A sustained-release adhesive fiber film patch and a preparation method thereof

Abstract

The application discloses a sustained-release adhesive fiber film patch and a preparation method thereof, and belongs to the technical field of external use patches. The sustained-release adhesive fiber film patch is prepared by placing an adhesive pressure-sensitive glue material in a shell layer of coaxial nanofibers and placing a drug in a core layer of the nanofibers on the basis of coaxial electrospinning technology, that is, the sustained-release adhesive fiber film patch is a "core-shell" type nanofiber transdermal patch. The thickness of the shell layer of the fiber film patch can be controlled by adjusting the concentration of the adhesive pressure-sensitive glue material in the shell layer, so that the sustained-release of the drug is realized. The spinning fiber with the "core-shell" type structure not only effectively inhibits drug crystallization and significantly improves the drug loading capacity, but also avoids the incompatibility problem between the adhesive pressure-sensitive glue material in the shell layer and the drug in the core layer, and expands the prescription selection and drug loading application range of the fiber film patch. The sustained-release adhesive fiber film patch prepared by the application is convenient and comfortable to use, has good compliance, has good sustained-release behavior of the drug, is beneficial to the transdermal penetration and treatment of the drug, and the like.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of external use patch, and particularly relates to a sustained-release adhesive fiber membrane patch and a preparation method thereof. BACKGROUND

[0002] The external use patch is used to deliver drugs to the human circulatory system or local lesion site in a non-invasive way through the skin to achieve the purpose of treatment, has unique advantages in the field of chronic disease treatment, can avoid the liver first-pass effect, avoid gastrointestinal adverse reactions, realize effective sustained-release of drugs, and improve patient medication compliance, and is the third largest drug delivery method after oral administration and injection.

[0003] The traditional patch has poor air permeability, which can easily cause skin irritation and allergic reactions; the drug molecules dispersed in the adhesive layer or the drug-loaded reservoir layer can gradually crystallize or degrade due to poor physicochemical compatibility, which not only limits the drug loading capacity and the application range of the drug, but also significantly reduces the drug absorption degree and the percutaneous penetration rate, thereby affecting the efficacy of the patch.

[0004] The fiber membrane patch prepared by using the electrospinning technology has high porosity, which can significantly improve the air permeability of the patch and reduce the incidence of skin adverse reactions; the high specific surface area can greatly improve the drug dispersibility, and the electrospinning-based fiber membrane patch has great prospects in the field of external use patch.

[0005] At present, there are mainly two strategies for combining pressure-sensitive adhesive and electrospinning technology: one is to directly coat the pressure-sensitive adhesive on the electrospinning fiber membrane, and the other is to incorporate the pressure-sensitive adhesive into the spinning solution and electrospinning. The former has the disadvantages of low drug release rate and weak patch cohesion, and the latter has the compatibility problem between the pressure-sensitive adhesive, the drug and the electrospinning polymer, which requires strict selection of the types of the drug, the pressure-sensitive adhesive and the pharmaceutical excipients, and seriously limits the prescription selection and the drug application range of the patch.

[0006] Therefore, it is necessary to develop a new preparation method of fiber membrane patch to effectively avoid the defects of the above-mentioned methods. SUMMARY

[0007] The present application aims at the deficiencies of the prior art, and provides a sustained-release adhesive fiber membrane patch and a preparation method thereof. The adhesive pressure-sensitive adhesive material is electrospun into the shell layer of the nanofiber membrane patch by the coaxial electrospinning method, and the drug is loaded in the core layer of the nanofiber membrane patch, which solves the problems of low drug release rate, weak patch cohesion, and compatibility between the pressure-sensitive adhesive, the drug and the electrospinning polymer on the basis of retaining the advantages of the nanofiber membrane, and realizes the sustained-release of the drug of the fiber membrane patch.

[0008] The technical scheme of the present application is as follows:

[0009] The present application provides a preparation method of a sustained-release adhesive fiber film patch, which is based on coaxial electrospinning technology, places an adhesive pressure-sensitive adhesive material in a shell layer of coaxial nanofibers, places a drug in a core layer of the nanofibers, and prepares a "core-shell" type nanofiber transdermal patch, namely the sustained-release adhesive fiber film patch.

[0010] In a preferred embodiment of the present application, the preparation method of the sustained-release adhesive fiber film patch comprises the following steps:

[0011] (1) The adhesive pressure-sensitive adhesive material is mixed in anhydrous ethanol, and stirred uniformly at room temperature to prepare a pressure-sensitive adhesive solution with a volume percentage of 20-30% as a shell layer spinning solution.

[0012] Anhydrous ethanol can well dissolve the adhesive pressure-sensitive adhesive and reduce the interfacial tension of the inner and outer layer solutions, thereby ensuring good miscibility. When the concentration of the pressure-sensitive adhesive is less than 20% or higher than 30%, beaded nanofiber films will appear on the nanofiber films. In the concentration range of 20-30%, nanofiber films with good morphology can be obtained.

[0013] (2) Polycaprolactone is dissolved in a mixed solvent of tetrahydrofuran and acetone, the volume ratio of the tetrahydrofuran and acetone is (1-3):1, and the polycaprolactone solution with a concentration of 10-20% is stirred uniformly at room temperature.

[0014] The core layer solvent tetrahydrofuran and acetone both have low surface energy (28.8 mN / m and 23.7 mN / m) and boiling points (66.0℃ and 56.5℃). Preferably, the mixture of the two in a ratio of 7:3 (v:v) has a high solubility for polycaprolactone PCL, and a small amount of acetone can also reduce the surface energy of the mixed solvent. The low concentration of 10% polycaprolactone PCL as the core layer spinning solution can ensure that the core layer can be electrospun into fiber filaments, and also prevent the viscosity from being too high to damage the "core-shell" structure of the fibers.

