Transdermal patch containing lidocaine as well as preparation method and application of transdermal patch

Abstract

The invention discloses a transdermal patch containing lidocaine, the transdermal patch comprises a polymer matrix layer, the polymer matrix layer comprises active ingredients lidocaine, an acrylic acid pressure-sensitive adhesive and a penetration enhancer, the weight content of the lidocaine is 21-33%, the weight content of the acrylic acid pressure-sensitive adhesive is 45-75%, the weight content of the penetration enhancer is 1-10%, and the weight content of the penetration enhancer is 1-10%. The weight content of the penetration enhancer is 3%-25%. The transdermal patch disclosed by the invention is simple in prescription and process, good in drug permeability and colloid application performance and high in stability, can be continuously used for a long time without causing skin irritation, and is suitable for treating peripheral nerve related pains, especially patients requiring long-term administration such as post-herpes zoster neuralgia.

Description

[0001] This application is a divisional application of Chinese invention patent application filed on December 28, 2023, with application number 202311839093.2 and invention title "Transdermal patch containing lidocaine and its preparation method and use". Technical Field

[0002] This invention belongs to the field of transdermal drug delivery technology, specifically relating to a lidocaine-containing transdermal patch, its preparation method, and its uses. Background Technology

[0003] Transdermal drug delivery systems (transdermal patches) deliver active ingredients into the body through the skin or mucous membranes to achieve local or systemic effects, which is a very common method of drug administration. Since the first scopolamine patch (Transdermal Scop) was introduced in 1979... ® Since its market launch, numerous attempts have been made to develop more transdermal drug delivery systems with therapeutic effects, and several patch products have been successfully commercialized. Based on the combination of active ingredients and other excipients, patches can be broadly classified into reservoir-type and drug-in-adhesive patches. Drug-in-adhesive patches involve uniformly dissolving or dispersing the active ingredient in a semi-solid composition consisting of one or more polymeric materials and other pharmaceutically acceptable excipients, forming a homogeneous drug-containing polymer matrix. If the polymeric material itself is a pressure-sensitive adhesive, then the polymer matrix acts as both a drug carrier and an adhesive to the skin at the application site.

[0004] Lidocaine is an amide-based local anesthetic that stabilizes nerve cell membranes and blocks nerve excitation and conduction by inhibiting sodium ion channels in nerve cell membranes. It is widely used clinically to treat various acute and chronic pain conditions, especially neuropathic pain. Common dosage forms include injections, ointments, sprays, and patches. Lidocaine gel patches can be used to treat localized pain with neurogenic and inflammatory characteristics, such as post-traumatic, post-operative, or musculoskeletal pain, and have become a first-line treatment for postherpetic neuralgia (PHN).

[0005] 5% lidocaine gel patch (brand name Lidoderm) ® Launched in the US in 1999, this product is indicated for PHN (problematic pharyngitis). Each patch measures 14.0cm x 10.0cm and contains 700mg of lidocaine. It also contains the following inactive ingredients: aluminum hydroxyacetate, disodium edetate, gelatin, glycerin, kaolin, methylparaben, polyacrylic acid, polyvinyl alcohol, propylene glycol, propylparaben, sodium carboxymethyl cellulose, sodium polyacrylate, sorbitol, tartaric acid, and urea. Lidoderm® Although it is a first-line drug for treating PHN, it has a low pain relief rate for moderate to severe patients, and the patch has poor adhesion, which can only be used for 12 hours, which is not conducive to the pain treatment of patients. In addition, its prescription is complicated, the lidocaine loading is too large, the drug utilization rate is low, and there are more drug residues.

[0006] The 60% lidocaine patch manufactured by Nitto Denko Co., Ltd. (brand name Penles) is already on the market. ® This is a hot melt adhesive patch, primarily used for procedural pain. It is a short-acting formulation; prolonged application is not feasible due to weak adhesion, and there is a risk of active pharmaceutical ingredient crystallization. To address the crystallization risk caused by excessive lidocaine loading, Penles... ® The crystallization-release method involves pre-forming tiny lidocaine crystals during patch preparation. Once applied to the skin, these pre-formed crystals gradually dissolve and are absorbed through the skin. However, this method is difficult to control in terms of stability and the process is unpredictable, making it impossible to achieve controlled drug delivery and posing a risk of fluctuating efficacy. Controlling the size and distribution of crystals in the patch is also a challenge in the production process, leading to complex processes and high production costs. Furthermore, the crystallization-redissolution process also delays the transdermal absorption of lidocaine. Additionally, the presence of crystals poses a risk of further transformation or growth of the active ingredient crystals during storage and use.

[0007] The applicant's earlier Chinese patent CN109316469B disclosed a stable, high-drug-loaded lidocaine transdermal patch and its preparation method. The patent disclosed that the polymer matrix layer of the transdermal patch contains 35% to 65% lidocaine by weight. Lidocaine is mixed with a non-functional acrylic pressure-sensitive adhesive, and then heated to 60-80°C to form a uniformly dispersed eutectic, thus creating the polymer matrix layer. This process inhibits the recrystallization of lidocaine, allowing for long-term stable storage. While this patent employs a special process to improve crystallization stability, the high drug concentration affects the adhesive properties of the pressure-sensitive adhesive, resulting in the adhesive application performance not yet meeting the requirements for 24-hour application.

[0008] US Patent 10307380B1 discloses compositions and methods for transdermal delivery of lidocaine, wherein the adhesive matrix layer contains about 3.0 to about 5.0 parts by weight of lidocaine base and uses a polyisobutylene adhesive. However, the lidocaine transdermal composition disclosed in this patent still suffers from problems such as poor drug permeability, failing to meet clinical needs. In particular, Example 2 of the patent discloses that "although the acrylic adhesive does allow for easy release from the release film and has suitable adhesive properties, the drug has a very high solubility in the adhesive, which is considered disadvantageous because more drug must be used to achieve the same drug delivery to the skin." Thus, this patent teaches that acrylic pressure-sensitive adhesives are disadvantageous for the transdermal delivery of lidocaine. Furthermore, it is known in the art that to achieve faster passive permeation, the active ingredient needs to reach or approach saturation solubility in the adhesive matrix. In acrylic adhesive systems, higher solubility requires higher drug content to approach or reach saturation, and lidocaine acts as a tackifier; the higher the content, the greater the adhesiveness of the prescription, leading to a decrease in the performance of the adhesive patch. Therefore, there are technical difficulties in developing products that simultaneously meet the clinical treatment requirements for drug penetration and have good long-term patch performance. To date, no commercially available product that meets these requirements has been successfully developed in this field.

[0009] Based on the above issues, it is still necessary to develop lidocaine transdermal drug delivery systems to address the problem of achieving the required drug penetration amount for clinical treatment while maintaining good patch performance during at least 24 hours of application, thus making them suitable for treating patients with PHN and other conditions requiring long-term drug administration. Summary of the Invention

[0010] Therefore, the purpose of this invention is to provide a lidocaine transdermal patch that can simultaneously meet the clinical treatment requirements for drug permeation, has good colloidal patch performance during long-term application, and exhibits good stability, as well as its preparation method and uses.

