, injecting nitrogen, performing ultrasonic treatment on the mixture of the liposome and the nitrogen at 110 w to 9 min, and filtering by using a 0.22 mu m filter membrane to obtain the drug-loaded liposome 10. The ABS was injected into the mold cavity and molded 700 s at 65 ℃ and 9 bar to produce the annular cladding structure 1. Mixing 30 mL of acetone solution containing 1.0% of ferrocene with 0.75 mL of 30% H 2O2 uniformly, reacting at 180 ℃ for 70H, cooling, washing, and re-dispersing into ethylene glycol (30 mg/mL) to obtain a dispersion liquid of magnetic nano particles 8; uniformly mixing 1.0 g N-isopropyl acrylamide, 0.1 mL acrylic acid and 30 mg of N, N' -methylene bisacrylamide, dissolving in a mixed solution of 1.5 mL ethanol and ethylene glycol (weight ratio of 1:1), and then adding 20 mu L of photoinitiator, and uniformly mixing in a dark place to obtain a hydrogel prepolymer solution; and then uniformly mixing the hydrogel prepolymerization solution, the dispersion liquid of the magnetic nano particles 8 and the collagen in a ratio of 30:10:1 in a dark place to obtain the magnetic hydrogel prepolymerization solution. Placing a glass mold containing the magnetic hydrogel prepolymerization solution in a 0.2T magnetic field and 356 nm ultraviolet light environment for polymerization reaction of 3 min to obtain magnetic hydrogel; the magnetic hydrogel is placed in a suspension of 80% drug-loaded liposome 10 and drug-loaded ethosome 9, and soaked at 25 ℃ for 72 h, so as to obtain the visualized drug storage and delivery system 3. Dissolving sucrose fatty acid ester in water to obtain 0.5% of emulsifier; dissolving maltodextrin and gum arabic in water according to a ratio of 5:1 to obtain 33% wall material solution; adding 2% of emulsifying agent, 20% of PNPG, 20% of methylene blue and 20% of tetrabromofluorescein sodium into the wall material solution, and uniformly mixing; ultrasonic embedding for 30 min, homogenizing under 30 MPa for 5 times, each time 1 min; spray drying (inlet air temperature 160 deg.C, feed flow 20 mL/min -1, outlet air temperature 80 deg.C) to obtain microcapsule; and adding 25% of microcapsules, 2% of carboxymethyl cellulose and 2% of starch into the purified water, and stirring and uniformly mixing to prepare the bacterial contamination indicating window coating. The annular coating structure 1 is inverted, the energy conducting sheet 2 is firstly placed, then the bacterial contamination indicating window coating is coated on the bacterial contamination indicating window 5 of the annular coating structure 1, the visual drug storage and delivery system 3 is attached to the energy conducting sheet 2 and completely covers the bacterial contamination indicating window coating, and then the tearable anti-sticking layer 4 is compounded, so that the functional ultrasonic controlled release puncture dressing 13 is obtained.
