Dexmedetomidine microneedle patch as well as preparation method and application thereof

Abstract

The invention relates to a dexmedetomidine microneedle patch as well as a preparation method and application thereof. The dexmedetomidine microneedle patch comprises a substrate and a needle body arranged on the surface of the substrate, wherein the needle body comprises dexmedetomidine hydrochloride, a framework material and a penetration enhancer; the penetration enhancer is prepared from one or more of dodecyl-beta-D-maltoside, ethylenediamine tetraacetic acid and tetrahydropiperine. The dexmedetomidine microneedle patch is higher in medicine cumulative penetration amount, facilitates shortening of sleep-aiding onset time and prolonging of 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, and in particular to a dexmedetomidine microneedle patch and a preparation method and application thereof. Background Art

[0002] Insomnia is a common sleep disorder, characterized by difficulty falling asleep, difficulty maintaining sleep, or being unable to fall asleep again after waking up early, accompanied by daytime dysfunction, etc. Insomnia patients often show symptoms of inattention, memory loss, slow reaction and emotional instability, which can seriously affect 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 and a variety of physical health problems. Studies have shown that the incidence of insomnia is high worldwide, with a prevalence of about 10% to 30% in the general population, and in specific populations, such as postoperative patients, the elderly, women, and people with chronic diseases or mental disorders, this proportion is even higher. With age, 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 rehabilitation process, including delaying the rehabilitation process, aggravating postoperative pain, increasing the risk of postoperative complications, prolonging hospitalization and increasing medical costs. Traditional drugs for treating insomnia include benzodiazepines, barbiturates, melatonin, etc. These drugs have varying degrees of addiction, drug tolerance, next-day residual effects, impaired cognitive function and other adverse reactions.

[0003] Dexmedetomidine is a highly selective α2 adrenergic receptor agonist that can produce corresponding hypnotic effects by acting on α2 receptors in the central nervous system and peripheral nervous system. Compared with other drugs for the treatment of insomnia, dexmedetomidine has unique advantages: it produces a hypnotic effect similar to natural human sleep; it has no respiratory depressant effect; it protects the upper respiratory tract; it reduces postoperative delirium; and it also shows low addiction and dependence, which is particularly important for patients who use sleep aids for a long time.

[0004] There is a method to combine dextran and dexmedetomidine hydrochloride to make soluble microneedles for preoperative sedation in children. However, compared with preoperative sedation in children, the treatment of insomnia requires a higher cumulative drug penetration of soluble microneedles to achieve the purpose of shortening the onset time of sleep-inducing effect and prolonging the duration of sleep-inducing effect, and the combination of dextran and dexmedetomidine hydrochloride cannot meet the demand. Summary of the invention

[0005] Based on this, the present application provides a dexmedetomidine microneedle patch with a higher cumulative drug permeation amount, which is beneficial for shortening the onset time of sleep-aiding effect, prolonging the sleep-aiding effect time, and having good therapeutic efficacy for insomnia, as well as a preparation method and application thereof.

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

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

[0008] In one embodiment, the penetration enhancer includes one or more of ethylenediaminetetraacetic acid (EDTA) and tetrahydropiperine.

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

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

[0011] In one embodiment, the mass percentage of the penetration enhancer in 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 skeleton material is 33.9% to 95.7%.

[0015] In one embodiment, the composition of the base includes one or more of polyvinyl pyrrolidone, polyvinyl alcohol, sodium hyaluronate, sodium carboxymethyl cellulose and hydroxypropyl methylcellulose.

[0016] The second aspect of the present application provides a method for preparing the dexmedetomidine microneedle patch according to the first aspect, comprising the following steps:

[0017] After mixing the skeleton material and the penetration enhancer with water, the dexmedetomidine hydrochloride is added to prepare a needle solution;

[0018] Mixing the components of the substrate with a solvent to swell, to prepare a substrate swelling solution;

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

[0020] The third aspect of the present application provides use of the dexmedetomidine microneedle patch described in the first aspect in the preparation of a drug for treating insomnia.

