Dexmedetomidine hydrochloride oral soluble film as well as preparation method and application thereof

Abstract

The invention relates to a dexmedetomidine hydrochloride oral soluble film, which is prepared from the following components in percentage by weight: 0.1 to 10 percent of dexmedetomidine hydrochloride and 90 to 99.9 percent of film forming material, the film forming material is selected from any one or a combination of copovidone, a polyvinyl caprolactam polyvinyl acetate polyethylene glycol grafted copolymer, hydroxypropyl methyl cellulose, hydroxy propyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol, polyoxyethylene, povidone and poloxamer. The dexmedetomidine hydrochloride oral soluble film has the advantages of fast disintegration time in the oral cavity, good mechanical extrusion performance, good film forming performance and high content uniformity, meets the requirements of cutting, packaging, transportation, clinical use and the like, significantly improves the dissolution rate, dissolution rate, stability and bioavailability, does not need to be taken with water, significantly improves the compliance of child patients, and has a good application prospect. The medication safety and effectiveness are ensured.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and in particular relates to a dexmedetomidine hydrochloride orodispersible film, a preparation method thereof and an application thereof. Background Art

[0002] Dexmedetomidine hydrochloride is a highly selective α2-adrenergic receptor agonist with an affinity for α2-adrenergic receptors that is 8 times that of clonidine. It achieves a sedative effect mainly by stimulating α2-adrenergic receptors in the locus coeruleus area of ​​the brain, inhibiting the release of norepinephrine and reducing the activity of sympathetic nerves.

[0003] Currently, there are dexmedetomidine hydrochloride injection and dexmedetomidine hydrochloride nasal spray on the market, but there are many problems. The injection is often used as a procedural sedation for patients during mechanical ventilation. It needs to be prepared with 0.9% sodium chloride solution to a concentration of 4μg / ml and slowly injected at a dose of 1μg / kg. The infusion time needs to exceed 10 minutes. For patients with short-term sedation requirements for minor clinical surgeries and examinations, the compliance of intravenous drip is poor, and the effective dose cannot be reached quickly. It is an invasive drug administration, and the compliance of children is not good; the market specification of the nasal spray is that the nasal cavity needs to be cleaned in advance, and each nostril needs 4 sprays. The administration time is long, which is easy to cause low compliance in children.

[0004] Existing studies have prepared dexmedetomidine hydrochloride into an orodispersible film, which absorbs the drug through the sublingual mucosa and takes effect quickly. However, orodispersible films are mostly prepared by solvent casting, which has the following defects: first, plasticizers are used to increase film-forming properties and ensure smooth demolding; second, the film-forming materials of the film are mostly polymer materials, which usually need to undergo a swelling and re-dissolution process, and a large number of bubbles are generated during the dissolution process, which are difficult to remove. This not only easily leads to unqualified content uniformity of the finished product, incomplete defoaming, poor film-forming properties, and multiple pores in the finished product, but also affects processing efficiency; third, it is necessary to undergo complex processes such as coating, drying, and demolding in the follow-up. The preparation of a batch of finished film preparations takes at least 2-3 days or even longer, resulting in increased energy consumption and increased production costs. Therefore, it is necessary to study more efficient and simple orodispersible dexmedetomidine hydrochloride films and preparation methods thereof. Summary of the invention

[0005] The object of the present invention is to provide a dexmedetomidine hydrochloride orodispersible film, which contains, by weight percentage, 0.1-10% of dexmedetomidine hydrochloride and 90%-99.9% of a film-forming material, wherein the film-forming material is selected from any one of copovidone, a polyethylene caprolactam polyvinyl acetate polyethylene glycol graft copolymer, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol, polyoxyethylene, povidone and poloxamer or a combination thereof.

[0006] In the preferred technical solution of the present invention, the content of the film-forming material in the orally dissolving film is 92-99.8% by weight, preferably 95%-99.7%.

[0007] In the preferred technical solution of the present invention, the orally dissolving film contains 0.2-5% of dexmedetomidine hydrochloride and 95%-99.8% of film-forming material in terms of weight percentage.

[0008] In the preferred technical solution of the present invention, the orally dissolving film contains, by weight percentage, 0.2-5% of dexmedetomidine hydrochloride, 25%-60% of hydroxypropyl cellulose and 35-70% of polyoxyethylene.

[0009] In the preferred technical solution of the present invention, the orally dissolving film contains, by weight percentage, 0.2-5% of dexmedetomidine hydrochloride, 35-70% of hydroxypropyl cellulose and 25%-60% of polyoxyethylene.

[0010] In the preferred technical solution of the present invention, the orally dissolving film contains, by weight percentage, 0.2-5% of dexmedetomidine hydrochloride, 35-70% of polyoxyethylene and 25%-60% of copovidone.

[0011] In the preferred technical solution of the present invention, the orally dissolving film contains, by weight percentage, 0.2-5% of dexmedetomidine hydrochloride, 25%-60% of polyoxyethylene, and 35-70% of polyethylene caprolactam polyvinyl acetate polyethylene glycol graft copolymer.

[0012] In a preferred technical solution of the present invention, the orally dissolving film optionally contains any one of a flavoring agent and a coloring agent.

[0013] In the preferred technical scheme of the present invention, the flavoring agent is selected from any one of neotame, sucralose, acesulfame potassium, saccharin, saccharin sodium, glucose, sucrose, aspartame, fructose, glycyrrhizin, stevioside, sorbitol, mannitol, xylitol, erythritol, menthol, and citric acid, or a combination thereof.

[0014] In the preferred technical solution of the present invention, the content of the flavor corrective in the orodispersible film is 0%-5% by weight, preferably 0.1%-1%.

