CN109908110B - Double-layer composite medicine-carrying adhesive patch as well as preparation method and application thereof - Google Patents
Double-layer composite medicine-carrying adhesive patch as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a double-layer composite drug-loaded adhesive patch and a preparation method and application thereof, belonging to the technical field of medical and biomedical materials. After the burst release medicament and the sustained-release medicament are respectively mixed with the high polymer, an electrostatic spinning device is used to prepare a burst release medicament layer and a sustained-release medicament layer, and then the burst release medicament layer and the sustained-release medicament layer are in accordance with the adhesive film to obtain the double-layer composite medicament-carrying adhesive patch. When the device is used, the burst release medicament layer and the slow release medicament layer can be loaded with different types of medicaments to form gradient release, so that the optimal treatment effect is achieved. The nanofiber membrane used as the carrier has the advantages of high specific surface area, high porosity, moisture and air permeability, small fiber diameter and the like, can increase the drug loading capacity, is high in porosity, is favorable for growth and proliferation of cells, promotes the rapid healing of wound surfaces, can simulate the natural environment of mucous membranes or skin through the moisture and air permeability, is favorable for the growth of new cells of the wound surfaces, can provide more growth sites for the cells due to the small fiber diameter, and can accelerate wound surface repair.
Description
Technical Field
The invention belongs to the technical field of medical and biomedical materials, and particularly relates to a double-layer composite medicine-carrying adhesive patch as well as a preparation method and application thereof.
Background
Canker sores are a common condition in which ulcerated lesions of the oral mucosa appear. When the oral ulcer is in attack, the affected part of the ulcer feels abnormal pain, which causes great pain to patients. There are currently two methods of treating oral ulcers: one is to achieve the purpose of antibiosis and antiphlogosis by oral medication so as to relieve the pain caused by canker sore; secondly, the medicine is directly applied on the ulcer surface, so that the medicine directly acts on the ulcer lesion part to achieve the purpose of treating the oral ulcer. However, both of these methods of treating canker sores have their disadvantages: the former is that the oral medicine can act on the ulcer lesion part only by digestion, decomposition of liver and blood transportation, and has the disadvantages of long medicine transportation path and increased liver burden, so the utilization efficiency of the medicine is very low; in the latter case, when the medicine is directly applied to the affected part of the ulcer, the moist environment in the oral cavity may seriously affect the action and effect of the medicine, and the medicine is likely to dissolve in saliva, resulting in the deterioration of the whole oral environment.
The optimal treatment scheme is to quickly reduce the pain of the wound surface and reduce the pain of the patient; then, the anti-inflammatory and antibacterial medicines are used for slow release to achieve the treatment effect. In recent years, the drug-carrying adhesive patch has relatively fast development at home and abroad, and the drug-carrying adhesive patch can effectively promote the healing of a wound surface. However, the effect of the drug loaded by the conventional drug-loaded adhesive patch is single, and the drug does not have the effect of gradient release; the existing drug carrier membrane has poor adhesion, is easy to fall off, and has limited drug loading capacity; the porosity is not high, the moisture permeability and the air permeability are poor, and the growth and the propagation of cells are not facilitated.
Disclosure of Invention
In order to solve the defects in the prior art, the invention aims to provide a double-layer composite drug-carrying adhesive patch and a preparation method and application thereof.
The invention is realized by the following technical scheme:
the invention discloses a preparation method of a double-layer composite medicine-carrying adhesive patch, which comprises the following steps:
step 1: respectively mixing the burst release medicament and the sustained release medicament with a high polymer and dissolving the mixture in a solvent to prepare a burst release medicament spinning solution and a sustained release medicament spinning solution; preparing an adhesive film solution for later use;
and 2, step: respectively putting the burst release agent spinning solution and the slow release agent spinning solution into electrostatic spinning equipment, and setting spinning parameters to prepare a nanofiber membrane loaded with a burst release agent and a nanofiber membrane loaded with a slow release agent;
and 3, step 3: and compounding the adhesive film solution, the nanofiber film loaded with the burst release medicament and the nanofiber film loaded with the slow release medicament to obtain the double-layer composite medicament-carrying adhesive patch.