[0015] (3) The drug is added to the polycaprolactone solution prepared in step (2), the mass ratio of the drug to polycaprolactone is (0.05-0.2):1, and the core layer spinning solution is dissolved by stirring at room temperature.

[0016] (4) The shell layer spinning solution is loaded into a syringe connected to the outer needle of a coaxial needle, and the core layer spinning solution is loaded into a syringe connected to the inner needle of the coaxial needle; a metal roller receiver is used to collect the spinning filaments, and a non-woven fabric is attached to the surface of the metal roller; the spinning parameters are set, and coaxial electrospinning is performed at room temperature to prepare spinning filaments with a "core-shell" structure; and the obtained spinning filaments are vacuum dried to prepare drug-loaded adhesive fiber films.

[0017] (5) covering the drug-loaded adhesive fiber membrane prepared in step (4) with a cover material, to obtain a sustained-release adhesive fiber membrane patch.

[0018] Further preferably, in step (1), the adhesive pressure-sensitive adhesive material is one or more of polyacrylate pressure-sensitive adhesives.

[0019] Further, in step (2), the average molecular weight M w is 20000-80000.

[0020] Further, in step (3), the drug is one or a combination of ibuprofen or curcumin.

[0021] Further, in step (4), the spinning parameters are as follows: the applied voltage is 15-22 kV, the receiving distance is 10-20 cm, the flow rate of the core layer spinning solution is 0.1-0.8 ml / h, the ratio of the push speed of the shell layer spinning solution to that of the core layer spinning solution is (2-5):1, and the rotation speed of the metal roller is 40-200 rpm.

[0022] Further, in step (4), the temperature for vacuum drying is 40-60℃, and the drying time is 12-24 h.

[0023] Further, in step (5), the cover material is a release paper, a plastic film or an aluminum foil-polyethylene composite film.

[0024] The application also provides a sustained-release adhesive fiber membrane patch prepared by the above preparation method.

[0025] Preferably, the diameter of the nanofiber is 800-2200 nm.

[0026] By adjusting the concentration of the shell adhesive pressure-sensitive adhesive material, the shell thickness of the fiber membrane patch can be controlled, thereby achieving the purpose of sustained release of the drug. The "core-shell" type spinning fiber not only effectively inhibits drug crystallization and significantly increases the drug loading capacity, but also avoids the incompatibility problem between the shell adhesive pressure-sensitive adhesive material and the core drug, thereby expanding the prescription selection and drug loading application range of the fiber membrane patch. The sustained-release adhesive fiber membrane patch prepared by the application is convenient and comfortable to use, has good compliance, good drug sustained release behavior, and is conducive to drug transdermal penetration and treatment.

[0027] Advantages:

[0028] (1) The present application adopts viscous pressure-sensitive adhesive as shell material, polycaprolactone and drug as core material, and carries out coaxial electrospinning to prepare nanofiber film patch. The drug release time can be easily controlled by adjusting the shell thickness, and the precise on-demand drug release kinetics regulation is realized. In addition, the drug and the pressure-sensitive adhesive are separated as the core layer and the shell layer, which can avoid the problems of reduced adhesion of pressure-sensitive adhesive and degradation of drug caused by incompatibility, and expand the selection range of drugs that can be made into transdermal patches. The shortcomings of the existing two strategies of combining pressure-sensitive adhesive with electrospinning technology are solved, i.e. low drug release rate, weak cohesion of the patch, and compatibility problems among pressure-sensitive adhesive, drug and electrospun material.

[0029] (2) Compared with single-axis nanofiber patch, the coaxial nanofiber patch has a stronger inhibitory effect on drug crystallization, which not only improves the drug loading capacity, but also makes the non-crystalline state of the drug more easily penetrate the skin, enhances the transdermal penetration ability, and is beneficial to the delivery of strong crystalline drugs.

[0030] (3) Compared with single-axis nanofiber patch, the coaxial electrospinning method adopted by the present application can avoid the initial burst release of the drug, ensure the effective therapeutic concentration of the drug, and reduce the risk of high drug concentration causing toxic side effects to the human body. BRIEF DESCRIPTION OF DRAWINGS

[0031] Figure 1 It is a structure diagram of the controlled-release viscous fiber film patch of the present application;

[0032] Among them, 1 is cover lining material, 2 is drug-loaded viscous fiber film, 3 is non-woven fabric, 4 is pressure-sensitive adhesive material located in the shell layer, and 5 is drug located in the core layer.

[0033] Figure 2 It is a transmission electron microscope (TEM) photo of the drug-loaded viscous fiber film prepared in Example 1;

[0034] Figure 3 It is a transmission electron microscope (TEM) photo of the drug-loaded viscous fiber film prepared in Example 2;

[0035] Figure 4 It is a transmission electron microscope (TEM) photo of the drug-loaded viscous fiber film prepared in Example 3;

[0036] Figure 5 It is an XRD curve of IBU, PCL / PSA-coaxial, 30% PSA-uniaxial and 30% PSA-coaxial nanofiber patch;

[0037] Figure 6 It is the in vitro release curve of ibuprofen in Example 1, Example 2 and Example 3;

[0038] Figure 7 Figure 6: In vitro release profile of ibuprofen from 20% PSA-uniaxial, 25% PSA- uniaxial and 30% PSA-uniaxial nanofiber patches compared to ibuprofen in Example 1, Example 2 and Example 3.

