A dexmedetomidine hydrochloride orally disintegrating film and its preparation method and application

Abstract

The present invention relates to a kind of dexmedetomidine hydrochloride orally disintegrating film, in which the orally disintegrating film contains dexmedetomidine hydrochloride 0.1-10% and film-forming material 90%-99.9% by weight, wherein the film-forming material is selected from any one of copolyvidone, polyethylene caprolactam polyvinyl acetate polyethylene glycol graft copolymer, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol, polyoxyethylene, povidone, and poloxamer or a combination thereof. The dexmedetomidine hydrochloride orally disintegrating film of the present invention has fast disintegration time in the oral cavity, good mechanical extrusion performance, good film-forming performance, high content uniformity, meets the requirements such as cutting, packaging, transportation and clinical use, significantly improves its dissolution and dissolution rate, stability and bioavailability, and does not need to be taken with water, significantly improves the compliance of children patients, and ensures safe and effective medication.

Description

Technical Field

[0001] The invention belongs to the technical field of medicine, and particularly relates to a dexmedetomidine hydrochloride orally disintegrating 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 mainly achieves a sedative effect by stimulating α2-adrenergic receptors in the locus coeruleus area of ​​the brain, inhibiting the release of norepinephrine and reducing the activity of the sympathetic nerves.

[0003] Currently available products include dexmedetomidine hydrochloride injection and dexmedetomidine hydrochloride nasal spray, but they present several challenges. The injection is commonly used clinically for procedural sedation during mechanical ventilation. It requires a 0.9% sodium chloride solution diluted to a concentration of 4 μg / ml and a slow intravenous infusion of 1 μg / kg over 10 minutes. For patients requiring short-term sedation for minor surgeries and examinations, intravenous infusion has poor compliance, and the effective dose cannot be quickly achieved. Furthermore, the invasive nature of the drug administration makes it difficult for children to comply. The nasal spray requires pre-clearing of the nasal cavity and requires four sprays per nostril, resulting in a lengthy administration time that can lead to poor compliance in children.

[0004] Studies have been conducted to prepare dexmedetomidine hydrochloride into an orally disintegrating film, which absorbs the drug through the sublingual mucosa and takes effect quickly. However, orally disintegrating films are mostly prepared using a solvent casting method, which has the following drawbacks: 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 undergo a swelling and then dissolving process, and a large number of bubbles are generated during the dissolution process, which is difficult to remove. This not only easily leads to unqualified content uniformity in the finished product, incomplete defoaming, poor film-forming properties, and multiple pores in the finished product, but also affects processing efficiency; third, the subsequent coating, drying, and demolding processes are complex, and the preparation of a batch of finished film 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 orally disintegrating dexmedetomidine hydrochloride films and their preparation methods. Summary of the Invention

[0005] The present invention aims to provide a dexmedetomidine hydrochloride orally disintegrating film. The orally disintegrating 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, polyethylene caprolactam polyvinyl acetate polyethylene glycol graft copolymer, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol, polyethylene oxide, povidone, and poloxamer, or a combination thereof.

[0006] In a 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 a preferred technical solution of the present invention, the orally disintegrating film contains 0.2-5% of dexmedetomidine hydrochloride and 95%-99.8% of film-forming material in terms of weight percentage.

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

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

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

[0011] In a preferred technical solution of the present invention, the orally disintegrating 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 disintegrating film optionally contains any one of a flavoring agent and a coloring agent.

[0013] In a preferred technical solution 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 a preferred technical solution of the present invention, the content of the flavoring agent in the orally dissolving 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 iron oxide red, iron oxide yellow, carmine, sunset yellow, or a combination thereof.

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

[0017] In a preferred technical solution of the present invention, the orally disintegrating 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 disintegrating film contains, by weight percentage, 0.48% dexmedetomidine hydrochloride, 32.98% hydroxypropyl cellulose, 66.34% polyoxyethylene, 0.1% neotame, and 0.1% sunset yellow.

[0019] In a preferred technical solution of the present invention, the orally disintegrating 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 disintegrating 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 disintegrating film contains, by weight percentage, 0.6% dexmedetomidine hydrochloride, 49.6% hydroxypropyl cellulose, 49.6% polyoxyethylene, 0.1% neotame, and 0.1% sunset yellow.