Example 5
Weighing egg yolk lecithin 100 mg, cholesterol 30 mg, vasodilator 30 mg and pain relieving 30 mg, stirring at 30deg.C to dissolve in absolute ethanol; measuring 5 mL% of ultrapure water, injecting into the absolute ethyl alcohol at a flow rate of 200 mu L/min, stirring for 30 min, performing 110 w ultrasonic treatment on the mixture 9 min (in an ice-water bath), and filtering the mixture with a 0.22 mu m filter membrane to obtain a drug-loaded ethosome 9. Weighing 200 mg of egg yolk lecithin, 65 mg of cholesterol and 50 mg of pain relieving medicine, fixing the volume to 10 mL by using a compound organic solvent, stirring for dissolution, evaporating under reduced pressure at 30 ℃ in water bath until a lipid film layer is formed, injecting nitrogen, adding 10 mL of 3% sodium cholate solution, steaming until liposome suspension is formed, injecting nitrogen, performing ultrasonic treatment of 105 w for 5 min, and filtering by using a 0.22 mu m filter membrane to obtain the drug-loaded liposome 10. The ABS was injected into the mold cavity and molded 700 s at 65 ℃ and 9 bar to produce the annular cladding structure 1. Mixing 30 mL of acetone solution containing 0.9% ferrocene with 0.6 mL of 30% H 2O2 uniformly, reacting at 180 ℃ for 70H, cooling, washing, and re-dispersing into ethylene glycol (30 mg/mL) to obtain a dispersion liquid of magnetic nano particles 8; uniformly mixing 0.83 g N-isopropyl acrylamide, 0.083 mL acrylic acid and 27 mg of N, N' -methylene bisacrylamide, dissolving in a mixed solution of 1.5 mL ethanol and ethylene glycol (weight ratio of 0.9:1), and then adding 18 mu L of photoinitiator, and uniformly mixing in a dark place to obtain a hydrogel prepolymer solution; and then uniformly mixing the hydrogel prepolymerization solution, the dispersion liquid of the magnetic nano particles 8 and collagen in a proportion of 25:10:1 in a dark place to obtain the magnetic hydrogel prepolymerization solution. Placing a glass mold containing the magnetic hydrogel prepolymerization solution in a 0.2T magnetic field and 356 nm ultraviolet light environment for polymerization reaction 4 min to obtain magnetic hydrogel; the magnetic hydrogel is placed in a 70% drug-loaded liposome 10 and drug-loaded ethosome 9 suspension, and soaked at 25 ℃ for 72 h, so that the visualized drug storage and delivery system 3 is obtained. Dissolving sucrose fatty acid ester in water to obtain 1.0% of emulsifier; dissolving maltodextrin and gum arabic in water according to a ratio of 3:1 to obtain 33% wall material solution; adding 3% of emulsifying agent, 25% of PNPG, 25% of methylene blue and 25% of tetrabromo sodium into the wall material solution, and uniformly mixing; ultrasonic embedding for 30 min, homogenizing under 30 MPa for 5 times, each time 1 min; spray drying (inlet air temperature 150 deg.C, feed flow rate 17 mL/min -1, outlet air temperature 75 deg.C) to obtain microcapsule; and adding 25% of microcapsules, 2% of carboxymethyl cellulose and 2% of starch into the purified water, and stirring and uniformly mixing to prepare the bacterial contamination indicating window coating. The annular coating structure 1 is inverted, the energy conducting sheet 2 is firstly placed, then the bacterial contamination indicating window coating is coated on the bacterial contamination indicating window 5 of the annular coating structure 1, the visual drug storage and delivery system 3 is attached to the energy conducting sheet 2 and completely covers the bacterial contamination indicating window coating, and then the tearable anti-sticking layer 4 is compounded, so that the functional ultrasonic controlled release puncture dressing 13 is obtained.
Example 6
Weighing egg yolk lecithin 300 mg, cholesterol 100 mg, vasodilator 70 mg and pain relieving 70 mg, stirring at 30deg.C to dissolve in absolute ethanol; measuring 3 mL of ultrapure water, injecting the mixture into the absolute ethyl alcohol at a flow rate of 200 mu L/min, stirring for 30 min, performing ultrasonic treatment on the mixture by 105 w for 5 min (in an ice-water bath), and filtering the mixture by a filter membrane with the thickness of 0.22 mu m to obtain a drug-loaded ethosome 9. Weighing egg yolk lecithin 100 mg, cholesterol 30 mg and pain relieving medicine 30 mg, fixing the volume to 10 mL by using a compound organic solvent, stirring for dissolution, evaporating under reduced pressure at 30 ℃ in a water bath until a lipid film layer is formed, injecting nitrogen, adding 1% sodium cholate solution 7 mL, steaming until liposome suspension is formed, injecting