[0039] Figure 8 Figure 7: In vitro transdermal permeation profile of ibuprofen from Example 1, Example 2 and Example 3. DETAILED DESCRIPTION

[0040] The technical solutions of the present application will be described in detail below through specific examples, but the protection scope of the present application is not limited to the examples.

[0041] The specific techniques or conditions not specified in the examples are carried out according to the techniques or conditions described in the literature in the art or according to the product instructions. The reagents or instruments not specified by the manufacturer are all conventional products that can be purchased through regular channels.

[0042] Polyacrylate pressure sensitive adhesive: product code: PE-PSA-1, product batch number: 210603; Jiangsu Kangbeide Pharmaceutical Co., Ltd.

[0043] Polyacrylate pressure sensitive adhesive: product code: Duro-Tak 87-2677, Jiangsu Kangbeide Pharmaceutical Co., Ltd.

[0044] Polyacrylate pressure sensitive adhesive: product code: Duro-Tak 87-4098, Jiangsu Kangbeide Pharmaceutical Co., Ltd.

[0045] Polycaprolactone (PCL, weight average molecular weight M w 80000): Tianjin Xinsisheng Biochemical Technology Co., Ltd.

[0046] Polycaprolactone (PCL, weight average molecular weight M w 50000): Tianjin Xinsisheng Biochemical Technology Co., Ltd.

[0047] Polycaprolactone (PCL, weight average molecular weight M w 20000): Tianjin Xinsisheng Biochemical Technology Co., Ltd.

[0048] Ibuprofen and curcumin were purchased from Anjieji Chemical;

[0049] Tetrahydrofuran, acetone, and anhydrous ethanol were purchased from National Pharmaceutical Group Chemical Reagent Co., Ltd.

[0050] The unit of mass volume percentage (w / v) in the examples is g / mL.

[0051] Explanation of terms:

[0052] Room temperature: has the meaning commonly known in the art, generally refers to 25±2℃.

[0053] Example 1

[0054] A preparation method of a sustained-release adhesive fibrous membrane patch, comprising the following steps:

[0055] (1) 2ml of polyacrylate pressure-sensitive adhesive (product code: PE-PSA-1) was added to 10ml of anhydrous ethanol, stirred at room temperature for 2h to completely dissolve, and prepared into a shell layer spinning solution with a volume percentage of 20%;

[0056] (2) 1g of polycaprolactone (PCL, weight average molecular weight M w 80000) was added to 10ml of a mixed solvent of tetrahydrofuran and acetone (the volume ratio of tetrahydrofuran to acetone was 7:3), stirred at room temperature for 5h to completely dissolve, and prepared into a polycaprolactone solution with a mass volume ratio of 0.1g / ml (i.e. a concentration of 10%);

[0057] (3) 0.1g of ibuprofen was added to the polycaprolactone solution, the mass ratio of ibuprofen to polycaprolactone was 1:10, stirred at room temperature for 2h to completely dissolve, and the final concentration of the core layer spinning solution was 0.11g / ml;

[0058] (4) The shell layer spinning solution was loaded into a 10mL syringe, and an outer needle with an inner diameter of 1.10mm was connected to the coaxial needle; the core layer spinning solution was loaded into a 5mL syringe, and an inner needle with an inner diameter of 0.40mm was connected to the coaxial needle; a metal roller receiver was used to collect the spinning, and a non-woven fabric was attached to the surface of the metal roller; the roller speed was set to 80rpm, the voltage was 17.5kV, the receiving distance was 10cm, the flow rate of the core layer spinning solution was 0.6mL / h, and the ratio of the push speed of the shell layer spinning solution to the core layer spinning solution was 2:1; coaxial electrospinning was carried out at room temperature and humidity of 25%-35% to prepare spinning fibers with a "core-shell" structure; the obtained spinning fibers were vacuum dried at 40℃ for 24h to prepare drug-loaded adhesive fibrous membranes.

[0059] (5) The adhesive fibrous membrane prepared in step (4) was taken out, and a release paper was added to the side without non-woven fabric, thereby obtaining a sustained-release adhesive fibrous membrane patch 20% PSA-coaxial.

[0060] The internal morphology of the coaxial nanofibrous membrane patch obtained in Example 1 was observed by transmission electron microscopy, and the results are shown in Figure 2 . It can be seen from Figure 2 that the obtained nanofibers have a clear coaxial structure, and the diameters of the core and shell layer are 892nm and 1365nm, respectively.

[0061] Example 2

[0062] A preparation method of a sustained-release adhesive viscous fiber film patch, comprising the following steps:

[0063] (1) 2.5 ml of polyacrylate pressure-sensitive adhesive (product code: PE-PSA-1) was added to 10 ml of anhydrous ethanol, stirred at room temperature for 2 h to completely dissolve, and prepared into a shell layer spinning solution with a volume percentage of 25%;

[0064] (2) 1 g of polycaprolactone (PCL, weight average molecular weight M w 80000) was added to 10 ml of a mixed solvent of tetrahydrofuran and acetone (the volume ratio of tetrahydrofuran to acetone was 7:3), stirred to completely dissolve, and prepared into a polycaprolactone solution with a mass-volume ratio of 0.1 g / ml (i.e. a concentration of 10%);

[0065] (3) 0.1 g of ibuprofen was added to the polycaprolactone solution, the mass ratio of the ibuprofen raw material to polycaprolactone was 1:10, stirred at room temperature to completely dissolve, and the final concentration of the core layer spinning solution was 0.11 g / ml;