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

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

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

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

[0026] In a preferred technical solution of the present invention, the orally disintegrating 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 disintegrating 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 disintegrating film is 0.1-0.2 mm.

[0029] In a preferred technical solution of the present invention, the orally disintegrating 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 disintegrating 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 disintegrating 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 disintegrating film is greater than 95%, preferably greater than 98%.

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

[0034] In a preferred technical solution of the present invention, the method for preparing the orally dissolving dexmedetomidine hydrochloride 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 extrusion temperature to 90-180° C., and forming a film.

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

[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 present invention aims to provide a method for preparing an orally disintegrating dexmedetomidine hydrochloride film. The orally disintegrating dexmedetomidine hydrochloride 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, a polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol, polyethylene oxide, povidone, and poloxamer, or a combination thereof. The method for preparing the orally disintegrating dexmedetomidine hydrochloride film comprises the following steps: mixing 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 a feeding rate of 20-100 rpm, a screw speed of 100-250 rpm, a film drawing speed of 1.0-3.5 m / min, and a film extrusion temperature of 90-180° C., and forming the film.

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

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

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

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

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

[0047] In a preferred technical solution of the present invention, the orally disintegrating 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 disintegrating film optionally contains any one of a flavoring agent and a coloring agent.

[0049] In a preferred technical solution 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 a preferred technical solution of the present invention, the content of the flavoring agent in the orally dissolving 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 iron oxide red, iron oxide yellow, carmine, sunset yellow, or a combination thereof.

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

[0053] In a preferred technical solution of the present invention, the orally disintegrating 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 disintegrating film contains, by weight percentage, 0.48% dexmedetomidine hydrochloride, 32.98% hydroxypropyl cellulose, 66.34% polyoxyethylene, 0.1% neotame, and 0.1% sunset yellow.

[0055] In a preferred technical solution of the present invention, the orally disintegrating 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 disintegrating 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 disintegrating film contains, by weight percentage, 0.6% dexmedetomidine hydrochloride, 49.6% hydroxypropyl cellulose, 49.6% polyoxyethylene, 0.1% neotame, and 0.1% sunset yellow.

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

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

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

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

[0062] In a preferred technical solution of the present invention, the orally disintegrating 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 disintegrating 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 disintegrating film is 0.1-0.2 mm.

[0065] In a preferred technical solution of the present invention, the orally disintegrating 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 disintegrating 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 disintegrating 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 disintegrating film is greater than 95%, preferably greater than 98%.

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

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

[0073] Another object of the present invention is to provide use of the dexmedetomidine hydrochloride orally disintegrating 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 percentages are volume / volume percentages; when the present invention relates to the percentage between liquids and solids, the percentages are volume / weight percentages; when the present invention relates to the percentage between solids and liquids, the percentages are weight / volume percentages; and 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 The test is performed by clamping on a tensile device.

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

[0079] 4. LC-MS analysis: The plasma samples to be tested were processed and then subjected to LC-MS analysis to obtain a standard curve. The LC-MS analysis method used 0.1% formic acid aqueous solution as mobile phase A, acetonitrile as mobile phase B, and gradient elution. The elution conditions were as follows: 0-0.3 min, mobile phase A 90%; 0.3-1.5 min, mobile phase A 90→5%; 1.5-2.0 min, mobile phase A 5%; 2.0-2.1 min, mobile phase A 5→90%; 2.1-3.0 min, 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 orally dissolving film, and uses a hot-melt extrusion method to disperse dexmedetomidine hydrochloride in a water-soluble high molecular weight polymer to prepare the orally dissolving film. The orally dissolving film 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. It significantly improves its solubility and dissolution rate, stability, and bioavailability. Moreover, the dexmedetomidine hydrochloride orally dissolving film does not require water for administration and dissolves and is absorbed sublingually, significantly improving the compliance of pediatric patients and ensuring safe and effective medication.

[0082] 2. The preparation method of the dexmedetomidine hydrochloride orally dissolving 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, and suitability for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0084] Figure 2 The drug-time curve of the dexmedetomidine hydrochloride orally disintegrating 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 for illustrative purposes only and are not intended to limit the scope of the present invention.

