Transdermal drug delivery patch with five-layer structure and application of transdermal drug delivery patch

Abstract

The invention discloses a transdermal drug delivery patch with a five-layer structure and application thereof, and belongs to the technical field of pharmaceutical preparations. The patch comprises a backing film, a donepezil hydrochloride-containing reservoir layer, a controlled release film, an organic alkali-containing adhesion layer and a release film. The release rate of the donepezil hydrochloride is controlled through the controlled release film, the donepezil hydrochloride is isolated from organic alkali, the drug stability is improved, the drug release rate is regulated and controlled, the donepezil hydrochloride passes through the controlled release film and then is subjected to an in-situ reaction with the organic alkali in the adhesion layer, and the donepezil hydrochloride is converted into donepezil free alkali for transdermal delivery. According to the patch, the drug stability is improved, the preparation process is simple, the local safety is high, and the transdermal permeability of donepezil can be remarkably improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of transdermal drug delivery preparations and is a method for preparing a multilayer patch that uses a controlled-release membrane to isolate donepezil hydrochloride from an organic base and control the release while simultaneously performing in-situ conversion. This technology can improve the stability of donepezil in the patch and ensure long-term steady-state transdermal delivery. Background Art

[0002] Transdermal Drug Delivery Systems (TDDS) have become a research hotspot in the drug delivery field due to their advantages such as non-invasiveness, avoidance of first-pass effect, and provision of sustained blood drug concentrations. Although salt-based drugs have good stability, their charge and low lipid solubility make it difficult for them to effectively penetrate the stratum corneum barrier, resulting in low transdermal efficiency. Currently, while traditional multilayer patches (such as reservoir-type and matrix-type patches) can achieve sustained drug release, they do not address the issue of drug morphological transformation during penetration. For example, Donepezil hydrochloride (DPH) may be chemically unstable when in direct contact with alkali, and liquid organic bases may cause local irritation or allergic reactions.

[0003] Patent applications CN109789105A and CN109789133A disclose transdermal formulations and delivery methods that utilize the in situ conversion of donepezil hydrochloride to donepezil base (DPB). The base, generated in situ by the reaction of donepezil hydrochloride with sodium bicarbonate in the reservoir layer, enters the adhesive layer after passing through the controlled-release membrane, thereby achieving transdermal drug delivery. The coexistence of donepezil hydrochloride and sodium bicarbonate in the pressure-sensitive adhesive matrix in these patents results in poor stability of donepezil. Furthermore, the chemical reaction involved in patch preparation complicates the manufacturing process, increases quality control challenges, and increases costs. Summary of the Invention

[0004] The present invention aims to overcome the problems of low delivery efficiency, poor drug stability caused by the coexistence of donepezil hydrochloride and an organic base, complex preparation process, and difficulty in quality control in existing donepezil hydrochloride transdermal delivery systems. By storing the drug separately in a reservoir layer, the organic base is selected as solid tromethamine or aminomethylpropanol powder. By optimizing the controlled-release membrane and the particle size of the organic base, the release rate and in-situ conversion rate of donepezil hydrochloride are controlled, thereby increasing the steady-state transdermal permeation rate of donepezil. This effectively solves the problems of poor drug stability, difficult preparation process, and difficult quality control in existing patents. To address these issues, this patent proposes isolating the organic base and hydrochloride salt, allowing in-situ conversion during the drug delivery process, and achieves good therapeutic effects.

[0005] The technical solution of the present invention is: a transdermal patch, which comprises a backing film, a reservoir layer, a controlled release membrane, an adhesive layer and a release film which are laminated in sequence;

[0006] The reservoir layer is a pressure-sensitive adhesive layer containing donepezil hydrochloride;

[0007] The adhesive layer contains an organic base; the organic base is tromethamine or aminomethyl propanol;

[0008] The controlled release membrane layer is a polypropylene film selected from Celgard 2500 or Celgard 2400;

[0009] The molar ratio of donepezil hydrochloride in the reservoir layer to the organic base in the adhesion layer is 1:1.

