Dexmedetomidine hydrochloride dissolvable microneedle

Abstract

The application provides a dexmedetomidine hydrochloride soluble microneedle; the dexmedetomidine hydrochloride soluble microneedle comprises a substrate and a drug-loaded needle body, the drug-loaded needle body comprises dexmedetomidine hydrochloride and a penetration enhancer; the penetration enhancer comprises at least two of laurocapram, polyvinylpyrrolidone and polysorbate; the weight average molecular weight of the polyvinylpyrrolidone is 2000 Da to 13000 Da. The dexmedetomidine hydrochloride soluble microneedle provided by the application can significantly improve the peak drug concentration after transdermal delivery under the promotion of the penetration enhancer, has a short onset time and a long duration, and can achieve the effects of rapid release, rapid onset and sustained effectiveness.

Description

Technical Field

[0001] This application relates to the field of microneedle technology, and in particular to a dexmedetomidine hydrochloride soluble microneedle. Background Technology

[0002] Dexmedetomidine hydrochloride, as a highly selective α2-adrenergic receptor agonist, has unique pharmacological effects mediated by targeting α2 receptors in the central and peripheral nervous systems, demonstrating outstanding advantages in the treatment of analgesia, sedation, and insomnia.

[0003] 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.

[0004] In the prior art, soluble microneedles developed for dexmedetomidine hydrochloride are mostly used for analgesia / sedation. For example, Chinese patent application CN20221084716.8 discloses a soluble microneedle for dexmedetomidine hydrochloride used for preoperative sedation in children. This microneedle uses dextran as the skeleton material of the needle body. Chinese patent application CN20251055850.5 discloses a dexmedetomidine hydrochloride microneedle prepared using 3D printing technology and its preparation method. The microneedle is used for analgesia, wherein the drug-loaded needle body layer is prepared by polyvinylpyrrolidone (K90) and dexmedetomidine hydrochloride in a certain mass ratio. The above microneedles are unsatisfactory in terms of release rate, onset time, and duration of action.

[0005] Therefore, it is necessary to provide a dexmedetomidine microneedle with high skin permeability, faster release speed, shorter onset time, and longer effective duration. Summary of the Invention

[0006] In view of the above, the purpose of this application is to provide a soluble microneedle of dexmedetomidine hydrochloride, which has excellent skin permeability, rapid release, rapid onset of action, and long duration of action. To achieve the above objective, this application provides the following technical solution:

[0007] In a first aspect, this application provides a dexmedetomidine hydrochloride soluble microneedle, comprising a substrate and a drug-loaded needle body, wherein the drug-loaded needle body contains dexmedetomidine hydrochloride and a penetration enhancer; the penetration enhancer comprises at least two of laurocapram, polyvinylpyrrolidone, and polysorbate; wherein the polyvinylpyrrolidone has a weight-average molecular weight of 2000 Da to 13000 Da.

[0008] In some embodiments, the mass ratio of dexmedetomidine hydrochloride to the penetration enhancer is 1:(0.2~8).

[0009] In some embodiments, the mass ratio of the drug-loaded needle body to the substrate is 1:(25~300).

[0010] In some embodiments, the mass ratio of dexmedetomidine hydrochloride to polyvinylpyrrolidone is 1:(0.2~4).

[0011] In some embodiments, the mass ratio of dexmedetomidine hydrochloride to polysorbate is 1:(0.2~4).

[0012] In some embodiments, the mass ratio of dexmedetomidine hydrochloride to laurocapram is 1:(0.2~4).

[0013] In some embodiments, the penetration enhancer includes polyvinylpyrrolidone and at least one selected from polysorbate and laurocapram.

[0014] In some embodiments, the mass ratio of the polyvinylpyrrolidone to the polysorbate is 1:(0.3~1).

[0015] In some embodiments, the mass ratio of the polyvinylpyrrolidone to the laurocapram is 1:(0.3~1).

[0016] In some embodiments, the mass ratio of the polyvinylpyrrolidone, the polysorbate, and the laurocapramone is 1:(0.3~1):(0.3~1).

[0017] In some embodiments, the soluble microneedles contain 0.05 mg to 0.5 mg of dexmedetomidine hydrochloride.

