Diphenhydroxazone hydrochloride tablet and preparation method thereof

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a tribenisole hydrochloride tablet and a preparation method thereof. According to the method, cyclopentyl methyl ether and cyclohexane are adopted as solvents for Grignard reaction, and iodine tablets are replaced by ultrasonic waves, so that the dissolution rate of chlorocyclohexane is increased, the Grignard reaction is initiated at normal temperature, and the explosion risk existing in a traditional diethyl ether solvent is eliminated; according to the present invention, by using the modified trihexylol hydrochloride-mannitol-tartaric acid complex as the rapid release layer and the hydroxypropyl methylcellulose-chitosan-grape seed ceramide complex as the slow release layer, the combination of the trihexylol hydrochloride and the peripheral anti-cholinergic receptor is reduced so as to gently fluctuate the blood concentration, and the glaucoma and the mental problem caused by the traditional trihexylol hydrochloride tablet are relieved;

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a benzhexol hydrochloride tablet and a preparation method thereof. Background Art

[0002] Parkinson's disease is a chronic neurodegenerative disease with the characteristics of hidden onset and slow progression. It can cause symptoms such as resting tremor and bradykinesia. Some patients also have sleep disorders and olfactory disorders. The main incidence group of Parkinson's disease is the elderly. The disease has a relatively complex pathogenesis, which is mainly due to the degeneration and death of dopamine neurons in the substantia nigra of the midbrain, which leads to a decrease in dopamine levels in the striatum and ultimately causes Parkinson's disease. Age factors, environmental factors and genetic factors are closely related to the onset of the disease. At present, there is no specific method for treating Parkinson's disease clinically. It is mainly through drug treatment to delay the progression of the patient's disease and improve symptoms.

[0003] Trihexyphenidyl hydrochloride is a commonly used drug for the treatment of Parkinson's disease. It belongs to the central anticholinergic drug, which can selectively block the striatal cholinergic nerve pathway, reduce the excitability of acetylcholine, thereby restoring the balance between dopamine and acetylcholine and alleviating clinical symptoms. The drug can also promote the metabolism of energy in the patient's brain, delay the degeneration of brain neurons, and thus improve the patient's condition. At present, the general synthesis route of trihexyphenidyl hydrochloride is to use acetophenone as a raw material, and to react with formaldehyde and piperidine hydrochloride in ethanol to obtain piperidine phenylacetone hydrochloride, and then to react with chlorocyclohexane and magnesium chips to obtain the result of Grignard hydrolysis. The preparation process of piperidine phenylacetone hydrochloride is relatively stable. The key to synthesizing benzhexol hydrochloride is the Grignard reagent. Currently, the main Grignard reagents used are anhydrous ether and anhydrous tetrahydrofuran. Although the crude product has a high yield and a good crystal form, it has a general anesthetic effect and is harmful to the human body if inhaled for a long time. Ether has a low boiling point, and its vapor and air can form an explosive mixture. It is very easy to burn and explode when exposed to open flames and high heat, which is not conducive to large-scale process production.

[0004] In the preparation method of benzhexol hydrochloride of announcement number CN102030723B, for the problem of safety in using ether as Grignard reaction solvent in the existing benzhexol hydrochloride preparation process, asymmetric methyl tert-butyl ether is used instead of ether, the steam generated in the reaction process can be used to isolate air, and the tert-butyl group in methyl tert-butyl ether can play a role in protecting hydroxyl groups in the reaction process, and the boiling point of methyl tert-butyl ether is higher than that of ether, and the reaction process is relatively gentle and easy to control. Although the safety problem that ether may cause as a solvent can be solved, iodine tablets are used in the production process, and the activity of iodine tablets is large, and the risk factor is also large. Not only is the reaction process difficult to control, affecting the product yield, but the iodine wastewater treatment after the reaction is also relatively complicated.

