A soluble microneedle patch for drug enrichment at the needle tip and its preparation method
By combining low-temperature centrifugal drying and room-temperature centrifugal drying, the drug is enriched at the tip of the microneedle, which solves the problem of low utilization rate of traditional soluble microneedle drugs and achieves more efficient drug delivery and biosafety.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- INSTITUTE OF BASIC MEDICINE & CANCER CHINESE ACADEMY OF SCIENCES (PREPARATORY)
- Filing Date
- 2023-06-02
- Publication Date
- 2026-05-26
AI Technical Summary
Traditional methods for preparing soluble microneedles result in low drug utilization rates in the skin, with some drugs failing to dissolve completely, leading to waste. Furthermore, organic solvents may affect drug activity or leave residues.
A combination of low-temperature centrifugal drying and room-temperature centrifugal drying is used to enrich the drug at the tip of the microneedle. The drug-loaded tip is formed by low-temperature centrifugal drying, while a soluble polymer is used to form the microneedle substrate to prevent the drug from diffusing to the entire needle body or substrate.
It improves drug utilization in the skin, reduces drug waste, maintains the bioactivity of drug molecules, avoids organic solvent residue, and achieves better puncture results.
Smart Images
Figure CN116747186B_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of microneedle technology, specifically relating to a soluble microneedle patch for enriching drugs at the needle tip and its preparation method. Background Technology
[0002] Soluble microneedles have many advantages, such as high safety, good biocompatibility, and biodegradability. However, soluble microneedles prepared by traditional methods cannot be fully utilized after entering the skin. Because the skin has a certain degree of elasticity, the microneedle body cannot be completely embedded in the skin. Only about half of the microneedle body can be completely dissolved in the skin, while the rest cannot be effectively utilized because they cannot be completely embedded below the stratum corneum. This limits the drug delivery efficiency and wastes some of the drug.
[0003] Chinese patent document CN107349175A discloses a microneedle patch loaded with a fat browning agent, comprising a substrate and a microneedle array. The microneedles are cone-shaped structures made of a polymer material, such as hyaluronic acid, polylactic acid-glycolic acid copolymer, or a mixture of both. The fat browning agent is loaded into the microneedle body by co-casting with the polymer material. This microneedle patch allows for direct subcutaneous drug delivery to the subcutaneous fat; a brief thumb press is sufficient to embed the drug-loaded microneedles into the skin for drug delivery, making the procedure simple. However, as mentioned above, the microneedles produced by this invention may result in drug waste.
[0004] Chinese patent document CN115969771A discloses a soluble drug-loaded microneedle. This invention first fills a polydimethylsiloxane microneedle mold with a soluble microneedle matrix through centrifugal extrusion, and then dries it to obtain a soluble microneedle shell with a certain mechanical strength. Next, volatile oils from traditional Chinese medicine are poured onto the mold surface, and excess volatile oils are removed after vacuum filling. Subsequently, a flexible backing material is poured onto the mold surface, and after vacuum extrusion and low-temperature treatment, it is leveled and air bubbles are removed. Finally, it is dried at low temperature to obtain the soluble microneedle. This method encapsulates the volatile oils from traditional Chinese medicine inside the needle body through the microneedle matrix and backing material, but the preparation method is relatively cumbersome.
[0005] When drugs accumulate near the microneedle tip, they can be released in maximum quantity during skin puncture. However, conventional manufacturing processes often result in drug diffusion into the substrate, further reducing drug utilization. Traditional methods typically require organic solvents to separate the drug-containing layer from the substrate layer. These solvents can reduce or inactivate the activity of macromolecular drugs and may also leave residues. Therefore, limiting drug diffusion and concentrating the drug near the needle tip will improve drug utilization. Summary of the Invention
[0006] This invention provides a method for preparing a soluble microneedle patch with drug enrichment at the needle tip. The method uses a two-step centrifugal drying process to enrich the drug at the tip of the microneedle, thereby enabling rapid release of the drug from the microneedle, improving drug utilization, and reducing waste caused by the inability of the soluble microneedle body to fully enter the skin.
[0007] The specific technical solution adopted is as follows:
[0008] A method for preparing a soluble microneedle patch for enriching drugs at the needle tip includes the following steps:
[0009] (1) A drug-loaded solution was prepared using hydrophilic drugs and soluble polymers as solutes, and the drug-loaded solution was injected into the needle body of the microneedle mold and dried by low-temperature centrifugation.
[0010] (2) Prepare a polymer solution using a soluble polymer as a solute, inject the polymer solution into the remaining part of the microneedle mold, centrifuge and dry it, and then demold to obtain the soluble microneedle patch with drug enriched at the needle tip.