[0015] In a preferred technical solution of the present invention, the colorant is selected from any one of red iron oxide, yellow iron oxide, carmine, sunset yellow, or a combination thereof.

[0016] In the preferred technical solution of the present invention, the content of the colorant in the orally dissolving film is 0%-0.5% by weight, preferably 0.1-0.2%.

[0017] In the preferred technical solution of the present invention, the orally dissolving film contains, by weight percentage, 0.48% of dexmedetomidine hydrochloride, 33.18% of hydroxypropyl cellulose, and 66.34% of polyoxyethylene.

[0018] In the preferred technical solution of the present invention, the orally dissolving film contains, by weight percentage, 0.48% of dexmedetomidine hydrochloride, 32.98% of hydroxypropyl cellulose, 66.34% of polyoxyethylene, 0.1% of neotame, and 0.1% of sunset yellow.

[0019] In the preferred technical solution of the present invention, the orally dissolving film contains, by weight percentage, 2.35% of dexmedetomidine hydrochloride, 32.55% of hydroxypropyl cellulose, and 65.09% of polyoxyethylene.

[0020] In the preferred technical solution of the present invention, the orally dissolving film contains, by weight percentage, 0.6% dexmedetomidine hydrochloride, 33.08% hydroxypropyl cellulose, 66.12% polyoxyethylene, 0.1% neotame, and 0.1% sunset yellow.

[0021] In the preferred technical solution of the present invention, the orally dissolving film contains, by weight percentage, 0.6% of dexmedetomidine hydrochloride, 49.6% of hydroxypropyl cellulose, 49.6% of polyoxyethylene, 0.1% of neotame, and 0.1% of sunset yellow.

[0022] In the preferred technical solution of the present invention, the orally dissolving film contains, by weight percentage, 0.6% dexmedetomidine hydrochloride, 65.28% hydroxypropyl cellulose, 24.7% polyoxyethylene, 0.1% neotame, and 0.1% yellow iron oxide.

[0023] In the preferred technical solution of the present invention, the orally dissolving film contains, by weight percentage, 0.6% dexmedetomidine hydrochloride, 66.12% hydroxypropyl cellulose, 33.08% polyoxyethylene, 0.1% neotame, and 0.1% yellow iron oxide.

[0024] In the preferred technical solution of the present invention, the orally dissolving film contains, by weight percentage, 0.6% dexmedetomidine hydrochloride, 66.12% hydroxypropyl cellulose, 33.08% polyoxyethylene, 0.1% neotame, and 0.1% yellow iron oxide.

[0025] In the preferred technical solution of the present invention, the orally dissolving film contains, by weight percentage, 0.6% of dexmedetomidine hydrochloride, 66.34% of polyoxyethylene, and 33.06% of copovidone.

[0026] In the preferred technical solution of the present invention, the orally dissolving film contains, by weight percentage, 0.6% of dexmedetomidine hydrochloride, 49.7% of polyoxyethylene, and 49.7% of polyethylene caprolactam polyvinyl acetate polyethylene glycol graft copolymer.

[0027] In a preferred technical solution of the present invention, the orally dissolving film dissolves in 37° C. constant temperature water within 1 minute, preferably within 30 seconds, and more preferably within 20 seconds.

[0028] In a preferred technical solution of the present invention, the thickness of the orally dissolving film is 0.1-0.2 mm.

[0029] In a preferred technical solution of the present invention, the orally dissolving film can withstand folding times greater than 20 times, preferably greater than 30 times.

[0030] In a preferred technical solution of the present invention, the elongation at break of the orally dissolving film is greater than 2%, preferably greater than 5%.

[0031] In the preferred technical solution of the present invention, the tensile strength of the orally dissolving film is greater than 15N / mm 2 , preferably greater than 25N / mm 2 .

[0032] In a preferred technical solution of the present invention, the content uniformity of the orally dissolving film is greater than 95%, preferably greater than 98%.

[0033] In a preferred technical solution of the present invention, the solubility of the orodispersible film in simulated saliva for 15 minutes is ≥85%, preferably ≥90%.

[0034] In the preferred technical scheme of the present invention, the preparation method of the dexmedetomidine hydrochloride orosoluble film comprises the following steps: mixing the required amounts of the components to obtain a total mixed material, adding the mixed material to a hot melt extruder, setting the temperature of different sections of the barrel to 90-170° C., setting the feeding speed to 20-100 rpm, the screw speed to 100-250 rpm, the film drawing speed to 1.0-3.5 m / min, the film mouth extrusion temperature to 90-180° C., and forming a film.

[0035] In the preferred technical solution of the present invention, the feeding speed is 20-50rpm.

[0036] In the preferred technical solution of the present invention, the screw speed is 100-200 rpm

[0037] In the preferred technical solution of the present invention, the extrusion temperature is 120-180°C.

[0038] The object of the present invention is to provide a method for preparing a dexmedetomidine hydrochloride orodispersible film. The dexmedetomidine hydrochloride orodispersible film contains, by weight percentage, 0.1-10% of dexmedetomidine hydrochloride and 90%-99.9% of a film-forming material, wherein the film-forming material is selected from any one of copovidone, polyvinyl caprolactam polyvinyl acetate polyethylene glycol graft copolymer, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol, polyoxyethylene, povidone and poloxamer or a combination thereof. The method for preparing the dexmedetomidine hydrochloride orodispersible film comprises the following steps: mixing required amounts of each component to obtain a total mixed material, adding the total mixed material to a hot melt extruder, setting the temperature of different sections of the barrel to 90-170° C., setting the feeding speed to 20-100 rpm, the screw speed to 100-250 rpm, the film drawing speed to 1.0-3.5 m / min, the film mouth extrusion temperature to 90-180° C., and forming a film.

