Melatonin receptor agonist complex, transdermal drug delivery system, and preparation method therefor and use thereof

Abstract

A melatonin receptor agonist complex, a transdermal drug delivery system, and a preparation method therefor and the use thereof. The complex comprises a polymer pressure-sensitive adhesive, a melatonin receptor agonist dispersed and miscible in the polymer pressure-sensitive adhesive, a penetration enhancer, and polyvinylpyrrolidone, wherein the polyvinylpyrrolidone is present in the polymer pressure-sensitive adhesive in the form of a dendritic nanoframework structure, and the melatonin receptor agonist and the penetration enhancer are adsorbed around the dendritic nanoframework structure. Compared with the prior art, the dendritic nanostructure can improve the transdermal delivery efficiency of the melatonin receptor agonist.

Description

Melatonin receptor agonist complex, transdermal drug delivery system, its preparation method and application

[0001] Cross-referencing related documents

[0002] This application claims priority to Chinese Patent Application No. CN2024115533267, filed on November 1, 2024, entitled “Melatonin Receptor Agonist Complex, Transdermal Drug Delivery System and Preparation Method and Application Thereof”, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to the field of pharmaceuticals, specifically to a melatonin receptor agonist complex, a transdermal drug delivery system, its preparation method, and its application. Background Technology

[0004] Currently, the main oral melatonin receptor agonist drugs include melatonin, agomelatine, ramelteon, and tasimelteon. Common problems with oral melatonin receptor agonists include: (1) a generally severe first-pass effect in the liver, increasing the burden on the liver and causing liver damage. For example, agomelatine has serious liver damage problems, and the FDA has a black box warning for liver damage. Liver function needs to be checked regularly before and during use. (2) low absolute bioavailability. For example, agomelatine has a bioavailability of about 3%, and ramelteon has a bioavailability of about 1.8%. The low bioavailability leads to a dosage that is much higher than the actual effective dose. (3) short half-life, resulting in a lack of sustained efficacy. For example, the plasma half-life of melatonin is 15-20 minutes, that of agomelatine is about 90 minutes, and that of tasimelteon is about 80 minutes. The short half-life leads to discontinuous oral efficacy, reaching peak plasma concentration in a short time and then rapidly declining. (4) Large individual variability. For example, agomelatine has extremely low bioavailability, resulting in large individual differences in bioavailability. There are large individual differences in peak serum concentration (Cmax) and area under the curve (AUC), affecting the efficacy and side effects of the drug. (5) Concerns about drug interactions. For example, agomelatine has a strong first-pass effect and shares liver enzymes for metabolism, making it difficult to use oral agomelatine in combination with other mainstream antidepressants. Another example is rameltein, whose AUC increases by 31% when taken with high-fat foods.

[0005] Transdermal drug delivery systems can significantly improve upon the shortcomings of traditional oral administration. First, they bypass the first-generation effect in the liver, reducing hepatotoxicity. Second, they can provide stable administration over a long period, resulting in very stable blood drug concentrations, and the administration rate is not affected by external factors such as diet. Finally, they have high bioavailability, generally up to 50%, as the entire drug enters the bloodstream through the skin, which is a significant improvement over oral administration.

[0006] While transdermal drug delivery systems offer significant advantages over oral administration, current systems still suffer from insufficient drug loading and low permeability. For example, commercially available agomelatine tablets are typically 25 mg per tablet, while transdermal drug delivery systems generally load less than 10 mg. Taking melatonin as an example, a typical oral dose (5-10 mg) can deliver over 0.5 mg into the bloodstream within one hour, reaching a peak plasma concentration of 200 pg / ml. With transdermal delivery, this requires maintaining an entry rate of over 100 μg / h for at least 8 hours. For transdermal drug delivery systems, increasing patch area is a common method to improve drug loading and permeability. However, larger patch areas reduce user compliance, increase the probability of side effects, and significantly increase production costs. Therefore, further research is needed to address the issues of insufficient drug loading and low permeability in transdermal drug delivery systems. Summary of the Invention

[0007] The purpose of this invention is to provide a transdermal drug delivery system containing a nano-dendritic structure in order to solve the above-mentioned problems.

[0008] The objective of this invention is achieved through the following technical solution:

[0009] In a first aspect, the present invention provides a melatonin receptor agonist complex.