[0005] In addition, traditional benzhexol hydrochloride tablets have a strong anticholinergic effect. After acting on the central nervous system, they can relieve the patient's clinical symptoms. When acting on the periphery, especially the pupillary sphincter of the eye, the pupillary sphincter is inhibited and the pupil dilates, resulting in narrowing of the anterior chamber angle, obstruction of aqueous humor outflow, and increased intraocular pressure. Long-term use of the drug can lead to glaucoma. In addition, the patient's blood drug concentration fluctuates greatly after taking the drug, and benzhexol hydrochloride can block M-type cholinergic receptors, leading to imbalance of the cholinergic-5-HT system. Studies have found that benzhexol hydrochloride can reduce the expression of 5-HT1A receptors in the hippocampus by 40-60%, causing psychotic symptoms such as mental confusion, anxiety, and hallucinations. Summary of the invention

[0006] The object of the present invention is to provide a benzhexol hydrochloride tablet and a preparation method thereof, so as to solve the above technical problems.

[0007] In order to achieve the above technical purpose, the technical solution of the present invention is: A method for preparing benzhexol hydrochloride tablets comprises the following steps: S1. Evenly mix acetophenone, paraformaldehyde and piperidine hydrochloride, add 5wt% 1-butyl-3-methylimidazolium chloride solution as a catalyst, react in a water bath at 40°C for 4-6h, and perform vacuum distillation after the reaction. Wash the obtained solid precipitate with anhydrous ethanol and vacuum dry to obtain acetophenone piperidine hydrochloride; S2, using cyclopentyl methyl ether and n-hexane as solvents, magnesium powder and phenylacetone piperidine hydrochloride were mixed and dissolved, and stirred for 3 hours in a water bath at 25-30°C and an ultrasonic power of 300W, and chlorocyclohexane was added thereto in a gradient dropwise manner; after stirring, hydrochloric acid was used to acidify, and supercritical CO was introduced. 2 Acetone was injected into the reactor at a pressure of 8 MPa and a temperature of 35°C, and needle-shaped crystals of benzhexol hydrochloride were obtained after crystallization; S3, dissolving benzhexol hydrochloride needle-shaped crystals, soybean lecithin and cholesterol in 70wt% ethanol solution, stirring and mixing in a 45°C water bath for 40min, and performing high-pressure homogenization after the stirring is completed to control the powder outlet particle size to be 160-200nm, and freeze-drying the obtained powder to obtain modified benzhexol hydrochloride; S4. The modified benzhexol hydrochloride, mannitol and tartaric acid are mixed evenly and then filled into the mold hole for compaction to serve as a quick-release layer. Under a nitrogen atmosphere, hydroxypropyl methylcellulose, chitosan and grape seed ceramide are compounded to serve as a sustained-release layer. Finally, double-layer simultaneous compression is performed, and after compression, the tablets are coated to obtain benzhexol hydrochloride tablets.

[0008] As a further improvement, in step S1, the mass ratio of the acetophenone, paraformaldehyde and piperidine hydrochloride is 1:1.1:1.05, and the added amount of the 1-butyl-3-methylimidazole chloride solution is 2 wt % of the acetophenone.

[0009] As a further improvement, in step S2, the mass ratio of cyclopentyl methyl ether to n-hexane is 1:1; the mass ratio of magnesium powder, chlorocyclohexane and propiophenone piperidine is 1.5:1:1.3; the concentration of hydrochloric acid used in the hydrochloric acid acidification is 10wt%~12wt%, and the pH of the solution after acidification is 1.5~2.0; the CO 2 The mass ratio of acetone is 9:1.

[0010] As a further improvement, in step S3, the mass ratio of the benzhexol hydrochloride needle-shaped crystals, soybean lecithin and cholesterol is 1:0.8:0.2; the high-pressure homogenization parameters are: homogenization pressure is 800 bar, cycle homogenization is performed 3 times, and outlet temperature is ≦50°C.

[0011] As a further improvement, in step S3, the specific steps of freeze drying are: drying at -40°C under normal pressure for 4 hours, then drying at -20~10°C under a vacuum of 0.1 mbar for 18 hours, and finally drying at 25°C under 0.05 mbar for 6 hours.