Preferably, in step 1, the specific steps for preparing the adhesive film solution are as follows:
a. weighing/measuring the ratio of the material liquid to the material liquid of 0.001-1 g: 0.01-1 ml:0.1 to 5ml of hydroxypropyl methyl cellulose, propylene glycol and deionized water are mixed and stirred evenly;
b. b, centrifuging the solution system obtained in the step a on a centrifuge at the speed of 1000-8000 r/min for 1-5 times, and then placing the solution system into a mold to obtain an adhesive film solution;
in the step 3, the compounding is carried out by placing the nanofiber membrane loaded with the burst release medicament and the nanofiber membrane loaded with the slow release medicament on the adhesive membrane solution, and then placing the mold in an environment with the temperature of 20-25 ℃ and the humidity of 30-70% for 24-72 h.
Preferably, in step 2, the specific spinning parameters are: the applied voltage is 20-80 kV, the receiving distance is 20-40 cm, the solution flow is 2-15 ml/h, the rotating speed of the metal roller is 60-800 rpm, the ambient temperature is 15-30 ℃, and the ambient relative humidity is 10-60%.
Preferably, the burst release medicament is one or more of hemostatic medicaments, antibacterial medicaments, analgesic medicaments and anesthetic medicaments; the slow release preparation is one or more of antiinflammatory medicine, antibiotic medicine, antioxidant medicine, and skin growth factor.
Preferably, in the step 2, the electrospinning device is a double-ring slit type electrospinning apparatus.
Further preferably, the spinning comprises the following specific steps:
step 2.1: forming jet flow of the slow-release agent spinning solution and collecting the jet flow on the metal roller, and after the solvent in the slow-release agent spinning solution is volatilized, forming nano fibers for solidification to obtain a nano fiber membrane which is deposited on the metal roller and is loaded with the slow-release agent;
step 2.2: forming jet flow of the burst-release agent spinning solution to gather on the nanofiber membrane loaded with the slow-release agent on the metal roller, and after the solvent in the burst-release agent spinning solution is volatilized, forming nanofibers to be solidified to obtain the composite nanofiber membrane loaded with the burst-release agent and the nanofiber membrane loaded with the slow-release agent.
Preferably, the burst release medicament spinning solution is prepared from diclofenac sodium, polyethylene oxide and deionized water with the mass part ratio of 1-5; the slow release agent spinning solution is prepared from 0.1-10 parts by mass of curcumin, levorotatory polylactic acid and hexafluoroisopropanol, wherein the mass part ratio of the curcumin to the levorotatory polylactic acid to the hexafluoroisopropanol is as follows.
The invention also discloses a double-layer compound drug-carrying adhesive patch prepared by the preparation method of the double-layer compound drug-carrying adhesive patch.
Preferably, the total thickness of the nanofiber membrane loaded with the burst medicament and the nanofiber membrane loaded with the slow-release medicament is 20-100 μm; the thickness of the adhesive film is 0.5-3 mm.
The invention also discloses application of the double-layer composite medicine-carrying adhesive patch as a medical adhesive patch.
Compared with the prior art, the invention has the following beneficial technical effects:
the invention discloses a preparation method of a double-layer composite medicine-carrying adhesive patch, which comprises the steps of mixing a burst release medicament and a sustained release medicament with a high polymer respectively, preparing a nanofiber membrane loaded with the burst release medicament as a burst release medicament layer and a nanofiber membrane loaded with the sustained release medicament as a sustained release medicament layer by using electrostatic spinning equipment, and then compounding the burst release medicament layer, the sustained release medicament layer and an adhesive membrane solution to obtain the double-layer composite medicine-carrying adhesive patch. When the device is used, the burst release medicament layer and the slow release medicament layer can load different types of medicaments, and are reasonably distributed according to the wound condition to form gradient release, so that the optimal treatment effect is achieved. The nanofiber membrane used as the carrier has the advantages of high specific surface area, high porosity, moisture and air permeability, small fiber diameter and the like, can increase the drug loading capacity, is high in porosity, is favorable for growth and proliferation of cells, promotes the rapid healing of wound surfaces, can simulate the natural environment of mucous membranes or skin through the moisture and air permeability, is favorable for the growth of new cells of the wound surfaces, can provide more growth sites for the cells due to the small fiber diameter, and can accelerate wound surface repair.