[0066] (4) The shell layer spinning solution was loaded into a 10 mL syringe, and an outer needle with an inner diameter of 1.10 mm was connected to the coaxial needle. The core layer spinning solution was loaded into a 5 mL syringe, and an inner needle with an inner diameter of 0.40 mm was connected to the coaxial needle. The spinning was collected using a metal roller receiver, and a non-woven fabric was attached to the surface of the metal roller. The roller speed was set to 80 rpm, the voltage was 17.5 kV, the receiving distance was 10 cm, the flow rate of the core layer spinning solution was 0.6 mL / h, and the ratio of the push speed of the shell layer spinning solution to the core layer spinning solution was 2:1. The coaxial electrospinning was carried out at room temperature and humidity of 25%-35% to prepare spinning fibers with a "core-shell" structure. The obtained spinning fibers were vacuum dried at 40°C for 24 h to prepare drug-loaded viscous fiber films.

[0067] (5) The viscous fiber film prepared in step (4) was taken out, and a release paper was added to the side without non-woven fabric, thereby obtaining a sustained-release adhesive viscous fiber film patch 25% PSA-coaxial.

[0068] The internal morphology of the coaxial nanofiber film patch obtained in Example 2 was observed by transmission electron microscopy, and the results are shown in Figure 3 From the Figure 3 it can be seen that the obtained nanofibers have a clear coaxial structure, and the diameters of the core and shell layers are 1282 nm and 1680 nm, respectively.

[0069] Example 3

[0070] A method for preparing a sustained-release viscous fiber membrane patch includes the following steps:

[0071] (1) Add 3 ml of polyacrylate pressure-sensitive adhesive (product code: PE-PSA-1) to 10 ml of anhydrous ethanol and stir at room temperature until completely dissolved to prepare a shell spinning solution with a volume percentage of 30%.

[0072] (2) 1g of polycaprolactone (PCL, weight-average molecular weight M) w Add 80000) to 10 ml of a mixed solvent of tetrahydrofuran and acetone (where the volume ratio of tetrahydrofuran to acetone is 7:3), stir until completely dissolved, and obtain a polycaprolactone solution with a mass-volume ratio of 0.1 g / ml (i.e., a concentration of 10%).

[0073] (3) Add 0.1g of ibuprofen to the polycaprolactone solution, wherein the mass ratio of ibuprofen raw material to polycaprolactone is 1:10, stir until completely dissolved, and the final concentration of the core spinning solution is 0.11g / ml;

[0074] (4) The shell spinning solution was loaded into a 10 mL syringe and connected to the outer needle of the coaxial needle with an inner diameter of 1.10 mm. The core spinning solution was loaded into a 5 mL syringe and connected to the inner needle of the coaxial needle with an inner diameter of 0.40 mm. The spinning was collected by a metal roller receiver and the nonwoven fabric was attached to the surface of the metal roller. The roller speed was set to 80 rpm, the voltage to 17.5 kV, the receiving distance to 10 cm, the core spinning solution flow rate to 0.6 mL / h, and the ratio of the injection speed of the shell spinning solution to the core spinning solution to 2:1. Coaxial electrospinning was carried out at room temperature and humidity of 25% to 35% to prepare spinning fibers with a "shell-core" structure. The obtained spinning fibers were vacuum dried at 40 °C for 24 h to obtain a drug-loaded viscous fiber membrane.

[0075] (5) Take out the adhesive fiber membrane obtained in step (4) and add anti-stick paper to the side without nonwoven fabric to obtain the slow-release adhesive fiber membrane patch 30% PSA-coaxial.

[0076] The internal morphology of the coaxial nanofiber membrane patch obtained in Example 3 was observed by transmission electron microscopy, and the results are shown in the figure. Figure 4 .Depend on Figure 4 It can be seen that the obtained nanofibers have a distinct coaxial structure, with core and shell diameters of 1276 nm and 2109 nm, respectively.

[0077] Example 4

[0078] A method for preparing a sustained-release viscous fiber membrane patch includes the following steps:

[0079] (1) 2.5 ml of polyacrylate pressure sensitive adhesive (product code: PE-PSA-1) was added into 10 ml of absolute ethanol, stirred on a magnetic stirrer at room temperature for 2 h until it became a transparent and uniform solution to prepare a pressure sensitive adhesive solution with a volume percentage of 25% as a shell layer spinning solution;

[0080] (2) 1.5 g of polycaprolactone (PCL, weight average molecular weight M w 50000) was added into 10 ml of a mixed solvent of tetrahydrofuran and acetone (volume ratio of tetrahydrofuran to acetone was 1:1), stirred on a magnetic stirrer at room temperature for 5 h until the mixture became a transparent and uniform solution to prepare a polycaprolactone solution with a mass volume ratio of 0.15 g / ml (i.e. a concentration of 15%);

[0081] (3) 0.225 g of curcumin raw material was added into the polycaprolactone solution of step (2), the mass ratio of the curcumin raw material to polycaprolactone was 0.15:1, stirred on a magnetic stirrer at room temperature for 2 h until the mixture became a transparent and uniform solution to obtain a core layer spinning solution;

[0082] (4) The shell layer spinning solution was loaded into a 30 mL syringe connected to an outer needle of a coaxial needle with an inner diameter of 1.20 mm, and the core layer spinning solution was loaded into a 10 mL syringe connected to an inner needle of the coaxial needle with an inner diameter of 0.60 mm, a metal roller receiver was used to collect the spinning, and a non-woven fabric was attached to the surface of the metal roller, the roller rotation speed was set to 120 rpm, the voltage was 20 kV, the receiving distance was 15 cm, the flow rate of the core layer spinning solution was 0.5 mL / h, and the ratio of the push injection speed of the shell layer spinning solution to the core layer spinning solution was 3:1, coaxial electrospinning was carried out at room temperature to prepare a spinning fiber with a "core-shell" structure, and the obtained spinning fiber was vacuum dried at a temperature of 50°C for 18 h to prepare a drug-loaded adhesive fiber membrane;

[0083] (5) The adhesive fiber membrane prepared in step (4) was taken out, and a release paper was added to the side without the non-woven fabric to obtain a sustained-release adhesive fiber membrane patch.