[0012] As a further improvement, in step S4, by mass, the modified benzhexol hydrochloride is 40-60 parts, mannitol is 35-55 parts, and tartaric acid is 5-8 parts; the hydroxypropyl methylcellulose is 60-70 parts, chitosan is 25-35 parts, and grape seed ceramide is 5 parts; the filling amount of the immediate release layer is 150 mg / hole, and the pre-compression pressure is 2 kN; the filling amount of the sustained release layer is 100 mg / hole; the parameters of the double-layer synchronous pressing are set as: initial pressure 5 kN pressing for 0.5 s, main pressure 7 kN pressing for 2.0 s, and holding pressure 5 kN pressing for 1.5 s.

[0013] As a further improvement, in step S4, the coating method of the benzhexol hydrochloride tablets is as follows: polyvinyl alcohol is dissolved in deionized water at a mass ratio of 6:100, stirred in a water bath at 80°C for 15 minutes, cooled to 40°C, filtered with a 0.22 μm filter membrane, and the inlet air temperature is set to 38~42°C, the outlet air temperature is 31~33°C, the atomization pressure is 1.0 bar, the pot speed is 12 rpm, and the spray rate is 20 mL / min for coating. After the tablet weight gain reaches 1.7~2.3%, the coating is stopped.

[0014] As a further improvement, in step S2, the gradient addition process of chlorocyclohexane is specifically as follows: adding at a speed of 1.5 mL / min, with each gradient interval of 10 min, and the addition gradient is 20%, 30%, 30%, and 20%.

[0015] Due to the adoption of the above technical solution, the beneficial effects of the present invention are: 1. Compared with ether solvent, the safety of cyclopentyl methyl ether and n-hexane solvent is significantly improved; the solubility of chlorocyclohexane in cyclopentyl methyl ether is low. As a non-polar solvent, n-hexane can be mixed with cyclopentyl methyl ether to form a gradient polarity system, which reduces the total cost of solvent and improves the solubility rate of chlorocyclohexane; ultrasonic wave replaces traditional iodine tablets to achieve Grignard reaction at room temperature, completely eliminating the explosion risk of traditional solvent ether; gradient addition of chlorocyclohexane, combined with precise flow rate control and supercritical CO 2 -Acetone composite crystallization, the product conversion rate can be increased to ≥95%, and the crystal purity can be ≥99.5%.

[0016] 2. Modified benzhexol hydrochloride, mannitol, and tartaric acid are used as the immediate release layer, and mannitol is used as the quick-dissolving skeleton. Through its own high porosity and high solubility, water can quickly penetrate and the drug can be quickly released, so as to achieve rapid disintegration of the immediate release layer and ensure that the immediate release layer can take effect in a short time; the nanoparticle size of the immediate release layer is controlled (160~200nm), the passive retention probability of benzhexol hydrochloride in peripheral capillaries (d>400nm) is reduced, the binding with peripheral cholinergic receptors is reduced, the anticholinergic effect of the drug on peripheral nerves is prevented, and the risk of patients suffering from glaucoma after taking the drug is reduced; soy lecithin and cholesterol have an effect on the effect of benzhexol hydrochloride on the peripheral capillaries (d>400nm). The phospholipid-encapsulated cholinergic peptide is modified by phospholipid encapsulation. The polar head of soybean phosphate contains a phosphate group, which is completely deprotonated under physiological pH conditions to form a stable negative charge, giving benzhexol hydrochloride negative charge. After entering the human body, it quickly adsorbs plasma proteins to form a protein corona, which is positively charged and produces electrostatic repulsion with positively charged peripheral cholinergic receptors, reducing the binding probability and enhancing the fat solubility of benzhexol hydrochloride tablets, promoting the binding and absorption with the electrically neutral cholinergic receptors of the central nervous system; tartaric acid can adjust the oral pH to be weakly acidic, reduce saliva secretion, reduce the flushing effect on drugs, prolong the drug residence time, and increase the absorption of drugs.

