Dexmedetomidine transdermal composition, transdermal patch and its preparation method and application

Abstract

The objective of the present invention is to provide a dexmedetomidine transdermal composition and transdermal patch which are highly stable, non-irritating to the skin, significantly safe to be attached to the human body, and capable of achieving a sustained release effect for 2 to 5 days, as well as a method for preparing and using the same. [Solution] This application discloses a dexmedetomidine transdermal composition, a transdermal patch, and the preparation method and application thereof. The composition includes dexmedetomidine, propylene glycol, and a metal chelating crosslinker, or includes dexmedetomidine, propylene glycol, a metal chelating crosslinker, and a pressure-sensitive adhesive. In addition, this application adds propylene glycol as a solubilizing agent to the dexmedetomidine transdermal composition, which can reduce the generation of impurities and improve the compatibility of raw materials and auxiliary materials, and uses a metal chelating crosslinker and a pressure-sensitive adhesive together to jointly form the skeletal structure of the product, which significantly improves the adhesive performance and provides a better adhesion to patients.

Description

[Technical Field]

[0001] This application claims priority from a Chinese invention patent application filed on August 23, 2021, with the invention title "Dexmedetomidine transdermal composition, transdermal patch and its preparation method and application" and application number 202110969146.7, the entire contents of which are incorporated herein by reference.

[0002] The present application relates to, but is not limited to, the field of drug formulations, and in particular to dexmedetomidine transdermal compositions, transdermal patches and their preparation methods and applications. [Background technology]

[0003] Currently, the only dexmedetomidine available on the market in China and overseas is dexmedetomidine hydrochloride injection, which can only be used under the supervision of professional medical personnel. Clinically, it is used to provide sedation during endotracheal intubation and ventilation in surgical patients undergoing general anesthesia. However, the half-life of dexmedetomidine after injection is only 2 hours, and the duration of its efficacy is short.

[0004] The prior art Chinese patent application no. CN201480059798.5 discloses a dexmedetomidine transdermal composition and measures the average dexmedetomidine flux with administration time for different dexmedetomidine transdermal compositions. The present inventors have found that the dexmedetomidine transdermal composition according to the application has a poor flux, and in one embodiment, the transdermal composition has a flux of 0.5 μg / cm 2 It was found that the transdermal diffusion rate reached a maximum at 24 hours.

[0005] Therefore, there is a need to develop a transdermal dexmedetomidine composition that can provide an excellent transdermal diffusion rate, can be stored stably, is convenient for patients to administer it themselves, significantly reduces the number of administrations, and significantly extends the duration of drug action in the body. Summary of the Invention

[0006] In view of this, the present application provides a dexmedetomidine transdermal composition, a transdermal patch, and its preparation and application methods, which have excellent transdermal diffusion rate, good stability, and can achieve a sustained release effect of 2 to 5 days.

[0007] The following is a summary of the subject matter described in this specification, which is not intended to limit the scope of protection of the present application.

[0008] In a first aspect, the present application provides a dexmedetomidine transdermal composition comprising dexmedetomidine, propylene glycol, and a metal chelating crosslinker; Alternatively, in parts by weight, the composition contains 0.30 to 3.00 parts dexmedetomidine, 0.40 to 8.00 parts propylene glycol, and 0.30 to 1.25 parts metal chelate crosslinker; or the mass ratio of the propylene glycol to the dexmedetomidine is (4:3) to (8:3).

[0009] In a second aspect, the present application provides a dexmedetomidine transdermal composition comprising dexmedetomidine, propylene glycol, a metal chelating crosslinker, and a pressure-sensitive adhesive; Alternatively, the composition may comprise, in parts by weight, 0.30 to 3.00 parts dexmedetomidine, 0.40 to 8.00 parts propylene glycol, 0.30 to 1.25 parts metal chelate crosslinker, and 50.00 to 99.00 parts pressure sensitive adhesive; And / or, the mass ratio of the propylene glycol to the dexmedetomidine is (4:3) to (8:3).

[0010] In a third aspect, the present application provides a dexmedetomidine transdermal patch, the transdermal patch comprising, in order, a backing layer, an adhesive layer and an anti-adhesive release film layer, the adhesive layer being formed from the dexmedetomidine transdermal composition according to the first or second aspect.

[0011] In a fourth aspect, the present application provides a method for preparing a dexmedetomidine transdermal composition according to the second aspect, said method comprising: dissolving a metal chelate crosslinking agent in a solvent to obtain a metal chelate crosslinking agent solution; mixing a pressure-sensitive adhesive and a metal chelate crosslinker solution to obtain a blank matrix solution; mixing dexmedetomidine, propylene glycol and a solvent to obtain a dexmedetomidine solution; Mixing the dexmedetomidine solution and the blank matrix solution, stirring, leaving to stand, and drying.

[0012] In a fifth aspect, the present application provides a method for preparing a dexmedetomidine transdermal patch according to the third aspect, dissolving a metal chelate crosslinking agent in a solvent to obtain a metal chelate crosslinking agent solution; mixing a pressure-sensitive adhesive and a metal chelate crosslinker solution to obtain a blank matrix solution; mixing dexmedetomidine, propylene glycol and a solvent to obtain a dexmedetomidine solution; mixing the dexmedetomidine solution and the blank matrix solution, stirring, and allowing to stand to obtain a drug-containing matrix solution; applying a drug-containing matrix solution to the anti-adhesion release film layer and drying it to obtain a composite layer of an adhesive layer and an anti-adhesion release film layer; and laminating a backing layer to the adhesive layer.

[0013] In a sixth aspect, the present application provides an application of the dexmedetomidine transdermal composition or dexmedetomidine transdermal patch in preparing a drug formulation for improving sleep disorders.

[0014] In a seventh aspect, the present application provides a method for improving a sleep disorder in an individual, comprising administering to the individual in need thereof the above-described dexmedetomidine transdermal composition or dexmedetomidine transdermal patch.

[0015] In a first aspect, the present application provides a dexmedetomidine transdermal composition comprising dexmedetomidine, propylene glycol, and a metal chelating crosslinker.

[0016] In some embodiments of the first aspect, the composition has, in parts by weight, 0.30 to 3.00 parts dexmedetomidine, 0.40 to 8.00 parts propylene glycol, and 0.30 to 1.25 parts metal chelate crosslinker. In some embodiments of the first aspect, the composition contains 0.72 to 3.00 parts dexmedetomidine, 1.20 to 8.00 parts propylene glycol, and 0.30 to 1.25 parts metal chelate crosslinker. In some embodiments of the first aspect, the composition contains 0.72 to 1.80 parts dexmedetomidine, 1.20 to 4.20 parts propylene glycol, and 0.30 to 0.80 parts metal chelate crosslinker. In some embodiments of the first aspect, the composition contains 0.72 to 1.45 parts dexmedetomidine, 1.20 to 4.20 parts propylene glycol, and 0.30 to 0.80 parts metal chelate crosslinker.

[0017] In some embodiments of the first aspect, the mass ratio of propylene glycol to dexmedetomidine in the composition is (4:3) to (8:3). In some embodiments of the first aspect, the mass ratio of propylene glycol to dexmedetomidine in the composition is (5:3) to (7:3). In some embodiments of the first aspect, the mass ratio of propylene glycol to dexmedetomidine in the composition is 5:3.

[0018] In some embodiments of the first aspect, the metal chelate crosslinker is selected from one or more of aluminum acetylacetonate, zirconium acetylacetonate, titanium acetylacetonate, and polybutyl titanate. In some embodiments of the first aspect, the metal chelate crosslinker is aluminum acetylacetonate or polybutyl titanate. In some embodiments of the first aspect, the titanium acetylacetonate of the metal chelate crosslinker is titanium (oxy)acetylacetonate or titanium tetraacetylacetonate, or a mixture thereof.

[0019] In a second aspect, the present application provides a dexmedetomidine transdermal composition comprising dexmedetomidine, propylene glycol, a metal chelating crosslinker, and a pressure-sensitive adhesive.

[0020] In some embodiments of the second aspect, in parts by weight, the composition comprises 0.30 to 3.00 parts dexmedetomidine, 0.40 to 8.00 parts propylene glycol, 0.30 to 1.25 parts metal chelate crosslinker, and 50.00 to 99.00 parts pressure sensitive adhesive. In some embodiments of the second aspect, the composition contains 0.30 to 3.00 parts dexmedetomidine, 0.40 to 8.00 parts propylene glycol, 0.30 to 1.25 parts metal chelate crosslinker, and 50.00 to 99.00 parts pressure-sensitive adhesive, and the mass ratio of the propylene glycol to the dexmedetomidine is (4:3) to (8:3). In some embodiments of the second aspect, the composition comprises 0.72 to 3.00 parts, 0.72 to 1.80 parts, 0.72 to 1.45 parts, or 1.00 to 1.80 parts of dexmedetomidine.