Furthermore, the burst release medicament adopts one or more of hemostatic medicaments, bactericidal medicaments, analgesic medicaments and anesthetic medicaments, can relieve the pain of a patient at the first time, stop bleeding, sterilize and prevent infection; the slow release medicament adopts one or more of anti-inflammatory medicaments, antibiotic medicaments, antioxidant medicaments and skin growth factors, is slowly released, and has good treatment and wound healing effects.
Furthermore, the electrostatic spinning device adopts a double-circular-ring slit type electrostatic spinning device, the batch preparation of the nano fibers is seriously limited due to the defects of low yield of the nano fibers, easy blockage of the needle head and difficult cleaning of the needle head existing in the traditional single-needle-head electrostatic spinning technology at present, and the double-circular-ring slit type electrostatic spinning device has high yield, no blockage of a spray head and simple and easy operation. Meanwhile, the double-ring slit type electrostatic spinning device is adopted to prepare the drug-loaded nanofiber membrane in batch, so that the problems of volatility, insufficient solution utilization, uncontrollable nanofiber structure and the like of a spinning solution in the spinning process can be solved, the industrial preparation of the nanofibers is realized in a real sense, and a new way is provided for the clinical application and the industrial development of the nanofiber membrane in the biomedical field.
Furthermore, the burst release medicament takes diclofenac sodium as a main component, the slow release medicament takes curcumin as a main component, the curcumin is yellow pigment extracted from rhizomes of curcuma longa and the like in the family of zingiberaceae, and a great deal of research shows that the curcumin has obvious pharmacological effects on the aspects of anti-inflammatory, antioxidant, anticancer, antibacterial performance and the like. Diclofenac sodium is a typical nonsteroidal medicament for promoting wound healing, and has the functions of antibiosis, analgesia and antiphlogosis. The curcumin-loaded nanofiber membrane is prepared, the diclofenac sodium-loaded nanofiber membrane is compounded on the curcumin-loaded nanofiber membrane, and the adhesive membrane is combined to prepare the double-layer compound drug-loaded adhesive patch, so that the gradient release effect and the comprehensive effect of the two drugs can quickly reduce the pain of a wound surface and achieve the effects of resisting bacteria and inflammation and quickly healing.
The double-layer composite drug-loaded adhesive patch prepared by the preparation method disclosed by the invention is simple in structure, the nanofiber membrane is used as a drug carrier, the double-layer composite drug-loaded adhesive patch has the advantages of high specific surface area, high porosity, moisture permeability and air permeability, fine fiber diameter and the like, and the burst drug layer and the sustained-release drug layer form gradient release to achieve the optimal treatment effect.
When the double-layer composite medicine-carrying adhesive patch disclosed by the invention is used as a medical adhesive patch for treating oral ulcer and trauma, the effect of stepped medicine release of the double-layer composite medicine-carrying adhesive patch disclosed by the invention can be better played symptomatically, the pain of a patient is relieved, and the healing of a wound surface is accelerated.
Drawings
FIG. 1 is a top view of a two-layer composite drug-loaded adhesive patch construction of the present invention;
fig. 2 is a cross-sectional view of a two-layer composite drug-loaded adhesive patch of the present invention;
fig. 3 is a drug release profile of a nanofiber membrane loaded with curcumin;
FIG. 4 shows the gene expression of inflammatory factor IFNG under different curcumin dosage conditions;
FIG. 5 is a graph showing the effect of the antibacterial performance of the double-layer composite drug-loaded adhesive patch;
fig. 6A is a photograph of a lower surface of a scanning electron microscope of a two-layer composite drug-loaded adhesive patch of the present invention;
fig. 6B is a photograph of a cross-section of a two-layer composite drug-loaded adhesive patch of the present invention under a scanning electron microscope;
FIG. 7A is a pictorial view of a bilayer composite drug-loaded adhesive patch of the present invention on the oral mucosa of a pig;
fig. 7B is a photograph of hematoxylin-eosin histological staining of the double-layer composite drug-loaded adhesive patch of the present invention on the mucous membrane of the oral cavity of a pig;
FIG. 8 is a graph of adhesion testing of bilayer composite drug loaded adhesive patches of different configurations;
wherein, 1 is a nano fiber film loaded with an abrupt release medicament, 2 is a nano fiber film loaded with a slow release medicament, and 3 is an adhesive film.
