Dexmedetomidine microneedle patch and preparation method and application thereof

Abstract

The application relates to a dexmedetomidine microneedle patch and a preparation method and application thereof. The dexmedetomidine microneedle patch comprises a substrate and a needle body arranged on the surface of the substrate, the composition of the needle body comprises dexmedetomidine hydrochloride, a skeleton material and a penetration enhancer; the penetration enhancer comprises one or more of dodecyl-beta-D-maltoside, ethylenediaminetetraacetic acid and tetrahydro-piperine. The dexmedetomidine microneedle patch has a higher drug cumulative permeation amount, is beneficial to shortening a sleep-aiding onset time, prolonging a sleep-aiding action time and has a good insomnia treatment effect.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a dexmedetomidine microneedle patch and a preparation method and application thereof. BACKGROUND

[0002] Insomnia is a common sleep disorder characterized by difficulty falling asleep, difficulty maintaining sleep, or waking up early and being unable to fall back asleep, accompanied by daytime dysfunction. Insomnia patients often exhibit symptoms such as lack of concentration, memory loss, sluggishness, and emotional instability, which can significantly impact work efficiency and quality of life. Insomnia is closely related to psychological disorders such as anxiety and depression, and can also lead to decreased immunity, resulting in various physical health problems. Studies have shown that the incidence of insomnia is high worldwide, with a prevalence rate of about 10% to 30% in the general population, and a higher rate in specific populations such as postoperative patients, the elderly, women, and people with chronic diseases or mental disorders. As age increases, the incidence of insomnia increases significantly, especially in people over 50 years old. For postoperative patients, insomnia can have a significant negative impact on the recovery process, including delaying recovery, exacerbating postoperative pain, increasing the risk of postoperative complications, prolonging hospital stays, and increasing medical costs. Traditional insomnia treatments include benzodiazepines, barbiturates, and melatonin, all of which have varying degrees of addiction, drug resistance, residual effects the next day, impaired cognitive function, and other adverse reactions.

[0003] Dexmedetomidine is a highly selective alpha2 adrenergic receptor agonist that can produce corresponding hypnotic effects by acting on alpha2 receptors in the central nervous system and peripheral nervous system. Compared to other insomnia treatments, dexmedetomidine has unique advantages: it produces a hypnotic effect similar to natural human sleep; it has no respiratory depression; it protects the upper respiratory tract; it reduces postoperative delirium; and it shows lower addiction and dependence, which is particularly important for patients who use sleep aids long-term.

[0004] There are methods to complex dexmedetomidine hydrochloride with dextrose to form a soluble microneedle for preoperative sedation in children. However, compared to preoperative sedation in children, the treatment of insomnia requires a higher drug cumulative permeation amount from the soluble microneedle to achieve a shorter onset time and longer duration of sleep aid. The complex of dexmedetomidine hydrochloride and dextrose cannot meet the requirements. SUMMARY

[0005] Therefore, the present application provides a dexmedetomidine microneedle patch with a higher drug cumulative permeation amount, which is beneficial for shortening the onset time and prolonging the duration of sleep aid, and has good efficacy for the treatment of insomnia.

[0006] In a first aspect of the present application, a dexmedetomidine microneedle patch is provided, comprising a substrate and a needle body arranged on the surface of the substrate, wherein the needle body comprises dexmedetomidine hydrochloride, a matrix material and a penetration enhancer.

[0007] The penetration enhancer comprises one or more of dodecyl-β-D-maltoside (DDM), ethylenediaminetetraacetic acid (EDTA) and tetrahydro-piperine.

[0008] In one embodiment, the penetration enhancer comprises one or more of ethylenediaminetetraacetic acid (EDTA) and tetrahydro-piperine.

[0009] In one embodiment, the mass percentage of the penetration enhancer in the composition of the needle body is 0.3% to 10%.

[0010] In one embodiment, the mass percentage of the penetration enhancer in the composition of the needle body is 0.5% to 5%.

[0011] In one embodiment, the mass percentage of the penetration enhancer in the composition of the needle body is 2% to 3%.

[0012] In one embodiment, the matrix material comprises dextran.

