Dexmedetomidine film agent and preparation method thereof

Abstract

The invention relates to a dexmedetomidine film agent and a preparation method thereof, the prescription components of the dexmedetomidine film agent comprise dexmedetomidine or a pharmaceutically acceptable salt thereof and a film-forming agent, and the mass ratio of dexmedetomidine to the film-forming agent is 1: (20-200); the film-forming agent is glucose polymer ether. The glucose polymer ether can be a cellulose ether derivative and / or a starch ether derivative. When the glucose polymer ether is a starch ether derivative, the formula further comprises a plasticizer. The preparation method comprises the following steps: coating slurry to prepare a film, and drying; the slurry comprises the prescription components of the dexmedetomidine and water. And the obtained film agent product is stable in quality.

Description

[0001] This application claims priority to Chinese patent application 2024115184251 with a filing date of 2024 / 10 / 29. This application incorporates the entirety of the aforementioned Chinese patent application. TECHNICAL FIELD

[0002] The present application relates to a dexmedetomidine film and a preparation method thereof. BACKGROUND

[0003] Dexmedetomidine is a highly selective alpha2-adrenergic receptor agonist. Its mechanism of action is mainly through stimulating the alpha2-adrenergic receptors in the locus coeruleus region of the brain to inhibit norepinephrine release and reduce sympathetic nerve activity.

[0004] Currently, the dexmedetomidine dosage form on the market is an injection, which is used for general anesthesia, sedation of patients with tracheal intubation and mechanical ventilation during surgery, and sedation of patients with intubation and use of breathing machines during intensive care treatment. That is, at present, dexmedetomidine is mainly used in the form of an injection in clinical practice.

[0005] On the other hand, patent CN201980050240.3 provides a dexmedetomidine-containing film for treating agitation in humans, which deposits a high concentration of dexmedetomidine onto the surface of a "placebo" substrate. This method requires special equipment to prepare and is not convenient.

[0006] Patent CN117771220B uses microfluidic air-jet spinning technology to prepare a dexmedetomidine-containing traditional Chinese medicine polysaccharide oral film. Microfluidic air-jet spinning technology requires the use of special equipment and is not convenient. Moreover, the dissolution in a pH 6.8 phosphate buffer solution prepared according to this method is not rapid, and the 40 min cumulative dissolution rate is only about 100%. SUMMARY

[0007] To solve the problems of slow dissolution and poor stability of dexmedetomidine film in the prior art, the present application provides a dexmedetomidine or pharmaceutically acceptable salt film and a preparation method thereof. The obtained film product has stable quality.

[0008] In the present application, unless otherwise stated or inferred, each parameter, especially the parameter with "about", refers to a value within a range of ±10% of the specific value; in the viscosity item, each parameter, especially the parameter with "about", refers to a value within a range of ±20% of the specific value.

[0009] To achieve the above-mentioned purpose, the present application adopts the following technical solutions:

[0010] In a first aspect, the present invention provides a dexmedetomidine film-forming agent, the formulation comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and a film-forming agent, wherein the mass ratio of dexmedetomidine to the film-forming agent is 1:(20-200); the film-forming agent is a glucose polymer ether.

[0011] In this invention, the pharmaceutically acceptable salt of dexmedetomidine can be dexmedetomidine hydrochloride. The dosage of dexmedetomidine or its pharmaceutically acceptable salt is calculated based on the dosage of dexmedetomidine.

[0012] In this invention, the glucose polymer ether can be a cellulose ether derivative and / or a starch ether derivative. The cellulose ether derivative can be a nonionic cellulose ether derivative. The nonionic cellulose ether derivative can be selected from one or more of methylcellulose, carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, cyanoethylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, and hydroxypropylmethylcellulose, preferably hydroxypropylcellulose and / or hydroxypropylmethylcellulose. The starch ether derivative can be a nonionic starch ether derivative. The nonionic starch ether derivative can be hydroxypropyl starch.

[0013] The weight-average molecular weight of the hydroxypropyl cellulose is approximately 40,000-180,000, preferably approximately 80,000-100,000, for example, approximately 40,000, approximately 80,000, approximately 95,000, approximately 100,000, approximately 140,000, or approximately 180,000, as measured by GPC. The viscosity of the hydroxypropyl cellulose in a 2 wt% aqueous solution at 20°C is approximately 2.0-20 mPa·s, for example, 2.0-2.9 mPa·s, 3.0-5.9 mPa·s, 6.0-10.0 mPa·s, 11-12 mPa·s, or 11-20 mPa·s. The Bruce viscosity of the hydroxypropyl cellulose in a 5 wt% aqueous solution is approximately 75-400 mPa·s, for example, 75-150 mPa·s or 150-400 mPa·s. The hydroxypropyl cellulose, when formulated into a 10 wt% aqueous solution, has a Burley viscosity of approximately 150-600 mPa·s, for example, 150-300 mPa·s or 300-600 mPa·s.

[0014] The hydroxypropyl methylcellulose, when formulated as a 2 wt% aqueous solution, has a viscosity at 20°C of less than 20 mPa·s, preferably about 2.8-15 mPa·s, for example, 2.8 mPa·s, 3 mPa·s, 4 mPa·s, 5 mPa·s, 6 mPa·s, or 15 mPa·s. The degree of methoxy substitution of the hydroxypropyl methylcellulose is about 22%-29%. The degree of hydroxypropoxy substitution of the hydroxypropyl methylcellulose is about 0-10%, for example, 0, 6%, 8%, or 10%.

[0015] The degree of hydroxypropoxy substitution of the hydroxypropyl starch can be 2.0%-7.0%.

[0016] In this invention, when the glucose polymer ether is a starch ether derivative, its formulation components also include a plasticizer. The plasticizer may be sorbitol, glycerol, glyceryl acetate, propylene glycol, polyethylene glycol, triethyl citrate, etc., preferably glycerol. The mass ratio of the starch ether derivative to the plasticizer may be (260.5-261):(42.5-43.5), for example, 260:43.

[0017] In some specific embodiments of the present invention, the film-forming agent is hydroxypropyl cellulose and hydroxypropyl methyl cellulose in a mass ratio of approximately 1:1.

[0018] In certain embodiments of the present invention, the film-forming agent is entirely hydroxypropyl cellulose. For example, hydroxypropyl cellulose with a weight average molecular weight of about 80,000 and hydroxypropyl cellulose with a weight average molecular weight of about 180,000 are used in a mass ratio of 150.5:149.5.

[0019] In certain embodiments of the present invention, the film-forming agent is entirely hydroxypropyl methylcellulose. Preferably, it is in a mass ratio of (1:3) to (3:1), for example, hydroxypropyl methylcellulose prepared in a mass ratio of 75.5:225, 1:1, 149.5:151, or 225:75.5, containing hydroxypropyl methylcellulose with a viscosity of approximately 3 mPa·s at 20°C in a 2 wt% aqueous solution and hydroxypropyl methylcellulose with a viscosity of approximately 15 mPa·s in a 2 wt% aqueous solution at 20°C. Another example is hydroxypropyl methylcellulose prepared in a mass ratio of approximately 1:1, containing hydroxypropyl methylcellulose with a viscosity of approximately 5-6 mPa·s at 20°C in a 2 wt% aqueous solution and hydroxypropyl methylcellulose with a viscosity of approximately 15 mPa·s in a 2 wt% aqueous solution at 20°C.

[0020] Unless otherwise specified, the "viscosity" mentioned in this invention is measured at 20°C.

[0021] In some specific embodiments of the present invention, the film-forming agent is entirely hydroxypropyl starch, and the mass ratio of the hydroxypropyl starch to the glycerol is (260.5-261): (42.5-43.5), for example 260: 43.

[0022] In this invention, the mass ratio of dexmedetomidine to the film-forming agent can be about 1:(30-120), more preferably about 1:(40-100), and even more preferably about 1:(40-70), for example, 6:260.5, 6:261, 6:300, 6:300.19, 6:300.25, 6:300.38, 6:300.5, 6:300.94, 6:303, 4.69:301.31, 4.5:300.9, 4.5:300.3, 4.5:301.5, 4.5:302.7, 4.5:300.6, 4.5:302.1, 4.5:301.8, 4.5:300.19, 4.5: 301.69, 4.5: 300.94, 4.5: 300 or 3: 302.44.

[0023] In this invention, the formulation components of the dexmedetomidine film agent may further include pigments. The preferred mass ratio of the pigment to dexmedetomidine is about (0.5-15):1, more preferably about (0.5-3):1, and even more preferably about (0.5-1.0):1, for example, 4.2:4.5, 4.6:6, 4.8:4.5, 5.1:6, 5.6:6, 5.65:6, 6:6, 6.1:6, 7.5:4.5, 9.6:4.5, 10.2:4.5, 10.5:4.5, 10.69:4.5, 11.63:4.5, 16.59:4.5, 17.81:4.69, 17.81:6, 18:3, 18.19:6, 18.56:4.5, 44.81: 6. 63.6:4.5 or 67.2:4.5. While pigments are not essential, dexmedetomidine film-forming compositions without added pigments will be colorless and transparent, which is detrimental to use. Based on the application of dexmedetomidine film-forming compositions in the preparation of sedative drugs, it is recommended to use pigments with a calming effect on the user, such as blue pigments. Simultaneously, considering that simply using pigments on the film may result in the film remaining transparent, it is recommended to add a certain amount of white pigment, such as TiO2. The pigment can be TiO2 and / or blue and / or green pigments, for example, TiO2 and blue pigment in a mass ratio of (4.5-6.0):0.1.

[0024] In this invention, the formulation of the dexmedetomidine film-forming agent may further include a flavoring agent. The mass ratio of the flavoring agent to dexmedetomidine may be (0.5-1.0):1, for example (5-6):6. The flavoring agent may be one or more of sucrose, stevia, sucralose, xylitol, sorbitol, or mannitol, preferably sucralose.

[0025] In this invention, the formulation components of the dexmedetomidine film agent may further include fragrances and flavorings.

[0026] In this invention, the formulation of the dexmedetomidine film agent may further include cyclodextrin; the mass ratio of cyclodextrin to dexmedetomidine is preferably (1-1.5):1, for example 1.25:1.

[0027] And / or, the formulation of the dexmedetomidine film agent may further include calcium carbonate; the mass ratio of calcium carbonate to dexmedetomidine is preferably (1-10):1, for example 5:1.

[0028] In this invention, the formulation components of the dexmedetomidine film agent may not include polyethylene oxide.

[0029] In this invention, the dexmedetomidine or a pharmaceutically acceptable salt thereof may be distributed in the film-forming agent.

[0030] In this invention, the dosage form of the dexmedetomidine film preparation can be a sublingual film preparation.

[0031] In this invention, the thickness of the dexmedetomidine film agent can be about 0.02-0.06 mm, for example 0.024 mm, 0.028 mm, 0.029 mm, 0.03 mm, 0.031 mm, 0.032 mm, 0.033 mm, 0.042 mm or 0.053 mm.