[0021] The above-mentioned dexmedetomidine microneedle patch, based on dexmedetomidine hydrochloride and skeleton materials, introduces one or more materials including dodecyl-β-D-maltoside (DDM), ethylenediaminetetraacetic acid (EDTA) and tetrahydropiperine as penetration enhancers, which can significantly improve the transdermal delivery efficiency of dexmedetomidine hydrochloride, promote its release into the blood, and significantly increase the cumulative skin penetration of dexmedetomidine hydrochloride in the microneedles, thereby achieving a good therapeutic effect on insomnia, shortening the onset time of sleep-aiding effect and prolonging the maintenance time of sleep-aiding effect.

[0022] At the same time, the study also found that compared with dexmedetomidine hydrochloride injection, the above-mentioned dexmedetomidine microneedle patch can achieve a shorter sleep latency and longer sleep time, indicating that the addition of the penetration enhancer promotes the treatment of insomnia by dexmedetomidine itself, and the two have a synergistic effect.

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

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

[0025] (2) No additional combined medication is required, especially no need to use it with drugs that have adverse reactions such as addiction, dependence, and hangover effects, which improves the safety of medication;

[0026] (3) The route of administration is transdermal administration, which is convenient for patients to take the medicine in familiar places outside of medical facilities. It is easy to carry and has good administration convenience. At the same time, it reduces the pain and irritation of traditional injection or nasal administration, improves patients' medication compliance, and has better clinical application value compared with dexmedetomidine injection and nasal spray. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 The cumulative permeability at each time point of the dexmedetomidine hydrochloride microneedle patch prepared in the examples and comparative examples.

[0028] Figure 2 To compare the sleep latency duration of each medication group in the dexmedetomidine hydrochloride microneedle prolonged pentobarbital sodium sleep efficacy test.

[0029] Figure 3 To compare the sleep duration of each medication group in the efficacy test of dexmedetomidine hydrochloride microneedle to prolong the sleep of pentobarbital sodium. DETAILED DESCRIPTION

[0030] The following is a further detailed description of the dexmedetomidine microneedle patch of the present application and its preparation method and application in conjunction with specific examples. The present application can be implemented 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 thoroughly understood.

[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application belongs. The terms used herein in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0032] The optional scope of the terms "and / or", "or / and", and "and / or" used in this article includes any one of two or more related listed items, and also includes any and all combinations of the related listed items, said any and all combinations include any combination of any two related listed items, any more related listed items, or all related listed items.

[0033] As used herein, "one or more" refers to any one, any two, or any two or more of the listed items.

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

[0035] In the present application, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0036] In this application, when it comes to numerical ranges, unless otherwise specified, the above numerical ranges are deemed to be continuous and include the minimum and maximum values ​​of the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges included therein.

[0037] The percentage contents involved in this application, unless otherwise specified, refer to mass percentage for solid-liquid mixing and solid-solid mixing, and refer to volume percentage for liquid-liquid mixing.

[0038] The percentage concentrations mentioned in this application, unless otherwise specified, refer to the final concentration, which refers to the percentage of the added component in the system after the addition of the component.

[0039] The temperature parameters in this application, unless otherwise specified, allow for both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows the temperature to fluctuate within the accuracy range of instrument control.

[0040] The room temperature in this application generally refers to 4°C~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 disposed on the surface of the substrate, wherein the needle body comprises dexmedetomidine hydrochloride, a skeleton material and a penetration enhancer;

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

[0043] In some examples, the penetration enhancer includes one or more of ethylenediaminetetraacetic acid (EDTA) and tetrahydropiperine. The use of a suitable penetration enhancer can achieve a higher cumulative drug permeation amount with a smaller dosage, thereby achieving a better therapeutic effect for insomnia.

[0044] In some of the 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 a higher cumulative drug penetration, thereby obtaining a better therapeutic effect on 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, in the composition of the needle body, the mass percentage of the penetration enhancer is 0.5%~5%. Furthermore, in the composition of the needle body, the mass percentage of the penetration enhancer is 2%~3%.