[0039] In the preferred technical solution of the present invention, the feeding speed is 20-50rpm.

[0040] In the preferred technical solution of the present invention, the screw speed is 100-200 rpm

[0041] In the preferred technical solution of the present invention, the extrusion temperature is 120-180°C.

[0042] In the preferred technical solution of the present invention, the content of the film-forming material in the orally dissolving film is 92-99.8% by weight, preferably 95%-99.7%.

[0043] In the preferred technical solution of the present invention, the orally dissolving film contains 0.2-5% of dexmedetomidine hydrochloride and 95%-99.8% of film-forming material in terms of weight percentage.

[0044] In the preferred technical solution of the present invention, the orally dissolving film contains, by weight percentage, 0.2-5% of dexmedetomidine hydrochloride, 25%-60% of hydroxypropyl cellulose and 35-70% of polyoxyethylene.

[0045] In the preferred technical solution of the present invention, the orally dissolving film contains, by weight percentage, 0.2-5% of dexmedetomidine hydrochloride, 35-70% of hydroxypropyl cellulose and 25%-60% of polyoxyethylene.

[0046] In the preferred technical solution of the present invention, the orally dissolving film contains, by weight percentage, 0.2-5% of dexmedetomidine hydrochloride, 35-70% of polyoxyethylene and 25%-60% of copovidone.

[0047] In the preferred technical solution of the present invention, the orally dissolving film contains, by weight percentage, 0.2-5% of dexmedetomidine hydrochloride, 25%-60% of polyoxyethylene, and 35-70% of polyethylene caprolactam polyvinyl acetate polyethylene glycol graft copolymer.

[0048] In a preferred technical solution of the present invention, the orally dissolving film optionally contains any one of a flavoring agent and a coloring agent.

[0049] In the preferred technical scheme of the present invention, the flavoring agent is selected from any one of neotame, sucralose, acesulfame potassium, saccharin, saccharin sodium, glucose, sucrose, aspartame, fructose, glycyrrhizin, stevioside, sorbitol, mannitol, xylitol, erythritol, menthol, and citric acid, or a combination thereof.

[0050] In the preferred technical solution of the present invention, the content of the flavor corrective in the orodispersible film is 0%-5% by weight, preferably 0.1%-1%.

[0051] In a preferred technical solution of the present invention, the colorant is selected from any one of red iron oxide, yellow iron oxide, carmine, sunset yellow, or a combination thereof.

[0052] In the preferred technical solution of the present invention, the content of the colorant in the orally dissolving film is 0%-0.5% by weight, preferably 0.1-0.2%.

[0053] In the preferred technical solution of the present invention, the orally dissolving film contains, by weight percentage, 0.48% of dexmedetomidine hydrochloride, 33.18% of hydroxypropyl cellulose, and 66.34% of polyoxyethylene.

[0054] In the preferred technical solution of the present invention, the orally dissolving film contains, by weight percentage, 0.48% of dexmedetomidine hydrochloride, 32.98% of hydroxypropyl cellulose, 66.34% of polyoxyethylene, 0.1% of neotame, and 0.1% of sunset yellow.

[0055] In the preferred technical solution of the present invention, the orally dissolving film contains, by weight percentage, 2.35% of dexmedetomidine hydrochloride, 32.55% of hydroxypropyl cellulose, and 65.09% of polyoxyethylene.

[0056] In the preferred technical solution of the present invention, the orally dissolving film contains, by weight percentage, 0.6% dexmedetomidine hydrochloride, 33.08% hydroxypropyl cellulose, 66.12% polyoxyethylene, 0.1% neotame, and 0.1% sunset yellow.

[0057] In the preferred technical solution of the present invention, the orally dissolving film contains, by weight percentage, 0.6% of dexmedetomidine hydrochloride, 49.6% of hydroxypropyl cellulose, 49.6% of polyoxyethylene, 0.1% of neotame, and 0.1% of sunset yellow.

[0058] In the preferred technical solution of the present invention, the orally dissolving film contains, by weight percentage, 0.6% dexmedetomidine hydrochloride, 65.28% hydroxypropyl cellulose, 24.7% polyoxyethylene, 0.1% neotame, and 0.1% yellow iron oxide.

[0059] In the preferred technical solution of the present invention, the orally dissolving film contains, by weight percentage, 0.6% dexmedetomidine hydrochloride, 66.12% hydroxypropyl cellulose, 33.08% polyoxyethylene, 0.1% neotame, and 0.1% yellow iron oxide.

[0060] In the preferred technical solution of the present invention, the orally dissolving film contains, by weight percentage, 0.6% dexmedetomidine hydrochloride, 66.12% hydroxypropyl cellulose, 33.08% polyoxyethylene, 0.1% neotame, and 0.1% yellow iron oxide.

[0061] In the preferred technical solution of the present invention, the orally dissolving film contains, by weight percentage, 0.6% of dexmedetomidine hydrochloride, 66.34% of polyoxyethylene, and 33.06% of copovidone.

[0062] In the preferred technical solution of the present invention, the orally dissolving film contains, by weight percentage, 0.6% of dexmedetomidine hydrochloride, 49.7% of polyoxyethylene, and 49.7% of polyethylene caprolactam polyvinyl acetate polyethylene glycol graft copolymer.

[0063] In a preferred technical solution of the present invention, the orally dissolving film dissolves in 37° C. constant temperature water within 1 minute, preferably within 30 seconds, and more preferably within 20 seconds.

[0064] In a preferred technical solution of the present invention, the thickness of the orally dissolving film is 0.1-0.2 mm.

