Lidocaine hydrochloride microneedle patch, preparation method thereof and isomalt in microneedle patch

Abstract

The application discloses a lidocaine hydrochloride microneedle patch, a preparation method thereof and application of isomalt in the microneedle patch, and belongs to the technical field of biomedical materials. The isomalt is used as a microneedle body matrix material, the content of the loaded lidocaine hydrochloride is significantly improved under the condition that the hardness, the dissolution rate and the formability of the microneedle meet the administration requirements, and the isomalt has the characteristics of high stability, non-hygroscopicity and non-blood sugar increase, so that the lidocaine hydrochloride microneedle patch with excellent anesthetic effect and long drug effect maintenance time is prepared, and has a wide application prospect.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials technology, specifically relating to a lidocaine hydrochloride microneedle patch and its preparation method, as well as the application of isomaltitol in microneedle patches, especially lidocaine hydrochloride microneedle patches. Background Technology

[0002] Lidocaine hydrochloride (LIDH), chemically named N-(2,6-dimethylyl)-2-(diethylamino)acetamide hydrochloride, is an amide-type local anesthetic. It has a strong anesthetic effect, rapid onset, and long duration of action, and is widely used in clinical practice for various local anesthesia procedures, such as minor dental and dermatological surgeries and biopsies. Currently, LIDH is available in injection, cream, gel, and spray formulations. Injections pose problems such as pain and the need for a specialized anesthesiologist; topical anesthetics such as creams have issues such as slow onset and insufficient efficacy.

[0003] Microneedles are widely used in transdermal drug delivery systems due to their high efficiency, safety, painlessness, and convenience. Dissolvable microneedles utilize biodegradable water-soluble polymers, sugars, etc., as matrix materials to encapsulate drugs within the needle body. Upon insertion into the skin, the microneedle dissolves, releasing the drug. Compared to other types of microneedles, they possess unique advantages such as high drug loading capacity and the absence of sharp waste. In the preparation and use of dissolvable microneedles, drug loading capacity is crucial, as it relates to the efficacy of the drug and directly affects the intensity of the therapeutic effect provided by the microneedle. Currently, the drug loading capacity of LIDH-loaded dissolvable microneedles is relatively low and needs improvement; therefore, selecting materials with good drug compatibility is very important.

[0004] Currently, matrix materials such as hydroxymethylcellulose (Pharmaceutics, 2020, 12(4)), hyaluronic acid (Pharmaceutics, 2020, 12(11)), hydroxypropyl methylcellulose and poly(methyl vinyl ether-conmaleic anhydride) composite matrix materials (Eur JPharm Sci, 2018, 121:330-337) have poor compatibility with LIDH. As a result, the drug loading capacity of microneedle patches prepared based on these matrix materials is difficult to increase, and the anesthetic effect and duration of drug efficacy are also limited. Summary of the Invention

[0005] To address the problems of existing technologies, this invention utilizes molecular dynamics simulations and related experimental techniques to discover a biomaterial with high affinity for lidocaine hydrochloride: isomalt (ISO). This biomaterial exhibits superior performance compared to existing materials, leading to the invention of a novel lidocaine hydrochloride microneedle patch with promising application prospects.

[0006] The present invention first provides a lidocaine hydrochloride microneedle patch (which includes a conventional base and a needle body), wherein the needle body material includes an active ingredient and a matrix material, the active ingredient including lidocaine hydrochloride, and the matrix material including isomaltitol.

[0007] In the aforementioned lidocaine hydrochloride microneedle patch, the mass ratio of lidocaine hydrochloride to isomaltitol is X:10-X, where X is 1 to 9.

[0008] Preferably, in the above-mentioned lidocaine hydrochloride microneedle patch, X is 4.8 to 9.

[0009] More preferably, in the above lidocaine hydrochloride microneedle patch, X is 7 to 9.

[0010] In the aforementioned lidocaine hydrochloride microneedle patch, the active ingredient, in addition to lidocaine hydrochloride, also includes other small organic molecule drugs. These other small organic molecule drugs are at least one of ibuprofen, ascorbyl glucoside, nicotinamide, nicardipine hydrochloride, hydrochlorothiazide, mesalazine, prednisolone, caffeine, acetaminophen, glimepiride, metformin, dextromethorphan hydrobromide, haloperidol, diclofenac sodium, budesonide, domperidone, glipizide, quinine, indomethacin, progesterone, aripiprazole, itraconazole, ritonavir, and ketoprofen.

