Soluble microneedle

Abstract

The invention relates to the technical field of microneedles, in particular to a soluble microneedle. The soluble microneedle comprises a substrate and a drug-loading needle body, wherein the drug-loading needle body contains an active drug, sodium hyaluronate and trehalose; the weight-average molecular weight of the sodium hyaluronate is 150 kDa to 280 kDa; the substrate is formed by a light-cured resin monomer, a photoinitiator and a solvent, and the light-cured resin monomer comprises diurea alkane dimethacrylate and / or triethylene glycol dimethacrylate. According to the soluble microneedle, the drug-loaded matrix containing the sodium hyaluronate with the specific molecular weight is combined with the substrate made of the specific material, so that the active drug is prevented from being diffused to the substrate, the accumulative permeability is improved, meanwhile, the interface bonding strength of the drug-loaded needle body and the substrate is guaranteed, and needle breakage is reduced.

Description

Technical Field

[0001] This application relates to the field of microneedle technology, and more particularly to a soluble microneedle. Background Technology

[0002] Soluble microneedle systems utilize biodegradable polymers, precisely fabricated into a micron-sized array of needle tips (typically integrated into a 1 square centimeter substrate). During application, the microneedles directly pierce the skin's stratum corneum barrier, allowing the medication to dissolve and be released rapidly in the epidermis or superficial dermis, significantly improving bioavailability and onset of action. Compared to traditional subcutaneous injections, microneedle patches provide painless or minimally painful drug delivery, reducing patient discomfort and improving compliance, making them particularly suitable for children and those prone to needle phobia.

[0003] However, there is still room for improvement in the cumulative permeability and the bonding strength between the drug-loaded needle and the substrate in existing soluble microneedles.

[0004] Therefore, it is necessary to provide a soluble microneedle with high cumulative skin permeability and stronger binding strength between the drug-loaded needle and the substrate. Summary of the Invention

[0005] In view of the above, the purpose of this application is to provide a soluble microneedle. To achieve the above objective, this application provides the following technical solution: In a first aspect, this application provides a soluble microneedle comprising a substrate and a drug-loaded needle body, wherein the drug-loaded needle body contains an active drug, sodium hyaluronate, and trehalose; the sodium hyaluronate has a weight-average molecular weight of 150 kDa to 280 kDa; the substrate comprises a photocurable resin, wherein the photocurable resin is formed from a photocurable resin monomer, a photoinitiator, and a solvent, and the photocurable resin monomer comprises diurea dimethacrylate and / or triethylene glycol dimethacrylate.

[0006] In some embodiments, the mass ratio of the drug-loaded needle body to the substrate is 1:(20~300).

[0007] In some embodiments, the sodium hyaluronate accounts for 2% to 10% of the total mass of the drug-loaded needle body.

[0008] In some embodiments, the mass ratio of sodium hyaluronate to trehalose is 1:(5~15).

[0009] In some embodiments, the photocurable resin monomer comprises triethylene glycol dimethacrylate and diurea dimethacrylate in a mass ratio of 1:(1.5~5.5).

[0010] In some embodiments, the photoinitiator comprises camphorquinone and dimethylaminoethyl methacrylate in a mass ratio of 1:(1~6).

[0011] In some embodiments, the solvent includes water.

[0012] In some embodiments, the mass ratio of the photocurable resin monomer to the photoinitiator is (10~30):1.

[0013] In some embodiments, the active pharmaceutical ingredient includes one or more of dexmedetomidine hydrochloride, lidocaine, ketorolac, buprenorphine, and zolpidem.

[0014] In some embodiments, the active pharmaceutical ingredient is dexmedetomidine hydrochloride; and the content of dexmedetomidine hydrochloride in the soluble microneedles is 0.05 mg to 0.5 mg.

[0015] In some embodiments, the drug-loaded needle body further includes a penetration enhancer, which includes at least two of laurocapram, polyvinylpyrrolidone, and polysorbate; wherein the polyvinylpyrrolidone has a weight-average molecular weight of 2000 Da to 13000 Da.

[0016] In some embodiments, the mass ratio of the active drug to the penetration enhancer is 1:(0.4~6).

[0017] In some embodiments, the penetration enhancer comprises polyvinylpyrrolidone and at least one selected from polysorbate and laurocapram; the mass ratio of polyvinylpyrrolidone to polysorbate is 1:(0.3~1), and / or the mass ratio of polyvinylpyrrolidone to laurocapram is 1:(0.3~1), and / or the mass ratio of polyvinylpyrrolidone to polysorbate and laurocapram is 1:(0.3~1):(0.3~1).