[0021] In some embodiments of the second aspect, the mass ratio of the pressure-sensitive adhesive to the metal chelate crosslinker in the composition is from (70:1) to (310:1). In some embodiments of the second aspect, the composition comprises 0.72 to 3.00 parts dexmedetomidine, 1.20 to 8.00 parts propylene glycol, 0.30 to 1.25 parts metal chelate crosslinker, and 87.00 to 99.00 parts pressure-sensitive adhesive. In some embodiments of the second aspect, the composition comprises 0.72 to 1.80 parts dexmedetomidine, 1.20 to 4.20 parts propylene glycol, 0.30 to 0.80 parts metal chelate crosslinker, and 93.00 to 99.00 parts pressure-sensitive adhesive. In some embodiments of the second aspect, the composition comprises 0.72 to 1.45 parts dexmedetomidine, 1.20 to 4.20 parts propylene glycol, 0.30 to 0.80 parts metal chelate crosslinker, and 95.00 to 99.00 parts pressure sensitive adhesive.

[0022] In some embodiments of the second aspect, the mass ratio of propylene glycol to dexmedetomidine in the composition is (4:3) to (8:3). In some embodiments of the second aspect, the mass ratio of propylene glycol to dexmedetomidine in the composition is (5:3) to (7:3). In some embodiments of the second aspect, the mass ratio of propylene glycol to dexmedetomidine in the composition is 5:3.

[0023] In some embodiments of the second aspect, the weight ratio of the pressure-sensitive adhesive to the metal chelate crosslinker in the composition is from (70:1) to (160:1), from (160:1) to (220:1), or from (220:1) to (310:1). In some embodiments of the second aspect, the weight ratio of the pressure-sensitive adhesive to the metal chelate crosslinker in the composition is from (160:1) to (220:1), from (160:1) to (210:1), from (160:1) to (200:1), or from (190:1) to (220:1). In some embodiments of the second aspect, the composition has a weight ratio of pressure sensitive adhesive to metal chelate crosslinker of 160:1, 170:1, 180:1, 190:1, 200:1, 210:1, or 220:1. In some embodiments of the second aspect, the composition has a weight ratio of pressure sensitive adhesive to metal chelate crosslinker of 190:1.

[0024] In some embodiments of the second aspect, the composition comprises 0.30 to 0.70 parts of a metal chelate crosslinker. In some embodiments of the second aspect, the composition comprises 0.40 to 0.60 parts of a metal chelate crosslinker. In some embodiments of the second aspect, the composition comprises 0.50 parts of a metal chelate crosslinker.

[0025] In some embodiments of the second aspect, the metal chelate crosslinker is selected from one or more of aluminum acetylacetonate, zirconium acetylacetonate, titanium acetylacetonate, and polybutyl titanate. In some embodiments of the second aspect, the metal chelate crosslinker is aluminum acetylacetonate or polybutyl titanate. In some embodiments of the second aspect, the titanium acetylacetonate of the metal chelate crosslinker is titanium (oxy)acetylacetonate or titanium tetraacetylacetonate, or a mixture thereof. In some embodiments of the second aspect, the pressure sensitive adhesive is selected from one or more of an acrylate pressure sensitive adhesive, a polyisobutylene pressure sensitive adhesive, a silicone pressure sensitive adhesive, a styrene-isoprene-styrene hot melt pressure sensitive adhesive (SIS type), and a vinyl acetate copolymer. In some embodiments of the second aspect, the acrylate pressure sensitive adhesive is DURO-TAK® 387-2510 or DURO-TAK® The number is 387-2287.

[0026] In a third aspect, the present application provides a dexmedetomidine transdermal patch, which sequentially comprises a backing layer, an adhesive layer, and an anti-adhesive release film layer, and the adhesive layer is formed from the dexmedetomidine transdermal composition. In some embodiments of the third aspect, the adhesive layer has a thickness of 25 μm to 100 μm.

[0027] In a fourth aspect, the present application provides a method for preparing the dexmedetomidine transdermal composition, the method comprising: dissolving a metal chelate crosslinking agent in a solvent to obtain a metal chelate crosslinking agent solution; mixing a pressure-sensitive adhesive and a metal chelate crosslinker solution to obtain a blank matrix solution; mixing dexmedetomidine, propylene glycol and a solvent to obtain a dexmedetomidine solution; Mixing the dexmedetomidine solution and the blank matrix solution, stirring, leaving to stand, and drying. In some embodiments of the fourth aspect, the solvent is selected from a mixture of one or both of absolute ethanol and n-heptane.

[0028] In a fifth aspect, the present application provides a method for preparing the dexmedetomidine transdermal patch, the method comprising: dissolving a metal chelate crosslinking agent in a solvent to obtain a metal chelate crosslinking agent solution; mixing a pressure-sensitive adhesive and a metal chelate crosslinker solution to obtain a blank matrix solution; mixing dexmedetomidine, propylene glycol and a solvent to obtain a dexmedetomidine solution; mixing the dexmedetomidine solution and the blank matrix solution, stirring, and allowing to stand to obtain a drug-containing matrix solution; applying a drug-containing matrix solution to the anti-adhesion release film layer and drying it to obtain a composite layer of an adhesive layer and an anti-adhesion release film layer; and laminating a backing layer to the adhesive layer. In some embodiments of the fifth aspect, the solvent is selected from a mixture of one or both of absolute ethanol and n-heptane.

[0029] In a sixth aspect, the present application provides an application of the dexmedetomidine transdermal composition or dexmedetomidine transdermal patch in preparing a drug formulation for improving sleep disorders. In some embodiments of the sixth aspect, the sleep disorder is one or more of perioperative sleep disorder, geriatric sleep disorder, and traumatic sleep disorder.

[0030] In a seventh aspect, the present application provides a method for improving a sleep disorder in an individual, comprising administering to the individual in need thereof the above-described dexmedetomidine transdermal composition or dexmedetomidine transdermal patch. In some embodiments of the seventh aspect, the sleep disorder is one or more of perioperative sleep disorder, geriatric sleep disorder, and traumatic sleep disorder.

[0031] The present application creatively adds a specific amount of propylene glycol to the dexmedetomidine composition, making the mass ratio of propylene glycol to the main drug dexmedetomidine between (4:3) and (8:3), and uses a metal chelating crosslinker and a pressure-sensitive adhesive together as the backbone structure of dexmedetomidine. As a result, the dexmedetomidine transdermal composition described in the present application has a high in vitro diffusion rate, stable product quality, and is more convenient to administer than commercially available dexmedetomidine hydrochloride injections, achieving continuous release for 2 to 5 days, and ensuring the patient's quality of sleep after use. [Brief explanation of the drawings]

[0032] The drawings are intended to provide a further understanding of the examples of the present application, are incorporated into the specification, and are used to interpret the examples of the present application together with the specific embodiments described below, but are not intended to limit the examples of the present application. [Figure 1] FIG. 1 is a schematic diagram of the preparation of a dexmedetomidine transdermal patch according to the present application. [Figure 2] 1A and 1B are structural schematic diagrams of a dexmedetomidine transdermal patch according to the present application, in which FIG. 1A is a side view of the dexmedetomidine transdermal patch, and FIG. 1B is a top view of the dexmedetomidine transdermal patch. [Figure 3] FIG. 1 is an in vitro transdermal diffusion curve diagram of dexmedetomidine transdermal patches of different thicknesses according to the present application. [Figure 4] 1A and 1B are crystal images of a dexmedetomidine composition according to the present application after storage for 6 months, where A is a 10x image and B is a 40x image. [Figure 5]1 is a line graph showing spontaneous activity data of mice in which the dexmedetomidine transdermal composition according to the present application was used to improve sleep. [Figure 6] 1 shows trend charts of cumulative time in rat sleep-wake structure over 72 hours for sleep improvement application of the dexmedetomidine transdermal composition of the present application, where A is a trend chart of cumulative wake time for each group within each time point in the rat sleep structure within 72 hours after patch administration, B is a trend chart of cumulative NREM time for each group within each time point within 72 hours after patch administration, and C is a trend chart of cumulative REM time for each group within each time point within 72 hours after patch administration, N=8. [Figure 7] 1 is a curve comparing the percutaneous diffusion rate per unit area of ​​Examples 4 and 7 of the present application with Comparative Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0033] In this application, the definitions of some terms are as follows: NREM sleep: non-rapid eye movement sleep, characterized by slowed activity of the brain and eyes, is a major stage of deep sleep and metabolic cycle. REM sleep (rapid eye movement sleep) is characterized by the fact that cerebral activity does not completely cease, and it is a stage of light sleep and dreaming.

[0034] In an embodiment of the present application, the dexmedetomidine composition according to the present application has the following calculation method for each component:

[0035] Weight percentage X(%)=X / (A+B+C+D*d)*100%

[0036] where A is the weight of dexmedetomidine, B is the weight of propylene glycol, C is the weight of metal chelating crosslinker, D is the weight of pressure-sensitive adhesive, d is the solids content corresponding to the type of pressure-sensitive adhesive used in the composition, and X can optionally be A, B, C, or D*d.

[0037] In an embodiment of the present application, the present application provides a dexmedetomidine transdermal composition comprising dexmedetomidine, propylene glycol, a metal chelate crosslinker, and a pressure-sensitive adhesive, wherein the content of the dexmedetomidine is 0.30 to 3.00 parts, and the content ratio of the propylene glycol to the dexmedetomidine is (4:3) to (8:3).