[0013] In one embodiment, the mass percentage of dexmedetomidine hydrochloride in the composition of the needle body is 4% to 56.5%; and / or

[0014] The mass percentage of the matrix material is 33.9% to 95.7%.

[0015] In one embodiment, the composition of the substrate comprises one or more of polyvinylpyrrolidone, polyvinyl alcohol, sodium hyaluronate, sodium carboxymethyl cellulose and hydroxypropyl methyl cellulose.

[0016] In a second aspect of the present application, a preparation method of the dexmedetomidine microneedle patch of the first aspect is provided, comprising the following steps:

[0017] The matrix material and the penetration enhancer are mixed with water, and then the dexmedetomidine hydrochloride is added to prepare a needle body solution;

[0018] The composition of the substrate is mixed with a solvent to swell and prepare a substrate swelling solution;

[0019] The needle body solution is formed in a mold and dried, and then the substrate swelling solution is added to the mold to form and dry, thereby forming the needle body and the substrate to prepare the dexmedetomidine microneedle patch.

[0020] In a third aspect of the present application, the dexmedetomidine microneedle patch of the first aspect is used for preparing a drug for treating insomnia.

[0021] The dexmedetomidine microneedle patch described above introduces one or more materials including dodecyl-β-D-maltoside (DDM), ethylenediaminetetraacetic acid (EDTA) and tetrahydro-piperine as a penetration enhancer on the basis of dexmedetomidine hydrochloride and a matrix material, which can significantly improve the transdermal delivery efficiency of dexmedetomidine hydrochloride, promote its release into blood, and significantly improve the skin cumulative permeation of dexmedetomidine hydrochloride in the microneedle, thereby achieving a good therapeutic effect for insomnia, shortening the onset time of sleep aid, and prolonging the maintenance time of sleep aid.

[0022] Meanwhile, it is found in the research that, compared with dexmedetomidine hydrochloride injection, the dexmedetomidine microneedle patch described above can achieve a shorter sleep latency and a longer sleep time, indicating that the addition of the penetration enhancer promotes the treatment of insomnia of dexmedetomidine itself, and the two have a synergistic effect.

[0023] In addition, compared with traditional insomnia treatment drugs, the dexmedetomidine microneedle patch described above has the following advantages:

[0024] (1) The dexmedetomidine hydrochloride microneedle patch has high bioavailability;

[0025] (2) No additional combination drug is needed, especially no drug with adverse reactions such as addiction, dependence, hangover effect, etc. is needed, which improves the safety of drug use;

[0026] (3) The administration route is transdermal administration, which is convenient for patients to use the drug in familiar places outside medical institutions, is convenient to carry, has good administration convenience, reduces the pain and irritation of traditional injection or nasal administration, improves the patient's medication compliance, and has better clinical application value compared with dexmedetomidine injection and nasal spray. BRIEF DESCRIPTION OF DRAWINGS

[0027] Figure 1 Cumulative permeation rates of dexmedetomidine hydrochloride microneedle patches prepared for examples and comparative examples at various time points.

[0028] Figure 2 Comparison of sleep latency of each administration group in the dexmedetomidine hydrochloride microneedle extension pentobarbital sodium sleep efficacy test.

[0029] Figure 3 Comparison of sleep duration of each administration group in the dexmedetomidine hydrochloride microneedle extension pentobarbital sodium sleep efficacy test. DETAILED DESCRIPTION

[0030] The dexmedetomidine microneedle patch, the preparation method and the application thereof of the present application will be further described in detail below in conjunction with specific embodiments. The present application can be realized in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present application more thorough and comprehensive.

[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs. The terminology used in the description of the present application herein only for the purpose of describing specific embodiments and is not intended to limit the present application.

[0032] The alternative scope of the terms "and / or", "or / and", "and / or" used herein includes any one of two or more related listed items, and also includes any and all combinations of related listed items, which includes any two related listed items, any more related listed items, or a combination of all related listed items.

[0033] Herein, "one or more" means any one, any two or any two or more of the listed items.

[0034] In the present application, "first aspect", "second aspect", "third aspect" and the like are only for the purpose of description and cannot be understood as indicating or implying relative importance or quantity, nor can it be understood as implicitly indicating the importance or quantity of the indicated technical features. Moreover, "first", "second", "third" and the like only serve the purpose of non-exhaustive enumeration and description, and should be understood as not constituting a closed limitation on the quantity.