[0011] In the aforementioned lidocaine hydrochloride microneedle patch, the matrix material, in addition to isomalt, also includes other matrix materials, namely, glucose, sucrose, maltose, trehalose, erythritol, arabinitol, xylitol, ribitol, mannitol, sorbitol, galactitol, polyvinylpyrrolidone, polyvinyl alcohol, sodium hyaluronate, hyaluronic acid, carboxymethyl cellulose, gum arabic, agar, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, alginate, polyvinyl alcohol, hydroxypropyl methylcellulose, sodium alginate, chitosan, polyglycolic acid or poly(lactide-co-glycolic acid), and triethyl citrate.

[0012] In the aforementioned lidocaine hydrochloride microneedle patch, the needle material further includes micro / nano particles, and the functional material is at least one of silicide nanoparticles or metal nanoparticles.

[0013] In the aforementioned lidocaine hydrochloride microneedle patch, the amount of other small organic molecule drugs, other matrix materials and / or micro / nano particles is such that the total mass of the three does not exceed 10% of the total mass of the needle body raw material.

[0014] In the aforementioned lidocaine hydrochloride microneedle patch, the microneedle has a shape that is pointed at the top and wide at the bottom.

[0015] Preferably, in the above-mentioned lidocaine hydrochloride microneedle patch, the shape of the microneedle is conical, tetrahedral, pentahedral, or hexahedral.

[0016] The base material of the lidocaine hydrochloride microneedle patch mentioned above includes at least one of the following: isomaltitol, glucose, sucrose, maltose, trehalose, erythritol, arabinitol, xylitol, ribitol, mannitol, sorbitol, galactitol, polyvinylpyrrolidone, polyvinyl alcohol, sodium hyaluronate, hyaluronic acid, carboxymethyl cellulose, gum arabic, agar, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, alginate, polyvinyl alcohol, hydroxypropyl methylcellulose, sodium alginate, chitosan, polyglycolic acid, or poly(lactide-co-glycolic acid).

[0017] Preferably, in the above-mentioned lidocaine hydrochloride microneedle patch, the substrate material and the matrix material are the same.

[0018] Preferably, in the above-mentioned lidocaine hydrochloride microneedle patch, the base material and the needle material are the same.

[0019] Among them, the lidocaine hydrochloride microneedle patch mentioned above is either a drug-loaded microneedle patch with drug loading only in the needle body or an integrated microneedle patch with drug loading in both the base and the needle body.

[0020] The present invention also provides a method for preparing the above-mentioned lidocaine hydrochloride microneedle patch, comprising the following steps: preparing the patch by means of a molten matrix material and an active ingredient mixture through a mold method or a melt-laminated molding technique.

[0021] In the above preparation method, the mold method includes the following steps:

[0022] The molten matrix material and active ingredient mixture are poured into a mold, vacuum pressed, the upper drug-containing matrix material is scraped off, the molten base material is poured into the mold, and after vacuum pressing, cooling and demolding, the drug-loaded microneedle patch is obtained.

[0023] Alternatively, the molten matrix material and active ingredient mixture can be poured into a mold, vacuum pressed, cooled, and demolded to obtain an integrated microneedle patch.

[0024] In the above preparation method, the melt-laminated molding technology includes the following steps:

[0025] Molten matrix material is processed into filaments and fed into a 3D printer. The filaments are heated and melted again, and then extruded through a nozzle to form a substrate. The mixture of molten matrix material and active ingredient is then processed into filaments and fed into a 3D printer. The filaments are heated and melted again, and then extruded through a nozzle to form a microneedle-like structure, thus obtaining a drug-loaded microneedle patch.

[0026] Alternatively, the molten matrix material and active ingredient mixture can be processed into filaments, fed into a 3D printer, and the filaments can be heated and melted again before being extruded through a nozzle to prepare the substrate and needle body, thus obtaining an integrated microneedle patch.

[0027] It should be noted that when the needle material also includes micro- and nano-particles, they are melted together with the matrix material and active ingredients and then used in mold making or melt-laminated molding technology.

[0028] The present invention also provides the application of the above-mentioned lidocaine hydrochloride microneedle patch in the preparation of local anesthetic drugs.

[0029] Preferably, in the above applications, the local anesthesia is transdermal local anesthesia or transmembrane local anesthesia.