[0084] The internal morphology of the coaxial nanofiber membrane patch obtained in Example 4 was observed by transmission electron microscopy, and it was found that the obtained nanofiber had a clear coaxial structure.

[0085] Example 5

[0086] A preparation method of a sustained-release adhesive fiber membrane patch, comprising the following steps:

[0087] (1) 3ml of polyacrylate pressure sensitive adhesive (product code: Duro-Tak 87-2677) was added into 10ml of absolute ethanol, stirred on a magnetic stirrer at room temperature for 2h until it became a transparent and uniform solution to prepare a pressure sensitive adhesive solution with a volume percentage of 30% as the shell layer spinning solution;

[0088] (2) 2g of polycaprolactone (PCL, weight average molecular weight M w = 20000) was added into 10ml of a mixed solvent of tetrahydrofuran and acetone (volume ratio of tetrahydrofuran to acetone was 6:4), stirred on a magnetic stirrer at room temperature for 5h until the mixture became a transparent and uniform solution to prepare a polycaprolactone solution with a mass volume percentage of 0.2g / ml (i.e. a concentration of 20%);

[0089] (3) 0.1g of ibuprofen raw material was added into the polycaprolactone solution of step (2), the mass ratio of ibuprofen raw material to polycaprolactone was 0.05:1, stirred on a magnetic stirrer at room temperature for 2h until the mixture became a transparent and uniform solution to obtain the core layer spinning solution;

[0090] (4) The shell layer spinning solution was loaded into a 20mL syringe connected to an outer needle of a coaxial needle with an inner diameter of 1.20mm, the core layer spinning solution was loaded into a 5mL syringe connected to an inner needle of a coaxial needle with an inner diameter of 0.60mm, a metal roller receiver was used to collect the spinning and a non-woven fabric was pasted on the surface of the metal roller, the roller rotation speed was set to 200rpm, the voltage was 22kV, the receiving distance was 20cm, the flow rate of the core layer spinning solution was 0.3mL / h, and the ratio of the push injection speed of the shell layer spinning solution to the core layer spinning solution was 4:1, coaxial electrospinning was carried out at room temperature to prepare spinning fibers with a "core-shell" structure, the obtained spinning fibers were vacuum dried at a temperature of 60°C for 12h to prepare a drug-loaded adhesive fiber membrane;

[0091] (5) The adhesive fiber membrane prepared in step (4) was taken out and an aluminum foil-polyethylene composite film was added to the side without non-woven fabric to obtain a sustained-release adhesive fiber membrane patch.

[0092] Transmission electron microscope observation was performed on the internal morphology of the coaxial nanofiber membrane patch obtained in Example 5, and it was found that the obtained nanofibers had obvious coaxial structure.

[0093] Example 6

[0094] A preparation method of a sustained-release adhesive fiber membrane patch, comprising the following steps:

[0095] (1) 2.5 ml of polyacrylate pressure sensitive adhesive (product code: Duro-Tak 87-4098) was added into 10 ml of absolute ethanol, stirred on a magnetic stirrer at room temperature for 2 h until it became a transparent and uniform solution to prepare a 25% volume percentage pressure sensitive adhesive solution as a shell layer spinning solution;

[0096] (2) 1 g of polycaprolactone (PCL, weight average molecular weight M w 80000) was added into 10 ml of a mixed solvent of tetrahydrofuran and acetone (volume ratio of tetrahydrofuran to acetone was 7:3), stirred on a magnetic stirrer at room temperature for 5 h until the mixture became a transparent and uniform solution to prepare a 0.1 g / ml (i.e. 10% concentration) polycaprolactone solution;

[0097] (3) 0.2 g of curcumin raw material was added into the polycaprolactone solution of step (2), the mass ratio of the curcumin raw material to polycaprolactone was 0.2:1, stirred on a magnetic stirrer at room temperature for 2 h until the mixture became a transparent and uniform solution to obtain a core layer spinning solution;

[0098] (4) The shell layer spinning solution was loaded into a 20 mL syringe connected to an outer needle of a coaxial needle, the inner diameter of the outer needle was 1.10 mm, the core layer spinning solution was loaded into a 10 mL syringe connected to an inner needle of the coaxial needle, the inner diameter of the inner needle was 0.40 mm, a metal roller receiver was used to collect the spinning, a non-woven fabric was attached to the surface of the metal roller, the roller rotation speed was set to 40 rpm, the voltage was 15 kV, the receiving distance was 20 cm, the flow rate of the core layer spinning solution was 0.4 mL / h, the ratio of the push speed of the shell layer spinning solution to the core layer spinning solution was 3:1, coaxial electrospinning was carried out at room temperature to prepare a spinning fiber with a "core-shell" structure, the obtained spinning fiber was vacuum dried at a temperature of 50°C for 24 h to prepare a drug-loaded adhesive fiber membrane;

[0099] (5) The adhesive fiber membrane prepared in step (4) was taken out, an aluminum foil-polyethylene composite film was added to the side without the non-woven fabric to obtain a sustained-release adhesive fiber membrane patch.