[0065] In a preferred technical solution of the present invention, the orally dissolving film can withstand folding times greater than 20 times, preferably greater than 30 times.

[0066] In a preferred technical solution of the present invention, the elongation at break of the orally dissolving film is greater than 2%, preferably greater than 5%.

[0067] In the preferred technical solution of the present invention, the tensile strength of the orally dissolving film is greater than 15N / mm 2 , preferably greater than 25N / mm 2 .

[0068] In a preferred technical solution of the present invention, the content uniformity of the orally dissolving film is greater than 95%, preferably greater than 98%.

[0069] In a preferred technical solution of the present invention, the solubility of the orodispersible film in simulated saliva for 15 minutes is ≥85%, preferably ≥90%.

[0070] Another object of the present invention is to provide use of the dexmedetomidine hydrochloride orodispersible film of the present invention in preparing sedative drugs.

[0071] In a preferred technical solution of the present invention, the sedative drug is any one of a preoperative sedative drug and a sedative drug for schizophrenia patients.

[0072] Another object of the present invention is to provide use of the dexmedetomidine hydrochloride orosoluble film of the present invention in preparing analgesic drugs.

[0073] Another object of the present invention is to provide use of the dexmedetomidine hydrochloride orosoluble film of the present invention in preparing an anti-insomnia drug.

[0074] Unless otherwise specified, when the present invention relates to the percentage between liquids, the percentage is volume / volume percentage; when the present invention relates to the percentage between liquids and solids, the percentage is volume / weight percentage; when the present invention relates to the percentage between solids and liquids, the percentage is weight / volume percentage; the rest are weight / weight percentages.

[0075] Unless otherwise stated, the present invention uses the following method for detection:

[0076] 1. Dissolution time determination method: Measure 10 ml of water and place it in a culture dish, then place it in a constant temperature water bath at 37°C. Take a 20 mg membrane and place it in the culture dish. Use a stopwatch to record the dissolution time and change the water each time.

[0077] 2. Tensile test method: Use a texture analyzer to cut the film to be tested into 2*6cm 2 Clamped on the tensile device for measurement.

[0078] 3. Folding endurance test method: Take the film material, lay it flat on the table, fold it in half repeatedly at the same position by hand, and record the number of times it breaks.

[0079] 4. LC-MS analysis: After the plasma sample to be tested is treated, LC-MS analysis is performed to obtain a standard curve; the LC-MS analysis method uses 0.1% formic acid aqueous solution as mobile phase A, acetonitrile as mobile phase B, and the elution mode is gradient elution. The elution conditions are as follows: 0-0.3min, mobile phase A 90%; 0.3-1.5min, mobile phase A 90→5%; 1.5-2.0min, mobile phase A 5%; 2.0-2.1min, mobile phase A 5→90%; 2.1-3.0min, mobile phase A 90%.

[0080] Compared with the prior art, the present invention has the following beneficial effects:

[0081] 1. The present invention scientifically screens the components and proportions of the dexmedetomidine hydrochloride orodispersible film, and adopts a hot melt extrusion method to disperse dexmedetomidine hydrochloride in a water-soluble high molecular polymer to prepare an orodispersible film, which has uniform color, fast disintegration time in the oral cavity, good mechanical extrusion performance, good film-forming performance, high content uniformity, and meets the requirements of cutting, packaging, transportation and clinical use, and significantly improves its solubility and dissolution rate, stability and bioavailability. In addition, the dexmedetomidine hydrochloride orodispersible film does not need to be taken with water, but is dissolved and absorbed under the tongue, which significantly improves the compliance of pediatric patients and ensures safe and effective medication.

[0082] 2. The preparation method of the dexmedetomidine hydrochloride orosoluble film of the present invention has the advantages of short processing time, which can be completed in only a few hours, simple operation, high yield, better cost, suitability for industrial production, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0083] Figure 1 The dissolution curve of the dexmedetomidine hydrochloride orosoluble film of the present invention.

[0084] Figure 2 The drug-time curve of the dexmedetomidine hydrochloride orodispersible film of the present invention in beagle dogs. DETAILED DESCRIPTION

[0085] The present invention is further described in detail by the following examples and experimental examples. These examples and experimental examples are only for illustrative purposes and are not intended to limit the scope of the present invention.

[0086] Example 1 Preparation of dexmedetomidine hydrochloride orodispersible film

[0087] The prescription composition of the dexmedetomidine hydrochloride orodispersible film of the present invention (2000 tablets, 25 mg / tablet)

[0088] Components Weight(g) Dexmedetomidine hydrochloride 0.24 Hydroxypropyl Cellulose ELF 16.59 Polyoxyethylene N80 33.17

[0089] The preparation method of the dexmedetomidine hydrochloride orodispersible film of the present invention:

[0090] (1) Dexmedetomidine hydrochloride, hydroxypropyl cellulose and polyoxyethylene are pre-sieved with a 60-mesh sieve, and then half of the prescribed amount of hydroxypropyl cellulose and the prescribed amount of dexmedetomidine hydrochloride are weighed and pre-mixed in a 500 ml aluminum can for 5 minutes, and the remaining hydroxypropyl cellulose is added and pre-mixed for another 5 minutes; finally, the prescribed amount of polyoxyethylene is added and mixed for 10 minutes to obtain a total mixed material;

[0091] (2) Add the total mixed material into the feeder of the hot melt extruder, set the feeding speed to 40 rpm, the screw speed to 150 rpm, and the film extrusion temperature to 155 ° C. The specific parameters of the extruder are as follows:

[0092] Die 8 7 6 5 4 3 2 Temperature(℃) 155 155 155 155 155 130 110 90

[0093] According to the method of the present invention, the prepared dexmedetomidine hydrochloride orodispersible film is light yellow and translucent, with uniform color, can be completely dissolved within 30 seconds, has a thickness of 0.12 mm, a folding endurance of 75 times, an elongation at break of 8.28%, and a tensile strength of 25.91 (N / mm 2 ), content uniformity 97.89 + 2.22%.

