Dexmedetomidine transdermal compositions, transdermal patches, and methods of making and using the same

Abstract

The application discloses a dexmedetomidine transdermal composition, a transdermal patch and a preparation method and application thereof. The composition comprises dexmedetomidine, propylene glycol, a metal chelate crosslinking agent or dexmedetomidine, propylene glycol, a metal chelate crosslinking agent and pressure-sensitive adhesive. In addition, by adding propylene glycol as a solubilizer in the dexmedetomidine transdermal composition, the generation of impurities can be reduced, the compatibility of raw and auxiliary materials is better, meanwhile, the metal chelate crosslinking agent and the pressure-sensitive adhesive are used to jointly form the skeleton structure of the product, so that the adhesion performance is significantly improved and the patient's fitting feeling is better. The product has good stability, no skin irritation, the safety of the product when being attached to the human body is significantly improved, and the slow-release effect of 2-5 days can be achieved.

Description

[0001] Related Applications

[0002] This application claims the priority benefit of Chinese Patent Application No. 202110969146.7, filed on August 23, 2021, entitled “Dexmedetomidine Transdermal Composition, Transdermal Patch and Preparation Method and Application Thereof,” the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0003] The present application relates to the field of pharmaceutical formulations, and in particular to dexmedetomidine transdermal compositions, transdermal patches and preparation methods and applications thereof. BACKGROUND

[0004] At present, dexmedetomidine on the market at home and abroad only has dexmedetomidine hydrochloride injection, and can only be used under the close supervision of professional medical personnel. It is clinically used for sedation of patients with tracheal intubation and ventilation during general anesthesia surgery. However, the half-life of dexmedetomidine injection is only 2 hours, and the duration of drug effect is short.

[0005] The prior art Chinese patent application No. CN201480059798.5 discloses a dexmedetomidine transdermal composition, and tests the average dexmedetomidine flux of different dexmedetomidine transdermal compositions with the change of application time. The present inventors found that the flux of the dexmedetomidine transdermal composition provided by the application is poor, and the transdermal composition provides less than 0.5ug / cm 2 *h flux in some embodiments, and the transdermal diffusion rate reaches the maximum at the 24th hour.

[0006] Therefore, it is urgent to develop a dexmedetomidine transdermal composition which can provide an optimal transdermal diffusion rate, is stable in storage, is convenient for patients to self-administer, significantly reduces the frequency of drug administration, and significantly prolongs the in vivo action time of the drug. SUMMARY

[0008] Therefore, the present application provides a dexmedetomidine transdermal composition, transdermal patch and preparation method and application thereof. The product has an optimal transdermal diffusion rate and good stability, and can achieve a sustained-release effect for 2-5 days.

[0009] The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of protection of the present application.

[0010] In one aspect, the present application provides a dexmedetomidine transdermal composition, which comprises dexmedetomidine, propylene glycol and a metal chelate crosslinking agent;

[0011] Optionally, in the composition, by weight,

[0012] Dexmedetomidine 0.30-3.00 parts

[0013] Propylene glycol 0.40-8.00 parts

[0014] Metal chelate crosslinking agent 0.30-1.25 parts

[0015] Alternatively, the mass ratio of the propylene glycol to the dexmedetomidine is (4:3)-(8:3).

[0016] In a second aspect, the present application provides a dexmedetomidine transdermal composition, which comprises dexmedetomidine, propylene glycol, a metal chelate crosslinking agent, and a pressure-sensitive adhesive.

[0017] Optionally, in the composition, by weight parts,

[0018]

[0019] Alternatively, the mass ratio of the propylene glycol to the dexmedetomidine is (4:3)-(8:3).

[0020] In a third aspect, the present application provides a dexmedetomidine transdermal patch, wherein the transdermal patch comprises, in sequence, a backing layer, an adhesive layer, and a release film layer; the adhesive layer is formed from the dexmedetomidine transdermal composition of the first aspect or the second aspect.

[0021] In a fourth aspect, the present application provides a preparation method of the dexmedetomidine transdermal composition of the second aspect, which comprises the following steps:

[0022] Dissolving the metal chelate crosslinking agent in a solvent to obtain a metal chelate crosslinking agent solution;

[0023] Mixing the pressure-sensitive adhesive with the metal chelate crosslinking agent solution to obtain a blank matrix solution;

[0024] Mixing the dexmedetomidine, the propylene glycol, and the solvent to obtain a dexmedetomidine solution;

[0025] Mixing the dexmedetomidine solution with the blank matrix solution, stirring, standing, and drying.

[0026] In a fifth aspect, the present application provides a preparation method of the dexmedetomidine transdermal patch of the third aspect, which comprises the following steps:

[0027] Dissolving the metal chelate crosslinking agent in a solvent to obtain a metal chelate crosslinking agent solution;

[0028] Mixing the pressure-sensitive adhesive with the metal chelate crosslinking agent solution to obtain a blank matrix solution;

[0029] The dexmedetomidine, propylene glycol and solvent are mixed to obtain a dexmedetomidine solution;

[0030] The dexmedetomidine solution is mixed with a blank matrix solution, stirred, and left to stand to obtain a drug-containing matrix solution;

[0031] The drug-containing matrix solution is coated on the anti-adhesion release film layer and dried to obtain a composite layer of the adhesive layer and the anti-adhesion release film layer;

[0032] The backing layer is compounded on the adhesive layer.

[0033] In a sixth aspect, the present application provides use of the above-mentioned dexmedetomidine transdermal composition or dexmedetomidine transdermal patch in the preparation of a sleep disorder-improving pharmaceutical preparation.

[0034] In a seventh aspect, the present application provides a method for improving sleep disorders in an individual, which comprises administering the above-mentioned dexmedetomidine transdermal composition or dexmedetomidine transdermal patch to an individual in need thereof.

[0035] In a first aspect, the present application provides a dexmedetomidine transdermal composition, which comprises dexmedetomidine, propylene glycol and a metal chelate crosslinking agent.

[0036] In some embodiments of the first aspect, in the composition,

[0037] dexmedetomidine 0.30-3.00 parts

[0038] propylene glycol 0.40-8.00 parts

[0039] metal chelate crosslinking agent 0.30-1.25 parts.

[0040] In some embodiments of the first aspect, in the composition,

[0041] dexmedetomidine 0.72-3.00 parts

[0042] propylene glycol 1.20-8.00 parts

[0043] metal chelate crosslinking agent 0.30-1.25 parts.

[0044] In some embodiments of the first aspect, in the composition,

[0045] dexmedetomidine 0.72-1.80 parts

[0046] propylene glycol 1.20-4.20 parts

[0047] metal chelate crosslinking agent 0.30-0.80 parts.

[0048] In some embodiments of the first aspect, the composition comprises, by weight parts,

[0049] Dexmedetomidine 0.72-1.45 parts

[0050] Propylene glycol 1.20-4.20 parts

[0051] Metal chelate-based crosslinking agent 0.30-0.80 parts.

[0052] In some embodiments of the first aspect, the mass ratio of propylene glycol to dexmedetomidine in the composition is (4:3)-(8:3).

[0053] In some embodiments of the first aspect, the mass ratio of propylene glycol to dexmedetomidine in the composition is (5:3)-(7:3).

[0054] In some embodiments of the first aspect, the mass ratio of propylene glycol to dexmedetomidine in the composition is 5:3.

[0055] In some embodiments of the first aspect, the metal chelate-based crosslinking agent is selected from one or more of aluminum acetylacetonate, zirconium acetylacetonate, titanium acetylacetonate, and polybutyl titanate.

[0056] In some embodiments of the first aspect, the metal chelate-based crosslinking agent is aluminum acetylacetonate or polybutyl titanate.

[0057] In some embodiments of the first aspect, the metal chelate-based crosslinking agent titanium acetylacetonate is (oxy) titanium acetylacetonate or titanium tetraacetylacetonate, or a mixture thereof.

[0058] In some embodiments of the second aspect, the composition comprises, by weight parts,

[0059] In some embodiments of the second aspect, the composition comprises, by weight parts,

[0060]

[0061]

[0062] In some embodiments of the second aspect, the composition comprises, by weight parts,

[0063]

[0064] The mass ratio of the propylene glycol to the dexmedetomidine is (4:3)-(8:3).

[0065] In some embodiments of the second aspect, the composition comprises dexmedetomidine in an amount of 0.72-3.00 parts, 0.72-1.80 parts, 0.72-1.45 parts, or 1.00-1.80 parts.

[0066] In some embodiments of the second aspect, the composition comprises a mass ratio of pressure sensitive adhesive to metal chelate-based crosslinking agent of (70:1)-(310:1).

[0067] In some embodiments of the second aspect, the composition comprises a mass ratio of pressure sensitive adhesive to metal chelate-based crosslinking agent of (70:1)-(310:1).

[0068]

[0069] In some embodiments of the second aspect, the composition comprises a mass ratio of pressure sensitive adhesive to metal chelate-based crosslinking agent of (70:1)-(310:1).

