Transdermal patch containing donepezil and preparation method therefor

Abstract

The present application provides a transdermal patch containing donepezil. The transdermal patch comprises a backing layer, a drug-containing matrix layer, and a release layer, wherein the drug-containing matrix layer comprises donepezil or a pharmaceutically acceptable salt thereof, a pressure-sensitive adhesive, and a permeation enhancer group; and the permeation enhancer group comprises at least three of lauryl lactate, sorbitan laurate, triethyl citrate, propylene glycol, sorbitan monolaurate, and isopropyl myristate. The donepezil or the pharmaceutically acceptable salt thereof in the transdermal patch of the present application can maintain the blood concentration for a long time, can improve the permeation efficiency of the transdermal patch and the bioavailability, and can also improve the adhesion of the transdermal patch, thereby improving the use comfort of a patient.

Description

Transdermal patch containing donepezil and preparation method thereof

[0001] This application claims priority to the Chinese patent application filed on November 16, 2023, with application number 202311546388.0 and invention name “Transdermal patch containing donepezil and preparation method thereof”, the contents of which should be understood as incorporated into this application by reference. Technical Field

[0002] The present application belongs to, but is not limited to, the field of pharmaceutical preparations, and specifically relates to a transdermal patch containing donepezil and a preparation method thereof. Background Art

[0003] Alzheimer's disease (AD), commonly known as senile dementia, is a degenerative disease of the central nervous system characterized by progressive cognitive impairment and memory loss. Its clinical manifestations mainly include memory impairment, cognitive impairment, and mental and behavioral disorders. AD is a major public health issue of common concern to countries around the world. With the development of the global aging process, the incidence of AD continues to increase. Deaths caused by AD rank fifth among the major causes of death in my country. At the same time, family caregivers will also face increased emotional distress and negative physical and mental health risks. Therefore, suffering from AD will seriously affect human health and quality of life (Ren Rujing et al., on behalf of the China Alzheimer's Disease Report Writing Group. China Alzheimer's Disease Report 2021 [J]. Diagnostics Theory and Practice, 2021, 20(04): 317-337 doi: 10.16150 / j.1671-2870.2021.04.001).

[0004] Donepezil, a hexahydropyridine oxide, is a second-generation, specific, reversible inhibitor of central acetylcholinesterase. Studies have shown that donepezil improves memory, cognition, and behavior in AD patients by inhibiting acetylcholine activity and increasing brain acetylcholine levels. Currently, oral donepezil hydrochloride is the most commonly used medication in clinical practice. However, oral medications pose challenges for AD patients, including difficulty remembering to take the medication and swallowing difficulties. Furthermore, oral administration can cause gastrointestinal reactions such as nausea and vomiting, and most patients are reluctant to comply with medication, making oral administration more difficult.

[0005] The marketed donepezil transdermal patch is used to treat mild, moderate, and severe Alzheimer's disease. However, researchers have discovered that the penetration efficiency and adhesion of the marketed donepezil transdermal patch (CN201780059393.5) need to be further improved. In particular, the patch is difficult to remove from the skin after use, resulting in poor patient compliance. Summary of the Invention

[0006] The present application aims to solve at least one of the technical problems existing in the prior art to a certain extent. To this end, the present application provides a transdermal donepezil patch that can release the drug smoothly, has high penetration efficiency, and is easy to tear, and a preparation method thereof.

[0007] In a first aspect, the present application provides a transdermal patch. According to an embodiment of the present application, the transdermal patch comprises a backing layer, a drug-containing matrix layer, and a peeling layer; wherein the drug-containing matrix layer comprises donepezil or a pharmaceutically acceptable salt thereof, a pressure-sensitive adhesive, and a permeation enhancer group; and the permeation enhancer group comprises three of lauryl lactate, sorbitan laureate, triethyl citrate, propylene glycol, isopropyl myristate, and N-methylpyrrolidone.

[0008] In a second aspect of the present application, the present application provides a method for preparing the transdermal patch described in the first aspect.

[0009] In the third aspect of the present application, the present application provides a use of the transdermal patch described in the first aspect or the transdermal patch prepared according to the method described in the second aspect in preparing a drug for improving or treating Alzheimer's disease.

[0010] In a fourth aspect of the present application, the present application provides the transdermal patch described in the first aspect or the transdermal patch prepared according to the method described in the second aspect, for use in improving or treating Alzheimer's disease.

[0011] In the fifth aspect of the present application, the present application provides a method for improving or treating a disease, which comprises administering a therapeutically effective amount of the transdermal patch described in the first aspect or the transdermal patch prepared according to the method described in the second aspect to a patient in need thereof.

[0012] Summary of the Figures

[0013] The above and / or additional aspects and advantages of the present application will become apparent and easily understood from the description of the embodiments in conjunction with the following drawings, in which:

[0014] FIG1 is a graph showing the cumulative permeation per unit area of ​​preparations 1-6 in Example 1 of the present application;

[0015] FIG2 is a graph showing the cumulative permeation per unit area of ​​Reference Preparation 7 and Preparations 8-11 in Example 1 of the present application;

[0016] FIG3 is a graph showing the cumulative permeation per unit area of ​​the reference preparation, preparations 10, and 13-15 in Example 1 of the present application.

[0017] Details

[0018] In the first aspect of the present application, the present application provides a transdermal patch. According to an embodiment of the present application, the transdermal patch includes a backing layer, a drug-containing matrix layer, and a peeling layer; wherein the drug-containing matrix layer includes donepezil or a pharmaceutically acceptable salt thereof, a pressure-sensitive adhesive, and a penetration enhancer group; the penetration enhancer group includes three of lauryl lactate (also known as lauryl lactate), sorbitan laurate (also known as sorbitan laurate 20, Span 20, sorbitan monolaurate), triethyl citrate, propylene glycol, isopropyl myristate, and N-methylpyrrolidone. Donepezil or a pharmaceutically acceptable salt thereof in the transdermal patch of the present application can be released steadily, can maintain blood drug concentration for a long time, can improve the penetration efficiency of the transdermal patch, improve bioavailability, and can also improve the adhesion of the transdermal patch, improving patient comfort.