[0038] In one embodiment of the present application, the dexmedetomidine transdermal composition according to the present application contains 0.72 to 1.45 parts or 1.00 to 1.80 parts of dexmedetomidine, preferably 0.72 to 1.00 parts, 1.00 to 1.45 parts, or 1.45 to 1.80 parts of dexmedetomidine.

[0039] In one embodiment of the present application, the dexmedetomidine transdermal composition of the present application comprises 0.72 parts, 1.00 parts, 1.45 parts, or 1.80 parts dexmedetomidine, more preferably 1.00 parts dexmedetomidine.

[0040] In one embodiment of the present application, the content ratio of propylene glycol to dexmedetomidine in the dexmedetomidine transdermal composition of the present application is 4:3, 5:3, 6:3, 7:3, or 8:3, preferably, the content ratio of propylene glycol to dexmedetomidine is (5:3) to (7:3), and more preferably, the content ratio of propylene glycol to dexmedetomidine is 5:3.

[0041] In one embodiment of the present application, the dexmedetomidine transdermal composition of the present application contains 0.40 to 8.00 parts, 1.20 to 4.20 parts, 1.31 to 2.42 parts, 1.44 to 2.42 parts, 1.44 to 1.67 parts, 1.44 to 4.20 parts, 1.44 to 8.00 parts, 1.31 to 1.67 parts, or 1.67 to 2.42 parts of propylene glycol, and preferably contains 1.20 to 4.20 parts of propylene glycol.

[0042] In one embodiment of the present application, the dexmedetomidine transdermal composition of the present application comprises 0.4 parts, 1.2 parts, 1.31 parts, 1.44 parts, 1.67 parts, 2.42 parts, 4.20 parts, or 8.00 parts propylene glycol, preferably 1.67 parts propylene glycol.

[0043] In one embodiment of the present application, in the dexmedetomidine transdermal composition of the present application, the mass ratio of the pressure-sensitive adhesive to the metal chelate crosslinker is (70:1) to (160:1), (160:1) to (220:1), or (220:1) to (310:1), preferably the mass ratio of the pressure-sensitive adhesive to the metal chelate crosslinker is (160:1) to (190:1) or (190:1) to (220:1), and more preferably the mass ratio of the pressure-sensitive adhesive to the metal chelate crosslinker is 190:1.

[0044] In one embodiment of the present application, in the dexmedetomidine transdermal composition of the present application, the metal chelate crosslinker is selected from one or more of aluminum acetylacetonate, zirconium acetylacetonate, titanium acetylacetonate, and polybutyl titanate.

[0045] In one embodiment of the present application, in the dexmedetomidine transdermal composition of the present application, the titanium acetylacetonate of the metal chelate crosslinking agent is selected from one or two of titanium (oxy)acetylacetonate and titanium tetraacetylacetonate.

[0046] In one embodiment of the present application, the content of the metal chelate crosslinking agent in the dexmedetomidine transdermal composition of the present application is in the range of 0.30 to 1.25 parts, 0.30 to 0.80 parts, 0.30 to 0.60 parts, 0.45 to 0.60 parts, 0.45 to 0.80 parts, 0.45 to 1.25 parts, or 0.30 to 0.50 parts, and preferably the content of the metal chelate crosslinking agent is in the range of 0.30 to 0.80 parts.

[0047] In one embodiment of the present application, the dexmedetomidine transdermal composition of the present application contains 0.30 parts, 0.45 parts, 0.50 parts, 0.60 parts, 0.80 parts, or 1.25 parts of the metal chelate crosslinker, and preferably contains 0.5 parts of the metal chelate crosslinker.

[0048] In an embodiment of the present application, the dexmedetomidine transdermal composition of the present application is such that the pressure-sensitive adhesive is selected from one or more of an acrylate pressure-sensitive adhesive, a polyisobutylene pressure-sensitive adhesive, a silicone pressure-sensitive adhesive, a styrene-isoprene-styrene hot-melt pressure-sensitive adhesive (SIS type), and a vinyl acetate copolymer.

[0049] The acrylate pressure-sensitive adhesive is DURO-TAK® 387-2287, DURO-TAK® 387-2510, DURO-TAK® 387-2516, DURO-TAK® 87-235A, DURO-TAK® 387-2353, DURO-TAK® 387-2852, DURO-TAK® 387-2051, DURO-TAK® 387-2052, DURO-TAK® 387-2054, DURO-TAK® 87-4287, DURO-TAK® 87-6908 and DURO-TAK® It is one of the pressure-sensitive adhesives with the model number 87-267.

[0050] In one embodiment of the present application, the dexmedetomidine transdermal composition according to the present application has a content ratio of the pressure-sensitive adhesive to the metal chelate crosslinker of (70:1) to (310:1), (70:1) to (220:1), (70:1) to (200:1), (110:1) to (310:1), (110:1) to (220:1), (110:1) to (200:1), (150:1) to (310:1), (150:1) to (220:1), (150:1) to (200:1), (180:1) to (310:1), (180:1) to (220:1), or (180:1) to (200:1).

[0051] In an embodiment of the present application, the dexmedetomidine transdermal composition of the present application contains 0.72 to 1.80 parts of dexmedetomidine, 0.30 to 0.80 parts of a metal chelate crosslinker, 93.00 to 99.00 parts of an acrylate pressure-sensitive adhesive, and propylene glycol, wherein the content ratio of the propylene glycol to the dexmedetomidine is (4:3) to (8:3).

[0052] In an embodiment of the present application, in the dexmedetomidine transdermal composition of the present application, the metal chelating crosslinker is polybutyl titanate or aluminum acetylacetonate.

[0053] In an embodiment of the present application, the dexmedetomidine transdermal composition according to the present application is DURO-TAK® 387-2510 or DURO-TAK® The number is 387-2287.

[0054] In one embodiment of the present application, the present application provides an application of a dexmedetomidine transdermal composition in the preparation of a transdermal patch.

[0055] In one embodiment, the present application provides a dexmedetomidine transdermal patch comprising a dexmedetomidine transdermal composition.

[0056] In one embodiment of the present application, the dexmedetomidine transdermal patch of the present application is such that the dexmedetomidine transdermal composition forms an adhesive layer of the transdermal patch.

[0057] In an embodiment of the present application, the thickness of the adhesive layer of the dexmedetomidine transdermal patch according to the present application is 25 μm to 100 μm.

[0058] In one embodiment of the present application, the dexmedetomidine transdermal patch according to the present application comprises a backing layer, an anti-adhesion release film layer, and an adhesive layer disposed between the backing layer and the anti-adhesion release film layer, the adhesive layer comprising 0.72 to 1.80 parts of dexmedetomidine, 0.30 to 0.80 parts of polybutyl titanate, 93.00 to 99.00 parts of an acrylic ester pressure-sensitive adhesive, and propylene glycol, the content ratio of the propylene glycol to the dexmedetomidine being (4:3) to (8:3), and the acrylic ester pressure-sensitive adhesive is DURO-TAK® 387-2510 or DURO-TAK® The number is 387-2287.

[0059] The material of the backing layer is selected from one or more of aluminum-polyester film, polyester-polyethylene composite film, polyethylene-aluminum-polyester / ethylene-vinyl acetate composite film, multi-layer polyester film, and polyester-ethylene acetate ethylene composite film.

[0060] The material of the release film is selected from one or more of siliconized polyester film, fluoropolymer-coated polyester film, aluminum foil-silicone grease composite, siliconized aluminum foil, and silicone paper.

[0061] In an embodiment of the present application, the method for preparing a dexmedetomidine transdermal patch according to the present application comprises: (a) dissolving a metal chelate crosslinking agent in a solvent to obtain a metal chelate crosslinking agent solution; (b) mixing a pressure-sensitive adhesive and a metal chelate crosslinker solution to obtain a blank matrix solution; (c) dissolving propylene glycol, a solvent, and dexmedetomidine, and then adding the mixture to the blank matrix solution and mixing to obtain a drug-containing matrix solution; (d) applying the drug-containing matrix solution to the release film and drying it to obtain a composite layer of an adhesive layer and an anti-adhesion release film layer; (e) laminating a backing film onto the adhesive layer to obtain a dexmedetomidine transdermal patch. The solvents include absolute ethanol and n-heptane.

[0062] In an embodiment of the present application, the present application provides an application of the dexmedetomidine transdermal composition or dexmedetomidine transdermal patch in improving sleep disorders, including perioperative sleep disorder, geriatric sleep disorder, and traumatic sleep disorder.

[0063] In an embodiment of the present application, the dexmedetomidine transdermal composition or dexmedetomidine transdermal patch of the present application can achieve sustained release for 2 to 5 days.

[0064] The propylene glycol used in the present application can exert a good dissolution-promoting effect on dexmedetomidine at a low concentration, can increase the solubility of dexmedetomidine in the backbone material, and has good compatibility with the raw drug dexmedetomidine.