[0010] Furthermore, the controlled-release membrane layer is used to regulate the migration rate of donepezil hydrochloride from the reservoir layer to the adhesion layer;

[0011] During the permeation process, donepezil hydrochloride enters the adhesive layer through the controlled-release membrane layer and reacts in situ with the organic base in the adhesive layer to generate donepezil base.

[0012] Furthermore, the reservoir layer includes an alcohol solubilizer, donepezil hydrochloride, a pressure-sensitive adhesive and a pressure-sensitive adhesive tackifier.

[0013] Furthermore, the alcohol solubilizer is glycerol or propylene glycol, the pressure-sensitive adhesive is acrylic acid / vinyl acetate pressure-sensitive adhesive, and the pressure-sensitive adhesive tackifier is polyvinyl pyrrolidone.

[0014] Furthermore, the mass percentage of the alcohol solubilizer in the reservoir layer is 10%wt~20%wt, the mass percentage of the pressure-sensitive adhesive tackifier in the reservoir layer is 5%wt~20%wt; the mass percentage of donepezil hydrochloride in the reservoir layer is 10%wt~25%wt; and the mass percentage of the pressure-sensitive adhesive in the reservoir layer is 30%wt~65%wt.

[0015] Furthermore, the adhesive layer contains an organic base, an ester solubilizer, a pressure-sensitive adhesive matrix and a tackifier.

[0016] Furthermore, the ester solubilizer is one or more of sorbitan monolaurate, lauryl lactate, isopropyl myristate, and triethyl citrate, the pressure-sensitive adhesive matrix is, and the tackifier is polyvinyl pyrrolidone;

[0017] The organic base is in the form of powder with a particle size of 1 to 10 microns.

[0018] Furthermore, the mass percentage of the ester solubilizer in the adhesive layer is 3% wt ~10% wt; the mass percentage of the tackifier in the adhesive layer is 5% wt ~20% wt; and the mass percentage of the pressure-sensitive adhesive matrix in the adhesive layer is 50% wt ~70% wt.

[0019] Furthermore, the backing film is Cotran TM 9726.

[0020] Furthermore, the donepezil in the patch satisfies a steady-state release of more than 12 hours and a transdermal penetration of more than 24 hours.

[0021] The patch uses a controlled-release membrane to physically separate the reservoir layer from the adhesive layer. The reservoir layer is loaded with donepezil hydrochloride, and tromethamine or aminomethyl propanol is ground into a 1-10 micron powder and evenly dispersed in the adhesive layer. This technology can control the release and conversion rate of donepezil hydrochloride while avoiding the skin irritation that may be caused by liquid organic bases. During the drug penetration process, donepezil hydrochloride diffuses through the controlled-release membrane to the adhesive layer, where it reacts in situ with tromethamine or aminomethyl propanol to generate the free base form of donepezil, which then penetrates into the skin.

[0022] The beneficial effects of the present invention are as follows: the limitation of low transdermal delivery rate of fat-soluble ionic drugs is overcome through the salt-base in situ conversion mechanism, the permeation flux is improved, and at the same time, the synergistic effect of the controlled release membrane and the in situ reaction realizes the steady-state release and transdermal delivery of donepezil, and has both sustained-release stability and high transdermal efficiency; the interlayer isolation design avoids the miscibility of donepezil hydrochloride and alkaline components during the storage of the drug preparation, thereby improving the drug stability; the particle size of tromethamine or aminomethylpropanol is controlled and uniformly dispersed, thereby improving the reaction efficiency and reducing skin irritation; in addition, the technical solution is simple to operate and has the advantages of strong process universality, good quality controllability, and a wide range of applications.

[0023] The advantages of the present invention are that donepezil hydrochloride and the organic base are respectively placed in the reservoir layer and the adhesive layer of the patch, and a controlled-release membrane is used for physical separation, thereby improving the stability of the drug during storage; in addition, the organic base in the adhesive layer is dispersed in the form of solid powder to prevent skin irritation. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 This is the structure of donepezil long-acting transdermal patch.

[0025] Figure 2 The process flow for preparing the reservoir layer of the donepezil patch.