[0032] In a specific embodiment of the present invention, the formulation of the dexmedetomidine film agent includes dexmedetomidine hydrochloride, hydroxypropyl cellulose tetrahydroxyl cellulose (HTP), and hydroxypropyl methylcellulose methyl cellulose (HMT); the mass ratio of dexmedetomidine, HTP, and HMT is 6:150:150; the weight-average molecular weight of HTP is approximately 100,000; and the viscosity of a 2 wt% aqueous solution of HMT prepared at 20°C is approximately 3 mPa·s.

[0033] In a specific embodiment of the present invention, the formulation components of the dexmedetomidine film agent include dexmedetomidine hydrochloride, second hydroxypropyl cellulose, and fourth hydroxypropyl methylcellulose; the mass ratio of dexmedetomidine, second hydroxypropyl cellulose, and fourth hydroxypropyl methylcellulose is 6:151.5:151.5, the weight-average molecular weight of the second hydroxypropyl cellulose is approximately 80,000, and the viscosity of the fourth hydroxypropyl methylcellulose in a 2wt% aqueous solution at 20°C is approximately 15 mPa·s.

[0034] In a specific embodiment of the present invention, the formulation of the dexmedetomidine film agent includes dexmedetomidine hydrochloride, first hydroxypropyl methylcellulose and fourth hydroxypropyl methylcellulose; the mass ratio of dexmedetomidine, first hydroxypropyl methylcellulose and fourth hydroxypropyl methylcellulose is 6:149.5:151, the viscosity of the first hydroxypropyl methylcellulose in a 2wt% aqueous solution at 20°C is about 3 mPa·s, and the viscosity of the fourth hydroxypropyl methylcellulose in a 2wt% aqueous solution at 20°C is about 15 mPa·s.

[0035] In a specific embodiment of the present invention, the formulation of the dexmedetomidine film agent includes dexmedetomidine hydrochloride, hydroxypropyl cellulose VI, and hydroxypropyl methylcellulose XI; the mass ratio of dexmedetomidine, the hydroxypropyl cellulose VI, and the hydroxypropyl methylcellulose XI is 6:150:150, the weight-average molecular weight of the hydroxypropyl cellulose VI is approximately 180,000, and the viscosity of the hydroxypropyl methylcellulose XI as a 2wt% aqueous solution at 20°C is approximately 3 mPa·s.

[0036] In a specific embodiment of the present invention, the formulation components of the dexmedetomidine film agent include dexmedetomidine hydrochloride, second hydroxypropyl cellulose, and sixth hydroxypropyl cellulose; the mass ratio of dexmedetomidine, second hydroxypropyl cellulose, and sixth hydroxypropyl cellulose is 6:150.5:149.5, the weight-average molecular weight of the second hydroxypropyl cellulose is approximately 80,000, and the weight-average molecular weight of the sixth hydroxypropyl cellulose is approximately 180,000.

[0037] In a specific embodiment of the present invention, the formulation components of the dexmedetomidine film agent include dexmedetomidine hydrochloride, first hydroxypropyl starch and glycerin; the mass ratio of dexmedetomidine, first hydroxypropyl starch and glycerin is 6:260.5:43.5, the degree of hydroxypropoxy substitution of the first hydroxypropyl starch is 2.0%-7.0%, and the labeled viscosity is medium viscosity grade.

[0038] In a specific embodiment of the present invention, the formulation components of the dexmedetomidine film agent include dexmedetomidine hydrochloride, second hydroxypropyl starch and glycerin; the mass ratio of dexmedetomidine, second hydroxypropyl starch and glycerin is 6:261:42.5, the degree of hydroxypropoxy substitution of the second hydroxypropyl starch is 2.0%-7.0%, and the labeled viscosity is a low viscosity grade.

[0039] In a specific embodiment of the present invention, the formulation components of the dexmedetomidine film agent include dexmedetomidine hydrochloride, first hydroxypropyl methylcellulose, and fourth hydroxypropyl methylcellulose; the mass ratio of dexmedetomidine, first hydroxypropyl methylcellulose, and fourth hydroxypropyl methylcellulose is 6:75.5:225, the viscosity of a 2wt% aqueous solution of first hydroxypropyl methylcellulose at 20°C is approximately 3 mPa·s, and the viscosity of a 2wt% aqueous solution of fourth hydroxypropyl methylcellulose at 20°C is approximately 15 mPa·s.

[0040] In a specific embodiment of the present invention, the formulation of the dexmedetomidine film agent includes dexmedetomidine hydrochloride, first hydroxypropyl methylcellulose, and fourth hydroxypropyl methylcellulose; the mass ratio of dexmedetomidine, first hydroxypropyl methylcellulose, and fourth hydroxypropyl methylcellulose is 6:225:75.5, the viscosity of a 2wt% aqueous solution of first hydroxypropyl methylcellulose at 20°C is approximately 3 mPa·s, and the viscosity of a 2wt% aqueous solution of fourth hydroxypropyl methylcellulose at 20°C is approximately 15 mPa·s.

[0041] In a specific embodiment of the present invention, the formulation of the dexmedetomidine film agent includes dexmedetomidine hydrochloride, second hydroxypropyl methylcellulose, and fourth hydroxypropyl methylcellulose; the mass ratio of dexmedetomidine, second hydroxypropyl methylcellulose, and fourth hydroxypropyl methylcellulose is 6:150:150; the viscosity of a 2wt% aqueous solution of second hydroxypropyl methylcellulose at 20°C is approximately 5 mPa·s; and the viscosity of a 2wt% aqueous solution of fourth hydroxypropyl methylcellulose at 20°C is approximately 15 mPa·s.

[0042] In a specific embodiment of the present invention, the formulation components of the dexmedetomidine film agent include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose (HMC), and hydroxypropyl methylcellulose (HMC); the mass ratio of dexmedetomidine, HMC, and HMC is 6:150:150; the viscosity of a 2 wt% aqueous solution of HMC prepared at 20°C is approximately 6 mPa·s; and the viscosity of a 2 wt% aqueous solution of HMC prepared at 20°C is approximately 15 mPa·s.

[0043] In a specific embodiment of the present invention, the formulation components of the dexmedetomidine film agent include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose (HMC), and hydroxypropyl cellulose (HMC); the mass ratio of dexmedetomidine, HMC, and HMC is 4.5:150.3:150.6; the viscosity of the 2wt% aqueous solution of HMC prepared at 20°C is 15 mPa·s; and the weight-average molecular weight of HMC is 100,000.

[0044] In a specific embodiment of the present invention, the formulation components of the dexmedetomidine film agent include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose (HMC), and hydroxypropyl cellulose (HMC); the mass ratio of dexmedetomidine, HMC, and HMC is 4.5:150:150.3; the viscosity of the 2wt% aqueous solution of HMC prepared at 20°C is 15 mPa·s; and the weight-average molecular weight of HMC is 100,000.

[0045] In a specific embodiment of the present invention, the formulation components of the dexmedetomidine film agent include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose (HMC), and hydroxypropyl cellulose (HMC); the mass ratio of dexmedetomidine, HMC, and HMC is 4.5:150.9:150.6; the viscosity of the 2wt% aqueous solution of HMC prepared at 20°C is 15 mPa·s; and the weight-average molecular weight of HMC is 100,000.

[0046] In a specific embodiment of the present invention, the formulation components of the dexmedetomidine film agent include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose (HMC), and hydroxypropyl cellulose (HMC); the mass ratio of dexmedetomidine, HMC, and HMC is 4.5:151.5:151.2; the viscosity of the 2wt% aqueous solution of HMC prepared at 20°C is 15 mPa·s; and the weight-average molecular weight of HMC is 100,000.

[0047] In a specific embodiment of the present invention, the formulation components of the dexmedetomidine film agent include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose (HMC), and hydroxypropyl cellulose (HMC); the mass ratio of dexmedetomidine, HMC, and HMC is 4.5:150.6:150; the viscosity of the 2wt% aqueous solution of HMC prepared at 20°C is 15 mPa·s; and the weight-average molecular weight of HMC is 100,000.

[0048] In a specific embodiment of the present invention, the formulation components of the dexmedetomidine film agent include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose (HMC), and hydroxypropyl cellulose (HMC); the mass ratio of dexmedetomidine, HMC, and HMC is 4.5:151.8:150.3; the viscosity of the 2wt% aqueous solution of HMC prepared at 20°C is 15 mPa·s; and the weight-average molecular weight of HMC is 100,000.

[0049] In a specific embodiment of the present invention, the formulation components of the dexmedetomidine film agent include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose (HMC), and hydroxypropyl cellulose (HMC); the mass ratio of dexmedetomidine, HMC, and HMC is 4.5:151.5:150.3; the viscosity of the 2wt% aqueous solution of HMC prepared at 20°C is 15 mPa·s; and the weight-average molecular weight of HMC is 100,000.

[0050] In a specific embodiment of the present invention, the formulation components of the dexmedetomidine film agent include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose (HMC), and hydroxypropyl cellulose (HMC); the mass ratio of dexmedetomidine, HMC, and HMC is 4.5:150.19:150; the viscosity of the 2wt% aqueous solution of HMC prepared at 20°C is 15 mPa·s; and the weight-average molecular weight of HMC is 100,000.

[0051] In a specific embodiment of the present invention, the formulation components of the dexmedetomidine film agent include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose (HMC), and hydroxypropyl cellulose (HMC); the mass ratio of dexmedetomidine, HMC, and HMC is 4.5:151.13:150.56; the viscosity of the 2wt% aqueous solution of HMC prepared at 20°C is 15 mPa·s; and the weight-average molecular weight of HMC is 100,000.

[0052] In a specific embodiment of the present invention, the formulation components of the dexmedetomidine film agent include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose (HMC), and hydroxypropyl cellulose (HMC); the mass ratio of dexmedetomidine, HMC, and HMC is 4.5:150.94:150; the viscosity of the 2wt% aqueous solution of HMC prepared at 20°C is 15 mPa·s; and the weight-average molecular weight of HMC is 100,000.

[0053] In a specific embodiment of the present invention, the formulation components of the dexmedetomidine film agent include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose (HMC), and hydroxypropyl cellulose (HMC); the mass ratio of dexmedetomidine, HMC, and HMC is 4.5:150.15:150.45; the viscosity of the 2wt% aqueous solution of HMC is 15 mPa·s at 20°C; and the weight-average molecular weight of HMC is 100,000.

[0054] In a specific embodiment of the present invention, the formulation of the dexmedetomidine film agent includes dexmedetomidine hydrochloride, hydroxypropyl methylcellulose (HMC), and hydroxypropyl cellulose (HMC); the mass ratio of dexmedetomidine, HMC, and HMC is 4.5:150:150; the viscosity of the 2wt% aqueous solution of HMC prepared at 20°C is 15 mPa·s; and the weight-average molecular weight of HMC is 100,000.