[0070]

[0071] In some embodiments of the second aspect, the composition comprises a mass ratio of pressure sensitive adhesive to metal chelate-based crosslinking agent of (70:1)-(310:1).

[0072]

[0073]

[0074] In some embodiments of the second aspect, the composition comprises a mass ratio of propylene glycol to dexmedetomidine of (4:3)-(8:3).

[0075] In some embodiments of the second aspect, the composition comprises a mass ratio of propylene glycol to dexmedetomidine of (5:3)-(7:3).

[0076] In some embodiments of the second aspect, the composition comprises a mass ratio of propylene glycol to dexmedetomidine of 5:3.

[0077] In some embodiments of the second aspect, the composition comprises a mass ratio of pressure sensitive adhesive to metal chelate-based crosslinking agent of (70:1)-(160:1), (160:1)-(220:1), or (220:1)-(310:1).

[0078] In some embodiments of the second aspect, the composition comprises a mass ratio of pressure sensitive adhesive to metal chelate-based crosslinking agent of (160:1)-(220:1), (160:1)-(210:1), (160:1)-(200:1), or (190:1)-(220:1).

[0079] In some embodiments of the second aspect, the mass ratio of the pressure sensitive adhesive to the metal chelate-based crosslinking agent in the composition is 160:1, 170:1, 180:1, 190:1, 200:1, 210:1, or 220:1.

[0080] In some embodiments of the second aspect, the mass ratio of the pressure sensitive adhesive to the metal chelate-based crosslinking agent in the composition is 190:1.

[0081] In some embodiments of the second aspect, the composition comprises 0.30-0.70 parts of the metal chelate-based crosslinking agent.

[0082] In some embodiments of the second aspect, the composition comprises 0.40-0.60 parts of the metal chelate-based crosslinking agent.

[0083] In some embodiments of the second aspect, the composition comprises 0.50 parts of the metal chelate-based crosslinking agent.

[0084] In some embodiments of the second aspect, the metal chelate-based crosslinking agent is selected from one or more of aluminum acetylacetonate, zirconium acetylacetonate, titanium acetylacetonate, and polybutyl titanate.

[0085] In some embodiments of the second aspect, the metal chelate-based crosslinking agent is aluminum acetylacetonate or polybutyl titanate.

[0086] In some embodiments of the second aspect, the metal chelate-based crosslinking agent titanium acetylacetonate is (oxo) titanium acetylacetonate or titanium tetraacetylacetonate, or a mixture thereof.

[0087] 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.

[0088] In some embodiments of the second aspect, the acrylate pressure sensitive adhesive is Duro-Tak 387-2510 or DURO-TAK 387-2287.

[0089] In a third aspect, the present application provides a dexmedetomidine transdermal patch, which comprises, in sequence, a backing layer, an adhesive layer, and a release film layer; the adhesive layer is formed from the dexmedetomidine transdermal composition described above.

[0090] In some embodiments of the third aspect, the thickness of the adhesive layer is 25 μm-100 μm.

[0091] In a fourth aspect, the present application provides a preparation method of the above-mentioned dexmedetomidine transdermal composition, which comprises the following steps:

[0092] dissolving the metal chelate type crosslinking agent in a solvent to obtain a metal chelate type crosslinking agent solution;

[0093] mixing the pressure-sensitive adhesive and the metal chelate type crosslinking agent solution to obtain a blank matrix solution;

[0094] mixing dexmedetomidine, propylene glycol and a solvent to obtain a dexmedetomidine solution;

[0095] mixing the dexmedetomidine solution and the blank matrix solution, stirring, standing and drying.

[0096] In some embodiments of the fourth aspect, the solvent is selected from one or a mixture of both of anhydrous ethanol and n-heptane.

[0097] In a fifth aspect, the present application provides a preparation method of the above-mentioned dexmedetomidine transdermal patch, which comprises the following steps:

[0098] dissolving the metal chelate type crosslinking agent in a solvent to obtain a metal chelate type crosslinking agent solution;

[0099] mixing the pressure-sensitive adhesive and the metal chelate type crosslinking agent solution to obtain a blank matrix solution;

[0100] mixing dexmedetomidine, propylene glycol and a solvent to obtain a dexmedetomidine solution;

[0101] mixing the dexmedetomidine solution and the blank matrix solution, stirring and standing to obtain a drug-containing matrix solution;

[0102] coating the drug-containing matrix solution on the anti-adhesion release film layer and drying to obtain a composite layer of the adhesive layer and the anti-adhesion release film layer;

[0103] compositing the backing layer on the adhesive layer.

[0104] In some embodiments of the fifth aspect, the solvent is selected from one or a mixture of both of anhydrous ethanol and n-heptane.

[0105] In a sixth aspect, the present application provides use of the above-mentioned dexmedetomidine transdermal composition or dexmedetomidine transdermal patch in preparation of a sleep disorder improving pharmaceutical preparation.

[0106] In some embodiments of the sixth aspect, the sleep disorder is one or more of perioperative sleep disorder, sleep disorder in the elderly and traumatic sleep disorder.

[0107] In a seventh aspect, the present application provides a method for improving sleep disorders in a subject, the method comprising administering the above dexmedetomidine transdermal composition or dexmedetomidine transdermal patch to a subject in need thereof.

[0108] In some embodiments of the seventh aspect, the sleep disorder is one or more of perioperative sleep disorders, sleep disorders in the elderly, and traumatic sleep disorders.

[0109] The present application adds a specific content of propylene glycol to the dexmedetomidine composition, and the mass ratio of propylene glycol to the main drug dexmedetomidine is (4:3)-(8:3), and a metal chelate crosslinking agent and a pressure-sensitive adhesive are selected as the skeleton structure of dexmedetomidine, so that the dexmedetomidine transdermal composition of the present application has a large in vitro diffusion rate, stable product quality; compared with the commercially available dexmedetomidine hydrochloride injection, it is convenient to administer, and can achieve sustained release for 2-5 days, and ensure the sleep quality of patients after use.

[0110] SUMMARY

[0111] The accompanying drawings are included to provide a further understanding of the embodiments of the present application, and constitute a part of the specification, and together with the specific embodiments below, serve to explain the embodiments of the present application, but do not constitute a limitation on the embodiments of the present application.

[0112] Figure 1 A preparation schematic diagram of a dexmedetomidine transdermal patch proposed by the present application is shown in the figure;

[0113] Figure 2 A structure schematic diagram of a dexmedetomidine transdermal patch proposed by the present application is shown in the figure; wherein A is a side view of the dexmedetomidine transdermal patch; B is a top view of the dexmedetomidine transdermal patch;

[0114] Figure 3 A transdermal diffusion curve diagram of a dexmedetomidine transdermal patch of different thicknesses proposed by the present application is shown in the figure;

[0115] Figure 4 A crystallization diagram of a dexmedetomidine transdermal composition proposed by the present application after being stored for 6 months is shown in the figure; wherein A is 10 times imaging, and B is 40 times imaging;

[0116] Figure 5 A mouse spontaneous activity data line graph for improving sleep by a dexmedetomidine transdermal composition proposed by the present application is shown in the figure;

[0117] Figure 6A 72h cumulative time trend chart of sleep-wake structure of rats for the improved sleep application of a dexmedetomidine transdermal composition provided in the present application; A: cumulative trend chart of Wake time of each group at each time node in the sleep structure of rats within 72h after patch administration; B: cumulative trend chart of NREM time of each group at each time node within 72h after patch administration; C: cumulative trend chart of REM time of each group at each time node within 72h after patch administration; N=8.

[0118] Figure 7 A unit area transdermal diffusion rate comparison curve of Example 4, Example 7 and Comparative Example 1 of the present application.

[0119] Detailed description

[0120] In the present application, some terms are defined as follows:

[0121] NREM sleep: non-rapid eye movement sleep, non-ocular rapid movement sleep, characterized by slowing down of brain and ocular activity, which belongs to the main stage of deep sleep and metabolism.

[0122] REM sleep: rapid eye movement sleep, ocular rapid movement sleep, characterized by incomplete cessation of brain activity, which belongs to the stage of light sleep and dreaming.

[0123] In the present application, the dexmedetomidine composition provided in the present application is provided, wherein the calculation method of each component is as follows:

[0124] Weight percentage X(%) = X / (A+B+C+D*d)*100%

[0125] Wherein, A is the weight of dexmedetomidine, B is the weight of propylene glycol, C is the weight of metal chelate crosslinking agent, D is the weight of pressure sensitive adhesive, and d is the solid content corresponding to the type of pressure sensitive adhesive used in the composition; wherein X can be A, B, C or D*d.

[0126] In the present application, the dexmedetomidine transdermal composition provided in the present application comprises dexmedetomidine, propylene glycol, metal chelate crosslinking agent and pressure sensitive adhesive, the content of dexmedetomidine is 0.30-3.00 parts, and the content ratio of propylene glycol to dexmedetomidine is (4:3)-(8:3).