[0026] Figure 3 This is the process flow for preparing the drug-containing layer of donepezil patch.

[0027] Figure 4This is the transdermal permeation amount-time curve of donepezil at different particle sizes of organic base powder.

[0028] Figure 5 This is the 24h cumulative permeability-time curve of donepezil under different pressure-sensitive adhesive functional groups.

[0029] Figure 6 This is the 1-hour cumulative release-time curve of donepezil hydrochloride under different concentrations of alcohol solubilizers.

[0030] Figure 7 This is the 24-hour cumulative permeability-time curve of donepezil under different concentrations of fatty acid esters.

[0031] Figure 8 This is the 24-hour cumulative permeability-time curve of donepezil under the combined use of fatty acid esters and carboxylic acid esters.

[0032] Figure 9 This is the 24-hour release concentration-time curve of donepezil from different organic base patches.

[0033] Figure 10 This is the 168-hour permeation concentration-time curve of donepezil patches with different organic bases.

[0034] Figure 11 This is the cumulative release rate-time curve of donepezil hydrochloride and donepezil base over 168 hours under the regulation of Celgard 2400 controlled-release membrane.

[0035] Figure 12 The concentration-time curve of donepezil hydrochloride release from the reservoir layer for 168 hours under different concentrations of alcohol solubilizers.

[0036] Figure 13 The cumulative release rate-time curve of donepezil hydrochloride over 168 hours under the regulation of three controlled-release membranes.

[0037] Figure 14 The release concentration-time curves of the reservoir layer under different backing films.

[0038] Figure 15 This is the 24h release concentration-time curve of donepezil hydrochloride-organic base patch.

[0039] Figure 16 This is the 168-h permeation concentration-time curve of donepezil hydrochloride-organic base patch.

[0040] Figure 17 This is a photo of the skin from the skin irritation test of donepezil hydrochloride-organic base patch. DETAILED DESCRIPTION

[0041] Example 1: Patch Preparation

[0042] (1) Preparation of reservoir layer

[0043] Mix an alcohol solubilizer, donepezil hydrochloride, and a tackifier, then add an organic solvent and stir thoroughly. Then, add an acrylic acid / vinyl acetate pressure-sensitive adhesive and continue stirring until the mixture is uniform. Apply the wet adhesive formulation onto a release liner, heat and dry it in an oven, and then laminate it onto a backing film to form a reservoir layer.

[0044] (2) Preparation of adhesion layer

[0045] Mix an ester solubilizer, an organic base powder containing donepezil hydrochloride in equal molar ratios, and a tackifier. Add the organic solvent and stir thoroughly. Then add the acrylic acid / vinyl acetate pressure-sensitive adhesive and continue stirring until the mixture is uniform. After the wet adhesive preparation is allowed to stand to remove air bubbles, it is coated on a release liner and placed in an oven for heating and drying to form an adhesive layer.

[0046] (3) Preparation of donepezil patches

[0047] The reservoir layer is laminated onto the controlled-release membrane. The adhesive layer is then laminated onto the other side of the controlled-release membrane. A release film is then pressed onto the adhesive layer and die-cut into a specific shape and size to prepare a 5-layer donepezil hydrochloride patch.

[0048] Example 2: Preparation of organic base powder

[0049] After pre-drying tromethamine or aminomethyl propanol, first use a crushing device to initially crush large particles, then take a small amount of organic base solid in batches, repeatedly sieve to obtain fine powder with a particle size of 1 to 10 microns, and seal it in a desiccator for later use.

[0050] The results observed: Figure 4 As shown in the figure, the 24-hour permeation of donepezil patch is inversely proportional to the particle size of the organic base powder, and the smaller the particle size, the higher the permeation.

[0051] Example 3: Donepezil Patch Prescription Study

[0052] (1) Effect of pressure-sensitive adhesives with different functional groups on the permeation of donepezil Donepezil hydrochloride was mixed with a pressure-sensitive adhesive, in which the drug accounted for 15% of the pressure-sensitive adhesive by weight. Three pressure-sensitive adhesives with different functional groups were selected as drug carriers, including Duro Tak-4098 without functional groups, Duro Tak-2852 with carboxyl functional groups, and DuroTak-2287 with hydroxyl functional groups. Transdermal patches with the same drug loading were prepared. The transdermal delivery capabilities of the three pressure-sensitive adhesive patches were compared through in vitro transdermal experiments.