[0019] According to an embodiment of the present application, the donepezil or a pharmaceutically acceptable salt thereof is donepezil (free base) or donepezil hydrochloride.

[0020] According to an embodiment of the present application, based on the total mass of the drug-containing matrix layer, the mass percentage of donepezil or a pharmaceutically acceptable salt thereof is 15% to 30%, for example, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, or a range value between any two values ​​thereof as endpoints, such as 18% to 26%, 18% to 22%, 16% to 26%, 20% to 25%, 16% to 25%, or 16% to 20%.

[0021] According to an embodiment of the present application, the penetration enhancer group consists of lauryl lactate, triethyl citrate and propylene glycol.

[0022] According to an embodiment of the present application, the penetration enhancer group consists of lauryl lactate, triethyl citrate and sorbitan lauryl.

[0023] According to an embodiment of the present application, the penetration enhancer group consists of N-methylpyrrolidone, triethyl citrate and sorbitan lauryl phosphate.

[0024] According to an embodiment of the present application, the penetration enhancer group consists of propylene glycol, triethyl citrate and sorbitan lauryl phosphate.

[0025] According to an embodiment of the present application, the penetration enhancer group consists of isopropyl myristate, triethyl citrate and sorbitan lauryl phosphate.

[0026] According to an embodiment of the present application, based on the total mass of the drug-containing matrix layer, the mass percentage of the penetration enhancer group is 0.1% to 15%, for example, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or a range value between any two of them as endpoint values, such as 1% to 15%, 2% to 10%, 4% to 6%, 4% to 15%, 5% to 15%, 5% to 10%, 8% to 12%, 9% to 11%.

[0027] According to an embodiment of the present application, in the penetration enhancer group, the mass ratio of lauryl lactate, isopropyl myristate, at least one of N-methylpyrrolidone and propylene glycol, triethyl citrate, and sorbitan lauryl is 1: (3.2-3.5): (0.6-0.7).

[0028] According to an embodiment of the present application, in the penetration enhancer group, the mass ratio of isopropyl myristate, at least one of N-methylpyrrolidone and propylene glycol, triethyl citrate, and sorbitan laurate is 1:(3.2-3.5):(0.6-0.7).

[0029] According to an embodiment of the present application, in the penetration enhancer group, the mass ratio of lauryl lactate, triethyl citrate and propylene glycol is 1:(3.2-3.5):(0.6-0.7).

[0030] According to an embodiment of the present application, the pressure-sensitive adhesive is an acrylic pressure-sensitive adhesive without terminal groups. The acrylic pressure-sensitive adhesive without terminal groups refers to an acrylic ester polymer that does not contain side chains or terminal functional groups (such as -COOH or -OH).

[0031] According to an embodiment of the present application, the pressure-sensitive adhesive is a polyisobutylene-based pressure-sensitive adhesive without terminal groups. The polyisobutylene-based pressure-sensitive adhesive without terminal groups refers to an isobutylene polymer that does not contain side chains or terminal functional groups (such as -COOH or -OH).

[0032] According to an embodiment of the present application, the acrylic pressure-sensitive adhesive without terminal groups or the polyisobutylene pressure-sensitive adhesive without terminal groups is selected from (Henkel), and At least one of .

[0033] According to an embodiment of the present application, based on the total mass of the drug-containing matrix layer, the mass percentage of the acrylic pressure-sensitive adhesive without terminal groups or the polyisobutylene pressure-sensitive adhesive without terminal groups is 40% to 65%, for example, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, or a range value between any two values ​​​​as endpoint values, such as 40% to 55%, 40% to 50%, or 45% to 50%.

[0034] According to an embodiment of the present application, the drug-containing matrix layer further includes a stabilizer and / or a co-solvent.

[0035] According to an embodiment of the present application, the stabilizer is a polymethacrylate compound (e.g. polymer) or polyvinyl pyrrolidone (or povidone).

[0036] According to an embodiment of the present application, the stabilizer is selected from PVP k90 (Povidone k90), PVP k30 (Povidone k30), and At least one of .

[0037] According to an embodiment of the present application, based on the total mass of the drug-containing matrix layer, the mass percentage of the stabilizer is 5% to 20%, for example, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, or a range value between any two values ​​thereof as endpoints, such as 8% to 15%, 9% to 15%, 10% to 15%, 8% to 16%, 9% to 16%, 10% to 16%, 12% to 17%, 14% to 17%, 14% to 16%, 8% to 12%, 9% to 11%.

[0038] According to an embodiment of the present application, the co-solvent is a fatty acid compound.

[0039] According to an embodiment of the present application, the co-solvent is selected from at least one of levulinic acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, 3-methylbutyric acid, isostearic acid, palmitoleic acid, linolenic acid, 11-octadecenoic acid, petroselinic acid, elaidic acid, arachidonic acid, gadoleic acid, erucic acid and medium-chain fatty acids (e.g., a mixture of C6-C12 saturated fatty acids).

[0040] According to an embodiment of the present application, based on the total mass of the drug-containing matrix layer, the mass percentage of the co-solvent is 5% to 20%, for example, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, or a range value between any two values ​​thereof as endpoint values, such as 8% to 15%, 9% to 15%, 10% to 15%, 8% to 16%, 9% to 16%, 10% to 16%, 8% to 12%, 9% to 11%.