[0010] The complex contains a dendritic nanoframework structure formed by polyvinylpyrrolidone, around which melatonin receptor agonists and permeation enhancers are adsorbed as active components.

[0011] Furthermore, the polyvinylpyrrolidone, together with the melatonin receptor agonist and permeation enhancer adsorbed thereon, are dispersed in the polymer pressure-sensitive adhesive.

[0012] The dendritic nanoskeleton structure (also known as dendritic structure) described in this invention can be defined as follows: From a morphological perspective, it exhibits a multi-level branching morphology similar to a tree branch, starting from a central core and growing outwards from primary branches. These primary branches then further grow into secondary branches, and so on, forming a complex multi-level branching structure.

[0013] This invention utilizes the dendritic nanoframework structure formed by polyvinylpyrrolidone to enhance the adsorption capacity of permeation enhancer ion pairs and active molecules in the composite colloid, thereby increasing the loading capacity. Simultaneously, it leverages the excellent water absorption of this nanostructure, preferentially absorbing moisture (from the skin) during use. This alters the local structure of the dendritic nanoframework, causing rapid phase separation along the nanoframework after water absorption. Physical pores are formed along the nano-dendritic structure, allowing diffusion to occur in all pores. Furthermore, the area near the nanoframework is already rich in permeation enhancers and melatonin receptor agonists, exhibiting the largest concentration gradient, thus preferentially releasing permeation enhancers and active molecules and improving delivery efficiency.

[0014] As a preferred embodiment of the present invention, the diameter of the branches of the dendritic nanoskeleton structure is 100-1000 nm, preferably 200-500 nm, and even more preferably 200-400 nm. Here, the diameter of the branches refers to the "thickness" of the branches.

[0015] As a preferred embodiment of the present invention, the polyvinylpyrrolidone is cross-linked and / or non-cross-linked polyvinylpyrrolidone; and / or, the weight percentage of the polyvinylpyrrolidone in the composite is 5-30%, preferably 5-20%, and most preferably 7-15%.

[0016] The polyvinylpyrrolidone (PVP) of this invention exhibits good water solubility and good solubility in polar solvents. High-molecular-weight pressure-sensitive adhesives (such as polyacrylate, silicone, and polyisobutylene adhesives) are highly hydrophobic. When the long-chain PPVP molecules uniformly dispersed in the adhesive reach a certain concentration, they spontaneously aggregate. As the solvent is gradually dried, the PPVP grows into a dendritic structure. This dendritic structure exhibits strong hydrophilicity relative to its surrounding hydrophobic environment, causing melatonin receptor agonist components and other hydrophilic components to adsorb around this structure.

[0017] As a preferred technical solution of the present invention, the polymer pressure-sensitive adhesive is a medical polymer pressure-sensitive adhesive, selected from one or more of the following: polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene vinyl acetate copolymer, rubber polymers, polyacrylates and their copolymers, polyurethane, polyisobutylene, chlorinated polyethylene, polyvinyl chloride, vinyl chloride-vinyl acetate copolymer, polymethyl methacrylate polymer, polyvinylidene chloride, polyethyl terephthalate, ethylene-vinyl alcohol copolymer, ethylene-vinylidene ethanol copolymer, silicone copolymers (such as polysiloxane-polymethyl methacrylate copolymer), cellulose polymers, ethyl cellulose, cellulose esters, polycarbonate, and polytetrafluoroethylene.

[0018] As a further preferred technical solution of the present invention, the polymer pressure-sensitive adhesive is a pressure-sensitive adhesive polymer containing acrylate groups, isobutylene groups or siloxane bonds, and is selected from one or more of polyacrylate, polyisobutylene, and silicone polymers;

[0019] Preferably, the polymer pressure-sensitive adhesive is Duro-tak4098, Duro-Tak 2287, Duro-Tak235A, PSA-7-4301, PSA-7-4302, BASF N50, BASF N80, BASF N100, BASF B12, or INEOS H-1500.

[0020] The polymeric pressure-sensitive adhesive comprises 30-90% by weight in the composite, preferably 70-90%, and most preferably 72-80%.

[0021] As a preferred technical solution of the present invention, the melatonin receptor agonist as the active component includes one or more of melatonin, agomelatine, rameltein, tasmetazine and their corresponding derivative compounds.