[0017] 3. Hydroxypropyl methylcellulose-chitosan-grape seed ceramide complex is used as the sustained-release layer. Hydroxypropyl methylcellulose is a hydrophilic gelling skeleton material with negative charge. It forms a dense polymer after combining with positively charged chitosan. When it meets water, the surface is rapidly absorbed, the molecular chain unfolds and forms a primary gel layer, and benzhexyphenidyl hydrochloride is slowly diffused and released through the pores of the gel layer; after water molecules enter the sustained-release layer, the hydroxyl group and hydrogen bond of the hydropropyl methylcellulose are broken to form a three-dimensional network gel structure, the viscosity is increased, and the diffusion of benzhexyphenidyl hydrochloride is further significantly blocked, and the blood concentration of the drug is reduced. degree fluctuation; chitosan combines with the negative charge of the gastrointestinal mucosa through its positive charge, prolonging the retention time of benzhexol hydrochloride tablets in the gastrointestinal tract, and its antibacterial property can also reduce the degradation of ceramide by intestinal flora; grape seed ceramide activates peroxisome proliferators, activates receptor γ and binds to the promoter region of the 5-hydroxytryptamine 1A receptor gene, drives its transcriptional activity to increase, inhibits the over-activation of γ-aminobutyric acid interneurons in the dorsal raphe nucleus, relieves the inhibition of anticholinergic drugs on serotonergic neurons, and antagonizes the psychiatric symptoms and side effects of central anticholinergic drugs.

[0018] 4. The drug release mechanism combines a quick-release layer with a sustained-release layer. The quick-release layer preferentially activates the M1 receptors of the central nervous system, quickly restores the balance between dopamine and acetylcholine, and quickly relieves acute symptoms such as resting tremor and muscle stiffness in Parkinson's patients. The gel skeleton of the sustained-release layer controls the slow release of the remaining benzhexol hydrochloride, reduces the fluctuation of blood drug concentration, continuously inhibits the activation of peripheral cholinergic receptors, and reduces the risk of glaucoma and mental symptoms. DETAILED DESCRIPTION

[0019] The technical scheme of the present invention will be clearly and completely described below in conjunction with specific embodiments, but it will be appreciated by those skilled in the art that the following described embodiments are part of embodiments of the present invention, rather than all embodiments, and are only used to illustrate the present invention, and should not be considered as limiting the scope of the present invention. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work, all belong to the scope of protection of the present invention. If specific conditions are not indicated in the embodiments, they are carried out according to normal conditions or conditions recommended by the manufacturer. If the manufacturer is not indicated in the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0020] Example 1 A method for preparing benzhexol hydrochloride tablets (1) Synthesis of phenylacetaldehyde piperidine hydrochloride: Acetophenone, paraformaldehyde and piperidine hydrochloride were mixed in a mass ratio of 1:1.1:1.05, and 5 wt% 1-butyl-3-methylimidazolium chloride solution was added as a catalyst in an amount of 2 wt% of acetophenone. The mixture was reacted in a water bath at 40°C for 4 h. After the reaction was completed, the mixture was distilled under reduced pressure at 10 mmHg and 115°C for 30 min. The solid precipitate was washed with anhydrous ethanol and vacuum dried at 60°C for 2 h to obtain phenylacetaldehyde piperidine hydrochloride.

[0021] (2) Preparation of benzhexol hydrochloride: Using cyclopentyl methyl ether and n-hexane as solvents, magnesium powder and phenylpropiophenone piperidine hydrochloride were mixed and dissolved, and stirred in a 25°C water bath under 300W ultrasonic power for 3 h. At the same time, chlorocyclohexane was added dropwise at a rate of 1.5 mL / min in a gradient ratio of 20%, 30%, 30%, and 20%, with an interval of 10 min between each gradient. After stirring, the mixture was acidified to pH 1.5 with 10 wt% hydrochloric acid, and supercritical CO was introduced. 2 Acetone was injected into the reactor at a pressure of 8 MPa and a temperature of 35°C for 2 hours to obtain needle-shaped crystals of benzhexyl hydrochloride; wherein the mass ratio of cyclopentyl methyl ether to n-hexane was 1:1, the mass ratio of magnesium powder, chlorocyclohexane and phenylpropiophenone piperidine was 1.5:1:1.3, and CO 2 The mass ratio of acetone is 9:1.