[0086] Example 1 Preparation of Dexmedetomidine Hydrochloride Orally Dissolving Film

[0087] The prescription composition of the dexmedetomidine hydrochloride orally dissolving 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 orally dissolving film of the present invention:

[0090] (1) Dexmedetomidine hydrochloride, hydroxypropyl cellulose, and polyoxyethylene were pre-sieved with a 60-mesh sieve. Half of the prescribed amount of hydroxypropyl cellulose and the prescribed amount of dexmedetomidine hydrochloride were weighed and pre-mixed in a 500 ml aluminum can for 5 minutes. The remaining hydroxypropyl cellulose was added and pre-mixed for another 5 minutes. Finally, the prescribed amount of polyoxyethylene was added and mixed for 10 minutes to obtain the total mixed material.

[0091] (2) Add the total mixed material to the hot melt extruder feeder, set the feed rate 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 orally dissolving 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 Orally Dissolving Film

[0095] The prescription composition of the dexmedetomidine hydrochloride orally dissolving 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 orally dissolving film of the present invention:

[0098] (1) Dexmedetomidine hydrochloride, hydroxypropyl cellulose, and polyoxyethylene were pre-sieved with a 60-mesh sieve. Half of the prescribed amount of hydroxypropyl cellulose and the prescribed amount of dexmedetomidine hydrochloride were weighed and pre-mixed in a 500 ml aluminum can for 5 minutes. The remaining hydroxypropyl cellulose was added and pre-mixed for another 5 minutes. Finally, the prescribed amount of polyoxyethylene, neotame, and sunset yellow were added and mixed for 10 minutes to obtain the total mixed material.

[0099] (2) Add the total mixed material to the hot melt extruder feeder, set the feed rate to 20 rpm, the screw speed to 100 rpm, and the film extrusion temperature to 120 ° C. 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 orally dissolving film is light yellow and translucent with uniform color, can be completely dissolved within 25 seconds, has a thickness of 0.15 mm, can withstand 80 folds, has 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 Orally Dissolving Film

[0103] The prescription composition of the dexmedetomidine hydrochloride orally dissolving 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 orally dissolving film of the present invention:

[0106] (1) Dexmedetomidine hydrochloride, hydroxypropyl cellulose, and polyoxyethylene were pre-sieved with a 60-mesh sieve. Half of the prescribed amount of hydroxypropyl cellulose and the prescribed amount of dexmedetomidine hydrochloride were weighed and pre-mixed in a 500 ml aluminum can for 5 minutes. The remaining hydroxypropyl cellulose was added and pre-mixed for another 5 minutes. Finally, the prescribed amount of polyoxyethylene was added and mixed for 10 minutes to obtain the total mixed material.

[0107] (2) Add the total mixed material to the hot melt extruder feeder, set the feed rate to 50 rpm, the screw speed to 200 rpm, and the film extrusion temperature to 180 ° C. 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 orally dissolving 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 Orally Dissolving Film

[0111] The prescription composition of the dexmedetomidine hydrochloride orally dissolving 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 orally dissolving film of the present invention:

[0114] (1) Dexmedetomidine hydrochloride raw material, hydroxypropyl cellulose and polyoxyethylene were pre-sieved with a 60-mesh sieve. Half of the prescribed amount of hydroxypropyl cellulose and the prescribed amount of dexmedetomidine hydrochloride were weighed and premixed in a 500 ml aluminum can for 5 minutes. The remaining hydroxypropyl cellulose was added and premixed for another 5 minutes. Finally, the prescribed amount of polyoxyethylene, neotame and sunset yellow were added and mixed for 10 minutes to obtain the total mixed material.

[0115] (2) Add the total mixed material to the hot melt extruder feeder, set the feed rate 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 orally dissolving 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 Orally Dissolving Film

[0119] The prescription composition of the dexmedetomidine hydrochloride orally dissolving 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 orally dissolving film of the present invention:

[0122] (1) Dexmedetomidine hydrochloride, hydroxypropyl cellulose, and polyoxyethylene were pre-sieved with a 60-mesh sieve. Half of the prescribed amount of hydroxypropyl cellulose and the prescribed amount of dexmedetomidine hydrochloride were weighed and pre-mixed in a 500 ml aluminum can for 5 minutes. The remaining hydroxypropyl cellulose was added and pre-mixed for another 5 minutes. Finally, the prescribed amount of polyoxyethylene, neotame, and sunset yellow were added and mixed for 10 minutes to obtain the total mixed material.