[0011] In step (1), the parameters for low-temperature centrifugal drying are: temperature 0-15℃, centrifugal speed 2000-5000rpm, and centrifugation time 30min-2.5h;
[0012] In step (2), the parameters for centrifugal drying are: temperature 0-40℃, centrifugal speed 1000-5000rpm, and centrifugation time 0.1-4h.
[0013] In step (1), if the centrifugation temperature is too low, the drug-loaded solution will freeze, making it difficult to dry and aggregate. If the centrifugation temperature is too high, the drug molecule solution will easily form a shell to envelop the entire needle body instead of aggregating to the needle tip, and the high temperature will affect the activity of the drug molecules. If the rotation speed is too low, the drug molecules cannot be fully aggregated to the needle tip, and the drying time will be too long. If the rotation speed is too high, the microneedle preparation cost will be too high. If the centrifugation time is too short, the drug-loaded solution cannot be fully dried. If the centrifugation time is too long, the microneedle preparation cost will be too high.
[0014] In the prior art, the centrifugation process is only used to fill the mold with solution and cannot be used for drying and drug enrichment at the needle tip. In step (1) of this invention, the purpose of low-temperature centrifugation drying is to dry the needle tip part to form a drug-loaded needle tip by centrifugation, while keeping the drug-loaded solution gathered at the needle tip part under the action of gravity, so as to achieve the effect of drug enrichment at the needle tip. The low temperature condition slows down the drying speed of the drug-loaded solution, which can slowly evaporate the solvent and maintain a certain compressed shape, avoiding the drug-loaded solution from drying too quickly and adhering to the inner wall of the needle cavity due to centrifugation at room temperature. At the same time, the low temperature condition helps drug molecules, especially biomolecules, to maintain better biological activity. In step (2), the centrifugation drying process can both accelerate the drying of the polymer solution to form a microneedle substrate by centrifugation and maintain sufficient gravity to prevent drug molecules from diffusing to the entire needle body or substrate. Finally, after the substrate dries, the drug is still gathered at the needle tip part.
[0015] This invention uses a process of first low-temperature centrifugal drying and then centrifugal drying to enrich the drug at the tip of the microneedle, and ensures that the drug-enriched tip portion and the rest of the needle are more tightly bound together.
[0016] The microneedle mold includes a backing part and a needle body part. After low-temperature centrifugation and drying in step (1), the volume of the drug-loaded solution injected into the needle body part of the microneedle mold is reduced. The polymer solution is injected into the remaining needle body part and backing part of the microneedle mold. After further centrifugation and drying, the soluble microneedle patch with drug enriched at the needle tip is prepared.
[0017] In steps (1) and (2), the soluble polymers include, but are not limited to, gelatin, carboxymethyl cellulose, polyacrylic acid, trehalose, hyaluronic acid, sucrose, starch, maltose, chondroitin sulfate, chitosan, dextran, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, or silk fibroin. The soluble polymers used in steps (1) and (2) may be the same or different.
[0018] The hydrophilic drug is selected from small molecule drugs and / or biological macromolecule drugs.
[0019] The aforementioned biological macromolecular drugs include, but are not limited to, vaccine antigens, peptides, proteins, growth factors, antibodies, and nucleic acids.
[0020] Preferably, in the drug-loaded solution, the concentration of the soluble polymer is 10 mg / mL to 10 g / mL, and the concentration of the hydrophilic drug is 1 μg / mL to 5 g / mL.
[0021] Preferably, the concentration of the soluble polymer in the polymer solution is 10 mg / mL to 10 g / mL.
[0022] Specifically, the solvent in the drug-loaded solution or polymer solution can be deionized water, PBS buffer, carbonate buffer, etc.
[0023] Preferably, in step (1), the parameters for low-temperature centrifugal drying are: temperature 4-10℃, centrifugation speed 3000-4500 rpm, and centrifugation time 0.5-1.5 h. Within the above-mentioned preferred parameters, there is a technical effect of improving the drug loading degree of the needle tip.
[0024] In step (2), the parameters for centrifugal drying are: temperature 20-40℃, centrifugal speed 3000-4000 rpm, and centrifugation time 0.5-2 h. Centrifugal drying under the above parameters consumes less energy, can accelerate the drying of the substrate, and takes less time with milder conditions.
[0025] The present invention also provides a method for preparing a soluble microneedle patch for enriching drugs at the needle tip, which yields the soluble microneedle patch for enriching drugs at the needle tip.