[0041] According to an embodiment of the present application, the thickness of the drug-containing matrix layer is 80-150 μm.

[0042] According to an embodiment of the present application, the drug-containing matrix layer includes: 15 to 30 parts by weight of donepezil or a pharmaceutically acceptable salt thereof, 40 to 65 parts by weight of an acrylic pressure-sensitive adhesive without terminal groups, 5 to 15 parts by weight of a penetration enhancer group, 5 to 20 parts by weight of a stabilizer, and 5 to 20 parts by weight of a solubility enhancer.

[0043] According to an embodiment of the present application, the drug-containing matrix layer includes: 15 to 30 parts by weight of donepezil or a pharmaceutically acceptable salt thereof, 40 to 65 parts by weight of a polyisobutylene-based pressure-sensitive adhesive without terminal groups, 5 to 15 parts by weight of a penetration enhancer group, 5 to 20 parts by weight of a stabilizer, and 5 to 20 parts by weight of a solubility enhancer.

[0044] According to an embodiment of the present application, the drug-containing matrix layer includes: 15 to 22 parts by weight of donepezil or a pharmaceutically acceptable salt thereof, 45 to 50 parts by weight of an acrylic pressure-sensitive adhesive without terminal groups, 8 to 12 parts by weight of a penetration enhancer group, 12 to 17 parts by weight of a stabilizer, and 8 to 12 parts by weight of a solubilizing agent.

[0045] According to an embodiment of the present application, the drug-containing matrix layer includes: 15 to 22 parts by weight of donepezil or a pharmaceutically acceptable salt thereof, 45 to 50 parts by weight of a polyisobutylene-based pressure-sensitive adhesive without terminal groups, 8 to 12 parts by weight of a penetration enhancer group, 12 to 17 parts by weight of a stabilizer, and 8 to 12 parts by weight of a solubility enhancer.

[0046] According to an embodiment of the present application, the drug-containing matrix layer comprises: 20 parts by weight of donepezil, 45 to 50 parts by weight of 2 parts by weight of lauryl lactate, 6.5-7 parts by weight of triethyl citrate, 1.2-1.4 parts by weight of sorbitan laureate, 12-15 parts by weight of PVP K90, and 10 parts by weight of levulinic acid.

[0047] According to an embodiment of the present application, the drug-containing matrix layer comprises: 20 parts by weight of donepezil, 45 parts by weight of 2 parts by weight of lauryl lactate, 6.7 parts by weight of triethyl citrate, 1.3 parts by weight of sorbitan lauryl, 15 parts by weight of PVP K90, and 10 parts by weight of levulinic acid.

[0048] According to an embodiment of the present application, the drug-containing matrix layer comprises: 16 parts by weight of donepezil hydrochloride, 45 to 50 parts by weight of 2.1 parts by weight of lauryl lactate, 7-7.5 parts by weight of triethyl citrate, 1.2-1.4 parts by weight of sorbitan laureate, 15-17 parts by weight of PVP K90, and 10-11 parts by weight of levulinic acid.

[0049] According to an embodiment of the present application, the drug-containing matrix layer comprises: 16 parts by weight of donepezil hydrochloride, 47.25 parts by weight of 2.1 parts by weight of lauryl lactate, 7-7.1 parts by weight of triethyl citrate, 1.3-1.4 parts by weight of sorbitan laureate, 15-16 parts by weight of PVP K90, and 10-11 parts by weight of levulinic acid.

[0050] According to an embodiment of the present application, the drug-containing matrix layer comprises: 20 parts by weight of donepezil, 45 to 50 parts by weight of 2 parts by weight of lauryl lactate, 6.5-7 parts by weight of triethyl citrate, 1.2-1.4 parts by weight of propylene glycol, 12-15 parts by weight of PVP K90, and 10 parts by weight of levulinic acid.

[0051] According to an embodiment of the present application, the drug-containing matrix layer comprises: 20 parts by weight of donepezil, 45 parts by weight of 2 parts by weight of lauryl lactate, 6.7 parts by weight of triethyl citrate, 1.3 parts by weight of propylene glycol, 15 parts by weight of PVP K90, and 10 parts by weight of levulinic acid.

[0052] According to an embodiment of the present application, the drug-containing matrix layer comprises: 15 to 22 parts by weight of donepezil or a pharmaceutically acceptable salt thereof, 45 to 50 parts by weight of 1.5-2.5 parts by weight of isopropyl myristate, N-methylpyrrolidone or propylene glycol, 6-7.5 parts by weight of triethyl citrate, 0.5-2 parts by weight of sorbitan laurate, 12-17 parts by weight of PVP K90, and 8-12 parts by weight of levulinic acid.

[0053] According to an embodiment of the present application, the drug-containing matrix layer comprises: 20 parts by weight of donepezil, 45 to 50 parts by weight of 2 parts by weight of isopropyl myristate, 6.5-7 parts by weight of triethyl citrate, 1.2-1.4 parts by weight of sorbitan laurate, 12-15 parts by weight of PVP K90, and 10 parts by weight of levulinic acid.

[0054] According to an embodiment of the present application, the drug-containing matrix layer comprises: 20 parts by weight of donepezil, 45 parts by weight of 2 parts by weight of isopropyl myristate, 6.7 parts by weight of triethyl citrate, 1.3 parts by weight of sorbitan laurate, 15 parts by weight of PVP K90, and 10 parts by weight of levulinic acid.

[0055] According to an embodiment of the present application, the drug-containing matrix layer comprises: 20 parts by weight of donepezil, 45 to 50 parts by weight of 2 parts by weight of N-methylpyrrolidone, 6.5-7 parts by weight of triethyl citrate, 1.2-1.4 parts by weight of sorbitan laurate, 12-15 parts by weight of PVP K90, and 10 parts by weight of levulinic acid.