[0045] In some of the examples, the skeleton material includes dextran. Suitable skeleton materials can dissolve quickly in the skin to release drugs, can concentrate the drugs at the needle tip to reduce drug migration, and improve drug delivery efficiency and utilization.

[0046] In some examples, the mass percentage of the skeleton material is 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 of the 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, in the composition of the needle body, the mass percentage of dexmedetomidine hydrochloride is 7% to 10%.

[0048] In some examples, the composition of the substrate includes one or more of polyvinyl pyrrolidone, polyvinyl alcohol, sodium hyaluronate, sodium carboxymethyl cellulose and hydroxypropyl methylcellulose. Without limitation, the polyvinyl pyrrolidone can be one or more of PVP K90, PVP K30 and PVP K60.

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

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

[0051] Mixing the components of the substrate with a solvent to swell, to prepare a substrate swelling solution;

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

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

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

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

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

[0057] The substrate swelling liquid is added to the microneedle negative mold including the dried needle body, centrifuged at 3500rpm~4500rpm for 1min~10min at 0℃~10℃, then vacuumed, and then centrifuged at 3500rpm~4500rpm for 1min~10min at 0℃~10℃.

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

[0059] Some other examples of the present application also provide the use of the dexmedetomidine microneedle patch as described above in the preparation of a drug for treating insomnia. Without limitation, treating insomnia means shortening sleep latency and / or prolonging sleep time.

[0060] For experimental parameters not specified in the following specific embodiments, reference is made to the instructions given in the present application document, and reference may also be made to experimental manuals in the art or other experimental methods known in the art, or to experimental conditions recommended by manufacturers.

[0061] The raw materials and reagents involved in the following specific examples can be obtained from commercial sources, or can be prepared by those skilled in the art according to known methods.

[0062] The preparation methods of the dexmedetomidine microneedle patches of the embodiments and comparative examples are as follows:

[0063] (1) Preparation of needle body solution: Weigh the corresponding proportions of skeleton material and penetration enhancer (no penetration enhancer was added in comparative example 1), add ultrapure water, and stir to dissolve to obtain an auxiliary material solution. Weigh dexmedetomidine hydrochloride and add it to the auxiliary material solution, and stir to dissolve to obtain a needle tip solution.

[0064] (2) Preparation of base solution: Weigh 17.5 g of PVP K90 into a centrifuge cup, add 100 mL of anhydrous ethanol, stir thoroughly, and leave overnight to obtain a base solution after it is fully swollen.

[0065] (3) Preparation of needle tip: Take 200 μL of the above needle tip solution and add it to the microneedle negative mold. Centrifuge at 4000 rpm for 10 min at 0℃~10℃. After centrifugation, flip the mold 180° and continue centrifugation at 4000 rpm for 10 min at 0℃~10℃. Then take out the microneedle mold and scrape off the residual needle tip solution on the upper layer. Then continue centrifugation at 4000 rpm for 30 min at 0℃~10℃. Take out the microneedle mold and put it in a moisture-proof cabinet to dry the needle tip.

[0066] (4) Preparation of substrate: Take 300 μL of the above substrate solution and add it to the negative mold after the needle tip is dried. Centrifuge at 4000 rpm for 3 minutes at 0℃~10℃ to evenly disperse the substrate solution on the mold. Take out the mold and place it in a vacuum drying oven. Evacuate the vacuum to a vacuum degree close to -0.1 MPa, then immediately open the air valve to restore the vacuum box to normal pressure. Repeat twice. Take out the mold and place it in a centrifuge. Centrifuge at 4000 rpm for 5 minutes at 0℃~10℃ to remove bubbles on the surface of the substrate. Take out the mold and place it in a 40℃ oven to dry for 12 hours.

[0067] (5) Demolding: The microneedles are peeled off from the mold to obtain the dexmedetomidine hydrochloride soluble microneedle patch.