[0018] This application has the following beneficial effects: The soluble microneedles of this application utilize a drug-loaded matrix containing sodium hyaluronate of a specific molecular weight combined with a substrate of a specific material. This approach helps reduce the diffusion of active drugs into the substrate, increases the cumulative penetration rate of active drugs, and simultaneously ensures the interfacial bonding strength between the drug-loaded needle and the substrate, thereby reducing needle breakage. Attached Figure Description

[0019] Figure 1 This is a microscope image of the dexmedetomidine hydrochloride soluble microneedles provided in Example 1 of this application; Figure 2 This is a microscopic photograph of the skin of a miniature pig after being punctured by a dexmedetomidine hydrochloride soluble microneedle according to Example 1, provided in this application. Detailed Implementation

[0020] To make the objectives, technical solutions, and advantages of this application clearer, the application will be further described in detail below with reference to the accompanying drawings. The described embodiments should not be regarded as limitations on this application. All other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.

[0021] Compared to traditional subcutaneous injection, soluble microneedles can achieve painless or minimally painful drug delivery, significantly improving patient compliance. However, to improve the cumulative penetration rate of active drugs, current soluble microneedles often use dextran as an excipient in the needle body. However, needles containing this excipient have poor adhesion to commonly used substrates, leading to easy breakage between the substrate and the drug-loaded needle body (hereinafter sometimes referred to as needle breakage). On the other hand, to reduce the breakage rate, povidone K90 is often used as a substrate to enhance adhesion to the drug-loaded needle body. However, such a substrate easily adsorbs the active drug, causing drug retention on the microneedle substrate and reducing the cumulative penetration rate. Therefore, current soluble microneedles struggle to achieve both high cumulative penetration rate and low breakage rate.

[0022] In view of the problems existing in the prior art, this application provides a soluble microneedle that can improve the cumulative penetration rate while ensuring the interfacial bonding strength between the drug-loaded needle and the substrate, reducing needle breakage and improving the qualification rate of soluble microneedle products.

[0023] Specifically, this application provides the following technical solutions: In a first aspect, this application provides a soluble microneedle comprising a substrate and a drug-loaded needle body, wherein the drug-loaded needle body contains an active drug, sodium hyaluronate, and trehalose; the sodium hyaluronate has a weight-average molecular weight of 150 kDa to 280 kDa; the substrate comprises a photocurable resin, wherein the photocurable resin is formed from a photocurable resin monomer, a photoinitiator, and a solvent, and the photocurable resin monomer comprises diurea dimethacrylate and / or triethylene glycol dimethacrylate.

[0024] The inventors of this application have discovered that the insufficient cumulative penetration rate of current soluble microneedles containing active drugs is mainly due to the following: During the preparation process, after the drug-loaded needle containing the active drug is dried and shaped, when it comes into contact with the uncured base solution, some of the active drug easily penetrates into the base solution. After the base solidifies, it becomes trapped in the base, resulting in loss of the active drug. This loss significantly weakens the cumulative penetration rate of the soluble microneedles, thus limiting their full efficacy.

[0025] Although the mechanism is not yet fully understood in this application, the inventors have discovered that using the aforementioned photocurable resin monomers to prepare the substrate material can effectively reduce the penetration of active drugs, especially dexmedetomidine hydrochloride, into the substrate, thereby reducing active drug loss and increasing the cumulative penetration rate. Simultaneously, the aforementioned photocurable resin monomers exhibit rapid curing characteristics during substrate formation, completing curing in 5 to 60 seconds under ultraviolet light (400 nm to 405 nm), further reducing the diffusion of active drugs into the substrate and contributing to a further increase in the cumulative penetration rate. Furthermore, the substrate material obtained from the aforementioned specific photocurable resin monomers has high mechanical strength, enhancing the support for the needle and thus contributing to increased needle penetration strength, thereby improving the cumulative penetration rate of the active drug.

[0026] In this application, the above-mentioned photocurable resin monomer only needs to be cured under ultraviolet light (400nm~405nm) for 5s~60s when forming the substrate, which greatly shortens the preparation time, simplifies the preparation process, and can effectively improve production efficiency. Moreover, the substrate formed thereby can fully meet the performance requirements of soluble microneedles.

[0027] Sodium hyaluronate can form a thin film with certain strength and toughness, which helps to shape soluble microneedles into sharp microneedle structures capable of piercing the stratum corneum of the skin. Furthermore, it is a naturally occurring component of human skin, exhibiting excellent biocompatibility and being non-toxic and non-irritating. In this application, by controlling the molecular weight of sodium hyaluronate in the drug-loaded needle body to 150kDa~280kDa, a denser network structure with smaller pores is achieved, which helps retain the active drug within the needle body and significantly reduces the diffusion of the active drug to the substrate. The high solubility of trehalose accelerates the dissolution rate of the drug-loaded needle body in the skin, allowing it to rapidly absorb tissue fluid and dissolve after insertion. The combined use of trehalose and sodium hyaluronate significantly reduces the diffusion of the active drug to the substrate without affecting its release, thereby increasing the cumulative penetration rate of the active drug. In addition, trehalose in the drug-loaded needle body can modulate the mechanical properties of sodium hyaluronate, making it harder and more flexible, which helps optimize the puncture efficiency of the microneedles.