[0022] And / or, the melatonin receptor agonist is present in the complex at a weight percentage of 1-15%, preferably 2-12%, and most preferably 2-10%.

[0023] As a preferred embodiment of the present invention, the permeation enhancer in the complex is a medium- and long-chain fatty acid composition.

[0024] Furthermore, the medium- and long-chain fatty acid composition comprises fatty acids with 8 to 22 carbons and their corresponding acyl amino acids, such as long-chain saturated and unsaturated fatty acids with 8 to 22 carbons and their derived acyl acids;

[0025] The fatty acid includes one or more of myristic acid, oleic acid, and lauric acid; and / or, the fatty acid in the complex is 1-8% by weight, preferably 2-4%;

[0026] The acyl amino acid includes one or more of lauroyl sarcosine, lauroyl glutamic acid, myristyl sarcosine, and oleoyl sarcosine. And / or, the weight percentage of the acyl amino acid in the complex is 1–8%, preferably 2–4%.

[0027] This invention employs a medium- and long-chain fatty acid composition, belonging to the category of transdermal drug delivery permeation enhancers. Its mechanism of action involves interfering with the arrangement of phospholipid molecules, thereby opening skin pathways and enhancing the skin's ability to penetrate melatonin receptor agonists. The fatty acids correspond to acyl acids with 8 to 22 carbon atoms, such as N-lauroyl sarcosine, N-lauroyl glutamate, and oleoyl sarcosine. Taking N-lauroyl sarcosine as an example, unlike sodium N-lauroyl sarcosine, which has a strong hydrophilic end as an amino acid salt, N-lauroyl sarcosine has weak hydrophilicity, ensuring its dispersion in a highly hydrophobic high-molecular-weight pressure-sensitive adhesive environment, while simultaneously adsorbing around the dendritic structure of polyvinylpyrrolidone.

[0028] As a preferred embodiment of the present invention, the complex further includes an antioxidant, which is selected from one or more of vitamin C, vitamin E, sodium metabisulfite, and 2,6-di-tert-butyl-p-cresol;

[0029] And / or, the antioxidant in the complex is 0.01 to 1% by weight, preferably 0.05 to 0.15%.

[0030] Secondly, the present invention provides a method for preparing a melatonin receptor agonist complex, comprising the following steps:

[0031] (1) Use a solvent to dissolve or disperse polyvinylpyrrolidone to obtain a polyvinylpyrrolidone solution;

[0032] (2) Add the polyvinylpyrrolidone solution and the polymer pressure-sensitive adhesive to a co-solvent that can dissolve the polymer pressure-sensitive adhesive, stir and mix evenly, add the remaining components, stir evenly and form a colloidal stock solution.

[0033] (3) After coating the colloidal stock solution, the solvent is dried by gradient heating at 50-90°C, so that polyvinylpyrrolidone forms a dendritic nanostructure in the polymer pressure-sensitive adhesive.

[0034] As a preferred technical solution of the present invention, the solvent in step (1) is an alcohol solvent, including one or more of methanol, ethanol, and isopropanol;

[0035] And / or, the co-solvent in step (2) includes one or more of ethyl acetate, heptane, and hexane;

[0036] And / or, in step (3), the product is dried at 55-65℃, 70-80℃, and 80-90℃ for 5-10 minutes respectively.

[0037] Preferably, step (3) is dried at 58-62℃, 72-78℃ and 82-88℃ for 5-10 minutes respectively. Most preferably, step (3) is dried at 60℃, 75℃ and 85℃ for 5-10 minutes respectively.

[0038] Thirdly, the present invention provides an application of a melatonin receptor agonist complex, wherein the complex is used as an active pharmaceutical ingredient in the preparation of transdermal formulations or patches.

[0039] Fourthly, the present invention provides a transdermal drug delivery system containing a dendritic nanostructure, comprising, from top to bottom, a backing layer, one or more drug-containing base layers, and a release film. The drug-containing base layer includes the aforementioned composite. During preparation, the adhesive solution of the drug-containing base layer is coated onto the surface of the release film, dried and cured, and then the backing layer is laminated to obtain the final product.