[0127] In an embodiment of the present application, the dexmedetomidine transdermal composition provided in the present application comprises dexmedetomidine 0.72-1.45 parts or 1.00-1.80 parts; preferably, comprises dexmedetomidine 0.72-1.00 parts, 1.00-1.45 parts or 1.45-1.80 parts.

[0128] In an embodiment of the present application, the transdermal composition of dexmedetomidine provided by the present application comprises dexmedetomidine 0.72 parts, 1.00 part, 1.45 parts or 1.80 parts; more preferably, comprises dexmedetomidine 1.00 part.

[0129] In an embodiment of the present application, the transdermal composition of dexmedetomidine provided by the present application, the content ratio of propylene glycol to dexmedetomidine is 4:3, 5:3, 6:3, 7:3 or 8:3; preferably, the content ratio of propylene glycol to dexmedetomidine is (5:3)-(7:3); more preferably, the content ratio of propylene glycol to dexmedetomidine is 5:3.

[0130] In an embodiment of the present application, the transdermal composition of dexmedetomidine provided by the present application comprises propylene glycol 0.40-8.00 parts, 1.20-4.20 parts, 1.31-2.42 parts, 1.44-2.42 parts, 1.44-1.67 parts, 1.44-4.20 parts, 1.44-8.00 parts, 1.31-1.67 parts or 1.67-2.42 parts; preferably, comprises propylene glycol 1.20-4.20 parts.

[0131] In an embodiment of the present application, the transdermal composition of dexmedetomidine provided by the present application comprises propylene glycol 0.40-8.00 parts, 1.20-4.20 parts, 1.31-2.42 parts, 1.44-2.42 parts, 1.44-1.67 parts, 1.44-4.20 parts, 1.44-8.00 parts, 1.31-1.67 parts or 1.67-2.42 parts; preferably, comprises propylene glycol 1.20-4.20 parts.

[0132] In an embodiment of the present application, the transdermal composition of dexmedetomidine provided by the present application, the mass ratio of the pressure-sensitive adhesive to the metal chelate-based crosslinking agent is (70:1)-(160:1), (160:1)-(220:1) or (220:1)-(310:1); preferably, the mass ratio of the pressure-sensitive adhesive to the metal chelate-based crosslinking agent is (160:1)-(190:1) or (190:1)-(220:1); more preferably, the mass ratio of the pressure-sensitive adhesive to the metal chelate-based crosslinking agent is 190:1.

[0133] In an embodiment of the present application, the transdermal composition of dexmedetomidine provided by the present application, the metal chelate-based crosslinking agent is selected from one or more of aluminum acetylacetonate, zirconium acetylacetonate, titanium acetylacetonate and polybutyl titanate.

[0134] In an embodiment of the present application, the transdermal composition of dexmedetomidine provided by the present application, the metal chelate-based crosslinking agent titanium acetylacetonate is selected from one or both of (oxo) titanium acetylacetonate and titanium tetraacetylacetonate.

[0135] In an embodiment of the present application, the transdermal composition of dexmedetomidine provided by the present application, the content of the metal chelate type crosslinking agent ranges from 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; preferably, the content of the metal chelate type crosslinking agent ranges from 0.30 to 0.80 parts.

[0136] In an embodiment of the present application, the transdermal composition of dexmedetomidine provided by the present application, the content of the metal chelate type crosslinking agent ranges from 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; preferably, the content of the metal chelate type crosslinking agent ranges from 0.30 to 0.80 parts.

[0137] In an embodiment of the present application, the transdermal composition of dexmedetomidine provided by the present application, the pressure-sensitive adhesive is selected from one or more of acrylate pressure-sensitive adhesive, polyisobutylene pressure-sensitive adhesive, silicone pressure-sensitive adhesive, styrene-isoprene-styrene hot melt pressure-sensitive adhesive (SIS type), and vinyl acetate copolymer.

[0138] In an embodiment of the present application, the transdermal composition of dexmedetomidine provided by the present application, the pressure-sensitive adhesive is selected from one or more of acrylate pressure-sensitive adhesive, polyisobutylene pressure-sensitive adhesive, silicone pressure-sensitive adhesive, styrene-isoprene-styrene hot melt pressure-sensitive adhesive (SIS type), and vinyl acetate copolymer.

[0139] In an embodiment of the present application, the transdermal composition of dexmedetomidine provided by the present application, the content ratio of the pressure-sensitive adhesive to the metal chelate type crosslinking agent ranges from (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).

[0140] In an embodiment of the present application, the dexmedetomidine transdermal composition provided by the present application comprises dexmedetomidine 0.72-1.80 parts, metal chelate crosslinking agent 0.30-0.80 parts, acrylic ester pressure sensitive adhesive 93.00-99.00 parts, and propylene glycol, wherein the content ratio of the propylene glycol to the dexmedetomidine is (4:3)-(8:3).

[0141] In an embodiment of the present application, the dexmedetomidine transdermal composition provided by the present application comprises polybutyl titanate or aluminum acetylacetonate as the metal chelate crosslinking agent.

[0142] In an embodiment of the present application, the dexmedetomidine transdermal composition provided by the present application comprises Duro-Tak 387-2510 or DURO-TAK 387-2287 as the acrylic ester pressure sensitive adhesive.

[0143] In an embodiment of the present application, the dexmedetomidine transdermal composition provided by the present application is used in the preparation of a transdermal patch.

[0144] In an embodiment of the present application, the dexmedetomidine transdermal patch provided by the present application comprises the dexmedetomidine transdermal composition.

[0145] In an embodiment of the present application, the dexmedetomidine transdermal patch provided by the present application comprises the dexmedetomidine transdermal composition as the adhesive layer of the transdermal patch.

[0146] In an embodiment of the present application, the dexmedetomidine transdermal patch provided by the present application comprises the dexmedetomidine transdermal composition as the adhesive layer of the transdermal patch, wherein the thickness of the adhesive layer is 25 μm-100 μm.

[0147] In an embodiment of the present application, the dexmedetomidine transdermal patch provided by the present application comprises a backing layer, a release film layer, and an adhesive layer disposed between the backing layer and the release film layer; the adhesive layer comprises dexmedetomidine 0.72-1.80 parts, polybutyl titanate 0.30-0.80 parts, acrylic ester pressure sensitive adhesive 93.00-99.00 parts, and propylene glycol; the content ratio of the propylene glycol to the dexmedetomidine is (4:3)-(8:3); and the acrylic ester pressure sensitive adhesive is Duro-Tak 387-2510 or DURO-TAK 387-2287.

[0148] In an embodiment of the present application, the dexmedetomidine transdermal patch provided by the present application comprises a backing layer, a release film layer, and an adhesive layer disposed between the backing layer and the release film layer; the adhesive layer comprises dexmedetomidine 0.72-1.80 parts, polybutyl titanate 0.30-0.80 parts, acrylic ester pressure sensitive adhesive 93.00-99.00 parts, and propylene glycol; the content ratio of the propylene glycol to the dexmedetomidine is (4:3)-(8:3); and the acrylic ester pressure sensitive adhesive is Duro-Tak 387-2510 or DURO-TAK 387-2287.

[0149] In an embodiment of the present application, the dexmedetomidine transdermal patch provided by the present application comprises a backing layer, a release film layer, and an adhesive layer disposed between the backing layer and the release film layer; the adhesive layer comprises dexmedetomidine 0.72-1.80 parts, polybutyl titanate 0.30-0.80 parts, acrylic ester pressure sensitive adhesive 93.00-99.00 parts, and propylene glycol; the content ratio of the propylene glycol to the dexmedetomidine is (4:3)-(8:3); and the acrylic ester pressure sensitive adhesive is Duro-Tak 387-2510 or DURO-TAK 387-2287.

[0150] In embodiments of the present application, the preparation method of the dexmedetomidine transdermal patch provided by the present application comprises the following steps:

[0151] (a) dissolving the metal chelate crosslinking agent in a solvent to obtain a metal chelate crosslinking agent solution;

[0152] (b) mixing the pressure-sensitive adhesive and the metal chelate crosslinking agent solution to obtain a blank matrix solution;

[0153] (c) dissolving the propylene glycol, the solvent and the dexmedetomidine, and then adding them to the blank matrix solution for mixing to obtain a drug-containing matrix solution;

[0154] (d) coating the drug-containing matrix solution on a release film, drying to obtain a composite layer of the adhesive layer and the anti-sticking release film layer;

[0155] (e) compounding the backing film on the adhesive layer to obtain the dexmedetomidine transdermal patch.

[0156] The solvent comprises anhydrous ethanol and n-heptane.

[0157] In embodiments of the present application, the dexmedetomidine transdermal composition or the dexmedetomidine transdermal patch provided by the present application can be used for improving sleep disorders, including perioperative sleep disorders, sleep disorders in the elderly and traumatic sleep disorders.

[0158] In embodiments of the present application, the dexmedetomidine transdermal composition or the dexmedetomidine transdermal patch provided by the present application can achieve slow release for 2-5 days.