nitrogen, performing ultrasonic treatment on 100 w for 1 min, and filtering by using a 0.22 mu m filter membrane to obtain the drug-loaded liposome 10. The ABS was injected into the mold cavity and molded 440 s at 62.5 ℃ and 5 bar ℃ to produce the annular cladding structure 1. Mixing 30 mL of acetone solution containing 1.1% of ferrocene with 0.9 mL of 30% H 2O2 uniformly, reacting at 180 ℃ for 70H, cooling, washing, and re-dispersing into ethylene glycol (30 mg/mL) to obtain a dispersion liquid of magnetic nano particles 8; 1.13 g N-isopropyl acrylamide, 0.113 mL acrylic acid and 33 mg of N, N' -methylene bisacrylamide are uniformly mixed and dissolved in a mixed solution of 1.5 mL ethanol and ethylene glycol (weight ratio of 1.1:1), and then 22 mu L of photoinitiator is added and uniformly mixed in a dark place, so that a hydrogel prepolymer solution is obtained; and then uniformly mixing the hydrogel prepolymerization solution, the dispersion liquid of the magnetic nano particles 8 and the collagen in a ratio of 35:10:1 in a dark place to obtain the magnetic hydrogel prepolymerization solution. Placing a glass mold containing a magnetic hydrogel prepolymerization solution in a 0.2T magnetic field and 356 nm ultraviolet light environment for polymerization reaction 2 min to obtain magnetic hydrogel; the magnetic hydrogel is placed in a suspension of 90% drug-loaded liposome 10 and drug-loaded ethosome 9, and soaked at 25 ℃ for 72 h, so as to obtain the visualized drug storage and delivery system 3. Dissolving sucrose fatty acid ester in water to obtain 0.1% emulsifier; dissolving maltodextrin and gum arabic in water according to a ratio of 5:1 to obtain a 40% wall material solution; adding 1% of emulsifying agent, 15% of PNPG, 15% of methylene blue and 15% of tetrabromo sodium into the wall material solution, and uniformly mixing; ultrasonic embedding for 30 min, homogenizing under 30 MPa for 5 times, each time 1 min; spray drying (inlet air temperature 160 deg.C, feed flow 20 mL/min -1, outlet air temperature 80 deg.C) to obtain microcapsule; adding 45% microcapsule, 6% carboxymethyl cellulose and 6% starch into purified water, stirring and mixing uniformly to obtain the bacterial contamination indicator window coating. The annular coating structure 1 is inverted, the energy conducting sheet 2 is firstly placed, then the bacterial contamination indicating window coating is coated on the bacterial contamination indicating window 5 of the annular coating structure 1, the visual drug storage and delivery system 3 is attached to the energy conducting sheet 2 and completely covers the bacterial contamination indicating window coating, and then the tearable anti-sticking layer 4 is compounded, so that the functional ultrasonic controlled release puncture dressing 13 is obtained.
Comparative example 1
Comparative example 1 is substantially the same as example 1 except that: in example 1, an annular coating structure 1 having a bacterial contamination indicating window 5 and a drug release indicating window 6 was used, whereas comparative example 1 had no annular coating structure 1, and simultaneously had no bacterial contamination indicating window 5 and no drug release indicating window 6.
Comparative example 2
Comparative example 2 is substantially the same as example 1 except that: in example 1, an energy conducting sheet 2 was used, and in comparative example 2, a layer of nonwoven fabric was used.
Comparative example 3
Comparative example 3 is substantially the same as example 1 except that: example 1a magnetic hydrogel was placed in 80% drug-loaded liposomes and drug-loaded ethosome suspension and soaked at 25 ℃ for 72 h to give a visualized drug storage delivery system 3; while comparative example 3 did not prepare an ethosome or liposome for loading and protecting the drug, except that the magnetic hydrogel was placed in a mixed solution of 80% vasodilator drug and pain-relieving drug (mass ratio of vasodilator drug to pain-relieving drug 1:1), and immersed in 72 h at 25 ℃.
Comparative example 4
Comparative example 4 is substantially the same as example 1 except that: example 1 contains both drug-loaded ethosome 9 and drug-loaded liposome 10, whereas comparative example 4 has only drug-loaded ethosome 9 and no drug-loaded liposome 10.
Comparative example 5
Comparative example 5 is substantially the same as example 1 except that: example 1 contains both drug-loaded liposomes 9 and drug-loaded liposomes 10, whereas comparative example 5 has only drug-loaded liposomes 10, without drug-loaded liposomes 9.