[0055] In a specific embodiment of the present invention, the formulation components of the dexmedetomidine film agent include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose (HMC), and hydroxypropyl cellulose (HMC); the mass ratio of dexmedetomidine, HMC, and HMC is 3:150.94:151.5; the viscosity of the 2wt% aqueous solution of HMC prepared at 20°C is 15 mPa·s; and the weight-average molecular weight of HMC is 100,000.

[0056] In a specific embodiment of the present invention, the formulation components of the dexmedetomidine film agent include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose (HMC), and hydroxypropyl cellulose (HMC); the mass ratio of dexmedetomidine, HMC, and HMC is 6:150:150.94; the viscosity of the 2wt% aqueous solution of HMC prepared at 20°C is 15 mPa·s; and the weight-average molecular weight of HMC is 100,000.

[0057] In a specific embodiment of the present invention, the formulation components of the dexmedetomidine film agent include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose (HMC), and hydroxypropyl cellulose (HMC); the mass ratio of dexmedetomidine, HMC, and HMC is 4.69: 150.56: 150.75; the viscosity of the 2wt% aqueous solution of HMC is 15 mPa·s at 20°C; and the weight-average molecular weight of HMC is 100,000.

[0058] In a specific embodiment of the present invention, the formulation components of the dexmedetomidine film agent include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose (HMC), and hydroxypropyl cellulose (HMC); the mass ratio of dexmedetomidine, HMC, and HMC is 6:150:150.19; the viscosity of the 2wt% aqueous solution of HMC prepared at 20°C is 15 mPa·s; and the weight-average molecular weight of HMC is 100,000.

[0059] In a specific embodiment of the present invention, the formulation components of the dexmedetomidine film agent include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose IV, and hydroxypropyl methylcellulose II; the mass ratio of dexmedetomidine, the hydroxypropyl methylcellulose IV, and the hydroxypropyl methylcellulose II is 6:150.19:150; the viscosity of the hydroxypropyl methylcellulose IV in a 2wt% aqueous solution at 20°C is 15 mPa·s; and the viscosity of the hydroxypropyl methylcellulose II in a 2wt% aqueous solution at 20°C is 5 mPa·s.

[0060] In a specific embodiment of the present invention, the formulation components of the dexmedetomidine film agent include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose (HMC), and hydroxypropyl cellulose (HMC); the mass ratio of dexmedetomidine, HMC, and HMC is 6:150.19:150.19; the viscosity of the 2wt% aqueous solution of HMC prepared at 20°C is 15 mPa·s; and the weight-average molecular weight of HMC is 100,000.

[0061] In a specific embodiment of the present invention, the formulation components of the dexmedetomidine film agent include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose (HMC), and hydroxypropyl cellulose (HMC); the mass ratio of dexmedetomidine, the HMC, and the HMC is 6:150:150; the hydroxypropyl methylcellulose, when prepared as a 2 wt% aqueous solution, has a viscosity of 15 mPa·s at 20°C; and the weight-average molecular weight of the HMC is 100,000. In a second aspect, the present invention provides a method for preparing the dexmedetomidine film agent as described above, comprising the following steps: coating a slurry to form a film and drying it; the slurry comprises the formulation components of dexmedetomidine and water.

[0062] In this invention, the mass ratio of dexmedetomidine to water in the slurry can be approximately 1:(125-250).

[0063] In this invention, the solid content of the slurry can be about 20wt%-31wt%, for example 20wt%, 20.23wt%, 20.24wt%, 20.25wt%, 20.31wt%, 20.34wt%, 20.36wt%, 20.37wt%, 20.50wt%, 29.93wt%, and 30.01wt%.

[0064] In this invention, the slurry can be prepared by the following steps:

[0065] S1. Under stirring, the formulation components other than the film-forming agent are added to a portion of water to obtain a mixture;

[0066] S2. While stirring, the film-forming agent and the remaining water are added to the mixture.

[0067] In this invention, the film thickness of the coating film can be about 200-500 μm, for example 200 μm, 300 μm, 400 μm or 500 μm.

[0068] In this invention, the coating speed for film formation can be 5-10 cm / min.

[0069] In this invention, the drying temperature can be about 40-90°C, for example 40-60°C or 80-90°C.

[0070] In this invention, the drying time can be approximately 20-40 minutes.

[0071] In this invention, in step S1, the amount of water used can be about half of all the water.

[0072] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0073] The reagents and raw materials used in this invention are all commercially available.

[0074] The positive and progressive effects of this invention are as follows:

[0075] (1) The dexmedetomidine film-forming agent of the present invention has good stability and the impurity content remains low after long-term storage;

[0076] (2) The dexmedetomidine film-forming agent of the present invention has good dissolution characteristics;

[0077] (3) The dexmedetomidine film-forming agent of the present invention has a uniform drug distribution;

[0078] (4) The dexmedetomidine film-forming agent of the present invention has good toughness;

[0079] (5) The dexmedetomidine film-forming agent of the present invention is easy to prepare. Attached Figure Description

[0080] Figure 1 The data curves for pharmacokinetic testing in Example 5 are shown. Detailed Implementation

[0081] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0082] In the following examples and comparative examples, the amount of dexmedetomidine or its pharmaceutically acceptable salts used was calculated based on dexmedetomidine. Specific parameters for some of the raw materials and procedures used are listed below:

[0083] Hydroxypropyl cellulose (HPC ELF), manufacturer: Ashland, labeled weight-average molecular weight 40,000, with a Burley viscosity of 150-300 mPa·s when prepared as a 10wt% aqueous solution.

[0084] Hydroxypropyl cellulose (HPC EF), manufacturer: Ashland, labeled weight-average molecular weight 80,000, with a Brussels viscosity of 300-600 mPa·s when prepared as a 10wt% aqueous solution.

[0085] Hydroxypropyl cellulose (HPC SL), manufacturer: Cao Da, labeled weight average molecular weight is 100,000, and the viscosity of a 2wt% aqueous solution at 20℃ is 3.0-5.9 mPa·s.

[0086] Hydroxypropyl cellulose (HPC JF), manufacturer: Ashland, labeled weight-average molecular weight is 140,000, and the Burley viscosity of a 5wt% aqueous solution is 150-400 mPa·s.

[0087] Hydroxypropyl cellulose (HPC LM), manufacturer: Cao Da, labeled weight-average molecular weight is 180,000, and the viscosity of a 2wt% aqueous solution at 20℃ is 11-20 mPa·s.

[0088] Hydroxypropyl cellulose (HPC GF), manufacturer: Ashland, labeled weight-average molecular weight 370,000, viscosity of 2wt% aqueous solution is 150-400 mPa·s.

[0089] Hydroxypropyl methylcellulose (HPMC E3), manufactured by Dow Chemical, has a viscosity of approximately 3 mPa·s at 20°C when prepared as a 2wt% aqueous solution, with a methoxy degree of substitution of 29% and a hydroxypropoxy degree of substitution of 10%.

[0090] Hydroxypropyl methylcellulose (HPMC E5), manufactured by Dow Chemical, has a viscosity of approximately 5 mPa·s at 20°C when prepared as a 2wt% aqueous solution, with a methoxy degree of substitution of 29% and a hydroxypropoxy degree of substitution of 10%.

[0091] Hydroxypropyl methylcellulose (HPMC E6), manufactured by Dow Chemical, has a viscosity of approximately 6 mPa·s at 20°C when prepared as a 2wt% aqueous solution, with a methoxy degree of substitution of 29% and a hydroxypropoxy degree of substitution of 10%.

[0092] Hydroxypropyl methylcellulose (HPMC E15), manufactured by Dow Chemical, has a viscosity of approximately 15 mPa·s at 20°C when prepared as a 2wt% aqueous solution, with a methoxy degree of substitution of 29% and a hydroxypropoxy degree of substitution of 10%.

[0093] Hydroxypropyl pea starch LYCOAT® RS 720, manufactured by Roquette, with a degree of hydroxypropoxy substitution ranging from 2.0% to 7.0%, and a medium viscosity grade.

[0094] Hydroxypropyl pea starch LYCOAT® RS 780, manufactured by Roquette, with a degree of hydroxypropoxy substitution ranging from 2.0% to 7.0%, and a low viscosity grade.

[0095] Polyoxyethylene 205, manufacturer: Dow Chemical, grade 205, labeled weight-average molecular weight is 600,000.

[0096] Cyclodextrin, manufacturer: Xi'an Deli Biochemical Co., Ltd., oral grade.

[0097] Example 1-200

[0098] The formulation of dexmedetomidine film-forming agents is shown in Table 1-1:

[0099] Table 1-1

[0100]

[0101] The preparation method of dexmedetomidine film-forming agent is as follows:

[0102] Prepare approximately 1250 portions of purified water according to the prescription ratio. Take approximately 600 portions of purified water and add dexmedetomidine hydrochloride, sucralose, blue pigment, and TiO2 while stirring to dissolve or disperse them.

[0103] Then, while stirring, add the film-forming agents: hydroxypropyl cellulose (HPC SL) + hydroxypropyl methyl cellulose (HPMC E15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is about 20 wt%.

[0104] The prepared solution was allowed to stand to defoam, then coated to form a film with a thickness of 200 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. Finally, it was cut and packaged according to specifications.

[0105] Example 1-300

[0106] The difference from Examples 1-200 is that in this example, the film thickness is 300 μm.

[0107] Example 1-400

[0108] The difference from Examples 1-200 is that in this example, the film thickness is 400 μm.

[0109] Example 1-500

[0110] The difference from Examples 1-200 is that in this example, the film thickness is 500 μm.

[0111] Example 2

[0112] The formulation of dexmedetomidine film-forming agents is shown in Table 1-2:

[0113] Table 1-2

[0114]

[0115] The preparation method of dexmedetomidine film-forming agent is as follows:

[0116] Prepare approximately 1243.5 parts of purified water according to the prescription ratio. Take approximately 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, blue pigment, and TiO2 while stirring to dissolve or disperse them.

[0117] Then, while stirring, add the film-forming agents: hydroxypropyl cellulose (HPC EF) + hydroxypropyl methyl cellulose (HPMC E15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is about 20.50 wt%.

[0118] The prepared solution was allowed to stand to defoam, then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. Finally, it was cut and packaged according to specifications.

[0119] Example 3

[0120] The formulation of dexmedetomidine film-forming agents is shown in Table 1-3:

[0121] Table 1-3

[0122]

[0123] The preparation method of dexmedetomidine film-forming agent is as follows:

[0124] Prepare approximately 1240 parts of purified water according to the prescription ratio. Take approximately 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, blue pigment, and TiO2 while stirring to dissolve or disperse them.

[0125] Then, while stirring, add the film-forming agents: hydroxypropyl methylcellulose (HPMC E3) + hydroxypropyl methylcellulose (HPMCE15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is approximately 20.36 wt%.

[0126] The prepared solution was allowed to stand to defoam, then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. Finally, it was cut and packaged according to specifications.