[0100] Transmission electron microscope observation was performed on the internal morphology of the coaxial nanofiber membrane patch obtained in Example 6, and it was found that the obtained nanofiber had a clear coaxial structure.

[0101] The coaxial nanofiber membrane PCL / PSA-coaxial of Comparative Example 1 did not load drug

[0102] (1) 3 ml of polyacrylate pressure sensitive adhesive was added into 10 ml of absolute ethanol, stirred at room temperature until completely dissolved to prepare a 30% volume percentage shell layer spinning solution;

[0103] (2) 1 g of polycaprolactone was added to 10 ml of a mixed solvent of tetrahydrofuran and acetone (the volume ratio of tetrahydrofuran to acetone was 7:3), and stirred until completely dissolved to prepare a polycaprolactone solution with a mass-volume ratio of 0.1 g / ml (i.e., a concentration of 10%);

[0104] (3) The shell layer spinning solution was loaded into a 10 mL syringe, and an outer needle with an inner diameter of 1.10 mm was connected to the coaxial needle. The core layer spinning solution was loaded into a 5 mL syringe, and an inner needle with an inner diameter of 0.40 mm was connected to the coaxial needle. A metal roller receiver was used to collect the spinning, and a non-woven fabric was attached to the surface of the metal roller. The roller speed was set to 80 rpm, the voltage was 17.5 kV, the receiving distance was 10 cm, the flow rate of the core layer spinning solution was 0.6 mL / h, and the ratio of the push speed of the shell layer spinning solution to the core layer spinning solution was 2:1. The coaxial electrospinning was performed at room temperature and humidity of 25%-35% to prepare a spinning fiber with a "core-shell" structure. The obtained spinning fiber was vacuum dried at 40°C for 24 h to prepare a drug-loaded adhesive fiber membrane.

[0105] (4) The adhesive fiber membrane prepared in step (3) was taken out, and a release paper was added to the side without the non-woven fabric to obtain a non-drug-loaded coaxial nanofiber membrane PCL / PSA-coaxial.

[0106] Comparative Example 2: Single-axis electrospinning of nanofiber membrane 20% PSA-uniaxial

[0107] (1) 2 ml of polyacrylate pressure-sensitive adhesive was added to 5 ml of anhydrous ethanol, and stirred at room temperature until completely dissolved;

[0108] (2) 1 g of polycaprolactone was added to 5 ml of a mixed solvent of tetrahydrofuran and acetone (the volume ratio of tetrahydrofuran to acetone was 7:3), and stirred until completely dissolved. 0.1 g of ibuprofen was added to the polycaprolactone solution, and the mass ratio of the ibuprofen raw material to polycaprolactone was 1:10. The mixture was stirred at room temperature until completely dissolved;

[0109] (3) The solution obtained in step (1) was added to the solution obtained in step (2) and stirred uniformly to obtain a spinning solution. The spinning solution was loaded into a 5 mL syringe with a needle diameter of 1.10 mm. A metal roller receiver was used to collect the spinning, and a non-woven fabric was attached to the surface of the metal roller. The roller speed was set to 80 rpm, the voltage was 17.5 kV, the receiving distance was 10 cm, and the flow rate of the spinning solution was 0.6 mL / h. Single-axis electrospinning was performed at room temperature and humidity of 25%-35%. The obtained spinning fiber was vacuum dried at 40°C for 24 h to prepare a drug-loaded adhesive fiber membrane.

[0110] (4) Take out the adhesive fiber film prepared in step (3), and add a release paper to the side without the non-woven fabric, to obtain a uniaxial nanofiber film 20% PSA-uniaxial.

[0111] Comparative Example 3 Electrospun uniaxial blended nanofiber film 25% PSA-uniaxial

[0112] (1) 2.5 ml of polyacrylate pressure-sensitive adhesive was added to 5 ml of anhydrous ethanol, and stirred at room temperature until completely dissolved;

[0113] (2) 1 g of polycaprolactone was added to 5 ml of a mixed solvent of tetrahydrofuran and acetone (with a volume ratio of tetrahydrofuran to acetone being 7:3), and stirred until completely dissolved; 0.1 g of ibuprofen was added to the polycaprolactone solution, with a mass ratio of ibuprofen raw material to polycaprolactone being 1:10, and stirred at room temperature until completely dissolved;

[0114] (3) The solution obtained in step (1) was added to the solution obtained in step (2) and stirred uniformly to obtain a spinning solution, the spinning solution was loaded into a 5 mL syringe, the needle diameter was 1.10 mm, a metal roller receiver was used to collect the spinning, and a non-woven fabric was attached to the surface of the metal roller, the roller rotation speed was set to 80 rpm, the voltage was 17.5 kV, the receiving distance was 10 cm, the flow rate of the spinning solution was 0.6 mL / h, and uniaxial electrospinning was carried out at room temperature and humidity of 25%-35%, the obtained spinning fiber was vacuum dried at 40°C for 24 h, to prepare a drug-loaded adhesive fiber film.

[0115] (4) Take out the adhesive fiber film prepared in step (3), and add a release paper to the side without the non-woven fabric, to obtain a uniaxial nanofiber film 20% PSA-uniaxial.