[0094] Example 2 Preparation of dexmedetomidine hydrochloride orodispersible film

[0095] The prescription composition of the dexmedetomidine hydrochloride orodispersible film of the present invention (2000 tablets, 25 mg / tablet)

[0096] Components Weight(g) Dexmedetomidine hydrochloride 0.24 Hydroxypropyl Cellulose ELF 16.59 Polyoxyethylene N80 33.17 Neotame 0.05 Sunset Yellow 0.05

[0097] The preparation method of the dexmedetomidine hydrochloride orodispersible film of the present invention:

[0098] (1) Dexmedetomidine hydrochloride, hydroxypropyl cellulose and polyoxyethylene are pre-sieved with a 60-mesh sieve, and then half of the prescribed amount of hydroxypropyl cellulose and the prescribed amount of dexmedetomidine hydrochloride are weighed and pre-mixed in a 500 ml aluminum can for 5 minutes, and the remaining hydroxypropyl cellulose is added and pre-mixed for another 5 minutes; finally, the prescribed amount of polyoxyethylene, neotame and sunset yellow are added and mixed for 10 minutes to obtain a total mixed material;

[0099] (2) Add the total mixed material into the feeder of the hot melt extruder, set the feeding speed to 20 rpm, the screw speed to 100 rpm, the film extrusion temperature to 120 ° C, and the specific parameters of the extruder are as follows:

[0100] Die 8 7 6 5 4 3 2 Temperature(℃) 120 120 120 120 120 110 100 80

[0101] According to the method of the present invention, the prepared dexmedetomidine hydrochloride orodispersible film is light yellow and translucent, with uniform color, can be completely dissolved within 25 seconds, has a thickness of 0.15 mm, a folding endurance of 80 times, an elongation at break of 9.49%, and a tensile strength of 27.2 (N / mm 2 ), content uniformity 97.77 + 1.92%.

[0102] Example 3 Preparation of dexmedetomidine hydrochloride orodispersible film

[0103] The prescription composition of the dexmedetomidine hydrochloride orodispersible film of the present invention (2500 tablets, 20 mg / tablet)

[0104] Components Weight(g) Dexmedetomidine hydrochloride 1.2 Hydroxypropyl Cellulose ELF 16.59 Polyoxyethylene N80 33.17

[0105] The preparation method of the dexmedetomidine hydrochloride orodispersible film of the present invention:

[0106] (1) Dexmedetomidine hydrochloride, hydroxypropyl cellulose and polyoxyethylene are pre-sieved with a 60-mesh sieve, and then half of the prescribed amount of hydroxypropyl cellulose and the prescribed amount of dexmedetomidine hydrochloride are weighed and pre-mixed in a 500 ml aluminum can for 5 minutes, and the remaining hydroxypropyl cellulose is added and pre-mixed for another 5 minutes; finally, the prescribed amount of polyoxyethylene is added and mixed for 10 minutes to obtain a total mixed material;

[0107] (2) Add the total mixed material into the feeder of the hot melt extruder, set the feeding speed to 50 rpm, the screw speed to 200 rpm, the film extrusion temperature to 180 ° C, and the specific parameters of the extruder are as follows:

[0108] Die 8 7 6 5 4 3 2 Temperature(℃) 180 180 180 180 180 150 130 110

[0109] According to the method of the present invention, the prepared dexmedetomidine hydrochloride orodispersible film is light yellow and translucent, with uniform color, can be completely dissolved within 30 seconds, has a thickness of 0.14 mm, a folding endurance of 78 times, an elongation at break of 8.15%, and a tensile strength of 23.27 (N / mm 2 ), content uniformity 96.30 + 3.93%.

[0110] Example 4 Preparation of dexmedetomidine hydrochloride orodispersible film

[0111] The prescription composition of the dexmedetomidine hydrochloride orodispersible film of the present invention (2500 tablets, 20 mg / tablet)

[0112] Components Weight(g) Dexmedetomidine hydrochloride 0.3 Hydroxypropyl Cellulose ELF 16.54 Polyoxyethylene N80 33.06 Neotame 0.05 Sunset Yellow 0.05

[0113] The preparation method of the dexmedetomidine hydrochloride orodispersible film of the present invention:

[0114] (1) Pre-screening the dexmedetomidine hydrochloride raw material, hydroxypropyl cellulose and polyoxyethylene through a 60-mesh sieve, then weighing half of the prescribed amount of hydroxypropyl cellulose and the prescribed amount of dexmedetomidine hydrochloride in a 500 ml aluminum can and premixing for 5 minutes, adding the remaining hydroxypropyl cellulose, and premixing for another 5 minutes; finally, adding the prescribed amount of polyoxyethylene, neotame and sunset yellow, and mixing for 10 minutes to obtain a total mixed material;

[0115] (2) Add the total mixed material into the feeder of the hot melt extruder, set the feeding speed to 40 rpm, the screw speed to 150 rpm, and the film extrusion temperature to 155 ° C. The specific parameters of the extruder are as follows:

[0116] Die 8 7 6 5 4 3 2 Temperature(℃) 155 155 155 155 155 130 110 90

[0117] According to the method of the present invention, the prepared dexmedetomidine hydrochloride orodispersible film is light yellow and translucent, with uniform color, can be completely dissolved within 25 seconds, has a thickness of 0.12 mm, a folding endurance of 96 times, an elongation at break of 11.5%, and a tensile strength of 21.33 (N / mm 2 ), content uniformity 98.21 + 1.15%.