[0127] Example 4

[0128] The formulation of dexmedetomidine film-forming agents is shown in Table 1-4:

[0129] Table 1-4

[0130]

[0131] The preparation method of dexmedetomidine film-forming agent is as follows:

[0132] Prepare approximately 1244 parts of purified water according to the prescription ratio. Take approximately 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, blue pigment, and TiO2 while stirring to dissolve or disperse them.

[0133] Then, while stirring, add the film-forming agents: hydroxypropyl cellulose (HPC LM) + hydroxypropyl methyl cellulose (HPMC E3) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is approximately 20.24 wt%.

[0134] The prepared solution was allowed to stand to defoam, then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. Finally, it was cut and packaged according to specifications.

[0135] Example 5

[0136] The formulation of dexmedetomidine film-forming agents is shown in Table 1-5:

[0137] Table 1-5

[0138]

[0139] The preparation method of dexmedetomidine film-forming agent is as follows:

[0140] Prepare approximately 1239.5 parts of purified water according to the prescription ratio. Take approximately 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, blue pigment, and TiO2 while stirring to dissolve or disperse them.

[0141] Then, while stirring, add the film-forming agents: hydroxypropyl cellulose (HPC EF) + hydroxypropyl cellulose (HPC LM) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is approximately 20.37 wt%.

[0142] The prepared solution was allowed to stand to defoam, then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. Finally, it was cut and packaged according to specifications.

[0143] Example 6

[0144] The formulation of dexmedetomidine film-forming agents is shown in Table 1-6:

[0145] Table 1-6

[0146]

[0147] The preparation method of dexmedetomidine film-forming agent is as follows:

[0148] Prepare approximately 750 parts of purified water according to the prescription ratio. Take approximately 300 parts of purified water and add dexmedetomidine hydrochloride, sucralose, blue pigment, and TiO2 while stirring to dissolve or disperse them.

[0149] Then, while stirring, add the film-forming agent hydroxypropyl pea starch (LYCOAT® RS720), glycerol, and the remaining purified water to dissolve and disperse it evenly, with a final solid content of approximately 30.01 wt%.

[0150] The prepared solution was allowed to stand to defoam, then coated to form a film with a thickness of 200 μm at a coating speed of 5 cm / min. The film was then dried at 40-60℃ for 20-40 min. Finally, it was cut and packaged according to specifications.

[0151] Example 7

[0152] The formulation of dexmedetomidine film-forming agents is shown in Table 1-7:

[0153] Table 1-7

[0154]

[0155] The preparation method of dexmedetomidine film-forming agent is as follows:

[0156] Prepare approximately 753 portions of purified water according to the prescription ratio. Take approximately 300 portions of purified water and add dexmedetomidine hydrochloride, sucralose, blue pigment, and TiO2 while stirring to dissolve or disperse them.

[0157] Then, while stirring, add the film-forming agent hydroxypropyl pea starch (LYCOAT® RS780), glycerol, and the remaining purified water to dissolve and disperse it evenly, with a final solid content of approximately 29.93 wt%.

[0158] The prepared solution was allowed to stand to defoam, then coated to form a film with a thickness of 200 μm at a coating speed of 5 cm / min. The film was then dried at 40-60℃ for 20-40 min. Finally, it was cut and packaged according to specifications.

[0159] Example 8

[0160] The formulation of dexmedetomidine film-forming agents is shown in Table 1-8:

[0161] Table 1-8

[0162]

[0163] The preparation method of dexmedetomidine film-forming agent is as follows:

[0164] Prepare approximately 1252.5 parts of purified water according to the prescription ratio. Take approximately 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, blue pigment, and TiO2 while stirring to dissolve or disperse them.

[0165] Then, while stirring, add the film-forming agents: hydroxypropyl methylcellulose (HPMC E3) + hydroxypropyl methylcellulose (HPMCE15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is approximately 20.23 wt%.

[0166] The prepared solution was allowed to stand to defoam, then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. Finally, it was cut and packaged according to specifications.

[0167] Example 9

[0168] The formulation of dexmedetomidine film-forming agents is shown in Table 1-9:

[0169] Table 1-9

[0170]

[0171] The preparation method of dexmedetomidine film-forming agent is as follows:

[0172] Prepare approximately 1251 parts of purified water according to the prescription ratio. Take approximately 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, blue pigment, and TiO2 while stirring to dissolve or disperse them.

[0173] Then, while stirring, add the film-forming agents: hydroxypropyl methylcellulose (HPMC E3) + hydroxypropyl methylcellulose (HPMCE15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is about 20.25 wt%.

[0174] The prepared solution was allowed to stand to defoam, then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. Finally, it was cut and packaged according to specifications.

[0175] Example 10

[0176] The formulation of dexmedetomidine film-forming agents is shown in Table 1-10:

[0177] Table 1-10

[0178]

[0179] The preparation method of dexmedetomidine film-forming agent is as follows:

[0180] Prepare approximately 1250 portions of purified water according to the prescription ratio. Take approximately 600 portions of purified water and add dexmedetomidine hydrochloride, sucralose, blue pigment, and TiO2 while stirring to dissolve or disperse them.

[0181] Then, while stirring, add the film-forming agents: hydroxypropyl methylcellulose (HPMC E5) + hydroxypropyl methylcellulose (HPMCE15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is about 20.31 wt%.

[0182] The prepared solution was allowed to stand to defoam, then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. Finally, it was cut and packaged according to specifications.

[0183] Example 11

[0184] The formulation of dexmedetomidine film-forming agents is shown in Table 1-11:

[0185] Table 1-11

[0186]

[0187] The preparation method of dexmedetomidine film-forming agent is as follows:

[0188] Prepare approximately 1252 portions of purified water according to the prescription ratio. Take approximately 600 portions of purified water and add dexmedetomidine hydrochloride, sucralose, blue pigment, and TiO2 while stirring to dissolve or disperse them.

[0189] Then, while stirring, add the film-forming agents: hydroxypropyl methylcellulose (HPMC E6) + hydroxypropyl methylcellulose (HPMCE15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is approximately 20.34 wt%.

[0190] The prepared solution was allowed to stand to defoam, then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. Finally, it was cut and packaged according to specifications.

[0191] Example 12

[0192] The formulation of dexmedetomidine film-forming solution is shown in the table below:

[0193]

[0194] The preparation method of dexmedetomidine film-forming agent is as follows:

[0195] Prepare approximately 1208.7 parts of purified water according to the prescription ratio. Take approximately 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, blue pigment, and TiO2 while stirring to dissolve or disperse them.

[0196] Then, while stirring, add the film-forming agents: hydroxypropyl cellulose (HPC SL) + hydroxypropyl methyl cellulose (HPMC E15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is approximately 20.86 wt%.

[0197] The prepared solution was allowed to stand to defoam, and then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. The resulting film was light blue and was cut and packaged according to specifications.

[0198] Example 13

[0199] The formulation of dexmedetomidine film-forming solution is shown in the table below:

[0200]

[0201] The preparation method of dexmedetomidine film-forming agent is as follows:

[0202] Prepare approximately 1202.4 parts of purified water according to the prescription ratio. Take approximately 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, and blue pigment while stirring to dissolve or disperse them.

[0203] Then, while stirring, add the film-forming agents: hydroxypropyl cellulose (HPC SL) + hydroxypropyl methyl cellulose (HPMC E15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is approximately 20.44 wt%.

[0204] The prepared solution was allowed to stand to defoam, then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. The resulting film was transparent and essentially colorless, and was cut and packaged according to specifications.

[0205] Example 14

[0206] The formulation of dexmedetomidine film-forming solution is shown in the table below:

[0207]

[0208] The preparation method of dexmedetomidine film-forming agent is as follows:

[0209] Prepare approximately 1220.4 parts of purified water according to the prescription ratio. Take approximately 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, and blue pigment while stirring to dissolve or disperse them.

[0210] Then, while stirring, add the film-forming agents: hydroxypropyl cellulose (HPC SL) + hydroxypropyl methyl cellulose (HPMC E15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is approximately 20.58 wt%.

[0211] The prepared solution was allowed to stand to defoam, then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. The resulting film was transparent, pale blue, and nearly colorless, and was cut and packaged according to specifications.

[0212] Example 15

[0213] The formulation of dexmedetomidine film-forming solution is shown in the table below:

[0214]

[0215] The preparation method of dexmedetomidine film-forming agent is as follows:

[0216] Prepare approximately 1203.3 parts purified water according to the prescription ratio. Take approximately 600 parts purified water and add dexmedetomidine hydrochloride, sucralose, and blue pigment while stirring to dissolve or disperse them.

[0217] Then, while stirring, add the film-forming agents: hydroxypropyl cellulose (HPC SL) + hydroxypropyl methyl cellulose (HPMC E15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is approximately 23.72 wt%.

[0218] The prepared solution was allowed to stand to defoam, then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. The resulting film was transparent and light blue, and was cut and packaged according to specifications.

[0219] Example 16

[0220] The formulation of dexmedetomidine film-forming solution is shown in the table below:

[0221]

[0222] The preparation method of dexmedetomidine film-forming agent is as follows:

[0223] Prepare approximately 1212.6 parts of purified water according to the prescription ratio. Take approximately 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, and green pigment while stirring to dissolve or disperse them.

[0224] Then, while stirring, add the film-forming agents: hydroxypropyl cellulose (HPC SL) + hydroxypropyl methyl cellulose (HPMC E15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is approximately 20.35 wt%.

[0225] The prepared solution was allowed to stand to defoam, then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. The resulting film was transparent and essentially colorless, and was cut and packaged according to specifications.

[0226] Example 17

[0227] The formulation of dexmedetomidine film-forming solution is shown in the table below:

[0228]

[0229] The preparation method of dexmedetomidine film-forming agent is as follows:

[0230] Prepare approximately 1201.5 parts of purified water according to the prescription ratio. Take approximately 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, and green pigment while stirring to dissolve or disperse them.

[0231] Then, while stirring, add the film-forming agents: hydroxypropyl cellulose (HPC SL) + hydroxypropyl methyl cellulose (HPMC E15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is approximately 20.88 wt%.

[0232] The prepared solution was allowed to stand to defoam, then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. The resulting film was transparent, pale green, and nearly colorless, and was cut and packaged according to specifications.

[0233] Example 18

[0234] The formulation of dexmedetomidine film-forming solution is shown in the table below:

[0235]

[0236] The preparation method of dexmedetomidine film-forming agent is as follows:

[0237] Prepare approximately 1200.9 parts of purified water according to the prescription ratio. Take approximately 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, and green pigment while stirring to dissolve or disperse them.

[0238] Then, while stirring, add the film-forming agents: hydroxypropyl cellulose (HPC SL) + hydroxypropyl methyl cellulose (HPMC E15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is about 23.55 wt%.

[0239] The prepared solution was allowed to stand to defoam, then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. The resulting film was transparent and light green (weaker than blue), and was cut and packaged according to specifications.

[0240] Example 19

[0241] The formulation of dexmedetomidine film-forming solution is shown in the table below:

[0242]

[0243] The preparation method of dexmedetomidine film-forming agent is as follows:

[0244] Prepare approximately 1201.13 parts of purified water according to the prescription ratio. Take approximately 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, blue pigment, and TiO2 while stirring to dissolve or disperse them.

