Dexmedetomidine sustained-release microneedle and preparation process thereof

Abstract

The invention provides a dexmedetomidine sustained-release microneedle and a preparation process thereof. The dexmedetomidine sustained-release microneedle comprises a first section of matrix containing 3.5 W% of hyaluronic acid and 3.5 W% of polyvinylpyrrolidone, the matrix is degraded within about 10 minutes and can provide rapid preliminary drug release, and a second section of matrix containing 15 W% of polyvinyl methyl ether-alt-maleic acid, the matrix is slowly degraded within about 3 hours and can provide rapid preliminary drug release. And sustained drug release is provided. According to the dexmedetomidine sustained-release microneedle and the preparation process thereof, the sustained-release microneedle adopts a two-section structure, and high-performance materials such as hyaluronic acid, polyvinylpyrrolidone and polyvinyl methyl ether-alt-maleic acid are combined, so that the release process of a medicine is divided into two stages of quick effect taking and long-acting sustained release. The first section of matrix is degraded within 10 minutes, 30% of medicine can be rapidly released, and rapid effect taking is achieved.

Description

Technical Field

[0001] The present invention relates to the technical field of dexmedetomidine sustained-release microneedles, and specifically to a dexmedetomidine sustained-release microneedle and its preparation process. Background Art

[0002] The dexmedetomidine microneedle combines the dexmedetomidine drug and microneedle technology, which is an innovative preparation aiming to provide a more continuous and stable drug release and optimize the patient's treatment experience. Dexmedetomidine is a highly selective α2-adrenergic receptor agonist, and its sedative effect mainly acts on the locus coeruleus in the brainstem, significantly reducing neuronal excitability, thereby inducing a sedative state similar to natural physiological sleep without disrupting the normal sleep structure. Compared with traditional hypnotics, dexmedetomidine can better maintain the proportion of rapid eye movement (REM) and non-rapid eye movement (NREM) sleep, which helps to improve the overall sleep quality of patients. Currently, dexmedetomidine is mainly administered by intravenous injection for sedation, analgesia, and intensive care management. However, the intravenous administration method is prone to large fluctuations in drug concentration, increasing the risk of side effects. In addition, the single-dose form of dexmedetomidine has problems such as a short release duration and insufficient drug support in the pre-sleep period when treating insomnia, which is not conducive to continuously improving sleep quality.

[0003] Microneedle technology realizes non-invasive transdermal drug delivery by loading drugs into a microneedle array. Dexmedetomidine microneedles can penetrate the skin to provide slow and stable drug release, avoiding large fluctuations in drug concentration, and at the same time reducing the fear and discomfort of patients towards traditional injection therapies. Microneedles are usually only a few hundred micrometers long, do not touch the nerves and blood vessels in the skin, and are almost painless, making it an optimal drug delivery method suitable for long-term treatment. Although microneedle technology has shown significant advantages, it still faces many challenges at present. For example, the release time of existing microneedles is difficult to cover the entire night sleep cycle, and the relatively low drug concentration in the pre-sleep period may affect the sleep induction effect. In addition, single-dose administration may lead to poor patient compliance and is difficult to meet the dual requirements of optimizing the sleep structure and continuous drug action. Summary of the Invention

[0004] In view of the deficiencies of the prior art, the present invention provides a dexmedetomidine sustained-release microneedle and its preparation process, which solve the problems of short administration time, poor patient compliance, and disruption of the sleep structure.

[0005] To achieve the above objectives, the present invention is realized through the following technical solutions: A dexmedetomidine sustained-release microneedle and its preparation process, including:

[0006] The first section of the matrix: contains 3.5W% hyaluronic acid and 3.5W% polyvinylpyrrolidone, and this matrix degrades within about 10 minutes, capable of providing a rapid initial drug release;

[0007] Second section matrix: containing 15W% polyvinyl methyl ether-alt-maleic acid, which slowly degrades within about 3 hours to provide sustained drug release;

[0008] Microneedle substrate: composed of 20W% polyvinylpyrrolidone, providing mechanical strength and stability for the microneedles.

[0009] Preferably, the dexmedetomidine is uniformly dispersed and loaded in the microneedle matrix. The drug loading amount of dexmedetomidine is 80 micrograms in the first section matrix and 120 micrograms in the second section matrix, ensuring that the drug can be uniformly released through the microneedle array and having good skin permeability.