[0011] Another object of the present invention is to provide a lidocaine-containing transdermal patch with improved product stability, a method for preparing the patch, and its use.

[0012] To improve the permeability of drugs in patches, common techniques involve increasing the drug content to enhance passive diffusion. However, as reported in existing technologies, excessively high drug content not only increases the risk of lidocaine crystallization during storage, affecting drug release and permeation, but also leads to poor adhesive patch performance (such as unsuitable peel viscosity and easy detachment). The inventors have attempted to improve crystallization and adhesive patch performance by adding various excipients commonly used in transdermal drug delivery technology, such as crystallization inhibitors, thickeners, plasticizers, and / or fillers, but without achieving satisfactory results in all aspects. Furthermore, during the research, it was found that adding a penetration enhancer had little effect on improving permeability when the lidocaine content was low. Later, through extensive experimental research, it was unexpectedly discovered that by adjusting the lidocaine content in the polymer matrix layer to an appropriate level, and simultaneously adding a certain amount of penetration enhancer, not only could the release and permeation of lidocaine be significantly improved, but the problems of poor adhesive patch performance, easy crystallization, and high skin irritation in existing technologies were also solved, thus completing this invention.

[0013] Furthermore, strict control of impurity content is necessary in drug development to avoid exceeding impurity limits. During their research, the inventors discovered that during storage at high temperatures, the presence of free lidocaine alkali in the patch and residual monomers, active functional groups such as carboxyl groups, and crosslinking agents in the pressure-sensitive adhesive pose a potential risk of reaction, leading to product quality defects. Further research revealed that impurities can be easily controlled by adjusting the content of the crosslinking agent in the pressure-sensitive adhesive, thus completing this invention.

[0014] The objective of this invention is achieved through the following technical solution: On one hand, the present invention provides a transdermal patch containing lidocaine, comprising a polymer matrix layer, wherein the polymer matrix layer contains the active ingredient lidocaine, acrylic pressure-sensitive adhesive and a penetration enhancer, wherein, based on the weight of the polymer matrix layer, the weight content of lidocaine is 21% to 33%, preferably 25% to 30%, the weight content of acrylic pressure-sensitive adhesive is 45% to 75%, preferably 55% to 68%, and the weight content of the penetration enhancer is 3% to 25%, preferably 5% to 15%.

[0015] The active ingredient used in this invention is lidocaine free base. Compared with lidocaine salts, using lidocaine free base can significantly improve drug permeability.

[0016] Preferably, the weight content of lidocaine in the polymer matrix layer is lower than the weight content at which it reaches saturation solubility in the acrylic pressure-sensitive adhesive.

[0017] The saturated solubility of lidocaine in acrylic pressure-sensitive adhesives can be determined using conventional methods in the art. By using acrylic pressure-sensitive adhesives with appropriate saturated solubility for lidocaine, the risk of drug crystallization can be effectively reduced.

[0018] Preferably, the acrylic pressure-sensitive adhesive is a cross-linked acrylic pressure-sensitive adhesive. The acrylic pressure-sensitive adhesive has a viscosity of 1500~8000 mPa·s at room temperature, preferably 1500~6500 mPa·s; The Tg value of the acrylic pressure-sensitive adhesive is -50℃ to -10℃, preferably -40℃ to -20℃; and / or The acrylic pressure-sensitive adhesive is selected from one or more of DURO-TAK 87-2852, DURO-TAK 87-900A, DURO-TAK 87-2074, DURO-TAK 387-2510 / 87-2510, DURO-TAK 387-2052 / 87-2052, DURO-TAK 87-2196, DURO-TAK 387-2051 / 87-2051, and DURO-TAK 87-4098.

[0019] By using cross-linked acrylic pressure-sensitive adhesive and / or selecting acrylic pressure-sensitive adhesives with viscosity and Tg values ​​within the preferred embodiments of the present invention, the permeability and adhesive application performance of lidocaine patches can be significantly improved. The resulting patches have good peel viscosity and greatly reduce residue, cold flow, and crystallization.

[0020] Of particular surprise, within the content range of this invention, when the acrylic pressure-sensitive adhesive is selected from DURO-TAK 87-2852 and DURO-TAK 87-2074, the resulting patch exhibits excellent drug release and permeation properties as well as adhesive application performance. DURO-TAK 87-2852 and DURO-TAK 87-2074 are acrylic pressure-sensitive adhesives containing -COOH and -COOH / -OH functional groups, respectively. According to conventional understanding in the art, the amino groups in the active ingredient lidocaine can interact with the -COOH and / or -OH functional groups in the pressure-sensitive adhesive, which is detrimental to the flowability of lidocaine in the polymer matrix, thereby affecting the drug release rate. Therefore, for drug active molecules containing basic groups, the conventional practice is to avoid using pressure-sensitive adhesives containing -COOH and / or -OH functional groups as much as possible.

[0021] To avoid being bound by theory, the unexpected results achieved in this invention are due to two main factors. First, lidocaine has a high solubility in the pressure-sensitive adhesive, allowing for a higher drug concentration, which facilitates passive drug diffusion and reduces the risk of drug crystallization. Second, within the content range of this invention, the combination of the pressure-sensitive adhesive with a penetration enhancer creates a microenvironment conducive to lidocaine permeation. Furthermore, the acrylic pressure-sensitive adhesive possesses suitable physical properties, resulting in patches made with it in combination with a penetration enhancer exhibiting suitable initial tack, holding power, cohesive force, and peel strength within the content range of this invention, thus providing excellent release and permeation performance as well as good application properties.

[0022] Preferably, the penetration enhancer is selected from one or more of fatty alcohols, monohydric alcohol esters, glycerides, and polyethylene glycol esters; more preferably, the penetration enhancer is selected from one or more of isopropyl palmitate, glyceryl monooleate, ethyl oleate, octyl dodecanol, triethyl citrate, terpineol, azone, cocoyl capryloyl decanoate, BASF cross-linked povidone PVPCL-M, glyceryl triacetate, and isopropyl myristate.

[0023] Preferably, the lidocaine-containing transdermal patch further comprises other pharmaceutically acceptable excipients; preferably, the other pharmaceutically acceptable excipients are antioxidants; more preferably, the antioxidant content is 0.01~0.1% by weight of the polymer matrix layer, preferably 0.02~0.05%; even more preferably, the antioxidant is selected from one or more of butylated hydroxytoluene, tocopherol, sodium metabisulfite, and ascorbyl palmitate.

[0024] Preferably, the polymer matrix layer does not contain other crystallization inhibitors, thickeners, plasticizers and / or fillers.

[0025] To improve the performance of colloid patches and address issues such as crystallization, the inventors have attempted various methods, such as adding excipients like crystallization inhibitors, tackifiers, plasticizers, and / or fillers. However, while adding these excipients may optimize certain properties (such as crystallization, peel viscosity, residual adhesive, or cold flow), it can also adversely affect other properties (such as other colloid patch performance, skin irritation, drug release and permeation, and formulation stability). Therefore, this invention preferably does not contain crystallization inhibitors, tackifiers, plasticizers, and / or fillers.