Comparative example 6
Weighing egg yolk lecithin 50 mg, cholesterol 150 mg, vasodilator 50 mg and pain relieving 50 mg, stirring at 30deg.C to dissolve in absolute ethanol; measuring 7 mL of ultrapure water, injecting the ultrapure water into the absolute ethyl alcohol at a flow rate of 200 mu L/min, stirring for 30 min, performing ultrasonic treatment on the mixture at 150 w for 12 min (in an ice-water bath), and filtering the mixture by using a 0.22 mu m filter membrane to obtain a drug-loaded ethosome 9. Weighing egg yolk lecithin 400 mg, cholesterol 20 mg and pain relieving medicine 50 mg, fixing the volume to 10 mL by using a compound organic solvent, stirring and dissolving, evaporating under reduced pressure at 30 ℃ in water bath until a lipid film layer is formed, injecting nitrogen, adding 3% sodium cholate solution 10 mL, steaming until liposome suspension is formed, injecting nitrogen, performing ultrasonic treatment on 15 min by 150 w, and filtering by using a 0.22 mu m filter membrane to obtain the drug-loaded liposome 10. The ABS was injected into the mold cavity and molded 440 s at 62.5 ℃ and 5 bar ℃ to produce the annular cladding structure 1. Mixing 30 mL of acetone solution containing 0.2% of ferrocene with 1.5 mL of 30% H 2O2 uniformly, reacting at 180 ℃ for 70H, cooling, washing, and re-dispersing into ethylene glycol (30 mg/mL) to obtain a dispersion liquid of magnetic nano particles 8; 1.8 g N-isopropyl acrylamide, 0.18 mL acrylic acid and 3 mg N, N' -methylene bisacrylamide are uniformly mixed and dissolved in a mixed solution of 1.5 mL ethanol and ethylene glycol (weight ratio of 1:1), and then 2 mu L of photoinitiator is added and uniformly mixed in a dark place to obtain a hydrogel prepolymer solution; and then uniformly mixing the hydrogel prepolymerization solution, the dispersion liquid of the magnetic nano particles 8 and the collagen in a ratio of 10:10:1 in a dark way to obtain the magnetic hydrogel prepolymerization solution. Placing a glass mold containing a magnetic hydrogel prepolymerization solution in a 0.2T magnetic field and 356 nm ultraviolet light environment for polymerization reaction 1 min to obtain magnetic hydrogel; the magnetic hydrogel is placed in 50% of a suspension of drug-loaded liposome 10 and drug-loaded ethosome 9, and soaked at 25 ℃ for 72 h, so that the visualized drug storage and delivery system 3 is obtained. Dissolving sucrose fatty acid ester in water to obtain 0.5% of emulsifier; dissolving maltodextrin and gum arabic in water according to a ratio of 3:1 to obtain a 40% wall material solution; adding 2% of emulsifying agent, 20% of PNPG, 20% of methylene blue and 20% of tetrabromofluorescein sodium into the wall material solution, and uniformly mixing; ultrasonic embedding for 30 min, homogenizing under 30 MPa for 5 times, each time 1 min; spray drying (inlet air temperature 150 deg.C, feed flow rate 17 mL/min -1, outlet air temperature 75 deg.C) to obtain microcapsule; adding 45% microcapsule, 6% carboxymethyl cellulose and 6% starch into purified water, stirring and mixing uniformly to obtain the bacterial contamination indicator window coating. The annular coating structure 1 is inverted, the energy conducting sheet 2 is firstly placed, then the bacterial contamination indicating window coating is coated on the bacterial contamination indicating window 5 of the annular coating structure 1, the visual drug storage and delivery system 3 is attached to the energy conducting sheet 2 and completely covers the bacterial contamination indicating window coating, and then the tearable anti-sticking layer 4 is compounded, so that the functional ultrasonic controlled release puncture dressing 13 is obtained.
The detection method of the functionalized ultrasonic controlled-release puncture dressing 13 in the invention comprises the following steps:
1. drug encapsulation efficiency determination of liposomes and ethosomes
High performance liquid chromatography is used for measurement.
2. Determination of drug recovery rate in functionalized ultrasonic controlled-release puncture dressing patch 13
High performance liquid chromatography is used for measurement.