[0159] The propylene glycol used in the present application can have a good solubilizing effect on dexmedetomidine at a lower concentration, can improve the solubility of dexmedetomidine in the matrix material, and has good compatibility with the raw material dexmedetomidine;

[0160] The metal chelate crosslinking agent used in the present application and the pressure-sensitive adhesive together serve as the matrix structure of the transdermal composition of the present application, cooperatively regulate the adhesion properties of the transdermal composition, and at the same time provide a drug-loaded matrix for dexmedetomidine;

[0161] The release film used in the present application can form a good compatibility relationship with the pressure-sensitive adhesive, ensuring that it can be firmly adhered to the surface of the pressure-sensitive adhesive and easily peeled off from the adhesive layer when removed, and at the same time can withstand the erosion of various raw materials and solvents during the preparation and storage of the transdermal patch;

[0162] The backing film used in the present application has good flexibility, solid and smooth texture, appropriate peel strength, and good compatibility with the raw materials of the transdermal patch of the present application;

[0163] The solvent used in the present application includes anhydrous ethanol and n-heptane, which are used to dissolve the raw drug dexmedetomidine and / or metal chelator crosslinking agent, and have the advantages of non-toxicity, non-irritation and good compatibility with raw and auxiliary materials.

[0164] The preparation process of the dexmedetomidine transdermal patch of the present application is shown in Figure 1 The detailed structure of the transdermal patch is shown in Figure 2 (A: side view of dexmedetomidine transdermal patch; B: top view of dexmedetomidine transdermal patch).

[0165] The release liner is overlapped and forms the current anti-sticking layer with the punched hole punched around the patch, so as to further reduce the risk of cold flow.

[0166] The use or administration method of the dexmedetomidine transdermal patch provided by the present application is to apply it to the smooth and flat skin surface of the human body trunk or upper arm which is not stimulated and not irradiated. If the administration is interrupted, the transdermal patch can be removed.

[0167] The reagents and instruments used in the present application can be purchased from the market. Instruments: HS-3 vertical mixing instrument, TB-04D precision coating machine for experiments, DGF302-BN electric heating drying oven, PL-3002-IC electronic balance, KQ-500VDE ultrasonic cleaner, MDC-25SX digital micrometer, XMTD-204 constant temperature magnetic stirrer, Franz transdermal diffusion instrument TK-24BL, GHP-9160 constant temperature incubator, WD-A drug stability tester.

[0168] Example 1: Compatibility and stability of dexmedetomidine and solubilizing agent

[0169] 1. Sample preparation

[0170] By setting up "dexmedetomidine + levulinic acid", "dexmedetomidine + oleic acid", "dexmedetomidine + laurocapram ", "dexmedetomidine + isopropyl myristate", "dexmedetomidine + propylene glycol" experimental groups, the experimental samples were prepared according to the ratio of dexmedetomidine: solubilizing agent = 1:10.

[0171] 2. Raw material compatibility experiment

[0172] The above experimental samples were prepared into 5 subgroups, namely the control group, the high temperature group, the high humidity group, the light group and the accelerated group, and the corresponding conditions are shown in Table 1 below. The sampling time points of high temperature, high humidity, light and acceleration are 0 days, 5 days and 10 days, which are used to investigate the impurity content of the mixture of dexmedetomidine and solubilizing agent under different conditions.

[0173] Evaluation criteria: Maximum unknown single impurity (%), total impurities (%), and total impurities (%).

[0174] Table 1. Test conditions for samples in the compatibility and stability study of raw and auxiliary materials.

[0175] Sample name Condition Control group / High temperature group 60℃ High humidity group 25°C / 95% RH Illumination group 4500±500lx Acceleration group 40°C / 75% RH

[0176] 3. Experimental Results

[0177] Table 2. Results of compatibility and stability tests of dexmedetomidine and levulinic acid.

[0178]

[0179]

[0180] ND indicates not detected.

[0181] As shown in the table above, the maximum single impurity content in the "API + levulinic acid" group was 1.99% and the maximum total impurity content was 5.53% under high temperature conditions; the maximum single impurity content was 0.94% and the maximum total impurity content was 3.35% under light irradiation conditions; and the maximum single impurity content was 0.60% and the maximum total impurity content was 1.85% under accelerated conditions. Under the above-mentioned conditions, the impurity content in the "API + levulinic acid" group exceeded the standard limits. Therefore, the compatibility and stability of dexmedetomidine and levulinic acid as raw materials and excipients are poor.

[0182] Table 3. Results of compatibility and stability tests of dexmedetomidine and oleic acid with raw materials.

[0183]

[0184] As shown in the table above, the maximum single impurity content of the "API + oleic acid" group was 1.22% and the maximum total impurity content was 4.76% under high temperature conditions; the maximum single impurity content was 0.64% and the maximum total impurity content was 2.68% under light irradiation conditions; and the maximum single impurity content was 0.88% and the maximum total impurity content was 2.12% under accelerated conditions. Under the above-mentioned conditions, the impurity content of the "API + oleic acid" group exceeded the standard limits. Therefore, the compatibility and stability of dexmedetomidine and oleic acid as raw materials and excipients are poor.

[0185] Table 4 Dexmedetomidine and Lauryl Azone Results of raw material compatibility and stability tests

[0186]

[0187] As shown in the table above, "raw material + lauryl azone" The maximum single impurity content in the group was 2.21% under high temperature conditions and 4.29% for the maximum total impurity content; under light conditions, the maximum single impurity content was 0.96% and the maximum total impurity content was 3.54%; under accelerated conditions, the maximum single impurity content was 0.97% and the maximum total impurity content was 3.86%. Under the above conditions, the "active drug + lauryl azone" "The impurity content of group A exceeds the standard limit; therefore, dexmedetomidine and lauryl azone are contraindicated." The compatibility and stability of the raw materials and auxiliary materials are relatively poor.

[0188] Table 5. Results of compatibility and stability tests of dexmedetomidine and isopropyl myristate with raw materials.

[0189]

[0190] As shown in the table above, the maximum single impurity content of the "API + Isopropyl myristate" group was 1.03% and the maximum total impurity content was 3.36% under high temperature conditions; the maximum single impurity content was 0.72% and the maximum total impurity content was 4.79% under light irradiation conditions; and the maximum single impurity content was 0.72% and the maximum total impurity content was 4.32% under accelerated conditions. Under the above-mentioned conditions, the impurity content of the "API + Isopropyl myristate" group exceeded the standard limits. Therefore, the compatibility and stability of dexmedetomidine and isopropyl myristate as raw materials are poor.

[0191] Table 6. Results of compatibility and stability tests of dexmedetomidine and propylene glycol.

[0192]

[0193] As shown in the table above, the maximum single impurity content of the "API + propylene glycol" group was 0.04% and the maximum total impurity content was 0.05% under all investigated conditions. Therefore, the compatibility and stability of dexmedetomidine and propylene glycol as raw materials and excipients are very good.

[0194] In summary, as shown in Tables 2-6, the following combinations are possible: "dexmedetomidine + levulinic acid", "dexmedetomidine + oleic acid", and "dexmedetomidine + laurocapram". The "dexmedetomidine + isopropyl myristate" group produced a large number of impurities under high temperature and light conditions, indicating poor compatibility and stability between the excipient and the active pharmaceutical ingredient (API) dexmedetomidine. In contrast, the "API + propylene glycol" group showed a maximum single impurity content of 0.04% and a maximum total impurity content of 0.05% under all tested conditions, indicating excellent compatibility and stability between the excipient and the API. Therefore, propylene glycol was chosen as the solubilizer for the transdermal composition of this application, as its addition can reduce the formation of subsequent impurities.

[0195] Experimental Example 2: Investigation of Propylene Glycol Dosage

[0196] 1. Prescription 1 - Transdermal Patch

[0197]

[0198] Wherein the acrylate pressure sensitive adhesive is Duro-Tak 387-2287 with a solids content of 53.8%.

[0199] The transdermal patch comprises a backing layer, an adhesive layer and a release liner layer, and the preparation method of the transdermal patch specifically comprises the following steps:

[0200] (1) Preparation of aluminum acetylacetonate solution: weigh 0.05 g of aluminum acetylacetonate, 1.01 g of anhydrous ethanol and 1.34 g of n-heptane into a 40 mL scientific vial, mix uniformly, and reserve;

[0201] (2) Preparation of blank matrix: weigh 20.12 g of acrylate pressure sensitive adhesive and the prepared aluminum acetylacetonate solution, and seal;

[0202] (3) Mixing: place the scientific vial containing the blank matrix on the vertical mixer, adjust the rotation speed to 20 rpm, and stir for 4 h;

[0203] (4) Preparation of drug-containing matrix: weigh 0.08 g of dexmedetomidine, add 0.16 g of propylene glycol and 2.24 g of anhydrous ethanol, stir until the dexmedetomidine is completely dissolved, then add to the blank matrix after stirring for 4 h, weigh 0.16 g of anhydrous ethanol to wash the empty bottle, and add to the drug-containing matrix for mixing, and seal;

[0204] (5) Mixing: place the scientific vial containing the drug-containing matrix on the vertical mixer, adjust the rotation speed to 20 rpm, stop stirring after 6 h, and stand overnight;

[0205] (6) Coating: coat the drug-containing matrix after standing overnight on the release liner Scotchpak 1022, adjust the thickness of the coating blade to the final thickness of the drug-containing layer of the transdermal patch to be 25 μm;

[0206] (7) Drying: place in an oven, adjust the temperature to 70°C, and take out after 20 min;

[0207] (8) Laminating: laminate the backing film Scotchpak 9722 on the drug-containing adhesive layer;

[0208] (9) Punching: punch into a circular patch with a diameter (D = 30 mm), and package.