[0123] (2) Add the total mixed material to the hot melt extruder feeder, set the feed rate to 30 rpm, the screw speed to 140 rpm, and the film extrusion temperature to 140 ° C. 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 orally dissolving 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 Orally Dissolving Film

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

[0128]

[0129]

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

[0131] (1) Dexmedetomidine hydrochloride, hydroxypropyl cellulose, and polyoxyethylene were pre-sieved with a 60-mesh sieve. Half of the prescribed amount of hydroxypropyl cellulose and the prescribed amount of dexmedetomidine hydrochloride were weighed and pre-mixed in a 500 ml aluminum can for 5 minutes. The remaining hydroxypropyl cellulose was added and pre-mixed for another 5 minutes. Finally, the prescribed amount of polyoxyethylene, neotame, and sunset yellow were added and mixed for 10 minutes to obtain the total mixed material.

[0132] (2) Add the total mixed material to the hot melt extruder feeder, set the feed rate 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 orally dissolving 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 Orally Dissolving Film

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

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

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

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

[0140] (2) Add the total mixed material to the hot melt extruder feeder, set the feed rate 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 orally dissolving 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 Orally Dissolving Film

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

[0145]

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

[0147] (1) Dexmedetomidine hydrochloride, Soluplus, and polyoxyethylene were pre-sieved with a 60-mesh sieve. 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. 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 the total mixed material.

[0148] (2) Add the total mixed material to the hot melt extruder feeder, set the feed rate 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 orally dissolving 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 of comparative example

[0152] Prescription composition of blank orally 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 with 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 the total mixed material.

[0155] (2) Add the total mixed material to the feeder of the hot melt extruder, set the feed rate to 40 rpm, the screw speed to 150 rpm, and the film extrusion temperature to 155 ° C to 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 Investigation of Dexmedetomidine Hydrochloride Orally Dissolving Film of the Present Invention

[0158] According to the dissolution and release determination method (Chinese Pharmacopoeia 2020 edition, Part IV, General Rules 0931, Second Method), 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 orally dissolving 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, and the dissolution was determined. The results are shown in FIG. Figure 1 .

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

[0160] Twelve adult male beagle dogs (weighing 10±0.5 kg) that passed 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 orally disintegrating film of Example 4 (containing 120 μg of dexmedetomidine hydrochloride)

[0162] Blank group: Each beagle dog was given 20 mg of the blank orally disintegrating film of the comparative example.

[0163] The dog was not allowed to eat or drink water one day before administration. Before administration, ensure that the administration site was free of keratinization and open the dog's mouth 20°-30° to ensure smooth administration and a stable state of the beagle. After administration, hold the dog's mouth tightly for 2-3 minutes and keep the beagle's head drooping to avoid swallowing the orodissolving film. After administration, recheck the sublingual area to ensure that the orodissolving film was 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 start time of the sedation maintenance period being the absence of response to gentle nudging and hand clapping and eyelid closure after the beagle was in the prone position), and awakening period (the duration of the beagle from prone position to upright position recovery, with the start time of the awakening period being the response to gentle nudging and hand clapping and eyelid opening after the beagle was in the prone position).

[0165] The results showed that the beagle dogs in the blank group remained upright and did not enter a sedated state. However, the beagle dogs in the drug group experienced a sedative latency period of 20-30 minutes, a sedative maintenance period of 2-2.5 hours, and a 20-30 minute recovery period, demonstrating a good sedative effect. After recovery, they were able to drink water normally and showed no significant aftereffects.

[0166] Experimental Example 3 Pharmacokinetic Study of Dexmedetomidine Hydrochloride Orally Dissolving Film of the Present Invention

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

[0168] 1. Experimental methods

[0169] A double-cross test was used for drug administration and the animals were randomly divided into two groups, with 3 animals in each group.

[0170] Experimental group: Each beagle dog was given 20 mg of the dexmedetomidine hydrochloride orally disintegrating 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 the tablet under the tongue. Hold the dog's mouth for approximately 3 minutes until the tablet dissolves completely. Inject the tablet into the cephalic vein of the dog's forelimb. Washout 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, namely 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 a heparin-containing EP tube 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. Whole blood sample pretreatment

[0176] Direct protein precipitation was used for sample pretreatment. After the frozen plasma samples were thawed at room temperature, an appropriate amount was transferred and quantitatively added to a 4-fold acetonitrile solution containing the internal standard propranolol (10 ng / mL) for precipitation. The samples were vortexed for 1 minute and centrifuged at 4000 rpm for 10 minutes. 120 μL of the supernatant was quantitatively sampled for analysis and LCMS / MS injection was performed. A standard curve and quality control samples were required for each analytical batch.