Detailed Description
The invention will now be described in further detail with reference to the following drawings and specific examples, which are to be construed as illustrative and not restrictive:
fig. 1 and fig. 2 are schematic plan view and sectional view of a double-layer composite drug-loaded adhesive patch structure of the present invention, which is formed by compounding a nanofiber membrane 1 loaded with a burst drug, a nanofiber membrane 2 loaded with a slow-release drug, and an adhesive membrane 3.
Example 1:
step 1: weighing 1 part of diclofenac sodium and 3 parts of polyoxyethylene, adding into 1800 parts of deionized water, stirring for 24 hours on a magnetic stirrer until the mixture becomes uniform milky white solution, and taking the uniform milky white solution as a burst release agent spinning solution for later use; weighing 0.1 part of curcumin and 10 parts of L-polylactic acid, adding into 100 parts of hexafluoroisopropanol, stirring for 24 hours on a magnetic stirrer until the mixture becomes a uniform and transparent yellow solution, and taking the yellow solution as a slow-release medicament spinning solution for later use;
0.001g of hydroxypropyl methyl cellulose, 0.01ml of propylene glycol and 0.1ml of deionized water are mixed in an injector to form a uniform solution, the uniform solution is placed on a centrifuge and centrifuged for 1 time at the speed of 1000r/min, then air bubbles in the solution are removed, and the uniform solution is injected into a round hole of a plastic silica gel mold for standby, and the thickness of the mold is 0.5mm.
Step 2: opening the double-ring slit type electrostatic spinning device under the working environment of 15 ℃ and 10% relative humidity, and setting spinning parameters: the voltage was applied at 20kV, the take-over distance was 20cm, the solution flow was 2ml/h, and the metal roller speed was 60rpm.
Loading a sustained-release agent spinning solution into an injector, connecting the injector with micropores at the bottom of an inner core of a circular narrow-slit nozzle by using a liquid conveying pipe, opening a micro-injection pump, conveying the sustained-release agent spinning solution into an annular slit of the circular narrow-slit nozzle through the liquid conveying pipe, opening a switch of a speed regulating motor, driving a metal roller to rotate by the speed regulating motor, opening a switch of a high-voltage electrostatic generator and gradually increasing voltage, forming a plurality of jet flows at the top end of the circular narrow-slit nozzle and flying to the rotating metal roller, volatilizing a solvent in the sustained-release agent spinning solution, solidifying formed nano fibers, and finally depositing on the metal roller to form a nano fiber film loaded with a sustained-release agent; after the nanofiber membrane loaded with the sustained-release medicament is spun, closing the micro-injection pump to stop supplying liquid, closing the high-voltage electrostatic generator, and closing the motor to stop the metal roller from rotating; the spinning solution in the injector is changed into burst release agent spinning solution, a micro injection pump is started, the spinning solution is conveyed into an annular slit of an annular narrow slit nozzle through a liquid conveying pipe, a speed regulating motor switch is started, a speed regulating motor drives a metal roller to rotate, a high-voltage electrostatic generator switch is started, voltage is gradually increased, a plurality of jet flows are formed at the top end of the annular narrow slit nozzle and fly to the rotating metal roller, the solvent in the burst release agent spinning solution is volatilized, formed fibers are solidified, and finally, the fibers are deposited on the metal roller to form a nanofiber membrane loaded with burst release agents; after spinning of the nanofiber membrane loaded with the burst medicament is finished, closing the double-ring slit type electrostatic spinning device to obtain a double-layer composite medicament-carrying nanofiber membrane compounded by the nanofiber membrane loaded with the burst medicament and the nanofiber membrane loaded with the slow-release medicament, and controlling the process to enable the thickness of the double-layer composite medicament-carrying nanofiber membrane to be 20 microns.
And step 3: cutting the double-layer composite drug-loaded nanofiber membrane obtained in the step 2 into a circle with the diameter of 7mm, and placing the circle at the center of the surface of the adhesive membrane solution to attach the circle to the surface of the adhesive membrane solution; then placing the double-layer compound drug-carrying adhesive patch in an environment with the temperature of 20 ℃ and the humidity of 30% for 24h to obtain the double-layer compound drug-carrying adhesive patch.