[0035] In the present application, the technical features described in an open-ended manner include both a closed technical solution consisting of listed features and an open technical solution containing listed features.

[0036] In the present application, if no special description is provided, the above numerical range is considered to be continuous and includes the minimum value and the maximum value of the range, as well as every value between the minimum value and the maximum value. Further, when the range refers to an integer, every integer between the minimum value and the maximum value of the range is included. In addition, when multiple ranges are provided to describe a feature or a characteristic, the ranges can be combined. In other words, unless otherwise indicated, all ranges disclosed herein should be understood to include any and all sub-ranges subsumed therein.

[0037] In the present application, the percentage content, if no special description is provided, refers to mass percentage for solid-liquid mixing and solid-solid mixing, and refers to volume percentage for liquid-liquid mixing.

[0038] The percentage concentration referred to in the present application, if not specified, refers to the final concentration. The final concentration refers to the proportion of the added ingredient in the system after the ingredient is added.

[0039] The temperature parameter in the present application, if not specifically limited, allows both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument.

[0040] The room temperature in the present application generally refers to 4-30°C, preferably 20±5°C.

[0041] Some examples of the present application provide a dexmedetomidine microneedle patch, comprising a substrate and a needle body arranged on the surface of the substrate, the composition of the needle body comprising dexmedetomidine hydrochloride, a matrix material and a penetration enhancer;

[0042] The penetration enhancer comprises one or more of dodecyl-β-D-maltoside (DDM), ethylenediaminetetraacetic acid (EDTA) and tetrahydro-piperine.

[0043] In some examples, the penetration enhancer comprises one or more of ethylenediaminetetraacetic acid (EDTA) and tetrahydro-piperine. The use of suitable penetration enhancers can achieve higher cumulative drug permeation with smaller amounts, thereby achieving better treatment of insomnia.

[0044] In some examples, the mass percentage of the penetration enhancer in the composition of the needle body is 0.3%-10%. Reasonable control of the mass percentage of the penetration enhancer can achieve higher cumulative drug permeation, thereby achieving better treatment of insomnia. Specifically, the mass percentage of the penetration enhancer in the composition of the needle body includes but is not limited to 0.3%, 0.5%, 0.6%, 0.8%, 1.0%, 1.2%, 1.5%, 1.8%, 2%, 2.4%, 3%, 3.5%, 4%, 4.8%, 6%, 8%, 9.6%, 10% or a range between any two of the foregoing. Further, the mass percentage of the penetration enhancer in the composition of the needle body is 0.5%-5%. Still further, the mass percentage of the penetration enhancer in the composition of the needle body is 2%-3%.

[0045] In some examples, the matrix material comprises dextran. Suitable matrix materials can dissolve rapidly in the skin to release the drug, concentrate the drug in the needle tip portion to reduce drug migration, and improve drug delivery efficiency and utilization.

[0046] In some examples, the skeleton material has a mass percentage of 33.9% to 95.7%. Specifically, the mass percentage of the skeleton material in the composition of the needle body includes, but is not limited to, 33.9%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 82%, 85%, 88%, 90%, 91%, 92.5%, 95.7%, or a range between any two of the foregoing. Further, the mass percentage of the skeleton material is 80% to 92.5%.

[0047] In some examples, the mass percentage of dexmedetomidine hydrochloride in the composition of the needle body is 4% to 56.5%. Specifically, the mass percentage of dexmedetomidine hydrochloride in the composition of the needle body includes, but is not limited to, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 56.5%, or a range between any two of the foregoing. Further, the mass percentage of dexmedetomidine hydrochloride in the composition of the needle body is 7% to 10%.

[0048] In some examples, the composition of the base includes one or more of polyvinylpyrrolidone, polyvinyl alcohol, sodium hyaluronate, sodium carboxymethyl cellulose, and hydroxypropyl methyl cellulose. Without limitation, the polyvinylpyrrolidone can be one or more of, for example, PVP K90, PVP K30, and PVP K60.