[0026] Preferably, the amount of lidocaine contained in the transdermal patch is 0.20 mg to 2.0 mg per square centimeter; preferably, the administration area of ​​the transdermal patch is 5 cm². 2 ~100cm 2 .

[0027] Preferably, the lidocaine-containing transdermal patch further comprises a backing layer and a protective layer; the polymer matrix layer is located between the backing layer and the protective layer.

[0028] Preferably, the weight ratio of the compound with the structure shown in formula (I) and / or acetylacetone to lidocaine in the transdermal patch is less than 0.4%, more preferably less than 0.3%, more preferably less than 0.2%, and particularly preferably less than 0.1%. .

[0029] In cross-linked acrylic pressure-sensitive adhesives, residual acetylacetone cross-linking agent exists. Although its content is low, it reacts with lidocaine during patch placement to form impurities with the structure shown in formula (I). The presence of these impurities affects product quality. This invention controls product quality by controlling the acetylacetone content in the transdermal patch to prevent related substances from exceeding limits during long-term placement.

[0030] More preferably, the transdermal patch is prepared by a method comprising the following steps: mixing a prescribed amount of lidocaine, acrylic pressure-sensitive adhesive and a penetration enhancer evenly to obtain a clear adhesive solution, and then drying it under ventilated conditions at 50°C to 60°C, preferably 55°C to 60°C.

[0031] The inventors unexpectedly discovered that when dried at 50°C to 60°C, preferably 55°C to 60°C, under ventilated conditions, the residual crosslinking agent acetylacetone in the pressure-sensitive adhesive can evaporate with the solvent, thereby significantly reducing the generation of related substances during storage. This invention controls the acetylacetone content in the transdermal patch by controlling the drying temperature under ventilated conditions during the preparation process, thus conveniently and easily controlling the generation of related substances and obtaining a transdermal patch that meets clinical stability requirements.

[0032] On the other hand, the present invention provides a transdermal patch containing lidocaine, comprising the active ingredient lidocaine, acrylic pressure-sensitive adhesive, and optional other pharmaceutically acceptable excipients, wherein the weight ratio of the compound with the structure shown in formula (I) and / or acetylacetone to lidocaine in the transdermal patch is less than 0.4%, preferably less than 0.3%, more preferably less than 0.2%, and particularly preferably less than 0.1%;

[0033] More preferably, the transdermal patch is prepared by a method comprising the following steps: mixing lidocaine, acrylic pressure-sensitive adhesive and other pharmaceutically acceptable excipients uniformly to obtain a clear adhesive solution, and then drying it under ventilated conditions at 50°C to 60°C, preferably 55°C to 60°C.

[0034] In another aspect, the present invention provides a method for preparing the lidocaine-containing transdermal patch of the present invention, comprising the following steps: (1) Mix the prescribed amounts of lidocaine, acrylic pressure-sensitive adhesive and penetration enhancer evenly to obtain a clear adhesive solution; (2) Apply the adhesive obtained in step (1) onto the protective layer and dry it; (3) The product obtained in step (2) is combined with the backing layer and cut to obtain the transdermal patch; Preferably, the mixing in step (1) is performed in the following manner: (a) First, mix the acrylic pressure-sensitive adhesive and the penetration enhancer evenly, then add lidocaine and mix again, or (b) First, mix the penetration enhancer and lidocaine evenly, then add the acrylic pressure-sensitive adhesive and mix. Preferably, step (1) further includes mixing other pharmaceutically acceptable excipients in prescription amounts with the lidocaine, acrylic pressure-sensitive adhesive and penetration enhancer; Preferably, in step (2), the drying is carried out at 50°C to 60°C, more preferably at 55°C to 60°C, under ventilated conditions.

[0035] Controlling the temperature during the drying process is crucial for obtaining patches with good stability. Drying at 80℃ leads to a rapid increase in related substances, resulting in substandard product quality. Furthermore, research revealed the formation of a new, unknown single impurity (impurity N) during sample storage. Further investigation confirmed that impurity N is generated by the reaction of lidocaine with residual acetylacetone, a crosslinking agent in the acrylic pressure-sensitive adhesive. When dried at 50℃~60℃ under ventilated conditions, the residual acetylacetone in the pressure-sensitive adhesive evaporates with the solvent, significantly reducing the formation of impurity N. By controlling the acetylacetone content in the transdermal patch, excessive levels of related substances during long-term storage can be avoided, allowing for convenient and easy control of product quality.

[0036] Preferably, after the drying step in step (2), the weight ratio of acetylacetone to lidocaine in the transdermal patch is less than 0.4%, preferably less than 0.3%, more preferably less than 0.2%, and particularly preferably less than 0.1%.

[0037] In another aspect, the present invention provides the use of the lidocaine-containing transdermal patch of the present invention in the preparation of a medicament for treating peripheral nerve-related pain, preferably, the peripheral nerve-related pain being selected from one or more of postherpetic neuralgia, trigeminal neuralgia, sciatica, and diabetic peripheral neuropathy.

[0038] Although the API content in the patch of this invention is much lower than that of the commercially available product Penles ®However, it achieves comparable permeability, and the permeability of the patch of this invention is far higher than that of Lidoderm. ® The patch formulation and manufacturing process of this invention are simple, simultaneously meeting the drug permeation requirements for clinical treatment. It exhibits excellent colloidal adhesion properties during long-term application, without crystallization, cold flow, or residue, demonstrating high stability and allowing for prolonged use without skin irritation. This reduces the frequency of patch replacement, improves patient compliance, and makes it suitable for treating peripheral nerve-related pain, particularly for patients requiring long-term medication, such as postherpetic neuralgia. Furthermore, this invention improves product stability by controlling the acetylacetone content in the transdermal patch to prevent the generation of related substances exceeding limits during long-term storage. Attached Figure Description

[0039] The embodiments of the present invention will now be described in detail with reference to the accompanying drawings, wherein: Figure 1 The unknown monohybrid 2 in embodiment 14 of the present invention is shown. 1 H-NMR spectrum; Figure 2 The patches of Examples 1-2 and Comparative Example 1 of the present invention, as well as the reference formulation Lidoderm, are shown. ® 24-hour average cumulative permeability-time curve of pig ear skin labeled skin1; the figures are labeled as 14%, 21%, 28%, and Lidoderm. ® The curves represent Comparative Example 1, Example 1, Example 2, and the reference formulation Lidoderm, respectively. ® The experimental results; Figure 3 The patch and reference formulation Lidoderm of Example 2 of the present invention are shown. ® and Penles ® The 24-hour average cumulative permeability-time curve of pig ear skin labeled skin2; 28% and Penles are marked in the figure. ® and Lidoderm ® The curves represent Example 2 and the reference formulation Penles, respectively. ® and Lidoderm ® The experimental results; Figure 4 The patches of Example 3 and Comparative Examples 2-3 of the present invention, as well as the reference formulation Lidoderm, are shown. ® The 4-hour average cumulative permeability-time curve of pig ear skin labeled skin3; the figures are labeled as 35% API, 30% API, 30% API + 10% IPP and Lidoderm. ®The curves represent Comparative Example 3, Comparative Example 2, Example 3, and the reference formulation Lidoderm, respectively. ® The experimental results; Figure 5 Comparative Examples 8-10 and the reference formulation Lidoderm are shown. ® The 24-hour average cumulative permeability-time curve of pig ear skin labeled skin4; the figures are labeled as 18% API, 18% API+IPM, 18% API+IPP, and Lidoderm. ® The curves represent comparative examples 8, 9, and 10, and the reference formulation Lidoderm, respectively. ® The experimental results; Figure 6 The distribution of drugs in various tissues of each animal in the 6-hour sampling group in Experiment Example 4 is shown. Figure 7 The distribution of drugs in various tissues of each animal in the 12-hour sampling group of Experiment Example 4 is shown. Figure 8 The distribution of drugs in various tissues of each animal in the 24-hour sampling group of Experiment Example 4 is shown. Detailed Implementation