Example 2:
step 1: weighing 5 parts of diclofenac sodium and 20 parts of polyethylene oxide, adding into 3500 parts of deionized water, stirring for 24 hours on a magnetic stirrer until the mixture becomes a uniform milky solution, and using as a burst release medicament spinning solution for later use; weighing 10 parts of curcumin and 100 parts of L-polylactic acid, adding into 500 parts of hexafluoroisopropanol, stirring for 24 hours on a magnetic stirrer until the mixture becomes a uniform and transparent yellow solution, and taking the yellow solution as a slow-release agent spinning solution for later use;
mixing 1g of hydroxypropyl methyl cellulose, 1ml of propylene glycol and 5ml of deionized water in an injector to form a uniform solution, placing the uniform solution on a centrifuge, centrifuging for 5 times at a speed of 8000r/min, removing bubbles in the solution, and injecting the solution into a round hole of a plastic silica gel mold for standby, wherein the thickness of the mold is 3mm.
Step 2: opening the double-ring slit type electrostatic spinning device under the working environment of 30 ℃ and 60% relative humidity, and setting spinning parameters: the voltage was applied at 80kV, the take-over distance was 40cm, the solution flow was 15ml/h, and the metal roller speed was 800rpm.
Loading a sustained-release agent spinning solution into an injector, connecting the injector with micropores at the bottom of an inner core of a circular narrow-slit nozzle by using a liquid conveying pipe, opening a micro-injection pump, conveying the sustained-release agent spinning solution into an annular slit of the circular narrow-slit nozzle through the liquid conveying pipe, opening a switch of a speed regulating motor, driving a metal roller to rotate by the speed regulating motor, opening a switch of a high-voltage electrostatic generator and gradually increasing voltage, forming a plurality of jet flows at the top end of the circular narrow-slit nozzle and flying to the rotating metal roller, volatilizing a solvent in the sustained-release agent spinning solution, solidifying formed nano fibers, and finally depositing on the metal roller to form a nano fiber film loaded with a sustained-release agent; after the nanofiber membrane loaded with the sustained-release medicament is spun, closing the micro-injection pump to stop supplying liquid, closing the high-voltage electrostatic generator, and closing the motor to stop the metal roller from rotating; the spinning solution in the injector is changed into burst release agent spinning solution, a micro injection pump is started, the spinning solution is conveyed into an annular slit of an annular narrow slit nozzle through a liquid conveying pipe, a speed regulating motor switch is started, a speed regulating motor drives a metal roller to rotate, a high-voltage electrostatic generator switch is started, voltage is gradually increased, a plurality of jet flows are formed at the top end of the annular narrow slit nozzle and fly to the rotating metal roller, the solvent in the burst release agent spinning solution is volatilized, formed fibers are solidified, and finally, the fibers are deposited on the metal roller to form a nanofiber membrane loaded with burst release agents; after spinning of the nanofiber membrane loaded with the burst medicament is finished, closing the double-ring slit type electrostatic spinning device to obtain a double-layer composite medicament-carrying nanofiber membrane compounded by the nanofiber membrane loaded with the burst medicament and the nanofiber membrane loaded with the slow-release medicament, and controlling the process to enable the thickness of the double-layer composite medicament-carrying nanofiber membrane to be 100 microns.
And step 3: cutting the double-layer composite drug-loaded nanofiber membrane obtained in the step 2 into a circle with the diameter of 10mm, and placing the circle at the center of the surface of the adhesive film solution to attach the circle to the surface of the adhesive film solution; then placing the double-layer compound drug-carrying adhesive patch in an environment with the temperature of 25 ℃ and the humidity of 70% for 72h to obtain the double-layer compound drug-carrying adhesive patch.
Example 3:
step 1: weighing 3 parts of diclofenac sodium and 12 parts of polyoxyethylene, adding into 2200 parts of deionized water, stirring for 24 hours on a magnetic stirrer until the mixture becomes uniform milky white solution, and taking the uniform milky white solution as a burst release agent spinning solution for later use; weighing 3 parts of curcumin and 50 parts of L-polylactic acid, adding into 300 parts of hexafluoroisopropanol, stirring for 24 hours on a magnetic stirrer until the mixture becomes a uniform and transparent yellow solution, and taking the yellow solution as a slow-release agent spinning solution for later use;
0.1g of hydroxypropyl methyl cellulose, 1ml of propylene glycol and 1ml of deionized water are mixed into a uniform solution in an injector, the uniform solution is placed on a centrifuge and centrifuged for 3 times at the speed of 3000r/min, then air bubbles in the solution are removed, and the uniform solution is injected into a round hole of a plastic silica gel mold for standby application, and the thickness of the mold is 1.5mm.