[0018] In some embodiments, the drug-loaded needle body further includes trehalose and sodium hyaluronate with a weight-average molecular weight of 150 kDa to 280 kDa.

[0019] In some embodiments, the mass ratio of dexmedetomidine hydrochloride to sodium hyaluronate is 1:(0.2~3).

[0020] In some embodiments, the mass ratio of sodium hyaluronate to trehalose is 1:(5~16).

[0021] In some embodiments, the substrate comprises a photocurable resin formed from a photocurable resin monomer, a photoinitiator, and a solvent, wherein the photocurable resin monomer comprises diurea dimethacrylate and / or triethylene glycol dimethacrylate.

[0022] In some embodiments, the photoinitiator includes camphorquinone and dimethylaminoethyl methacrylate.

[0023] In some embodiments, the solvent includes water.

[0024] In some embodiments, the mass ratio of the photocurable resin monomer to the photoinitiator is (10~30):1.

[0025] This application has the following beneficial effects:

[0026] The dexmedetomidine hydrochloride soluble microneedles of this application, through the use of specific penetration enhancers, significantly increase the peak concentration of the drug after transdermal delivery, with a short onset time and long duration of action, achieving rapid release, rapid onset of action, and sustained effectiveness. Compared with traditional drug delivery methods, this improves compliance and provides a better treatment option for insomnia patients. Attached Figure Description

[0027] Figure 1 This is a microscope image of the dexmedetomidine hydrochloride soluble microneedles provided in Example 1 of this application;

[0028] Figure 2 These are microscopic photographs of the skin of miniature pigs after being punctured by dexmedetomidine hydrochloride soluble microneedles as described in Examples 1-2, provided in this application. Detailed Implementation

[0029] 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.

[0030] Soluble microneedles utilize a step-by-step drying process to ensure drug stability, offering advantages such as being painless, minimally invasive, highly effective, and having minimal impact. They allow for targeted penetration of the stratum corneum and physiological barriers, increasing the contact area and depth with the wound. Once the microneedles penetrate the stratum corneum, they rapidly dissolve upon contact with subcutaneous fluid, facilitating the rapid release of the drug components carried by the needle. This process effectively overcomes the stratum corneum barrier, significantly improving the transdermal penetration efficiency and bioavailability of water-soluble drugs, ultimately achieving highly efficient absorption and rapid onset of action in subcutaneous tissue.

[0031] In this application, the term "penetration enhancer" refers to a substance that can improve the permeability of skin tissue and promote the delivery of drugs through the skin.

[0032] One well-known class of permeation enhancers is enzymes, which improve tissue permeability by breaking down the extracellular matrix. Commonly used enzymes such as hyaluronidase and papain are widely applied, but enzyme-based permeation enhancers have a relatively slow onset of action. Another class of permeation enhancers improves tissue permeability through chemical / biological action. For example, Chinese patent application CN20241167605.3 discloses the use of dodecyl-β-D-maltose glycoside (DDM), ethylenediaminetetraacetic acid (EDTA), and tetrahydropiperidine as permeation enhancers, but their permeation-enhancing effect on dexmedetomidine hydrochloride has not yet met expectations, and their onset speed does not meet practical needs.

[0033] In response to the above situation, the first aspect of this application provides a dexmedetomidine hydrochloride soluble microneedle, comprising a substrate and a drug-loaded needle body, wherein the drug-loaded needle body contains dexmedetomidine hydrochloride and a penetration enhancer; the penetration enhancer comprises at least two of laurocapram, polyvinylpyrrolidone, and polysorbate; wherein the polyvinylpyrrolidone has a weight-average molecular weight of 2000 Da to 13000 Da.

[0034] In existing technologies, high molecular weight polyvinylpyrrolidone (PVP) is typically used as a framework material, base material, or penetration enhancer. For example, high molecular weight PVP such as K90 is frequently used as a framework 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, a lower molecular weight PVP within the aforementioned range is selected as a penetration enhancer, which helps to transform dexmedetomidine hydrochloride 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.

[0035] 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 dexmedetomidine hydrochloride in biomembranes.

[0036] Therefore, by using at least two of the above three penetration enhancers in the dexmedetomidine hydrochloride soluble microneedles in this application, the penetration enhancement effect can be synergistically enhanced. Under the synergistic effect of the above penetration enhancers, dexmedetomidine hydrochloride can be rapidly penetrated and released, thereby obtaining further improved cumulative penetration rate, onset time and duration of efficacy.