[0028] Meanwhile, the inventors discovered that sodium hyaluronate with the above molecular weight has a certain interfacial bonding force with the above-mentioned specific photocurable resin monomer. The mutual diffusion between the two before curing can promote the mechanical interlocking of the drug-loaded needle and the substrate material, thereby improving the bonding strength between the drug-loaded needle and the substrate material and reducing the needle breakage rate.

[0029] For example, the weight-average molecular weight of sodium hyaluronate can be 150 kDa, 160 kDa, 170 kDa, 180 kDa, 190 kDa, 200 kDa, 210 kDa, 220 kDa, 230 kDa, 240 kDa, 250 kDa, 260 kDa, 270 kDa, or 280 kDa, or a range of values ​​with any two of the above values ​​as endpoints. Optionally, the weight-average molecular weight of sodium hyaluronate is 150 kDa to 180 kDa. Sodium hyaluronate in the above-mentioned low molecular weight range is more conducive to the release of active drugs.

[0030] In some embodiments, the sodium hyaluronate includes one or more of HA-21, HA-25.3, and HA-26.9. Optionally, the sodium hyaluronate includes HA-21.

[0031] In some embodiments, the mass ratio of the drug-loaded needle to the substrate is 1:(20~300). By controlling the mass ratio of the drug-loaded needle to the substrate within the above range, the binding strength between the carrier needle and the substrate can be improved without affecting the efficacy of the active drug, thus avoiding needle breakage. For example, the mass ratio of the drug-loaded needle to the substrate can be a value within a range of 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, 1:150, 1:200, 1:250, 1:300, or any combination thereof.

[0032] In some embodiments, the sodium hyaluronate accounts for 2% to 10% of the total mass of the drug-loaded needle. Controlling the sodium hyaluronate content in the drug-loaded needle within this range helps to improve the bonding strength between the sodium hyaluronate-containing drug-loaded needle and the substrate, while further increasing the cumulative permeability. For example, the sodium hyaluronate content, based on the total mass of the drug-loaded needle, can be a value within the range of 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, or any combination thereof. Optionally, the sodium hyaluronate content, based on the total mass of the drug-loaded needle, is 2% to 6%.

[0033] In some embodiments, the mass ratio of sodium hyaluronate to trehalose is 1:(5~15). By controlling the dosage relationship of sodium hyaluronate and trehalose within the above range, the cumulative penetration rate can be further improved by regulating the drug release kinetics. Exemplarily, the mass ratio of the active drug to sodium hyaluronate can be 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, or 1:15, or a range of values ​​with any two of the above values ​​as endpoints. Optionally, the mass ratio of sodium hyaluronate to trehalose is 1:(6~15).

[0034] In some embodiments, the photocurable resin monomer comprises triethylene glycol dimethacrylate and diurea dimethacrylate in a mass ratio of 1:(1.5~5.5). Compared to diurea dimethacrylate or triethylene glycol dimethacrylate alone, the combination of the two helps to improve the bonding strength between the substrate and the drug-loaded matrix, and can further improve the cumulative drug penetration rate. Exemplarily, the mass ratio of triethylene glycol dimethacrylate to diurea dimethacrylate can be 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, or 1:5.5, or a range of values ​​with any two of the above values ​​as endpoints.

[0035] In some embodiments, the photoinitiator comprises camphorquinone and dimethylaminoethyl methacrylate in a mass ratio of 1:(1~6).

[0036] In some embodiments, the solvent includes water.

[0037] In some embodiments, the mass ratio of the photocurable resin monomer to the photoinitiator is (10~30):1. Exemplarily, the mass ratio of the photocurable resin monomer to the photoinitiator can be 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, or 30:1, or a range of ratios with any two of the above ratios as endpoints. Optionally, the mass ratio of the photocurable resin monomer to the photoinitiator is (10~25):1.

[0038] In this application, those skilled in the art may add other additives, organic solvents, etc., to the substrate to improve its performance, as needed, and no limitation is made herein.

[0039] In some embodiments, the active pharmaceutical ingredient includes one or more of dexmedetomidine hydrochloride, lidocaine, ketorolac, buprenorphine, and zolpidem.