[0040] Terminology Definition : Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly used in the field to which this invention pertains. For the purposes of interpreting this specification, the following definitions will apply, and where appropriate, terms used in the singular will also include the plural forms, and vice versa.

[0041] The terms "transdermal drug delivery" or "transdermal drug delivery" as used in this invention refer to a method of drug administration in which an active ingredient is delivered into a local or systemic system through the skin or mucous membrane. In this invention, they have the same meaning and are interchangeable.

[0042] As used in this invention, the terms "polymer matrix layer" or "colloidal matrix layer" refer to the material combination of polymeric pressure-sensitive adhesive, lidocaine, and any other pharmaceutically acceptable excipients included in a transdermal drug delivery system. Generally, the polymer matrix layer is located between the release film and the backing film. As the drug delivery layer of the transdermal drug delivery system, the polymer matrix layer forms a drug-gel hybrid transdermal drug delivery system. In this invention, "polymer matrix layer" and "colloidal matrix layer" have the same meaning and are interchangeable.

[0043] The term "transdermal patch" or "transdermal drug delivery system" as used in this invention refers to a system containing an active ingredient for transdermal drug delivery, generally comprising a backing layer and a release film, and a polymer matrix drug delivery layer located between the two layers. Based on the combination of the active ingredient and other components in the polymer matrix drug delivery layer, it can generally be classified into reservoir type and gel-drug hybrid type. Transdermal drug delivery systems can also be simply referred to as patches or transdermal patches; these names are interchangeable in this invention. The polymer matrix drug delivery layer generally contains an active ingredient, a penetration enhancer, and / or other pharmaceutical excipients suitable for transdermal drug delivery patches, including but not limited to pressure-sensitive adhesives, fillers, crosslinking agents, antioxidants, ultraviolet absorbers, antibacterial agents, etc.

[0044] The term "permeability" used in this invention refers to the passive diffusion of a drug through the skin or mucous membrane, driven by the concentration difference of the active ingredient across the skin. The cumulative permeation amount per unit time and unit area can be used as an indicator of the patch's permeability, generally denoted as flux, with units of μg / cm². 2 / h. Alternatively, the cumulative transmittance per unit area at each time point can be used for evaluation, generally denoted as Q. t The unit is μg / cm³ 2 .

[0045] The term "lidocaine" as used in this invention refers to the free base of lidocaine.

[0046] The term "pressure-sensitive adhesive" or "adhesive" as used in this invention refers to a class of viscoelastic polymer materials that, when in contact with most other material surfaces, can adhere together with only a light pressure and maintain long-term adhesion. Pressure-sensitive adhesives generally include two types: one is inherently pressure-sensitive, while the other can achieve pressure-sensitive adhesive functions by adding tackifiers or plasticizers. Pressure-sensitive adhesives possess satisfactory physical properties at room temperature, such as good skin adhesion, maintaining adhesion for a certain period, peeling without damaging the skin, and controllable cold flow, thus meeting application requirements. They generally include acrylic pressure-sensitive adhesives, silicone pressure-sensitive adhesives, and rubber pressure-sensitive adhesives, as well as new hybrid pressure-sensitive adhesives formed by physical mixing or chemical bonding of the above-mentioned pressure-sensitive adhesives, in order to control the properties of the pressure-sensitive adhesive to meet specific requirements.

[0047] The term "acrylic pressure-sensitive adhesive" as used in this invention includes dimer polymers, trimer polymers, and polymers, such as acrylic homopolymers, copolymers, and polymers. Monomers that can be used to prepare the acrylic pressure-sensitive adhesive of this invention include acrylates, such as unsubstituted acrylates and methyl-substituted acrylates. Specifically, monomers that can be used to prepare the acrylic pressure-sensitive adhesive of this invention include methyl acrylate, ethyl acrylate, propyl acrylate, butyl acrylate, amyl acrylate, hexyl acrylate, heptyl acrylate, octyl acrylate, nonyl acrylate, decyl acrylate, lauryl acrylate, myristyl acrylate, methyl methacrylate, ethyl methacrylate, propyl methacrylate, butyl methacrylate, amyl methacrylate, hexyl methacrylate, heptyl methacrylate, octyl methacrylate, nonyl methacrylate, decyl methacrylate, lauryl methacrylate, myristyl methacrylate, etc. Monomers that can be used to prepare the acrylic pressure-sensitive adhesive of this invention also include acrylamides, such as acrylamide and methacrylamide. Further, the acrylic pressure-sensitive adhesive of this invention includes dimers or polymers formed from acrylic monomers and non-acrylic monomers. The non-acrylic pressure-sensitive adhesive refers to an adhesive whose polymeric monomers are not acrylic compounds, such as vinyl acetate and acrylic monomers forming a copolymer. In some embodiments, the acrylic pressure-sensitive adhesive of the present invention comprises only one type of acrylic polymer. In other embodiments, the acrylic pressure-sensitive adhesive of the present invention comprises two or more types of acrylic polymers. For adhesives containing two or more acrylic polymers, the required physical and pharmacokinetic properties, such as wearing performance and lidocaine permeation rate, can be obtained by adjusting the proportion of each component.

[0048] The term "penetration enhancer" as used in this invention refers to a substance that can alter the rate at which an active ingredient diffuses into the skin. It is typically miscible with the active ingredient and uniformly dispersed in the polymer matrix layer.

[0049] The term "antioxidant" as used in this invention refers to substances that can inhibit the oxidation of active ingredients, such as phenols and ascorbic acid.

[0050] The term "crystallization inhibitor" as used in this invention refers to polymers commonly used in the art that can inhibit the release of active components from colloidal matrices, such as polyethylene glycol 1000, succinate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, poloxamer, sodium dodecyl sulfate, polysorbate, povidones, cellulose, etc.

[0051] The term "by weight of the polymer matrix layer, ... the weight content of ..." used in this invention refers to the dry weight ratio of each component to the polymer matrix.