[0068] Comparative Example 1

[0069] This comparative example is a dexmedetomidine microneedle patch, which is composed of a substrate and a needle body arranged on the surface of the substrate:

[0070] Substrate material: polyvinyl pyrrolidone (PVPK90);

[0071] The materials of the needle body are shown in Table 1 below:

[0072] Table 1

[0073]

[0074] Comparative Example 2

[0075] This comparative example is a dexmedetomidine microneedle patch, which is composed of a substrate and a needle body arranged on the surface of the substrate:

[0076] Substrate material: polyvinyl pyrrolidone (PVPK90);

[0077] The materials of the needle body are shown in Table 2 below:

[0078] Table 2

[0079]

[0080] Example 1

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

[0082] Substrate material: polyvinyl pyrrolidone (PVPK90);

[0083] The materials of the needle body are shown in Table 3 below:

[0084] Table 3

[0085]

[0086] Example 2

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

[0088] Substrate material: polyvinyl pyrrolidone (PVPK90);

[0089] The materials of the needle body are shown in Table 4 below:

[0090] Table 4

[0091]

[0092] Example 3

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

[0094] Substrate material: polyvinyl pyrrolidone (PVPK90);

[0095] The materials of the needle body are shown in Table 5 below:

[0096] Table 5

[0097]

[0098] Example 4

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

[0100] Substrate material: polyvinyl pyrrolidone (PVPK90);

[0101] The materials of the needle body are shown in Table 6 below:

[0102] Table 6

[0103]

[0104] Example 5

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

[0106] Substrate material: polyvinyl pyrrolidone (PVPK90);

[0107] The materials of the needle body are shown in Table 7 below:

[0108] Table 7

[0109]

[0110] Example 6

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

[0112] Substrate material: polyvinyl pyrrolidone (PVPK90);

[0113] The materials of the needle body are shown in Table 8 below:

[0114] Table 8

[0115]

[0116] Example 7

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

[0118] Substrate material: polyvinyl pyrrolidone (PVPK90);

[0119] The materials of the needle body are shown in Table 9 below:

[0120] Table 9

[0121]

[0122] Example 8

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

[0124] Substrate material: polyvinyl pyrrolidone (PVPK90);

[0125] The materials of the needle body are shown in Table 10 below:

[0126] Table 10

[0127]

[0128] Test example:

[0129] (1) In vitro transdermal study

[0130] Experimental method: Fix the pig skin on the storage table directly below the probe of the tensile tester, and fix the microneedle patch on the probe of the tensile tester with the needle tip facing downward. Set the parameters of the tensile tester to maintain the drug administration state for 3 minutes under a force of 100N. After the drug administration, transfer the pig skin to the Franz diffusion cell for drug transdermal study. Samples were taken at 1h, 2h, 6h, 16h, and 24h to detect the drug content, and the cumulative release amount was calculated. Each time point was tested three times in parallel. The 24h cumulative permeability of the drug is shown in Table 11 below. The cumulative permeability at each time point is shown in Table 11 below. Figure 1 As shown:

[0131] Table 11

[0132]

[0133] (2) Experimental study on the efficacy of dexmedetomidine hydrochloride microneedle in prolonging sleep time with sodium pentobarbital

[0134] 2.1 Test preparation:

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

[0136] Experimental animals: 20 male SD rats, SPF grade, weighing 180-200 g.

[0137] 2.2 Test methods:

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

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

[0140] Table 12

[0141]

[0142] Note: iv: intravenous injection; TDDs: transdermal administration.

[0143] According to the results of the preliminary experiment, after the rats were intraperitoneally injected with 30 mg / kg sodium pentobarbital, the rats' righting reflex disappeared in about 10 minutes, and the suprathreshold dose of sodium pentobarbital in rats was set at 30 mg / kg. Each dose of drug was given according to Table 12, and the suprathreshold dose of sodium pentobarbital 30 mg / kg was injected intraperitoneally immediately after administration. The injection time of sodium pentobarbital, the time of disappearance of righting reflex, and the time of recovery of righting reflex were recorded. The disappearance of bilateral righting reflex of rats for 60 seconds was used as the standard for falling asleep. The sleep latency and sleep time were calculated respectively.