[0209] All anhydrous ethanol and n-heptane will be removed during the preparation process and will not be present in the final product.

[0210] 2. Experimental grouping

[0211] Different amounts of propylene glycol were selected for prescription optimization screening propylene glycol. Specifically, the weight ratio of propylene glycol to dexmedetomidine was 3:3, 4:3, 5:3, 6:3, 7:3, 8:3, 9:3, and a blank group (no propylene glycol was added in prescription 1) was set.

[0212] 3. Related substance detection

[0213] The following 8 groups of samples (n = 6) were subjected to impurity detection, and the results of related substance impurities are shown in Table 7.

[0214] Table 7 Results of related substance impurities in propylene glycol dosage screening

[0215] Group Propylene glycol: dexmedetomidine Single impurity (%) Total impurities (%) 1 0:3 0.5 0.8 2 3:3 0.5 0.7 3 4:3 0.5 0.8 4 5:3 0.5 0.8 5 6:3 0.4 0.7 6 7:3 0.4 0.7 7 8:3 0.4 0.8 8 9:3 0.5 0.8

[0216] From the above table, it can be seen that the amount of propylene glycol has no obvious effect on the related substances of the transdermal patch of the present example.

[0217] 4. Adhesion performance test

[0218] Eight groups of samples (n = 6) were subjected to propylene glycol dosage screening, and the eight groups of samples were pasted on the smooth skin of the back of the hands of eight volunteers. After 30 minutes, the adhesion performance of the transdermal patch of the present application was observed by observing whether there was residual glue on the skin and whether there was a painful feeling.

[0219] Adhesion performance score index:

[0220] 1: weak adhesion performance;

[0221] 2: slightly sticky edge residue, good adhesion performance;

[0222] 3: no residue on the edge of adhesion, good adhesion performance;

[0223] 4: painful when removed, including keratinized skin abrasions.

[0224] The results of the adhesion experiment of dexmedetomidine solubility and transdermal patch are shown in Table 8.

[0225] Table 8 Results of propylene glycol dosage screening test

[0226] Group Propylene glycol: dexmedetomidine In vitro adhesion performance evaluation 1 0:3 1 2 3:3 1 3 4:3 2 4 5:3 3 5 6:3 3 6 7:3 3 7 8:3 4 8 9:3 4

[0227] From the above table, when the transdermal patch does not contain propylene glycol and the mass ratio of propylene glycol to dexmedetomidine is 3:3, the sample adhesion performance is weaker, when the mass ratio of propylene glycol to dexmedetomidine is 4:3 or more, the sample adhesion performance is better; but when the feeding ratio exceeds 8:3, some samples are painful when they are removed; when the feeding ratio is in the range of (5:3)-(7:3), the adhesion performance of the patch on the skin surface is better; when the feeding ratio is 5:3, the adhesion performance of the transdermal patch on the skin surface is best, and there is no residue on the skin surface and no pain when all samples are removed.

[0228] Experimental Example 3 Investigation of the amount of metal chelate crosslinking agent

[0229] 1. Prescription preparation

[0230] ① Prescription 2

[0231]

[0232] Among them, the acrylic pressure-sensitive adhesive is Duro-Tak 387-2287, and the solid content is 53.8%.

[0233] The preparation method of prescription 2 is the same as that of prescription 1, except that the Scotchpak 9754 backing film is compounded on the drug-containing adhesive layer.

[0234] The amount and content of dexmedetomidine and propylene glycol in prescription 2 are kept unchanged, and the amount and content of the metal chelate crosslinking agent-polybutyl titanate are adjusted to obtain prescription 2'(0.07g, about 0.30 parts), prescription 2"(0.09g, about 0.40 parts), prescription 2"'(0.14g, about 0.60 parts) and prescription 2""(0.16g, about 0.70 parts) respectively, and the acrylic pressure-sensitive adhesive in the corresponding prescription is adjusted accordingly (in prescription 2'-2"", the amount of acrylic pressure-sensitive adhesive is 41.33g, 40.91g, 40.49g and 41.37g respectively).

[0235] ② Prescription 3

[0236]

[0237] Among them, the acrylic pressure-sensitive adhesive is Duro-Tak 387-2287; the preparation method is the same as that of prescription 2.

[0238] The amounts and contents of dexmedetomidine and propylene glycol were kept unchanged, and the amounts and contents of the metal chelate crosslinking agent were adjusted to obtain Formulation 3' (0.07 g, about 0.30 parts), Formulation 3" (0.09 g, about 0.40 parts), Formulation 3"' (0.14 g, about 0.60 parts), and Formulation 3"" (0.16 g, about 0.70 parts), respectively. The acrylate pressure-sensitive adhesive corresponding to the formulations was adjusted accordingly (in Formulations 3'-3"", the amounts of the acrylate pressure-sensitive adhesive were 41.33 g, 40.91 g, 40.49 g, and 41.37 g, respectively).

[0239] ③ Formulation 4

[0240]

[0241]

[0242] The acrylate pressure-sensitive adhesive was Duro-Tak 387-2287, and the preparation method was the same as that of Formulation 2.

[0243] The amounts and contents of dexmedetomidine and propylene glycol were kept unchanged, and the amounts and contents of the metal chelate crosslinking agent were adjusted to obtain Formulation 4' (0.07 g, about 0.30 parts), Formulation 4" (0.09 g, about 0.40 parts), Formulation 4"' (0.14 g, about 0.60 parts), and Formulation 4"" (0.16 g, about 0.70 parts), respectively. The acrylate pressure-sensitive adhesive corresponding to the formulations was adjusted accordingly (in Formulations 4'-4"", the amounts of the acrylate pressure-sensitive adhesive were 41.33 g, 40.91 g, 40.49 g, and 41.37 g, respectively).

[0244] ④ Formulation 5

[0245]

[0246] The acrylate pressure-sensitive adhesive was Duro-Tak 387-2287, and the preparation method was the same as that of Formulation 2.

[0247] The amounts and contents of dexmedetomidine and propylene glycol were kept unchanged, and the amounts and contents of the metal chelate crosslinking agent were adjusted to obtain Formulation 5' (0.07 g, about 0.30 parts), Formulation 5" (0.09 g, about 0.40 parts), Formulation 5"' (0.14 g, about 0.60 parts), and Formulation 5"" (0.16 g, about 0.70 parts), respectively. The acrylate pressure-sensitive adhesive corresponding to the formulations was adjusted accordingly (in Formulations 5'-5"", the amounts of the acrylate pressure-sensitive adhesive were 41.33 g, 40.91 g, 40.49 g, and 41.37 g, respectively).

[0248] ⑤ Formulation 6

[0249]

[0250]

[0251] The acrylic pressure sensitive adhesive is Duro-Tak 387-2510, and the solid content is 42.7%. The preparation method is the same as that of prescription 1, except that the Scotchpak 9754 backing film is used to compound the adhesive layer.

[0252] The amounts and contents of dexmedetomidine and propylene glycol are kept unchanged, and the amounts and contents of the metal chelate crosslinking agent are adjusted to obtain prescription 6' (0.06 g, about 0.30 parts), prescription 6'' (0.08 g, about 0.40 parts), prescription 6''' (0.12 g, about 0.60 parts) and prescription 6'''' (0.14 g, about 0.70 parts), respectively, and the corresponding prescription acrylic pressure sensitive adhesive is adjusted (in prescriptions 6'-6'', the amounts of the acrylic pressure sensitive adhesive are 45.01 g, 44.97 g, 44.87 g and 44.83 g, respectively).

[0253] (6) Prescription 7

[0254]

[0255] The acrylic pressure sensitive adhesive is Duro-Tak 387-2510, and the preparation method is the same as that of prescription 6.

[0256] The amounts and contents of dexmedetomidine and propylene glycol are kept unchanged, and the amounts and contents of the metal chelate crosslinking agent are adjusted to obtain prescription 7' (0.06 g, about 0.30 parts), prescription 7'' (0.08 g, about 0.40 parts), prescription 7''' (0.12 g, about 0.60 parts) and prescription 7'''' (0.14 g, about 0.70 parts), respectively, and the corresponding prescription acrylic pressure sensitive adhesive is adjusted (in prescriptions 7'-7'', the amounts of the acrylic pressure sensitive adhesive are 45.01 g, 44.97 g, 44.87 g and 44.83 g, respectively).