[0049] Some examples of the present application provide a method of preparing the dexmedetomidine microneedle patch as described above, including the following steps:

[0050] After mixing the skeleton material and the penetration enhancer with water, the dexmedetomidine hydrochloride is added to prepare a needle body solution;

[0051] The composition of the base is mixed with a solvent to swell to prepare a base swelling solution;

[0052] The needle body solution is shaped in a mold, dried, and then the base swelling solution is added to the mold to shape and dry to form the needle body and the base, thereby preparing the dexmedetomidine microneedle patch.

[0053] In some examples, the solvent in the preparation of the base swelling solution includes anhydrous ethanol.

[0054] In some examples, the step of shaping the needle body solution in a mold includes:

[0055] The needle body solution is added to the microneedle negative mold, centrifuged at 3500 rpm to 4500 rpm for 5 min to 15 min at 0°C to 10°C, the mold is turned over 180° after centrifugation, and then centrifuged at 3500 rpm to 4500 rpm for 5 min to 15 min at 0°C to 10°C; the excess needle body solution is removed, and centrifugation is continued at 3500 rpm to 4500 rpm for 25 min to 35 min at 0°C to 10°C.

[0056] In some examples, the base swelling solution is added to the mold, and the forming step includes:

[0057] The base swelling solution is added to the microneedle negative mold containing the aforementioned dried needle body, centrifuged at 3500 rpm to 4500 rpm for 1 min to 10 min at 0°C to 10°C, then vacuumized, and then centrifuged at 3500 rpm to 4500 rpm for 1 min to 10 min at 0°C to 10°C.

[0058] It can be understood that after the needle body and the base are formed, the right dexmedetomidine microneedle patch can be prepared by demolding.

[0059] In some examples of the present application, the use of the right dexmedetomidine microneedle patch as described above in the preparation of a drug for treating insomnia is also provided. Without limitation, treating insomnia refers to shortening sleep latency and / or prolonging sleep time.

[0060] In the following specific examples, the experimental parameters not written in the examples are preferably referred to the guidance given in the present application, and can also be referred to the experimental manual in the art or other experimental methods known in the art, or to the experimental conditions recommended by the manufacturer.

[0061] In the following specific examples, the raw materials and reagents involved can be obtained by commercial purchase, or can be prepared by known means by those skilled in the art.

[0062] The preparation method of the right dexmedetomidine microneedle patch in the examples and comparative examples is as follows:

[0063] (1) Preparation of needle body solution: the corresponding proportion of matrix material and penetration enhancer (no penetration enhancer is added in comparative example 1) is weighed, and ultrapure water is added. After stirring and dissolving, an auxiliary solution is obtained. Hydrochloric acid dexmedetomidine is weighed and added to the auxiliary solution, and stirred and dissolved to obtain a needle tip solution.

[0064] (2) Preparation of base solution: 17.5 g of PVP K90 is weighed into a centrifugal cup, 100 mL of anhydrous ethanol is added, and stirred thoroughly. After standing overnight, the base solution is fully swelled.

[0065] (3) Preparation of the tip: 200 μL of the tip solution was added to the microneedle negative mold, and centrifuged at 4000 rpm for 10 min at 0-10°C. After centrifugation, the mold was turned over by 180°, and centrifuged at 4000 rpm for another 10 min at 0-10°C. Then the microneedle mold was taken out, and the residual tip solution on the top was scraped off. The microneedle mold was then centrifuged at 4000 rpm for 30 min at 0-10°C, and was placed in a moisture-proof cabinet for drying of the tip.

[0066] (4) Preparation of the base: 300 μL of the base solution was added to the tip-dried negative mold, and centrifuged at 4000 rpm for 3 min at 0-10°C to make the base solution evenly distributed on the mold. The mold was taken out and placed in a vacuum drying oven, and vacuumized to a vacuum degree close to -0.1 MPa. Then the valve was opened immediately to restore the normal pressure, and the process was repeated twice. The mold was taken out and centrifuged at 4000 rpm for 5 min at 0-10°C to remove the bubbles on the surface of the base. The mold was taken out and dried in a 40°C oven for 12 h.