[0040] For the different active drugs mentioned above, the soluble microneedles of this application can achieve an increase in cumulative penetration rate to varying degrees, and enhance the interfacial bonding strength between the drug-loaded needle and the substrate.

[0041] In some embodiments, the active drug is dexmedetomidine hydrochloride; the content of dexmedetomidine hydrochloride in the soluble microneedles is 0.05 mg to 0.5 mg. In this application, when the active drug is dexmedetomidine hydrochloride, the cumulative drug penetration rate can be further improved, and the interfacial bonding strength between the drug-loaded needle and the substrate can be enhanced.

[0042] In this application, the "content of dexmedetomidine hydrochloride" in the soluble microneedles refers to the total mass of dexmedetomidine hydrochloride in each soluble microneedle patch.

[0043] In some embodiments, the drug-loaded needle body further includes a penetration enhancer, which includes at least two of polyvinylpyrrolidone, polysorbate, and laurocapram; the weight-average molecular weight of the polyvinylpyrrolidone is 2000 Da to 13000 Da.

[0044] In existing technologies, high molecular weight polyvinylpyrrolidone (PVP) is typically used as a matrix material, base material, or penetration enhancer. For example, high molecular weight PVP such as K90 is frequently used as a matrix or base material for microneedles, while medium molecular weight PVP such as K30 can also be used as a penetration enhancer due to its higher viscosity and sustained-release effect. In this application, low molecular weight PVP within the aforementioned range is selected as a penetration enhancer, which helps to transform the active drug from a stable crystalline state to a high-free-energy, high-solubility amorphous state. When the needle is inserted into the skin, the aforementioned low molecular weight PVP can be rapidly hydrated, and the amorphous dexmedetomidine dissolves at an extremely high rate and concentration, forming a large and continuous concentration gradient, providing a key driving force for passive drug diffusion.

[0045] Lauryl azelastone, with its specific alkyl chain length and polar head group, penetrates deep into the lipid bilayer of the stratum corneum, and can even disrupt the cell membrane lipids of epidermal cells and dermal cells, breaking their tight crystalline arrangement and creating more permeation microchannels, reducing the diffusion resistance of drugs in all these biological membranes. When polyvinylpyrrolidone (PVP) binds to lauryl azelastone, the large concentration gradient provided by PPVP facilitates the efficient forward penetration of drug molecules through these permeation microchannels. Simultaneously, the micelles formed by polysorbate (Tween) can "encapsulate" and "solubilize" the high concentration of drug released by PPVP, preventing its re-precipitation at the interface due to supersaturation and maintaining stable delivery under the large concentration gradient. Furthermore, the combined action of aqueous PPVP and the surfactant Tween further optimizes the hydrophilic-lipophilic balance of the formulation system, promoting the distribution of drugs from the matrix to the skin's lipid environment. In addition, polysorbate (Tween) can extract some lipids from the stratum corneum, making it easier for laurocapram to enter and disrupt the lipid structure, further reducing the diffusion resistance of the active drug in the biomembrane.

[0046] Therefore, by using at least two of the above three penetration enhancers in soluble microneedles, the penetration enhancement effect can be synergistically enhanced. Under the synergistic effect of the above penetration enhancers, the active drug can be rapidly penetrated and released, thereby obtaining further improved cumulative penetration rate, onset time and duration of efficacy.

[0047] For example, the weight-average molecular weight of the polyvinylpyrrolidone can be 2000 Da, 2500 Da, 3000 Da, 3500 Da, 4000 Da, 5000 Da, 6000 Da, 7000 Da, 8000 Da, 9000 Da, 10000 Da, 11000 Da, 12000 Da, 12500 Da, or 13000 Da, or a range of values ​​with any two of the above values ​​as endpoints. Optionally, the weight-average molecular weight of the polyvinylpyrrolidone is 8000 Da to 12000 Da. Polyvinylpyrrolidone with a molecular weight of 8000 Da to 12000 Da can promote the efficient diffusion of active drugs while taking into account the continuity and stability of diffusion, thereby better synergizing with laurocapram and / or polysorbate, and further enhancing the penetration-enhancing effect.

[0048] In some embodiments, the polyvinylpyrrolidone may be selected from one or more of K17, K15 and K12; optionally, the polyvinylpyrrolidone is K17.

[0049] In some embodiments, the polysorbate includes one or more of Tween 20, Tween 40, Tween 60 and Tween 80; optionally, the polysorbate is Tween 80.