[0030] This invention also provides the application of isomaltitol in organic small molecule drug microneedle patches, wherein the organic small molecule drug is at least one of lidocaine hydrochloride, ibuprofen, ascorbate glucoside, nicotinamide, nicardipine hydrochloride, hydrochlorothiazide, mesalazine, prednisolone, caffeine, acetaminophen, glimepiride, metformin, dextromethorphan hydrobromide, haloperidol, diclofenac sodium, budesonide, domperidone, glipizide, quinine, indomethacin, progesterone, aripiprazole, itraconazole, ritonavir, and ketoprofen.

[0031] Preferably, the present invention provides the application of isomaltitol in lidocaine hydrochloride microneedle patches.

[0032] The beneficial effects of this invention are:

[0033] This invention ensures that the prepared microneedles meet the requirements for microneedle administration in terms of hardness, dissolution, and moldability. Isomaltitol can load 1.7 to 10 times more LIDH than polymer materials such as hyaluronic acid, carboxymethyl cellulose, hydroxypropyl methyl cellulose, chondroitin sulfate methacrylate, and polyvinylpyrrolidone. Furthermore, isomaltitol possesses high stability, non-hygroscopicity, and does not raise blood glucose levels. This invention yields a high-drug-load lidocaine hydrochloride microneedle patch (LIDH-ISO-MNs), which exhibits excellent anesthetic effects and a long duration of efficacy, showing promising application prospects. Attached Figure Description

[0034] Figure 1 This is a schematic diagram of the process for preparing lidocaine hydrochloride microneedle patches using a mold method; where a is a schematic diagram of the PDMS mold preparation process, b is a schematic diagram of the process for preparing lidocaine hydrochloride microneedle patches loaded with drug on needles, and c is a schematic diagram of the process for preparing integrated lidocaine hydrochloride microneedle patches.

[0035] Figure 2 A schematic diagram of the process for preparing lidocaine hydrochloride microneedle patches using melt-laminated deposition modeling (MLM) technique; a is a schematic diagram of the process for preparing lidocaine hydrochloride microneedle patches loaded with drug on needles; b is a schematic diagram of the process for preparing integrated lidocaine hydrochloride microneedle patches.

[0036] Figure 3 This is a photograph of the lidocaine hydrochloride microneedle patch of the present invention.

[0037] Figure 4 High-performance liquid chromatograms of LIDH in LIDH active pharmaceutical ingredient and lidocaine hydrochloride microneedle patch.

[0038] Figure 5 This image shows a fluorescence microscope image of a microneedle patch containing Rhodamine B inserted into a skin section.

[0039] Figure 6 This is the DSC spectrum of the lidocaine hydrochloride microneedle patch.

[0040] Figure 7 The image shows the XRD pattern of lidocaine hydrochloride microneedle patch. Detailed Implementation

[0041] Specifically, a lidocaine hydrochloride microneedle patch has needle material comprising an active ingredient and a matrix material, wherein the active ingredient comprises lidocaine hydrochloride and the matrix material comprises isomaltitol.

[0042] This invention has found that, while ensuring that the prepared microneedles meet the requirements for microneedle administration in terms of hardness, dissolution, and formability, isomaltitol can load 1.7 to 10 times more LIDH than polymer materials such as hyaluronic acid (HA), carboxymethyl cellulose (CMC), hydroxypropyl methyl cellulose (HPMC), chondroitin sulfate methacrylate (CS-MA), and polyvinylpyrrolidone (PVP).

[0043] Due to the high drug loading capacity of isomaltitol, the mass ratio of lidocaine hydrochloride to matrix material can be controlled as X:10-X, where X is 1 to 9. Based on the high drug loading capacity of isomaltitol, X is preferably 4.8 to 9; more preferably, X is 7 to 9, at which point the lidocaine hydrochloride microneedle patch exhibits superior efficacy.