[0056] According to an embodiment of the present application, the drug-containing matrix layer comprises: 20 parts by weight of donepezil, 45 parts by weight of 2 parts by weight of N-methylpyrrolidone, 6.7 parts by weight of triethyl citrate, 1.3 parts by weight of sorbitan laurate, 15 parts by weight of PVP K90, and 10 parts by weight of levulinic acid.

[0057] According to an embodiment of the present application, the drug-containing matrix layer comprises: 20 parts by weight of donepezil, 45 to 50 parts by weight of 2 parts by weight of propylene glycol, 6.5-7 parts by weight of triethyl citrate, 1.2-1.4 parts by weight of sorbitan laurate, 12-15 parts by weight of PVP K90, and 10 parts by weight of levulinic acid.

[0058] According to an embodiment of the present application, the drug-containing matrix layer comprises: 20 parts by weight of donepezil, 45 parts by weight of 2 parts by weight of propylene glycol, 6.7 parts by weight of triethyl citrate, 1.3 parts by weight of sorbitan laurate, 15 parts by weight of PVP K90, and 10 parts by weight of levulinic acid.

[0059] According to an embodiment of the present application, the backing material is aluminum-polyester film, polyester-polyethylene composite film, polyethylene-aluminum-polyester / ethylene-vinyl acetate composite film, multilayer polyester film or polyester-ethylene-vinyl acetate composite film; in another embodiment, the backing layer is Scotchpak TM 9723.

[0060] According to an embodiment of the present application, the material of the peeling layer is siliconized polyester film, fluoropolymer-coated polyester film, aluminum foil-silicone grease composite, siliconized aluminum foil or silicon paper; in another embodiment, the peeling layer is PET 4400B.

[0061] In a second aspect, the present application provides a method for preparing the transdermal patch described in the first aspect. According to an embodiment of the present application, the method comprises: mixing donepezil or a pharmaceutically acceptable salt thereof, a permeation enhancer group, and a pressure-sensitive adhesive; coating the mixed product on a release layer to obtain a drug-containing matrix layer, wherein the release layer and the drug-containing matrix layer are in contact; and covering the drug-containing matrix layer with a backing layer to obtain the transdermal patch. The preparation method of the present application is simple, and the resulting transdermal patch exhibits advantages such as transdermal release and good permeation.

[0062] According to an embodiment of the present application, the method further comprises: mixing a cosolvent and / or a stabilizer with donepezil or a pharmaceutically acceptable salt thereof, a penetration enhancer group, and a pressure-sensitive adhesive.

[0063] According to an embodiment of the present application, before the mixing process, the donepezil or a pharmaceutically acceptable salt thereof is dissolved in advance using an organic solvent.

[0064] According to an embodiment of the present application, the organic solvent is selected from at least one of ethyl acetate and ethanol.

[0065] In an optional embodiment of the present application, the organic solvent is anhydrous ethanol.

[0066] In an optional embodiment of the present application, the organic solvent is ethyl acetate.

[0067] According to an embodiment of the present application, the stabilizer exists in the form of a solution.

[0068] According to an embodiment of the present application, the method further comprises: pre-mixing the cosolvent, stabilizer, penetration enhancer group and pressure-sensitive adhesive, and then mixing the pre-mixed product and the dissolved product.

[0069] According to an embodiment of the present application, after the mixing process, the mixed product is dried.

[0070] According to an embodiment of the present application, the drying process is performed (or continued) at 65° C. to 75° C. for 10 to 30 minutes.

[0071] According to an embodiment of the present application, after the backing layer is covered on the drug-containing matrix layer, punching and packaging are sequentially performed to obtain the transdermal patch.

[0072] According to an embodiment of the present application, the present application provides a transdermal patch prepared according to the method described in the second aspect.

[0073] In the third aspect of the present application, the present application provides a use of the transdermal patch described in the first aspect or the transdermal patch prepared according to the method described in the second aspect in preparing a drug for improving or treating Alzheimer's disease.

[0074] In a fourth aspect of the present application, the present application provides the transdermal patch described in the first aspect or the transdermal patch prepared according to the method described in the second aspect, for use in improving or treating Alzheimer's disease.

[0075] In the fifth aspect of the present application, the present application provides a method for improving or treating a disease, which comprises administering a therapeutically effective amount of the transdermal patch described in the first aspect or the transdermal patch prepared according to the method described in the second aspect to a patient in need thereof.

[0076] In the third to fifth aspects of the present application, the transdermal patch is applied to the skin of an individual or patient.

[0077] In the third to fifth aspects of the present application, the transdermal patch is applied to the skin of an individual or patient once a week.

[0078] In the third to fifth aspects of the present application, the transdermal patch administration dose is 1-25 mg / 24 hours, preferably, 5-10 mg / 24 hours.

[0079] Additional aspects and advantages of the present application will be given in part in the following description and in part will be obvious from the following description or learned through practice of the present application.

[0080] Definitions and General Terms

[0081] The endpoints of the ranges and any values ​​disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0082] In this document, the terms "include" or "comprising" are open expressions, that is, including the contents specified in this application, but not excluding other contents.

[0083] As used herein, the terms "optionally," "optional," or "optionally" generally mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0084] As used herein, the term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammal to be treated therewith. Preferably, "pharmaceutically acceptable" as used herein means approved by federal regulatory agencies or national governments or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeias for use in animals, particularly humans.

[0085] As used herein, the term "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.

[0086] As used herein, the term "%" refers to weight percent, which is interpreted as the content of a substance or the proportion of a substance in a mixture. For example, in this application, the weight percentage of donepezil or a pharmaceutically acceptable salt thereof refers to the proportion of donepezil or a pharmaceutically acceptable salt thereof in the drug-containing matrix layer. DETAILED DESCRIPTION

[0087] The following embodiments of the present invention are described in detail. The following embodiments are exemplary and are only used to explain the present invention, and should not be understood as limiting the present invention.