[0050] In some embodiments, the mass ratio of the active drug to the penetration enhancer is 1:(0.4~6). By controlling the dosage relationship between the penetration enhancer and the active drug, the penetration enhancer can function better, resulting in good skin penetration of the active drug and rapid release from the needle. Exemplarily, the mass ratio of the active drug to the penetration enhancer can be 1:0.4, 1:0.5, 1:1, 1:2, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, or 1:6, or a range of values ​​with any two of the above values ​​as endpoints. Optionally, the mass ratio of the active drug to the penetration enhancer is 1:(0.4~4). In some embodiments, the penetration enhancer includes polyvinylpyrrolidone and at least one selected from polysorbate and laurocapram, specifically, it can be a mixture of polyvinylpyrrolidone and polysorbate, a mixture of polyvinylpyrrolidone and laurocapram, or a mixture of polyvinylpyrrolidone, polysorbate, and laurocapram.

[0051] In some embodiments, the mass ratio of the polyvinylpyrrolidone to the polysorbate is 1:(0.3~1). Exemplarily, the mass ratio of the polyvinylpyrrolidone to the polysorbate can be 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, or a value within a range of any two of these ratios.

[0052] In some embodiments, the mass ratio of polyvinylpyrrolidone to laurocapram is 1:(0.3~1). Exemplarily, the mass ratio of polyvinylpyrrolidone to laurocapram can be 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, or a value within a range of any two of these ratios.

[0053] In some embodiments, the mass ratio of the polyvinylpyrrolidone, the polysorbate, and the laurocapram is 1:(0.3~1):(0.3~1). Exemplarily, the mass ratio of the polyvinylpyrrolidone, the polysorbate, and the laurocapram can be 1:0.3:0.3, 1:0.3:1, 1:0.4:0.3, 1:0.4:1, 1:0.5:0.3, 1:0.5:1, 1:0.6:0.3, 1:0.6:1, 1:0.7:0.3, 1:0.7:1, 1:0.8:0.3, 1:0.8:1, 1:0.9:0.3, 1:0.9:1, 1:1.0:0.3, 1:1:1, or a value within a range of any two of these ratios.

[0054] In this application, by controlling the dosage relationship between the penetration enhancers, the synergistic effect can be further improved, enabling the active drug to be released into the bloodstream quickly, and allowing the soluble microneedles to achieve a good skin accumulation penetration rate, which helps the active drug to achieve rapid release, rapid onset of action, and sustained effectiveness.

[0055] In some embodiments, the mass ratio of the active pharmaceutical ingredient to the polyvinylpyrrolidone is 1:(0.2~4). By controlling the amounts of the active pharmaceutical ingredient and the polyvinylpyrrolidone, it is helpful to convert the active pharmaceutical ingredient into a more soluble and easily released amorphous form, thereby achieving highly efficient penetration enhancement. Exemplarily, the mass ratio of the active pharmaceutical ingredient to the polyvinylpyrrolidone can be 1:0.2, 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, or 1:3, or a range of values ​​with any two of the above values ​​as endpoints. Optionally, the mass ratio of the active pharmaceutical ingredient to the polyvinylpyrrolidone is 1:(0.2~3).

[0056] In some embodiments, the mass ratio of the active pharmaceutical ingredient to the polysorbate is 1:(0.2~4). By controlling the amount of the active pharmaceutical ingredient and the polysorbate, it is helpful to further reduce the diffusion resistance of the active pharmaceutical ingredient in the biomembrane, making it easier for laurocapram to enter and disrupt the lipid structure. Exemplarily, the mass ratio of the active pharmaceutical ingredient to the polysorbate can be 1:0.2, 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, or 1:3, or a range of values ​​with any two of the above values ​​as endpoints. Optionally, the mass ratio of the active pharmaceutical ingredient to the polysorbate is 1:(0.2~3).

[0057] In some embodiments, the mass ratio of the active drug to laurocapram is 1:(0.2~4). By controlling the dosage relationship between the active drug and laurocapram, it is helpful to rapidly reduce the diffusion resistance of the active drug and significantly enhance the transdermal absorption of the drug. Exemplarily, the mass ratio of the active drug to laurocapram can be 1:0.2, 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, or 1:3, or a range of values ​​with any two of the above values ​​as endpoints. Optionally, the mass ratio of the active drug to laurocapram is 1:(0.2~3).

[0058] Secondly, this application provides a method for preparing the soluble microneedles of the active drug, comprising: S1, mix the photocurable resin monomer, photoinitiator and solvent to obtain the base liquid; mix the active drug, penetration enhancer, sodium hyaluronate, trehalose and aqueous solvent to obtain the needle solution; S2, add the needle solution to the mold, degas under vacuum and then dry; S3, continue to add the base liquid to the mold obtained in S2, and then cure it under ultraviolet light after vacuum degassing; S4, demolding, packaging, and irradiation sterilization.

[0059] In this application, in step S1, in order to improve the uniformity of the needle solution, the needle solution can be centrifuged after mixing. Optionally, the centrifugation can be performed at 4000rpm~6000rpm for 3min~10min.