[0026] The present invention also provides the application of the aforementioned needle tip-enriched drug-soluble microneedle patch as a transdermal drug delivery formulation.
[0027] Compared with the prior art, the beneficial effects of the present invention are as follows:
[0028] Traditional methods for preparing soluble microneedle patches mainly rely on natural drying. Naturally dried microneedles have a uniform drug distribution within the needle body. However, when applied to the skin, the needle body cannot completely dissolve, leading to drug waste and inaccurate dosage. This invention improves the preparation process by using a combination of low-temperature centrifugal drying and subsequent centrifugal drying to prepare drug-loaded soluble microneedles. This concentrates the drug near the needle tip, allowing the needle tip to dissolve rapidly upon skin puncture, thus delivering the drug completely into the skin. This solves the problem of inaccurate drug delivery. Furthermore, the low temperature helps maintain the activity of the drug molecules. Additionally, using a soluble matrix avoids organic solvent residue, resulting in good biocompatibility and excellent puncture efficacy. Attached Figure Description
[0029] Figure 1 In Example 7, 'a' represents the technical roadmap, and 'b' represents the microneedle morphology and drug distribution in the soluble microneedle patch with drug enrichment at the needle tip prepared in Example 7.
[0030] Figure 2 In the diagram, 'a' represents the technical roadmap for Comparative Example 1, and 'b' represents the microneedle morphology and drug distribution in the soluble microneedle patch prepared in Comparative Example 1.
[0031] Figure 3In the diagram, 'a' represents the technical roadmap for Comparative Example 2, and 'b' represents the microneedle morphology and drug distribution in the soluble microneedle patch prepared in Comparative Example 2.
[0032] Figure 4 In the diagram, 'a' represents the technical roadmap for Comparative Example 3, and 'b' represents the microneedle morphology and drug distribution in the soluble microneedle patch prepared in Comparative Example 3. Detailed Implementation
[0033] The present invention will be further illustrated below with reference to the embodiments and accompanying drawings. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Operating methods not specifically specified in the following embodiments are generally performed under conventional conditions or as recommended by the manufacturer.
[0034] Example 1
[0035] A drug loading solution was prepared by mixing vascular endothelial growth factor (VEGF) and gelatin and dissolving them in PBS buffer. The concentration of VEGF in the drug loading solution was 10 μg / mL and the concentration of gelatin was 100 mg / mL. The drug loading solution was injected into the needle body of the microneedle mold and centrifuged and dried at 15°C and 3000 rpm for 30 minutes.
[0036] Gelatin was dissolved in PBS buffer to prepare a polymer solution with a gelatin concentration of 250 mg / mL. The polymer solution was injected into the remaining part of the microneedle mold, and the microneedle was centrifuged and dried at 25°C and 3000 rpm for 30 minutes. The microneedle was then demolded to obtain the soluble microneedle patch with drug enrichment at the needle tip.
[0037] Example 2
[0038] Luciferase mRNA (mLuc) and polyvinylpyrrolidone (PVP) were mixed and dissolved in PBS buffer to prepare a drug loading solution. The concentration of luciferase mRNA (mLuc) in the drug loading solution was 5 μg / μL and the concentration of PVP was 500 mg / mL. The drug loading solution was injected into the needle body of the microneedle mold and centrifuged and dried at 4℃ and 2000 rpm for 30 minutes.
[0039] PVP was dissolved in deionized water to prepare a polymer solution with a PVP concentration of 1 g / mL. The polymer solution was injected into the remaining part of the microneedle mold and dried by centrifugation at 20°C and 3000 rpm for 40 min. The mold was then demolded to obtain the soluble microneedle patch with drug enrichment at the needle tip.
[0040] Example 3
[0041] PD-1 monoclonal antibody and trehalose were mixed and dissolved in deionized water to prepare a drug loading solution. The concentration of PD-1 monoclonal antibody in the drug loading solution was 5 μg / μL and the concentration of trehalose was 50 mg / mL. The drug loading solution was injected into the needle body of the microneedle mold and centrifuged and dried at 12℃ and 3500 rpm for 40 minutes.
[0042] Polyvinyl alcohol (PVA) and sucrose solution were dissolved in deionized water at a mass ratio of 2:1 to prepare a polymer solution with a PVA concentration of 100 mg / mL and a sucrose concentration of 50 mg / mL. The polymer solution was injected into the remaining part of the microneedle mold and dried by centrifugation at 25°C and 4500 rpm for 60 min. The mold was then demolded to obtain the soluble microneedle patch with drug enriched at the needle tip.