[0067] (5) Demolding: the microneedle was peeled off from the mold, and the dexmedetomidine soluble microneedle patch was obtained.

[0068] Comparative Example 1

[0069] The comparative example was a dexmedetomidine microneedle patch, which was composed of a base and a needle body arranged on the surface of the base.

[0070] The material of the base was polyvinylpyrrolidone (PVP K90).

[0071] The material of the needle body was shown in Table 1.

[0072] Table 1

[0073]

[0074] Comparative Example 2

[0075] The comparative example was a dexmedetomidine microneedle patch, which was composed of a base and a needle body arranged on the surface of the base.

[0076] The material of the base was polyvinylpyrrolidone (PVP K90).

[0077] The material of the needle body was shown in Table 2.

[0078] Table 2

[0079]

[0080] Example 1

[0081] The embodiment is a dexmedetomidine microneedle patch, which is composed of a substrate and a needle body arranged on the surface of the substrate.

[0082] The material of the substrate is polyvinylpyrrolidone (PVP K90).

[0083] The material of the needle body is shown in Table 3.

[0084] Table 3

[0085]

[0086] Embodiment 2

[0087] The embodiment is a dexmedetomidine microneedle patch, which is composed of a substrate and a needle body arranged on the surface of the substrate.

[0088] The material of the substrate is polyvinylpyrrolidone (PVP K90).

[0089] The material of the needle body is shown in Table 4.

[0090] Table 4

[0091]

[0092] Embodiment 3

[0093] The embodiment is a dexmedetomidine microneedle patch, which is composed of a substrate and a needle body arranged on the surface of the substrate.

[0094] The material of the substrate is polyvinylpyrrolidone (PVP K90).

[0095] The material of the needle body is shown in Table 5.

[0096] Table 5

[0097]

[0098] Embodiment 4

[0099] The embodiment is a dexmedetomidine microneedle patch, which is composed of a substrate and a needle body arranged on the surface of the substrate.

[0100] The material of the substrate is polyvinylpyrrolidone (PVP K90).

[0101] The material of the needle body is shown in Table 6.

[0102] Table 6

[0103]

[0104] Embodiment 5

[0105] The embodiment is a dexmedetomidine microneedle patch, which is composed of a substrate and a needle body arranged on the surface of the substrate.

[0106] The material of the substrate is polyvinylpyrrolidone (PVP K90).

[0107] The material of the needle body is shown in Table 7.

[0108] Table 7

[0109]

[0110] Example 6

[0111] The embodiment is a dexmedetomidine microneedle patch, which is composed of a substrate and a needle body arranged on the surface of the substrate.

[0112] The material of the substrate is polyvinylpyrrolidone (PVP K90).

[0113] The material of the needle body is shown in Table 8.

[0114] Table 8

[0115]

[0116] Example 7

[0117] The embodiment is a dexmedetomidine microneedle patch, which is composed of a substrate and a needle body arranged on the surface of the substrate.

[0118] The material of the substrate is polyvinylpyrrolidone (PVP K90).

[0119] The material of the needle body is shown in Table 9.

[0120] Table 9

[0121]

[0122] Example 8

[0123] The embodiment is a dexmedetomidine microneedle patch, which is composed of a substrate and a needle body arranged on the surface of the substrate.

[0124] The material of the substrate is polyvinylpyrrolidone (PVP K90).

[0125] The material of the needle body is shown in Table 10.

[0126] Table 10

[0127]

[0128] Test Example:

[0129] (1) In vitro transdermal study

[0130] Experimental method: The pigskin was fixed on the workbench directly below the probe of the tensile tester, and the microneedle patch was fixed on the probe of the tensile tester with the needle tip facing down. The parameters of the tensile tester were set to maintain the drug delivery state for 3 min under the action of 100 N force. After the drug delivery was completed, the pigskin was transferred to the Franz diffusion cell for drug transdermal study. The drug content was detected at 1 h, 2 h, 6 h, 16 h, and 24 h, respectively, and the cumulative release amount was calculated. Each time point was detected in triplicate. The 24 h cumulative permeation rate of the drug is shown in Table 11, and the cumulative permeation rate at each time point is shown in Table 12. Figure 1

[0131] Table 11

[0132]

[0133] (2) Dexmedetomidine hydrochloride microneedle prolongs the sleep efficacy of pentobarbital sodium

[0134] 2.1 Test preparation:

[0135] Reagents: 0.9% sodium chloride solution, 1.5% pentobarbital sodium, dexmedetomidine hydrochloride microneedle (Example 4), commercially available dexmedetomidine hydrochloride injection (100 μg / mL);

[0136] Test animals: 20 male SD rats, SPF level, body weight 180-200 g.