[0060] In some embodiments, in S1, the mass percentage of the active drug is 0.02% to 20.0% based on the total mass of the needle solution. For example, the mass percentage of the active drug, based on the total mass of the needle solution, can be 0.02%, 0.1%, 0.2%, 0.5%, 0.8%, 1%, 2%, 3%, 4%, 5%, 8%, 10%, 12%, 15%, 18%, or 20.0%, or a range of values ​​with any two of the above values ​​as endpoints; optionally, it is 0.5% to 15.0%.

[0061] In this application, in S2, the vacuum degree of vacuum degassing is -0.1MPa to -0.08MPa, the vacuum degassing time is 10min to 60min, and drying is carried out at 20℃ to 80℃ for 1h to 5h.

[0062] In this application, in S3, the vacuum degree of vacuum degassing is -0.1MPa to -0.08MPa, and the vacuum degassing time is 10min to 60min.

[0063] In this application, in step S3, after vacuum degassing, UV curing is performed for 5 to 60 seconds.

[0064] In this application, in step S4, the irradiation dose for sterilization is 15kGy to 25kGy.

[0065] Thirdly, this application provides the application of the above-mentioned soluble microneedles or soluble microneedles prepared by the above-mentioned method in the preparation of drugs for treating insomnia, wherein the active drug in the soluble microneedles is dexmedetomidine hydrochloride.

[0066] In soluble microneedles, the loss of active drug, as mentioned above, is low and has minimal impact at high doses, but it is significantly amplified at low doses, easily leading to insufficient effective drug dosage. For dexmedetomidine hydrochloride, its effective dose for treating insomnia is far lower than its dose for analgesia or sedation. This means that when soluble microneedles for dexmedetomidine hydrochloride are used to treat insomnia, compared to their use for analgesia or sedation, the problem of insufficient transdermal drug absorption efficiency is further exacerbated. This application, by optimizing the skeleton material and substrate of the drug-loaded needle, helps reduce the diffusion of dexmedetomidine hydrochloride into the directional substrate, further improving the cumulative penetration rate of low-dose dexmedetomidine hydrochloride.

[0067] Example To further illustrate the technical solution of this application, the following embodiments are provided.

[0068] In the following examples and comparative examples, the weight-average molecular weight of HA-21 is approximately 150 kDa to 180 kDa; the weight-average molecular weight of HA-25.3 is approximately 220 kDa to 250 kDa; the weight-average molecular weight of HA-26.9 is approximately 240 kDa to 280 kDa; the weight-average molecular weight of HA-28 is approximately 290 kDa to 320 kDa; the weight-average molecular weight of PVP K17 is approximately 10,000 Da; and the weight-average molecular weight of PVP K90 is approximately 1,200,000 Da.

[0069] Example 1 This embodiment provides a dexmedetomidine hydrochloride soluble microneedle, the preparation method of which includes the following steps: (1) Preparation of the needle solution: Weigh each component of the drug-loaded needle according to Table 1-1 and add it to a centrifuge tube. Centrifuge at 5000 rpm for 5 min to obtain the needle solution.

[0070] Table 1-1

[0071] (2) Preparation of the base solution: Triethylene glycol dimethacrylate (TEGDMA), diurea dimethacrylate (UDMA), and photoinitiator (dimethylaminoethyl methacrylate (DMAEMA) and camphorquinone (CQ) in a mass ratio of 3:1) were mixed with water for injection (mass ratio of 30:20:2:48) and stirred until homogeneous.

[0072] (3) Preparation of soluble microneedles: Pipette 100µL of the above needle body solution onto a silicone mold, degas under vacuum at -0.1MPa for 40 min, and then dry the needle tip at 50℃ for 2 h to remove excess solvent, thus obtaining the drug-loaded needle body.

[0073] 60µL of the above-mentioned base liquid was drawn onto the above-mentioned silicone mold containing the drug-loaded needle, and the mold was degassed under vacuum at -0.1MPa for 60min. Then the mold was placed under ultraviolet light with a wavelength of 400nm~405nm and cured for 10s to obtain the photocurable resin and then demolded.

[0074] (4) Packaging and sterilization: After packaging, sterilize at 25 kGy and store at room temperature.

[0075] In this embodiment, the content of dexmedetomidine hydrochloride soluble microneedles obtained using the above-described formula and preparation method is 0.1 mg in one microneedle patch.

[0076] The component composition of the dexmedetomidine hydrochloride soluble microneedle product is shown in Table 1-2 below: Table 1-2

[0077] Examples 2-5, Comparative Examples 1-2 Prepared in the same manner as in Example 1, except that the weight-average molecular weight of sodium hyaluronate and the photoinitiating resin monomer were adjusted according to Table 1.