[0052] The term "backing layer" as used in this invention refers to the layer in a transdermal drug delivery patch that the drug cannot permeate. One surface of the backing layer is directly connected to the polymer matrix layer. During use, the backing layer protects the polymer matrix layer from contact with the surrounding environment, preventing drug loss. The raw material corresponding to the backing layer is generally called the backing film. Backing layer materials generally include polyester, polyethylene-polyvinyl acetate composite film, polyvinyl chloride, polyurethane, metal foil composite film, nonwoven fabric, and elastic fabric, with a thickness generally ranging from 10 to 200 μm. For example, ScotchPak™ 9730, 9701, 9720, and 9723 from 3M (USA), Xiaoshan Elastic Fabric 6015A from China, Baoling Nonwoven Fabric EW2080 and EW2083 from Japan, or Shanghai Winco PE3601 can be used. Different backing films have different physicochemical properties, such as extensibility, breathability, oxygen permeability, and light-blocking properties. In this invention, the backing layer or backing film has the same meaning and can be used interchangeably.

[0053] The term "release film" used in this invention can also be referred to as a protective layer, which is directly connected to the other surface of the polymer matrix layer. The release film is removed before use of the transdermal patch.

[0054] As used in this invention, the terms "through effective dose," "through the amount required to achieve a therapeutic effect," or "effectiveness" refer to the ability of an active ingredient to be delivered through the skin in sufficient quantities to achieve the desired local or systemic effect during the use of a transdermal patch, thereby achieving a specific pharmacological action, such as curing, alleviating, or controlling a disease or symptom. These terms are interchangeable in this invention.

[0055] The term "patch performance" as used in this invention refers to all processes including the peel force (peel force) of the patch detaching from the release film, the peel force (peel force) of the patch detaching from the application site after application, initial tack, holding tack, and cold flow. Specifically: "peel force" refers to the force required to remove the patch from the release film or from the skin after application using the backing layer containing the polymer matrix layer; the peel force should not be too high, as this could lead to peeling failure or adhesive residue on the skin. "Initial tack" refers to the degree of wetting between the backing layer containing the polymer matrix layer and the application site, reducing the risk of detachment during application. "Holding tack" refers to the degree of displacement of the patch at the application site, reflecting the patch strength during application. "Cold flow" refers to the viscoelastic creep of the polymer matrix layer, which can cause the patch to develop a dark ring during wear and may adhere to the protective layer and packaging container during storage, affecting patient safety and effectiveness. Generally, patches need to balance properties such as peel force, initial tack, holding tack, and cold flow.

[0056] To make the technical solution and beneficial effects of the present invention more apparent and understandable, a detailed description is provided below in conjunction with the accompanying drawings and specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they are generally performed according to conventional techniques or conditions described in the literature in the art, or according to product instructions. Unless otherwise specified, the reagents, materials, or instruments used are all conventional products that can be purchased through legitimate commercial channels.

[0057] In the following examples, comparative examples, and test cases, the pressure-sensitive adhesive models and abbreviations are shown in Table 1. Table 1: Pressure-Sensitive Adhesive Models and Abbreviations

[0058] For ease of writing, the letter parts of each pressure-sensitive adhesive are omitted in the embodiments, comparative examples and test examples of this invention, and only abbreviated numbers are used instead.

[0059] The physicochemical properties of each pressure-sensitive adhesive in Table 1 are listed in Table 2 below: Table 2 Physicochemical properties of each pressure-sensitive adhesive

[0060] In the following examples, comparative examples, and experimental cases, the English abbreviations are shown in Table 3.

[0061] Table 3 English Abbreviations

[0062] The reference formulation Lidoderm used in the following examples, comparative examples, and test cases ® Purchased from Teikoku Seiyaku Co., Ltd., Penles ® Purchased from Nitto Denko Corporation.

[0063] Examples 1-13: Preparation of the transdermal patch of the present invention Examples 1-13 provide a lidocaine-containing transdermal patch comprising a polymer matrix layer containing the active ingredient lidocaine, an acrylic pressure-sensitive adhesive, a penetration enhancer, and optional other pharmaceutically acceptable excipients (such as antioxidants). The lidocaine content is 21% to 33% by weight, the acrylic pressure-sensitive adhesive content is 45% to 75% by weight, the penetration enhancer content is 3% to 25% by weight, and the optional antioxidant content is 0.01% to 0.1% by weight.

[0064] Transdermal patches containing different weight contents of lidocaine, acrylic pressure-sensitive adhesive, penetration enhancer, and other optional pharmaceutically acceptable excipients (such as antioxidants) were prepared according to the following preparation method. The specific components and contents are shown in Table 4 below (the contents in the table are the weight percentage of each component in the total polymer matrix layer after drying).

[0065] Preparation method: Weigh the prescribed amount of penetration enhancer, acrylic pressure-sensitive adhesive, and other optional pharmaceutically acceptable excipients (such as antioxidants), and stir until homogeneous. Then add lidocaine and continue stirring until homogeneous to obtain a clear adhesive solution. Coat the prepared adhesive solution onto a selected release film, with the coating thickness determined according to the application requirements. Dry the coated polymer matrix at 50-60°C under ventilated conditions. Subsequently, laminate the dried product with a selected backing film, cut it to the appropriate size and shape according to the application requirements, and package it. The release film is model 1022 (purchased from 3M), the backing film is model 1109 (purchased from 3M), and the coating thickness is 150 μm.

[0066] Table 4. Types and contents of each component in the patches of Examples 1-13

[0067] Example 14: Investigation of factors affecting formulation stability The effect of drying temperature on patch quality was investigated using the intermediate adhesive solution of Example 2, with related substances as the evaluation index. The results are shown in Table 5-1.

[0068] Table 5-1 Effect of drying temperature on related substances

[0069] Controlling the temperature during the drying process is crucial for obtaining patches with good stability. Drying at 80℃ will cause a rapid increase in related substances, resulting in substandard product quality.

[0070] In addition, further high-temperature stability studies on samples numbered 1-4 revealed that a new unknown single impurity 2 was generated during storage at 40°C and 60°C. This impurity was detected to be close to or exceeded the limit after 25 days of storage at 40°C and 60°C. The results are shown in Tables 5-2 and 5-3.

[0071] Table 5-2 Results of stability test at 40℃

[0072] Table 5-3 Results of stability test at 60℃

[0073] Further investigation confirmed that the unknown single impurity 2 was an impurity produced by the reaction of lidocaine with acetylacetone, a residual crosslinking agent in the acrylic pressure-sensitive adhesive. High-resolution mass spectrometry indicated that the sample's molecular formula was C. 15 H 17 NO3; the 1H NMR spectrum yielded 17 hydrogen signals, including 12 methyl hydrogens, 4 methine hydrogens, and 1 reactive hydrogen signal (see appendix). Figure 1 ). 13 The C-NMR spectrum yielded 15 carbon signals, which, combined with the DEPT 135 spectrum, confirmed the presence of 4 methyl carbons, 4 methine carbons, and 7 quaternary carbons. The 1D-NMR data, combined with 2D-NMR (HSQC, HMBC, and COSY) data, suggested a structure as shown in equation (I):

[0074] Molecular formula: C 15 H 17 NO3 Molecular weight: 259.31 The specific reaction process is speculated to be as follows:

[0075] The presence of this impurity affects the quality of the patch product. In this invention, it is preferred that the weight ratio of the compound of formula (I) in the transdermal patch (also referred to as unknown monoimpurity 2 or impurity N in the context of this invention) to lidocaine is less than 0.4%, more preferably less than 0.3%, more preferably less than 0.2%, and particularly preferably less than 0.1%.