[0010] Preferably, the polyvinyl methyl ether-alt-maleic acid can decompose in the body to produce water-soluble products, ensuring the sustained release of the drug when the microneedle matrix degrades and not affecting the drug effect due to the accumulation of degradation products.

[0011] A preparation process for dexmedetomidine sustained-release microneedles includes the following steps:

[0012] a. Preparation of the first section matrix: Hyaluronic acid and polyvinylpyrrolidone are mixed in a ratio of 3.5W%:3.5W%, dissolved in water to prepare a first section matrix solution. The dissolution temperature of hyaluronic acid and PVP is 25°C - 30°C to ensure complete dissolution. This first section matrix degrades within about 10 minutes and can provide rapid drug release;

[0013] b. Preparation of the second section matrix: Polyvinyl methyl ether-alt-maleic acid and PVP are mixed in a ratio of 15W%: appropriate ratio, dissolved in an aqueous solution at 30°C - 40°C to ensure complete dissolution, forming a uniform second section matrix solution. This second section matrix slowly degrades within about 3 hours to provide sustained drug release;

[0014] c. Preparation of the dexmedetomidine stock solution: Prepare a high-concentration dexmedetomidine stock solution using ethanol;

[0015] d. Preparation of the microneedle array mold: Use a silicone mold or a metal mold to prepare a microneedle array template. The tip shape of the microneedles can be conical or multi-tipped to optimize the penetration effect;

[0016] e. Injection of the microneedle matrix: Mix the second section matrix solution and the dexmedetomidine stock solution in a predetermined ratio, and use a precision injection system to inject the solution into the microneedle array mold (the matrix liquid fills the middle of the microneedle cavity), and then perform vacuum drying; subsequently, mix the first section matrix solution and the dexmedetomidine stock solution in a predetermined ratio and inject it into the microneedle array to ensure that the second matrix liquid fills each microneedle;

[0017] f. Freeze-drying: Freeze the mold injected with the matrix solution;

[0018] g. Micro - needle demolding and trimming: Take out the solidified micro - needle array from the mold, check whether the micro - needles are intact, trim the micro - needles to ensure the sharpness of the needle tips, avoid broken and irregular parts, and ensure that they can penetrate the skin smoothly;

[0019] h. Packaging and aseptic treatment: Package the micro - needles using a medical - grade sterile packaging bag to ensure their sterility, and perform aseptic treatment using irradiation sterilization or ethylene oxide sterilization methods to ensure the safety of the micro - needle products;

[0020] i. Quality inspection: Conduct quality testing on the final product, mainly including drug release rate, mechanical strength of the micro - needles, sterility, and drug stability, etc. Use in - vitro release experiments to measure the drug release rate of the micro - needles in a simulated skin environment to ensure that it meets the predetermined release time;

[0021] j. Setting of storage conditions: The storage temperature of the micro - needle products should be controlled between 5°C and 25°C to avoid the influence of high temperature on the drug and micro - needle materials;

[0022] k. Clinical testing: Conduct preliminary clinical testing to verify the effects of the micro - needles on patients, including drug sustained - release, compliance, and clinical safety. Ensure the long - term effects of the drug by monitoring the continuous sedative effect of the drug and its impact on sleep structure;

[0023] l. Optimization and improvement: Further optimize the drug release characteristics by adjusting the proportion of matrix materials, drug loading, and degradation rate to meet different clinical needs.

[0024] Preferably, the tip length of the micro - needles is 50 to 500 microns to ensure that they can penetrate the skin smoothly and release the drug.

[0025] Preferably, the drug loading is 80 micrograms in the first - stage matrix and 120 micrograms in the second - stage matrix to ensure that dexmedetomidine is evenly dispersed in the matrix solution, avoid the aggregation of dexmedetomidine, ensure the mechanical properties of the micro - needles, and have good skin permeability.

[0026] Preferably, the freezing temperature is - 40°C to - 20°C, the drying temperature is 25°C to 40°C, and the freeze - drying time is 8 to 12 hours to ensure that the moisture in the matrix is completely removed to form a stable micro - needle structure.

[0027] Preferably, the storage humidity should be controlled between 30% and 70% to ensure the stability of the product.