[0040] As a preferred technical solution of the present invention, the materials suitable for the backing layer include high-density polyethylene, low-density polyethylene, polypropylene film, polyvinyl chloride, polyurethane, polyester and other polyethylene terephthalate, metal foil, polymer film laminated with metal foil, textile fabric, etc., preferably multilayer composite materials, such as polymer film and metal foil (e.g., aluminum foil).

[0041] As a preferred technical solution of the present invention, the release film can be made of the materials used for the backing layer, which can be obtained after siliconization or fluorination treatment. Other release films (protective layers) include polytetrafluoroethylene, treated paper, propofol, polyvinyl chloride, etc.

[0042] Fourthly, the present invention provides an application of a transdermal drug delivery system containing a dendritic nanostructure, wherein the transdermal drug delivery system is used as a transdermal drug delivery patch, and is applied to the skin surface after removing the release film.

[0043] Compared with the prior art, the present invention has the following beneficial effects:

[0044] This invention utilizes the excellent water solubility of polyvinylpyrrolidone (PVP) and its good solubility in polar solvents, along with the strong hydrophobicity of the high-molecular-weight pressure-sensitive adhesive. Therefore, PPVP long-chain molecules uniformly dispersed in the pressure-sensitive adhesive spontaneously aggregate and grow into a dendritic nanostructure after reaching a certain concentration. This dendritic structure exhibits strong hydrophilicity relative to its surrounding hydrophobic environment, allowing melatonin receptor agonists and penetration enhancers to be adsorbed around this structure. The adsorption of penetration enhancer ion pairs and active molecules by the dendritic structure in the colloid helps to increase the loading capacity. Simultaneously, leveraging the high water absorption of PPVP, a small amount of water molecules on the skin preferentially enters the PPVP as a dendritic nanostructure framework during patch application, altering this structure. The increased water content weakens the adsorption of active components and penetration enhancers by the PPVP framework, leading to rapid release to the skin surface. The penetration enhancer opens skin pathways, improving the transdermal delivery efficiency of the melatonin receptor agonist. When this invention uses an in vitro permeation model for investigation, for different melatonin receptor agonists, the permeation rate per unit area increases by more than 5 times between 8 and 24 hours after administration. Attached Figure Description

[0045] Figure 1 shows the permeation rate curve of the in vitro permeation simulation experiment in Example 1;

[0046] Figure 2 shows the permeation rate curve of the in vitro permeation simulation experiment in Example 2;

[0047] Figure 3 is a microstructure diagram of group 2 in Example 2;

[0048] Figure 4 shows the permeation rate curve of the in vitro permeation simulation experiment in Example 3;

[0049] Figure 5 is a microstructure diagram of group 1 in Example 3;

[0050] Figure 6 shows the permeation rate curve of the in vitro permeation simulation experiment in Example 4;

[0051] Figure 7 shows the permeation rate curve of the in vitro permeation simulation experiment in Example 5;

[0052] Figure 8 is a microstructure diagram of group 1 in Example 5;

[0053] Figure 9 is a microstructure diagram of group 2 in Example 5;

[0054] Figures 10 to 12 are microstructure diagrams of groups 1 to 3 in Example 6, respectively. Detailed Implementation

[0055] The present invention will now be described in detail with reference to specific embodiments.

[0056] The transdermal drug delivery patch provided by this invention has a three-layer structure: the first layer is a backing layer (made of polyethylene and ethylene vinyl acetate copolymer), the middle layer is a drug-containing base layer, and the third layer is a release film (made of siliconized or fluorinated PET film).

[0057] The drug-containing base layer is composed of the following components by mass percentage:

[0058] The gel-drug hybrid transdermal drug delivery patch is prepared using the following laboratory process:

[0059] Preparation of wet base

[0060] (1) First, use the solvent ethanol to dissolve or disperse the polyvinylpyrrolidone skeleton;

[0061] (2) After the mixture is completely dissolved and evenly dispersed, add ethyl acetate and stir slowly to mix. Disperse the polyvinylpyrrolidone skeleton evenly in the high molecular pressure-sensitive adhesive. Add the remaining components and stir slowly for more than 4 hours until uniform.

[0062] Patch preparation

[0063] 1. Lay the glass plate flat on the table and keep it clean and dry. Place the release film on the glass plate, mark the smooth side up, and secure it with tape.