[0022] (3) Modification of benzhexol hydrochloride: benzhexol hydrochloride needle crystals, soybean lecithin and cholesterol were dissolved in 70 wt% ethanol solution at a mass ratio of 1:0.8:0.2, and stirred in a water bath at 45°C for 40 min. After stirring, high-pressure homogenization was performed at a homogenization pressure of 800 bar. The homogenization was repeated 3 times with an outlet temperature ≤ 50°C and the outlet particle size was controlled to be 200 nm. If the particle size was > 200 nm, 5% lecithin was added and homogenization was repeated. The outlet particles were freeze-dried: first, dried at -40°C at normal pressure for 4 h, then dried at 0.1 mbar and -20°C for 18 h, and finally dried at 0.05 mbar and 25°C for 6 h to obtain modified benzhexol hydrochloride.

[0023] (4) Preparation of benzhexol hydrochloride tablets: 40 parts of modified benzhexol hydrochloride, 55 parts of mannitol and 5 parts of tartaric acid were mixed evenly by mass, and then filled into the mold holes for compaction, with a filling amount of 150 mg / hole and a pre-compression pressure of 2 kN. Then, 60 parts of hydroxypropyl methylcellulose, 35 parts of chitosan and 5 parts of grape seed ceramide were compounded by mass under a nitrogen atmosphere, with a filling amount of 100 mg / hole. Finally, double-layer synchronous compression was performed, with an initial compression of 3 kN for 0.5 s to initially fix the particles of the immediate-release layer; a main compression of 7 kN for 2.0 s; and a holding pressure of 5 kN for 1.5 s to eliminate the internal stress between the two layers and prevent delamination.

[0024] (5)Coating of Trihexyphenidyl Hydrochloride Tablets: Polyvinyl alcohol was dissolved in deionized water at a mass ratio of 6:100, stirred in a water bath at 80 °C for 15 min, cooled to 40 °C, filtered through a 0.22 μm filter membrane, and then coated with an inlet air temperature of 38 °C, an outlet air temperature of 31 °C, an atomization pressure of 1.0 bar, a pan rotation speed of 12 rpm, and a liquid spraying rate of 20 mL / min until the tablet weight gain reached 1.7%, and then the coating was stopped.

[0025] Example 2 Preparation method of a trihexyphenidyl hydrochloride tablet (1)Synthesis of phenylpropiophenone piperidine hydrochloride: Acetophenone, paraformaldehyde and piperidine hydrochloride were mixed at a mass ratio of 1:1.1:1.05, 5 wt% of 1-butyl-3-methylimidazolium chloride solution was added as a catalyst, and the addition amount was 2 wt% of acetophenone. The reaction was carried out in a water bath at 40 °C for 5 h. After the reaction, vacuum distillation was carried out at 10 mmHg and 115 °C for 30 min. The obtained solid precipitate was washed with absolute ethanol and then vacuum dried at 60 °C for 3 h to obtain phenylpropiophenone piperidine hydrochloride.

[0026] (2)Preparation of trihexyphenidyl hydrochloride: Using cyclopentyl methyl ether and n-hexane as solvents, magnesium powder and phenylpropiophenone piperidine hydrochloride were mixed and dissolved, and the reaction was stirred in a water bath at 30 °C and an ultrasonic power of 300 W for 3 h. At the same time, chlorocyclohexane was added dropwise at a dropping rate of 1.5 mL / min according to the proportion gradient of 20%, 30%, 30%, and 20%, and each gradient interval was 10 min; after stirring, it was acidified with 12 wt% hydrochloric acid to pH 2.0, and then introduced into a supercritical CO 2 reactor. At a pressure of 8 MPa and a temperature of 35 °C, acetone was injected and crystallized for 3 h to obtain trihexyphenidyl hydrochloride needle crystals; among them, the mass ratio of cyclopentyl methyl ether to n-hexane was 1:1, and the mass ratio of magnesium powder, chlorocyclohexane and phenylpropiophenone was 1.5:1:1.3, and the mass ratio of CO 2 to acetone was 9:1.