[0065] The metal chelate crosslinker and pressure-sensitive adhesive used in the present application jointly serve as the backbone structure of the transdermal composition of the present application, cooperating to adjust the adhesive properties of the transdermal composition and providing a drug-carrying matrix for dexmedetomidine.

[0066] The release film used in this application has a good compatibility with the pressure-sensitive adhesive, can adhere securely to the surface of the pressure-sensitive adhesive, can easily separate from the adhesive layer when peeled off, and can withstand the corrosion of various raw materials, auxiliary materials, and solvents during the preparation and storage of the transdermal patch.

[0067] The backing film used in this application has good flexibility, a durable and smooth texture, suitable peel strength, and relatively good compatibility with the raw materials and auxiliary materials of the transdermal patch of this application.

[0068] The solvents used in this application include absolute ethanol and n-heptane, which are used to dissolve the raw drug dexmedetomidine and / or the metal chelating crosslinker, and have the advantages of being non-toxic, non-irritating, and having good compatibility with raw materials and auxiliary materials.

[0069] The preparation flow of the dexmedetomidine transdermal patch according to the present application is shown in FIG. 1, and the detailed structure of the transdermal patch is shown in FIG. 2 (A is a side view of the dexmedetomidine transdermal patch, and B is a top view of the dexmedetomidine transdermal patch).

[0070] The release film is an overlapping type, which, together with the punched recesses around the patch, forms a current anti-adhesion layer, further reducing the risk of cold flow.

[0071] The method of use or administration of the dexmedetomidine transdermal patch according to the present application involves applying it to a smooth, flat, unirritated skin surface on the trunk or upper arm of a human body, and removing the transdermal patch when administration is to be discontinued.

[0072] All reagents and equipment used in this application are commercially available. Equipment: HS-3 vertical mixer, TB-04D laboratory precision coating machine, DGF302-BN electric heating drying box, PL-3002-IC electronic balance, KQ-500VDE ultrasonic cleaning machine, MDC-25SX digital micrometer, XMTD-204 thermostatic magnetic stirrer, Franz transdermal diffuser TK-24BL, GHP-9160 thermostatic incubator, WD-A drug stability tester.

[0073] Example 1: Study on compatibility and stability of dexmedetomidine with solubilizing agents 1. Sample composition Establish experimental groups of "dexmedetomidine + levulinic acid", "dexmedetomidine + oleic acid", "dexmedetomidine + laurocapram", "dexmedetomidine + isopropyl myristate", and "dexmedetomidine + propylene glycol", and mix the experimental samples at a ratio of dexmedetomidine:solubilizer = 1:10.

[0074] 2. Compatibility testing of raw materials and auxiliary materials The above experimental samples were each formulated into five subgroups, namely, a control group, a high temperature group, a high humidity group, a light irradiation group, and an accelerated group, and the corresponding conditions are shown in Table 1. The sampling times for high temperature, high humidity, light irradiation, and accelerated testing were 0 days, 5 days, and 10 days, to investigate the impurity content of the mixture of dexmedetomidine and solubilizing agents of the present application under different conditions. Evaluation standards: maximum unknown single impurity (%, ≤ 0.5%), total impurities (%, ≤ 2.0%).

[0075] [Table 1]

[0076] 3. Experimental results [Table 2]

[0077] As can be seen from the table above, for the "drug substance + levulinic acid" group, the maximum single impurity content under high temperature conditions was 1.99%, and the maximum total impurity content was 5.53%; under light irradiation conditions, the maximum single impurity content was 0.94%, and the maximum total impurity content was 3.35%; under accelerated conditions, the maximum single impurity content was 0.60%, and the maximum total impurity content was 1.85%. Under the above investigation conditions, the impurity content of the "drug substance + levulinic acid" group exceeded the standard limits, indicating that the compatibility and stability of the raw materials and auxiliary materials of dexmedetomidine and levulinic acid were poor.

[0078] [Table 3]

[0079] As can be seen from the table above, for the "drug raw material + oleic acid" group, the maximum single impurity content under high temperature conditions was 1.22%, and the maximum total impurity content was 4.76%; under light irradiation conditions, the maximum single impurity content was 0.64%, and the maximum total impurity content was 2.68%; under accelerated conditions, the maximum single impurity content was 0.88%, and the maximum total impurity content was 2.12%. Under the above investigation conditions, the impurity content of the "drug raw material + oleic acid" group exceeded the standard limits, indicating that the compatibility and stability of the raw materials and auxiliary materials of dexmedetomidine and oleic acid were poor.

[0080] [Table 4]

[0081] As can be seen from the table above, the "drug raw material + laurocapram" group has a maximum single impurity content of 2.21% and a maximum total impurity content of 4.29% under high temperature conditions, a maximum single impurity content of 0.96% and a maximum total impurity content of 3.54% under light irradiation conditions, and a maximum single impurity content of 0.97% and a maximum total impurity content of 3.86% under accelerated conditions. Under the above investigation conditions, the impurity content of the "drug raw material + laurocapram" group exceeds the standard limit, indicating that the compatibility and stability of the raw materials and auxiliary materials of dexmedetomidine and laurocapram are poor.

[0082] [Table 5]

[0083] As can be seen from the table above, the "drug substance + isopropyl myristate" group has a maximum single impurity content of 1.03% and a maximum total impurity content of 3.36% under high temperature conditions, a maximum single impurity content of 0.72% and a maximum total impurity content of 4.79% under light irradiation conditions, and a maximum single impurity content of 0.72% and a maximum total impurity content of 4.32% under accelerated conditions. Under the above investigation conditions, the impurity content of the "drug substance + isopropyl myristate" group exceeds the standard limit, indicating that the compatibility and stability of the raw materials and auxiliary materials of dexmedetomidine and isopropyl myristate are poor.

[0084] [Table 6]

[0085] As can be seen from the table above, the maximum single impurity content in the "drug substance + propylene glycol" group under all investigation conditions was 0.04% The maximum total impurity content is 0.05%, so the compatibility and stability of the raw materials and auxiliary materials of dexmedetomidine and propylene glycol are very good.

[0086] As can be seen from Tables 2 to 6 above, the groups "dexmedetomidine + levulinic acid", "dexmedetomidine + oleic acid", "dexmedetomidine + laurocapram", and "dexmedetomidine + isopropyl myristate" all produced large amounts of impurities under high temperature and light irradiation conditions, which indicated that the compatibility and stability of the above auxiliary materials with the raw drug dexmedetomidine was poor. On the other hand, the group "raw drug + propylene glycol" had the highest single impurity content under all investigated conditions. 0.04% The maximum total impurity content is 0.05%, which indicates that the compatibility and stability of the auxiliary materials and the raw drug are very good. Therefore, by selecting and adding propylene glycol as a solubilizing agent for the transdermal composition of the present application, the subsequent generation of impurities can be reduced.

[0087] Experimental Example 2: Propylene glycol usage survey 1. Prescription 1 - Transdermal patch Dexmedetomidine 0.08g Acrylate ester pressure-sensitive adhesive 20.12g Aluminum acetylacetonate 0.05g Propylene glycol 0.16g 3.41g absolute ethanol n-heptane 1.34g The model number of the acrylic ester pressure-sensitive adhesive is DURO-TAK® 387-2287 and has a solids content of 53.8%.

[0088] The transdermal patch comprises a backing layer, an adhesive layer and an anti-adhesion release film layer, and the method for preparing the transdermal patch specifically comprises the following steps (1) to (9). (1) Preparation of aluminum acetylacetonate solution: 0.05 g of aluminum acetylacetonate, 1.01 g of absolute ethanol, and 1.34 g of n-heptane are weighed into a 40 mL vial, mixed uniformly, and then prepared for use. (2) Formulation of blank matrix: 20.12 g of acrylate pressure sensitive adhesive and the formulated aluminum acetylacetonate solution are weighed and sealed. (3) Mixing: Place the vial containing the blank matrix in a vertical mixer, adjust the rotation speed to 20 rpm, and mix for 4 hours. (4) Formulation of the drug-containing matrix: Weigh out 0.08 g of dexmedetomidine, add 0.16 g of propylene glycol and 2.24 g of absolute ethanol, and stir until the dexmedetomidine is completely dissolved. Add this to the blank matrix that has been stirred for another 4 hours. Weigh out 0.16 g of absolute ethanol, wash the empty bottle with a brush, add it to the drug-containing matrix, mix, and seal. (5) Mixing: The vial containing the drug-containing matrix was placed in a vertical mixer, the rotation speed was adjusted to 20 rpm, and after stirring for 6 hours, the mixture was stopped and allowed to stand overnight. (6) Coating: The drug-containing matrix that has been left overnight is coated onto a Scotchpak 1022 release film, and the thickness of the coating blade is adjusted until the thickness of the drug-containing layer of the transdermal patch is 25 μm. (7) Drying: Place in a drying oven, adjust the temperature to 70°C, and remove after 20 minutes. (8) Coating: A backing film, Scotchpak 9722, is laminated onto the drug-containing adhesive layer. (9) Punching: Punch into circular patches with a diameter D of 30 mm and package.

[0089] All absolute ethanol and n-heptane are removed during the preparation process and do not appear in the final product.