[0064] 2. Place the coating blade on top of the release film (without extending beyond the release film), and apply a coating thickness of 200 / 300 μm.

[0065] 3. Pour an appropriate amount of colloid along the edge of the coating blade in a straight line.

[0066] 4. Hold both ends of the coating blade with both hands and apply the coating slowly and evenly from top to bottom.

[0067] 5. Check whether the coated surface is flat and even, and whether there are any air bubbles.

[0068] 6. Place the coated patch into an oven and dry it at 60℃, 75℃, and 85℃ for 5-10 minutes respectively, then remove it and laminate it.

[0069] 7. Use a backing film for lamination.

[0070] 8. The overlapping process should proceed from bottom to top and from left to right, moving slowly and at a constant speed.

[0071] 9. Avoid generating air bubbles during the lamination process; clean the coating knife with ethyl acetate.

[0072] 10. Slice the material using a cutter of the corresponding size. The preparation is now complete.

[0073] Example 1

[0074] The backing layer uses 3M 9723 backing film.

[0075] S10-010 release film is selected as the release film.

[0076] The specific composition of the drug-containing basal layer is detailed in Table 1.

[0077] Table 1

[0078] The test was conducted in vitro using a simulation experiment. The specific experimental parameters are shown in Table 2.

[0079] Table 2

[0080] Figure 1 shows the permeation rate curves of Group 1 and Group 2 in Example 1. Compared with Group 1, Group 2 increased the permeation rate of melatonin by more than 5 times within 12 hours.

[0081] Example 2

[0082] Unlike Example 1, the specific composition and proportion of the drug-containing base layer are shown in Table 3.

[0083] Table 3

[0084] The same in vitro permeation simulation experiment as in Example 1 was conducted, and the test results are shown in Figure 2. As can be seen from Figure 2, the permeation rate of melatonin can be increased by more than 6 times within 12 hours using the transdermal drug delivery system of the present invention.

[0085] The typical microstructure diagram of group 2 in Example 2 is shown in Figure 3, which forms a dendritic structure. The scale is marked in Figure 3. It can be seen that the diameter (or thickness) of the branches of the dendritic structure shown in Figure 3 is about 200nm to 1000nm.

[0086] Example 3

[0087] Unlike Example 1, the composition of the drug-containing base layer is shown in Table 4.

[0088] Table 4

[0089] The same in vitro permeation simulation experiment as in Example 1 was conducted, and the test results are shown in Figure 4. As can be seen from Figure 4, the permeation rate of melatonin can be increased by more than 6 times within 4 hours using the transdermal drug delivery system of the present invention, and a high permeation rate can be maintained for a longer period of time.

[0090] The typical microstructure diagram of group 1 in Example 3 is shown in Figure 5. The microstructure shows that the diameter of the branches is 200nm to 1000nm.

[0091] Example 4

[0092] The backing layer uses 3M 9723 backing film;

[0093] The release film used is 3M 9755 release film;

[0094] For details on the composition of the drug-containing base layer, please refer to Table 5.

[0095] Table 5

[0096] The same in vitro permeation simulation experiment as in Example 1 was conducted, and the test results are detailed in Figure 6. As can be seen from Figure 6, the permeation rate of melatonin can be increased by 4 times within 4 hours using the transdermal drug delivery system of the present invention, and a high permeation rate can be maintained for a longer period of time. However, when only polyvinylpyrrolidone is used and no fatty acids and corresponding acyl acids are added, the permeation efficiency is greatly reduced.

[0097] Example 5

[0098] The backing layer uses 3M 9723 backing film;

[0099] The release film used is 3M 9755 release film;

[0100] For details on the composition of the drug-containing base layer, please refer to Table 6;

[0101] Table 6

[0102] Using the same in vitro permeation simulation experiment as in Example 1, the test results are detailed in Figure 7. It can be seen that in the rameltethan percutaneous system, without the addition of polyvinylpyrrolidone, a dendritic structure cannot be formed (as shown in Figure 8). With the addition of only fatty acids and corresponding acyl acids, the permeation efficiency decreases by half.

[0103] The typical microstructure diagram of group 2 in Example 5 is shown in Figure 9. Figure 9 indicates the scale, and its microstructure shows that the diameter (or thickness) of the branches is about 200nm to 500nm.