[0118] Example 5 Preparation of dexmedetomidine hydrochloride orodispersible film

[0119] The prescription composition of the dexmedetomidine hydrochloride orodispersible film of the present invention (2000 tablets, 25 mg / tablet)

[0120] Components Weight(g) Dexmedetomidine hydrochloride 0.3 Hydroxypropyl Cellulose ELF 24.8 Polyoxyethylene N80 24.8 Neotame 0.05 Sunset Yellow 0.05

[0121] The preparation method of the dexmedetomidine hydrochloride orodispersible film of the present invention:

[0122] (1) Dexmedetomidine hydrochloride, hydroxypropyl cellulose and polyoxyethylene are pre-sieved with a 60-mesh sieve, and then half of the prescribed amount of hydroxypropyl cellulose and the prescribed amount of dexmedetomidine hydrochloride are weighed and pre-mixed in a 500 ml aluminum can for 5 minutes, and the remaining hydroxypropyl cellulose is added and pre-mixed for another 5 minutes; finally, the prescribed amount of polyoxyethylene, neotame and sunset yellow are added and mixed for 10 minutes to obtain a total mixed material;

[0123] (2) Add the total mixed material into the feeder of the hot melt extruder, set the feeding speed to 30 rpm, the screw speed to 140 rpm, the film extrusion temperature to 140 ° C, and the specific parameters of the extruder are as follows:

[0124] Die 8 7 6 5 4 3 2 Temperature(℃) 140 140 140 140 140 130 110 90

[0125] According to the method of the present invention, the prepared dexmedetomidine hydrochloride orodispersible film is light yellow and translucent, with uniform color, can be completely dissolved within 45 seconds, has a thickness of 0.15 mm, a folding endurance of 60 times, an elongation at break of 5.3%, and a tensile strength of 19.2 (N / mm 2 ), content uniformity 97.41 + 0.52%.

[0126] Example 6 Preparation of dexmedetomidine hydrochloride orodispersible film

[0127] The prescription composition of the dexmedetomidine hydrochloride orodispersible film of the present invention (2000 tablets, 25 mg / tablet)

[0128]

[0129]

[0130] The preparation method of the dexmedetomidine hydrochloride orodispersible film of the present invention:

[0131] (1) Dexmedetomidine hydrochloride, hydroxypropyl cellulose and polyoxyethylene are pre-sieved with a 60-mesh sieve, and then half of the prescribed amount of hydroxypropyl cellulose and the prescribed amount of dexmedetomidine hydrochloride are weighed and pre-mixed in a 500 ml aluminum can for 5 minutes, and the remaining hydroxypropyl cellulose is added and pre-mixed for another 5 minutes; finally, the prescribed amount of polyoxyethylene, neotame and sunset yellow are added and mixed for 10 minutes to obtain a total mixed material;

[0132] (2) Add the total mixed material into the feeder of the hot melt extruder, set the feeding speed to 40 rpm, the screw speed to 150 rpm, and the film extrusion temperature to 155 ° C. The specific parameters of the extruder are as follows:

[0133] Die 8 7 6 5 4 3 2 Temperature(℃) 155 155 155 155 155 130 110 90

[0134] According to the method of the present invention, the prepared dexmedetomidine hydrochloride orodispersible film is light yellow and translucent, with uniform color, can be completely dissolved within 15 seconds, has a thickness of 0.12 mm, a folding endurance of 25 times, an elongation at break of 3.4%, and a tensile strength of 17 (N / mm 2 ), content uniformity 99.22 + 1.02%.

[0135] Example 7 Preparation of dexmedetomidine hydrochloride orodispersible film

[0136] The prescription composition of the dexmedetomidine hydrochloride orodispersible film of the present invention (2000 tablets, 25 mg / tablet)

[0137] Components Weight(g) Dexmedetomidine hydrochloride 0.3 Polyoxyethylene N80 33.17 Copolyvinylpyrrolidone VA64 16.53

[0138] The preparation method of the dexmedetomidine hydrochloride orodispersible film of the present invention:

[0139] (1) Dexmedetomidine hydrochloride, copovidone and polyoxyethylene are pre-sieved with a 60-mesh sieve, and then half of the prescribed amount of copovidone and the prescribed amount of dexmedetomidine hydrochloride are weighed and premixed in a 500 ml aluminum can for 5 minutes, and the remaining copovidone is added and premixed for another 5 minutes; finally, the prescribed amount of polyoxyethylene is added and mixed for 10 minutes to obtain a total mixed material;

[0140] (2) Add the total mixed material into the feeder of the hot melt extruder, set the feeding speed to 40 rpm, the screw speed to 150 rpm, and the film extrusion temperature to 155 ° C. The specific parameters of the extruder are as follows:

[0141] Die 8 7 6 5 4 3 2 Temperature(℃) 155 155 155 155 155 130 110 90

[0142] According to the method of the present invention, the prepared dexmedetomidine hydrochloride orodispersible film is light yellow and translucent, with uniform color, can be completely dissolved within 15 seconds, has a thickness of 0.23 mm, a folding endurance of 25 times, an elongation at break of 5.3%, and a tensile strength of 15.2 (N / mm 2 ), content uniformity 95.41 + 0.75%.