[0257] (7) Prescription 8

[0258]

[0259] The acrylic pressure sensitive adhesive is Duro-Tak 387-2510, and the preparation method is the same as that of prescription 6.

[0260] The amounts and contents of dexmedetomidine and propylene glycol were kept unchanged, and the amounts and contents of metal chelate crosslinking agent were adjusted to obtain Formulation 8' (0.06 g, about 0.30 parts), Formulation 8" (0.08 g, about 0.40 parts), Formulation 8"' (0.12 g, about 0.60 parts), and Formulation 8"" (0.14 g, about 0.70 parts), respectively. The acrylate pressure-sensitive adhesive corresponding to the formulations was adjusted accordingly (in Formulations 8'-8"", the amounts of acrylate pressure-sensitive adhesive were 45.01 g, 44.97 g, 44.87 g, and 44.83 g, respectively).

[0261] 7. Formulation 9

[0262]

[0263] The acrylate pressure-sensitive adhesive used was Duro-Tak 387-2510. The preparation method was the same as that of Formulation 6.

[0264] The amounts and contents of dexmedetomidine and propylene glycol were kept unchanged, and the amounts and contents of metal chelate crosslinking agent were adjusted to obtain Formulation 9' (0.06 g, about 0.30 parts), Formulation 9" (0.08 g, about 0.40 parts), Formulation 9"' (0.12 g, about 0.60 parts), and Formulation 9"" (0.14 g, about 0.70 parts), respectively. The acrylate pressure-sensitive adhesive corresponding to the formulations was adjusted accordingly (in Formulations 9'-9"", the amounts of acrylate pressure-sensitive adhesive were 45.01 g, 44.97 g, 44.87 g, and 44.83 g, respectively).

[0265] 2. Adhesion performance test

[0266] According to the "General Rule 0952 Adhesion Test" in the 2020 edition of the Chinese Pharmacopoeia, the holding adhesion and 180° peeling strength of 8 groups of samples (n = 3) of Formulations 2-9 were tested, and the in vivo adhesion performance of 8 groups of samples of Formulations 2-9 was evaluated: the samples were peeled off after 30 min of sticking, and the in vivo adhesion performance was evaluated. The scoring criteria are as follows:

[0267] Scoring criteria:

[0268] 1: The in vivo adhesion performance is relatively weak;

[0269] 2: There is a little residual edge, and the adhesion performance is good;

[0270] 3: There is no residual edge, and the adhesion performance is good;

[0271] 4: It is painful when peeled off, including keratinized skin abrasion.

[0272] The adhesion performance test results after the above operation are shown in Tables 9-16.

[0273] 3. Experimental results

[0274] Table 9 Adhesion performance test results of prescription 2 - prescription 2"

[0275]

[0276] From the above table, with the increase of the amount of polybutyl titanate, the 180° peeling strength presents a trend of first decreasing and then increasing, and the holding adhesion force presents a trend of greatly rising within a certain range. Among them, when the content of polybutyl titanate is 0.30 parts, the sample has a slight pain when it is torn off; when the content of polybutyl titanate is 0.70 parts, the sample has a slight residue on the adhesive edge when it is torn off; when the content of polybutyl titanate is in the range of 0.40-0.60 parts, all the tested samples have good adhesion performance, and there is no residue on the adhesive edge.

[0277] Table 10 Adhesion performance test results of prescription 3 - prescription 3"

[0278]

[0279] From the above table, with the increase of the amount of aluminum acetylacetonate, the 180° peeling strength presents a trend of first decreasing and then increasing, and the holding adhesion force presents a trend of greatly rising within a certain range. Among them, when the content of aluminum acetylacetonate is in the range of 0.30-0.40 parts, the sample has a slight pain when it is torn off; when the content of aluminum acetylacetonate is 0.70 parts, the sample has a slight residue on the adhesive edge when it is torn off; when the content of aluminum acetylacetonate is in the range of 0.50-0.60 parts, all the tested samples have good adhesion performance, and there is no residue on the adhesive edge.

[0280] Table 11 Adhesion performance test results of prescription 4 - prescription 4"

[0281]

[0282]

[0283] From the above table, with the increase of the amount of zirconium acetylacetonate, the 180° peeling strength presents a trend of first decreasing and then increasing, and the holding adhesion force presents a trend of greatly rising within a certain range. Among them, when the content of zirconium acetylacetonate is in the range of 0.30-0.40 parts, the sample has a slight pain when it is torn off; when the content of zirconium acetylacetonate is 0.70 parts, the sample has a slight residue on the adhesive edge when it is torn off; when the content of zirconium acetylacetonate is in the range of 0.50-0.60 parts, all the tested samples have good adhesion performance, and there is no residue on the adhesive edge.

[0284] Table 12 Adhesion performance test results of prescription 5 - prescription 5"

[0285]

[0286] From the above table, it can be seen that as the amount of titanium (oxy) acetylacetonate increases, the 180° peel strength shows a trend of first decreasing and then increasing, and the holding adhesion shows a trend of greatly increasing within a certain range. Among them, when the content of titanium (oxy) acetylacetonate is 0.30-0.40 parts, the sample has a slight pain when it is torn off; when the content of titanium (oxy) acetylacetonate is 0.70 parts, the sample has a slight residue of the adhesive edge when it is torn off; when the content of titanium (oxy) acetylacetonate is 0.50-0.60 parts, all the tested samples have good adhesion performance, and the adhesive edge has no residue.

[0287] Table 13 Adhesion performance test results of prescription 6-prescription 6"

[0288]

[0289] From the above table, it can be seen that as the amount of titanium (oxy) acetylacetonate increases, the 180° peel strength shows a trend of first decreasing and then increasing, and the holding adhesion shows a trend of greatly increasing within a certain range. Among them, when the content of titanium (oxy) acetylacetonate is 0.30-0.40 parts, the sample has a slight pain when it is torn off; when the content of titanium (oxy) acetylacetonate is 0.70 parts, the sample has a slight residue of the adhesive edge when it is torn off; when the content of titanium (oxy) acetylacetonate is 0.50-0.60 parts, all the tested samples have good adhesion performance, and the adhesive edge has no residue.

[0290] Table 14 Adhesion performance test results of prescription 7-prescription 7"

[0291]

[0292] From the above table, it can be seen that as the amount of titanium (oxy) acetylacetonate increases, the 180° peel strength shows a trend of first decreasing and then increasing, and the holding adhesion shows a trend of greatly increasing within a certain range. Among them, when the content of titanium (oxy) acetylacetonate is 0.30-0.40 parts, the sample has a slight pain when it is torn off; when the content of titanium (oxy) acetylacetonate is 0.70 parts, the sample has a slight residue of the adhesive edge when it is torn off; when the content of titanium (oxy) acetylacetonate is 0.50-0.60 parts, all the tested samples have good adhesion performance, and the adhesive edge has no residue.

[0293] Table 15 Adhesion performance test results of prescription 8-prescription 8"

[0294]

[0295] From the above table, with the increase of the amount of zirconium acetylacetonate, the 180° peeling strength showed a trend of first decreasing and then increasing, and the holding adhesion showed a trend of greatly increasing within a certain range. Among them, when the content of zirconium acetylacetonate was about 0.30-0.40 parts, the sample had a slight pain when it was torn off; when the content of zirconium acetylacetonate was about 0.70 parts, the sample had a little residual adhesive edge when it was torn off; when the content of zirconium acetylacetonate was about 0.50-0.60 parts, all the tested samples had good adhesive properties, and the adhesive edge had no residual trace.

[0296] Table 16 Adhesion test results of prescription 9-prescription 9"

[0297]

[0298] From the above table, with the increase of the amount of zirconium acetylacetonate, the 180° peeling strength showed a trend of first decreasing and then increasing, and the holding adhesion showed a trend of greatly increasing within a certain range. Among them, when the content of zirconium acetylacetonate was about 0.30-0.40 parts, the sample had a slight pain when it was torn off; when the content of zirconium acetylacetonate was about 0.70 parts, the sample had a little residual adhesive edge when it was torn off; when the content of zirconium acetylacetonate was about 0.50-0.60 parts, all the tested samples had good adhesive properties, and the adhesive edge had no residual trace.

[0299] In summary, the addition of metal chelate crosslinking agent can improve the adhesion of the dexmedetomidine transdermal patch of the present application. Through the comprehensive evaluation of holding adhesion, 180° peeling strength and in vivo adhesion, it can be known that the amount of metal chelate crosslinking agent of the transdermal patch of the present application is 0.30-0.70 parts, the preferred amount is 0.40-0.60 parts, and the more preferred amount is 0.50 parts.

[0300] Example 4 Prescription 10

[0301]

[0302] Among them, the acrylic ester pressure sensitive adhesive is Duro-Tak 387-2287, and the solid content is 53.8%.

[0303] The preparation method of prescription 10 is the same as that of prescription 1, except that the coating uses release film Scotchpak9709, and the lamination uses backing film Scotchpak 9723.