[0027] (3)Modification of trihexyphenidyl hydrochloride: Trihexyphenidyl hydrochloride needle crystals, soy lecithin and cholesterol were dissolved in a 70 wt% ethanol solution at a mass ratio of 1:0.8:0.2, stirred and mixed in a water bath at 45 °C for 40 min. After stirring, high-pressure homogenization was carried out, and the homogenization pressure was 800 bar, and the cycle homogenization was carried out 3 times, and the outlet temperature was ≤50 °C, and the particle outlet diameter was controlled to be 180 nm; the outlet particles were freeze-dried: first dried at normal pressure and -40 °C for 4 h, then dried at 0.1 mbar and 0 °C for 18 h, and finally dried at 0.05 mbar and 25 °C for 6 h to obtain modified trihexyphenidyl hydrochloride.

[0028] (4) Preparation of benzhexol hydrochloride tablets: 50 parts of modified benzhexol hydrochloride, 42 parts of mannitol, and 8 parts of tartaric acid were mixed evenly by mass, and then filled into the mold holes for compaction, with a filling amount of 150 mg / hole and a pre-compression pressure of 2 kN. Then, 65 parts of hydroxypropyl methylcellulose, 25 parts of chitosan, and 5 parts of grape seed ceramide were compounded by mass under a nitrogen atmosphere, with a filling amount of 100 mg / hole. Finally, double-layer synchronous compression was performed, with an initial compression of 3 kN for 0.5 s to initially fix the immediate-release layer particles; a main compression of 7 kN for 2.0 s; and a holding pressure of 5 kN for 1.5 s to eliminate the internal stress between the two layers and prevent delamination.

[0029] (5) Coating of benzhexol hydrochloride tablets: Dissolve polyvinyl alcohol in deionized water at a mass ratio of 6:100, stir in a water bath at 80°C for 15 min, cool to 40°C, filter using a 0.22 μm filter membrane, and set the inlet air temperature to 40°C, outlet air temperature to 32°C, atomization pressure to 1.0 bar, pot speed to 12 rpm, and spray rate to 20 mL / min for coating. Stop coating when the tablet weight gain reaches 2.0%.

[0030] Example 3 A method for preparing benzhexol hydrochloride tablets (1) Synthesis of phenylacetaldehyde piperidine hydrochloride: Acetophenone, paraformaldehyde and piperidine hydrochloride were mixed in a mass ratio of 1:1.1:1.05, and 5 wt% 1-butyl-3-methylimidazolium chloride solution was added as a catalyst in an amount of 2 wt% of acetophenone. The mixture was reacted in a water bath at 40°C for 6 h. After the reaction was completed, the mixture was distilled under reduced pressure at 10 mmHg and 115°C for 30 min. The solid precipitate was washed with anhydrous ethanol and dried in a vacuum at 60°C for 4 h to obtain phenylacetaldehyde piperidine hydrochloride.

[0031] (2) Preparation of benzhexol hydrochloride: Using cyclopentyl methyl ether and n-hexane as solvents, magnesium powder and phenylpropiophenone piperidine hydrochloride were mixed and dissolved, and stirred in a 25°C water bath under 300W ultrasonic power for 3 h. At the same time, chlorocyclohexane was added dropwise at a rate of 1.5 mL / min in a gradient ratio of 20%, 30%, 30%, and 20%, with an interval of 10 min between each gradient. After stirring, the mixture was acidified to pH 1.8 with 10 wt% hydrochloric acid, and supercritical CO was introduced. 2 Acetone was injected into the reactor at a pressure of 8 MPa and a temperature of 35°C for 4 hours to obtain needle-shaped crystals of benzhexyl hydrochloride; wherein the mass ratio of cyclopentyl methyl ether to n-hexane was 1:1, the mass ratio of magnesium powder, chlorocyclohexane and phenylpropiophenone piperidine was 1.5:1:1.3, and CO 2 The mass ratio of acetone is 9:1.