[0043] Example 4
[0044] The IL-17 monoclonal antibody and dextran were mixed and dissolved in deionized water to prepare a drug loading solution. The concentration of IL-17 monoclonal antibody in the drug loading solution was 0.5 μg / μL and the concentration of dextran was 200 mg / mL. The drug loading solution was injected into the needle body of the microneedle mold and centrifuged and dried at 15℃ and 4500 rpm for 50 minutes.
[0045] A polymer solution was prepared by dissolving dextran and hyaluronic acid solutions in deionized water at a mass ratio of 1:1, with a dextran concentration of 150 mg / mL and a hyaluronic acid concentration of 150 mg / mL. The polymer solution was injected into the remaining part of the microneedle mold and dried by centrifugation at 25°C and 3200 rpm for 1.5 h. The soluble microneedle patch with drug enrichment at the needle tip was obtained by demolding.
[0046] Example 5
[0047] Insulin and trehalose were mixed and dissolved in deionized water to prepare a drug loading solution. The concentration of insulin in the drug loading solution was 5 μg / μL and the concentration of trehalose was 50 mg / mL. The drug loading solution was injected into the needle body of the microneedle mold and centrifuged and dried at 15℃ and 3600 rpm for 40 minutes.
[0048] Dextran was dissolved in deionized water to prepare a polymer solution with a concentration of 500 mg / mL. The polymer solution was injected into the remaining part of the microneedle mold and dried by centrifugation at 25°C and 4500 rpm for 1.5 h. The soluble microneedle patch with drug enrichment at the needle tip was obtained by demolding.
[0049] Example 6
[0050] Lidocaine and chitosan were mixed and dissolved in acetic acid solution to prepare a drug loading solution. The concentration of lidocaine in the drug loading solution was 50 μg / μL and the concentration of chitosan was 50 mg / mL. The drug loading solution was injected into the needle body of the microneedle mold and centrifuged and dried at 12℃ and 3500 rpm for 40 minutes.
[0051] Hyaluronic acid was dissolved in deionized water to prepare a polymer solution with a hyaluronic acid concentration of 250 mg / mL. The polymer solution was injected into the remaining part of the microneedle mold, and the microneedle was centrifuged and dried at 30°C and 4500 rpm for 2 hours. The microneedle was then demolded to obtain the soluble microneedle patch with drug enrichment at the needle tip.
[0052] Example 7
[0053] Ovalbumin (OVA) and hyaluronic acid were mixed and dissolved in deionized water to prepare a drug loading solution. The concentration of ovalbumin (OVA) in the drug loading solution was 5 μg / μL and the concentration of hyaluronic acid was 50 mg / mL. The drug loading solution was injected into the needle body of the microneedle mold and centrifuged and dried at 10℃ and 3500 rpm for 50 minutes.
[0054] Hyaluronic acid was dissolved in deionized water to prepare a polymer solution with a hyaluronic acid concentration of 350 mg / mL. The polymer solution was injected into the remaining part of the microneedle mold and dried by centrifugation at 25°C and 4000 rpm for 1.5 h. The soluble microneedle patch with drug enrichment at the needle tip was obtained by demolding.
[0055] The technical roadmap of this embodiment is as follows: Figure 1 As shown in Figure a, the morphology of microneedles and the distribution of drugs in the prepared soluble microneedle patches with enriched drug at the needle tip are as follows: Figure 1 As shown in b, the results indicate that the process of the present invention can concentrate the drug at a position close to the tip of the microneedle.
[0056] Comparative Example 1
[0057] The technical roadmap for this comparative example is as follows: Figure 2 As shown in a, ovalbumin (OVA) and hyaluronic acid were mixed and dissolved in deionized water to prepare a drug loading solution. The concentration of ovalbumin (OVA) in the drug loading solution was 5 μg / μL and the concentration of hyaluronic acid was 50 mg / mL. The drug loading solution was injected into the needle body of the microneedle mold and centrifuged and dried at 10℃ and 3500 rpm for 50 minutes.
[0058] Hyaluronic acid was dissolved in deionized water to prepare a polymer solution with a hyaluronic acid concentration of 350 mg / mL. The polymer solution was injected into the remaining part of the microneedle mold. The remaining part of the microneedle mold was filled by centrifugation at 25°C and 3000 rpm for 5 min. After drying at room temperature, the microneedle patch was demolded to obtain a soluble microneedle patch.
[0059] In this comparative example, the microneedle morphology and drug distribution in the soluble microneedle patch are shown in the figure below. Figure 2 As shown in Figure b, it can be seen that centrifugation, filling, and room temperature drying in step (2) cannot achieve the technical effect of enriching drugs at the needle tip.