[0177] 4. Analysis of pharmacokinetic results

[0178] The concentration-time curve of dexmedetomidine hydrochloride orally disintegrating film in beagle dogs is shown in Figure 2 Pharmacokinetic analysis was performed using Phoenix 8.1 software, yielding the following pharmacokinetic parameters: the plasma elimination half-life in the control group was approximately 2.12 hours, with an area under the concentration-time curve of approximately 32.21 h*ng / mL; the plasma elimination half-life in the experimental group was approximately 2.33 hours, with an area under the concentration-time curve of approximately 25.01 h*ng / mL. The bioavailability of the intravenous injection was 1, and the absolute bioavailability of the orally disintegrating film was approximately 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 can 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 fall within the scope of protection of the claims of the present invention.

Claims

1. A dexmedetomidine hydrochloride orally disintegrating film, comprising, by weight, 0.2-5% dexmedetomidine hydrochloride, 25%-60% hydroxypropyl cellulose, and 35-70% polyoxyethylene; Alternatively, the orally disintegrating film is made of 0.2-5% dexmedetomidine hydrochloride, 35-70% hydroxypropyl cellulose and 25%-60% polyoxyethylene. Alternatively, the orally disintegrating film is made of 0.2-5% dexmedetomidine hydrochloride, 35-70% polyethylene oxide, and 25%-60% copovidone; Alternatively, the orally disintegrating film is made of 0.2-5% dexmedetomidine hydrochloride, 25%-60% polyoxyethylene, and 35-70% polyethylene caprolactam polyvinyl acetate polyethylene glycol graft copolymer; Alternatively, the orally disintegrating film is made of 0.2-5% dexmedetomidine hydrochloride, 25%-60% hydroxypropyl cellulose, 35-70% polyoxyethylene, 0.1%-1% flavoring agent, and 0.1-0.2% coloring agent; Alternatively, the orally disintegrating film is made of 0.2-5% dexmedetomidine hydrochloride, 35-70% hydroxypropyl cellulose, 25%-60% polyoxyethylene, 0.1%-1% flavoring agent, and 0.1-0.2% coloring agent. in, The orally dissolving film is prepared by a hot melt extrusion method. The orally dissolving film has a folding endurance of more than 20 times and a content uniformity of more than 95%. The hot melt extrusion method comprises the following steps: mixing the required amounts of the components, adding the prepared total mixed material into a hot melt extruder, setting the barrel section temperature 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 the film.

2. The dexmedetomidine hydrochloride orally disintegrating film according to claim 1, wherein 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.

3. The dexmedetomidine hydrochloride orally disintegrating film according to claim 1, wherein the colorant is selected from any one of iron oxide red, iron oxide yellow, carmine, and sunset yellow, or a combination thereof.

4. The dexmedetomidine hydrochloride orally disintegrating film according to claim 1, wherein the orally disintegrating film is composed of 0.48% dexmedetomidine hydrochloride, 33.18% hydroxypropyl cellulose and 66.34% polyoxyethylene, based on weight percentage.

5. The dexmedetomidine hydrochloride orally disintegrating film according to claim 1, wherein the orally disintegrating film is composed of 0.48% dexmedetomidine hydrochloride, 32.98% hydroxypropyl cellulose, 66.34% polyoxyethylene, 0.1% neotame, and 0.1% sunset yellow, in terms of weight percentage.

6. The dexmedetomidine hydrochloride orally disintegrating film according to claim 1, wherein the orally disintegrating film is composed of 2.35% dexmedetomidine hydrochloride, 32.55% hydroxypropyl cellulose and 65.09% polyoxyethylene, based on weight percentage.

7. The dexmedetomidine hydrochloride orally disintegrating film according to claim 1, wherein the orally disintegrating film is composed of 0.6% dexmedetomidine hydrochloride, 33.08% hydroxypropyl cellulose, 66.12% polyoxyethylene, 0.1% neotame, and 0.1% sunset yellow, by weight percentage.

