A fast drug release microneedle matrix composition and use thereof

Abstract

The present application relates to a fast drug release microneedle matrix composition and its application. The fast drug release microneedle matrix composition comprises, based on the total weight of the matrix composition as 100%, water-soluble polymer material: 10-40%; low molecular weight polysaccharide: 35-80%; and small molecule sugar alcohol: 1-30%. The present application realizes the synergistic improvement of the microneedle in multiple performance dimensions by reasonable selection and proportioning of the water-soluble polymer material, low molecular weight polysaccharide and small molecule sugar alcohol, and constructs a composite matrix system: good formability (smooth surface, no precipitate, complete demolding, intact needle tip); the mechanical strength meets the skin puncture requirement, and the puncture performance is excellent; it is beneficial to the rapid release of drugs; the preparation process is simple; it has good adaptability to higher drug loading and / or high hygroscopic active ingredients. The matrix composition of the present application is especially suitable for preparing fast drug release microneedle patches containing local anesthetic drugs and other active ingredients that need to be quickly effective.

Description

Technical Field

[0001] This invention belongs to the field of transdermal drug delivery technology, specifically relating to a rapid-release microneedle matrix composition and its application. Background Technology

[0002] Rapid-release microneedle patches have promising applications in local anesthesia and skin analgesia due to their advantages such as minimally invasiveness, convenient drug delivery, and rapid onset of action. However, existing microneedle matrix compositions may still encounter problems in preparing rapid-release microneedles, such as difficulty in balancing microneedle shapeability and mechanical strength, slow drug release rate, unsuitability for high drug loading, and complex preparation processes.

[0003] Patent CN 111991344 B discloses a microneedle patch suitable for local anesthesia, using hyaluronic acid (i.e., hyaluronic acid) or polyvinylpyrrolidone with a molecular weight of 40-800 kDa as the matrix material. However, the inventors found that when using the matrix system disclosed in this patent to prepare local anesthesia microneedles, problems such as white rings appearing on the microneedle backplate and easy breakage upon demolding easily occur, and the puncture performance and drug release performance still need to be improved.

[0004] Patent CN 110799238 B discloses a fast-acting dental local anesthetic preparation using water-soluble polymers and low-molecular-weight monosaccharides or disaccharides as base agents. Further research by the inventors revealed that when using this matrix system to prepare microneedles, issues such as demolding and deformation easily occur, and there is still room for further optimization of its puncture resistance and drug release performance.

[0005] Therefore, it is necessary to develop a novel microneedle matrix system that combines good formability, mechanical properties, and rapid drug release performance, and is suitable for systems with high drug loading capacity and simple preparation process, in order to meet the application requirements of rapidly effective drugs. Summary of the Invention

[0006] The purpose of this invention is to overcome the problem in the prior art that soluble microneedles are difficult to balance in terms of rapid drug release, mechanical properties, and formability. This invention provides a rapid drug release microneedle matrix composition and its application. This matrix composition can achieve rapid drug release while maintaining good formability and mechanical strength. It is suitable for drugs that require rapid onset of action, such as local anesthetics, and is also suitable for high drug loading systems. The preparation process is simple.

[0007] To improve the solubility and drug release performance of microneedles, the inventors attempted to optimize the matrix system by introducing low molecular weight components. However, research revealed that when the content of low molecular weight components was high, the mechanical strength and toughness of the microneedles significantly decreased, leading to problems such as demolding breakage, appearance defects, and tip breakage, making it difficult to meet the requirements for puncture use. Furthermore, the inventors tried increasing the proportion of polymeric materials to improve mechanical properties, but found that this method often resulted in a decrease in the solubility and drug release performance of the microneedles. These results indicate that it is difficult to simultaneously achieve good moldability, mechanical properties, and release performance through adjustments to a single component.

[0008] Further research revealed that by combining water-soluble polymers, low-molecular-weight polysaccharides, and small-molecule sugar alcohols within a specific ratio range, a synergistic composite matrix system can be formed, thereby achieving rapid drug release while maintaining good formability and mechanical properties.

[0009] The matrix composition of this invention is suitable for drugs requiring rapid onset of action. Studies using lidocaine hydrochloride as a representative model drug have shown that, even with high drug concentrations, this invention can still produce microneedle patches with good formability, sufficient mechanical strength, and good drug release performance. Since lidocaine hydrochloride also has high hygroscopicity, the above results indicate that the matrix system of this invention has good compatibility with highly drug-loaded and / or highly hygroscopic active pharmaceutical ingredients. Furthermore, the matrix system of this invention also has advantages such as short drying time.

[0010] The objective of this invention is achieved through the following technical solution:

[0011] The first aspect of the present invention provides a rapid drug-release microneedle matrix composition, wherein, based on 100% of the total weight of the matrix composition, it comprises:

[0012] Water-soluble polymer materials: 10~40%;

[0013] Low molecular weight polysaccharides: 35-80%; and

[0014] Small molecule sugar alcohols: 1~30%.