[0304] Example 5 Prescription 11

[0305]

[0306] The acrylic pressure-sensitive adhesive is designated as Duro-Tak 387-2510, with a solid content of 42.7%.

[0307] The preparation method of Formula 11 is the same as that of Formula 1, except that: the coating uses Scotchpak 9709 release film and the lamination uses Scotchpak 9723 backing film.

[0308] Example 6 Prescription 12

[0309]

[0310] The acrylic pressure-sensitive adhesive is designated as Duro-Tak 387-2510, with a solid content of 42.7%.

[0311] The preparation method of Formula 8 is the same as that of Formula 1, except that Scotchpak 9745 backing film is laminated onto the drug-containing adhesive layer.

[0312] Example 7 Prescription 13

[0313]

[0314]

[0315] The acrylic pressure-sensitive adhesive is designated as Duro-Tak 387-2510, with a solid content of 42.7%.

[0316] The preparation method of Formula 9 is the same as that of Formula 1, except that: Scotchpak 9709 is used as the release film; Scotchpak 9745 is used as the backing film; and the thickness of the drug-containing layer is adjusted to 50 μm during coating.

[0317] Example 8 Prescription 14

[0318]

[0319] The acrylic pressure-sensitive adhesive is designated as Duro-Tak 387-2510, with a solid content of 42.7%.

[0320] The preparation method of Formula 10 is the same as that of Formula 1, except that: Scotchpak 9709 is used as the release film; Scotchpak 9745 is used as the backing film; and the thickness of the drug-containing layer is adjusted to 50 μm during coating.

[0321] Example 9 Prescription 15

[0322]

[0323] The acrylic pressure sensitive adhesive is Duro-Tak 387-2510 with a solid content of 42.7%.

[0324] The prescription 11 was prepared according to the prescription 1, except that the release film was Scotchpak 9709 and the backing film was Scotchpak 9745, and the thickness of the drug-containing layer was adjusted to 50 μm.

[0325] Example 10 Prescription 16

[0326]

[0327] The acrylic pressure sensitive adhesive is Duro-Tak 387-2510 with a solid content of 42.7%.

[0328] The prescription 12 was prepared according to the prescription 1, except that the release film was Scotchpak 9709 and the backing film was Scotchpak 9745, and the thickness of the drug-containing layer was adjusted to 50 μm.

[0329] Example 11 Prescription 17

[0330]

[0331] The acrylic pressure sensitive adhesive is Duro-Tak 387-2510 with a solid content of 42.7%.

[0332] The prescription 13 was prepared according to the prescription 1, except that the release film was Scotchpak 9709 and the backing film was Scotchpak 9745, and the thickness of the drug-containing layer was adjusted to 50 μm.

[0333] Example 11 Coating thickness investigation

[0334] 1. Method

[0335] The sample prepared according to the prescription 13 (D = 14 mm) was adjusted to have a drug-containing layer thickness of 25 μm, 50 μm and 100 μm, and was divided into three groups.

[0336] The prepared transdermal patch was removed from the release liner and applied to the surface of the pig skin, and the pig skin was pressed against the patch with the fingers to ensure good adhesion of the pig skin to the patch. Then the pig skin was attached to the Franz diffusion cell between the rotor and the supply chamber, the backing layer was in contact with the air, and was fixed with an iron clamp; 9 mL of the receiving medium was added to the receiving chamber with a pipette, and a magnetic stirrer was added for stirring at a constant temperature (32±0.5°C) and a constant speed (180 r / min). At the predetermined time points, 0.8 mL of the sample was taken with a 1 mL syringe, and the same amount of blank receiving liquid at the same temperature was added. The removed sample was immediately sent to the high performance liquid chromatograph for determination of the content. The in vitro transdermal diffusion results are shown in the following table.

[0337] 2. Experimental results

[0338] Table 17 Cumulative permeation per unit area of samples of different thicknesses

[0339]

[0340] Specifically, the in vitro transdermal diffusion curves of the patches of different thicknesses are shown in Figure 3 It can be seen from Figure 3 that the thickness of the dexmedetomidine matrix transdermal patch is related to the action time, and increasing the thickness of the transdermal patch can prolong the action time of the transdermal patch. The dexmedetomidine transdermal patch with a thickness of 25 μm reaches the drug release platform at 48 h; the patch with a thickness of 50 μm reaches the drug release platform at 72 h; and the patch with a thickness of 100 μm reaches the drug release platform at 120 h. Therefore, the dexmedetomidine patch formulation of the present application with a thickness of 25 μm-100 μm can achieve sustained release for 2-5 days.

[0341] Test Example 1 Skin reaction test of transdermal patch

[0342] Evaluation index:

[0343] Skin reaction grades include:

[0344] Grade 4: erythema, blistering and bulla formation;

[0345] Grade 3: erythema, blistering, no bulla;

[0346] Grade 2: erythema covers the entire patch area; no blistering;

[0347] Grade 1: slight erythema covers less than the entire patch area;

[0348] Grade 0: minimal or no reaction at the patch site;

[0349] Two samples of each of the formulations 1-17 were taken, and were applied to the backs of 18 depilated rats for 24 h. It was found that the products of the formulations 1-17 had no skin irritation, and the grade was 0.

[0350] Formulation stability study of Test Example 2

[0351] The samples (n=3) of the above Formulations 1-17 were subjected to the influence factor test for the related substance investigation, and the average values were taken. The impurity content limits were as follows, and the investigation results were as follows.

[0352] Table 18 Test results of related substances in the influence factor investigation of the formulation

[0353]

[0354]

[0355] As shown in the above table, under the high temperature condition for 10 days, under the high temperature condition for 30 days, and under the accelerated condition, the storage of the dexmedetomidine transdermal patch of the present application is relatively stable.

[0356] Test Example 3 Crystallization study of dexmedetomidine

[0357] The sample prepared by Formulation 13 was used to observe the long-term crystallization of the dexmedetomidine transdermal patch of the present application, and to confirm whether the dexmedetomidine would crystallize in the formulation.

[0358] The crystallization observation results of the sample after 6 months of storage are shown in Figure 4 (A is 10 times imaging, and B is 40 times imaging) As shown, by observing the crystallization condition by a polarizing microscope, the dexmedetomidine transdermal patch prepared by the present application did not produce crystallization within 6 months of long-term storage.

[0359] Test Example 4 Monitoring of mouse spontaneous activity

[0360] 1. Method

[0361] After the mice were depilated for 24 h, the mice were placed in the activity instrument for adaptive training, and after 10 min, the activity monitoring within 5 min was started, and the result was recorded as the activity at 0 h. The drug-containing patch prepared by Formulation 13 was given according to the mouse pharmacodynamics experiment scheme in Table 19, and was placed in the mouse activity instrument for monitoring of the mouse activity after administration. When the late monitoring time was reached, the mouse activity monitoring was continued, and the monitoring time points were 1 h, 3 h, 6 h, 8 h, 12 h, and 24 h.

[0362] After the 24 h monitoring was completed, the patch on the back of the mouse was removed, and the mouse activity monitoring was continued, and the monitoring time was 27 h and 30 h, and the monitoring method was the same as above.

[0363] Evaluation index: record the number of activities within 5 min.

[0364] Table 19 Mouse pharmacodynamics experiment scheme

[0365]

[0366]

[0367] 2. Experimental Results

[0368] Mouse spontaneous activity data such as Figure 5 As shown, compared with the blank control, dexmedetomidine transdermal patch can significantly reduce the activity level of mice and shows a clear dose-effect relationship, indicating that dexmedetomidine has a significant effect on improving sleep.

[0369] Experiment 5: Rat EEG and EMG Monitoring Experiment

[0370] 1. Grouping

[0371] Before administration, the experimental animals were weighed and randomly grouped according to their weight, as follows:

[0372] Table 20 Grouping of rat myocomputational electrophysiology test

[0373]

[0374] 2. Methods

[0375] Male SD rats (SPF grade) were acclimatized for 7 days in a 12-hour light-dark cycle environment (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 acetaminophen (ip, 20 mg / kg) and thiamethoxam (ip, 8 mg / kg). After anesthesia, the rats were fixed in place using a stereotaxic apparatus. After shaving and disinfection of the head, the scalp was cut open, and the four corners were clamped with hemostatic forceps to fully expose the skull. The periosteum was dissected, and the skull was cleaned with dry cotton until the surface was dry. Holes were drilled in the skull, and electrodes were implanted. Two electromyographic electrodes were inserted parallel to each other into the neck muscles and fixed at both ends with sutures to prevent their ends from contacting each other. A reference electrode was similarly inserted into the neck muscles on the opposite side and fixed. The implant was then placed subcutaneously, and the surgical wound was sutured and disinfected. Postoperatively, the rats were carefully placed in clean recovery cages in a lateral recumbent position to ensure a clear airway. They were housed individually in a shielded recovery room with a 12-hour automatic light-dark cycle: lights off at 7:00 AM and lights on at 7:00 PM. Animals received 3 days of postoperative care, and the surgical incision was treated with cephalexin powder. Gentamicin 4-8 mg / kg was administered subcutaneously, followed by subcutaneous injection of meloxicam 0.1 ml / animal for 3 consecutive days. Experiments were conducted 7-10 days after surgery, and animals were randomly grouped according to their body weight. EEG and EMG were continuously monitored for 24 hours after grouping as baseline signals.