[0088] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be understood to indicate or imply relative importance or implicitly specify the number of the technical features indicated. Therefore, features defined as "first" or "second" may explicitly or implicitly include one or more of such features. Furthermore, in the description of this application, unless otherwise specified, "plurality" means two or more.

[0089] Below in conjunction with embodiment, the scheme of the present application will be explained.It will be appreciated by those skilled in the art that the following examples are merely for illustration of the present invention and should not be considered as limiting the scope of the present invention.In the embodiment, if no specific technology or conditions are indicated, the technology or conditions described in the literature in this area or the product instructions are used. Reagents used or instruments that do not indicate the manufacturer are conventional products that can be obtained commercially.

[0090] The raw materials and equipment used in the specific embodiments of this application are all known commercially available products.

[0091] Instruments: HS-3 vertical mixer, C&D360 coater / electric blast drying oven, PL-3002-IC electronic balance, KQ-500VDE ultrasonic cleaning machine, MDC-25SX digital micrometer, XMTD-204 constant temperature magnetic stirrer, Franz transdermal diffusion instrument TK-24BL, GHP-9160 constant temperature incubator, WD-A drug stability tester.

[0092] In this application, acrylic pressure-sensitive adhesive The solid content of 87-4098 is 42.4%. In this article, the content of the pressure-sensitive adhesive is the solid content of the pressure-sensitive adhesive (ie, the solid content of the pressure-sensitive adhesive = the amount of raw materials added to the pressure-sensitive adhesive × the solid content of the pressure-sensitive adhesive).

[0093] Example 1: Screening of penetration enhancer types and contents

[0094] Human skin is a major barrier to transdermal drug absorption. To ensure that the patch achieves and maintains the expected drug release rate during its lifetime, screening for suitable transdermal penetration enhancers is key to developing transdermal drug delivery systems. Ideal transdermal penetration enhancers should reversibly alter the barrier kinetics of the skin's stratum corneum without damaging any active cells. This example screened commonly used penetration-enhancing excipients for transdermal dosage forms and conducted in vitro transdermal diffusion experiments using a Franz transdermal diffusion instrument, TK-24BL, and excised Bama miniature pig skin as the skin barrier.

[0095] 1. Prepare different preparations containing a single penetration enhancer according to Table 1. The preparation method comprises the following steps:

[0096] (1) Preparation of 25% PVP K90 solution: Weigh 25 g of PVP K90 and slowly add it into 75 g of anhydrous ethanol that is being stirred. Stir with a magnetic stirrer until the solution becomes clear and transparent to obtain a 25% PVP K90 solution. Stir for 1 hour and seal with plastic wrap for later use.

[0097] (2) Preparation of the mixed solution: According to the ratio in Table 1, the prescribed amount of donepezil and an appropriate amount of ethyl acetate were mixed in order, shaken until the donepezil was completely dissolved, and then the prescribed amount of levulinic acid, 25% PVP K90 solution, 87-4098, and one of lauryl lactate, triethyl citrate, sorbitan lauryl, propylene glycol, isopropyl myristate, and N-methylpyrrolidone.

[0098] (3) Mixing: Place the mixed solution in step (2) on a vertical mixer and stir evenly at a mixing speed of 20 rpm for 6 h to obtain a drug-containing matrix layer mixed solution.

[0099] (4) Coating: The drug-containing matrix layer mixture is coated on the release film 4400B with a coating thickness of 370 μm.

[0100] (5) Drying: The material in step (4) was placed in an oven at 70°C and dried for 20 min.

[0101] (6) Composite: Composite the backing film 9723 onto the drug-containing dry base layer.

[0102] (7) Punching: Punch the drug-containing layer into 10cm 2 The round patches were packaged to obtain finished patches of preparations 1 to 6, respectively.

[0103] Table 1: Donepezil transdermal compositions of Formulations 1-6

[0104] Table 2: Average cumulative permeation per unit area for formulations 1-6

[0105] The finished patches of preparations 1 to 6 prepared above were used to conduct transdermal diffusion tests. Using pH 7.4 phosphate buffer as the receptor for transdermal diffusion, the selected patches were applied to experimental pig skin and placed in the interlayer of the diffusion instrument. The release was sustained at a temperature of 32°C and a rotation speed of 180 rpm, and 1.5 mL of the receptor solution was collected at 4 h, 8 h, 12 h, 24 h, 36 h, 48 h, 60 h, and 72 h to detect the content of the main drug. Based on the transdermal diffusion data, transdermal diffusion curves of different types of penetration enhancers were drawn. The results are shown in Table 2 and Figure 1. After 72 hours of sustained release, the cumulative permeation per unit area of ​​the finished patches of preparations 1 to 6 was less than 900 μg / cm 2 , the cumulative permeation per unit area is low and cannot reach the effective dose of the drug, indicating that the use of a single type of permeation enhancer has a poor permeation effect, and the permeation effects of different types of permeation enhancers vary greatly.

[0106] 2. This example uses a variety of penetration enhancers to prepare different preparations.

[0107] 2.1. Prescription and preparation process of reference preparation 7

[0108] prescription:

[0109] The preparation steps of reference preparation 7 refer to the preparation method of Example 2 of CN109789133A.

[0110] 2.2 Different preparations 8 to 11 containing multiple penetration enhancers were prepared according to Table 3. The preparation method thereof is similar to step 1 of this embodiment, with the only difference being that multiple penetration enhancers were added simultaneously.