[0037] 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 dexmedetomidine hydrochloride while taking into account the continuity and stability of the diffusion, thereby better synergizing with laurocapram and / or polysorbate, and further enhancing the penetration-enhancing effect.

[0038] In some embodiments, the polyvinylpyrrolidone may be selected from one or more of K17, K15 and K12; optionally, the polyvinylpyrrolidone is K17.

[0039] 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.

[0040] In some embodiments, the mass ratio of dexmedetomidine hydrochloride to the penetration enhancer is 1:(0.2~8). By controlling the dosage relationship between the penetration enhancer and dexmedetomidine hydrochloride, the penetration enhancer can function better, resulting in good skin permeability of dexmedetomidine hydrochloride and rapid release from the needle. Exemplarily, the mass ratio of dexmedetomidine hydrochloride to the penetration enhancer can be 1:0.2, 1:0.4, 1:0.6, 1:0.8, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:65, 1:7, 1:75, 1:88, or a range of values ​​with any two of the above values ​​as endpoints. Optionally, the mass ratio of dexmedetomidine hydrochloride to the penetration enhancer is 1:(0.4~6). Optionally, the mass ratio of dexmedetomidine hydrochloride to the penetration enhancer is 1:(0.4~4).

[0041] In some embodiments, the mass ratio of the drug-loaded needle to the substrate is 1:(25~300). 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 dexmedetomidine hydrochloride, thus avoiding needle breakage. For example, the mass ratio of the drug-loaded needle to the substrate can be 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, or 1:200, or a range of ratios with any two of the above ratios as endpoints.

[0042] In some embodiments, the mass ratio of dexmedetomidine hydrochloride to polyvinylpyrrolidone is 1:(0.2~4). By controlling the amounts of dexmedetomidine hydrochloride and polyvinylpyrrolidone, it is helpful to convert dexmedetomidine hydrochloride into a more soluble and easily released amorphous form, thereby achieving efficient permeation enhancement. Exemplarily, the mass ratio of dexmedetomidine hydrochloride to 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 dexmedetomidine hydrochloride to polyvinylpyrrolidone is 1:(0.2~3).

[0043] In some embodiments, the mass ratio of dexmedetomidine hydrochloride to polysorbate is 1:(0.2~4). By controlling the amount of dexmedetomidine hydrochloride and polysorbate, it helps to further reduce the diffusion resistance of dexmedetomidine hydrochloride in biological membranes, making it easier for laurocapram to enter and disrupt the lipid structure. Exemplarily, the mass ratio of dexmedetomidine hydrochloride to 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 dexmedetomidine hydrochloride to polysorbate is 1:(0.2~3).

[0044] In some embodiments, the mass ratio of dexmedetomidine hydrochloride to laurocapram is 1:(0.2~4). By controlling the dosage relationship of dexmedetomidine hydrochloride and laurocapram, it is helpful to rapidly reduce the diffusion resistance of dexmedetomidine hydrochloride and significantly enhance the transdermal absorption of the drug. Exemplarily, the mass ratio of dexmedetomidine hydrochloride 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 dexmedetomidine hydrochloride to laurocapram is 1:(0.2~3).

[0045] In some embodiments, the penetration enhancer includes polyvinylpyrrolidone and at least one selected from polysorbate and laurocapram, specifically, it may be a mixture of polyvinylpyrrolidone and polysorbate, a mixture of polyvinylpyrrolidone and laurocapram, or a mixture of polyvinylpyrrolidone, polysorbate and laurocapram.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] In this application, by controlling the dosage relationship between the penetration enhancers, the synergistic effect can be further improved, enabling dexmedetomidine hydrochloride to be released into the bloodstream quickly, allowing the soluble microneedles to achieve good skin accumulation and penetration rate, which helps to achieve rapid release, rapid onset of action, and sustained effectiveness of dexmedetomidine hydrochloride.