[0028] The present invention provides a dexmedetomidine sustained - release micro - needle and its preparation process. It has the following beneficial effects:

[0029] The dexmedetomidine sustained-release microneedle and its preparation process. The sustained-release microneedle adopts a double-section structure and combines high-performance materials such as hyaluronic acid, polyvinylpyrrolidone, and polyvinyl methyl ether-alt-maleic acid, enabling the drug release process to be divided into two stages: rapid onset and long-acting sustained release. The first-section matrix degrades within 10 minutes, rapidly releasing 30% of the drug to achieve rapid onset; the second-section matrix degrades slowly within 3 hours, steadily releasing the remaining drug to ensure the effective concentration is maintained for a long time. Compared with intravenous injection and nasal spray methods, this solution significantly prolongs the action time of the drug, avoiding the disadvantage of drastic fluctuations in drug concentration in traditional drug delivery methods. The sustained-release microneedle is a non-invasive drug delivery method, and its characteristic of stable drug release can reduce the frequency of nighttime medication and avoid interrupting the sleep structure due to frequent drug administration. At the same time, the microneedle design has good mechanical strength, is easy to penetrate the skin and release the drug, is convenient to use, and reduces the compliance burden on patients. Therefore, this technical solution not only has better efficacy duration than traditional methods but also greatly improves the patient's usage experience and treatment effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 It is a comparison chart of drug concentration-time curves for different drug delivery methods of the present invention.

[0031] Figure 2 Comparison chart of key indicators for different drug delivery methods.

[0032] Figure 3 It is a comparison chart of drug release of the dexmedetomidine sustained-release microneedle. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0033] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0034] Example 1:

[0035] As Figures 1-3 shown, the embodiment of the present invention provides a dexmedetomidine sustained-release microneedle and its preparation process, including: the first-section matrix: containing 3.5W% hyaluronic acid and 3.5W% polyvinylpyrrolidone, and this matrix degrades within about 10 minutes, capable of providing rapid initial drug release.

[0036] The second-section matrix: containing 15W% polyvinyl methyl ether-alt-maleic acid, and this matrix degrades slowly within about 3 hours, providing continuous drug release.

[0037] Microneedle Substrate: Composed of 20W% polyvinylpyrrolidone, it provides the mechanical strength and stability of the microneedles. Dexmedetomidine is directly loaded into the microneedle matrix. The drug loading amount of dexmedetomidine is 80 micrograms in the first-section matrix and 120 micrograms in the second-section matrix, ensuring that the drug can be evenly released through the microneedle array and has good skin permeability. Polyvinyl methyl ether-alt-maleic acid can decompose in the body and produce water-soluble products, ensuring the sustained release of the drug when the microneedle matrix degrades and not affecting the drug effect due to the accumulation of degradation products.

[0038] A preparation process for sustained-release dexmedetomidine microneedles includes the following steps:

[0039] a. Preparation of the first-section matrix: Hyaluronic acid and polyvinylpyrrolidone are mixed in a ratio of 3.5W%:3.5W% and dissolved in water to prepare the first-section matrix solution. The dissolution temperature of hyaluronic acid and PVP is 25°C - 30°C to ensure complete dissolution. This first-section matrix degrades within about 10 minutes and can provide rapid release of the drug.

[0040] b. Preparation of the second-section matrix: Polyvinyl methyl ether-alt-maleic acid and PVP are mixed in a ratio of 15W%:appropriate ratio and dissolved in an aqueous solution at 30°C - 40°C to ensure complete dissolution, forming a uniform second-section matrix solution. This second-section matrix degrades slowly within about 3 hours, providing sustained release of the drug.

[0041] c. Preparation of the dexmedetomidine stock solution: Use ethanol to prepare a high-concentration dexmedetomidine stock solution.

[0042] d. Preparation of the microneedle array mold: Use a silicone mold or a metal mold to prepare the microneedle array template. The tip shape of the microneedles can be conical or multi-tipped to optimize the penetration effect. The tip length of the microneedles is 50 to 500 microns to ensure smooth penetration of the skin and release of the drug.

[0043] e. Injection of the microneedle matrix: Mix the second-section matrix solution and the dexmedetomidine stock solution in a predetermined ratio, and use a precision injection system to inject the solution into the microneedle array mold (the matrix liquid fills the middle of the microneedle cavity), and then perform vacuum drying; subsequently, mix the first-section matrix solution and the dexmedetomidine stock solution in a predetermined ratio and inject them into the microneedle array to ensure that the second matrix liquid fills each microneedle.

[0044] f. Freeze-drying: Freeze the mold injected with the matrix solution at a freezing temperature of -40°C to -20°C, and the drying temperature is 25°C to 40°C. The freeze-drying time is 8 hours to 12 hours to ensure that the moisture in the matrix is completely removed, forming a stable microneedle structure.