[0015] In some embodiments, based on the total weight of the matrix composition (100%), the weight percentage of the water-soluble polymeric material can be 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, or any decimal or integer value within the above ranges; the weight percentage of the low molecular weight polysaccharide can be 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%. The weight percentage of the small molecule sugar alcohol can be 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, or any decimal or integer value within the above range.

[0016] Preferably, the water-soluble polymer material is selected from one or more of hyaluronic acid or its salts, water-soluble cellulose derivatives, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, and pullulan.

[0017] Preferably, the low molecular weight polysaccharide is selected from one or more of dextran, dextrin, chitosan, and alginate or their salts.

[0018] Preferably, the small molecule sugar alcohol is selected from one or more of erythritol, mannitol, sorbitol and xylitol.

[0019] Preferably, the water-soluble cellulose derivative is selected from one or more of carboxymethyl cellulose or its salts, hydroxypropyl cellulose or its salts, hydroxyethyl cellulose or its salts, methyl cellulose or its salts, and hydroxypropyl methyl cellulose or its salts.

[0020] Preferably, the viscosity of a 2% aqueous solution of the water-soluble cellulose derivative at 25°C is 15~13000 mPa·s; for example, it can be 15 mPa·s, 30 mPa·s, 50 mPa·s, 60 mPa·s, 100 mPa·s, 200 mPa·s, 300 mPa·s, 400 mPa·s, 500 mPa·s, 600 mPa·s, 700 mPa·s, 800 mPa·s, 1000 mPa·s, 1500 mPa·s, 2000 mPa·s, 2500 mPa·s, 3000 mPa·s, 6000 mPa·s, 10000 mPa·s, 12000 mPa·s, 13000 mPa·s, or any decimal or integer value within the above range. More preferably, a 2% aqueous solution of the water-soluble cellulose derivative has a viscosity of 15-700 mPa·s at 25°C. The inventors further discovered that adding an appropriate amount of water-soluble cellulose derivative to the matrix composition helps improve the formability and mechanical properties of the microneedles. Preferably, using a low-viscosity water-soluble cellulose derivative can improve the formability and mechanical properties of the microneedles while maintaining good solubility and drug release performance.

[0021] Preferably, the weight-average molecular weight of the water-soluble polymer material is 10 kDa to 2000 kDa, for example, it can be 10 kDa, 40 kDa, 60 kDa, 80 kDa, 100 kDa, 200 kDa, 300 kDa, 400 kDa, 500 kDa, 600 kDa, 700 kDa, 800 kDa, 900 kDa, 1000 kDa, 1100 kDa, 1200 kDa, 1300 kDa, 1400 kDa, 1500 kDa, 1600 kDa, 1700 kDa, 1800 kDa, 1900 kDa, 2000 kDa, or any decimal or integer value within the above range; more preferably, the weight-average molecular weight of the water-soluble polymer material is 40 kDa to 1000 kDa. As the molecular weight of water-soluble polymer materials increases, their dosage can be appropriately reduced; as the molecular weight decreases, their dosage can be appropriately increased to obtain suitable formability and mechanical properties.

[0022] Preferably, the weight-average molecular weight of the low molecular weight polysaccharide is 10 kDa to 80 kDa, for example, it can be 10 kDa, 20 kDa, 30 kDa, 40 kDa, 50 kDa, 60 kDa, 70 kDa, 80 kDa, or any decimal or integer value within the above range; more preferably, the weight-average molecular weight of the low molecular weight polysaccharide is 10 kDa to 50 kDa.

[0023] Preferably, the weight-average molecular weight of the small molecule sugar alcohol is 100 Da to 300 Da, for example, it can be 100 Da, 110 Da, 120 Da, 130 Da, 140 Da, 150 Da, 160 Da, 170 Da, 180 Da, 190 Da, 200 Da, 210 Da, 220 Da, 230 Da, 240 Da, 250 Da, 260 Da, 270 Da, 280 Da, 290 Da, 300 Da, or any decimal or integer value within the above range; more preferably, the weight-average molecular weight of the small molecule sugar alcohol is 120 Da to 250 Da.

[0024] Preferably, the weight-average molecular weight of at least one of the water-soluble polymeric materials is greater than the weight-average molecular weight of any one of the low molecular weight polysaccharides, and the weight-average molecular weight of at least one of the low molecular weight polysaccharides is greater than the weight-average molecular weight of any one of the small molecule sugar alcohols.

[0025] Preferably, the content of the water-soluble polymer material is 15-30%.

[0026] Preferably, the content of the low molecular weight polysaccharide is 38-78%.

[0027] Preferably, the content of the small molecule sugar alcohol is 5-25%.