3. Stability test of functional ultrasonic controlled-release puncture dressing patch 13
Considering the influence of illumination, humidity and temperature on the properties and the drug content of the functionalized ultrasonic controlled-release puncture dressing 13 (the drug-loaded ethosome 9 in the functionalized ultrasonic controlled-release puncture dressing 13 is selected as a measurement object). Setting conditions: light (colorless transparent sealed plastic bag, 4500 Lx, relative humidity 50%, constant temperature 25 ℃, standing for 30 days), humidity (black sealed plastic bag, relative humidity 75%, constant temperature 25 ℃, standing for 30 days), temperature (black sealed plastic bag, relative humidity 75%, constant temperature 60 ℃, standing for 30 days).
4. In-vitro percutaneous release test of medicine in functionalized ultrasonic controlled-release puncture dressing patch 13
The in vitro diffusion method is adopted for testing, and the diffusion membrane is the in vitro abdomen skin of the mouse.
5. Skin irritation test of functionalized ultrasonic controlled release puncture dressing patch 13
The measurement was performed using symmetrical hairless skin on both sides of the back of the rabbits.
6. Bacterial contamination indicator window 5 and drug release indicator window 6 display efficacy test
(1) (1) Bacterial contamination indicator window 5 display: 0.5 mL of 3X 10 8 CFU/mL of strain 1 (Escherichia coli) and 0.5 mL strain 2 (Staphylococcus aureus) are respectively dripped near the bacterial contamination indicator window 5 of the embodiments 1-6, and the bacterial contamination indicator window 5 is left stand for 5min, and the color of the bacterial contamination indicator window 5 is observed with normal naked eyes indoors;
(2) Drug release indicator window 6 displays: the clinical use process was simulated, and the color change of the drug release indicator window 6 was observed with a normal naked eye indoors.
7. Clinical trial effects
Clinical protocol: 240 cases of operation patients needing to be punctured by the venous indwelling needle are selected, 60 cases are observation groups, and example 1 is adopted as a test sample; 60 cases are placebo groups, and gauze stained with physiological saline is used as a test sample; 60 cases are comparative group 1, and comparative example 4 is used as a test article; 60 cases are comparative group 2, and comparative example 5 is used as a test article; all groups of puncture parts are 1-2 cm away from the proximal end of the wrist joint by the left-hand head vein, and ultrasonic treatment is carried out by combining an ultrasonic technology;
(1) After the puncture is finished, inquiring the pain feeling of the patient in the puncture operation process in a way of oral question and answer, dividing the pain level of the patient according to the VAS score, and judging the pain level of the patient so as to evaluate the rapid pain relieving effect of the functional ultrasonic controlled-release puncture dressing 13;
(2) After the puncture is finished, inquiring a doctor in a way of oral question and answer, recording the puncture operation difficulty and confirming whether the first puncture is successful or not, thereby evaluating the vasodilation effect of the functionalized ultrasonic controlled-release puncture dressing 13;
(3) After the puncture is finished, the pain feeling of the patient at rest in the ward is inquired in a way of oral question answering, the pain level of the patient is divided according to the VAS score, and the pain degree of the patient is judged, so that the continuous pain relieving effect of the functional ultrasonic controlled-release puncture dressing 13 is evaluated.
The drug encapsulation efficiency, recovery rate, stability, in vitro percutaneous permeability, skin irritation and other properties of the functionalized ultrasonic controlled-release puncture dressing 13 were detected and the clinical trial therapeutic effects were observed according to the detection methods, and the results are shown in tables 1, 2, 3, 4,5, 6 and 7.
TABLE 1 detection results tables of examples 1 to 6 of the present invention
TABLE 2 comparative examples 1-6 test results Table of the present invention
TABLE 3 results of stability test (drug content,%) of inventive examples 1-6
TABLE 4 results of stability test (drug content,%) of comparative examples 1-6 of the present invention
TABLE 5 evaluation results of pain class during and after puncture
TABLE 6 evaluation results of dilated blood vessel
As can be seen from table 1 to table 6, fig. 6 and fig. 7, the functionalized ultrasonic controlled-release puncture dressing patch 13 designed by the invention has higher ethosome encapsulation rate, liposome encapsulation rate and drug recovery rate, and the protection of the annular coating structure 1 ensures that the dressing patch has more stable properties, including external properties, drug release and drug content, and is hardly influenced by illumination, high temperature and high humidity; has no irritation to skin and good skin affinity; by combining the ultrasonic technology, the drug-loaded ethosome 9 can be basically completely released about 10 min before puncture, and then the sustained release effect of the drug-loaded liposome 10 can also continuously and stably release the analgesic drug; meanwhile, the two indication windows can monitor bacterial pollution and drug release degree; finally, according to clinical research results, the invention can effectively relieve pain before and after puncture, and simultaneously can dilate blood vessels to be punctured, reduce puncture difficulty, improve puncture success rate and further relieve pain of patients.