[0044] To ensure that the lidocaine hydrochloride microneedle patch achieves excellent anesthetic effects while also possessing other pharmacological effects, the active ingredient in the lidocaine hydrochloride microneedle patch of this invention may include other small organic molecule drugs in addition to lidocaine hydrochloride. These other small organic molecule drugs are at least one of the following heat-resistant drugs: ibuprofen, ascorbate glucoside, nicotinamide, nicardipine hydrochloride, hydrochlorothiazide, mesalazine, prednisolone, caffeine, acetaminophen, glimepiride, metformin, dextromethorphan hydrobromide, haloperidol, diclofenac sodium, budesonide, domperidone, glipizide, quinine, indomethacin, progesterone, aripiprazole, itraconazole, ritonavir, and ketoprofen. To further improve the performance of lidocaine hydrochloride microneedle patches, the matrix material of the lidocaine hydrochloride microneedle patch of the present invention, in addition to isomalt, also includes other matrix materials. These other matrix materials are at least one of glucose, sucrose, maltose, trehalose, erythritol, arabinitol, xylitol, ribitol, mannitol, sorbitol, galactitol, polyvinylpyrrolidone, polyvinyl alcohol, sodium hyaluronate, hyaluronic acid, carboxymethyl cellulose, gum arabic, agar, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, alginate, polyvinyl alcohol, hydroxypropyl methylcellulose, sodium alginate, chitosan, polyglycolic acid or poly(lactide-co-glycolic acid), and triethyl citrate. To further improve the performance of lidocaine hydrochloride microneedle patches, the needle material of the lidocaine hydrochloride microneedle patch of the present invention also includes micro / nano particles, and the functional material is at least one of silicate nanoparticles or metal nanoparticles.

[0045] To ensure the anesthetic effect of lidocaine hydrochloride microneedle patch, when adding other components, the total mass of other small organic molecule drugs, other matrix materials and / or micro / nano particles shall not exceed 10% of the total mass of the needle body raw material, that is, to ensure that the total content of lidocaine hydrochloride and isomalt in the needle body is not less than 90%.

[0046] The lidocaine hydrochloride microneedle patch of this invention can have needles in various shapes, such as conical, tetrahedral, pentahedral, and hexahedral, with a pointed top and a wide bottom, to facilitate skin penetration. The size of the patch, the arrangement of the microneedles, and the length and diameter of the microneedles can be designed according to conventional specifications in the art.

[0047] In the lidocaine hydrochloride microneedle patch of the present invention, the base material of the microneedle patch includes at least one of isomaltulitol, glucose, sucrose, maltose, trehalose, erythritol, arabinitol, xylitol, ribitol, mannitol, sorbitol, galactitol, polyvinylpyrrolidone, polyvinyl alcohol, sodium hyaluronate, hyaluronic acid, carboxymethyl cellulose, gum arabic, agar, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, alginate, polyvinyl alcohol, hydroxypropyl methylcellulose, sodium alginate, chitosan, polyglycolic acid, or poly(lactide-co-glycolic acid).

[0048] The microneedle patch of this invention can be prepared as a drug-loaded microneedle patch by loading the drug only onto the needle body; alternatively, to simplify the process, it can be prepared as a single-piece microneedle patch, where both the substrate and the needle body contain the drug. To reduce costs and simplify the process, preferably, the substrate material and the matrix material are the same, or the substrate material and the needle body material are the same.

[0049] The present invention also provides a method for preparing the above-mentioned lidocaine hydrochloride microneedle patch, comprising the following steps: preparing the patch by means of a molten matrix material and an active ingredient mixture through a mold method or a melt-laminated molding technique.

[0050] In the above preparation method, the mold method includes the following steps:

[0051] The molten matrix material and active ingredient mixture is poured into a mold, vacuum pressed, the upper drug-containing matrix material is scraped off, the molten base material is poured into the mold, and after vacuum pressing, cooling and demolding, the drug-loaded microneedle patch is obtained.

[0052] Alternatively, the molten matrix material and active ingredient mixture can be poured into a mold, vacuum pressed, cooled, and demolded to obtain an integrated microneedle patch.

[0053] In the mold method, the pressing effect is generally achieved by vacuuming for 1 to 30 minutes. During vacuuming, a suitable temperature can be selected based on the chosen matrix material and / or the physicochemical properties of the drug. For example, in this embodiment of the invention, isomaltitol is used as the matrix material, and the vacuuming temperature is 140 to 150°C.