[0053] The results observed: Figure 5As shown in the figure, the drug permeation rate of the pressure-sensitive adhesive without functional groups is the highest, followed by the hydroxyl pressure-sensitive adhesive, and the carboxyl pressure-sensitive adhesive has the lowest permeability.

[0054] (2) Effect of alcohol solubilizers on the release of donepezil hydrochloride Donepezil hydrochloride was mixed with Duro Tak-2287 pressure-sensitive adhesive, in which the drug accounted for 15% of the pressure-sensitive adhesive by mass; then glycerol was added at 10%, 15%, and 20% of the mixture by mass, respectively, and drug release experiments were carried out.

[0055] The results observed: Figure 6 As shown in the figure, increasing the proportion of glycerol can significantly enhance the drug release rate.

[0056] (3) Effect of ester solubilizers on donepezil permeation

[0057] Donepezil hydrochloride was mixed with the pressure-sensitive adhesive Duro Tak-2287, with the drug accounting for 15% of the pressure-sensitive adhesive by weight. 3%, 6%, and 10% sorbitan monolaurate were then added to the mixture, respectively. Furthermore, a patch combining lauryl lactate and sorbitan monolaurate (mass ratio 1:1) was added to the mixture at a concentration of 6%. These patches were then compared with a blank donepezil patch (i.e., without the addition of an ester solubilizer) in an in vitro permeation experiment.

[0058] The results observed: Figure 7 As shown in the figure, the drug penetration efficiency of the blank group is the lowest, and as the proportion of sorbitan monolaurate increases, the penetration of donepezil also increases. The combination of sorbitan monolaurate and lauryl lactate shows a better transdermal penetration effect, such as Figure 8 shown.

[0059] (4) Effect of tackifier on peel strength of pressure-sensitive adhesive

[0060] The holding force of the adhesive layer of the donepezil patch was determined according to the third method specified in General Chapter 0952 of Part 4 of the "Chinese Pharmacopoeia 2020 Edition".

[0061] Patches containing different concentrations of the tackifier, polyvinyl pyrrolidone (0%, 5%, 10%, 15%, and 20%), were prepared by mixing the pressure-sensitive adhesive Duro Tak-2287 with polyvinyl pyrrolidone. Before testing, the patches were conditioned at 18–25°C and a relative humidity of 40%–70% for at least 2 hours. The patch backing was secured to the test plate with double-sided tape, ensuring that the test sample lay flat on the plate. The adhesive side of the patch was bonded to a clean polyester film, and then a 2000 g roller was rolled back and forth over the test sample three times to ensure that no bubbles formed at the bond. After bonding, the test sample was allowed to stand at room temperature for 20–40 minutes before testing. The free end of the polyester film was folded in half (180°), and the free end of the film and the test plate were clamped in a testing machine, with the upper and lower ends clamped, respectively. The test machine continuously peeled the sample at a descending speed of 300 mm / min ± 10 mm / min. The peel curve was plotted and the experimental data recorded using an automatic recorder.

[0062] The results showed that, as shown in Table 1, the 180° peel strength and shear strength of the patch first increased and then decreased with the increase of the tackifier concentration.

[0063] Table 1 Hydroxyl PSA adhesion test results at different PVP concentrations

[0064]

[0065] Example 4: Screening of organic bases for the adhesion layer

[0066] Three candidate organic bases (triethanolamine, tromethamine powder, and aminomethylpropanol powder) were selected, accurately weighed in a 1:1 molar ratio with donepezil hydrochloride, and added to the adhesive layer. After the patch was prepared, release and permeation experiments were performed.

[0067] Table 2 Physical and chemical properties of organic bases

[0068]

[0069] The results observed: Figure 9 、 10 The results showed that the triethanolamine patch exhibited obvious burst release behavior within 24 hours, and excessively high drug concentrations may cause skin irritation, while the tromethamine and aminomethylpropanol patches showed slow release and penetration behavior.