[0045] g. Micro-needle Demolding and Trimming: Take out the solidified micro-needle array from the mold, check if the micro-needles are intact, trim the micro-needles to ensure the sharpness of the needle tips, avoid broken and irregular parts, and ensure smooth penetration of the skin.

[0046] h. Packaging and Sterilization: Package the micro-needles using medical-grade sterile packaging bags to ensure their sterility, and perform sterilization treatment using irradiation sterilization or ethylene oxide sterilization methods to ensure the safety of the micro-needle products.

[0047] i. Quality Inspection: Conduct quality testing on the final products, mainly including drug release rate, mechanical strength of the micro-needles, sterility, and drug stability, etc. Use in vitro release experiments to measure the drug release rate of the micro-needles in a simulated skin environment and ensure it meets the predetermined release time.

[0048] j. Setting of Storage Conditions: The storage temperature of the micro-needle products should be controlled between 5°C and 25°C to avoid the influence of high temperature on the drug and micro-needle materials, and the storage humidity should be controlled between 30% and 70% to ensure the stability of the products.

[0049] k. Clinical Testing: Conduct preliminary clinical tests to verify the effects of the micro-needles on patients, including drug sustained release, compliance, and clinical safety. Ensure the long-term effects of the drug by monitoring the continuous sedative effect of the drug and its impact on sleep structure.

[0050] l. Optimization and Improvement: Further optimize the drug release characteristics by adjusting the proportion of matrix materials, drug loading, and degradation rate to meet different clinical needs.

[0051] Example Two

[0052] Experimental Objectives

[0053] Verify the superiority of the dexmedetomidine sustained-release micro-needles prepared by this technical solution in terms of drug release performance and sustained-release effect.

[0054] Experimental Contents

[0055] In Vitro Release Experiment

[0056] Immerse the micro-needles in a simulated skin environment (phosphate buffer solution with pH 7.4);

[0057] Sample every 30 minutes to detect the release amount of dexmedetomidine;

[0058] Use high-performance liquid chromatography to analyze the drug concentration and plot the release curve.

[0059] Pharmacodynamic Persistence Test

[0060] Perform in vivo drug concentration determination on animal models (such as rats);

[0061] Measure the concentration of dexmedetomidine in plasma and plot the plasma drug concentration-time curve.

[0062] Mechanical property test

[0063] Measure the mechanical strength of the microneedles using a hardness tester;

[0064] Detect whether the microneedles can penetrate the simulated skin (such as a silicone membrane) smoothly.

[0065] 4. Experimental results

[0066] Drug release curve

[0067] In the initial stage of microneedle release (0 - 10 minutes), 30% of dexmedetomidine is rapidly released for rapid onset of action;

[0068] In the next 3 hours, the drug is slowly released with a stable concentration, and the release amount reaches 90%.

[0069] Duration of drug effect

[0070] The effective concentration times of intravenous injection and nasal spray drugs are 1.5 hours and 3 hours respectively;

[0071] The effective concentration maintenance time of the sustained-release microneedles is 4.5 hours, which is significantly better than the traditional methods.

[0072] Mechanical properties

[0073] The average hardness of the microneedle tips reaches 150 MPa, which can penetrate the simulated skin smoothly without tip breakage.

[0074] 5. Conclusion

[0075] This example verifies the feasibility of the preparation process of dexmedetomidine sustained-release microneedles. The prepared microneedles show excellent performance in drug release properties, sustained-release effect and mechanical properties. Its significant advantages include:

[0076] Rapid onset + long-acting sustained release: The drug release curve conforms to the expected design and meets the clinical needs;

[0077] Excellent mechanical strength: It can ensure that the microneedles penetrate the skin smoothly;

[0078] Improve compliance: It is easy to use and does not require frequent drug administration.

[0079] Although the embodiments of the present invention have been shown and described, it will be understood by those of ordinary skill in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the present invention. The scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A dexmedetomidine sustained-release microneedle, characterized in that: include: Section 1 Matrix: Contains 3.5W% hyaluronic acid and 3.5W% polyvinylpyrrolidone. The matrix degrades in about 10 minutes and can provide rapid initial drug release; Section 2 Matrix: Contains 15W% polyvinyl methyl ether-alt-maleic acid, which slowly degrades in about 3 hours, providing sustained drug release; Microneedle substrate: composed of 20W% polyvinyl pyrrolidone, providing mechanical strength and stability of the microneedle.