[0054] In the mold method, the mold can be prepared using PDMS, a common material in the field, and common processes. For example, a microneedle array image is drawn using Photoshop software, with white representing the exposed area and black representing the non-exposed area, and then imported into the printer software. Photosensitive resin is poured into a liquid tank as the photosensitive material, and a glass slide is placed on top. DLP 3D printing technology is then used. The light source is adjusted into digital light by a DMD chip, and then further controlled by a high-magnification micromirror to improve printing accuracy. The digital light passes through the transparent glass slide and enters the photosensitive material. The photosensitive material exhibits light intensity distribution according to the projected digital light, resulting in one-step polymerization to form a microneedle array, thus obtaining the template microneedles. After blowing away any residual resin on the template microneedles with a blower, the template microneedles are scraped off the glass slide with a blade, cleaned, and then subjected to secondary curing in a UV curing chamber. Place the template microneedles into a container with a flat bottom, spray with a release agent, pour PDMS into the container until the microneedles are submerged, vacuum for 30 minutes, dry at high temperature, and demold to obtain the PDMS mold of lidocaine hydrochloride microneedle patch.

[0055] In the above preparation method, the melt-laminated molding technology includes the following steps:

[0056] Molten matrix material is processed into filaments and fed into a 3D printer. The filaments are heated and melted again, and then extruded through a nozzle to form a substrate. The molten matrix material and active ingredient mixture is then processed into filaments and fed into a 3D printer. The filaments are heated and melted again, and then extruded through a nozzle to form a microneedle-like structure, thus obtaining a drug-loaded microneedle patch.

[0057] Alternatively, the molten matrix material and active ingredient mixture can be processed into filaments, fed into a 3D printer, and then melted again by heating and extruded through a nozzle to prepare the substrate and needle body, thus obtaining an integrated microneedle patch.

[0058] It should be noted that when the needle material also includes micro- and nano-particles, they are melted together with the matrix material and active ingredients for use in mold making or melt-laminated molding technology.

[0059] This invention also provides the application of the above-mentioned lidocaine hydrochloride microneedle patch in the preparation of local anesthetic drugs; preferably, the local anesthesia is transdermal local anesthesia or transmembrane local anesthesia (e.g., spinal dura mater, cornea of ​​the eye, and other soft tissues requiring rapid drug delivery via microchannels). Based on the high loading capacity of isomaltitol, this invention also provides the application of isomaltitol in organic small molecule drug microneedle patches.

[0060] The organic small molecule drugs in this invention can be lidocaine hydrochloride, ibuprofen, ascorbyl glucoside, nicotinamide, or nicardipine hydrochloride, hydrochlorothiazide, mesalazine, prednisolone, caffeine, acetaminophen, glimepiride, metformin, dextromethorphan hydrobromide, haloperidol, diclofenac sodium, budesonide, domperidone, glipizide, quinine, indomethacin, progesterone, aripiprazole, itraconazole, ritonavir, ketoprofen, and other heat-resistant drugs; preferably lidocaine hydrochloride.

[0061] The present invention will be further described in detail below through embodiments, but the scope of protection of the present invention is not limited to the embodiments described herein.

[0062] Example 1

[0063] The essence of compatibility lies in the intermolecular interactions between the components, and molecular dynamics simulations can accurately characterize the strength of these interactions. Firstly, molecular dynamics simulations were used to characterize the strength of intermolecular interactions in the mixed system. The simulations allowed for the calculation of the total interaction energy in the mixed system. A negative interaction energy indicates mutual attraction; the larger the negative value, the stronger the attraction, indicating a stable system and better intermolecular compatibility. Therefore, this experimental example used molecular dynamics simulations with lidocaine hydrochloride and 11 matrix materials, including isomaltulitol (ISO), maltose (MAL), hyaluronic acid (HA), sodium hyaluronate (SA), carboxymethyl cellulose (CMC), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), methyl vinyl ether-conmaleic anhydride (PMVE / MA), hydroxypropyl methylcellulose (HPMC), polyglycolic acid or poly(lactide-co-glycolic acid) (PLGA), and chitosan (CTS). As shown in Table 1, the results indicate that the LIDH / ISO system exhibits the best compatibility.