[0245] Then, while stirring, add the film-forming agents: hydroxypropyl cellulose (HPC SL) + hydroxypropyl methyl cellulose (HPMC E15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is approximately 20.85 wt%.

[0246] The prepared solution was allowed to stand to defoam, then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. The resulting film was transparent with almost no base color, and the blue hue was generally uniform. It was then cut and packaged according to specifications.

[0247] Example 20

[0248] The formulation of dexmedetomidine film-forming solution is shown in the table below:

[0249]

[0250] The preparation method of dexmedetomidine film-forming agent is as follows:

[0251] Prepare approximately 1201.13 parts of purified water according to the prescription ratio. Take approximately 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, blue pigment, and TiO2 while stirring to dissolve or disperse them.

[0252] Then, while stirring, add the film-forming agents: hydroxypropyl cellulose (HPC SL) + hydroxypropyl methyl cellulose (HPMC E15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is approximately 20.87 wt%.

[0253] The prepared solution was allowed to stand to defoam, then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. The resulting film was transparent with almost no base color, and the blue hue was generally uniform. It was then cut and packaged according to specifications.

[0254] Example 21

[0255] The formulation of dexmedetomidine film-forming solution is shown in the table below:

[0256]

[0257] The preparation method of dexmedetomidine film-forming agent is as follows:

[0258] Prepare approximately 1204.5 parts of purified water according to the prescription ratio. Take approximately 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, blue pigment, and TiO2 while stirring to dissolve or disperse them.

[0259] Then, while stirring, add the film-forming agents: hydroxypropyl cellulose (HPC SL) + hydroxypropyl methyl cellulose (HPMC E15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is approximately 21.20 wt%.

[0260] The prepared solution was allowed to stand to defoam, and then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. The resulting film was light blue and was cut and packaged according to specifications.

[0261] Example 22

[0262] The formulation of dexmedetomidine film-forming solution is shown in the table below:

[0263]

[0264] The preparation method of dexmedetomidine film-forming agent is as follows:

[0265] Prepare approximately 1212.75 parts of purified water according to the prescription ratio. Take approximately 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, blue pigment, and TiO2 while stirring to dissolve or disperse them.

[0266] Then, while stirring, add the film-forming agents: hydroxypropyl cellulose (HPC SL) + hydroxypropyl methyl cellulose (HPMC E15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is approximately 20.49 wt%.

[0267] The prepared solution was allowed to stand to defoam, then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. The resulting film was transparent with almost no base color, and the blue hue was generally uniform. It was then cut and packaged according to specifications.

[0268] Example 23

[0269] The formulation of dexmedetomidine film-forming solution is shown in the table below:

[0270]

[0271] The preparation method of dexmedetomidine film-forming agent is as follows:

[0272] Prepare approximately 1200.9 parts of purified water according to the prescription ratio. Take approximately 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, blue pigment, and TiO2 while stirring to dissolve or disperse them.

[0273] Then, while stirring, add the film-forming agents: hydroxypropyl cellulose (HPC SL) + hydroxypropyl methyl cellulose (HPMC E15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is about 21.1 wt%.

[0274] The prepared solution was allowed to stand to defoam, then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. The resulting film was transparent, almost colorless, and had a consistent shade of blue. It was then cut and packaged according to specifications.

[0275] Example 24

[0276] The formulation of dexmedetomidine film-forming solution is shown in the table below:

[0277]

[0278] The preparation method of dexmedetomidine film-forming agent is as follows:

[0279] Prepare approximately 1204.13 parts of purified water according to the prescription ratio. Take approximately 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, blue pigment, and TiO2 while stirring to dissolve or disperse them.

[0280] Then, while stirring, add the film-forming agents: hydroxypropyl cellulose (HPC SL) + hydroxypropyl methyl cellulose (HPMC E15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is approximately 21.17 wt%.

[0281] The prepared solution was allowed to stand to defoam, and then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. The resulting film was light blue and was cut and packaged according to specifications.

[0282] Example 25

[0283] The formulation of dexmedetomidine film-forming solution is shown in the table below:

[0284]

[0285] The preparation method of dexmedetomidine film-forming agent is as follows:

[0286] Prepare approximately 1212.75 parts of purified water according to the prescription ratio. Take approximately 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, blue pigment, and TiO2 while stirring to dissolve or disperse them.

[0287] Then, while stirring, add the film-forming agents: hydroxypropyl cellulose (HPC SL) + hydroxypropyl methyl cellulose (HPMC E15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is approximately 21.14 wt%.

[0288] The prepared solution was allowed to stand to defoam, and then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. The resulting film was light blue and was cut and packaged according to specifications.

[0289] Example 26

[0290] The formulation of dexmedetomidine film-forming solution is shown in the table below:

[0291]

[0292] The preparation method of dexmedetomidine film-forming agent is as follows:

[0293] Prepare approximately 1206.75 parts of purified water according to the prescription ratio. Take approximately 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, blue pigment, and TiO2 while stirring to dissolve or disperse them.

[0294] Then, while stirring, add the film-forming agents: hydroxypropyl cellulose (HPC SL) + hydroxypropyl methyl cellulose (HPMC E15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is approximately 21.16 wt%.

[0295] The prepared solution was allowed to stand to defoam, and then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. The resulting film was light blue and was cut and packaged according to specifications.

[0296] Example 27

[0297] The formulation of dexmedetomidine film-forming solution is shown in the table below:

[0298]

[0299] The preparation method of dexmedetomidine film-forming agent is as follows:

[0300] Prepare approximately 1200.19 parts of purified water according to the prescription ratio. Take approximately 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, blue pigment, and TiO2 while stirring to dissolve or disperse them.

[0301] Then, while stirring, add the film-forming agents: hydroxypropyl cellulose (HPC SL) + hydroxypropyl methyl cellulose (HPMC E15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is approximately 21.26 wt%.

[0302] The prepared solution was allowed to stand to defoam, and then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. The resulting film was light blue and was cut and packaged according to specifications.

[0303] Example 28

[0304] The formulation of dexmedetomidine film-forming solution is shown in the table below:

[0305]

[0306] The preparation method of dexmedetomidine film-forming agent is as follows:

[0307] Prepare approximately 1200.19 parts of purified water according to the prescription ratio. Take approximately 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, blue pigment, and TiO2 while stirring to dissolve or disperse them.

[0308] Then, while stirring, add the film-forming agents: hydroxypropyl methylcellulose (HPMC E5) + hydroxypropyl methylcellulose (HPMCE15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is approximately 21.26 wt%.

[0309] The prepared solution was allowed to stand to defoam, and then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. The resulting film was light blue and was cut and packaged according to specifications.

[0310] Example 29

[0311] The formulation of dexmedetomidine film-forming solution is shown in the table below:

[0312]

[0313] The preparation method of dexmedetomidine film-forming agent is as follows:

[0314] Prepare approximately 1200.56 parts of purified water according to the prescription ratio. Take approximately 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, blue pigment, and CaCO3 while stirring to dissolve or disperse them.

[0315] Then, while stirring, add the film-forming agents: hydroxypropyl cellulose (HPC SL) + hydroxypropyl methyl cellulose (HPMC E15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is approximately 22.63 wt%.

[0316] The prepared solution was allowed to stand to defoam, and then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. The resulting film was light blue and was cut and packaged according to specifications.

[0317] Example 30

[0318] The formulation of dexmedetomidine film-forming solution is shown in the table below:

[0319]

[0320] The preparation method of dexmedetomidine film-forming agent is as follows:

[0321] Prepare approximately 1200.38 parts of purified water according to the prescription ratio. Take approximately 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, cyclodextrin, blue pigment, and TiO2 while stirring to dissolve or disperse them.

[0322] Then, while stirring, add the film-forming agents: hydroxypropyl cellulose (HPC SL) + hydroxypropyl methyl cellulose (HPMC E15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is approximately 21.66 wt%.

[0323] The prepared solution was allowed to stand to defoam, and then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. The resulting film was light blue and was cut and packaged according to specifications.

[0324] Example 31

[0325] The formulation of dexmedetomidine film-forming solution is shown in the table below:

[0326]

[0327] The preparation method of dexmedetomidine film-forming agent is as follows:

[0328] Prepare approximately 1200.19 parts of purified water according to the prescription ratio. Take approximately 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, and TiO2 while stirring to dissolve or disperse them.

[0329] Then, while stirring, add the film-forming agents: hydroxypropyl cellulose (HPC SL) + hydroxypropyl methyl cellulose (HPMC E15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is approximately 20.63 wt%.

[0330] The prepared solution was allowed to stand to defoam, then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. The resulting film was white and cut and packaged according to specifications.

[0331] Example 32

[0332] The formulation of dexmedetomidine film-forming solution is shown in the table below:

[0333]

[0334] The preparation method of dexmedetomidine film-forming agent is as follows:

[0335] Prepare approximately 1200.75 parts of purified water according to the prescription ratio. Take approximately 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, cyclodextrin, blue pigment, and CaCO3 while stirring to dissolve or disperse them.

[0336] Then, while stirring, add the film-forming agents: hydroxypropyl methylcellulose (HPMC E5) + hydroxypropyl methylcellulose (HPMCE15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is approximately 21.63 wt%.

[0337] The prepared solution was allowed to stand to defoam, then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. The resulting film was transparent and light blue, and was cut and packaged according to specifications.

[0338] Example 33

[0339] The formulation of dexmedetomidine film-forming solution is shown in the table below:

[0340]

[0341] The preparation method of dexmedetomidine film-forming agent is as follows:

[0342] Prepare approximately 1200.56 parts of purified water according to the prescription ratio. Take approximately 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, cyclodextrin and CaCO3 while stirring to dissolve or disperse them.

[0343] Then, while stirring, add the film-forming agents: hydroxypropyl methylcellulose (HPMC E5) + hydroxypropyl methylcellulose (HPMCE15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is approximately 21.03 wt%.

[0344] The prepared solution was allowed to stand to defoam, then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. The resulting film was transparent and cut and packaged according to specifications.

[0345] Example 34

[0346] The formulation of dexmedetomidine film-forming solution is shown in the table below:

[0347]

[0348] The preparation method of dexmedetomidine film-forming agent is as follows:

[0349] Prepare approximately 1200.13 parts of purified water according to the prescription ratio. Take approximately 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, cyclodextrin, blue pigment, and TiO2 while stirring to dissolve or disperse them.

[0350] Then, while stirring, add the film-forming agents: hydroxypropyl methylcellulose (HPMC E5) + hydroxypropyl methylcellulose (HPMCE15) and the remaining purified water, and dissolve and disperse them evenly. The final solid content is approximately 21.66 wt%.