[0070] Example 5: Comparison of reservoir release of donepezil base and donepezil hydrochloride

[0071] Pure donepezil hydrochloride reservoir layer and reservoir layer of donepezil hydrochloride and sodium bicarbonate mixed in a 1:1 molar ratio were prepared respectively. After coating with controlled release membrane, release experiments were carried out simultaneously to observe the release of donepezil base and donepezil hydrochloride in the same matrix environment.

[0072] The results observed: Figure 11 As shown in the data, under the same controlled-release membrane system, donepezil hydrochloride exhibited a lower release behavior than donepezil base, which indicated that the lower cumulative permeation of tromethamine and aminomethylpropanol patches over 168 h may be due to the difference in transmembrane rates of donepezil hydrochloride and donepezil base through the controlled-release membrane.

[0073] Based on this, the release efficiency of donepezil hydrochloride was confirmed: donepezil hydrochloride was mixed with Duro Tak-2287 pressure-sensitive adhesive, in which the mass percentage of the drug in the pressure-sensitive adhesive was 15%; glycerol was added to the mixture at 4%, 8%, 12%, and 16% of the mass; a donepezil hydrochloride reservoir layer patch was prepared, and after coating with a controlled-release membrane, a drug release experiment was performed simultaneously.

[0074] The results observed: Figure 12 As shown in the results, the increase of alcohol solubilizer content can significantly improve the release efficiency of donepezil hydrochloride through the controlled release membrane.

[0075] Therefore, increasing the proportion of alcohol solubilizers can significantly increase the drug release rate and also improve the release efficiency of the controlled release membrane.

[0076] Example 6: Screening of controlled release membranes

[0077] Donepezil hydrochloride, pressure-sensitive adhesive Duro Tak-2287, and glycerol were mixed, with the drug accounting for 15%, the pressure-sensitive adhesive accounting for 70%, and the glycerol accounting for 15%, to prepare the reservoir layer. Three types of controlled-release membranes (Celgard 2400, Celgard 2500, Cotran TM 9728) to study the release of donepezil hydrochloride from the reservoir layer.

[0078] Table 3 Properties of three controlled-release membranes

[0079]

[0080] The results observed: Figure 13 The results showed that the expanded pore size of Celgard 2500 significantly enhanced the release of donepezil hydrochloride. TM 9728 showed the lowest release, indicating that the release mechanism of donepezil hydrochloride is pore size-dependent, which is related to the reduction of molecular diffusion resistance and the expansion of effective diffusion pathways.

[0081] Example 7: Screening of backing membranes

[0082] Donepezil hydrochloride, Duro Tak-2287 pressure-sensitive adhesive, and glycerol were mixed, with the drug accounting for 15%, the pressure-sensitive adhesive for 70%, and the glycerol for 15%. Reservoir layers of equal thickness were prepared. Drug release experiments were conducted after lamination using backing films of different materials. Detailed backing film data is shown in Table 4.

[0083] Table 4 Properties of backing films of different materials

[0084]

[0085] a Moiture vapor transmission. Indicates the water permeability of the membrane material

[0086] b Oxygen transmission. Indicates the permeability of the membrane material

[0087] c Not detected

[0088] The results observed: Figure 14 Show, Scotchpak TM The PET backing film group of 9733 had the highest release amount, followed by EVA, PE, and PU.

[0089] Example 8: Donepezil patch release and permeation studies

[0090] Donepezil hydrochloride, polyvinyl pyrrolidone and glycerol were mixed evenly, and then pressure-sensitive adhesive Duro Tak-2287 was added and mixed evenly to obtain a reservoir layer; the drug accounted for 11%, the pressure-sensitive adhesive accounted for 59%, the glycerol accounted for 16%, and the polyvinyl pyrrolidone accounted for 14%.