[0060] Comparative Example 2
[0061] The technical roadmap for this comparative example is as follows: Figure 3 As shown in a, ovalbumin (OVA) and hyaluronic acid were mixed and dissolved in deionized water to prepare a drug loading solution. The concentration of ovalbumin (OVA) in the drug loading solution was 5 μg / μL and the concentration of hyaluronic acid was 50 mg / mL. The drug loading solution was injected into the needle body of the microneedle mold and centrifuged at 25°C and 3500 rpm for 3 minutes to fill the needle body with the drug loading solution. The needle body was then left to dry completely at room temperature.
[0062] Hyaluronic acid was dissolved in deionized water to prepare a polymer solution with a concentration of 350 mg / mL. The polymer solution was injected into the remaining part of the microneedle mold and centrifuged at 25°C and 4000 rpm for 1.5 h. The soluble microneedle patch was then demolded.
[0063] In this comparative example, the microneedle morphology and drug distribution in the soluble microneedle patch are shown in the figure below. Figure 3 As shown in Figure b, it can be seen that centrifugation, filling, and room temperature drying in step (1) cannot achieve the technical effect of enriching drugs at the needle tip.
[0064] Comparative Example 3
[0065] The technical roadmap for this comparative example is as follows: Figure 4 As shown in a, ovalbumin (OVA) and hyaluronic acid were mixed and dissolved in deionized water to prepare a drug loading solution. The concentration of ovalbumin (OVA) in the drug loading solution was 5 μg / μL and the concentration of hyaluronic acid was 50 mg / mL. The solution was centrifuged at 25°C and 3500 rpm for 3 minutes to fill the needle body with the drug loading solution and then placed at room temperature until completely dry.
[0066] Hyaluronic acid was dissolved in deionized water to prepare a polymer solution with a hyaluronic acid concentration of 350 mg / mL. The polymer solution was injected into the remaining part of the microneedle mold. The remaining part of the microneedle mold was filled by centrifugation at 25°C and 3000 rpm for 5 min. After drying at room temperature, the microneedle patch was demolded to obtain a soluble microneedle patch.
[0067] In this comparative example, the microneedle morphology and drug distribution in the soluble microneedle patch are shown in the figure below. Figure 4 As shown in Figure b, it can be seen that the conventional two-step centrifugation filling and room temperature drying cannot achieve the technical effect of needle tip enrichment of drugs.
[0068] The embodiments described above provide a detailed explanation of the technical solutions of the present invention. It should be understood that the above descriptions are merely specific embodiments of the present invention and are not intended to limit the present invention. Any modifications, additions, or similar substitutions made within the scope of the principles of the present invention should be included within the protection scope of the present invention.
Claims
1. A method for preparing a soluble microneedle patch for enriching drugs at the needle tip, characterized in that, Includes the following steps: (1) A drug loading solution was prepared using hydrophilic drugs and soluble polymers as solutes, and the drug loading solution was injected into the needle body of the microneedle mold and dried by low-temperature centrifugation. (2) Prepare a polymer solution using a soluble polymer as a solute, inject the polymer solution into the remaining part of the microneedle mold, centrifuge and dry it, and then demold to obtain the soluble microneedle patch with drug enriched at the needle tip. In step (1), the parameters for low-temperature centrifugal drying are: temperature 4-10℃, centrifugal speed 3000-4500rpm, and centrifugation time 0.5-1.5h; In step (2), the parameters for centrifugal drying are: temperature 20-40℃, centrifugal speed 3000-4000rpm, and centrifugation time 0.5-4h; In steps (1) and (2), the soluble polymer is selected from hyaluronic acid.
2. The method for preparing a soluble microneedle patch for enriching drug at the needle tip according to claim 1, characterized in that, The hydrophilic drug is selected from small molecule drugs and / or biological macromolecule drugs.
3. The method for preparing a soluble microneedle patch for enriching drug at the needle tip according to claim 1, characterized in that, In the drug-loaded solution, the concentration of the soluble polymer is 10 mg / mL to 10 g / mL, and the concentration of the hydrophilic drug is 1 μg / mL to 5 g / mL.
4. The method for preparing a soluble microneedle patch for enriching drug at the needle tip according to claim 1, characterized in that, In the polymer solution, the concentration of the soluble polymer is 10 mg / mL to 10 g / mL.
5. A soluble microneedle patch for enriching drug at the needle tip, prepared by the method described in any one of claims 1-4.
6. The application of the soluble microneedle patch for drug enrichment at the needle tip according to claim 5 in the preparation of transdermal drug delivery formulations.