[0143] Example 8 Preparation of dexmedetomidine hydrochloride orodispersible film

[0144] The prescription composition of the dexmedetomidine hydrochloride orodispersible film of the present invention (2000 tablets, 25 mg / tablet)

[0145]

[0146] The preparation method of the dexmedetomidine hydrochloride orodispersible film of the present invention:

[0147] (1) Dexmedetomidine hydrochloride, Soluplus and polyoxyethylene were pre-sieved with a 60-mesh sieve, and then half of the prescribed amount of Soluplus and the prescribed amount of dexmedetomidine hydrochloride were weighed and premixed in a 500 ml aluminum can for 5 minutes, and the remaining Soluplus was added and premixed for another 5 minutes; finally, the prescribed amount of polyoxyethylene was added and mixed for 10 minutes to obtain a total mixed material;

[0148] (2) Add the total mixed material into the feeder of the hot melt extruder, set the feeding speed to 40 rpm, the screw speed to 150 rpm, and the film extrusion temperature to 155 ° C. The specific parameters of the extruder are as follows:

[0149] Die 8 7 6 5 4 3 2 Temperature(℃) 155 155 155 155 155 130 110 90

[0150] According to the method of the present invention, the prepared dexmedetomidine hydrochloride orodispersible film is light yellow and translucent, with uniform color, can be completely dissolved within 50 seconds, has a thickness of 0.13 mm, a folding endurance of 50 times, an elongation at break of 8.21%, and a tensile strength of 21.2 (N / mm 2 ), content uniformity 96.25 + 0.87%.

[0151] Preparation of blank dissolving film in comparative example

[0152] Prescription composition of blank oral dissolving film (20mg / tablet)

[0153] Components Weight(g) Polyoxyethylene N80 33.36 Polypropylcellulose ELF 16.54 Neotame 0.05 Sunset Yellow 0.05

[0154] (1) Pre-screen hydroxypropyl cellulose and polyoxyethylene through a 60-mesh sieve, then weigh half of the prescribed amount of hydroxypropyl cellulose in a 500 ml aluminum can and pre-mix for 5 minutes, add the remaining hydroxypropyl cellulose, and pre-mix for another 5 minutes; finally, add the prescribed amount of polyoxyethylene, neotame, and sunset yellow, and mix for 10 minutes to obtain a total mixed material;

[0155] (2) Add the total mixed material into the feeder of the hot melt extruder, set the feeding speed to 40 rpm, the screw speed to 150 rpm, the film extrusion temperature to 155°C, and obtain a blank melt film. The specific parameters of the extruder are as follows:

[0156] Die 8 7 6 5 4 3 2 Temperature(℃) 155 155 155 155 155 130 110 90

[0157] Test Example 1 Dissolution Study of Dexmedetomidine Hydrochloride Oral Disintegrating Film of the Present Invention

[0158] According to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0931, Method 2), simulated saliva was used as the dissolution medium, the dissolution method was the paddle method, the medium volume was 500 ml, the rotation speed was 50 revolutions per minute, and 20 mg of dexmedetomidine hydrochloride orodispersible film of Example 1, Example 4, Example 6, Example 7, and Example 8 were taken respectively, with a sampling volume of 5 ml and a rehydration volume of 5 ml. The operation was carried out in accordance with the law, and samples were taken at 3 min, 5 min, 10 min, 15 min, 20 min, and 30 min, respectively, and the dissolution was determined. The results are shown in FIG. Figure 1 .

[0159] Experimental study on the efficacy of dexmedetomidine hydrochloride orodispersible film of the present invention

[0160] Twelve adult male beagle dogs (weight 10±0.5kg) that passed the quarantine were selected and divided into a drug-treated group and a blank group, with 6 dogs in each group:

[0161] Dosing group: Each beagle dog was given 20 mg of the dexmedetomidine hydrochloride orosoluble film of Example 4 (containing 120 μg of dexmedetomidine hydrochloride)

[0162] Blank group: each beagle dog was given 20 mg of the blank oral dissolving film of the comparative example.

[0163] Do not eat or drink water one day before administration. Before administration, make sure that the administration site is not keratinized and open the dog's mouth 20°-30° to ensure smooth administration and stable state of the beagle. After administration, hold the dog's mouth for 2-3 minutes and keep the beagle's head drooping to avoid swallowing of the orodispersible film. After administration, check the sublingual area to ensure that the orodispersible film is completely dissolved.

[0164] The sedation state was recorded, and the overall process was divided into sedation latency (the duration of the beagle from upright to prone position), sedation maintenance period (the duration of the beagle from prone position to lateral position and then to prone position recovery, with the beagle's no response to gentle push and clapping and eyelid closure after being in prone position as the starting time point of sedation maintenance period) and awakening period (the duration of the beagle from prone position to upright recovery, with the beagle's response to gentle push and clapping and open eyelids after being in prone position as the starting time point of awakening period).

[0165] The results showed that the beagles in the blank group were always upright and did not enter a sedated state. However, the beagles in the drug group had a sedation latency of 20-30 minutes, a sedation maintenance period of 2-2.5 hours, and a waking period of 20-30 minutes, with a good sedative effect. After waking up, they could drink water normally and had no significant sequelae of medication.

[0166] Experimental Example 3 Pharmacokinetic Study of Dexmedetomidine Hydrochloride Oral Disintegrating Film of the Present Invention

[0167] Six adult male beagles (weight 10±0.5 kg) that passed the quarantine were selected. The beagles were fed with dog food at 2%-3% of their body weight and drinking water at 1.5%-2.0% of their body weight daily. They were fasted (with free drinking water) overnight before the experiment.

[0168] 1. Experimental methods

[0169] The drugs were administered in a double crossover test and randomly divided into 2 groups, with 3 mice in each group.