[0091] After Span 20, lauryl lactate, triethyl citrate, organic base and polyvinyl pyrrolidone are evenly mixed, the pressure-sensitive adhesive Duro Tak-2287 is added and mixed evenly to obtain an adhesion layer; wherein Span 20 accounts for 1.2%, lauryl lactate accounts for 1%, triethyl citrate accounts for 5.8%, organic base accounts for 6%, polyvinyl pyrrolidone accounts for 15%, and the pressure-sensitive adhesive accounts for 71%.

[0092] Based on the above screening results, the controlled release membrane is Celgard 2500 and the backing membrane is Scotchpak TM 9733, to investigate the release and permeation of the patch under three systems: triethanolamine, tromethamine, and aminomethylpropanol.

[0093] The results observed: Figure 15 、 16As shown, donepezil transdermal patches can maintain prolonged release and transdermal delivery in triethanolamine, tromethamine, and aminomethylpropanol organic base systems.

[0094] Example 9: Skin safety study

[0095] Healthy adult Japanese white rabbits (2.5 ± 0.3 kg, male) were used for the experiment. A left-right comparison method was used. Twenty-four hours before the experiment, the skin on both sides of the rabbit's spine was shaved with an electric shaver and cleaned with depilatory cream to ensure no mechanical damage. A 2 cm × 2 cm patch (DPH-TEOA, DPH-TRIS, and DPH-AMP 95) was applied to the prepared area and secured with medical tape for 7 days. Scoring and discussion were performed 1, 24, 48, and 72 hours after patch removal, as shown in Table 5.

[0096] Table 5 Skin irritation scoring criteria

[0097]

[0098] DPH-TEOA patch:

[0099] Mix 0.4g of glycerol, 0.225g of donepezil hydrochloride, and 0.3g of polyvinyl pyrrolidone, add ethyl acetate and stir thoroughly. Then add 1.09825g of pressure-sensitive adhesive Duro Tak-4098 and continue stirring until the mixture is uniform. The wet adhesive formulation is coated on a release liner and placed in an oven to heat and dry. The backing film Scotchpak TM 9733 obtained the reservoir layer.

[0100] Mix 0.015g of Span 20, 0.0225g of lauryl lactate, an equimolar ratio of donepezil hydrochloride to triethanolamine, and 0.15g of polyvinyl pyrrolidone. Add ethyl acetate and stir thoroughly. Then add 0.96525g of Duro Tak-4098 pressure-sensitive adhesive and continue stirring until the mixture is uniform. After the wet adhesive formulation is allowed to stand to remove air bubbles, it is coated on a release liner and placed in an oven to dry to form an adhesive layer.

[0101] The reservoir layer was laminated on the controlled-release membrane Celgard 2500, and then the adhesive layer was laminated on the other side of the controlled-release membrane Celgard 2500. The release film was pressed on the adhesive layer, and die-cutting was performed to obtain the donepezil hydrochloride patch.

[0102] DPH-TRIS Patch:

[0103] The preparation method is the same as that of the DP-TEOA patch, except that the organic base triethanolamine is replaced by tromethamine, wherein the tromethamine is a fine powder with a particle size of 1 to 10 microns.

[0104] DPH-AMP 95 Patch:

[0105] The preparation method is the same as that of the DP-TRIS patch, except that the organic base triethanolamine is replaced by aminomethyl propanol, wherein the aminomethyl propanol is a fine powder with a particle size of 1 to 10 microns.

[0106] The results observed: Figure 17 As shown in Table 6, no erythema or edema was detected in the tromethamine group and the aminomethylpropanol group during the entire observation period, while mild erythema appeared in the triethanolamine group 7 days after patch application, indicating that the donepezil hydrochloride-tromethamine system and the donepezil hydrochloride-aminomethylpropanol system had no significant effect on the skin barrier.

[0107] Table 6 Skin irritation reaction scoring criteria

[0108]

[0109] This study evaluated the effects of three organic bases—trolamine, tromethamine, and aminomethylpropanol—in the adhesive layer of a five-layer transdermal drug delivery patch on drug release and permeation performance. By optimizing the alcohol solubilizer concentration and controlled-release membrane material in the reservoir layer, the release flux of donepezil hydrochloride was significantly improved. Furthermore, the safety of the patch was tested using skin irritation tests. The experimental results confirmed that using tromethamine or aminomethylpropanol as the organic base in the adhesive layer of the patch safely and efficiently ensures prolonged release and transdermal delivery of donepezil hydrochloride.