[0116] Comparative Example 4 Electrospun uniaxial blended nanofiber film 30% PSA-uniaxial

[0117] (1) 3 ml of polyacrylate pressure-sensitive adhesive was added to 5 ml of anhydrous ethanol, and stirred at room temperature until completely dissolved;

[0118] (2) 1 g of polycaprolactone was added to 5 ml of a mixed solvent of tetrahydrofuran and acetone (with a volume ratio of tetrahydrofuran to acetone being 7:3), and stirred until completely dissolved; 0.1 g of ibuprofen was added to the polycaprolactone solution, with a mass ratio of ibuprofen raw material to polycaprolactone being 1:10, and stirred at room temperature until completely dissolved;

[0119] (3) The solution obtained in step (1) is added to the solution obtained in step (2) and stirred to obtain a spinning solution. The spinning solution is loaded into a 5 mL syringe with a needle diameter of 1.10 mm. A metal roller is used as a receiving device to collect the spinning, and a non-woven fabric is attached to the surface of the metal roller. The roller speed is set to 80 rpm, the voltage is 17.5 kV, the receiving distance is 10 cm, and the flow rate of the spinning solution is 0.6 mL / h. Uniaxial electrospinning is carried out at room temperature and humidity of 25% to 35%. The obtained spinning fibers are vacuum dried at 40°C for 24 h to obtain a drug-loaded adhesive fiber membrane.

[0120] (4) The adhesive fiber membrane prepared in step (3) is removed and a release paper is attached to the side without the non-woven fabric to obtain a uniaxial nanofiber membrane 30% PSA-uniaxial.

[0121] Example 7

[0122] X-ray diffractometry is used to compare IBU, uniaxial nanofiber membrane PCL / PSA-coaxial (Comparative Example 1), electrospun uniaxial blended nanofiber membrane 30% PSA-uniaxial (Comparative Example 4), and 30% PSA-coaxial prepared in Example 3. The experimental results are shown in Figure 2. Figure 5

[0123] Figure 5 It is shown that there are obvious Bragg reflections in the XRD curve of IBU, indicating that it has a crystal structure. The four characteristic diffraction peaks are at 2θ = 6.1°, 2θ = 12.3°, 2θ = 16.8°, and 2θ = 22.4°. In the curve of 30% PSA-uniaxial, there are also the above diffraction peaks, but the intensity is weaker than that of IBU, indicating that 30% PSA-uniaxial has a certain inhibitory effect on crystallization. The characteristic diffraction peaks of IBU do not appear in the curve of 30% PSA-coaxial, indicating that IBU exists in the patch in an amorphous state. The results of XRD show that the coaxial nanofiber patch has a stronger inhibitory effect on drug crystallization than the uniaxial nanofiber patch.

[0124] Example 8

[0125] ​Drug release experiments were performed for the coaxial nanofiber patches in Example 1, Example 2, and Example 3. Each nanofiber patch was cut into 50 mg and placed in 10 mL of PBS buffer with pH 7.4. The drug release experiment was performed in a 37°C constant temperature shaker with a rotation speed of 110 rpm. 1.0 mL of the receiving solution was taken at 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h, 72 h, 96 h, and 120 h, respectively, and an equal amount of PBS buffer at the same temperature was added to the receiving pool to ensure that the leakage condition was met. The receiving solution was filtered with a 0.22 μm microporous filter, and then the IBU content in the receiving solution was determined by HPLC. The drug release curve was plotted with the release time as the abscissa and the cumulative release rate as the ordinate, and the results are shown in Figure 6

[0126] As can be seen from the figure, the PSA concentration significantly affects the drug release behavior of the patches. In the first 4 h, there is no significant difference in the release of the three nanofiber patches. After 4 h, the IBU release rate of the 30% PSA-coaxial nanofiber patch is significantly slower than that of the other two patches. After 12 h, there is a significant difference in the cumulative release percentage of IBU among the three patches. The IBU release rate is negatively correlated with the PSA concentration, and the drug release rate of the 20% PSA-coaxial patch is the fastest, with a cumulative release rate of 80.0 ± 4.5% after 120 h, while that of the 30% PSA-coaxial patch is only 59.9 ± 4.9%. This is because the increase in the shell layer PSA concentration makes the shell layer barrier more difficult for drug diffusion, resulting in slower drug release and lower cumulative release rate. This indicates that the controlled release effect can be achieved by changing the PSA concentration.

[0127] Example 9

[0128] Referring to the drug release experiment method of Example 6, the release of IBU from the 20% PSA-uniaxial (Comparative Example 2), 25% PSA-uniaxial (Comparative Example 3), and 30% PSA-uniaxial (Comparative Example 4) nanofiber patches was determined. The coaxial nanofiber patches were compared to further evaluate the sustained release performance of the coaxial nanofiber patches, and the results are shown in Figure 7

[0129] ​​It can be seen from the figure that the three uniaxial nanofiber patches all reach the release equilibrium at about 24 h, which has a significant difference with the coaxial nanofiber patch. In addition, the cumulative release rate of IBU of the uniaxial nanofiber patch is more than 60% in the first 4 h, which is easy to cause the local drug concentration to be too high in the early stage of administration, leading to the occurrence of toxic side effects. On the contrary, the coaxial nanofiber patch can control the IBU release to be less than 30% in the first 4 h, indicating that it has a good ability to inhibit the initial burst release of drugs, can stabilize the early local drug concentration in a suitable range, and ensure the safety of drug use.