[0076] During the investigation of the formation conditions of impurity N, it was found that lidocaine + acetylacetone produced impurity N after being placed at a high temperature of 60°C for 15 days, but the amount was small. When acrylic pressure-sensitive adhesive was added to lidocaine + acetylacetone and placed at 60°C for 5 days, impurity N was produced. After 15 days, the amount of impurity N increased, and it was produced faster and in greater quantities than that produced by lidocaine + acetylacetone under the same conditions. This indicates that the addition of acrylic pressure-sensitive adhesive accelerated the reaction.

[0077] The inventors unexpectedly discovered that when dried at 50°C to 60°C, preferably 55°C to 60°C, and under ventilated conditions, the residual crosslinking agent acetylacetone in the pressure-sensitive adhesive can evaporate with the solvent, thereby significantly reducing the generation of impurity N during storage. By controlling the acetylacetone content in the patch, the excessive generation of impurity N during long-term storage can be avoided, thus easily controlling product quality. The acetylacetone content in the patch can be further reduced by increasing the ventilation or extending the drying time. Preferably, the weight ratio of acetylacetone to lidocaine in the patch is controlled to be less than 0.4%, preferably less than 0.3%, more preferably less than 0.2%, and particularly preferably less than 0.1%. More preferably, the sum of the weight ratio of the compound of formula (I) to lidocaine and the weight ratio of acetylacetone to lidocaine in the patch is less than 0.4%, preferably less than 0.3%, more preferably less than 0.2%, and particularly preferably less than 0.1%.

[0078] Comparative Examples 1-13: Preparation of Patches with Different Components and Contents The patches were prepared according to the preparation methods described in Examples 1-13, except that the components and their contents are shown in Table 6 below.

[0079] Table 6. Types and contents of each component in the patches of Comparative Examples 1-13

[0080] Comparative Example 14: A lidocaine patch was prepared according to the formulation and method of Example 1 of patent CN109316469B, wherein the weight contents of lidocaine and acrylic pressure-sensitive adhesive in the polymer matrix layer were 60% and 39.8%, respectively, and the balance was 0.2% of antioxidant BHA, as detailed below: Weigh out the required amount of the acrylic pressure-sensitive adhesive DURO-TAK 87-4098 and add it to ethanol, stirring until homogeneous. Then, while maintaining stirring, add lidocaine in batches, stirring until completely dissolved. Finally, add the antioxidant BHA and continue stirring until a uniform, transparent solution is formed. Coat the prepared solution onto a release film. Dry the coated polymer matrix in an oven with ventilation function at 60-80 °C for 5-15 minutes to allow the lidocaine and acrylic pressure-sensitive adhesive to form a uniformly dispersed eutectic and remove organic solvents. Then, laminate the dried product with a backing film, cut it to the appropriate size and shape, and package it.

[0081] Experimental Example 1: In vitro transdermal experiment In vitro transdermal assays were performed using a Franz vertical diffusion cell. Skin from healthy pig ears (labeled skin1, skin2, skin3, and skin4) was used. The keratin layer of the skin was obtained using a standard thermal separation method. A LOGAN SYSTEM 918-12 dry-heated automated transdermal system was employed. The receiving solution was pH 6.5 phosphate buffer, the diffusion cell volume was 12 ml, the penetration diameter was 15 mm, the sampling volume was 5 ml, the temperature was 32°C, the system was in full exhaust mode, and the rotation speed was 600 rpm. The procedure was followed, and samples were taken at predetermined time points. Examples 1-3, Comparative Examples 1-3 and 8-10, and the reference formulation Lidoderm were used. ® and Penles ® Each sample group was prepared in triplicate, with one blank control also included. The cumulative transmittance at each time point was calculated based on the results, as shown in the table below. Figures 2-5 .

[0082] Figure 2 The patches of Examples 1-2 and Comparative Example 1 of the present invention, as well as the reference formulation Lidoderm, are shown. ® The 24-hour average cumulative permeability-time curve of pig ear skin labeled skin1. The results show that when the API content is 14%, the 24-hour cumulative permeability of the sample is similar to that of Lidoderm. ® The results were largely consistent; with increasing API concentration, the 24-hour cumulative permeability tended to increase. When the API content was 21% and 28%, the 24-hour cumulative permeability of the samples was significantly higher than that of Lidoderm. ® Lidoderm ® The cumulative amount is about 2 or 3 times the amount of water that passes through.

[0083] Figure 3 The patch and reference formulation Lidoderm of Example 2 of the present invention are shown. ® and Penles ® The 24-hour average cumulative permeability-time curve of pig ear skin labeled skin2. The results show that the 24-hour cumulative permeability of the patch of the present invention is significantly higher than that of Lidoderm. ® and Penles ® Approaching. Among them, Lidoderm ® Penles is a gel patch containing 5% lidocaine. ® This is a hot melt adhesive patch containing 60% lidocaine. Although the API content of the patch of this invention is much lower than that of Penles... ® However, it achieves comparable permeability, and the permeability of the patch of this invention is far higher than that of Lidoderm. ®It is evident that this invention, by selecting an appropriate formulation with a suitable API content, achieves a permeability essentially equivalent to that of a formulation with the highest saturation content, and the permeability is far superior to that of gel patches, indicating better efficacy to meet the clinical needs of treating peripheral neuralgia.

[0084] Figure 4 The patches of Example 3 and Comparative Examples 2-3 of the present invention, as well as the reference formulation Lidoderm, are shown. ® The average cumulative permeability-time curve of pig ear skin labeled skin3 over 4 hours is shown. The results indicate that, without the addition of a permeability enhancer, the permeability of Comparative Example 2 (containing 30% API) and Comparative Example 3 (containing 35% API) is essentially equivalent, only slightly better than the reference formulation Lidoderm. ® The permeability of the patches was significantly lower than that of the patch of this invention, which contained 30% API and 10% penetration enhancer. This result was unexpected, as previous studies by the inventors showed that adding a penetration enhancer did not significantly improve permeability when the API content was 18% (see details). Figure 5 ).

[0085] Figure 5 Comparative Examples 8-10 and the reference formulation Lidoderm are shown. ® The 24-hour average cumulative permeability-time curve of pig ear skin labeled skin4. The results show that the addition of a permeability enhancer has no significant effect on improving permeability when lidocaine content is low.

[0086] Experimental Example 2: Colloidal Adhesion Performance and Colloidal Property Stability Test The lidocaine patches and the reference formulation Lidoderm in Examples 1-13 and Comparative Examples 1-14 were measured according to the following evaluation indicators and methods. ® and Penles ® The adhesive application performance and colloidal property stability (whether it crystallizes).