[0028] Preferably, the total content of the low molecular weight polysaccharide and the small molecule sugar alcohol is 60% to 90%. For example, the total content of the low molecular weight polysaccharide and the small molecule sugar alcohol can be 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, or any decimal or integer value within the above range.

[0029] More preferably, the total content of the low molecular weight polysaccharide and the small molecule sugar alcohol is 70% to 85%.

[0030] Preferably, the water-soluble polymeric material comprises a mixture of hyaluronic acid or its salt and a water-soluble cellulose derivative.

[0031] Preferably, the low molecular weight polysaccharide comprises dextran, and the dextran is preferably selected from one or more of dextran 20, dextran 40 and dextran 70.

[0032] Preferably, the small molecule sugar alcohol comprises sorbitol and / or mannitol.

[0033] More preferably, the water-soluble polymeric material is composed of hyaluronic acid or its salt and a water-soluble cellulose derivative. More preferably, the weight ratio of the hyaluronic acid or its salt to the water-soluble cellulose derivative is 1:1 to 100:1. For example, the weight ratio of the hyaluronic acid or its salt to the water-soluble cellulose derivative is 1:1, 1.5:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1, 60:1, 65:1, 70:1, 75:1, 80:1, 85:1, 90:1, 95:1, 100:1, or any decimal or integer value within the above range. More preferably, the weight ratio of the hyaluronic acid or its salt to the water-soluble cellulose derivative is 5:1 to 50:1.

[0034] A second aspect of the present invention provides a rapid drug-release microneedle patch comprising the matrix composition described in the first aspect of the present invention and a drug for which rapid onset of action is required.

[0035] Preferably, the drug is selected from one or more of local anesthetic drugs and fast-acting anti-inflammatory and analgesic drugs.

[0036] More preferably, the local anesthetic drug is selected from one or more of lidocaine, prilocaine, tetracaine, benzocaine, levobupivacaine, ropivacaine, and their pharmaceutically acceptable salts; and / or the rapid-acting anti-inflammatory and analgesic drug is selected from one or more of ibuprofen sodium, diclofenac sodium, and ketorolac tromethamine.

[0037] Preferably, the weight ratio of the drug to the matrix composition is 1:0.2 to 50; for example, the weight ratio of the drug to the matrix composition is 1:0.2, 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1: 22, 1:23, 1:24, 1:25, 1:26, 1:27, 1:28, 1:29, 1:30, 1:31, 1:32, 1:33, 1:34, 1:35, 1:36, 1:37, 1:38, 1:39, 1:40, 1:41, 1:42, 1:43, 1:44, 1:45, 1:46, 1:47, 1:48, 1:49, 1:50, or any decimal or integer value within the range above.

[0038] More preferably, the weight ratio of the drug to the matrix composition is 1:0.5~10.

[0039] More preferably, the weight ratio of the drug to the matrix composition is 1:1 to 2.

[0040] A third aspect of the present invention provides a method for preparing the rapid drug-release microneedle patch described in the second aspect of the present invention, comprising the following steps:

[0041] S1: The matrix composition described in the first aspect of the present invention is mixed evenly with the drug requiring rapid onset of action in a solvent and injected into a microneedle mold; and

[0042] S2: Dry and demold to obtain the microneedle patch.

[0043] Preferably, the solvent is selected from one or more of water, methanol, ethanol, isopropanol, propylene glycol, glycerol, dimethyl sulfoxide, N,N-dimethylacetamide, and N-methylpyrrolidone.

[0044] Preferably, the process includes stirring and / or centrifugation before injection molding.

[0045] Preferably, a vacuum is applied below the mold during the injection molding process.

[0046] Preferably, the drying is carried out at 15~45°C, more preferably the drying is carried out at room temperature.

[0047] Preferably, the drying is carried out at a relative humidity of 10% to 40%.

[0048] The fourth aspect of the present invention provides the use of the matrix composition described in the first aspect of the present invention in the preparation of rapid-release microneedle patches.

[0049] Preferably, the rapid-release microneedle patch contains a local anesthetic drug and / or a fast-acting anti-inflammatory and analgesic drug;

[0050] More preferably, the local anesthetic drug is selected from one or more of lidocaine, prilocaine, tetracaine, benzocaine, levobupivacaine, ropivacaine, and their pharmaceutically acceptable salts; and / or the rapid-acting anti-inflammatory and analgesic drug is selected from one or more of ibuprofen sodium, diclofenac sodium, and ketorolac tromethamine.

[0051] This invention constructs a composite matrix system through the rational selection and ratio of water-soluble polymer materials, low molecular weight polysaccharides, and small molecule sugar alcohols, achieving synergistic improvement in multiple performance dimensions of microneedles: good formability (smooth surface, no exudates, complete demolding, and intact needle tip), mechanical strength meeting the requirements for skin puncture, excellent punctureability, which is conducive to rapid drug release, and the preparation process is simple, requiring no harsh conditions such as heating and melting, which is beneficial for the formulation development of heat-sensitive drugs.