[0090] 2. Experimental group assignment Different amounts of propylene glycol were selected for formulation optimization, and the propylene glycol was selected. Specifically, the weight ratios of propylene glycol to dexmedetomidine were 3:3, 4:3, 5:3, 6:3, 7:3, 8:3, and 9:3. A blank group (no propylene glycol added to formulation 1) was also set up.

[0091] 3. Related substance measurement Impurity measurements were performed on the following eight groups of samples (n=6), and the related substance impurity results are shown in Table 7.

[0092] [Table 7]

[0093] As can be seen from the above table, the amount of propylene glycol used does not significantly affect the related substances of the transdermal patch of this example.

[0094] 4. Adhesion performance test The amount of propylene glycol used was selected for eight groups of samples (n=6), and the eight groups of samples were attached to the smooth skin on the backs of the hands of eight volunteers. After 30 minutes, the samples were peeled off and the presence or absence of adhesive residue on the skin and the occurrence of pain were observed to investigate the adhesive performance of the transdermal patch of this application. Adhesion performance evaluation index: 1: Poor adhesion to the body 2: There are some traces of adhesive margins, but the adhesive performance is good. 3: No residue on the adhesive edge, good adhesive performance 4: Painful when peeling, including abrasions of keratinized skin The experimental results of dexmedetomidine solubility and transdermal patch adhesion are shown in Table 8.

[0095] [Table 8]

[0096] As can be seen from the above table, when the transdermal patch does not contain propylene glycol and the dosage ratio of propylene glycol to dexmedetomidine is 3:3, the sample adhesion performance is weak; when the mass ratio of propylene glycol to dexmedetomidine is 4:3 or more, the sample adhesion performance is excellent, but when the dosage ratio exceeds 8:3, pain is felt when some of the samples are peeled off; when the dosage ratio ranges from (5:3) to (7:3), the adhesion performance of the transdermal patch of this example to the skin surface is better; and when the dosage ratio is 5:3, the adhesion performance of the transdermal patch of this example to the skin surface is optimal, and when all of the samples are peeled off, there is no residue on the skin surface and no pain is felt.

[0097] Experimental Example 3: Investigation of the amount of metal chelate crosslinking agent used 1. Formulated 1 Prescription 2 Dexmedetomidine 0.18g Acrylate ester pressure-sensitive adhesive 41.32g Polybutyl titanate 0.12g Propylene glycol 0.30g 5.70g absolute ethanol n-heptane 6.19g The model number of the acrylic ester pressure-sensitive adhesive is DURO-TAK® 387-2287 and has a solids content of 53.8%. The preparation method for Formulation 2 is the same as Formulation 1, except that a Scotchpak 9754 backing film is laminated onto the drug-containing adhesive layer. The amounts of dexmedetomidine and propylene glycol in Formula 2 were kept unchanged, while the amounts of the metal chelating crosslinker polybutyl titanate were adjusted to obtain Formula 2' (0.07 g, approximately 0.30 parts), Formula 2'' (0.09 g, approximately 0.40 parts), Formula 2''' (0.14 g, approximately 0.60 parts), and Formula 2'''' (0.16 g, approximately 0.70 parts), respectively. The amounts of the acrylate pressure-sensitive adhesive in the corresponding formulas were adjusted accordingly (Formulas 2' to 2'''' had the amounts of acrylate pressure-sensitive adhesive of 41.33 g, 40.91 g, 40.49 g, and 41.37 g, respectively).

[0098] 2 Prescription 3 Dexmedetomidine 0.18g Acrylate ester pressure-sensitive adhesive 41.32g Aluminum acetylacetonate 0.12g Propylene glycol 0.30g 5.70g absolute ethanol n-heptane 6.19g The model number of the acrylic ester pressure-sensitive adhesive is DURO-TAK® 387-2287, and the preparation method is the same as formulation 2. The amounts of dexmedetomidine and propylene glycol were kept constant, while the amounts of the metal chelating crosslinker were adjusted to obtain Formulation 3' (0.07 g, approximately 0.30 parts), Formulation 3'' (0.09 g, approximately 0.40 parts), Formulation 3''' (0.14 g, approximately 0.60 parts), and Formulation 3'''' (0.16 g, approximately 0.70 parts), respectively. The amounts of the acrylate pressure-sensitive adhesive in the corresponding formulations were adjusted accordingly (Formulations 3' to 3'''' were 41.33 g, 40.91 g, 40.49 g, and 41.37 g, respectively).

[0099] 3 Prescription 4 Dexmedetomidine 0.18g Acrylate ester pressure-sensitive adhesive 41.32g Zirconium acetylacetonate 0.12g Propylene glycol 0.30g 5.70g absolute ethanol n-heptane 6.19g The model number of the acrylic ester pressure-sensitive adhesive is DURO-TAK® 387-2287, and the preparation method is the same as formulation 2. The amounts of dexmedetomidine and propylene glycol were kept constant, while the amounts of the metal chelating crosslinker were adjusted to obtain Formulation 4' (0.07 g, approximately 0.30 parts), Formulation 4'' (0.09 g, approximately 0.40 parts), Formulation 4''' (0.14 g, approximately 0.60 parts), and Formulation 4'''' (0.16 g, approximately 0.70 parts), respectively. The amounts of the acrylate pressure-sensitive adhesive in the corresponding formulations were adjusted accordingly (Formulations 4' to 4'''' were 41.33 g, 40.91 g, 40.49 g, and 41.37 g, respectively).

[0100] 4 Prescription 5 Dexmedetomidine 0.18g Acrylate ester pressure-sensitive adhesive 41.32g Titanium (oxy)acetylacetonate 0.12g Propylene glycol 0.30g 5.70g absolute ethanol n-heptane 6.19g The model number of the acrylic ester pressure-sensitive adhesive is DURO-TAK® 387-2287, and the preparation method is the same as formulation 2. The amounts of dexmedetomidine and propylene glycol were kept constant, while the amounts of the metal chelating crosslinker were adjusted to obtain Formulation 5' (0.07 g, approximately 0.30 parts), Formulation 5'' (0.09 g, approximately 0.40 parts), Formulation 5''' (0.14 g, approximately 0.60 parts), and Formulation 5'''' (0.16 g, approximately 0.70 parts), respectively. The amounts of the acrylate pressure-sensitive adhesive in the corresponding formulations were adjusted accordingly (Formulations 5' to 5'''' were 41.33 g, 40.91 g, 40.49 g, and 41.37 g, respectively).

[0101] 5 Prescription 6 Dexmedetomidine 0.18g Acrylate ester pressure-sensitive adhesive 44.85g Polybutyl titanate 0.10g Propylene glycol 0.32g 6.62g absolute ethanol n-heptane 1.93g The acrylate pressure-sensitive adhesive DURO-TAK® 387-2510, with a solids content of 42.7%. The preparation method for Formulation 6 is the same as that for Formulation 1, except that a Scotchpak 9754 backing film is laminated onto the drug-containing adhesive layer. The amounts of dexmedetomidine and propylene glycol were kept constant, while the amounts of the metal chelating crosslinker were adjusted to obtain Formulation 6' (0.06 g, approximately 0.30 parts), Formulation 6'' (0.08 g, approximately 0.40 parts), Formulation 6''' (0.12 g, approximately 0.60 parts), and Formulation 6'''' (0.14 g, approximately 0.70 parts), respectively. The amounts of the acrylate pressure-sensitive adhesive in the corresponding formulations were adjusted accordingly (Formulations 6' to 6'''' were 45.01 g, 44.97 g, 44.87 g, and 44.83 g, respectively).

[0102] 6 Prescription 7 Dexmedetomidine 0.18g Acrylate ester pressure-sensitive adhesive 44.85g Aluminum acetylacetonate 0.10g Propylene glycol 0.32g 6.62g absolute ethanol n-heptane 1.93g The model number of the acrylic ester pressure-sensitive adhesive is DURO-TAK® 387-2510, and the preparation method is the same as formulation 6. The amounts of dexmedetomidine and propylene glycol were kept constant, while the amounts of the metal chelating crosslinker were adjusted to obtain Formula 7' (0.06 g, approximately 0.30 parts), Formula 7'' (0.08 g, approximately 0.40 parts), Formula 7''' (0.12 g, approximately 0.60 parts), and Formula 7'''' (0.14 g, approximately 0.70 parts), respectively. The amounts of the acrylate pressure-sensitive adhesive in the corresponding formulas were adjusted accordingly (Formulas 7' to 7'''' were 45.01 g, 44.97 g, 44.87 g, and 44.83 g, respectively).

[0103] 7 Prescription 8 Dexmedetomidine 0.18g Acrylate ester pressure-sensitive adhesive 44.85g Zirconium acetylacetonate 0.10g Propylene glycol 0.32g 6.62g absolute ethanol n-heptane 1.93g The model number of the acrylic ester pressure-sensitive adhesive is DURO-TAK® 387-2510, and the preparation method is the same as formulation 6. The amounts of dexmedetomidine and propylene glycol were kept constant, while the amounts of the metal chelating crosslinker were adjusted to obtain Formulation 8' (0.06 g, approximately 0.30 parts), Formulation 8'' (0.08 g, approximately 0.40 parts), Formulation 8''' (0.12 g, approximately 0.60 parts), and Formulation 8'''' (0.14 g, approximately 0.70 parts), respectively. The amounts of the acrylate pressure-sensitive adhesive in the corresponding formulations were adjusted accordingly (Formulations 8' to 8'''' were 45.01 g, 44.97 g, 44.87 g, and 44.83 g, respectively).