[0064] Table 1. Interaction energy between LIDH and matrix materials (Kcal / mol)

[0065] Hybrid system <![CDATA[E total ]]> <![CDATA[E LIDH ]]> <![CDATA[E matrix ]]> <![CDATA[E inter ]]> LIDH / ISO 566.30 287.11 309.31 -30.13 LDIH / MAL 575.72 287.11 309.78 -21.17 LIDH / PVA -199.48 -23.62 -165.96 -9.91 LIDH / CTS 1279.79 -23.62 1299.82 3.59 LIDH / PVP -25.87 -23.62 -26.71 24.45 LIDH / HPMC 175.10 -23.62 199.80 -1.07 LIDH / CMC -268.44 -23.62 -262.66 17.84 LIDH / HA -9.48 -23.62 -18.85 32.99 LIDH / SA -200.92 -23.62 -227.02 49.73 LIDH / PLGA 141.08 -23.62 146.67 18.03 LIDH / PMVE / MA -199.95 -23.62 -181.78 5.45

[0066] The formula for calculating the interaction energy between mixed systems: E inter =E total -(E LIDH +E matrix In the formula: E total It is the total energy of the mixed system; E LIDH It is a mixed system containing only the energy of LIDH; E matrix It is the energy of the matrix material in the hybrid system; E inter This represents the interaction energy between LIDH and the microneedle tip matrix material.

[0067] Ultimately, isomaltitol was selected as the matrix material with good compatibility with LIDH. A lidocaine hydrochloride microneedle patch (LIDH-ISO-MNs) was then prepared using isomaltitol as the matrix material. This patch consists of a needle body and a base. The needle body is composed of isomaltitol and lidocaine hydrochloride; the base is composed of isomaltitol. Because the base does not contain the drug, it ensures that the drug loaded on each microneedle patch is fully utilized, avoiding waste.

[0068] Example 2

[0069] The specific preparation process of lidocaine hydrochloride microneedle patches is as follows:

[0070] (1) Preparation of PDMS microneedle molds Figure 1 a) First, prepare the template microneedles, which are prepared using a previously reported method (refer to Liu X et al. Fast Customization of Microneedle Arrays by StaticOptical Projection Lithography[J].ACS Appl Mater Interfaces,2021,13(50):60522-60530). Then, prepare the PDMS microneedle mold, a commonly used method for preparing soluble microneedles. Specifically: place the template microneedles in a container with a flat bottom, mix PDMS and curing agent at a weight ratio of 10:1 until the microneedles are submerged, vacuum the mixture, and dry it at high temperature to cure the PDMS. Then, demold the PDMS microneedle mold to obtain the final product.

[0071] (2) Preparation of lidocaine hydrochloride microneedle patch: Lidocaine hydrochloride patch can be prepared as a microneedle patch containing only the needle body containing the drug, or it can be prepared as an integrated microneedle patch to simplify the process and reduce the difficulty of production.

[0072] The preparation process of the drug-eluting microneedle patch is as follows ( Figure 1 b) First, prepare the needle body: Accurately weigh lidocaine hydrochloride and isomaltitol in a mass ratio of 8:2 using a balance. Melt the isomaltitol using a hot air gun, then quickly pour the lidocaine hydrochloride into the molten isomaltitol and stir until dissolved to obtain the drug-containing matrix material. Pour the drug-containing matrix material into a PDMS mold and vacuum-dry in a 140–150°C oven for 15–30 minutes. Remove from the vacuum drying oven and scrape off the top layer of drug-containing matrix material. Next, prepare the base: Melt the isomaltitol to obtain the matrix material, pour the molten matrix material into a PDMS mold, and vacuum-dry in a 140–150°C oven for 1–5 minutes. Remove from the vacuum drying oven and cool at room temperature. Demold to obtain the lidocaine hydrochloride microneedle patch.

[0073] The fabrication process of the integrated microneedle patch is as follows ( Figure 1 c) Accurately weigh the drug and matrix material in a mass ratio of lidocaine hydrochloride to isomaltitol of 8:2 using a balance. Melt the isomaltitol using a hot air gun, then quickly pour the lidocaine hydrochloride into the molten isomaltitol and stir until dissolved to obtain the drug-containing matrix material. Pour the drug-containing matrix material into a PDMS mold and vacuum-dry in a 140–150°C oven for 15–30 minutes. After removal and cooling at room temperature, demold to obtain the lidocaine hydrochloride microneedle patch.

[0074] The fabrication process of the integrated microneedle patch is as follows ( Figure 2 a) Accurately weigh lidocaine hydrochloride and isomaltitol in a mass ratio of 8:2 using a balance. Melt the isomaltitol using a hot air gun, then quickly pour the lidocaine hydrochloride into the molten isomaltitol and stir until dissolved to obtain the drug-containing matrix material. Process the molten drug-containing matrix material into filaments, input them into a 3D printer, and after heating, melt them again and extrude them through a nozzle to prepare the substrate and needles, thus obtaining an integrated microneedle patch.