[0111] Table 3: Donepezil transdermal compositions of Formulations 8-11

[0112] Table 4: Summary of Cumulative Transmission Permeation per Unit Area for Reference Preparation 7 and Preparations 8-11

[0113] 2.3 Transdermal diffusion tests were conducted using the finished patches prepared using the reference preparations 7 and preparations 8-11 prepared above. Using pH 7.4 phosphate buffer as the receptor for transdermal diffusion, the selected patches were applied to experimental pig skin and placed in the interlayer of the diffusion instrument. The release was sustained at a temperature of 32°C and a rotation speed of 180 rpm. 1.5 mL of receptor solution was collected at 4 h, 8 h, 12 h, 24 h, 36 h, 48 h, 60 h, 72 h, 96 h, 120 h, 144 h, and 168 h to detect the active ingredient content. Transdermal diffusion curves for different types of penetration enhancers were drawn based on the transdermal diffusion data, and the results are shown in Figure 2.

[0114] As shown in Figure 2, the transdermal permeation efficiency of the preparation containing three specific permeation enhancers is significantly better than that of the preparation containing two specific permeation enhancers.

[0115] 2.4 Adhesion test

[0116] The adhesion test mainly measures the adhesion of transdermal patches based on three indicators: holding force, peel strength and in vivo adhesion performance.

[0117] Adhesion reflects the patch's ability to resist deformation or breakage caused by persistent external forces. Peel strength indicates the patch's resistance to peeling from the skin, while in vivo adhesion performance indicates the patch's effect on the skin after attachment.

[0118] 2.4.1 Determination of holding force:

[0119] 1) The prepared donepezil transdermal patches of Reference Preparation 7, Preparation 10, and Preparation 11, together with their packaging materials, were placed at 18-25° C. and a relative humidity of 40%-70% for more than 2 hours.

[0120] 2) Clean the test plate and loading plate with a wiper dampened with anhydrous ethanol, then carefully dry them with a clean, dust-free cloth. Repeat this process three times until the surfaces of the test plate and loading plate are visually clean. Do not touch the cleaned test plate and loading plate with your hands or other objects.

[0121] 3) Take three transdermal patch test pieces prepared from Reference Preparation 7, Preparation 10, and Preparation 11, respectively, and adhere the test pieces to the center of the adjacent test plate and loading plate, parallel to the longitudinal direction of the plates. Roll the test pieces back and forth three times with a 2000g roller.

[0122] 4) After the test sample is attached to the board, it is placed at room temperature for 20 minutes. It is then fixed to the test stand and the time it takes for the sample to fall off is recorded. The experimental results are shown in Table 5.

[0123] Table 5: Test results of the persistence of donepezil transdermal compositions

[0124] As shown in Table 5, the sustained adhesion time of Reference Preparation 7 on the skin is significantly lower than that of Preparations 10 and 11. The insufficient adhesive force may cause the transdermal patch to fall off during use and fail to fully exert its true effect.

[0125] 2.4.2 Determination of peel strength:

[0126] 1) The prepared donepezil transdermal patches of Reference Preparation 7, Preparation 10, and Preparation 11, together with their packaging materials, were placed at 18-25° C. and a relative humidity of 40%-70% for more than 2 hours.

[0127] 2) Prepare several 20 cm x 22 mm release film strips and distinguish the front and back sides.

[0128] 3) Wipe the test board with a wiper dipped in anhydrous ethanol, then carefully dry it with a clean, dust-free cloth. Repeat this process three times until the surface of the test board is visually clean. Do not touch the cleaned test board with your hands or other objects.

[0129] 4) Take three transdermal patch test pieces prepared from Reference Preparation 7, Preparation 10, and Preparation 11, respectively, and adhere each test piece to the center of the test plate parallel to the long side of the plate, leaving a 5 mm gap on the right side of the patch for adhering to the reverse side of the release film strip in Step 2. Use a 2000 g roller to roll back and forth over the test piece three times to ensure that there are no bubbles in the adhesive joint.

[0130] 5) After the test sample is pasted on the board, let it stand at room temperature for 20-40 minutes. Fold the free end of the release film in half (180°), and clamp the free end of the release film and the test board on the testing machine respectively, so that the peeling surface is consistent with the testing machine line.

[0131] 6) Select the "peel" button of the testing machine. When the green light is on, start the "test" button and peel continuously at a speed of 300mm / min±10mm / min. The automatic recorder will draw the peeling curve and print the peeling strength data.

[0132] The experimental results are shown in Table 6.

[0133] Table 6: Donepezil transdermal composition peel strength test results

[0134] As shown in Table 6, the 180 peel strength (N / m) of Reference Preparation 7 on the skin is significantly greater than that of Preparations 10 and 11. The greater the peel strength, the more obvious pain the patient will experience during the use of the transdermal patch, resulting in poor patient compliance.

[0135] 2.4.3 In vivo adhesion performance test

[0136] The donepezil transdermal patch samples (n=6) of the reference preparations 7, 10, and 11 prepared above were used for in vivo adhesion performance testing to observe the dissolution of donepezil in each group. The three groups of samples were affixed to the smooth back skin of the hands of five volunteers and peeled off after 30 minutes to observe whether any colloid remained on the skin and whether any pain was caused, thereby investigating the adhesion performance of the transdermal patch of the present application.

[0137] Adhesion performance scoring indicators:

[0138] 1: The adhesion performance in the body is relatively weak.

[0139] 2: Slightly sticky, with colloid remaining on the edge, and poor adhesion.

[0140] 3: Good adhesive performance, no pain.

[0141] 4: Pain during removal, including abrasion of keratinized skin.

[0142] Table 7: In vivo adhesive performance test results of donepezil transdermal composition

[0143] As shown in Table 7, in the in vivo adhesion performance test, Reference Preparation 7 was difficult to peel off from the skin, was painful when peeled off, and caused damage to the stratum corneum of the skin, resulting in poor patient compliance.