[0052] Furthermore, experimental results using lidocaine hydrochloride as a representative model drug demonstrate that the matrix composition of this invention exhibits good compatibility with high drug loading and / or highly hygroscopic active pharmaceutical ingredients. Even in systems with high drug content or containing highly hygroscopic active pharmaceutical ingredients, it maintains good microneedle formability, mechanical strength, and drug release performance, and can be dried and shaped at room temperature with a short drying time. The matrix composition of this invention is particularly suitable for preparing rapid-release microneedle patches containing locally anesthetic drugs or other pharmaceutically active ingredients requiring rapid onset of action. Attached Figure Description

[0053] The accompanying drawings, which are included to provide a further understanding of this application and form part of this application, illustrate exemplary embodiments and are used to explain this application, but do not constitute an undue limitation of this application. In the drawings:

[0054] Figure 1 The microneedle morphology of the microneedle patch of Embodiment 1 of the present invention is shown under a microscope;

[0055] Figure 2 The in vitro release curve of the microneedle patch of Embodiment 3 of the present invention is shown;

[0056] Figure 3 A photograph of the microneedle patch of Comparative Example 4 is shown.

[0057] Figure 4 The microneedle morphology of the microneedle patch in Comparative Example 12 is shown under a microscope. Detailed Implementation

[0058] This invention constructs a composite matrix system through the synergistic combination of different types of components, thereby achieving multidimensional synergy among microstructure, intermolecular interactions, and macroscopic properties, and realizing a good balance between formability, mechanical strength, and drug release rate. Not limited by any specific theory, the technical effects of this invention may be based on the following synergistic mechanisms, but the invention is not limited thereto.

[0059] (1) The complementary chemical structures of each component enable multiple interactions.

[0060] The various components selected in this invention generally contain polar groups such as hydroxyl, carboxyl, and amide groups, which may form multi-point hydrogen bond interactions in the mixed system. Water-soluble polymers can serve as the main hydrogen bond interaction sites, constructing the basic network structure, providing mechanical support for the system, and helping to improve microneedle formation. Low molecular weight polysaccharides have a high density of hydroxyl groups, which are believed to form bridging effects between polymers and small molecules, helping to enhance the interfacial bonding between different components, improve system homogeneity, and help reinforce the structure, while also promoting the water absorption and dissolution of the microneedle matrix. The multi-hydroxyl structure of small molecule sugar alcohols can participate in the construction of hydrogen bond networks, helping to improve system homogeneity and microneedle formation. At the same time, their high hydrophilicity facilitates water penetration into the matrix, thereby promoting microneedle dissolution and drug release.

[0061] Through the aforementioned multiple interactions, a stable intermolecular network may be formed within the system, with each component working synergistically. This helps to improve the dissolution and drug release performance of microneedles while maintaining good formability and mechanical properties.

[0062] (2) Gradient molecular weight distribution further constructs a composite framework structure

[0063] In a preferred embodiment of the present invention, the weight-average molecular weight of at least one of the water-soluble polymeric materials is greater than that of any one of the low molecular weight polysaccharides, and the weight-average molecular weight of at least one of the low molecular weight polysaccharides is greater than that of any one of the small molecule sugar alcohols, thereby forming a molecular weight gradient structure from high to low. This gradient structure is believed to help further optimize the microstructure and performance balance of the composite matrix system. Higher molecular weight water-soluble polymeric materials are beneficial for forming a continuous framework structure, medium molecular weight low molecular weight polysaccharides help fill the gaps in the framework network and enhance structural continuity, while lower molecular weight small molecule sugar alcohols are more easily dispersed within the system and promote water penetration. The synergistic effect of components at different molecular weight levels may form a hierarchical composite network structure, thereby further helping to balance the formability, mechanical properties, and solubility / drug dissolution properties of microneedles.

[0064] (3) Content ratio regulation achieves performance balance and synergistic enhancement

[0065] Within the content ratio range of the present invention, the proportion of the solubilizing component can be increased while maintaining the microneedle's shapeability, mechanical properties, and puncture resistance, thereby improving the dissolution and drug release behavior of the microneedle.

[0066] It is worth noting that the proportions of each component have a significant impact on the system's performance. For example, excessively high levels of low molecular weight polysaccharides may cause the system to become brittle and prone to breakage; excessively high levels of small molecule sugar alcohols may lead to a decrease in mechanical properties, making the microneedles softer or even deformable; and excessively high levels of polymers may result in a decrease in drug release rate and excessively high solution viscosity during preparation, making it impossible to form needles. The proportions defined in this invention are not arbitrarily chosen, but rather achieve a good balance between microneedle formability, mechanical properties, and drug release performance, resulting in a synergistic improvement in overall performance.