[0104] 8 Prescription 9 Dexmedetomidine 0.18g Acrylate ester pressure-sensitive adhesive 44.85g Titanium (oxy)acetylacetonate 0.10g Propylene glycol 0.32g 6.62g absolute ethanol n-heptane 1.93g The model number of the acrylic ester pressure-sensitive adhesive is DURO-TAK® 387-2510, and the preparation method is the same as formulation 6. The amounts of dexmedetomidine and propylene glycol were kept constant, while the amounts of the metal chelating crosslinker were adjusted to obtain Formulation 9' (0.06 g, approximately 0.30 parts), Formulation 9'' (0.08 g, approximately 0.40 parts), Formulation 9''' (0.12 g, approximately 0.60 parts), and Formulation 9'''' (0.14 g, approximately 0.70 parts), respectively. The amounts of the acrylate pressure-sensitive adhesive in the corresponding formulations were adjusted accordingly (Formulations 9' to 9'''' were 45.01 g, 44.97 g, 44.87 g, and 44.83 g, respectively).

[0105] 2. Adhesion performance test According to the "General Rule 0952 Adhesion Measurement Method" of the 2020 edition of the "Chinese Pharmacopoeia," eight groups of samples (n=3) from Formulations 2 to 9 were tested for continuous adhesion and 180° peel strength, and eight groups of samples (n=3) from Formulations 2 to 9 were evaluated for internal adhesion performance. That is, the samples were attached for 30 minutes and then peeled off to evaluate their internal adhesion performance. The evaluation criteria are as follows: Evaluation metrics: 1: Poor adhesion to the body 2: There are some traces of adhesive margins, but the adhesive performance is good. 3: No residue on the adhesive edge, good adhesive performance 4: Painful when peeling, including abrasions of keratinized skin The adhesion performance test results after the above operations are shown in Tables 9 to 16.

[0106] 3. Experimental results [Table 9]

[0107] As can be seen from the table above, as the amount of polybutyl titanate used increases, the 180° peel strength initially decreases but then increases, and the lasting adhesive strength shows a significant improvement within a certain range. When the polybutyl titanate content is 0.30 parts, there is a slight pain when peeling the sample. When the polybutyl titanate content is 0.70 parts, there is a slight adhesive margin mark when peeling the sample. When the polybutyl titanate content is in the range of 0.40 to 0.60 parts, all test samples have good adhesive performance and no adhesive margin mark.

[0108] [Table 10]

[0109] As can be seen from the table above, as the amount of aluminum acetylacetonate used increases, the 180° peel strength initially decreases but then increases, and the lasting adhesive strength shows a significant improvement within a certain range. When the aluminum acetylacetonate content ranged from 0.30 to 0.40 parts, there was a slight pain when peeling the sample; when the aluminum acetylacetonate content was 0.70 parts, there was a slight adhesive margin mark when peeling the sample; when the aluminum acetylacetonate content ranged from 0.50 to 0.60 parts, all test samples had good adhesive performance and no adhesive margin mark.

[0110] [Table 11]

[0111] As can be seen from the table above, as the amount of zirconium acetylacetonate used increases, the 180° peel strength initially decreases but then increases, and the lasting adhesive strength shows a significant improvement within a certain range. When the zirconium acetylacetonate content ranges from 0.30 to 0.40 parts, there is a slight pain when peeling the sample. When the zirconium acetylacetonate content ranges from 0.70 parts, there is a slight adhesive margin mark when peeling the sample. When the zirconium acetylacetonate content ranges from 0.50 to 0.60 parts, all test samples have good adhesive performance and no adhesive margin mark.

[0112] [Table 12]

[0113] As can be seen from the table above, as the amount of titanium(oxy)acetylacetonate used increases, the 180° peel strength initially decreases but then increases, and the lasting adhesive strength shows a significant improvement within a certain range. When the titanium(oxy)acetylacetonate content ranged from 0.30 to 0.40 parts, there was a slight pain when the sample was peeled off, when the titanium(oxy)acetylacetonate content was 0.70 parts, there was a slight adhesive margin mark when the sample was peeled off, and when the titanium(oxy)acetylacetonate content ranged from 0.50 to 0.60 parts, all test samples had good adhesive performance and no adhesive margin mark.

[0114] [Table 13]

[0115] As can be seen from the table above, as the amount of polybutyl titanate used increases, the 180° peel strength initially decreases but then increases, and the lasting adhesive strength shows a significant improvement within a certain range. When the polybutyl titanate content is about 0.30 parts, there is a slight pain when peeling the sample. When the polybutyl titanate content is about 0.70 parts, there is a slight adhesive edge mark when peeling the sample. When the polybutyl titanate content is in the range of about 0.40 to 0.60 parts, all test samples have good adhesive performance and no adhesive edge mark.

[0116] [Table 14]

[0117] As can be seen from the table above, as the amount of aluminum acetylacetonate used increases, the 180° peel strength initially decreases but then increases, and the lasting adhesive strength shows a significant improvement within a certain range. When the aluminum acetylacetonate content ranged from about 0.30 to 0.40 parts, there was a slight pain when peeling the sample. When the aluminum acetylacetonate content was about 0.70 parts, there was a slight adhesive margin mark when peeling the sample. When the aluminum acetylacetonate content ranged from about 0.50 to 0.60 parts, all test samples had good adhesive performance and no adhesive margin mark.

[0118] [Table 15]

[0119] As can be seen from the table above, as the amount of zirconium acetylacetonate used increases, the 180° peel strength initially decreases but then increases, and the lasting adhesive strength shows a significant improvement within a certain range. When the zirconium acetylacetonate content ranged from about 0.30 to 0.40 parts, there was a slight pain when the sample was peeled off. When the zirconium acetylacetonate content ranged from about 0.70 parts, there was a slight adhesive margin mark when the sample was peeled off. When the zirconium acetylacetonate content ranged from about 0.50 to 0.60 parts, all test samples had good adhesive performance and no adhesive margin mark.

[0120] [Table 16]

[0121] As can be seen from the table above, as the amount of titanium (oxy)acetylacetonate used increases, the 180° peel strength initially decreases but then increases, and the lasting adhesive strength shows a tendency to improve significantly within a certain range. When the titanium (oxy)acetylacetonate content ranged from about 0.30 to 0.40 parts, there was a slight pain when the sample was peeled off. When the titanium (oxy)acetylacetonate content was about 0.70 parts, there was a slight adhesive margin mark when the sample was peeled off. When the titanium (oxy)acetylacetonate content ranged from about 0.50 to 0.60 parts, all test samples had good adhesive performance and no adhesive margin mark.

[0122] As described above, the addition of a metal chelate crosslinker can improve the adhesiveness of the dexmedetomidine transdermal patch of the present invention. Based on the integrated evaluation of three tests, namely, lasting adhesive strength, 180° peel strength, and internal adhesiveness, the amount of metal chelate crosslinker used in the transdermal patch of the present invention is 0.30 to 0.70 parts, preferably 0.40 to 0.60 parts, and more preferably 0.50 parts.

[0123] Example 4 Formulation 10 Dexmedetomidine 0.18g Acrylate ester pressure-sensitive adhesive 32.40g Polybutyl titanate 0.09g Propylene glycol 0.3g 5.70g absolute ethanol n-heptane 1.33g The model number of the acrylic ester pressure-sensitive adhesive is DURO-TAK® 387-2287 and has a solids content of 53.8%. The preparation method of Formulation 10 is the same as Formulation 1, except that a release film Scotchpak 9709 is used for coating and a backing film Scotchpak 9723 is used for lamination.

[0124] Example 5 Formulation 11 Dexmedetomidine 0.09g Acrylate ester pressure-sensitive adhesive 18.71g Polybutyl titanate 0.05g Propylene glycol 0.15g 3.04g absolute ethanol n-heptane 0.96g The model number of the acrylic ester pressure-sensitive adhesive is DURO-TAK® 387-2510 and has a solids content of 42.7%. The preparation method of Formulation 11 is the same as Formulation 1, except that a release film Scotchpak 9709 is used for coating and a backing film Scotchpak 9723 is used for lamination.

[0125] Example 6 Formulation 12 Dexmedetomidine 0.14g Acrylate ester pressure-sensitive adhesive 32.66g Aluminum acetylacetonate 0.07g Propylene glycol 0.24g 7.64g absolute ethanol n-heptane 2.50g The model number of the acrylic ester pressure-sensitive adhesive is DURO-TAK® 387-2510 and has a solids content of 42.7%. The preparation method of Formulation 8 is the same as that of Formulation 1, except that a backing film, Scotchpak 9745, is laminated onto the drug-containing adhesive layer.