Step 2: opening the double-ring slit type electrostatic spinning device under the working environment of 20 ℃ and 40% relative humidity, and setting spinning parameters: the voltage was applied at 60kV, the take-up distance was 30cm, the solution flow was 8ml/h, and the metal roller speed was 300rpm.
Loading a slow-release agent spinning solution into an injector, connecting the injector with micropores at the bottom of an inner core of a circular narrow slit nozzle by using a liquid conveying pipe, opening a micro-injection pump, conveying the slow-release agent spinning solution into an annular slit of the circular narrow slit nozzle through the liquid conveying pipe, opening a switch of a speed regulating motor, driving a metal roller to rotate by the speed regulating motor, opening a switch of a high-voltage electrostatic generator and gradually increasing voltage, forming a plurality of jet flows at the top end of the circular narrow slit nozzle and flying to the rotating metal roller, volatilizing a solvent in the slow-release agent spinning solution, solidifying formed nano fibers, and finally depositing on the metal roller to form a nano fiber film loaded with a slow-release agent; after the nanofiber membrane loaded with the sustained-release medicament is spun, closing the micro-injection pump to stop supplying liquid, closing the high-voltage electrostatic generator, and closing the motor to stop the metal roller from rotating; the spinning solution in the injector is changed into burst release agent spinning solution, a micro injection pump is started, the spinning solution is conveyed into an annular slit of an annular narrow slit nozzle through a liquid conveying pipe, a speed regulating motor switch is started, a speed regulating motor drives a metal roller to rotate, a high-voltage electrostatic generator switch is started, voltage is gradually increased, a plurality of jet flows are formed at the top end of the annular narrow slit nozzle and fly to the rotating metal roller, the solvent in the burst release agent spinning solution is volatilized, formed fibers are solidified, and finally, the fibers are deposited on the metal roller to form a nanofiber membrane loaded with burst release agents; after spinning of the nanofiber membrane loaded with the burst drug is finished, the double-ring slit type electrostatic spinning device is closed to obtain a double-layer composite drug-loaded nanofiber membrane compounded by the nanofiber membrane loaded with the burst drug and the nanofiber membrane loaded with the slow-release drug, and the thickness of the double-layer composite drug-loaded nanofiber membrane is 40 micrometers through process control.
And 3, step 3: cutting the double-layer composite medicine-carrying nanofiber membrane obtained in the step 2 into a circle with the diameter of 8mm, and placing the circle at the center of the surface of the adhesive membrane solution to enable the circle to be attached to the surface of the adhesive membrane solution; then placing the double-layer compound drug-carrying adhesive patch in an environment with the temperature of 23 ℃ and the humidity of 50% for 48h to obtain the double-layer compound drug-carrying adhesive patch.
Relevant in vitro performance tests and results:
1) Drug sustained-release performance test of nanofiber membrane loaded with sustained-release medicament curcumin
As shown in figure 3, the curcumin serving as the sustained-release medicament can be gradually released along with the increase of time. Under the same time condition, the more the curcumin is added into the spinning solution, the larger the drug amount finally released from the curcumin nanofiber membrane loaded with the sustained-release medicament is.
2) Anti-inflammatory performance test of nanofiber membrane loaded with sustained-release medicament curcumin
As shown in fig. 4, the relative expression of the inflammatory factor IFNG gene was 1 in the case where curcumin was not added, and was reduced after the addition of curcumin. The relative expression of the inflammatory factor IFNG gene is gradually reduced along with the increase of the mass fraction of the curcumin. The relative expression of the gene of the inflammatory factor IFNG represents the inflammation degree of the wound surface, so the results of fig. 4 show that curcumin has a very good anti-inflammatory effect.