[0067] The inventors further discovered that the composite matrix system of the present invention exhibits good compatibility with highly drug-loaded and / or highly hygroscopic pharmaceutical active ingredients. Theoretically, higher drug loading may weaken the continuity of the microneedle matrix, thus adversely affecting its formability and mechanical properties; while highly hygroscopic pharmaceutical active ingredients may affect the drying process and storage stability of the microneedles. It is believed that the composite matrix system of the present invention can maintain good structural integrity and formability in systems with high drug loading and containing highly hygroscopic pharmaceutical active ingredients through the synergistic effect between different components, while maintaining mechanical properties that meet usage requirements, thereby facilitating the development of such drug microneedle formulations.

[0068] The present invention will be described in detail below through 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. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional experimental conditions. Unless otherwise specified, all reagents and raw materials used in the present invention are commercially available.

[0069] The evaluation methods for microneedle shapeability, mechanical strength, puncture resistance, and in vitro release test (IVRT) examined in the embodiments and comparative examples of this invention are summarized below:

[0070] 1. Evaluation method for microneedle shapeability

[0071] After the microneedles are dried, observe whether the surface of the microneedles in the mold is flat and whether there are any precipitates. Use tweezers to vertically and steadily remove the microneedles with flat surfaces and no precipitates from the mold, and observe and record whether the microneedles deform or break during the demolding process. If there are no such phenomena, place the microneedles under a microscope to observe whether the needle tip is intact. Microneedles that meet the following conditions are judged to have good formability: (1) flat surface, no obvious depressions or cracks; (2) no precipitates visible to the naked eye; (3) complete demolding, no deformation or breakage or other abnormal phenomena; (4) intact needle tip under a microscope. Otherwise, they are judged to have poor formability, and the specific defect type is recorded.

[0072] 2. Evaluation methods for the mechanical strength and puncture resistance of microneedles

[0073] (1) Mechanical strength evaluation method (at least 3 samples per group, average value): Using a high-precision insertion and extraction force testing machine, fix the microneedle patch with the needle tip facing upward on the testing stage. Move the probe of the testing machine vertically downward at a speed of 100 mm / min and measure the force applied by the probe and the vertical displacement curve of the needle tip. If the average vertical displacement of the needle tip exceeds one-third of the original needle length when an axial force of 15 mN / needle is applied, or if the microneedle has broken when an axial force of 15 mN / needle is applied, then the mechanical strength is deemed unqualified. Under the condition that the mechanical strength is qualified, the puncture resistance of the microneedle is examined.

[0074] (2) Puncture evaluation method (at least 3 samples per group, average value): A small amount of trypan blue was added to the prescription solution to prepare trypan blue-stained microneedles. Using a high-precision insertion and extraction force tester, an axial force of 60 mN / needle was applied to the trypan blue-stained microneedles, causing the needle tip to be perpendicularly inserted into the detached pigskin. After 60 seconds, the microneedles were removed, and the number of blue punctures (A) on the detached pigskin was recorded. The puncture rate was calculated based on the total number of microneedles (B). Puncture rate = (A / B) × 100%.

[0075]

[0076] 3. In vitro release assay (IVRT)

[0077] The drug content was determined according to Method 4 (Basket Method) of General Chapter 0931, Part IV, Chinese Pharmacopoeia 2025 Edition. The dissolution medium was pH 7.4 phosphate buffer, 500 mL in volume, at 32℃ and 50 rpm. One microneedle patch was placed in the basket, and samples were taken at predetermined time points, with an equal volume of fresh medium replenished at the same temperature. After filtration, the drug content was determined by HPLC (General Chapter 0512), and the cumulative release rate (%) at each time point was calculated according to the relevant provisions of the Chinese Pharmacopoeia.

[0078] The embodiments and comparative examples of this invention use lidocaine hydrochloride as a model drug to evaluate the effects of different matrix systems on microneedle shapeability, mechanical properties, and drug release performance.

[0079] Examples 1-12

[0080] The microneedle patches of Examples 1-12 of the present invention were prepared according to the microneedle prescriptions listed in Table 1 by following these steps:

[0081] (1) Weigh each material according to the prescription and place it in a vial. Add an appropriate amount of water as a solvent, stir to completely dissolve the matrix material, centrifuge to remove air bubbles, and obtain a microneedle solution.

[0082] (2) Add microneedle solution to the microneedle mold, spread the solution evenly, draw a vacuum at the bottom of the mold to allow the solution to enter the mold cavity, and place it at room temperature to dry;

[0083] (3) Remove the microneedles from the mold.

[0084] Table 1. Formulation composition and performance results of microneedle patches in Examples 1-12

[0085]

[0086] The dry weight composition of the matrix compositions used in each formulation of Examples 1-12 of the present invention is shown in Table 2 below.