[0170] Experimental group: Each beagle dog was given 20 mg of the dexmedetomidine hydrochloride orodispersible film of Example 4 (containing 120 μg of dexmedetomidine hydrochloride)

[0171] Control group: beagle dogs were given 0.6 mL of 200 μg / mL dexmedetomidine hydrochloride injection (0.2 g dexmedetomidine hydrochloride was dissolved in 1000 mL of normal saline to prepare an injection) at a dose of 120 μg dexmedetomidine hydrochloride per dog.

[0172] Dosage: Hold the beagle's mouth open with tweezers, cut the appropriate size and place it under the tongue, hold the dog's mouth for about 3 minutes, and wait for it to dissolve completely; the injection is injected into the dog's front limb head vein. Washing period: one week.

[0173] 2. Blood sample collection and processing

[0174] Blank blood was collected before administration. After administration, 0.5 ml of blood was collected from the cephalic vein of the forelimb at 11 blood collection time points, including 5 min, 10 min, 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, and 6 h. The blood sample was placed in an EP tube containing heparin and centrifuged at 5000 r / min for 10 min at 4 °C. The upper plasma was aspirated and stored frozen at -40 °C until testing.

[0175] 3. Pretreatment of whole blood samples

[0176] Direct protein precipitation method was used for sample pretreatment. After the frozen plasma samples were thawed at room temperature, an appropriate amount was transferred and quantitatively added with 4 times acetonitrile solution containing internal standard propranolol (10 ng / mL) for precipitation. The samples were vortexed for 1 minute and centrifuged at 4000 r / min for 10 min. 120 μL of the supernatant was quantitatively taken for sample analysis and LCMS / MS sample determination. Each analytical batch required a standard curve and quality control samples.

[0177] 4. Analysis of pharmacokinetic results

[0178] The concentration-time curve of dexmedetomidine hydrochloride orodispersible film in beagle dogs Figure 2 . Phoenix 8.1 software was used to analyze the pharmacokinetic parameters, and the pharmacokinetic parameters were as follows: the plasma elimination half-life of the control group was about 2.12h, and the area under the drug-time curve was about 32.21h*ng / mL; the plasma elimination half-life of the experimental group was about 2.33h, and the area under the drug-time curve was about 25.01h*ng / mL. The bioavailability of intravenous administration was 1, and the absolute bioavailability of the orodispersible film was about 77.63%.

[0179] The above description of the specific embodiments of the present invention does not limit the present invention. Those skilled in the art may make various changes or modifications based on the present invention. As long as they do not depart from the spirit of the present invention, they should all fall within the scope of protection of the claims of the present invention.

Claims

1. A dexmedetomidine hydrochloride orodispersible film, comprising, by weight percentage, 0.1-10% dexmedetomidine hydrochloride and 90%-99.9% film-forming material, wherein: The film-forming material is selected from any one of copolyvidone, polyvinyl caprolactam polyvinyl acetate polyethylene glycol graft copolymer, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol, polyoxyethylene, povidone, poloxamer or a combination thereof.

2. The dexmedetomidine hydrochloride orodispersible film according to claim 1, wherein the orodispersible film contains, by weight percentage, 0.2-5% of dexmedetomidine hydrochloride and 95%-99.8% of film-forming material.

3. The dexmedetomidine hydrochloride orodispersible film according to any one of claims 1 to 2, wherein the orodispersible film contains, by weight percentage, 0.2-5% of dexmedetomidine hydrochloride, 25%-60% of hydroxypropyl cellulose and 35-70% of polyoxyethylene.

4. The dexmedetomidine hydrochloride orodispersible film according to any one of claims 1 to 3, wherein the orodispersible film contains, by weight percentage, 0.2-5% of dexmedetomidine hydrochloride, 35-70% of hydroxypropyl cellulose and 25%-60% of polyoxyethylene.

5. The dexmedetomidine hydrochloride orodispersible film according to any one of claims 1 to 4, wherein the orodispersible film contains, by weight percentage, 0.2-5% of dexmedetomidine hydrochloride, 35-70% of polyoxyethylene and 25%-60% of copovidone.

6. The dexmedetomidine hydrochloride orodispersible film according to any one of claims 1 to 5, wherein the orodispersible film contains, by weight percentage, 0.2-5% of dexmedetomidine hydrochloride, 25%-60% of polyoxyethylene, and 35-70% of polyethylene caprolactam polyvinyl acetate polyethylene glycol graft copolymer.

7. The dexmedetomidine hydrochloride orodispersible film according to any one of claims 1 to 6, wherein the orodispersible film optionally contains any one of a flavoring agent and a coloring agent.

8. The dexmedetomidine hydrochloride orosoluble film according to any one of claims 1 to 7, wherein the preparation method of the dexmedetomidine hydrochloride orosoluble film comprises the following steps: mixing the required amounts of the components to obtain a total mixed material, adding the mixed material to a hot melt extruder, setting the temperature of different sections of the barrel to 90-170° C., setting the feeding speed to 20-100 rpm, the screw speed to 100-250 rpm, the film drawing speed to 1.0-3.5 m / min, the film mouth extrusion temperature to 90-180° C., and forming a film.

9. The method for preparing the orosoluble dexmedetomidine hydrochloride film according to any one of claims 1 to 8, comprising the steps of: mixing the required amounts of the components to obtain a total mixed material, adding the mixed material to a hot melt extruder, setting the temperature of different sections of the barrel to 90-170° C., setting the feeding speed to 20-100 rpm, the screw speed to 100-250 rpm, the film drawing speed to 1.0-3.5 m / min, the film extrusion temperature to 90-180° C., and forming a film.

10. Use of the dexmedetomidine hydrochloride orosoluble film according to any one of claims 1 to 8 in preparing sedatives, analgesics and anti-insomnia drugs.

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