[0351] The prepared solution was allowed to stand to defoam, then coated to form a film with a thickness of 300 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for 20-40 min. The resulting film was light blue and was cut and packaged according to specifications. (Comparative Example 1)

[0352] The formulation of dexmedetomidine film-forming agents is shown in Table 1-12:

[0353] Table 1-12

[0354]

[0355] The preparation method of dexmedetomidine film-forming agent is as follows:

[0356] Prepare approximately 3700 parts of purified water according to the prescription ratio. Take 600 parts of purified water and add dexmedetomidine hydrochloride, sucralose, blue pigment, and TiO2 while stirring to dissolve or disperse them.

[0357] Then, while stirring, add the film-forming agent (hydroxypropyl cellulose (HPC ELF), hydroxypropyl cellulose (HPC JF), hydroxypropyl cellulose (HPC GF), polyoxyethylene 205) and the remaining purified water to dissolve and disperse them evenly, with a final solid content of approximately 8 wt%.

[0358] The prepared solution was allowed to stand to defoam, then coated to form a film with a thickness of 400 μm at a coating speed of 10 cm / min. The film was then dried at 80-90℃ for at least 40 min, resulting in an actual film thickness of approximately 0.03 mm. The film was then cut and packaged according to specifications.

[0359] The mass fractions of film-forming agents used in the formulations of the above embodiments and comparative examples are listed in Tables 1-13 below, with blank spaces in the tables representing "0".

[0360] Table 1-13

[0361]

[0362] Example 1: Dissolution curve determination

[0363] 1. Test subjects: the film formulations of Examples 1-300, Examples 1-400 and Example 34.

[0364] 2. Test Method: Dissolution and release determination was performed according to the method (Chinese Pharmacopoeia General Chapter 0931, Method II, with sedimentation basket). 900 ml of pH 6.8 phosphate buffer was used as the dissolution medium, and the rotation speed was 50 rpm. After 5 min, 10 min, 15 min, 20 min, and 30 min, appropriate amounts of the solution were taken and filtered. The filtrate was used as the test solution. An appropriate amount of dexmedetomidine hydrochloride reference standard was accurately weighed, dissolved in the dissolution medium, and prepared into a solution containing 0.36 μg of dexmedetomidine hydrochloride per ml. The test solution and reference solution were accurately measured and injected separately into the liquid chromatograph, and the chromatograms were recorded. The amount of dissolved per tablet at different times was calculated using the external standard method based on peak area.

[0365] 3. Test results: as shown in Table 2-1.

[0366] Table 2-1

[0367]

[0368] Example 2: Stability Study

[0369] 1. Test subjects: the film formulations of Examples 1-300, Examples 27 to 34, and the film formulation of Comparative Example 1.

[0370] 2. Testing Method:

[0371] (1) Stability test under high temperature conditions: Take the above samples, use simulated commercial packaging, and place them at 60±2℃ for 3 months. During this period, take samples in the first and third months to test their properties, content, moisture and related substances.

[0372] (2) Stability test under accelerated conditions: Take the above samples, use simulated commercial packaging, and place them at 40±2℃ and 75%±5%RH for 6 months. During this period, samples were taken in the 1st month, 3rd month and 6th month to test the properties, content, moisture and related substances.

[0373] (3) Stability test under illumination: The above samples were taken and packaged in simulated commercial packaging and transparent self-sealing bags, respectively, and tested under cool white fluorescent lamps (illuminance of 4500±500 lx, and total illuminance of the light source not less than 1.2×10⁻⁶ lx). 6 lux·hr, near-ultraviolet lamp energy not less than 200W·hr / m 2 The samples were placed at 25±2℃ and 60%±5%RH for 3 months. During this period, samples were taken on the 14th day, the 1st month, and the 3rd month to test their properties, content, and related substances.

[0374] (4) Stability study under long-term conditions: Take the above samples, use simulated commercial packaging, and place them at 25±2℃ and 60%±5%RH for 6 months. During this period, take samples in the 3rd and 6th months to detect properties, content, moisture and related substances. (5) Content detection: Determine according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 edition, Part IV, General Chapter 0512). Specifically, weigh an appropriate amount of the test sample into a 10 ml volumetric flask, add an appropriate amount of diluent, shake and sonicate, dilute to the mark with diluent, shake well, centrifuge, and use as the test sample solution. Weigh an appropriate amount of dexmedetomidine reference standard and dilute quantitatively with diluent to prepare a solution containing about 0.4 mg per 1 ml, as the reference solution. Use octadecylsilane-bonded silica gel as the packing material; use phosphate solution-methanol (volume ratio 40:60) as the mobile phase; the flow rate is 1.0 ml per minute; the detection wavelength is 220 nm; and the injection volume is 20 μl. Accurately measure the test solution and reference solution, inject them separately into the liquid chromatograph, record the chromatograms, and calculate the peak area using the external standard method.

[0375] (6) Detection of related substances: The determination shall be performed according to the high performance liquid chromatography method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512). Specifically, weigh an appropriate amount of the test sample into a 10 ml volumetric flask, add an appropriate amount of diluent, shake and sonicate, dilute to the mark with diluent, shake well, centrifuge, and use as the test solution. Prepare the excipient solution in the same way. Weigh an appropriate amount of dexmedetomidine reference standard and quantitatively dilute with diluent to prepare a solution containing approximately 0.4 μg per ml, as the reference solution. Transfer an appropriate amount of dexmedetomidine reference standard solution and quantitatively dilute with diluent to prepare a solution containing approximately 0.16 μg per ml, as the sensitivity solution. Use octadecylsilane-bonded silica gel as the stationary phase; use phosphate solution-methanol (volume ratio 40:60) as the mobile phase; the flow rate is 1.0 ml per minute; the detection wavelength is 220 nm; and the injection volume is 20 μl. Accurately measure the test solution, sensitivity solution, and reference solution, inject them separately into the liquid chromatograph, record the chromatograms, and calculate the impurity content by peak area using the external standard method.

[0376] (7) Moisture content determination: determined according to the first method of moisture determination in Part IV, Chinese Pharmacopoeia 2020 edition, 0832.

[0377] 3. Test Results:

[0378] (1) The results of the stability test under high temperature conditions are shown in Table 2-2-1.

[0379] Table 2-2-1

[0380] .

[0381] .

[0382] .

[0383] (2) The results of the stability test under accelerated conditions are shown in Table 2-2-2.

[0384] Table 2-2-2

[0385] .

[0386] .

[0387]

[0388] (3) The results of the stability test under light conditions (without packaging) are shown in Table 2-2-3.

[0389] Table 2-2-3

[0390]

[0391] (4) The results of the stability test under light conditions (with packaging) are shown in Table 2-2-4.

[0392] Table 2-2-4

[0393]

[0394] (5) The results of the long-term stability test are shown in Table 2-2-5.

[0395] Table 2-2-5

[0396] .

[0397] .

[0398]

[0399] Example 3: Membrane Mechanical Property Testing

[0400] 1. Test subjects: Samples from all the above embodiments.

[0401] 2. Testing Method:

[0402] (1) Actual membrane thickness: The thickness of each membrane was measured using a micrometer.

[0403] (2) Mechanical property test: The tensile strength and other properties of the membrane were measured using a texture analyzer. The high tensile strength and breaking strength values ​​indicate that the sample has good tensile properties. The good elongation at break value indicates that the sample has good toughness.

[0404] 3. Test results: as shown in Table 2-3

[0405] Table 2-3

[0406]

[0407] Example 4: Disintegration time and content uniformity test

[0408] 1. Test subjects: Samples from all the above embodiments.

[0409] 2. Testing Method:

[0410] (1) Disintegration time: The disintegration time test method (General Chapter 0921) under the Tablets section of Part IV of the 2020 Chinese Pharmacopoeia was performed. Six 15 mm × 20 mm tablets were placed in six baskets respectively. The disintegration time of the last disintegrating tablet was recorded when the tablet came into contact with water.

[0411] (2) Content uniformity: According to the content uniformity test method (General Rule 0941) under the characteristic test method of Part IV of the Chinese Pharmacopoeia 2020 edition, the content uniformity A+2.2S should be less than 20.

[0412] 3. Test results: as shown in Table 2-4

[0413] Table 2-4

[0414]

[0415] Example 5: Pharmacokinetic Test in Beagle Dogs

[0416] 1. Test subject: The sublingual film obtained in Example 34.

[0417] 2. Test method: Four healthy male beagle dogs weighing 8-12 kg were selected for a single-dose two-cycle crossover trial.

[0418] Fasting for at least 12 hours prior to the experiment and administration of 30 mL of water 5 minutes before administration. Experimental group (T): Dexmedetomidine sublingual film (Example 34), 0.18 mg; Control group (R): Existing dexmedetomidine sublingual film (trade name: IGALMI), 0.18 mg.

[0419] Place the film under the tongue of the beagle and keep its mouth closed for 3 minutes to check for complete dissolution. If the drug is not completely dissolved, continue closing the mouth for another 3 minutes and observe again. The animal can access water 2 hours after administration and food 4 hours after administration.

[0420] After sample collection, beagle dogs were cross-administered the drug after a washout period of at least 2 days. Blood samples were collected before administration (0 h) and at 5 min, 15 min, 30 min, 45 min, 60 min, 75 min, 90 min, 2 h, 3 h, 4 h, 6 h, and 8 h after administration.

[0421] 3. Test results: See the table below.

[0422]

[0423] The specific pharmacokinetic data for the experimental group (T) are shown in the table below:

[0424]

[0425] The specific pharmacokinetic data for the control group (R) are shown in the table below:

[0426]

[0427] Pharmacokinetic curves are shown belowFigure 1 As shown in the figure. In summary, the dexmedetomidine film-forming agent of the present invention has good stability and low impurity content even after long-term storage; the dexmedetomidine film-forming agent has good dissolution characteristics and good toughness; and its drug distribution is uniform. Furthermore, the film-forming agent of the present invention has higher pharmacokinetic parameters and lower in vivo variability compared to existing film-forming agents.

Claims

1. A dexmedetomidine film-forming agent, characterized in that, Its formulation components include dexmedetomidine or a pharmaceutically acceptable salt thereof and a film-forming agent, wherein the mass ratio of dexmedetomidine to the film-forming agent is 1:(20-200); the film-forming agent is a glucose polymer ether.

2. The dexmedetomidine film-forming agent according to claim 1, characterized in that, The glucose polymer ether is a cellulose ether derivative and / or a starch ether derivative; The cellulose ether derivative is preferably a nonionic cellulose ether derivative; the nonionic cellulose ether derivative is preferably selected from one or more of methylcellulose, carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, cyanoethylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose and hydroxypropylmethylcellulose, such as hydroxypropylcellulose and / or hydroxypropylmethylcellulose; The starch ether derivative is preferably a nonionic starch ether derivative; the nonionic starch ether derivative is preferably hydroxypropyl starch.