[0075] The preparation process of the drug-eluting microneedle patch is as follows ( Figure 2 b): Molten isomalt is processed into filaments and fed into a 3D printer. The filaments are heated and melted again, then extruded through a nozzle to form a substrate. A precise mass ratio of lidocaine hydrochloride to isomalt is weighed using a balance, with the drug and substrate material measured at 8:2. The isomalt is melted using a hot air gun, and lidocaine hydrochloride is quickly poured into the molten isomalt, stirred until dissolved, and the resulting drug-containing substrate material is obtained. The mixture of the molten substrate material and active ingredient is then processed into filaments and fed into the 3D printer. The filaments are heated and melted again, then extruded through a nozzle to form a microneedle-like structure, thus obtaining a drug-loaded microneedle patch.

[0076] Example 3

[0077] The lidocaine hydrochloride microneedle patch obtained in Example 2 ( Figure 1Quantitative analysis of the drug content in (b) was performed using high-performance liquid chromatography (HPLC) to detect the drug concentration (mobile phase: phosphate buffer: acetonitrile = 50:50 (pH adjusted to 8.0 with H3PO4); chromatographic column: C18 column; detection wavelength: 263 nm). The drug loading of the 10×10 array lidocaine hydrochloride microneedle patch was approximately 13.02 mg, which is 1.7 to 10 times higher than that of lidocaine hydrochloride microneedles using polymers (HA, CMC, HPMC, CS-MA, PVP, etc.) as matrix materials. Furthermore, the chromatogram showed that ISO, as the matrix material of the needle, maintained stable drug quality even with high drug loading. Figure 3 .

[0078] The microneedle patch prepared by the method of this invention allows the drug to exist in an amorphous state within the microneedle patch. Scanning calorimetry (DSC) and X-ray diffraction (XRD) analyses were performed on the needle body, ISO, and LIDH active pharmaceutical ingredient (API) of the lidocaine hydrochloride microneedle patch. The results showed that the LIDH API exhibited characteristic endothermic peaks typical of crystals, while no endothermic peaks were observed in the lidocaine hydrochloride microneedle patch, indicating that the drug exists in an amorphous state. The XRD pattern of the LIDH API showed sharp peaks, indicating that the drug is crystalline, while the XRD pattern of the lidocaine hydrochloride microneedle patch showed diffuse peaks, indicating that the drug is distributed amorphously within the matrix material. Figure 5 and Figure 6 This all indicates that LIDH is uniformly dispersed in the microneedles.

[0079] Adding a small amount of Rhodamine B to microneedle patches and observing the frozen sections under a fluorescence microscope showed that lidocaine hydrochloride microneedle patches could effectively deliver the drug. Figure 4 ).

[0080] Example 3

[0081] The anesthetic efficacy of the microneedle patch was evaluated using rat behavioral studies. The lidocaine hydrochloride microneedle patch (LIDH-ISO-MNs) obtained in Example 2 was used. Figure 1 b) The microneedle patch was applied to the skin of the rat paw. Timing was started from the moment the patch was removed, and the pain threshold of the rat paw was tested at 2, 15, 30, 60, 120, and 180 minutes using the von Frey method. The pain threshold was compared with that of the untreated group (Sham), the blank microneedle patch without lidocaine hydrochloride (ISO-MNs), compound lidocaine hydrochloride cream (LIDH-CR), and lidocaine hydrochloride injection (LIDH-IH) (n=6), with the dosage kept consistent.

[0082] The results are shown in Table 2. Compared with the cream group, the experimental group significantly improved the anesthetic effect in rats. There was no significant difference between the ISO-MNs group and the Sham group, indicating that ISO-MNs had no anesthetic effect. At 2 minutes after administration, both the experimental and injection groups showed significant differences in pain threshold compared to before administration, demonstrating that both lidocaine hydrochloride microneedle patches and LIDH-IH began to take effect 2 minutes after administration. Furthermore, the efficacy of the lidocaine hydrochloride microneedle patch lasted for more than 120 minutes, superior to the injection. There was no significant difference in pain threshold between the experimental and injection groups at 15 minutes, indicating that both have high pain tolerance at the same dosage. In conclusion, the anesthetic effect of this microneedle patch is significantly stronger than that of the cream, and its duration of effect exceeds 120 minutes, which is longer than that of the injection. Compared to current lidocaine hydrochloride-loaded microneedle patches used for rapid local anesthesia, LIDH-ISO-MNs exhibit better anesthetic effects and longer duration of action (Pharmaceutics, 2020, 12(4))(Pharmaceutics, 2020, 12(11))(Eur J PharmSci, 2018, 121:330-337). Therefore, the lidocaine hydrochloride microneedle patch of this invention has broad clinical application prospects and clinical translational value.