[0137] 2.2 Test method:

[0138] According to the body weight, the animals were randomly divided into 4 groups, namely normal control group, dexmedetomidine hydrochloride microneedle 4 μg / rat (low dose) group, dexmedetomidine hydrochloride microneedle 6 μg / rat (high dose) group, and dexmedetomidine hydrochloride injection 4 μg / rat group.

[0139] 2.3 The test scheme is shown in Table 12:

[0140] Table 12

[0141]

[0142] Note: i.v. intravenous injection; TDDs transdermal drug delivery.

[0143] ​According to the results of the pre-experiment, the rats were injected intraperitoneally with 30 mg / kg of sodium pentobarbital, and the righting reflex of the rats disappeared about 10 min later. The threshold dose of sodium pentobarbital for the rats was determined to be 30 mg / kg. The drugs at various doses were administered according to Table 12, and immediately after administration, the threshold dose of sodium pentobarbital 30 mg / kg was injected intraperitoneally. The injection time of sodium pentobarbital, the disappearance time of righting reflex, and the recovery time of righting reflex were recorded. The disappearance of righting reflex in both sides of the rats for 60 s was taken as the standard for falling asleep. The sleep latency and sleep time were calculated respectively.

[0144] Sleep latency = disappearance time of righting reflex - injection time of sodium pentobarbital;

[0145] Sleep time = recovery time of righting reflex - disappearance time of righting reflex.

[0146] 2.4 Data analysis

[0147] The injection time of sodium pentobarbital, the disappearance time of righting reflex, and the recovery time of righting reflex were recorded. The sleep latency and sleep time were calculated respectively. The data were plotted using GraphPad Prism 8 software, and the statistical analysis and regression calculation of the sleep latency of rats were performed using SPSS software. The sleep latency and sleep time of each dose group were subjected to homogeneity of variance test. If the variance was homogeneous (p>0.05), one-way analysis of variance was performed,

[0148] If there was a significant difference (p≤0.05), Dunnett's test was performed between each dose group and the normal control group; otherwise, the test was ended. If the variance was not homogeneous (p≤0.05), non-parametric test (Kruskal-Wallis H test, i.e., K-W H test) was performed. If there was a statistically significant difference (p≤0.05) in K-W H test, Mann-Whitney U test was performed between each dose group and the control group; otherwise, the test was ended.

[0149] 2.5 The test results are shown in Tables 13 and Figure 2 、 Figure 3

[0150] Table 13 Effect of various dexmedetomidine hydrochloride preparations on the hypnotic effect of threshold dose of sodium pentobarbital (Mean ± SD)

[0151]

[0152] Note: compared with the normal control group, ***P<0.001, ****P<0.0001; compared with the dexmedetomidine hydrochloride injection, ##P<0.01

[0153] ​It can be seen that after intraperitoneal injection of 30 mg / kg sodium pentobarbital, the sleep latency of normal rats is about 11.4 min. The microneedle of dexmedetomidine hydrochloride at 4 and 6 μg per microneedle is dose-dependent in shortening the sleep latency of rats, and there is a significant difference compared with the solvent control group (p<0.0001). At the same dose, the effect of dexmedetomidine hydrochloride microneedle in shortening the sleep latency is equivalent to that of injection solution. At the dose of 6 μg per microneedle, dexmedetomidine hydrochloride microneedle can significantly shorten the sleep latency of rats, and there is also a significant difference compared with the injection solution at the dose of 4 μg per microneedle (P<0.01).