8. The dexmedetomidine hydrochloride orally disintegrating film according to claim 1, wherein the orally disintegrating film is composed of 0.6% dexmedetomidine hydrochloride, 49.6% hydroxypropyl cellulose, 49.6% polyoxyethylene, 0.1% neotame, and 0.1% sunset yellow, in terms of weight percentage.

9. The dexmedetomidine hydrochloride orally disintegrating film according to claim 1, wherein the orally disintegrating film is composed of 0.6% dexmedetomidine hydrochloride, 66.12% hydroxypropyl cellulose, 33.08% polyoxyethylene, 0.1% neotame, and 0.1% iron oxide yellow, in terms of weight percentage.

10. The dexmedetomidine hydrochloride orally disintegrating film according to claim 1, wherein the orally disintegrating film is made of 0.6% dexmedetomidine hydrochloride, 66.34% polyoxyethylene and 33.06% copovidone, based on weight percentage.

11. The dexmedetomidine hydrochloride orally disintegrating film according to claim 1, wherein the orally disintegrating film is made of 0.6% dexmedetomidine hydrochloride, 49.7% polyoxyethylene, and 49.7% polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, by weight percentage.

12. The dexmedetomidine hydrochloride orally disintegrating film according to any one of claims 1 to 11, which dissolves in 37°C constant temperature water within 1 minute. The dexmedetomidine hydrochloride orally disintegrating film according to claim 12 , which dissolves in 37° C. constant temperature water within 30 seconds. The dexmedetomidine hydrochloride orally disintegrating film according to claim 13 , which dissolves in 37° C. constant temperature water within 20 seconds.

15. The dexmedetomidine hydrochloride orally disintegrating film according to any one of claims 1 to 11, wherein the thickness of the orally disintegrating film is 0.1 to 0.2 mm. The dexmedetomidine hydrochloride orally disintegrating film according to claim 1 , wherein the orally disintegrating film has a folding resistance of more than 30 times.

17. The dexmedetomidine hydrochloride orally disintegrating film according to any one of claims 1 to 11, wherein the elongation at break of the orally disintegrating film is greater than 2%. The dexmedetomidine hydrochloride orally disintegrating film according to claim 17 , wherein the elongation at break of the orally disintegrating film is greater than 5%.

19. The dexmedetomidine hydrochloride orally disintegrating film according to any one of claims 1 to 11, wherein the tensile strength of the orally disintegrating film is greater than 15 N / mm 2 .

20. The dexmedetomidine hydrochloride orally disintegrating film according to claim 19, wherein the tensile strength of the orally disintegrating film is greater than 25 N / mm 2 . The dexmedetomidine hydrochloride orally disintegrating film according to claim 1 , wherein the content uniformity of the orally disintegrating film is greater than 98%.

22. The dexmedetomidine hydrochloride orally disintegrating film according to any one of claims 1 to 11, wherein the dissolution rate of the orally disintegrating film in simulated saliva after 15 minutes is ≥85%. The dexmedetomidine hydrochloride orally disintegrating film according to claim 22 , wherein the dissolution rate of the orally disintegrating film in simulated saliva after 15 minutes is ≥90%. The dexmedetomidine hydrochloride orally disintegrating film according to claim 1 , wherein the feeding speed is 20-50 rpm. The dexmedetomidine hydrochloride orally dissolving film according to claim 1 , wherein the screw speed is 100-200 rpm. The dexmedetomidine hydrochloride orally dissolving film according to claim 1 , wherein the extrusion temperature is 120-180° C.

27. A method for preparing the orally dissolving dexmedetomidine hydrochloride film according to any one of claims 1 to 26, comprising the steps of: mixing the required amounts of the components, adding the resulting mixture to a hot melt extruder, setting the barrel section temperature to 90-170° C., the feeding rate 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 the film.

28. Use of the dexmedetomidine hydrochloride orally disintegrating film according to any one of claims 1 to 26 in preparing sedative drugs.

29. The use according to claim 28, wherein the sedative drug is any one of a preoperative sedative drug and a sedative drug for schizophrenia patients.

30. Use of the dexmedetomidine hydrochloride orally disintegrating film according to any one of claims 1 to 26 in preparing analgesic drugs.

31. Use of the dexmedetomidine hydrochloride orally disintegrating film according to any one of claims 1 to 26 in preparing an anti-insomnia drug.

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