As can be seen from examples 1-6 of table 1 and comparative example 1 of table 2, the edge of the dressing patch is severely deformed without the protection of the annular coating structure 1, and the phenomena of dry cracking, breakage and delamination occur, so that the product is disqualified, and the bacteria pollution indication window 5 and the drug release indication window 6 are not provided, which is inconvenient to use; meanwhile, as is clear from comparative example 1 of examples 1 to 6 and 4 of table 3, without the protection of the annular cladding structure 1, the visual drug storage and delivery system 3 is damaged, in which the drug storability is deteriorated, and is susceptible to environmental factors, particularly temperature; furthermore, as can be seen from fig. 6 and 7, the total drug release, release rate and release stability are also reduced without the protection of the annular cladding structure 1.
As is clear from comparative examples 2 of tables 1 to 6 and 2, tables 3 and 4, and fig. 6 and 7, the visual drug storage and delivery system 3 was exposed to air without the energy transmission sheet 2, and it was also found that the problems such as cracking, breakage, inactivation of the drug, unstable drug release, and low drug release were caused, and the desired therapeutic effect was not achieved.
As can be seen from examples 1-6 of table 1, comparative example 3 of table 2, table 3, table 4, and fig. 6 and 7, there is no nanocarrier (ethosome, liposome) for loading and protecting the drug, the drug recovery rate is very low, and the drug loading is also low as can be seen from the color change of the indication window; in addition, the drug cannot effectively penetrate the skin into the target tissue, and the release amount is low and slow, and the slow release effect is not achieved.
As can be seen from table 5, example 1 (observation group) contains both drug-loaded liposome 10 and drug-loaded ethosome 9, which can reduce the pain during and after the operation; in contrast, comparative example 4 (control group 1) has no drug-loaded liposome 10 and only drug-loaded ethosome 9, so that the drug-loaded ethosome has better effects of stopping pain and dilating blood vessels before operation, but has no continuous effect of stopping pain after operation; in contrast, comparative example 5 (control group 2) has no drug-loaded ethosome 9 and only drug-loaded liposome 10, so that the drug-loaded ethosome has a better postoperative continuous analgesic effect, but has no preoperative analgesic and vasodilatory effects.
As can be seen from table 6, the degree of reduction of the surgical difficulty after the use of the functionalized ultrasonic controlled release puncture dressing 13 improves the success rate of the first puncture.
As can be seen from comparative examples 6 of examples 1-6 and tables 2,3 and 4, and FIGS. 6 and 7, comparative example 6 has unsuitable preparation process parameters, so that the ethosome encapsulation efficiency, the liposome encapsulation efficiency, and the adjuvant patch drug recovery rate, and the dressing stability, the adjuvant patch skin irritation, and the indicator window color development effect test indexes of the functionalized ultrasonic controlled-release puncture dressing 13 are all not ideal.
The result shows that the functional ultrasonic controlled-release puncture dressing 13 designed by the invention has good properties and clinical application value.
While the present invention has been described in detail through the foregoing description of the preferred embodiment, it should be understood that the foregoing description is not to be considered as limiting the invention. Many modifications and substitutions of the present invention will become apparent to those of ordinary skill in the art upon reading the foregoing description, and any variations that would occur to those skilled in the art are intended to be within the scope of the invention.