[0126] Example 7 Formulation 13 Dexmedetomidine 0.18g Acrylate ester pressure-sensitive adhesive 40.82g Polybutyl titanate 0.09g Propylene glycol 0.30g 5.70g absolute ethanol n-heptane 1.44g The model number of the acrylic ester pressure-sensitive adhesive is DURO-TAK® 387-2510 and has a solids content of 42.7%. The preparation method for Formulation 9 is the same as that for Formulation 1, except that the release film is Scotchpak 9709, the backing film is Scotchpak 9745, and the thickness of the drug-containing layer is adjusted to 50 μm during application.

[0127] Example 8 Formulation 14 Dexmedetomidine 0.03g Pressure-sensitive adhesive 23.00g Aluminum acetylacetonate 0.03g Propylene glycol 0.04g 2.50g absolute ethanol n-heptane 1.25g The model number of the acrylic ester pressure-sensitive adhesive is DURO-TAK® 387-2510 and has a solids content of 42.7%. The preparation method for Formulation 10 is the same as that for Formulation 1, except that the release film is Scotchpak 9709, the backing film is Scotchpak 9745, and the thickness of the drug-containing layer is adjusted to 50 μm during application.

[0128] Example 9 Formulation 15 Dexmedetomidine 0.09g Pressure-sensitive adhesive 28.45g Polybutyl titanate 0.04g Propylene glycol 0.15g 5.70g absolute ethanol n-heptane 1.44g The model number of the acrylic ester pressure-sensitive adhesive is DURO-TAK® 387-2510 and has a solids content of 42.7%. The preparation method for Formulation 11 is the same as that for Formulation 1, except that the release film is Scotchpak 9709, the backing film is Scotchpak 9745, and the thickness of the drug-containing layer is adjusted to 50 μm during application.

[0129] Example 10 Formulation 16 Dexmedetomidine 0.36g Pressure-sensitive adhesive 43.50g Aluminum acetylacetonate 0.16g Propylene glycol 0.84g 5.70g absolute ethanol n-heptane 6.80g The model number of the acrylic ester pressure-sensitive adhesive is DURO-TAK® 387-2510 and has a solids content of 42.7%. The preparation method for Formulation 12 is the same as that for Formulation 1, except that the release film is Scotchpak 9709, the backing film is Scotchpak 9745, and the thickness of the drug-containing layer is adjusted to 50 μm during application.

[0130] Example 11 Formulation 17 Dexmedetomidine 0.72g Pressure-sensitive adhesive 49.20g Polybutyl titanate 0.30g Propylene glycol 1.92g 5.60g absolute ethanol n-heptane 9.50g The model number of the acrylic ester pressure-sensitive adhesive is DURO-TAK® 387-2510 and has a solids content of 42.7%. The preparation method for Formulation 13 is the same as that for Formulation 1, except that the release film is Scotchpak 9709, the backing film is Scotchpak 9745, and the thickness of the drug-containing layer is adjusted to 50 μm during application.

[0131] Example 11 Coating thickness investigation 1, method The samples (D=14 mm) prepared by formulation 13 were used, and the thickness of the drug-containing layer was adjusted to 25 μm, 50 μm, and 100 μm, and divided into three groups. The anti-adhesive layer was removed from the prepared transdermal patch, which was then attached to the surface of the pigskin and gently pressed with a finger to ensure good adhesion between the pigskin and the patch. The pigskin was then attached between the Franz diffusion cell with the rotor and the supply chamber, with the backing layer exposed to air and securely fixed with an iron clamp. 9 mL of receiving medium was measured using a pipette and added to the receiving chamber. A magnetic stirrer was inserted and stirred at a constant temperature (32±0.5°C) and a constant speed (180 rpm). At predetermined time points, 0.8 mL of sample was taken using a 1 mL syringe and an equal amount of blank receiving medium was added at the same temperature. The content of the removed sample was immediately measured using high-performance liquid chromatography. The in vitro transdermal diffusion results are shown in the table below.

[0132] 2. Experimental results [Table 17]

[0133] Specifically, the in vitro transdermal diffusion curves of patches of different thicknesses are shown in Figure 3. As can be seen from Figure 3, the thickness of the dexmedetomidine backbone transdermal patch is related to the duration of action, and increasing the thickness of the transdermal patch can extend the duration of action of the transdermal patch. A dexmedetomidine transdermal patch with a thickness of 25 μm reaches a stable drug release period after 48 hours, a patch with a thickness of 50 μm reaches a stable drug release period after 72 hours, and a patch with a thickness of 100 μm reaches a stable drug release period after 120 hours. Therefore, the dexmedetomidine patch formulation of the present application with a thickness of 25 μm to 100 μm can achieve continuous sustained release for 2 to 5 days.

[0134] Test Example 1: Skin reaction test for transdermal patches Evaluation indicators Skin reaction grades include the following grades: Grade 4: Erythema, swelling and blisters Grade 3: Erythema, swelling, no blisters Grade 2: Erythema covers the entire patch area, no swelling Grade 1: Mild erythema covering part of the patch area Grade 0: Minimal or no reaction at the patch site Two samples of each of the formulations 1 to 17 of the present application were taken and applied to 18 rats with hair loss on their backs for 24 hours. As a result, it was found that none of the products of formulations 1 to 17 caused any skin irritation and were rated as Grade 0.

[0135] Test Example 2: Stability study of formulations Using the circular patches of the above prescription 1 to prescription 17 samples (n=3), a stress test was conducted to investigate related substances, and the average value was taken. The impurity content limits for each item are as follows, and the investigation results are as follows:

[0136] [Table 18]

[0137] As can be seen from the above table, the dexmedetomidine transdermal patch of the present invention is stable when stored under high temperature conditions for 10 days, high temperature conditions for 30 days, and under accelerated conditions.

[0138] Test Example 3: Study of dexmedetomidine crystals Using the sample prepared according to formulation 13, the long-term crystallization status of the dexmedetomidine transdermal patch of the present application is observed to confirm whether dexmedetomidine crystals are formed in the formulation. The crystal observation results after the sample was stored for 6 months are shown in Figure 4 (A is a 10x image, and B is a 40x image). As can be seen from observing the crystal state using a polarizing microscope, the dexmedetomidine transdermal patch of the present application did not form crystals even after long-term storage for 6 months.

[0139] Test Example 4: Monitoring spontaneous activity in mice 1, method 24 hours after the mice were depilated, the mice were placed in the exercise machine for adaptation training, and activity monitoring was performed within 5 minutes after 10 minutes, and the results were recorded as 0-hour activity. According to the mouse pharmacological experiment design in Table 19, the drug-containing patch prepared by Formula 13 was administered, and the mice were placed in the exercise machine, and activity monitoring was performed after administration, and activity monitoring was continued after the late monitoring time, and the monitoring time points were 1 hour, 3 hours, 6 hours, 8 hours, 12 hours, and 24 hours, respectively. After the 24-hour monitoring, the patch on the back of the mouse was removed, and the mouse activity was then monitored. The monitoring time was 27 hours and 30 hours, and the monitoring method was the same as above. The evaluation index is to record the number of activities within 5 minutes.

[0140] [Table 19]

[0141] 2. Experimental results The spontaneous activity data for mice is shown in Figure 5. Compared with the blank control, the dexmedetomidine transdermal patch significantly reduced the activity of mice, demonstrating a significant dose-effect relationship, indicating that dexmedetomidine has a significant effect in improving sleep.

[0142] Test Example 5: EEG and EMG monitoring experiment in rats 1. Grouping Before administration, the experimental animals were weighed and randomly assigned to groups based on their weights, as follows:

[0143] [Table 20]

[0144] 2, method SD rats (SPF, male) were placed in a 12-hour light-dark alternating cycle and allowed to adapt for 7 days (lights off at 7:00 AM, lights on at 7:00 PM). On the day of the experiment, the animals were anesthetized with a combination of Zoletil (ip, 20 mg / kg) and xylazine (ip, 8 mg / kg). After anesthesia, the animals were fixed in a stereotaxic apparatus. The head was shaved and disinfected. The scalp was then incised with scissors, the four corners were clamped with hemostat forceps to fully expose the skull, the periosteum was peeled off, and the surface was wiped with dry absorbent cotton until dry and clean. A hole was drilled in the skull and the electrodes were implanted. Two EMG electrodes were inserted parallel to each other into the neck muscles and secured at both ends with sutures to prevent the ends from touching each other. A reference electrode was similarly inserted and secured into the opposing neck muscle. The implants were then placed subcutaneously, and the surgical wound was sutured and disinfected. After surgery, rats were carefully placed in clean recovery cages in a lateral position with a free airway. They were housed in single cages in an enclosed recovery room with a 12-hour automatic light-dark cycle, with lights off at 7:00 AM and lights on at 7:00 PM. After surgery, the animals were cared for for 3 days, during which time cephradine powder was administered topically at the surgical incision site, gentamicin was administered subcutaneously at 4-8 mg / kg, and meloxicam was administered subcutaneously at 0.1 ml / animal for 3 consecutive days. Experiments were conducted after 7-10 days of recovery, with animals randomly assigned to groups based on their weight. After group assignment, EEG and EMG were monitored continuously for 24 hours, providing baseline signals. Except for the sham group, each group of rats had skin and fascia incisions approximately 2cm long made on the back and sole of the foot, then sutured.After all animal models were established, each group of rats was cleaned at the administration site using an animal razor, and the corresponding drug was administered (the patch was located on the back and fixed to the skin, to prevent the patch from falling off and causing administration failure).Then, the rats were recorded for 72 hours, and the EEG and EMG signals of the rats were monitored during this period, and the structural changes of postoperative wakefulness, light sleep or rapid eye movement sleep (REM), and deep sleep or non-rapid eye movement sleep (NREM) were analyzed.