3) Antibacterial performance test of double-layer composite drug-loaded adhesive patch
As shown in fig. 5, in the figure, the site # 1 is a nanofiber membrane without curcumin added and a nanofiber membrane without diclofenac sodium added, the site # 2 is a nanofiber membrane with 4% (w/w) curcumin added and a nanofiber membrane without diclofenac sodium added, the site # 3 is a nanofiber membrane without curcumin added and a nanofiber membrane with 30% (w/w) diclofenac sodium added, and the site # 4 is a nanofiber membrane with 4% (w/w) curcumin added and a nanofiber membrane with 30% (w/w) diclofenac sodium added.
As can be seen from the figure, the positions 3# and 4# have very obvious inhibition zones, and the result shows that the addition of the diclofenac sodium can achieve very good antibacterial effect. Therefore, the nanofiber membrane loaded with the burst release agent is attached to the oral wound surface, so that good antibacterial performance can be achieved, bacterial breeding is inhibited, pain of the wound surface is relieved, and rapid healing of the wound is promoted.
4) Morphology testing of double-layer composite drug-loaded adhesive patch
Fig. 6A is a photograph of the lower surface of the double-layer composite drug-loaded adhesive patch under a scanning electron microscope, fig. 6B is a photograph of the cross section of the double-layer composite drug-loaded adhesive patch under the scanning electron microscope, white solid line arrows indicate double-layer drug-loaded composite nanofiber membranes, and white dotted line arrows indicate adhesive membranes.
Microscopic test analysis through a scanning electron microscope shows that the double-layer drug-loaded composite nanofiber membrane is well attached to the adhesive membrane, and no gap or separation phenomenon occurs. Therefore, the medical adhesive patch which has both appearance and structure and can be used for wound treatment and repair can be prepared by the invention.
5) Adhesion Performance test of double-layer composite drug-loaded adhesive Patch
In order to further verify the adhesion performance of the double-layer compound drug-loaded adhesive patch on oral mucosa, the oral mucosa of a pig is selected to simulate the oral mucosa of a human body for in vitro test. As can be seen from FIG. 7A, the adhesive patch was well attached to the mucosal surface of the oral cavity of swine. The interface state of the adhesive patch and the oral mucosa of the pig is tested by adopting a hematoxylin-eosin histological staining method, and the result is shown in fig. 7B, which shows that the adhesive patch can be well adhered to the oral mucosa of the pig, and the separation phenomenon does not occur between the adhesive patch and the oral mucosa of the pig. Therefore, the adhesive patch prepared according to the invention can be closely attached to the oral mucosa of a human body which is very similar to the oral mucosa of a pig in structure and physiological characteristics.
6) Adhesion testing of a double-layer composite drug-loaded adhesive patch
As shown in fig. 8, the adhesion between the bilayer composite drug-loaded adhesive patch of different structure and the oral mucosa of pig was tested, a is PLLA nanofiber membrane loaded with curcumin; b is an adhesive film; c is the curcumin-loaded PLLA nanofiber membrane + adhesive membrane; d is diclofenac sodium loaded PEO nanofiber membrane + curcumin loaded PLLA nanofiber membrane + adhesive membrane.
As can be seen from the figure, compared with other single-layer or combined structures, the double-layer composite drug-loaded adhesive patch, namely the adhesive patch with the structure of the diclofenac sodium-loaded PEO nanofiber membrane, the curcumin-loaded PLLA nanofiber membrane and the adhesive membrane, has the maximum adhesive force on the oral mucosa of the pig, and the value can reach about 0.6N. Therefore, the double-layer composite medicine-carrying adhesive patch prepared by the invention can have higher adhesive force on oral mucosa and cannot fall off due to the movement of muscles in the oral cavity, so that the adhesive patch can be stably adhered to a wound surface part to continuously release medicines to promote the healing of wounds.
7) Comprehensive effect of double-layer composite medicine-carrying adhesive patch for treating dental ulcer
In order to verify the comprehensive effect of the adhesive patch on treating oral ulcer, the drug action time of the double-layer composite drug-carrying adhesive patch is tested, when one surface of the nano-fiber membrane loaded with the burst drug diclofenac sodium in the double-layer composite drug-carrying adhesive patch is attached to the oral mucosa of a pig, the nano-fiber membrane loaded with the diclofenac sodium is completely dissolved within 1min, the drug is completely released and directly acts on the wound surface, the pain of the wound surface is quickly relieved, and the bacterial growth is inhibited; then the curcumin medicament in the nanofiber membrane loaded with curcumin is gradually released, the occurrence of wound inflammation is inhibited, the wound is gradually repaired, and the oral ulcer wound can be completely repaired in about 3-5 days.