Claims (8)
1. The functional ultrasonic controlled release puncture dressing patch is characterized by comprising a double-layer parallel structure, an annular cladding structure and a tearable anti-sticking layer; the double-layer parallel structure is used as a core material and consists of an energy conducting sheet and a visual drug storage and delivery system, and is arranged concentrically and vertically; the energy conducting sheet is made of an ultrasonic wave transmission material; the visual drug storage and delivery system consists of hydrogel embedded with drug-carrying alcohol bodies, drug-carrying liposomes, magnetic nanoparticles and collagen; the annular coating structure is used as a coating material and comprises a bacterial pollution indication window and a drug release indication window, and is used for connecting, fixing and protecting the integral frame and indicating the bacterial pollution and drug release degree, and is prepared through a mould pressing process;
The preparation method comprises the following steps:
(1) Preparation of drug-loaded ethosome: weighing egg yolk lecithin, cholesterol, a vasodilator and a pain relieving medicine according to a formula, stirring and dissolving the egg yolk lecithin, the cholesterol, the vasodilator and the pain relieving medicine in absolute ethyl alcohol at 30 ℃; injecting ultrapure water into the absolute ethyl alcohol at the flow rate of 200 mu L/min, stirring for 30min, performing ice water bath ultrasonic treatment, and filtering with a 0.22 mu m filter membrane to obtain a drug-carrying ethosome;
(2) Preparation of drug-loaded liposome: weighing egg yolk lecithin, cholesterol, pain relieving medicine and compound organic solvent according to a formula, stirring, mixing and dissolving; evaporating under reduced pressure in 30deg.C water bath to form a lipid film layer, injecting nitrogen, adding sodium cholate solution, removing organic solvent by rotary evaporation to form liposome suspension, injecting nitrogen again, performing ultrasonic treatment, and filtering with 0.22 μm filter membrane to obtain drug-loaded liposome;
(3) Preparing an annular cladding structure: injecting ABS into a mold cavity, and performing a mold pressing process to obtain an annular coating structure containing a bacterial contamination indication window and a drug release indication window;
(4) Preparation of magnetic hydrogel prepolymerization solution: uniformly mixing an acetone solution containing ferrocene with 30% H 2O2, reacting for 70 hours at 180 ℃, cooling, and washing and redispersing to obtain a magnetic nanoparticle dispersion liquid; uniformly mixing N-isopropyl acrylamide, acrylic acid and N, N' -methylene bisacrylamide, dissolving the mixture in an ethanol and ethylene glycol mixed organic solution, and then adding a photoinitiator, and uniformly mixing the mixture in a dark place to obtain a hydrogel prepolymerization solution; uniformly mixing the hydrogel prepolymerization solution, the magnetic nanoparticle dispersion liquid and the collagen according to a proportion in a dark place to obtain a magnetic hydrogel prepolymerization solution;
(5) Visual drug storage delivery system preparation: placing a glass mold containing the magnetic hydrogel prepolymerization solution in a 0.2T magnetic field and 356nm ultraviolet light environment for polymerization reaction to obtain magnetic hydrogel; placing the magnetic hydrogel in a drug-loaded liposome and drug-loaded ethosome suspension, and soaking at 25 ℃ for 72h to obtain a visual drug storage and delivery system;
(6) The preparation of the coating for the bacterial contamination indicator window comprises the following steps: stirring sucrose fatty acid ester and dissolving in water to obtain an emulsifier; uniformly mixing maltodextrin and gum arabic according to a proportion, and dissolving the mixture in water to obtain a wall material solution; adding an emulsifying agent and PNPG into the wall material solution, emulsifying, adding methylene blue and tetrabromo sodium fluorescein, and uniformly mixing again; mixing, ultrasonic embedding for 30min, homogenizing under 30MPa for 5 times, and 1min each time; homogenizing, and then spray drying to obtain microcapsules; adding the microcapsule, the carboxymethyl cellulose and the starch into the purified water according to the formula, and stirring and uniformly mixing to prepare the coating for the bacterial contamination indicator window;
(7) Preparation of a functional ultrasonic controlled-release puncture dressing patch: inverting the annular coating structure, firstly placing an energy conducting sheet, then coating the bacterial contamination indication window coating on the bacterial contamination indication window of the annular coating structure, then attaching a visual drug storage and delivery system on the energy conducting sheet and completely covering the bacterial contamination indication window coating, and then compounding a tearable anti-sticking layer to obtain the functional ultrasonic controlled release puncture dressing.