[0130] Example 10

[0131] The in vitro transdermal penetration experiments of the coaxial nanofiber patches in Example 1, Example 2 and Example 3 were carried out. Fresh pig ear skin was cut into circles with a diameter of about 20 mm, washed clean with normal saline and fixed on the receiving chamber of the TK-24BL transdermal diffusion tester with the dermis facing the receiving chamber and the stratum corneum facing the supply chamber. The 20% PSA-coaxial, 25% PSA-coaxial and 30% PSA-coaxial nanofiber patches were cut into circular slices with a diameter of 15 mm and attached to the stratum corneum side, respectively. 7 mL of ultrasonically degassed PBS buffer (pH 7.4) was injected into the receiving chamber as the receiving liquid, 0.5% Tween 80 was added as the solubilizer, the circulating water bath temperature was maintained at 32°C, and the magnetic rotor stirring speed was 200 rpm. 4 mL of transdermal receiving liquid was drawn at 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h and 24 h, and an equal amount of fresh medium at the same temperature was added in time, and the bubbles were discharged to ensure that the receiving liquid was in complete contact with the skin. The receiving liquid was filtered with a 0.22 μm microporous filter, and the IBU content in the receiving liquid was determined by HPLC method. The results are shown in Table 1. Figure 8

[0132] The results show that the 24 h cumulative penetration per unit area of the three nanofiber patches is 749.18 μg / cm 2 , 612.69 μg / cm 2 and 473.46 μg / cm 2 , respectively. With the increase of the concentration of the adhesive pressure-sensitive adhesive material PSA, the cumulative penetration per unit area decreases in turn, which is because the increase of the concentration of PSA leads to the increase of the shell thickness of the fiber, the increase of the drug release resistance, and then the decrease of the cumulative transdermal penetration. The three patches basically reach a stable transdermal rate after 2 h, and the transdermal rate gradually starts to decrease after 12-24 h.

[0133] It can be seen that by adjusting the concentration of the shell adhesive pressure-sensitive adhesive material, the shell thickness of the fiber membrane patch can be controlled, and then the purpose of controlled release of drugs is achieved, and the drug release time increases with the increase of the shell thickness.​

[0134] The present application is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the drawings. The application is capable of other embodiments and of being practiced or being carried out in various ways.

[0135] While the application has been described and illustrated with reference to specific preferred embodiments, it is not intended that it be limited to these particulars. Various modifications and changes can occur to one skilled in the art (e.g., variations in sizes, dimensions, structures, shapes and proportions of the various elements, values of parameters, mounting arrangements, use of materials, orientations, etc.) without departing from the spirit and scope of the present application. It is therefore intended to cover in the appended claims all such changes and modifications that fall within the scope of the application.

Claims

1. A method of preparing a controlled release adhesive fibrous film patch, characterized by, Based on coaxial electrospinning technology, a "core-shell" type nanofiber transdermal patch is prepared by placing an adhesive pressure-sensitive adhesive material in the shell layer of the coaxial nanofiber and placing a drug in the core layer of the nanofiber, i.e. the adhesive fiber film patch for sustained and controlled release; The preparation method comprises the following steps: (1) The adhesive pressure-sensitive adhesive material is mixed in anhydrous ethanol, and stirred uniformly at room temperature to prepare a pressure-sensitive adhesive solution with a volume percentage of 20-30% as the shell layer spinning solution; (2) Polycaprolactone is dissolved in a mixed solvent of tetrahydrofuran and acetone, and the volume ratio of tetrahydrofuran to acetone is (1-3):1, and stirred uniformly at room temperature to prepare a polycaprolactone solution with a concentration of 0.1-0.2 g / mL; (3) The drug is added to the polycaprolactone solution prepared in step (2), and the mass ratio of the drug to polycaprolactone is (0.05-0.2):1, and stirred and dissolved at room temperature to obtain the core layer spinning solution; (4) The shell layer spinning solution is loaded into a syringe connected to the outer needle of a coaxial needle, and the core layer spinning solution is loaded into a syringe connected to the inner needle of a coaxial needle; a metal roller receiver is used to collect the spinning, and a non-woven fabric is attached to the surface of the metal roller; the spinning parameters are set, and coaxial electrospinning is carried out at room temperature to prepare spinning fibers with a "core-shell" structure, and the obtained spinning fibers are vacuum dried to prepare drug-loaded adhesive fiber films; (5) The drug-loaded adhesive fiber film prepared in step (4) is covered with a backing material to obtain the sustained and controlled release adhesive fiber film patch; In step (1), the adhesive pressure-sensitive adhesive material is one or more of polyacrylate pressure-sensitive adhesives; In step (2), the average molecular weight M w of the polycaprolactone is 20,000 to 80,000; In step (4), the spinning parameters are as follows: the applied voltage is 15-22 kV, the receiving distance is 10-20 cm, the core layer spinning solution flow rate is 0.1-0.8 ml / h, the ratio of the push speed of the shell layer spinning solution to the core layer spinning solution is (2-5):1, and the rotation speed of the metal roller is 40-200 rpm.

2. The production method according to claim 1, characterized by, In step (3), the drug is one or a combination of ibuprofen or curcumin.

3. The preparation method according to claim 1, characterized in that, In step (4), the temperature of the vacuum drying is 40-60°C, and the time is 12-24 h.

4. The method of claim 1, wherein, In step (5), the backing material is a non-stick paper, a plastic film or an aluminum foil-polyethylene composite film.

5. The sustained and controlled release adhesive fiber film patch prepared by the preparation method of any one of claims 1-4.

6. The extended release adhesive fiber film patch of claim 5, wherein, The diameter of the nanofiber in the patch is 800-2200 nm.

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