[0104] Example 6

[0105] The backing layer uses 3M 9723 backing film;

[0106] The release film used is 3M 9755 release film;

[0107] For details on the composition of the drug-containing basal layer, please refer to Table 7;

[0108] Table 7

[0109] The microstructure diagrams of groups 1 to 3 in Example 6 are shown in Figures 10 to 12. Different concentrations of polyvinylpyrrolidone affect the density of the dendritic structure.

[0110] The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.

Claims

1. A melatonin receptor agonist complex, characterized in that, The complex contains a dendritic nanoframework structure formed by polyvinylpyrrolidone, around which melatonin receptor agonists and permeation enhancers are adsorbed as active components.

2. The melatonin receptor agonist complex according to claim 1, characterized in that, The polyvinylpyrrolidone, along with the melatonin receptor agonist and permeation enhancer adsorbed thereon, are dispersed together in a high molecular weight pressure-sensitive adhesive.

3. The melatonin receptor agonist complex according to claim 1, characterized in that, The diameter of the branches of the dendritic nanoskeleton structure is 100–1000 nm.

4. The melatonin receptor agonist complex according to claim 1, characterized in that, The polyvinylpyrrolidone is cross-linked and / or non-cross-linked polyvinylpyrrolidone; And / or, the polyvinylpyrrolidone in the composite is 5-30% by weight, preferably 5-20%, and most preferably 7-15%.

5. A melatonin receptor agonist complex according to any one of claims 1 to 4, characterized in that, Melatonin receptor agonists, which are active components, include one or more of melatonin, agomelatine, rameltein, tasmegron, and their corresponding derivatives. And / or, the melatonin receptor agonist is present in the complex at a weight percentage of 1-15%, preferably 2-12%, and most preferably 2-10%.

6. The melatonin receptor agonist complex according to claim 5, characterized in that, The permeation enhancer in the complex is a medium- and long-chain fatty acid composition; The medium- and long-chain fatty acid composition comprises fatty acids with 8 to 22 carbons and their corresponding acyl amino acids; And / or, the fatty acids include one or more of myristic acid, oleic acid, and lauric acid; And / or, the fatty acid in the complex is 1-8% by weight, preferably 2-4%; And / or, the acyl amino acid includes one or more of lauroyl sarcosine, lauroyl glutamic acid, myristyl sarcosine, and oleyl sarcosine; and / or, the weight percentage of the acyl amino acid in the complex is 1-8%, preferably 2-4%.

7. A method for preparing a melatonin receptor agonist complex according to any one of claims 1 to 6, characterized in that, Includes the following steps: (1) Use a solvent to dissolve or disperse polyvinylpyrrolidone to obtain a polyvinylpyrrolidone solution; (2) Add the polyvinylpyrrolidone solution and the polymer pressure-sensitive adhesive to a co-solvent that can dissolve the polymer pressure-sensitive adhesive, stir and mix evenly, add the remaining components, stir evenly and form a colloidal stock solution. (3) After coating the colloidal stock solution, the solvent is dried by gradient heating at 50-90°C, so that polyvinylpyrrolidone forms a dendritic nanostructure in the high molecular pressure-sensitive adhesive. The solvent in step (1) is an alcohol solvent, including one or more of methanol, ethanol, and isopropanol; And / or, the co-solvent in step (2) includes one or more of ethyl acetate, heptane, and hexane; And / or, in step (3), the product is dried at 55-65℃, 70-80℃, and 80-90℃ for 5-10 minutes respectively.

8. The application of the melatonin receptor agonist complex as described in any one of claims 1 to 6, characterized in that, The complex is used as an active pharmaceutical ingredient in the preparation of transdermal formulations or patches.

9. A transdermal drug delivery system containing a dendritic nanostructure, comprising, from top to bottom, a backing layer, one or more drug-containing substrate layers, and a release film, characterized in that, The drug-containing base layer includes the complex as described in any one of claims 1 to 6. During preparation, the adhesive of the drug-containing base layer is applied to the surface of the release film, dried and cured, and then laminated with the backing layer.

10. The application of a transdermal drug delivery system containing a dendritic nanostructure as described in claim 9, characterized in that, The transdermal drug delivery system is used as a transdermal patch. When in use, the release film is removed and the patch is applied to the skin surface.

Images