2. The method for preparing a functionalized ultrasonic controlled release dressing patch according to claim 1, wherein the formula in step (1) is as follows: 3 to 7 percent of egg yolk lecithin, 0.1 to 1.1 percent of cholesterol, 4 to 6 percent of vasodilator, 4 to 6 percent of pain relieving medicine, 30 to 40 percent of absolute ethyl alcohol and 58.9 to 39.9 percent of ultrapure water; the vasodilator is one of nitroglycerin and phentolamine; the pain relieving medicine is one of lidocaine and tetracaine hydrochloride; the ultrasonic treatment is carried out with parameters of ultrasonic power of 100-110 w and ultrasonic time of 1-9 min.
3. The method for preparing a functionalized ultrasonic controlled release dressing patch according to claim 1, wherein the formula in step (2) is as follows: 1 to 5 percent of egg yolk lecithin, 0.5 to 1.5 percent of cholesterol, 4 to 6 percent of pain relieving medicine, 42 to 52 percent of compound organic solvent and 52.5 to 42.5 percent of sodium cholate solution; the compound organic solvent is prepared by mixing chloroform and methanol according to a volume ratio of 1:1; the concentration of the sodium cholate solution is 1-5%; the ultrasonic treatment is carried out with parameters of ultrasonic power of 100-110 w and ultrasonic time of 1-9 min.
4. The method for preparing a functionalized ultrasonic controlled-release puncture dressing according to claim 1, wherein the molding process parameters in step (3) are as follows: the temperature of the die is 60-65 ℃, the die pressing time is 180-700 s, and the die pressing pressure is 1-9 bar.
5. The method for preparing the functionalized ultrasonic controlled-release puncture dressing patch according to claim 1, wherein the concentration of the acetone solution containing ferrocene in the step (4) is 0.9-1.1%, and the adding amount of 30% H 2O2 is 2.0-3.0%; the redispersion refers to redispersing magnetic nano particles with certain mass into glycol solution, so that the concentration of the magnetic nano particles in the solution is 30mg/mL; the concentrations of the N-isopropyl acrylamide, the acrylic acid and the N, N' -methylene bisacrylamide in the ethanol and ethylene glycol mixed solution are respectively 0.55-0.75 g/mL, 5.5-7.5% and 18-22 mg/mL; the weight ratio of the ethanol to the glycol in the ethanol and glycol mixed solution is (0.9-1.1): 1; the photoinitiator is one of 2,4, 6-trimethylbenzoyl diphenyl phosphine oxide and 2,4, 6-trimethylbenzoyl phenyl ethyl phosphonate, and the addition amount of the photoinitiator is 1.25-1.45%; the ratio of the hydrogel prepolymerization solution to the magnetic nanoparticle dispersion liquid to the collagen is (25-35) 10:1.
6. The method for preparing the functionalized ultrasonic controlled-release puncture dressing patch according to claim 1, wherein the size of the glass mold in the step (5) is consistent with that of the annular coating structure, and the polymerization reaction time is 2-4 min; the solute of the suspension is a mixture of the drug-carrying liposome and the drug-carrying ethosome according to the mass ratio of 1:1, and the concentration of the mixture in the suspension is 70-90%.
7. The method for preparing the functionalized ultrasonic controlled-release puncture dressing patch according to claim 1, wherein the concentration of the emulsifier in the step (6) is 0.1-1.0%; the mixing proportion of maltodextrin and gum arabic is (1-5): 1; the wall material concentration is 33-47%; adding an emulsifier, PNPG, methylene blue and tetrabromo sodium into the wall material solution, wherein the concentration of the PNPG, the methylene blue and the tetrabromo sodium are respectively 1-3%, 15-25% and 15-25%; the spray drying parameters were: the air inlet temperature is 140-160 ℃, the feeding flow is 15-20 mL/min -1, and the air outlet temperature is 70-80 ℃; the paint formula for the bacterial contamination indicator window comprises 25-65% of microcapsule, 2-10% of carboxymethyl cellulose and 2-10% of starch.
8. The method for preparing a functionalized ultrasonic controlled-release puncture dressing according to claim 1, wherein the ultrasonic transmission material used in the energy transmission sheet in the step (7) is one of metal, ceramic and plastic; the tearable anti-sticking layer is one of a polystyrene film, an aluminum foil, a siliconized polyvinyl chloride film and a polycarbonate film.
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