[0032] (3) Modification of benzhexol hydrochloride: benzhexol hydrochloride needle crystals, soybean lecithin and cholesterol were dissolved in 70 wt% ethanol solution at a mass ratio of 1:0.8:0.2, and stirred in a water bath at 45°C for 40 min. After stirring, high-pressure homogenization was performed at a homogenization pressure of 800 bar, and the homogenization was repeated 3 times. The outlet temperature was ≤50°C, and the outlet particle size was controlled to be 160 nm. The outlet particles were freeze-dried: first, dried at -40°C at normal pressure for 4 h, then dried at 0.1 mbar and 10°C for 18 h, and finally dried at 0.05 mbar and 25°C for 6 h to obtain modified benzhexol hydrochloride.

[0033] (4) Preparation of benzhexol hydrochloride tablets: 60 parts of modified benzhexol hydrochloride, 35 parts of mannitol, and 5 parts of tartaric acid were mixed evenly by mass and filled into the mold holes with a filling amount of 150 mg / hole and a pre-compression pressure of 2 kN for compaction; then, 60 parts of hydroxypropyl methylcellulose, 35 parts of chitosan, and 5 parts of grape seed ceramide were compounded by mass under a nitrogen atmosphere with a filling amount of 100 mg / hole; finally, double-layer synchronous pressing was performed with an initial pressing of 3 kN for 0.5 s to initially fix the particles of the immediate release layer; a main pressing of 7 kN for 2.0 s; and a holding pressure of 5 kN for 1.5 s to eliminate the internal stress between the two layers and prevent delamination.

[0034] (5) Coating of benzhexol hydrochloride tablets: Dissolve polyvinyl alcohol in deionized water at a mass ratio of 6:100, stir in a water bath at 80°C for 15 min, cool to 40°C, filter using a 0.22 μm filter membrane, and set the inlet air temperature to 42°C, outlet air temperature to 33°C, atomization pressure to 1.0 bar, pot speed to 12 rpm, and spray rate to 20 mL / min for coating. Stop coating when the tablet weight gain reaches 2.3%.

[0035] Comparative Example 1 A method for preparing benzhexol hydrochloride tablets, which is different from Example 1 in that the modification step of benzhexol hydrochloride is removed, and the sustained-release layer complex in the benzhexol hydrochloride tablets is removed, as follows: (1) Synthesis of phenylacetaldehyde piperidine hydrochloride: Acetophenone, paraformaldehyde and piperidine hydrochloride were mixed in a mass ratio of 1:1.1:1.05, and 5 wt% 1-butyl-3-methylimidazolium chloride solution was added as a catalyst in an amount of 2 wt% of acetophenone. The mixture was reacted in a water bath at 40°C for 4 h. After the reaction was completed, the mixture was distilled under reduced pressure at 10 mmHg and 115°C for 30 min. The solid precipitate was washed with anhydrous ethanol and vacuum dried at 60°C for 2 h to obtain phenylacetaldehyde piperidine hydrochloride.

[0036] (2) Preparation of benzhexol hydrochloride: Using cyclopentyl methyl ether and n-hexane as solvents, magnesium powder and phenylpropiophenone piperidine hydrochloride were mixed and dissolved, and stirred in a 25°C water bath under 300W ultrasonic power for 3 h. At the same time, chlorocyclohexane was added dropwise at a rate of 1.5 mL / min in a gradient ratio of 20%, 30%, 30%, and 20%, with an interval of 10 min between each gradient. After stirring, the mixture was acidified to pH 1.5 with 10 wt% hydrochloric acid, and supercritical CO was introduced. 2 Acetone was injected into the reactor at a pressure of 8 MPa and a temperature of 35°C for 2 hours to obtain needle-shaped crystals of benzhexyl hydrochloride; wherein the mass ratio of cyclopentyl methyl ether to n-hexane was 1:1, the mass ratio of magnesium powder, chlorocyclohexane and phenylpropiophenone piperidine was 1.5:1:1.3, and CO 2 The mass ratio of acetone is 9:1.