[0376] Except for the Sham group, the skin and fascia of the back and the sole of the foot of each group of rats were taken longitudinally about 2 cm, and then sutured. After all the animals were modeled, the drug administration site of each group of rats was cleaned with an animal hair clipper, and the corresponding drug was administered (the patch was placed on the back and fixed on the skin to prevent the patch from falling off during the administration and causing administration failure). The EEG and EMG signals of the rats were monitored for 72 h, and the changes in the wake, light sleep or rapid eye movement sleep (REM) and deep sleep or non-ocular (NREM) sleep structure after the operation were analyzed.

[0377] 3. Data analysis

[0378] The raw data was collected by the DSI system Ponemah software and analyzed by the NeuroScore software. The experimental data was represented by the mean ± standard error (Mean ± S.E.M.), and the statistical analysis was performed by using the Graph Pad Prism 7.0 software and the Two-way ANOVA and One-way ANOVA, P<0.05 represented a significant difference, P<0.01 represented a very significant difference, and P<0.001 represented an extremely significant difference.

[0379] 4. Experimental results

[0380] As shown in Figure 6 A: the cumulative trend chart of the wake time of each group at each time node within 72 h after the administration of the patch; B: the cumulative trend chart of the NREM time of each group at each time node within 72 h after the administration of the patch; C: the cumulative trend chart of the REM time of each group at each time node within 72 h after the administration of the patch; N=8.

[0381] Figure 6 The experimental data showed that:

[0382] Compared with the normal group, the wake time of the rats in the drug-containing group within 72 h gradually decreased with the increase of the dose of dexmedetomidine, and there was no significant difference in the wake time within 72 h between the low-dose group and the normal group; compared with the postoperative model group, the wake time of the rats in the drug-containing patch group within 72 h was significantly reduced.

[0383] Compared with the normal group, the slow wave sleep time of the rats in the drug-containing group within 72 h gradually increased with the increase of the dose of dexmedetomidine, and there was no significant difference in the slow wave sleep time within 72 h between the low-dose group and the normal group; compared with the postoperative model group, the slow wave sleep time of the rats in the drug-containing patch group within 72 h was significantly prolonged.

[0384] Overall, the dexmedetomidine transdermal patch of the present application can effectively prolong the non-rapid eye movement sleep (NREM) time, reduce the rapid eye movement sleep (REM) time of the postoperative rats, and can very effectively improve the sleep quality. The transdermal patch of high dose has a greater influence on the sleep time of SD rats, so that the length of the wake-up period is significantly shortened, which will affect the normal circadian rhythm of the animals to a certain extent. The transdermal patch of medium and high doses can effectively improve the postoperative sleep disorder of rats for 72 hours, promote sleep quality, and has a longer effective time than the low dose (0.88 mg / kg), but the low dose group can not only significantly improve the sleep quality, but also will not change the circadian rhythm like the medium and high dose groups. The total slow wave sleep time and the total wake-up time of the low dose group within 72 hours are basically consistent with those of the normal group.

[0385] Comparative Example 1

[0386] 1. Formulation prescription

[0387] The comparative example of the present application is prepared according to the formulation 33 in the comparative document CN201480059798.5, and the specific prescription is as follows:

[0388] Dexmedetomidine 0.18g

[0389] Levulinic acid 0.11g

[0390] Acrylate pressure sensitive adhesive 32.92g

[0391] Among them, the acrylate pressure sensitive adhesive is Duro-Tak 87-2287, and the solid content is 53.8%.

[0392] The dexmedetomidine transdermal patch of the present application is prepared according to the preparation method of dexmedetomidine transdermal composition recorded in the comparative document: dexmedetomidine and pressure sensitive adhesive are mixed in an organic solvent, and then mixed to prepare a formulation. Once a uniform mixture is formed, the solution is cast on a release liner and dried at 60-80°C for 10-90 minutes. Then the single layer adhesive film is laminated to a PET backing, cut to the desired size and put into a bag. In this comparative example, levulinic acid is added to the adhesive composition.

[0393] The solvent contained in the pressure sensitive adhesive and the organic solvent added during preparation are removed during the drying process.

[0394] 2. In vitro transdermal diffusion test

[0395] Three patches prepared in Example 7, Example 4 and Comparative Example 1 of the present application are taken respectively, and the release film layer is removed for in vitro transdermal diffusion test, and the test method is the same as that of Example 12.

[0396] 3. Experimental results

[0397] The in vitro transdermal diffusion curves of the three groups of transdermal patches are shown in Figure 7 Figure 7 It can be seen that the overall trend of the diffusion rates of the three groups of transdermal patches is that Example 7 is better than Example 4, which is better than Comparative Example 1. The transdermal diffusion rate per unit area of the dexmedetomidine transdermal patch prepared in Example 7 reaches a maximum of 1.1 μg / cm 2 *h at 12 hours, which is about 2 times that of Comparative Example 1, and the patch prepared in Comparative Example 1 reaches the maximum transdermal diffusion rate per unit area at 24 h. Overall, the in vitro diffusion rate of the transdermal patch prepared in the present application is better than that of Comparative Example 1.

[0398] The above only describes the preferred embodiments of the present application, and it should be noted that for those skilled in the art, several improvements and refinements can be made without departing from the principles of the present application, and these improvements and refinements should also be considered within the scope of protection of the present application.​

Claims

1. A transdermal composition for dexmedetomidine, wherein, The composition comprises, by weight, the following components: Dexmedetomidine 0.30 - 3.00 doses Propylene glycol 0.40 - 8.00 parts Metal chelate crosslinking agent: 0.30 - 1.25 parts Pressure-sensitive adhesive 50.00 - 99.00 parts The mass ratio of propylene glycol to dexmedetomidine is (4:3) - (8:3); The pressure-sensitive adhesive is selected from one or more of the following: acrylate pressure-sensitive adhesive, polyisobutylene pressure-sensitive adhesive, silicone pressure-sensitive adhesive, styrene-isoprene-styrene hot melt pressure-sensitive adhesive, and vinyl acetate copolymer. The metal chelate crosslinking agent is selected from one or more of aluminum acetylacetonate, zirconium acetylacetonate, titanium acetylacetonate, and polytetrate; The mass ratio of the pressure-sensitive adhesive to the metal chelate crosslinking agent is (70:1) – (310:1).

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

3. The dexmedetomidine transdermal composition according to claim 2, wherein, The mass ratio of propylene glycol to dexmedetomidine in the composition is 5:

3.

4. The dexmedetomidine transdermal composition according to claim 1, wherein, The mass ratio of the pressure-sensitive adhesive to the metal chelate crosslinking agent is (70:1) – (160:1), (160:1) – (220:1), or (220:1) – (310:1); or, (160:1) – (210:1), (160:1) – (200:1), or (190:1) – (220:1); or, 160:1, 170:1, 180:1, 190:1, 200:1, 210:1, or 220:

1.

5. A dexmedetomidine transdermal patch, wherein, The dexmedetomidine transdermal patch comprises a backing layer, an adhesive layer, and an anti-adhesion release film layer in sequence; the adhesive layer is formed from the dexmedetomidine transdermal composition according to any one of claims 1 to 4.

6. The dexmedetomidine transdermal patch according to claim 5, wherein, The thickness of the adhesive layer is 25μm - 100μm.

7. A method for preparing the dexmedetomidine transdermal patch according to claim 5 or 6, comprising the following steps: A metal chelate crosslinking agent is dissolved in a solvent to obtain a metal chelate crosslinking agent solution; The pressure-sensitive adhesive was mixed with the metal chelate crosslinking agent solution to obtain a blank matrix solution; Dexmedetomidine, propylene glycol and solvent were mixed to obtain a dexmedetomidine solution; The dexmedetomidine solution was mixed with the blank matrix solution, stirred, and allowed to stand to obtain a drug-containing matrix solution. The drug-containing matrix solution is coated onto the anti-adhesion release film layer and dried to obtain a composite layer of adhesive layer and anti-adhesion release film layer; The backing layer is laminated onto the adhesive layer.

8. The preparation method according to claim 7, wherein, The solvent is selected from anhydrous ethanol and n-heptane, or a mixture of both.

9. The use of the dexmedetomidine transdermal composition according to any one of claims 1 to 4 or the dexmedetomidine transdermal patch according to claim 5 or 6 in the preparation of a pharmaceutical formulation for improving sleep disorders.

10. The application according to claim 9, wherein, The sleep disorder is one or more of the following: perioperative sleep disorder, elderly sleep disorder, and traumatic sleep disorder.

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