3. The dexmedetomidine film-forming agent according to claim 2, characterized in that, The glucose polymer ether satisfies at least one of the following conditions ①-⑦: ①The weight-average molecular weight of the hydroxypropyl cellulose is 40,000-180,000, preferably 80,000-100,000, for example 40,000, 80,000, 95,000, 100,000, 140,000 or 180,000, as determined by GPC; ② The hydroxypropyl cellulose, when prepared as a 2wt% aqueous solution, has a viscosity of 2.0-20 mPa·s at 20℃, for example, 2.0-2.9 mPa·s, 3.0-5.9 mPa·s, 6.0-10.0 mPa·s, 11-12 mPa·s, or 11-20 mPa·s; ③ The hydroxypropyl cellulose, when prepared into a 5wt% aqueous solution, has a Buchner viscosity of 75-400 mPa·s, for example, 75-150 mPa·s or 150-400 mPa·s; ④ The hydroxypropyl cellulose, when prepared into a 10 wt% aqueous solution, has a Buchner viscosity of 150-600 mPa·s, for example, 150-300 mPa·s or 300-600 mPa·s; ⑤ The hydroxypropyl methylcellulose, when prepared as a 2wt% aqueous solution, has a viscosity of less than 20 mPa·s at 20°C, preferably 2.8-15 mPa·s, for example 2.8 mPa·s, 3 mPa·s, 4 mPa·s, 5 mPa·s, 6 mPa·s or 15 mPa·s; ⑥ The degree of methoxy substitution of the hydroxypropyl methylcellulose is 22%-29%; the degree of hydroxypropoxy substitution of the hydroxypropyl methylcellulose is 0-10%, for example 0, 6%, 8% or 10%; ⑦ The degree of hydroxypropoxy substitution of the hydroxypropyl starch is 2.0%-7.0%.

4. The dexmedetomidine film-forming agent according to claim 1, characterized in that, When the glucose polymer ether is a starch ether derivative, its formulation components also include plasticizers; The plasticizer is preferably sorbitol, glycerol, glyceryl acetate, propylene glycol, polyethylene glycol, or triethyl citrate, such as glycerol; The preferred mass ratio of the starch ether derivative to the plasticizer is (260.5-261): (42.5-43.5), for example, 260:

43.

5. The dexmedetomidine film-forming agent according to claim 4, characterized in that, The film-forming agent satisfies at least one of the following conditions ①-⑤: ①The film-forming agent is hydroxypropyl cellulose and hydroxypropyl methyl cellulose in a mass ratio of 1:1; ②The film-forming agent is hydroxypropyl cellulose; for example, hydroxypropyl cellulose with a weight average molecular weight of 80,000 and hydroxypropyl cellulose with a weight average molecular weight of 180,000 in a mass ratio of 150.5:149.

5. ③The film-forming agent is hydroxypropyl methylcellulose; preferably, it is in a mass ratio of (1:3) to (3:1), for example, hydroxypropyl methylcellulose prepared into a 2wt% aqueous solution with a viscosity of 3 mPa·s at 20°C and hydroxypropyl methylcellulose prepared into a 2wt% aqueous solution with a viscosity of 15 mPa·s at 20°C in a mass ratio of 75.5:225, 1:1, 149.5:151 or 225:75.

5. ④ The film-forming agent is hydroxypropyl methylcellulose; for example, hydroxypropyl methylcellulose prepared into a 2wt% aqueous solution with a viscosity of 5-6 mPa·s at 20°C and hydroxypropyl methylcellulose prepared into a 2wt% aqueous solution with a viscosity of 15 mPa·s at 20°C, with a mass ratio of 1:

1. ⑤ The film-forming agent is hydroxypropyl starch; the preferred mass ratio of the hydroxypropyl starch to the glycerol is (260.5-261): (42.5-43.5), for example, 260:

43.

6. The dexmedetomidine film-forming agent according to claim 1, characterized in that, The mass ratio of dexmedetomidine to the film-forming agent is 1:(30-120), preferably 1:(40-100), and more preferably 1:(40-70), for example, 6:260.5, 6:261, 6:300, 6:300.19, 6:300.25, 6:300.38, 6:300.5, 6:300.94, 6:303, 4.69:301.31, 4.5:300.9, 4.5:300.3, 4.5:301.5, 4.5:302.7, 4.5:300.6, 4.5:302.1, 4.5:301.8, 4.5:300.19, 4.5: 301.69, 4.5: 300.94, 4.5: 300, or 3: 302.44; And / or, the formulation of the dexmedetomidine film-forming agent further includes a pigment; the mass ratio of the pigment to dexmedetomidine is preferably (0.5-15):1, more preferably (0.5-3):1, and even more preferably (0.5-1.0):1, for example 4.2:4.5, 4.6:6, 4.8:4.5, 5.1:6, 5.6:6, 5.65:6, 6:6, 6.1:6, 7.5:4.5, 9.6:4.5, 10.2:4.5, 10.5:4.5, 10.69:4.5, 11.63:4.5, 16.59:4.5, 17.81:4.69, 17.81:6, 18:3, 18.19:6, 18.56: 4.5, 44.81:6, 63.6:4.5 or 67.2:4.5; the pigment is preferably TiO2 and / or blue pigment and / or green pigment, for example, TiO2 and blue pigment in a mass ratio of (4.5-6.0):0.1; And / or, the formulation of the dexmedetomidine film-forming agent further includes a flavoring agent; the mass ratio of the flavoring agent to dexmedetomidine is preferably (0.5-1.0): 1, for example (5-6): 6; the flavoring agent is preferably one or more of sucrose, stevia, sucralose, xylitol, sorbitol or mannitol, for example sucralose; And / or, the formulation components of the dexmedetomidine film-forming agent also include fragrances and flavorings; And / or, the formulation of the dexmedetomidine film-forming agent further includes cyclodextrin; the mass ratio of cyclodextrin to dexmedetomidine is preferably (1-1.5):1, for example 1.25:1; And / or, the formulation of the dexmedetomidine film-forming agent further includes calcium carbonate; the mass ratio of calcium carbonate to dexmedetomidine is preferably (1-10):1, for example 5:1; And / or, the formulation components of the dexmedetomidine film-forming agent do not include polyethylene oxide.

7. The dexmedetomidine film-forming agent according to claim 1, characterized in that, The dexmedetomidine or a pharmaceutically acceptable salt thereof is distributed in the film-forming agent; And / or, the dexmedetomidine film formulation is a sublingual film formulation; And / or, the thickness of the dexmedetomidine film is 0.02-0.06 mm, for example 0.024 mm, 0.028 mm, 0.029 mm, 0.03 mm, 0.031 mm, 0.032 mm, 0.033 mm, 0.042 mm or 0.053 mm.

8. The dexmedetomidine film-forming agent according to claim 1, characterized in that, The formulation of the dexmedetomidine film-forming agent is any one of the following formulations: Formula 1: The formula components include dexmedetomidine hydrochloride, hydroxypropyl cellulose tetrahydrovirginate (HPV) and hydroxypropyl methylcellulose methylhydrovirginate (HPV); the mass ratio of dexmedetomidine, HPV, and HPV is 6:150:150, the weight-average molecular weight of HPV is 100,000, and the viscosity of a 2 wt% aqueous solution of HPV at 20°C is 3 mPa·s. Formula 2: The formula components include dexmedetomidine hydrochloride, second hydroxypropyl cellulose, and fourth hydroxypropyl methylcellulose; the mass ratio of dexmedetomidine, second hydroxypropyl cellulose, and fourth hydroxypropyl methylcellulose is 6:151.5:151.5, the weight average molecular weight of second hydroxypropyl cellulose is 80,000, and the viscosity of fourth hydroxypropyl methylcellulose in a 2wt% aqueous solution at 20°C is 15 mPa·s; Prescription 3: The prescription components include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose (HMC) and hydroxypropyl methylcellulose (HMC). The mass ratio of dexmedetomidine, the first hydroxypropyl methylcellulose, and the fourth hydroxypropyl methylcellulose is 6:149.5:

151. The viscosity of the first hydroxypropyl methylcellulose in a 2 wt% aqueous solution at 20°C is 3 mPa·s, and the viscosity of the fourth hydroxypropyl methylcellulose in a 2 wt% aqueous solution at 20°C is 15 mPa·s. Formula 4: The formula components include dexmedetomidine hydrochloride, hydroxypropyl cellulose VI, and hydroxypropyl methylcellulose XI; the mass ratio of dexmedetomidine, the hydroxypropyl cellulose VI, and the hydroxypropyl methylcellulose XI is 6:150:150, the weight-average molecular weight of the hydroxypropyl cellulose VI is 180,000, and the viscosity of the hydroxypropyl methylcellulose XI as a 2wt% aqueous solution at 20°C is 3 mPa·s. Formula 5: The formula components include dexmedetomidine hydrochloride, second hydroxypropyl cellulose, and sixth hydroxypropyl cellulose; the mass ratio of dexmedetomidine, second hydroxypropyl cellulose, and sixth hydroxypropyl cellulose is 6: 150.5: 149.5, the weight average molecular weight of second hydroxypropyl cellulose is 80,000, and the weight average molecular weight of sixth hydroxypropyl cellulose is 180,000; Formula 6: The formula components include dexmedetomidine hydrochloride, hydroxypropyl starch, and glycerin; the mass ratio of dexmedetomidine, hydroxypropyl starch, and glycerin is 6: 260.5: 43.5, and the degree of hydroxypropoxy substitution of the hydroxypropyl starch is 2.0%-7.0%; Formula 7: The formula components include dexmedetomidine hydrochloride, second hydroxypropyl starch, and glycerin; the mass ratio of dexmedetomidine, second hydroxypropyl starch, and glycerin is 6:261:42.5, and the degree of hydroxypropoxy substitution of the second hydroxypropyl starch is 2.0%-7.0%; Prescription 8: The prescription components include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose and hydroxypropyl methylcellulose; The mass ratio of dexmedetomidine, the first hydroxypropyl methylcellulose, and the fourth hydroxypropyl methylcellulose is 6:75.5:

225. The first hydroxypropyl methylcellulose, when prepared as a 2wt% aqueous solution, has a viscosity of 3 mPa·s at 20°C. The fourth hydroxypropyl methylcellulose, when prepared as a 2wt% aqueous solution, has a viscosity of 15 mPa·s at 20°C. Prescription Nine: The prescription components include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose and hydroxypropyl methylcellulose; The mass ratio of dexmedetomidine, the first hydroxypropyl methylcellulose, and the fourth hydroxypropyl methylcellulose is 6:225:75.