[0078] Comparative Example 3 Prepared in the same manner as in Example 1, except that trehalose is not used and is replaced with an equal amount of sodium hyaluronate.

[0079] Comparative Example 4 Prepared in the same manner as in Example 1, except that the substrate was replaced with an equal amount of PVP K90.

[0080] Soluble microneedle performance testing (1) Needle breakage rate The soluble microneedle patches prepared in each example and comparative example were examined and photographed under a high-power microscope (stereo microscope, zoom lens magnification 0.75x-13.5x) to observe needle breakage. The microscope photograph of the soluble microneedle patch in Example 1 is shown below. Figure 1 .

[0081] The method for calculating the pass rate is as follows: Taking Example 1 as an example, a batch of 100 soluble microneedle patches prepared in Example 1 are qualified if the needle breakage rate of each microneedle is less than 5%, and unqualified if the needle breakage rate of each microneedle is greater than 5%.

[0082] Needle breakage rate = number of broken needles per soluble microneedle patch / total number of needles per soluble microneedle patch.

[0083] The pass rate = the number of qualified soluble microneedle patches in a batch / the total number of soluble microneedle patches in a batch.

[0084] The pass rate test results are shown in Tables 2, 5 and 6-2.

[0085] (2) Puncture test Soluble microneedles prepared using the examples and comparative examples were used to perform puncture experiments on miniature pig skin (purchased from Hebang Technology Co., Ltd.). After pressing (8N, 30s), the skin was stained and visually observed using a high-power microscope (stereo microscope, zoom magnification 0.75x-13.5x). Microscopic photographs of the skin punctured by the soluble microneedles in Example 1 are shown below. Figure 2 As shown.

[0086] (3) 24h cumulative transmittance Experiments were conducted using qualified soluble microneedles prepared in each example and comparative example, with each sample tested in parallel three times.

[0087] Specifically, miniature pig skin (purchased from Hebang Technology Co., Ltd.) was used for IVPT experiments in a Franz diffusion cell (LOGAN DSC-800). Sampling time points were 1h, 2h, 4h, 6h, 8h, 12h, 18h, and 24h, and the results were analyzed using a liquid chromatography analyzer (Agilent 1260). The cumulative drug permeation rate over 24 hours was calculated as the cumulative permeation amount divided by the actual drug loading per microneedle patch. The results are shown in Tables 2, 5, and 6-2 below.

[0088] Table 2

[0089] Note: In Table 2, "mass percentage" refers to the mass percentage of a certain component based on the total mass of the base solution.

[0090] As shown in Table 2, incorporating trehalose and sodium hyaluronate with a weight-average molecular weight of 150kDa~280kDa into the drug-loaded needle body improves biocompatibility with the substrate and results in a lower needle breakage rate for the prepared soluble microneedles. Furthermore, sodium hyaluronate with the aforementioned molecular weight helps to block the penetration of dexmedetomidine hydrochloride drug molecules into the substrate, reducing its retention on the substrate and thus increasing the cumulative drug penetration rate. In addition, the substrate material formed by the photocurable resin monomers of TEGDMA and / or UDMA exhibits excellent compatibility with the drug-loaded needle material containing sodium hyaluronate and trehalose with the molecular weights specified in this application, resulting in high bonding strength between the substrate and the needle body, a low needle breakage rate, and a high yield.

[0091] Example 6 The same preparation method as in Example 1 was used, except that the total mass ratio of sodium hyaluronate and trehalose was kept constant, and the content of sodium hyaluronate and trehalose was adjusted according to Table 5.

[0092] Example 7 The preparation was carried out in the same manner as in Example 1, except that the formulations of the drug-loaded needles in the needle solution and the soluble microneedle product were adjusted according to Tables 3-1 and 3-2, respectively: Table 3-1

[0093] Table 3-2

[0094] Example 8 The preparation was carried out in the same manner as in Example 1, except that the formulations of the drug-loaded needles in the needle solution and the soluble microneedle product were adjusted according to Tables 4-1 and 4-2, respectively: Table 4-1

[0095] Table 4-2

[0096] Examples 9-14 The preparation was carried out in the same manner as in Example 1, except that in Examples 9-12, the photocurable resin monomer and photoinitiator were adjusted according to Table 5; and in Examples 13-14, the mass ratio of the drug-loaded matrix and the substrate was adjusted according to Table 5.

[0097] Table 5

[0098] In Table 5, the mass percentage of sodium hyaluronate refers to the mass percentage of sodium hyaluronate based on the total mass of the drug-loaded needles in the soluble microneedles.