[0050] In this application, the drug-loaded needle contains an effective amount of dexmedetomidine hydrochloride for treating insomnia. In some embodiments, the content of dexmedetomidine hydrochloride in the soluble microneedle is 0.05 mg to 0.5 mg. Exemplarily, the content of dexmedetomidine hydrochloride can be 0.05 mg, 0.10 mg, 0.15 mg, 0.20 mg, 0.25 mg, 0.30 mg, 0.35 mg, 0.40 mg, 0.45 mg, or 0.5 mg, or a range of values ​​with any two of the above values ​​as endpoints.

[0051] During the preparation of soluble microneedles, after the drug-loaded needle containing dexmedetomidine hydrochloride is dried and shaped, some dexmedetomidine hydrochloride easily permeates into the uncured base solution upon contact. After the base solidifies, this portion remains trapped within, resulting in loss of the active drug. While this loss is minimal at high doses, it is significantly amplified at low doses, potentially leading to insufficient effective drug concentration. For dexmedetomidine hydrochloride, the effective dose for treating insomnia is far lower than that for analgesia or sedation. This further exacerbates the problem of insufficient transdermal absorption when using soluble microneedles for insomnia treatment, compared to their use for analgesia or sedation. This application, by optimizing the selection and dosage of penetration enhancers, helps improve the transdermal absorption efficiency of low-dose dexmedetomidine hydrochloride, ensuring that low-dose soluble microneedles achieve the target effective blood drug concentration when treating insomnia.

[0052] 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.

[0053] In some embodiments, the drug-loaded needle further includes trehalose and sodium hyaluronate with a weight-average molecular weight of 150 kDa to 280 kDa. Exemplarily, 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 these values ​​as endpoints. Optionally, the weight-average molecular weight of sodium hyaluronate is 150 kDa to 180 kDa. Sodium hyaluronate in the aforementioned low molecular weight range is more conducive to the release of dexmedetomidine hydrochloride.

[0054] 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 with the aforementioned molecular weight 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.

[0055] 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.

[0056] In some embodiments, the mass ratio of dexmedetomidine hydrochloride to sodium hyaluronate is 1:(0.2~3). Exemplarily, the mass ratio of dexmedetomidine hydrochloride to sodium hyaluronate can be 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 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.

[0057] In some embodiments, the mass ratio of sodium hyaluronate to trehalose is 1:(5~16). Exemplarily, the mass ratio of sodium hyaluronate to trehalose can be 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, or 1:16, or a range of values ​​with any two of the above values ​​as endpoints.

[0058] In this application, the drug-loaded needle body also contains an aqueous solvent, which is a small amount of residue left after the soluble microneedles are dried during the preparation process. Optionally, the aqueous solvent includes water.

[0059] In some embodiments, the substrate described above in this application includes a photocurable resin, which is formed from a photocurable resin monomer, a photoinitiator, and a solvent, wherein the photocurable resin monomer includes diurea dimethacrylate and / or triethylene glycol dimethacrylate.

[0060] In some embodiments, the photoinitiator includes camphorquinone and dimethylaminoethyl methacrylate.

[0061] 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.

[0062] 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.

[0063] Meanwhile, the inventors discovered that the specific photocurable resin monomers mentioned above have a certain interfacial bonding force with the sodium hyaluronate of the molecular weight mentioned above in this application. The mutual diffusion between the two before curing can promote the mechanical interlocking of the drug-loaded needle body and the substrate material, thereby improving the bonding strength between the drug-loaded needle body and the substrate material and reducing the needle breakage rate.

[0064] In some embodiments, the photocurable resin monomer comprises triethylene glycol dimethacrylate and diurea dimethacrylate in a mass ratio of 1:(1~5). 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, 1:2, 1:3, 1:4 or 1:5, or a range of values ​​with any two of the above values ​​as endpoints.

[0065] In some embodiments, the solvent includes water.

[0066] 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, 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.

[0067] In some embodiments, the mass ratio of camphorquinone to dimethylaminoethyl methacrylate in the photoinitiator is 1:(1~5). Exemplarily, the mass ratio of the photocurable resin monomer to the photoinitiator can be 1:1, 1:2, 1:3, 1:4, or 1:5, or a range of ratios with any two of the above ratios as endpoints.

[0068] 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.