2. The dexmedetomidine sustained-release microneedle according to claim 1, characterized in that: The dexmedetomidine is directly loaded into the microneedle matrix, and the dexmedetomidine drug loading is 80 micrograms in the first section of the matrix and 120 micrograms in the second section of the matrix, ensuring that the drug can be evenly released through the microneedle array and has good skin permeability.

3. The dexmedetomidine sustained-release microneedle according to claim 1, characterized in that: The polyvinyl methyl ether-alt-maleic acid can be decomposed in the body and produce water-soluble products. When the microneedle matrix is ​​degraded, the continuous release of the drug is ensured, and the drug effect is not affected by the accumulation of degradation products.

4. A process for preparing dexmedetomidine sustained-release microneedles, characterized in that: The following steps are involved: a. Preparation of the first section matrix: hyaluronic acid and polyvinyl pyrrolidone are mixed in a ratio of 3.5W%:3.5W%, dissolved in water, and prepared into the first section matrix solution. The dissolution temperature of hyaluronic acid and PVP is 25°C-30°C to ensure complete dissolution. The first section matrix degrades within about 10 minutes and can provide rapid release of the drug; b. Preparation of the second section matrix: polyvinyl methyl ether-alt-maleic acid and PVP are mixed in an appropriate ratio of 15W%, dissolved in an aqueous solution at 30°C-40°C, and complete dissolution is ensured to form a uniform second section matrix solution, which slowly degrades within about 3 hours to provide sustained drug release; c. Preparation of dexmedetomidine mother solution: using ethanol to prepare a high concentration of dexmedetomidine mother solution; d. Preparation of microneedle array mold: Use a silicone mold or a metal mold to prepare a microneedle array template. The tip shape of the microneedle can be conical or multi-pointed to optimize the penetration effect; e. Microneedle matrix injection: The second section matrix solution and the dexmedetomidine mother solution are mixed in a predetermined ratio, and the solution is injected into the microneedle array mold using a precision injection system. The matrix liquid fills the middle of the microneedle cavity and is vacuum dried. Subsequently, the first section matrix solution and the dexmedetomidine mother solution are mixed in a predetermined ratio and injected into the microneedle array to ensure that the second matrix liquid fills each microneedle; f. Freeze drying: freeze the mold after injecting the matrix solution; g. Microneedle demoulding and trimming: Remove the solidified microneedle array from the mold, check whether the microneedles are intact, and trim the microneedles to ensure the sharpness of the needle tip, avoid breakage and irregular parts, and ensure that they can penetrate the skin smoothly; h. Packaging and aseptic processing: Use medical-grade sterile packaging bags to package the microneedles to ensure their sterility, and use irradiation sterilization or ethylene oxide sterilization methods for aseptic processing to ensure the safety of microneedle products; i. Quality inspection: Quality inspection of the final product, mainly including drug release rate, mechanical strength of microneedles, sterility and drug stability, etc. In vitro release experiments are used to measure the drug release rate of microneedles in a simulated skin environment to ensure that it meets the predetermined release time; j. Storage condition setting: The storage temperature of microneedle products should be controlled between 5°C and 25°C to avoid the impact of high temperature on drugs and microneedle materials; k. Clinical testing: Conduct preliminary clinical testing to verify the effects of microneedles on patients, including the sustained release, compliance and clinical safety of the drug, and ensure the long-term effects of the drug by monitoring the drug's sustained sedative effect and impact on sleep structure; l. Optimization and improvement: By adjusting the proportion of matrix materials, drug loading and degradation rate, the drug release characteristics can be further optimized to meet different clinical needs.

5. A process for preparing dexmedetomidine sustained-release microneedles according to claim 4, characterized in that: The tip length of the microneedle is 50 to 500 microns, ensuring that it can smoothly penetrate the skin and release the drug.

6. A process for preparing dexmedetomidine sustained-release microneedles according to claim 4, characterized in that: The drug loading is 50 micrograms to 500 micrograms, ensuring that the drug is evenly dispersed in the matrix solution, avoiding particle aggregation, ensuring uniform drug release, and having good skin permeability.

7. A process for preparing dexmedetomidine sustained-release microneedles according to claim 4, characterized in that: The freezing temperature is -40°C to -20°C, the drying temperature is 25°C to 40°C, and the freeze-drying time is 8 hours to 12 hours, ensuring that the moisture in the matrix is ​​completely removed to form a stable microneedle structure.

8. A process for preparing dexmedetomidine sustained-release microneedles according to claim 4, characterized in that: The storage humidity should be controlled between 30% and 70% to ensure the stability of the product.

Images