[0087] Table 2. Dry weight composition of the matrix compositions used in each formulation of Examples 1-12

[0088]

[0089] As can be seen from Tables 1 and 2, the microneedle patches prepared using the matrix composition of the present invention in Examples 1 to 12 have good formability, smooth surface, no visible exudates, and can be completely demolded while the needle tips remain intact (taking Example 1 as an example, its microneedle morphology is as follows). Figure 1 (As shown); its mechanical strength meets the requirements for skin puncture and it has good punctureability; at the same time, it exhibits good drug release performance and is suitable for drug delivery that requires rapid onset of action.

[0090] Figure 2 The in vitro release curve of the microneedle patch of Example 3 of the present invention is shown. The results show that the drug was essentially completely released within 30 minutes.

[0091] The matrix composition of this invention, by combining water-soluble polymers, low-molecular-weight polysaccharides, and small-molecule sugar alcohols within a specific ratio range to form a composite matrix system, achieves good drug release performance while maintaining good formability and mechanical properties. This matrix composition is suitable for drugs requiring rapid onset of action and exhibits good compatibility with highly hygroscopic active ingredients such as lidocaine hydrochloride. In the embodiments of this invention, the drug content can reach 50%. Furthermore, microneedles prepared using the matrix composition of this invention can be dried and shaped within 24 hours at room temperature, demonstrating good process adaptability.

[0092] Comparative Examples 1-8

[0093] The performance of microneedles prepared from different matrix formulations as described in existing patents and screened during the research and development process is compared below to illustrate the superiority of the formulation system of this invention.

[0094] Microneedle patches of Comparative Examples 1 to 8 were prepared according to the methods of Examples 1 to 12. The formulation composition and performance results are shown in Table 3 below.

[0095] Table 3. Formulation composition and performance results of microneedle patches in Comparative Examples 1-8

[0096]

[0097] The dry weight composition of the matrix compositions used in Comparative Examples 1 to 8 of this invention is shown in Table 4 below, based on calculations.

[0098] Table 4. Dry weight composition of the matrix compositions used in each formulation of Comparative Examples 1-8

[0099]

[0100] Comparative Example 1 was prepared according to the formulation of Example 9 in existing patent CN 110799238 B, using a composition of 70% polyvinyl alcohol (PVA) and 30% maltose as the matrix material. The prepared microneedle patch was relatively soft and easily deformed upon demolding, and its in vitro drug release rate was significantly lower than that of Example 1 at the same drug content. Comparative Example 2 used the same matrix material composition as Comparative Example 1, but increased the drug content. The prepared microneedles were also relatively soft and easily deformed upon demolding. The mechanical strength of the microneedles prepared from this matrix material composition met the test requirements, but the puncture resistance was only at a general level.

[0101] Comparative Examples 3 and 4 were prepared according to the formulations of Examples 4 and 1 of the existing patent CN 111991344 B, respectively. The microneedles of Comparative Example 3 were fragile upon demolding, resulting in a low yield of intact microneedle patches and poor molding stability. In Comparative Example 4, a white ring (precipitated solid) phenomenon was observed in the microneedle backing layer (e.g., Figure 3 As shown in the figure, the in vitro drug release rate is low.

[0102] Furthermore, the microneedle patches of Comparative Examples 1-3 required a long time to fully dry, and were not completely dry even after being left at room temperature for 72 hours. In contrast, the microneedle patches of Examples 1-12 of the present invention were dried and formed within 24 hours at room temperature, and showed good demolding properties.

[0103] Comparative Examples 5-8 attempted to improve microneedle formability and drug release rate by combining sodium hyaluronate of different molecular weights with small molecule disaccharides. However, the microneedles prepared by the formulations of Comparative Examples 5-6 were easily brittle upon demolding, and the backing layer of the microneedles in Comparative Examples 7-8 showed white rings or local white spots (precipitated solids), all of which had obvious forming defects.

[0104] As can be seen from the results of Comparative Examples 1 to 8, the single polymer system or simple compound system of polymer and disaccharide used in the existing technology and screened in the research and development process are difficult to simultaneously take into account the microneedle formation, mechanical properties and drug release performance.

[0105] Comparative Examples 9-13

[0106] The following comparative examples 9-13 examine the performance of microneedles after the absence of any one component (water-soluble polymer, low molecular weight polysaccharide or small molecule sugar alcohol) in the matrix composition of the present invention.

[0107] Microneedle patches of Comparative Examples 9-13 were prepared according to the methods of Examples 1-12. The specific formulation composition and performance results are shown in Table 5.

[0108] Table 5. Formulation composition and performance results of microneedle patches in Comparative Examples 9–13

[0109]

[0110] The dry weight composition of the matrix compositions used in the formulations of Comparative Examples 9 to 13 of this invention is shown in Table 6 below, based on calculations.