[0069] Secondly, this application provides a method for preparing the dexmedetomidine hydrochloride soluble microneedles, comprising:

[0070] S1, mix the photocurable resin monomer, photoinitiator and solvent to obtain the base liquid; mix dexmedetomidine hydrochloride, penetration enhancer, sodium hyaluronate, trehalose and aqueous solvent to obtain the needle solution;

[0071] S2, add the needle solution to the mold, degas under vacuum and then dry;

[0072] S3, continue to add the base liquid to the mold obtained in S2, and then cure it under ultraviolet light after vacuum degassing;

[0073] S4, demolding, packaging, and irradiation sterilization.

[0074] 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.

[0075] In some embodiments, in S1, the mass percentage of dexmedetomidine hydrochloride is 0.02% to 20.0% based on the total mass of the needle solution. For example, the mass percentage of dexmedetomidine hydrochloride, 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%.

[0076] 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.

[0077] 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.

[0078] In this application, in step S3, after vacuum degassing, UV curing is performed for 5 to 60 seconds.

[0079] In this application, in step S4, the irradiation dose for sterilization is 15kGy to 25kGy.

[0080] Thirdly, this application provides the application of the above-mentioned dexmedetomidine hydrochloride soluble microneedles or the dexmedetomidine hydrochloride soluble microneedles prepared by the above-mentioned preparation method in the preparation of drugs for treating insomnia.

[0081] Example

[0082] To further illustrate the technical solution of this application, the following embodiments are provided.

[0083] In the following examples and comparative examples, the weight-average molecular weight of HA-21 is 150kDa~180kDa; the weight-average molecular weight of HA-25.3 is 220kDa~250kDa; the weight-average molecular weight of HA-26.9 is 240kDa~280kDa; the weight-average molecular weight of PVP K17 is approximately 10000Da; the weight-average molecular weight of PVP K15 is approximately 8000Da; the weight-average molecular weight of PVP K12 is approximately 2000Da; the weight-average molecular weight of PVP K30 is approximately 50000Da; and the weight-average molecular weight of PVP K90 is approximately 1200000Da.

[0084] Example 1

[0085] This embodiment provides a dexmedetomidine hydrochloride soluble microneedle, the preparation method of which includes the following steps:

[0086] (1) Preparation of the needle solution:

[0087] 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.

[0088] Table 1-1

[0089]

[0090] (2) Preparation of the base solution:

[0091] 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.

[0092] (3) Preparation of soluble microneedles:

[0093] 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.

[0094] 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.

[0095] (4) Packaging and sterilization: After packaging, sterilize at 25 kGy and store at room temperature.

[0096] 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.

[0097] The component composition of the dexmedetomidine hydrochloride soluble microneedle product is shown in Table 1-2 below:

[0098] Table 1-2

[0099]

[0100] Examples 2-6, Comparative Examples 1-4

[0101] The preparation was carried out in the same manner as in Example 1, except that the types of penetration enhancers were adjusted according to Tables 2-1 and 2-2. Table 2-1 shows the dosage relationship of the components in the needle solution during the preparation of the soluble microneedle product; Table 2-2 shows the dosage relationship of the components in the soluble microneedle product.

[0102] Comparative Example 5

[0103] The preparation steps for dexmedetomidine hydrochloride soluble microneedles are the same as in Example 1, except that an equal amount of DDM (dodecyl-β-D-maltodextrin) is used as a penetration enhancer.

[0104] Soluble microneedle performance testing

[0105] (1) Pass rate

[0106] 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 The pass rate is calculated as follows: Taking Example 1 as an example, a batch of 100 soluble microneedle patches prepared in Example 1 is considered qualified if the breakage rate of each microneedle is less than 5%, and unqualified if the breakage rate of each microneedle is greater than 5%.

[0107] Needle breakage rate = number of broken needles per soluble microneedle patch / total number of needles per soluble microneedle patch.

[0108] The pass rate = the number of qualified soluble microneedle patches in a batch / the total number of soluble microneedle patches in a batch.

[0109] The pass rate test results are shown in Table 6-2.

[0110] (2) Puncture test

[0111] 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 Examples 1 and 2 are shown below. Figure 2 As shown.

[0112] (3) 24h cumulative transmittance

[0113] The qualified soluble microneedles prepared in each example and comparative example were used for experiments, with each test performed in triplicate. 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 2-2, 4-2, and 6-2 below.

[0114] (4) Pharmacokinetic studies

[0115] The soluble microneedles prepared in Examples 1-6 and Comparative Examples 1-5 were used to conduct pharmacokinetic studies on Bama miniature pigs as experimental animals.