[0083] Table 2 evaluates the anesthetic effects of different administration routes.

[0084] Time (min) LIDH-ISO-MNs(g) LIDH-IH(g) LIDH-CR(g) ISO-MNs(g) 0 8.74 8.14 7.14 8.14 2 93.96 129.3 11.29 9.41 15 148.13 284.18 32.74 10.03 30 268.49 288.97 60.81 6.94 60 274.45 156.43 108.88 8.02 120 54.32 16.88 16.55 7.13 180 15.48 13.14 9.41 9.24

Claims

1. A lidocaine hydrochloride microneedle patch, characterized in that, The needle body is made of an active ingredient and a matrix material. The active ingredient is lidocaine hydrochloride, and the matrix material is isomaltitol. The mass ratio of lidocaine hydrochloride to isomaltitol is X:10-X, where X is 7~9.

2. The lidocaine hydrochloride microneedle patch according to claim 1, characterized in that, The microneedle has a pointed top and a wide bottom shape.

3. The lidocaine hydrochloride microneedle patch according to claim 2, characterized in that, The microneedle has a cone shape, a tetrahedral cone shape, a pentahedral cone shape, or a hexahedral cone shape.

4. The lidocaine hydrochloride microneedle patch according to claim 1, characterized in that, The base material of the microneedle patch includes at least one of isomaltitol, glucose, sucrose, maltose, trehalose, erythritol, arabinitol, xylitol, ribitol, mannitol, sorbitol, galactitol, polyvinylpyrrolidone, polyvinyl alcohol, sodium hyaluronate, hyaluronic acid, carboxymethyl cellulose, gum arabic, agar, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, alginate, hydroxypropyl methyl cellulose, sodium alginate, chitosan, polyglycolic acid, or poly(lactide-co-glycolic acid).

5. The lidocaine hydrochloride microneedle patch according to claim 4, characterized in that, The base material and the matrix material are the same, or the base material and the needle material are the same.

6. The lidocaine hydrochloride microneedle patch according to claim 4, characterized in that, It is either a drug-loaded microneedle patch with drug loading only in the needle body or an integrated microneedle patch with drug loading in both the substrate and the needle body.

7. The method for preparing the lidocaine hydrochloride microneedle patch according to any one of claims 1 to 6, characterized in that, Includes the following steps: It is prepared by using a mixture of molten matrix material and active ingredients through a molding method or melt lamination molding technology.

8. The preparation method according to claim 7, characterized in that, The mold method includes the following steps: The molten matrix material and active ingredient mixture is poured into a mold, vacuum pressed, the upper drug-containing matrix material is scraped off, the molten base material is poured into the mold, and after vacuum pressing, cooling and demolding, the drug-loaded microneedle patch is obtained. Alternatively, the molten matrix material and active ingredient mixture can be poured into a mold, and then vacuum pressed, cooled, and demolded to obtain an integrated microneedle patch. The melt-laminated deposition modeling technology includes the following steps: Molten matrix material is processed into filaments and fed into a 3D printer. The filaments are heated and melted again, and then extruded through a nozzle to form a substrate. The molten matrix material and active ingredient mixture is then processed into filaments and fed into a 3D printer. The filaments are heated and melted again, and then extruded through a nozzle to form a microneedle-like structure, thus obtaining a drug-loaded microneedle patch. Alternatively, the molten matrix material and active ingredient mixture can be processed into filaments, fed into a 3D printer, and the filaments can be heated and melted again before being extruded through a nozzle to prepare the substrate and needle body, thus obtaining an integrated microneedle patch.

9. The use of the lidocaine hydrochloride microneedle patch according to any one of claims 1 to 6 in the preparation of local anesthetic drugs.

10. The application according to claim 9, characterized in that, The local anesthesia is transdermal local anesthesia or transmembrane local anesthesia.

11. The use of isomaltitol in the preparation of lidocaine hydrochloride microneedle patches according to any one of claims 1 to 6.

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