[0099] As shown in Table 5, within a certain range, adjusting the content of sodium hyaluronate, trehalose, and photocurable resin monomers resulted in soluble microneedles with high cumulative permeability, strong interfacial bonding between the drug-loaded needle and the substrate, and a high product qualification rate. Furthermore, when the mass ratio of the drug-loaded needle to the substrate was 1:(20~300), the resulting soluble microneedles also exhibited high cumulative permeability, strong interfacial bonding between the drug-loaded needle and the substrate, and a high product qualification rate.

[0100] Examples 15-24 The preparation was carried out in the same manner as in Example 1, except that the type and content of the penetration enhancer were adjusted according to Tables 6-1 and 6-2. Table 6-1 shows the dosage relationship of the components in the needle solution during the preparation of the soluble microneedle product; Table 6-2 shows the dosage relationship of the components in the soluble microneedle product.

[0101] Table 6-1

[0102] Note: In Table 6-1, "mass percentage" refers to the mass percentage of a certain component based on the total mass of the needle solution.

[0103] Table 6-2

[0104] Note: In Table 6-2, "mass percentage" refers to the mass percentage of a certain component based on the total mass of the drug-loaded needle in the soluble microneedle.

[0105] As shown in Tables 6-1 and 6-2, when other components in the substrate and drug-loaded needle remain unchanged, using at least two of laurocapram, polysorbate, and low molecular weight polyvinylpyrrolidone as penetration enhancers results in soluble microneedles with high cumulative permeability, strong interfacial bonding between the drug-loaded needle and the substrate, and a high product qualification rate. Furthermore, when the mass ratio of dexmedetomidine hydrochloride to the penetration enhancer is within the range of 1:(0.4~6), the resulting soluble microneedles also exhibit high cumulative permeability, strong interfacial bonding between the drug-loaded needle and the substrate, and a high product qualification rate.

[0106] The above description is merely an embodiment of this application and is not intended to limit the scope of protection of this application. Any modifications, equivalent substitutions, and improvements made within the spirit and scope of this application are included within the scope of protection of this application.

Claims

1. A soluble microneedle, comprising a base and a drug-loaded needle body, characterized in that, The drug-loaded needle contains an active drug, sodium hyaluronate, and trehalose; the weight-average molecular weight of the sodium hyaluronate is 150 kDa to 280 kDa. The substrate comprises a photocurable resin, which is formed from a photocurable resin monomer, a photoinitiator, and a solvent. The photocurable resin monomers include diurea dimethacrylate and / or triethylene glycol dimethacrylate.

2. The soluble microneedles according to claim 1, characterized in that, The mass ratio of the drug-loaded needle to the substrate is 1:(20~300).

3. The soluble microneedles according to claim 2, characterized in that, Based on the total mass of the drug-loaded needle, the sodium hyaluronate accounts for 2% to 10% of the total mass, and / or, The mass ratio of sodium hyaluronate to trehalose is 1:(5~15).

4. The soluble microneedles according to claim 1, characterized in that, The photocurable resin monomers include triethylene glycol dimethacrylate and diurea dimethacrylate in a mass ratio of 1:(1.5~5.5).

5. The soluble microneedles according to claim 1, characterized in that, The photoinitiator comprises camphorquinone and dimethylaminoethyl methacrylate in a mass ratio of 1:(1~6); and / or, The solvent includes water; and / or, The mass ratio of the photocurable resin monomer to the photoinitiator is (10~30):

1.

6. The soluble microneedles according to claim 1, characterized in that, The active pharmaceutical ingredient includes one or more of dexmedetomidine hydrochloride, lidocaine, ketorolac, buprenorphine, and zolpidem.

7. The soluble microneedles according to claim 6, characterized in that, The active drug is dexmedetomidine hydrochloride; in the soluble microneedles, the content of dexmedetomidine hydrochloride is 0.05 mg to 0.5 mg.

8. The soluble microneedles according to any one of claims 1 to 7, characterized in that, The drug-loaded needle also includes a penetration enhancer, which includes at least two of polyvinylpyrrolidone, polysorbate, and laurocapram; the weight-average molecular weight of the polyvinylpyrrolidone is 2000 Da to 13000 Da.

9. The soluble microneedles according to claim 8, characterized in that, The mass ratio of the active drug to the penetration enhancer is 1:(0.4~6).

10. The soluble microneedles according to claim 8, characterized in that, The penetration enhancer includes polyvinylpyrrolidone and at least one selected from polysorbate and laurocapram; The mass ratio of the polyvinylpyrrolidone to the polysorbate is 1:(0.3~1), and / or, The mass ratio of the polyvinylpyrrolidone to the laurocapramone is 1:(0.3~1), and / or, The mass ratio of the polyvinylpyrrolidone, the polysorbate, and the laurocapram is 1:(0.3~1):(0.3~1).

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