[0111] Table 6. Dry weight composition of the matrix compositions used in each formulation of Comparative Examples 9-13

[0112]

[0113] Of these, Comparative Examples 9-11 contained only water-soluble polymers and low-molecular-weight polysaccharides in their formulations. While Comparative Example 9 exhibited good microneedle demolding, its drug release rate was slow. Comparative Example 10 attempted to combine a lower molecular weight polymer with a low-molecular-weight polysaccharide, but the backing plate broke during demolding, resulting in poor microneedle formability. Comparative Example 11 attempted to add low-molecular-weight polyvinylpyrrolidone to improve microneedle formability and drug release rate, but the prepared microneedles were soft, easily deformed during demolding, and had poor puncture resistance. Comparative Example 12's microneedle formulation contained only water-soluble polymers and small-molecule sugar alcohols; the prepared microneedles were whitish, and microscopic observation revealed an uneven surface and abnormal morphology (e.g., ...). Figure 4 (As shown). The microneedle formulation of Comparative Example 13 contained only low molecular weight polysaccharides and small molecule sugar alcohols, and the backing plate broke during demolding, making complete demolding impossible.

[0114] Therefore, it is evident that each component in the matrix composition of this invention makes a significant contribution to the overall performance of the microneedles. Specifically, the absence of small-molecule sugar alcohols significantly reduces the drug release rate and may affect the formability and mechanical properties of the microneedles; the absence of low-molecular-weight polysaccharides affects the formability of the microneedles; and the absence of water-soluble polymers makes it difficult to obtain a complete microneedle structure with sufficient mechanical strength.

[0115] As can be seen from the above examples and comparative results, the present invention combines water-soluble polymer materials, low molecular weight polysaccharides and small molecule sugar alcohols in a specific ratio, and the components have a good synergistic effect, which can achieve rapid drug release while maintaining good microneedle shapeability and mechanical properties.

[0116] Experiment Example 1: Anesthesia Effect in Guinea Pigs

[0117] Three healthy guinea pigs were selected for each group, female, weighing 260-280g. Hair was removed from the backs of the guinea pigs before administration. Microneedle patches from Examples 1-3 and Comparative Examples 1-3 and 9 were applied to the hairless skin, pressed for 15 seconds, and removed after 5 minutes. The skin pain response at the administration site was tested using a needle prick method: a 34G needle syringe was inserted vertically into the administration site to a depth of approximately 1.2mm. One prick was applied to each side every 2 minutes from the moment the patch was removed, with skin contraction and spasm as the observation indicator. The onset time was the time when the skin showed no needle prick response for the first time after patch removal; the expiration time was the time when the number of responses in one round of testing first reached or exceeded half of the total number of pricks; the interval between the onset time and the expiration time was recorded as the anesthesia duration. The experimental results are shown in Table 7 below.

[0118] Table 7. Anesthesia Efficacy Evaluation in Examples and Comparative Cases

[0119]

[0120] As can be seen from the results in Table 7, the samples of each embodiment and comparative example took effect immediately after being removed from the patch. Under the same conditions of active pharmaceutical ingredient content, the microneedle patches of Examples 1-3 prepared using the matrix composition of the present invention all showed a significantly longer duration of anesthesia, and their in vivo anesthetic effect was significantly better than that of the microneedle patches of Comparative Examples 1-3 and Comparative Example 9 prepared using other matrix compositions.

[0121] The above results indicate that the drug-loaded microneedles prepared from the matrix composition of the present invention not only have good microneedle shapeability, mechanical properties and in vitro release performance, but also have significantly improved in vivo drug release and delivery effects, thereby better meeting the application needs of drugs that require rapid onset of action.

[0122] The matrix composition of this invention is suitable for drugs requiring rapid onset of action. Examples of this invention were studied using lidocaine hydrochloride as a representative model drug. Experimental results show that, even at high drug concentrations, this invention can still produce microneedle patches with good formability, sufficient mechanical strength, and rapid drug release. Since lidocaine hydrochloride also has strong hygroscopic properties, the above results further indicate that the matrix composition of this invention has good compatibility and application potential for highly drug-loaded and / or highly hygroscopic active pharmaceutical ingredients.

[0123] For different drugs, those skilled in the art can make appropriate adjustments to the specific prescription composition and process parameters according to their physicochemical properties without affecting the implementation of the present invention.

[0124] The above embodiments are for illustrative purposes only and are not intended to limit the scope of protection of the present invention. Various modifications, equivalent substitutions, or improvements made by those skilled in the art without departing from the spirit and substance of the present invention should fall within the scope of protection of the present invention.

Claims

1. A rapid-release microneedle matrix composition, wherein, Based on 100% of the total weight of the matrix composition, it comprises: Water-soluble polymer materials: 10~40%; Low molecular weight polysaccharides: 35-80%; and Small molecule sugar alcohols: 1~30%.

2. The matrix composition according to claim 1, wherein, The water-soluble polymer material is selected from one or more of hyaluronic acid or its salts, water-soluble cellulose derivatives, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, and pullulan; and / or The low molecular weight polysaccharide is selected from one or more of dextran, dextrin, chitosan, and alginate or their salts; and / or The small molecule sugar alcohol is selected from one or more of erythritol, mannitol, sorbitol and xylitol.