5. The viscosity of the first hydroxypropyl methylcellulose in a 2 wt% aqueous solution at 20°C is 3 mPa·s, and the viscosity of the fourth hydroxypropyl methylcellulose in a 2 wt% aqueous solution at 20°C is 15 mPa·s. Prescription 10: The prescription components include dexmedetomidine hydrochloride, second-hydroxypropyl methylcellulose, and fourth-hydroxypropyl methylcellulose; The mass ratio of dexmedetomidine, the second hydroxypropyl methylcellulose, and the fourth hydroxypropyl methylcellulose is 6:150:

150. The second hydroxypropyl methylcellulose, when prepared as a 2wt% aqueous solution, has a viscosity of 5 mPa·s at 20°C. The fourth hydroxypropyl methylcellulose, when prepared as a 2wt% aqueous solution, has a viscosity of 15 mPa·s at 20°C. Prescription 11: The prescription components include dexmedetomidine hydrochloride, tertiary hydroxypropyl methylcellulose, and tertiary hydroxypropyl methylcellulose; The mass ratio of dexmedetomidine, the third hydroxypropyl methylcellulose, and the fourth hydroxypropyl methylcellulose is 6:150:

150. The viscosity of the third hydroxypropyl methylcellulose in a 2 wt% aqueous solution at 20°C is 6 mPa·s, and the viscosity of the fourth hydroxypropyl methylcellulose in a 2 wt% aqueous solution at 20°C is 15 mPa·s. Formula 12: The formula components include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose, and hydroxypropyl cellulose; the mass ratio of dexmedetomidine, the hydroxypropyl methylcellulose, and the hydroxypropyl cellulose is 4.5:150.3:150.6; the hydroxypropyl methylcellulose is prepared into a 2wt% aqueous solution with a viscosity of 15 mPa·s at 20°C; and the weight-average molecular weight of the hydroxypropyl cellulose is 100,000. Formula 13: The formula components include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose, and hydroxypropyl cellulose; the mass ratio of dexmedetomidine, the hydroxypropyl methylcellulose, and the hydroxypropyl cellulose is 4.5:150:150.3; the hydroxypropyl methylcellulose is prepared into a 2wt% aqueous solution with a viscosity of 15 mPa·s at 20°C; and the weight-average molecular weight of the hydroxypropyl cellulose is 100,000. Formula Fourteen: The formula components include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose, and hydroxypropyl cellulose; the mass ratio of dexmedetomidine, the hydroxypropyl methylcellulose, and the hydroxypropyl cellulose is 4.5:150.9:150.6; the hydroxypropyl methylcellulose is prepared into a 2wt% aqueous solution with a viscosity of 15 mPa·s at 20°C; and the weight-average molecular weight of the hydroxypropyl cellulose is 100,000. Prescription 15: The prescription components include dexmedetomidine hydrochloride, tetrahydroxypropyl methylcellulose, and tetrahydroxypropyl cellulose; The mass ratio of dexmedetomidine, the fourth hydroxypropyl methylcellulose, and the fourth hydroxypropyl cellulose is 4.5:151.5:151.

2. The viscosity of the fourth hydroxypropyl methylcellulose in a 2 wt% aqueous solution at 20°C is 15 mPa·s. The weight-average molecular weight of the fourth hydroxypropyl cellulose is 100,000. Prescription 16: The prescription components include dexmedetomidine hydrochloride, tetrahydroxypropyl methylcellulose, and tetrahydroxypropyl cellulose; The mass ratio of dexmedetomidine, the fourth hydroxypropyl methylcellulose, and the fourth hydroxypropyl cellulose is 4.5:150.6:

150. The viscosity of the fourth hydroxypropyl methylcellulose in a 2 wt% aqueous solution at 20°C is 15 mPa·s. The weight-average molecular weight of the fourth hydroxypropyl cellulose is 100,000. Formula 17: The formula components include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose, and hydroxypropyl cellulose; the mass ratio of dexmedetomidine, the hydroxypropyl methylcellulose, and the hydroxypropyl cellulose is 4.5:151.8:150.3; the hydroxypropyl methylcellulose is prepared into a 2wt% aqueous solution with a viscosity of 15 mPa·s at 20°C; and the weight-average molecular weight of the hydroxypropyl cellulose is 100,000. Formula 18: The formula components include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose, and hydroxypropyl cellulose; the mass ratio of dexmedetomidine, the hydroxypropyl methylcellulose, and the hydroxypropyl cellulose is 4.5:151.5:150.3; the hydroxypropyl methylcellulose is prepared into a 2wt% aqueous solution with a viscosity of 15 mPa·s at 20°C; and the weight-average molecular weight of the hydroxypropyl cellulose is 100,000. Prescription 19: The prescription components include dexmedetomidine hydrochloride, tetrahydroxypropyl methylcellulose, and tetrahydroxypropyl cellulose; The mass ratio of dexmedetomidine, the fourth hydroxypropyl methylcellulose, and the fourth hydroxypropyl cellulose is 4.5:150.19:

150. The viscosity of the fourth hydroxypropyl methylcellulose in a 2 wt% aqueous solution at 20°C is 15 mPa·s. The weight-average molecular weight of the fourth hydroxypropyl cellulose is 100,000. Prescription 20: The prescription components include dexmedetomidine hydrochloride, 4-hydroxypropyl methylcellulose, and 4-hydroxypropyl cellulose; The mass ratio of dexmedetomidine, the fourth hydroxypropyl methylcellulose, and the fourth hydroxypropyl cellulose is 4.5:151.13:150.

56. The viscosity of the fourth hydroxypropyl methylcellulose in a 2 wt% aqueous solution at 20°C is 15 mPa·s. The weight-average molecular weight of the fourth hydroxypropyl cellulose is 100,000. Formula 21: The formula components include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose, and hydroxypropyl cellulose; the mass ratio of dexmedetomidine, the hydroxypropyl methylcellulose, and the hydroxypropyl cellulose is 4.5:150.94:150; the hydroxypropyl methylcellulose is prepared into a 2wt% aqueous solution with a viscosity of 15 mPa·s at 20°C; and the weight-average molecular weight of the hydroxypropyl cellulose is 100,000. Prescription 22: The prescription components include dexmedetomidine hydrochloride, 4-hydroxypropyl methylcellulose, and 4-hydroxypropyl cellulose; The mass ratio of dexmedetomidine, the fourth hydroxypropyl methylcellulose, and the fourth hydroxypropyl cellulose is 4.5:150.15:150.

45. The viscosity of the fourth hydroxypropyl methylcellulose in a 2 wt% aqueous solution at 20°C is 15 mPa·s. The weight-average molecular weight of the fourth hydroxypropyl cellulose is 100,000. Prescription 23: The prescription components include dexmedetomidine hydrochloride, 4-hydroxypropyl methylcellulose, and 4-hydroxypropyl cellulose; The mass ratio of dexmedetomidine, the fourth hydroxypropyl methylcellulose, and the fourth hydroxypropyl cellulose is 4.5:150:

150. The viscosity of the fourth hydroxypropyl methylcellulose in a 2 wt% aqueous solution at 20°C is 15 mPa·s. The weight-average molecular weight of the fourth hydroxypropyl cellulose is 100,000. Formula 24: The formula components include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose, and hydroxypropyl cellulose; the mass ratio of dexmedetomidine, the hydroxypropyl methylcellulose, and the hydroxypropyl cellulose is 3:150.94:151.5; the hydroxypropyl methylcellulose is prepared into a 2wt% aqueous solution with a viscosity of 15 mPa·s at 20°C; and the weight-average molecular weight of the hydroxypropyl cellulose is 100,000. Formula 25: The formula components include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose, and hydroxypropyl cellulose; the mass ratio of dexmedetomidine, the hydroxypropyl methylcellulose, and the hydroxypropyl cellulose is 6:150:150.94; the hydroxypropyl methylcellulose is prepared into a 2wt% aqueous solution with a viscosity of 15 mPa·s at 20°C; and the weight-average molecular weight of the hydroxypropyl cellulose is 100,000. Prescription 26: The prescription components include dexmedetomidine hydrochloride, 4-hydroxypropyl methylcellulose, and 4-hydroxypropyl cellulose; The mass ratio of dexmedetomidine, the fourth hydroxypropyl methylcellulose, and the fourth hydroxypropyl cellulose is 4.69:150.56:150.

75. The viscosity of the fourth hydroxypropyl methylcellulose in a 2 wt% aqueous solution at 20°C is 15 mPa·s. The weight-average molecular weight of the fourth hydroxypropyl cellulose is 100,000. Prescription 27: The prescription components include dexmedetomidine hydrochloride, 4-hydroxypropyl methylcellulose, and 4-hydroxypropyl cellulose; The mass ratio of dexmedetomidine, the fourth hydroxypropyl methylcellulose, and the fourth hydroxypropyl cellulose is 6:150:150.

19. The viscosity of the fourth hydroxypropyl methylcellulose in a 2wt% aqueous solution at 20°C is 15 mPa·s. The weight-average molecular weight of the fourth hydroxypropyl cellulose is 100,000. Formula 28: The formula components include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose IV, and hydroxypropyl methylcellulose II; the mass ratio of dexmedetomidine, the hydroxypropyl methylcellulose IV, and the hydroxypropyl methylcellulose II is 6:150.19:150; the viscosity of the hydroxypropyl methylcellulose IV in a 2wt% aqueous solution at 20°C is 15 mPa·s; and the viscosity of the hydroxypropyl methylcellulose II in a 2wt% aqueous solution at 20°C is 5 mPa·s. Formula 29: The formula components include dexmedetomidine hydrochloride, hydroxypropyl methylcellulose, and hydroxypropyl cellulose; the mass ratio of dexmedetomidine, the hydroxypropyl methylcellulose, and the hydroxypropyl cellulose is 6:150.19:150.19; the hydroxypropyl methylcellulose is prepared into a 2wt% aqueous solution with a viscosity of 15 mPa·s at 20°C; and the weight-average molecular weight of the hydroxypropyl cellulose is 100,000. Prescription 30: The prescription components include dexmedetomidine hydrochloride, 4-hydroxypropyl methylcellulose, and 4-hydroxypropyl cellulose; The mass ratio of dexmedetomidine, the fourth hydroxypropyl methylcellulose, and the fourth hydroxypropyl cellulose is 6:150:

150. The viscosity of the fourth hydroxypropyl methylcellulose in a 2wt% aqueous solution at 20°C is 15 mPa·s. The weight-average molecular weight of the fourth hydroxypropyl cellulose is 100,000.

9. A method for preparing a dexmedetomidine film-forming agent as described in any one of claims 1-8, characterized in that, It includes the following steps: coating the slurry to form a film and drying it; the slurry includes the formulation components of the dexmedetomidine and water.

10. The method for preparing the dexmedetomidine film-forming agent according to claim 9, characterized in that, In the slurry, the mass ratio of dexmedetomidine to water is 1:(125-250); And / or, the solid content of the slurry is 20wt%-31wt%, for example 20wt%, 20.23wt%, 20.24wt%, 20.25wt%, 20.31wt%, 20.34wt%, 20.36wt%, 20.37wt%, 20.50wt%, 29.93wt%, 30.01wt%; And / or, the slurry is prepared by the following steps: S1. Under stirring, the formulation components other than the film-forming agent are added to a portion of water to obtain a mixture; S2. While stirring, add the film-forming agent and the remaining water to the mixture; And / or, the film thickness of the coating film is 200-500 μm, for example 200 μm, 300 μm, 400 μm or 500 μm; And / or, the coating speed of the coating film is 5-10 cm / min; And / or, the drying temperature is 40-90°C, for example 40-60°C or 80-90°C; And / or, the drying time is 20-40 min.

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