[0087] Evaluation indicators and methods: A. Adhesion: Peel viscosity and residual adhesive were used as evaluation indicators.

[0088] Peel viscosity: The peel viscosity of a d=2cm lidocaine circular patch after 24 hours of application to the skin was used as the evaluation index. The strength description is shown in Table 7. + and ++ are acceptable.

[0089] Table 7 Description of peel viscosity and strength

[0090] Residual adhesive: The degree of residual adhesive after peeling off a 2cm lidocaine circular patch after 24 hours of application to the skin was used as the evaluation index. Strength description is shown in Table 8, with + and ++ being acceptable.

[0091] Table 8 Description of Residual Adhesive Degree and Strength

[0092] B. Cold flow: Microscopic / visual inspection: After cutting the intermediate roll material, place it in a packaging bag and let it stand. Visually inspect or use a microscope to check whether there is adhesive seepage at the edges and whether it sticks to the packaging bag. Cold flow intensity is described in Table 9; + and ++ are acceptable.

[0093] Table 9 Description of Cold Flow Intensity

[0094] C. Crystallization: Visual inspection method: Leave the lidocaine patch exposed at room temperature and observe periodically to see if crystals precipitate.

[0095] The experimental results are shown in Table 10 below.

[0096] D. Skin irritation Visual inspection method: After the lidocaine patch is applied to the skin for 24 hours, observe whether the skin turns red after removing it.

[0097] Table 10 Comparison of various performance characteristics of lidocaine patches and reference formulations in Examples 1-13, Comparative Examples 1-14

[0098] The experimental results above show that the reference formulation Lidoderm ® and Penles ® The adhesive application performance is poor and cannot meet the 24-hour application requirement, and Penles ® Crystallization also exists.

[0099] The patches described in Examples 1-13 of this invention significantly improve the adhesive properties of the patches by including an appropriate amount of lidocaine in the polymer matrix layer, along with a certain amount of penetration enhancer and optional antioxidant. The resulting patches exhibit suitable peel viscosity after 24 hours of application, with little or no residue and cold flow (all within acceptable ranges), no skin irritation, and no crystallization even after long-term storage. In particular, when cross-linked acrylic pressure-sensitive adhesives and / or pressure-sensitive adhesives with suitable viscosity and Tg values ​​(e.g., pressure-sensitive adhesives 2852 and 2074) are used, patches with extremely excellent peel viscosity, residue, cold flow, crystallization, and skin irritation are obtained. Furthermore, the patches also demonstrate extremely excellent release and permeation capabilities.

[0100] Comparative Examples 1-14 represent other formulations that the inventors attempted to use during the research and development process to solve the technical problem to be addressed in this invention. However, due to the complexity of patch development, conventional methods, such as using commonly used pressure-sensitive adhesives like polyisobutylene and polysiloxane, or by adding commonly used plasticizers, fillers, and / or crystallization inhibitors, failed to yield satisfactory results in all aspects.

[0101] Experimental Example 3: Long-term stability and accelerated stability experiments Long-term stability and accelerated stability tests were conducted at temperatures of 25℃±2℃ and relative humidity of 60%RH±5%RH, and at temperatures of 40℃±2℃ and relative humidity of 75%RH±5%RH, respectively. The content of related substances and APIs in the sample of Example 4 was examined periodically, and the results are shown in Tables 11-12 below.

[0102] Table 11 Results of Long-Term Stability Tests

[0103] Table 12 Accelerated stability test results

[0104] As can be seen from the results in Tables 11-12, the patch of the present invention exhibits stable levels of related substances, release rate, and API content during long-term stability and accelerated stability tests, meeting the limit requirements, and no other unknown impurities are generated, indicating that the patch of the present invention has good stability.

[0105] Experimental Example 4: Local Tissue Distribution Study of Lidocaine in Bama Miniature Pigs Six ordinary Bama miniature pigs, three males and three females, were selected. All administration was via transdermal patch, using a self-made formulation (lidocaine patch of Example 2 of this invention) and a reference formulation (Lidoderm). ® All studies used clinically intended dosages for comparison. The self-made formulation was used at a specification of 78 mg / patch, with a single patch application area of ​​7 cm × 10 cm. The reference formulation was Lidoderm. ® The dosage is 700mg / patch, and the application area of ​​a single patch is 10cm×14cm / patch. Each animal was given 3 patches of the self-made formulation and 3 patches of the reference formulation on the left and right backs, respectively, corresponding to the time points of 6 h (6 h after application), 12 h (12 h after application) and 24 h (12 h after application) after administration.

[0106] The inverted application method was used. Animals were sacrificed at the endpoint, and skin, muscle, and subcutaneous fat samples were collected at the corresponding time points. Blank control samples were also collected from non-drug application sites to assess potential cross-interference. After collection, tissue samples were washed with physiological saline, blotted dry with filter paper, and stored at -80 °C for later analysis.

[0107] Table 13 Dosage information for each group

[0108] The concentration of lidocaine in tissues was determined by LC-MS / MS. Tissue concentration data were processed using DAS 3.2, and the main pharmacokinetic parameters were calculated using a non-compartmental model.

[0109] Results: After a single application of the lidocaine patch of the present invention to Bama miniature pigs, lidocaine concentrations in all tissues reached their peak at 12 h post-administration. After removing the patch at 12 h post-administration, drug concentrations in all tissues decreased significantly by 24 h post-administration. A single application of Lidoderm to Bama miniature pigs... ® Subsequently, lidocaine concentrations in all tissues peaked 12 hours after administration. After 12 hours of application and removal of the patch, drug concentrations in all tissues decreased significantly by 24 hours after administration.

[0110] like Figure 6-8 As shown, a single application of the lidocaine patch or Lidoderm of the present invention to Bama miniature pigs... ® Subsequently, at different time points, the drug concentration was consistently higher in skin than in subcutaneous fat than in muscle, with the drug concentration in skin tissue being significantly higher than that in subcutaneous fat and muscle. Six hours after administration, the drug concentrations of the lidocaine patch of this invention in both skin and fat were higher than those in Lidoderm. ® 24 hours after administration (12 hours after application), the drug concentrations of the lidocaine patch of the present invention in the skin, fat, and muscle were all lower than those in Lidoderm. ® Drug exposure (AUC) in fat and muscle after administration of the lidocaine patch of the present invention. （0-24h） ) and Lidoderm ® Comparable, while the drug exposure in the skin (AUC) （0-24h） ) is approximately Lidoderm ® 1.3 times that.

[0111] Conclusion: A single application of the lidocaine patch of this invention to Bama miniature pigs is comparable to Lidoderm. ® Subsequently, the drug concentration in the skin, fat, and muscle at the administration site reached its peak 12 hours after administration. After 12 hours of application and removal of the patch, the drug concentration in each tissue decreased significantly by 24 hours after administration. The drug concentration at different time points after administration was skin > subcutaneous fat > muscle.