3. The matrix composition according to claim 2, wherein, The water-soluble cellulose derivative is selected from one or more of carboxymethyl cellulose or its salts, hydroxypropyl cellulose or its salts, hydroxyethyl cellulose or its salts, methyl cellulose or its salts, and hydroxypropyl methyl cellulose or its salts. Preferably, the viscosity of a 2% aqueous solution of the water-soluble cellulose derivative at 25°C is 15~13000 mPa·s; more preferably, the viscosity of a 2% aqueous solution of the water-soluble cellulose derivative at 25°C is 15~700 mPa·s.

4. The matrix composition according to any one of claims 1 to 3, wherein: The water-soluble polymer material has a weight-average molecular weight of 10 kDa to 2000 kDa, preferably 40 kDa to 1000 kDa; and / or The weight-average molecular weight of the low molecular weight polysaccharide is 10 kDa to 80 kDa, preferably 10 kDa to 50 kDa; and / or The weight-average molecular weight of the small molecule sugar alcohol is 100 Da to 300 Da, preferably 120 Da to 250 Da; Preferably, the weight-average molecular weight of at least one of the water-soluble polymeric materials is greater than the weight-average molecular weight of any one of the low molecular weight polysaccharides, and the weight-average molecular weight of at least one of the low molecular weight polysaccharides is greater than the weight-average molecular weight of any one of the small molecule sugar alcohols.

5. The matrix composition according to any one of claims 1 to 4, wherein, Based on the total weight of the matrix composition being 100%, The content of the water-soluble polymer material is 15-30%; and / or The content of the low molecular weight polysaccharide is 38-78%; and / or The content of the small molecule sugar alcohol is 5-25%; and / or The total content of the low molecular weight polysaccharide and small molecule sugar alcohol is 60% to 90%, preferably 70% to 85%.

6. The matrix composition according to any one of claims 1 to 5, wherein, The water-soluble polymeric material comprises a mixture of hyaluronic acid or its salt and a water-soluble cellulose derivative; and / or The low molecular weight polysaccharide comprises dextran, which is preferably selected from one or more of dextran 20, dextran 40, and dextran 70; and / or The small molecule sugar alcohols include sorbitol and / or mannitol; Preferably, the water-soluble polymer material is composed of hyaluronic acid or its salt and a water-soluble cellulose derivative; more preferably, the weight ratio of the hyaluronic acid or its salt to the water-soluble cellulose derivative is 1:1 to 100:1, preferably 5:1 to 50:

1.

7. A rapid-release microneedle patch comprising the matrix composition of any one of claims 1 to 6 and a drug requiring rapid onset of action.

8. The microneedle patch according to claim 7, wherein, The drug is selected from one or more of local anesthetic drugs and fast-acting anti-inflammatory and analgesic drugs; Preferably, the local anesthetic drug is selected from one or more of lidocaine, prilocaine, tetracaine, benzocaine, levobupivacaine, ropivacaine, and pharmaceutically acceptable salts thereof; and / or the rapid-acting anti-inflammatory and analgesic drug is selected from one or more of ibuprofen sodium, diclofenac sodium, and ketorolac tromethamine. Preferably, the weight ratio of the drug to the matrix composition is 1:0.2~50; More preferably, the weight ratio of the drug to the matrix composition is 1:0.5~10; More preferably, the weight ratio of the drug to the matrix composition is 1:1 to 2.

9. A method for preparing a rapid drug-release microneedle patch as described in claim 7 or 8, comprising the following steps: S1: The matrix composition according to any one of claims 1 to 6 is mixed evenly with the drug requiring rapid onset of action in a solvent and injected into a microneedle mold; and S2: Dry and demold to obtain the microneedle patch; Preferably, the solvent is selected from one or more of water, methanol, ethanol, isopropanol, propylene glycol, glycerol, dimethyl sulfoxide, N,N-dimethylacetamide, and N-methylpyrrolidone; and / or the process includes stirring and / or centrifugation before molding; and / or applying a vacuum under the mold during molding; and / or the drying is carried out at 15~45°C, more preferably at room temperature; and / or the drying is carried out at a relative humidity of 10%~40%.

10. Use of the matrix composition according to any one of claims 1 to 6 in the preparation of rapid-release microneedle patches; Preferably, the rapid-release microneedle patch contains a local anesthetic drug and / or a fast-acting anti-inflammatory and analgesic drug; More preferably, the local anesthetic drug is selected from one or more of lidocaine, prilocaine, tetracaine, benzocaine, levobupivacaine, ropivacaine, and their pharmaceutically acceptable salts; and / or the rapid-acting anti-inflammatory and analgesic drug is selected from one or more of ibuprofen sodium, diclofenac sodium, and ketorolac tromethamine.

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