[0110] Furthermore, after the donepezil hydrochloride in the transdermal patch passes through the controlled-release membrane and enters the adhesive layer, it reacts in situ with tromethamine to form donepezil base and tromethamine hydrochloride. Tromethamine hydrochloride is commonly used as a buffer or acid-base regulator in the pharmaceutical and cosmetic fields. It has very low skin irritation because its pH is typically acidic (approximately 4.5-5.5), close to the weakly acidic environment of the skin. Furthermore, tromethamine hydrochloride is commonly used in injections, ophthalmic preparations, topical creams, etc., which also indicates its high safety.

[0111] The above embodiments are only used to illustrate the present invention. Any equivalent transformations and improvements based on the technical solution of the present invention should not be excluded from the protection scope of the present invention.

Claims

1. A transdermal patch, characterized in that The patch comprises a backing film, a reservoir layer, a controlled-release film, an adhesive layer and a release film which are laminated in sequence; The reservoir layer is a pressure-sensitive adhesive layer containing donepezil hydrochloride; The adhesive layer contains an organic base; the organic base is tromethamine or aminomethyl propanol; the organic base is a powder of 1 to 10 microns; The controlled release membrane layer is a polypropylene film selected from Celgard 2500 or Celgard 2400; The molar ratio of donepezil hydrochloride in the reservoir layer to the organic base in the adhesion layer is 1:

1.

2. A transdermal patch according to claim 1, characterized in that: The controlled-release membrane layer is used to adjust the migration rate of donepezil hydrochloride from the reservoir layer to the adhesion layer; During the permeation process, donepezil hydrochloride enters the adhesive layer through the controlled-release membrane layer and reacts in situ with the organic base in the adhesive layer to generate donepezil base.

3. A transdermal patch according to claim 1, characterized in that: The reservoir layer comprises an alcohol solubilizer, donepezil hydrochloride, a pressure-sensitive adhesive and a pressure-sensitive adhesive tackifier.

4. A transdermal patch according to claim 3, characterized in that: The alcohol solubilizer is glycerol or propylene glycol, the pressure-sensitive adhesive is acrylic acid / vinyl acetate pressure-sensitive adhesive, and the pressure-sensitive adhesive tackifier is polyvinyl pyrrolidone.

5. A transdermal patch according to claim 3, characterized in that: The mass percentage of the alcohol solubilizer in the reservoir layer is 10%wt~20%wt, the mass percentage of the pressure-sensitive adhesive tackifier in the reservoir layer is 5%wt~20%wt; the mass percentage of donepezil hydrochloride in the reservoir layer is 10%wt~25%wt; and the mass percentage of the pressure-sensitive adhesive in the reservoir layer is 30%wt~65%wt.

6. A transdermal patch according to claim 1, characterized in that: The adhesive layer comprises an organic base, an ester solubilizer, a pressure-sensitive adhesive matrix and a tackifier.

7. A transdermal patch according to claim 6, characterized in that: The ester solubilizer is one or more of sorbitan monolaurate, lauryl lactate, isopropyl myristate, and triethyl citrate; the pressure-sensitive adhesive matrix is ​​acrylic acid / vinyl acetate pressure-sensitive adhesive; and the tackifier is polyvinyl pyrrolidone.

8. A transdermal patch according to claim 6, characterized in that: The mass percentage of the ester solubilizer in the adhesive layer is 3%wt~10%wt; the mass percentage of the tackifier in the adhesive layer is 5%wt~20%wt; and the mass percentage of the pressure-sensitive adhesive matrix in the adhesive layer is 50%wt~70%wt.

9. A transdermal patch according to claim 1, characterized in that: The backing film is a PET backing film selected from Scotchpak TM 9733.

10. A transdermal patch according to claim 1, characterized in that, Donepezil in the patch can achieve steady-state release for more than 12 hours and transdermal penetration for more than 24 hours.

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