[0116] Experimental method: In accordance with ethical requirements, 33 Bama miniature pigs aged 3-4 months and weighing 7-8 kg were selected and divided into 11 groups of 3 pigs each, which were used for Examples 1-6 and Comparative Examples 1-5, respectively.

[0117] Administration method: Hair was removed from the back of each animal beforehand to ensure that the skin was not damaged. The drug was administered transdermally on the back of each animal. The patch was removed 2 hours after administration. The dosage for each group was 0.1 mg / animal.

[0118] Blood was collected at 0h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h after drug administration. Blood was collected using centrifuge tubes coated with sodium heparin. Plasma was separated by centrifugation after collection and stored at -20℃. Blood drug concentration was determined by LC / MS, and the results are shown in Table 3 (mean values ​​are given). A drug concentration plot was drawn based on the blood drug concentrations in Table 3. The time curves were used to calculate pharmacokinetic parameters, and the results are shown in Table 3.

[0119] Table 2-1

[0120]

[0121] Note: In Table 2-1, "mass percentage" refers to the mass percentage of a certain component based on the total mass of the needle solution.

[0122] Table 2-2

[0123]

[0124] Note: In Table 2-2, "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.

[0125] Table 3

[0126]

[0127] Note: In Table 3, "NC" means not detected.

[0128] As shown in the table above, when the mass ratio of dexmedetomidine hydrochloride to the penetration enhancer is the same, compared with the comparative example, in Examples 1-6, using at least two of laurocapram, polysorbate, and low molecular weight polyvinylpyrrolidone as penetration enhancers resulted in a higher cumulative permeation rate of the prepared soluble microneedles over 24 hours, demonstrating excellent penetration enhancement effects. Furthermore, the prepared soluble microneedles showed a significantly reduced Tmax and a significantly increased maximum required concentration (Cmax), indicating a shorter onset time and a higher peak concentration. Simultaneously, the drug's duration of action exceeded 8 hours (the effective concentration of dexmedetomidine hydrochloride for treating insomnia is 100 pg / mL), indicating a longer drug duration.

[0129] Examples 7-15

[0130] The preparation was carried out in the same manner as in Example 1, except that the content of the penetration enhancer and the mass ratio of the drug-loaded needle to the substrate were adjusted according to Tables 4-1 and 4-2. Specifically, in Examples 7-10, the content of the penetration enhancer was adjusted according to Tables 4-1 and 4-2, while the total mass of the needle solution and the solvent mass remained unchanged, and other components were adjusted according to the proportions in Example 1. Table 4-1 shows the dosage relationship of the components in the needle solution during the preparation of the soluble microneedle product; Table 4-2 shows the dosage relationship of the components in the soluble microneedle product.

[0131] Table 4-1

[0132]

[0133] Note: In Table 4-1, "mass percentage" refers to the mass percentage of a certain component based on the total mass of the needle solution.

[0134] Table 4-2

[0135]

[0136] Note: In Table 4-2, "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.

[0137] As shown in Tables 4-1 and 4-2, the results of Examples 7 to 13 indicate that a better cumulative permeability is achieved by maintaining the mass ratio of dexmedetomidine hydrochloride to the penetration enhancer within the range of 1:(0.4~8). The results of Examples 14 and 15 show that when the mass ratio of the drug-loaded needle body to the substrate is 1:(25~300), the prepared soluble microneedles exhibit excellent cumulative permeability.

[0138] Examples 16-17

[0139] Prepared in the same manner as in Example 1, except that the weight-average molecular weight of sodium hyaluronate was adjusted according to Tables 6-1 and 6-2.

[0140] Example 18

[0141] The preparation was carried out in the same manner as in Example 1, except that the formulation of the needle solution is shown in Table 5-1:

[0142] Table 5-1

[0143]

[0144] The component composition of the dexmedetomidine hydrochloride soluble microneedle product is shown in Table 5-2 below:

[0145] Table 5-2

[0146]

[0147] Example 19

[0148] 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 Tables 6-1 and 6-2.

[0149] Examples 20-22

[0150] Prepared in the same manner as in Example 1, except that the base formulation was adjusted according to Tables 6-1 and 6-2.