[0154] After intraperitoneal injection of 30 mg / kg sodium pentobarbital, the sleep time of normal rats is about 108 min. The microneedle of dexmedetomidine hydrochloride at 4 and 6 μg per microneedle is dose-dependent in prolonging the sleep time of rats, and there is a significant difference compared with the solvent control group (p<0.0001). At the same dose, the effect of dexmedetomidine hydrochloride microneedle in prolonging the sleep time is equivalent to that of injection solution. At the dose of 6 μg per microneedle, dexmedetomidine hydrochloride microneedle can significantly prolong the sleep time of rats, and the effect is slightly better than that of the injection solution at the dose of 4 μg per microneedle.

[0155] The technical features of the above-described embodiments can be combined in any manner. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described, but as long as the combinations of the technical features do not contradict, they should be considered within the scope of the present disclosure.

[0156] The above-described embodiments only express several implementation manners of the present application, facilitate specific and detailed understanding of the technical solutions of the present application, but cannot be understood as limiting the patent protection scope. It should be noted that for those skilled in the art, on the premise of not departing from the concept of the present application, a number of modifications and improvements can be made, which are within the protection scope of the present application. It should be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited experiments on the basis of the technical solutions provided by the present application are within the protection scope of the appended claims of the present application. Therefore, the patent protection scope of the present application should be subject to the contents of the appended claims, and the description can be used to explain the contents of the claims.

Claims

1. A dexmedetomidine microneedle patch characterized by, The base and the needle body arranged on the surface of the base, the composition of the needle body comprising dexmedetomidine hydrochloride, a skeleton material and a penetration enhancer; The penetration enhancer is dodecyl-β-D-maltoside, and the mass percentage of the penetration enhancer in the composition of the needle body is 2% to 3%; or, The penetration enhancer is ethylenediaminetetraacetic acid, and the mass percentage of the penetration enhancer in the composition of the needle body is 0.3% to 0.8%; or, The penetration enhancer is tetrahydro-piperine, and the mass percentage of the penetration enhancer in the composition of the needle body is 0.8% to 1.2%.

2. The dexmedetomidine microneedle patch of claim 1, wherein, The penetration enhancer is dodecyl-β-D-maltoside, and the mass percentage of the penetration enhancer in the composition of the needle body is 2.4%.

3. The dexmedetomidine microneedle patch of claim 1, wherein, The penetration enhancer is ethylenediaminetetraacetic acid, and the mass percentage of the penetration enhancer in the composition of the needle body is 0.5%.

4. The dexmedetomidine microneedle patch of claim 1, wherein, The penetration enhancer is tetrahydro-piperine, and the mass percentage of the penetration enhancer in the composition of the needle body is 1%.

5. The dexmedetomidine microneedle patch of claim 1, wherein, The skeleton material comprises dextran.

6. The dexmedetomidine microneedle patch of any one of claims 1-5, wherein the dexmedetomidine microneedle patch is formulated to provide a plasma concentration of dexmedetomidine of about 0.5 ng / mL to about 2 ng / mL. The mass percentage of dexmedetomidine hydrochloride in the composition of the needle body is 4% to 56.5%.

7. The dexmedetomidine microneedle patch of any one of claims 1-5, wherein the dexmedetomidine microneedle patch is formulated to provide a plasma concentration of dexmedetomidine of about 0.5 ng / mL to about 2 ng / mL. The mass percentage of the skeleton material is 33.9% to 95.7%.

8. The dexmedetomidine microneedle patch of any one of claims 1-5, wherein, The composition of the base comprises one or more of polyvinylpyrrolidone, polyvinyl alcohol, sodium hyaluronate, sodium carboxymethyl cellulose and hydroxypropyl methyl cellulose.

9. A process for the preparation of dexmedetomidine microneedle patch according to any one of claims 1 to 8, characterized by, The steps comprise: Mixing the skeleton material and the penetration enhancer with water, and then adding dexmedetomidine hydrochloride to prepare a needle body solution; Mixing the composition of the base with a solvent to swell the base and prepare a base swelling solution; Forming the needle body solution in a mold, drying, then adding the base swelling solution to the mold, forming and drying to form the needle body and the base, thereby preparing the dexmedetomidine microneedle patch.

10. Use of the dexmedetomidine microneedle patch of any one of claims 1 to 8 in the preparation of a drug for treating insomnia.

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