Research shows that the pig oral mucosa is very similar to the human oral mucosa in the aspects of morphology, permeability barrier function, lipid composition and the like. The porcine oral mucosa was therefore selected as the subject of the in vitro test.
The adhesive patch prepared by the process method has the characteristics of excellent pain alleviation, bacteria breeding inhibition and inflammation elimination, has potential advantages in wound repair and has very wide market prospect.
Claims (4)
1. A preparation method of a double-layer composite medicine-carrying adhesive patch is characterized by comprising the following steps:
step 1: respectively mixing the burst release medicament and the sustained release medicament with a high polymer and dissolving the mixture in a solvent to prepare a burst release medicament spinning solution and a sustained release medicament spinning solution; preparing an adhesive film solution for later use; the preparation method of the adhesive film solution comprises the following specific steps:
a. weighing and measuring a feed liquid ratio of 0.001 to 1g:0.01 to 1ml:0.1 to 5ml of hydroxypropyl methyl cellulose, propylene glycol and deionized water are mixed and stirred uniformly;
b. b, centrifuging the solution system obtained in the step a on a centrifuge at the speed of 1000-8000 r/min for 1-5 times, and then placing the solution system into a mold to obtain an adhesive film solution;
step 2: respectively putting the burst release agent spinning solution and the slow release agent spinning solution into electrostatic spinning equipment, and setting spinning parameters to prepare a nanofiber membrane loaded with a burst release agent and a nanofiber membrane loaded with a slow release agent; the electrostatic spinning equipment is a double-ring slit type electrostatic spinning device, and the spinning comprises the following specific steps:
step 2.1: forming jet flow of the slow-release agent spinning solution and gathering the jet flow on the metal roller, and after the solvent in the slow-release agent spinning solution is volatilized, forming nano fibers for solidification to obtain a nano fiber film which is deposited on the metal roller and is loaded with the slow-release agent;
step 2.2: forming jet flow of the burst release agent spinning solution to gather on the nanofiber membrane loaded with the sustained release agent, and after the solvent in the burst release agent spinning solution is volatilized, forming nanofibers for solidification to obtain a composite nanofiber membrane loaded with the burst release agent and the nanofiber membrane loaded with the sustained release agent;
the burst release agent spinning solution is prepared from diclofenac sodium, polyethylene oxide and deionized water, wherein the mass ratio of the diclofenac sodium to the polyethylene oxide is 1-5; the sustained-release medicament spinning solution is prepared from 0.1 to 10 parts by mass of curcumin, levorotatory polylactic acid and hexafluoroisopropanol, wherein the mass ratio of the curcumin to the levorotatory polylactic acid to the hexafluoroisopropanol is as follows;
and step 3: compounding the adhesive film solution, the nanofiber film loaded with the burst medicament and the nanofiber film loaded with the slow-release medicament to obtain a double-layer composite medicament-carrying adhesive patch;
and 3, in the compounding, the nanofiber membrane loaded with the burst medicament and the nanofiber membrane loaded with the slow-release medicament are placed on the adhesive film solution, and then the mold is placed in an environment with the temperature of 20-25 ℃ and the humidity of 30-70% for 24-72h to obtain the composite material.
2. The preparation method of the double-layer composite drug-loaded adhesive patch according to claim 1, wherein in the step 2, the specific spinning parameters are as follows: the applied voltage is 20 to 80kV, the receiving distance is 20 to 40cm, the solution flow is 2 to 15ml/h, the rotating speed of the metal roller is 60 to 800rpm, the ambient temperature is 15 to 30 ℃, and the ambient relative humidity is 10 to 60%.
3. A double-layer composite drug-loaded adhesive patch prepared by the preparation method of the double-layer composite drug-loaded adhesive patch according to any one of claims 1 or 2.
4. The double-layer composite adhesive patch carrying the drug according to claim 3, wherein the total thickness of the nanofiber membrane carrying the burst drug and the nanofiber membrane carrying the sustained-release drug is 20 to 100 μm; the thickness of the adhesive film is 0.5 to 3mm.
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