[0151] Example 23

[0152] Prepared in the same manner as in Example 1, except that the substrate was replaced with an equal amount of PVP K90.

[0153] Table 6-1 below shows the dosage relationship of components in the needle body solution and base solution during the preparation of soluble microneedle products; Table 6-2 shows the dosage relationship of components in soluble microneedle products.

[0154] Table 6-1

[0155]

[0156] Note: In Table 6-1, the mass percentages of TEGDMA, UDMA, polyethylene glycol diacrylate, and photoinitiator refer to the mass percentage of a certain component based on the total mass of the base solution. The mass percentages of dexmedetomidine hydrochloride and penetration enhancer refer to the mass percentage of a certain component based on the total mass of the needle solution.

[0157] Table 6-2

[0158]

[0159] As shown in Tables 6-1 and 6-2, the choice of substrate affects the compatibility between the needle tip and the substrate material to a certain extent, thus affecting the bonding strength between the two. Specifically, drug-loaded needles containing trehalose and sodium hyaluronate with a weight-average molecular weight of 150kDa~280kDa exhibit better biocompatibility with the substrate, resulting in soluble microneedles with a lower breakage rate. Furthermore, sodium hyaluronate with the aforementioned molecular weight helps to promote the penetration of dexmedetomidine hydrochloride drug molecules towards the needle tip, reducing its retention in the substrate and thereby increasing the cumulative drug penetration rate. In addition, substrate materials formed by photocurable resin monomers of TEGDMA and / or UDMA have excellent compatibility with drug-loaded needle materials containing sodium hyaluronate and trehalose with the molecular weights specified in this application, resulting in high bonding strength between the substrate and the needle, low breakage rate, and high yield.

[0160] 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 dexmedetomidine hydrochloride soluble microneedle, comprising a base and a drug-loaded needle body, characterized in that, The drug-loaded needle contains dexmedetomidine hydrochloride and a penetration enhancer; The penetration enhancer includes at least two of laurocapram, polyvinylpyrrolidone, and polysorbate; the weight-average molecular weight of the polyvinylpyrrolidone is 2000 Da to 13000 Da. The mass ratio of dexmedetomidine hydrochloride to the penetration enhancer is 1:(0.2~8). The mass ratio of the drug-loaded needle to the substrate is 1:(25~300). The mass ratio of dexmedetomidine hydrochloride to the polysorbate is 1:(0.2~4), and / or, The mass ratio of dexmedetomidine hydrochloride to polyvinylpyrrolidone is 1:(0.2~4), and / or, The mass ratio of dexmedetomidine hydrochloride to laurocapram is 1:(0.2~4).

2. The dexmedetomidine hydrochloride soluble microneedles according to claim 1, characterized in that, The penetration enhancer includes polyvinylpyrrolidone and at least one selected from polysorbate and laurocapram.

3. The dexmedetomidine hydrochloride soluble microneedles according to claim 2, characterized in that, 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).

4. The dexmedetomidine hydrochloride soluble microneedles according to any one of claims 1 to 3, characterized in that, The soluble microneedles contain 0.05 mg to 0.5 mg of dexmedetomidine hydrochloride.

5. The dexmedetomidine hydrochloride soluble microneedles according to any one of claims 1 to 3, characterized in that, The drug-loaded needle also includes trehalose and sodium hyaluronate with a weight-average molecular weight of 150 kDa to 280 kDa.

6. The dexmedetomidine hydrochloride soluble microneedles according to claim 5, characterized in that, The mass ratio of dexmedetomidine hydrochloride to sodium hyaluronate is 1:(0.2~3), and / or, The mass ratio of sodium hyaluronate to trehalose is 1:(5~16).

7. The dexmedetomidine hydrochloride soluble microneedles according to claim 5, characterized in that, The substrate comprises a photocurable resin, which is formed from a photocurable resin monomer, a photoinitiator, and a solvent. The photocurable resin monomer includes diurea dimethacrylate and / or triethylene glycol dimethacrylate; and / or, The photoinitiator includes camphorquinone and dimethylaminoethyl methacrylate; and / or, The solvent includes water.

8. The dexmedetomidine hydrochloride soluble microneedles according to claim 7, characterized in that, The mass ratio of the photocurable resin monomer to the photoinitiator is (10~30):1.

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