[0144] Adhesion test results show that Reference Formulation 7 was difficult to peel and caused significant pain during use. Formulations 10 and 11 not only showed improved adhesion, peel strength, and in vivo adhesion performance compared to the Reference Formulation, but also exhibited better transdermal efficacy than Reference Formulation 7. Therefore, Formulations 10 and 11 significantly improved the adhesive loading capacity, adhesive tolerance, and skin compatibility of donepezil transdermal pharmaceutical compositions, while also enhancing transdermal penetration efficiency.

[0145] 3. Furthermore, this embodiment uses a variety of penetration enhancers to prepare different preparations.

[0146] 3.1 In this example, different formulations 10, 13-15 containing multiple penetration enhancers were prepared according to Table 8. The preparation method thereof is similar to step 1 of this example, with the only difference being that multiple penetration enhancers were added simultaneously.

[0147] Table 8: Donepezil transdermal compositions of formulations 10, 13-15

[0148] Table 9: Cumulative permeation per unit area of ​​homemade products with different permeation enhancer dosages

[0149] Transdermal diffusion tests were conducted using the finished patches of Preparations 10, 13-15 prepared above, following the method of Step 2 in Example 1. The results are shown in Table 9 and Figure 3. The results showed that replacing triethyl citrate or lauryl lactate in Preparation 10 reduced the transdermal efficacy of the preparation.

[0150] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present application. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0151] Although the embodiments of the present application have been shown and described above, it will be understood that the above embodiments are exemplary and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A transdermal patch, characterized in that: It includes a backing layer, a drug-containing matrix layer and a peeling layer; Wherein, the drug-containing matrix layer comprises donepezil or a pharmaceutically acceptable salt thereof, a pressure-sensitive adhesive, and a penetration enhancer group; The penetration enhancer group includes three of lauryl lactate, sorbitan lauryl, triethyl citrate, propylene glycol, isopropyl myristate or N-methylpyrrolidone.

2. The transdermal patch according to claim 1, characterized in that Based on the total mass of the drug-containing matrix layer, the mass percentage of donepezil or a pharmaceutically acceptable salt thereof is 15% to 30%, preferably 16% to 26%, 18% to 26%.

3. The transdermal patch according to claim 1, characterized in that The penetration enhancer group consists of lauryl lactate, triethyl citrate and propylene glycol; Optionally, the penetration enhancer group consists of lauryl lactate, triethyl citrate and sorbitan lauryl; Optionally, the penetration enhancer group consists of isopropyl myristate, triethyl citrate and sorbitan laurate; Optionally, the penetration enhancer group consists of N-methylpyrrolidone, triethyl citrate and sorbitan laurate; Optionally, the penetration enhancer group consists of propylene glycol, triethyl citrate and sorbitan laurate; Optionally, based on the total mass of the drug-containing matrix layer, the mass percentage of the penetration enhancer group is 0.1% to 15%, preferably 5% to 15%, 8% to 12%; Optionally, in the penetration enhancer group, the mass ratio of lauryl lactate, isopropyl myristate, at least one of N-methylpyrrolidone and propylene glycol, triethyl citrate, and sorbitan lauryl is 1:(3.2-3.5):(0.6-0.7).

4. The transdermal patch according to claim 1, characterized in that The pressure-sensitive adhesive is an acrylic pressure-sensitive adhesive without terminal groups or a polyisobutylene pressure-sensitive adhesive without terminal groups; Optionally, the acrylic pressure-sensitive adhesive without terminal groups or the polyisobutylene pressure-sensitive adhesive without terminal groups is selected from at least one of Duro-Tak 87-4098, Duro-Tak 87-900A, Duro-Tak 87-9301 and Duro-Tak 87-6908; Optionally, based on the total mass of the drug-containing matrix layer, the mass percentage of the acrylic pressure-sensitive adhesive without terminal groups or the polyisobutylene pressure-sensitive adhesive without terminal groups is 40% to 65%, preferably 45% to 50%.

5. The transdermal patch according to claim 1, characterized in that The drug-containing matrix layer further includes a stabilizer and / or a cosolvent; Optionally, the stabilizer is a polymethacrylate compound or polyvinyl pyrrolidone; Optionally, the stabilizer is selected from at least one of PVP k90, PVP k30, Eudragit Plastoid B, Eudragit EPO, Eudragit L100, Eudragit L100-55, Eudragit S100, Eudragit RL100, Eudragit RLPO, Eudragit RS100 and Eudragit RSPO; Optionally, the mass percentage of the stabilizer is 5% to 20%, preferably 10% to 15%, based on the total mass of the drug-containing matrix layer; Optionally, the cosolvent is a fatty acid compound; Optionally, the cosolvent is selected from at least one of levulinic acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, 3-methylbutyric acid, isostearic acid, palmitoleic acid, linolenic acid, 11-octadecenoic acid, petroselinic acid, elaidic acid, arachidonic acid, gadoleic acid, erucic acid and medium-chain fatty acids; Optionally, based on the total mass of the drug-containing matrix layer, the mass percentage of the co-solvent is 5% to 20%, preferably 8% to 12%.