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

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

[0146] 2.4 Data Analysis

[0147] The time of sodium pentobarbital injection, the time of righting reflex disappearance, and the time of righting reflex recovery were entered into Excel software and calculated into sleep latency and sleep time. GraphPad Prism8 software was used for drawing, and SPSS software was used for statistical analysis and regression calculation of rat sleep latency ED 50. The sleep latency and sleep time of each dose group were tested for variance homogeneity. If the variance was homogeneous (p>0.05), a one-way analysis of variance was performed.

[0148] If there is a significant difference (p≤0.05), a Dunnett test will be performed between each dose group and the normal control group; otherwise, the test will be terminated. If the variance is unequal (p≤0.05), a non-parametric test (Kruskal-Wallis H test, i.e., KW H test) will be performed. If the KW H test shows a statistical difference (p≤0.05), a Mann-Whitney U test will be performed between each dose group and the control group; otherwise, the test will be terminated.

[0149] 2.5 The test results are shown in Table 13 and Figure 2 , Figure 3 As shown:

[0150] Table 13 Effects of various dexmedetomidine hydrochloride formulations on the hypnotic effect of pentobarbital sodium suprathreshold dose (Mean ± SD)

[0151]

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

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

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

[0155] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0156] The above-described embodiments only express several implementation methods of the present application, which is convenient for understanding the technical solution of the present application in detail, but it cannot be understood as limiting the scope of protection of the patent application. It should be pointed out that for ordinary technicians in this field, without departing from the concept of the present application, several modifications and improvements can be made, which all belong to the scope of protection 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 in the present application are all within the scope of protection of the claims attached to the present application. Therefore, the scope of protection of the patent of this application shall be based on the content of the attached claims, and the description can be used to interpret the content of the claims.

Claims

1. A dexmedetomidine microneedle patch, characterized in that: It comprises a substrate and a needle body arranged on the surface of the substrate, wherein the needle body comprises dexmedetomidine hydrochloride, a skeleton material and a penetration enhancer; The penetration enhancer includes one or more of dodecyl-β-D-maltoside, ethylenediaminetetraacetic acid and tetrahydropiperine.

2. The dexmedetomidine microneedle patch according to claim 1, characterized in that The penetration enhancer includes one or more of ethylenediaminetetraacetic acid and tetrahydropiperine.

3. The dexmedetomidine microneedle patch according to claim 1, characterized in that In the composition of the needle body, the mass percentage of the penetration enhancer is 0.3% to 10%.

4. The dexmedetomidine microneedle patch according to claim 3, characterized in that: In the composition of the needle body, the mass percentage of the penetration enhancer is 0.5% to 5%.

5. The dexmedetomidine microneedle patch according to claim 4, characterized in that: In the composition of the needle body, the mass percentage of the penetration enhancer is 2% to 3%.

6. The dexmedetomidine microneedle patch according to claim 1, characterized in that: The framework material includes dextran.

7. The dexmedetomidine microneedle patch according to any one of claims 1 to 6, characterized in that: In the composition of the needle body, the mass percentage of dexmedetomidine hydrochloride is 4% to 56.5%; and / or The mass percentage of the skeleton material is 33.9% to 95.7%.

8. The dexmedetomidine microneedle patch according to any one of claims 1 to 6, characterized in that: The composition of the base includes one or more of polyvinyl pyrrolidone, polyvinyl alcohol, sodium hyaluronate, sodium carboxymethyl cellulose and hydroxypropyl methylcellulose.

9. The method for preparing the dexmedetomidine microneedle patch according to any one of claims 1 to 8, characterized in that: The steps include: After mixing the skeleton material and the penetration enhancer with water, the dexmedetomidine hydrochloride is added to prepare a needle solution; Mixing the components of the substrate with a solvent to swell, to prepare a substrate swelling solution; The needle body solution is molded and dried in a mold, and then the substrate swelling solution is added to the mold, molded and dried to form the needle body and the substrate, thereby preparing the dexmedetomidine microneedle patch.

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

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