[0145] 3. Data analysis The original data was collected using DSI System Ponemah software and analyzed using NeuroScore software. The experimental data were presented as mean ± standard error (Mean ± SEM). Statistical analysis was performed using GraphPad Prism 7.0 software by two-way ANOVA and one-way ANOVA. P<0.05 indicated significant difference, P<0.01 indicated highly significant difference, and P<0.001 indicated highly significant difference.

[0146] 4. Experimental results As shown in Figure 6, A is a trend chart of the cumulative wake time for each group at each time point in the rat sleep structure within 72 hours after patch administration, B is a trend chart of the cumulative NREM time for each group at each time point within 72 hours after patch administration, and C is a trend chart of the cumulative REM time for each group at each time point within 72 hours after patch administration, where N=8. As shown by the experimental data in Figure 6, compared with the normal group, the wakefulness time within 72 hours of the drug-containing group rats gradually decreased with increasing dexmedetomidine dose, there was no significant difference in the wakefulness time within 72 hours between the low-dose group and the normal group, and compared with the post-operative model group, the wakefulness time length within 72 hours of the drug-containing group rats was significantly decreased. Compared with the normal group, the slow-wave sleep time within 72 hours in the drug-containing group rats gradually increased with increasing dexmedetomidine dose, and there was no significant difference in the length of slow-wave sleep within 72 hours between the low-dose group and the normal group. Compared with the post-operative model group, the slow-wave sleep time within 72 hours in the drug-containing group rats was significantly increased. Overall, the dexmedetomidine transdermal patch of the present invention can effectively extend non-rapid eye movement (NREM) sleep time and reduce rapid eye movement (REM) sleep time in postoperative rats, thereby effectively improving sleep quality. High-dose transdermal patches significantly affected sleep time in SD rats, significantly shortening the proportion of awake time and affecting the animals' normal circadian rhythm to a certain extent. Transdermal patches at medium and high doses effectively improved postoperative sleep disorders and promoted sleep quality in rats over a 72-hour period. Compared with the low dose (0.88 mg / kg), the effect time was longer. The low-dose group not only significantly improved sleep quality, but also did not alter the circadian rhythm as the medium and high-dose groups did. The total length of slow-wave sleep and wakefulness in the low-dose group over a 72-hour period was essentially consistent with that of the normal group.

[0147] Comparative Example 1 1. Pharmaceutical formulation The comparative example of the present application was prepared based on formulation 33 in the reference document CN201480059798.5, and the specific formulation is as follows: Dexmedetomidine 0.18g Levulinic acid 0.11g Acrylate ester pressure-sensitive adhesive 32.92g The model number of the acrylic ester pressure-sensitive adhesive is DURO-TAK® 87-2287 and has a solids content of 53.8%. The dexmedetomidine transdermal patch of Comparative Example 1 was prepared according to the method for preparing a dexmedetomidine transdermal composition described in the cited reference. Specifically, the formulation was prepared by mixing dexmedetomidine and a pressure-sensitive adhesive in an organic solvent and then adhesively blending. After forming a homogeneous mixture, the solution was poured onto a release liner and dried at 60°C to 80°C for 10 to 90 minutes. The single-layer adhesive film was then pressed onto a PET backing, divided into required sizes, and packaged. In this comparative example, levulinic acid was added to the adhesive composition. Any solvent contained in the pressure-sensitive adhesive and any organic solvent added during the preparation process are removed during the drying process.

[0148] 2. In vitro transdermal diffusion test Three patches were taken from each of the patches prepared in Example 7, Example 4 and Comparative Example 1 of the present application, and the release film layer was removed from each. An in vitro transdermal diffusion experiment was conducted using the same test method as in Example 12.

[0149] 3. Experimental results The in vitro transdermal diffusion curves of the three transdermal patches are shown in Figure 7. As can be seen from Figure 7, the overall tendency of the diffusion rate of the three transdermal patches is that Example 7 is superior to Example 4, which is superior to Comparative Example 1. The percutaneous diffusion rate per unit area of ​​the dexmedetomidine transdermal patch prepared in Example 7 reached a maximum at 12 hours, reaching 1.1 μg / cm. 2 *h, which is about twice that of Comparative Example 1, and the patch prepared in Comparative Example 1 reaches the maximum percutaneous diffusion rate per unit area at 24 hours. Overall, the in vitro diffusion rate of the transdermal patch prepared in this application is Comparative Example 1 is better than.

[0150] The above is only a preferred embodiment of the present application, and those skilled in the art may make some improvements and modifications without departing from the principles of the present application, and these improvements and modifications should also be considered as part of the protection scope of the present application.

Claims

1. A dexmedetomidine transdermal composition comprising dexmedetomidine, propylene glycol, a metal chelating crosslinker, and a pressure-sensitive adhesive; In parts by weight, the composition comprises 0.30 to 3.00 parts of dexmedetomidine, 0.40 to 7.00 parts of propylene glycol, 0.30 to 1.25 parts of a metal chelate crosslinker, and 50.00 to 99.00 parts of a pressure sensitive adhesive; the mass ratio of the propylene glycol to the dexmedetomidine is (4:3) to (7:3); the metal chelate crosslinking agent is selected from one or more of aluminum acetylacetonate, zirconium acetylacetonate, titanium acetylacetonate, and polybutyl titanate; A dexmedetomidine transdermal composition, wherein the pressure sensitive adhesive is an acrylate pressure sensitive adhesive.

2. 2. The dexmedetomidine transdermal composition according to claim 1, wherein the mass ratio of propylene glycol to dexmedetomidine in the composition is from (5:3) to (7:3), or the mass ratio of propylene glycol to dexmedetomidine in the composition is 5:

3.

3. 2. The dexmedetomidine transdermal composition of claim 1, wherein the mass ratio of the pressure-sensitive adhesive to the metal chelate crosslinker is from 70:1 to 310:

1.

4. 4. The dexmedetomidine transdermal composition of claim 3, wherein the mass ratio of the pressure-sensitive adhesive to the metal chelate crosslinker is from (70:1) to (160:1), from (160:1) to (220:1), or from (220:1) to (310:1), alternatively from (160:1) to (220:1), from (160:1) to (210:1), from (160:1) to (200:1), or from (190:1) to (220:1), alternatively 160:1, 170:1, 180:1, 190:1, 200:1, 210:1, or 220:

1.

5. The acrylate pressure sensitive adhesives include DURO-TAK® 387-2287, DURO-TAK® 387-2510, DURO-TAK® 87-235A, DURO-TAK® 387-2353, DURO-TAK® 387-2852, DURO-TAK® 387-2051, DURO-TAK® 387-2052, DURO-TAK® 387-2054, DURO-TAK® 87-4287, DURO-TAK® 87-6908, and DURO-TAK® 10. The dexmedetomidine transdermal composition of claim 1, which is one of the pressure sensitive adhesives of model number 87-267.

6. A dexmedetomidine transdermal patch comprising a backing layer, an adhesive layer, and an anti-adhesive release film layer in that order, wherein the adhesive layer is formed from the dexmedetomidine transdermal composition of claim 1.

7. The dexmedetomidine transdermal patch according to claim 6, wherein the adhesive layer has a thickness of 25 μm to 100 μm.

8. A method for preparing the dexmedetomidine transdermal patch according to claim 6 or 7, comprising: dissolving a metal chelate crosslinking agent in a solvent to obtain a metal chelate crosslinking agent solution; mixing a pressure-sensitive adhesive with the metal chelate crosslinker solution to obtain a blank matrix solution; mixing dexmedetomidine, propylene glycol and a solvent to obtain a dexmedetomidine solution; mixing the dexmedetomidine solution and the blank matrix solution, stirring, and allowing to stand to obtain a drug-containing matrix solution; applying a drug-containing matrix solution to the anti-adhesion release film layer and drying it to obtain a composite layer of an adhesive layer and an anti-adhesion release film layer; and laminating a backing layer to an adhesive layer.

9. 9. The method of claim 8, wherein the solvent is selected from the group consisting of absolute ethanol and n-heptane, or a mixture of both.

10. 8. Use of the dexmedetomidine transdermal composition according to any one of claims 1 to 5 or the dexmedetomidine transdermal patch according to claim 6 or 7 in the preparation of a drug formulation for improving sleep disorders.

11. The application of claim 10, wherein the sleep disorder is one or more of perioperative sleep disorder, geriatric sleep disorder, and traumatic sleep disorder.

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