[0112] Following a single dose of the lidocaine patch of the present invention, the effect is similar to a single dose of Lidoderm. ® In comparison, drug exposure levels (AUC) in fat and muscle were... （0-24h） ) and Lidoderm ® Comparable, while the drug exposure in the skin (AUC) （0-24h）(Significantly higher than Lidoderm) ® Approximately Lidoderm ® 1.3 times that.

[0113] Experimental Example 5: Investigation of Pain Sensation During Human Body Application The self-made formulation (the lidocaine patch of Example 2 of this invention) and the reference formulation (Lidoderm) were examined. ® The difference in pain sensation after 0.75 h, 1.5 h, 3 h, 6 h, and 12 h of application was measured using a circular patch with an application area of ​​d=2cm.

[0114] Volunteers A, B, C, and D applied the patches to the inner forearm using an upside-down method. The patches were removed simultaneously, and the affected areas were pricked with a sharp object to assess pain. Evaluation criteria: Pain level was 5 for the untreated area; lower values ​​indicated less pain.

[0115] Table 14 Results of Pain Assessment During Human Body Application

[0116] Conclusion: The pain of volunteers with the self-made preparation was significantly reduced after 3 hours of application, with a pain rating of 1-3. The pain of three volunteers with the reference preparation was slightly reduced after 6-12 hours of application, and the pain of one volunteer was significantly reduced after about 3 hours. The pain of volunteers with the self-made preparation applied for the same area and time was significantly lower than that of volunteers with the reference preparation after 3 hours.

Claims

1. A lidocaine-containing transdermal patch comprising a polymer matrix layer, wherein the polymer matrix layer contains the active ingredient lidocaine, an acrylic pressure-sensitive adhesive, and a penetration enhancer. The lidocaine content, preferably 25% to 30%, is 21% to 33% by weight, based on the weight of the polymer matrix layer; the acrylic pressure-sensitive adhesive content, preferably 55% to 68%, is 45% to 75% by weight; and the penetration enhancer content, preferably 5% to 15%, is 3% to 25% by weight.

2. The transdermal patch according to claim 1, wherein: The acrylic pressure-sensitive adhesive is a cross-linked acrylic pressure-sensitive adhesive. The viscosity of the acrylic pressure-sensitive adhesive at room temperature is 1500~8000 mPa·s, preferably 1500~6500 mPa·s; The Tg value of the acrylic pressure-sensitive adhesive is -50℃ to -10℃, preferably -40℃ to -20℃; and / or The acrylic pressure-sensitive adhesive is selected from one or more of DURO-TAK 87-2852, DURO-TAK 87-900A, DURO-TAK 87-2074, DURO-TAK 387-2510 / 87-2510, DURO-TAK 387-2052 / 87-2052, DURO-TAK 87-2196, DURO-TAK387-2051 / 87-2051, and DURO-TAK 87-4098.

3. The transdermal patch according to claim 1 or 2, wherein the penetration enhancer is selected from one or more of fatty alcohols, monohydric alcohol esters, glycerides, and polyethylene glycol esters; preferably, the penetration enhancer is selected from one or more of isopropyl palmitate, glyceryl monooleate, ethyl oleate, octyl dodecanol, triethyl citrate, terpineol, azone, cocoyl capryloyl decanoate, BASF cross-linked povidone PVPCL-M, glyceryl triacetate, and isopropyl myristate.

4. The transdermal patch according to any one of claims 1 to 3, further comprising other pharmaceutically acceptable excipients; Preferably, the other pharmaceutically acceptable excipients are antioxidants; More preferably, the antioxidant content, based on the weight of the polymer matrix layer, is 0.01~0.1%, preferably 0.02~0.05%; More preferably, the antioxidant is selected from one or more of butylated hydroxytoluene, tocopherol, sodium metabisulfite, and ascorbyl palmitate.

5. The transdermal patch according to any one of claims 1 to 4, wherein the amount of lidocaine contained in the transdermal patch is 0.20 mg to 2.0 mg per square centimeter; preferably, the administration area of ​​the transdermal patch is 5 cm². 2 ~100cm 2 .

6. The transdermal patch according to any one of claims 1 to 5, further comprising a backing layer and a protective layer; wherein the polymer matrix layer is located between the backing layer and the protective layer.

7. The transdermal patch according to any one of claims 1 to 6, wherein the weight ratio of the compound with the structure shown in formula (I) and / or acetylacetone to lidocaine in the transdermal patch is less than 0.4%, preferably less than 0.3%, more preferably less than 0.2%, and particularly preferably less than 0.1%; ； More preferably, the transdermal patch is prepared by a method comprising the following steps: mixing a prescribed amount of lidocaine, acrylic pressure-sensitive adhesive and a penetration enhancer evenly to obtain a clear adhesive solution, and then drying it under ventilated conditions at 50°C to 60°C, preferably 55°C to 60°C.

8. A transdermal patch containing lidocaine, comprising the active ingredient lidocaine, an acrylic pressure-sensitive adhesive, and optionally other pharmaceutically acceptable excipients, wherein, The weight ratio of the compound with the structure shown in formula (I) and / or acetylacetone to lidocaine in the transdermal patch is less than 0.4%, preferably less than 0.3%, more preferably less than 0.2%, and particularly preferably less than 0.1%. ； More preferably, the transdermal patch is prepared by a method comprising the following steps: uniformly mixing lidocaine, acrylic pressure-sensitive adhesive and other pharmaceutically acceptable excipients to obtain a clear adhesive solution, and then drying it under ventilated conditions at 50°C to 60°C, preferably 55°C to 60°C.

9. A method for preparing the transdermal patch according to any one of claims 1 to 8, comprising the following steps: (1) Mix the prescribed amounts of lidocaine, acrylic pressure-sensitive adhesive and penetration enhancer evenly to obtain a clear adhesive solution; (2) Apply the adhesive obtained in step (1) onto the protective layer and dry it; (3) The product obtained in step (2) is combined with the backing layer and cut to obtain the transdermal patch; Preferably, the mixing in step (1) is performed in the following manner: (a) First, mix the acrylic pressure-sensitive adhesive and the penetration enhancer evenly, then add lidocaine and mix again, or (b) First, mix the penetration enhancer and lidocaine evenly, then add the acrylic pressure-sensitive adhesive and mix. Preferably, step (1) further includes mixing other pharmaceutically acceptable excipients in prescription amounts with the lidocaine, acrylic pressure-sensitive adhesive and penetration enhancer; Preferably, in step (2), the drying is carried out at 50°C to 60°C, more preferably at 55°C to 60°C, under ventilated conditions; Preferably, after the drying step in step (2), the weight ratio of acetylacetone to lidocaine in the transdermal patch is less than 0.4%, preferably less than 0.3%, more preferably less than 0.2%, and particularly preferably less than 0.1%.

10. Use of the transdermal patch of any one of claims 1 to 8 in the preparation of a medicament for treating peripheral nerve-related pain, preferably, wherein the peripheral nerve-related pain is selected from one or more of postherpetic neuralgia, trigeminal neuralgia, sciatica, and diabetic peripheral neuropathy.

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