6. The transdermal patch according to any one of claims 1 to 5, characterized in that The thickness of the drug-containing matrix layer is 80-150 μm; Optionally, the drug-containing matrix layer comprises: 15 to 30 parts by weight of donepezil or a pharmaceutically acceptable salt thereof, 40 to 65 parts by weight of an acrylic pressure-sensitive adhesive having no terminal group or a polyisobutylene pressure-sensitive adhesive having no terminal group, 5 to 15 parts by weight of a penetration enhancer group, 5 to 20 parts by weight of a stabilizer, and 5 to 20 parts by weight of a co-solvent; Optionally, the drug-containing matrix layer comprises: 15 to 22 parts by weight of donepezil or a pharmaceutically acceptable salt thereof, 45 to 50 parts by weight of an acrylic pressure-sensitive adhesive having no terminal group or a polyisobutylene pressure-sensitive adhesive having no terminal group, 8 to 12 parts by weight of a penetration enhancer group, 12 to 17 parts by weight of a stabilizer, and 8 to 12 parts by weight of a co-solvent; Optionally, the drug-containing matrix layer comprises: 15 to 22 parts by weight of donepezil, 45-50 parts by weight 1.5 to 2.5 parts by weight of isopropyl myristate, N-methylpyrrolidone or propylene glycol, 6 to 7.5 parts by weight of triethyl citrate, 0.5 to 2 parts by weight of sorbitan laurel, 12 to 17 parts by weight of PVP K90, and 8 to 12 parts by weight of levulinic acid.

7. The transdermal patch according to any one of claims 1 to 5, characterized in that The drug-containing matrix layer comprises: Optionally, the drug-containing matrix layer comprises: The drug-containing matrix layer comprises: 20 parts by weight of donepezil, 45-50 parts by weight 2 parts by weight of lauryl lactate, 6.5 to 7 parts by weight of triethyl citrate, 1.2 to 1.4 parts by weight of sorbitan laurel, 12 to 15 parts by weight of PVP K90, and 10 parts by weight of levulinic acid; Optionally, the drug-containing matrix layer comprises: 20 parts by weight of donepezil, 45-50 parts by weight 2 parts by weight of lauryl lactate, 6.5 to 7 parts by weight of triethyl citrate, 1.2 to 1.4 parts by weight of propylene glycol, 12 to 15 parts by weight of PVP K90, and 10 parts by weight of levulinic acid; Optionally, the drug-containing matrix layer comprises: 20 parts by weight of donepezil, 45-50 parts by weight 2 parts by weight of isopropyl myristate, 6.5 to 7 parts by weight of triethyl citrate, 1.2 to 1.4 parts by weight of sorbitan laurel, 12 to 15 parts by weight of PVP K90, and 10 parts by weight of levulinic acid; Optionally, the drug-containing matrix layer comprises: 20 parts by weight of donepezil, 45-50 parts by weight 2 parts by weight of N-methylpyrrolidone, 6.5 to 7 parts by weight of triethyl citrate, 1.2 to 1.4 parts by weight of sorbitan laurel, 12 to 15 parts by weight of PVP K90, and 10 parts by weight of levulinic acid; Optionally, the drug-containing matrix layer comprises: 20 parts by weight of donepezil, 45-50 parts by weight 2 parts by weight of propylene glycol, 6.5 to 7 parts by weight of triethyl citrate, 1.2 to 1.4 parts by weight of sorbitan laurel, 12 to 15 parts by weight of PVP K90, and 10 parts by weight of levulinic acid; Optionally, the drug-containing matrix layer comprises: 16 parts by weight of donepezil hydrochloride, 45-50 parts by weight 2.1 parts by weight of lauryl lactate, 7 to 7.5 parts by weight of triethyl citrate, 1.2 to 1.4 parts by weight of sorbitan laurel, 15-17 parts by weight of PVP K90, and 10 to 11 parts by weight of levulinic acid.

8. A method for preparing the transdermal patch according to any one of claims 1 to 7, comprising: Mixing donepezil or a pharmaceutically acceptable salt thereof, a penetration enhancer group and a pressure-sensitive adhesive; coating the mixed product on the peeling layer to obtain a drug-containing matrix layer, wherein the peeling layer is in contact with the drug-containing matrix layer; The backing layer is covered on the drug-containing matrix layer to obtain the transdermal patch.

9. The method according to claim 8, further comprising: Mixing a cosolvent and / or a stabilizer with donepezil or a pharmaceutically acceptable salt thereof, a penetration enhancer group and a pressure-sensitive adhesive; Optionally, before the mixing process, the donepezil or a pharmaceutically acceptable salt thereof is dissolved in advance using an organic solvent; Optionally, the organic solvent is selected from at least one of ethyl acetate and ethanol; Optionally, the stabilizer is in the form of a solution; Optionally, further comprising: Pre-mixing the cosolvent, stabilizer, penetration enhancer group and pressure-sensitive adhesive, and then mixing the pre-mixed product and the dissolved product; Optionally, after the mixing process, the mixed product is dried; Optionally, the drying process is carried out at 65°C to 75°C for 10 to 30 minutes; Optionally, after the backing layer is covered on the drug-containing matrix layer, punching treatment and packaging treatment are performed in sequence to obtain the transdermal patch.

10. Use of the transdermal patch according to any one of claims 1 to 7 or the transdermal patch prepared according to the method according to any one of claims 8 to 9 in preparing a medicament for improving or treating Alzheimer's disease.

11. The transdermal patch according to any one of claims 1 to 7 or the transdermal patch prepared by the method according to any one of claims 8 to 9, for use in improving or treating Alzheimer's disease.

12. A method for improving or treating a disease, comprising administering a therapeutically effective amount of the transdermal patch according to any one of claims 1 to 7 or the transdermal patch prepared according to the method of any one of claims 8 to 9 to a patient in need thereof.

13. The use according to claim 10, the transdermal patch for use according to claim 11, or the method according to claim 12, wherein The transdermal patch is applied to the skin of an individual or patient, optionally once a week.

14. The use according to claim 10, the transdermal patch for use according to claim 11, or the method according to claim 12, wherein The transdermal patch administration dosage is 1-25 mg / 24 hours, preferably, 5-10 mg / 24 hours.

Images