[0037] (3) Preparation of benzhexol hydrochloride tablets: According to mass proportion, 40 parts of benzhexol hydrochloride needle-shaped crystals, 55 parts of mannitol and 5 parts of tartaric acid were mixed evenly and filled into the mold holes, with a filling amount of 250 mg / hole; the initial pressure was 3 kN for 0.5 s to initially fix the particles, the main pressure was 7 kN for 2.0 s, and the holding pressure was 5 kN for 1.5 s.

[0038] (4) Coating of benzhexol hydrochloride tablets: Dissolve polyvinyl alcohol in deionized water at a mass ratio of 6:100, stir in a water bath at 80°C for 15 min, cool to 40°C, filter using a 0.22 μm filter membrane, and set the inlet air temperature to 38°C, outlet air temperature to 31°C, atomization pressure to 1.0 bar, pot speed to 12 rpm, and spray rate to 20 mL / min for coating. Stop coating when the tablet weight gain reaches 1.7%.

[0039] In order to test the technical effect of the benzhexol hydrochloride tablets obtained in the above embodiment, the benzhexol hydrochloride tablets obtained in the above embodiment and the benzhexol hydrochloride tablets sold on the market were applied to rabbits and beagles respectively, and the benzhexol hydrochloride tablets sold on the market were recorded as comparative example 2. The experimental results obtained by the test are as follows: 1. Release mechanism of immediate-release layer and sustained-release layer 20 healthy male rabbits weighing 2.5-3.0kg were selected and randomly divided into five groups. The rabbits were adapted to the experimental environment for 3-5d before the experiment, and normal diet and drinking water were given during the experiment. The hydrochloride benzhexol tablets obtained in each group of examples were given to each group of rabbits in a single dose orally, and blood samples were collected from the rabbit ear vein at 0.25, 0.5, 1, 2, 4, 8, 12, and 24h after administration, and 1-2mL of blood was collected each time and placed in a centrifuge tube containing an anticoagulant. The collected blood samples were centrifuged at 3000-4000rpm for 10-15min at low temperature to separate plasma, and the plasma was transferred to a centrifuge tube and stored at -20°C for testing. The concentration of hydrochloride benzhexol in plasma after different administration times was detected by high performance liquid chromatograph, and data such as peak time and duration of action were calculated, and the calculation results were as follows: Table 1 Pharmacokinetic comparison parameter Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Peak time / h 0.8 0.5 0.6 1.3 2.2 Duration of action / h 10 13 12 6.4 5 Half-life / h 7.4 8.3 7.8 3.6 2.8 Fluctuation coefficient of blood drug concentration 1.8 1.6 1.9 3.9 4.2 As can be seen from Table 1, after Examples 1 to 3 are used in rabbits, the time for the drug concentration in the rabbit blood to reach the peak value is higher than that in Comparative Examples 1 to 2, indicating that after the quick-release layer is modified by phospholipid encapsulation of benzhexol hydrochloride by soybean lecithin and cholesterol, the fat solubility of the benzhexol hydrochloride tablets is enhanced, and the absorption by the cholinergic receptors of the central nervous system with neutral charge is promoted. Combined with the high porosity of mannitol and tartaric acid to adjust the oral pH, the benzhexol hydrochloride component is effective as soon as 30 minutes; in Examples 1 to 3, the duration of drug action can be up to 13 hours, which is because the hydroxypropyl methylcellulose gel skeleton combined with chitosan in the present invention forms a dense gel layer when it meets water, which can maintain the stable release of the remaining benzhexol hydrochloride for 13 hours. Compared with the benzhexol hydrochloride tablets sold on the market, the onset speed is increased by 77%, and in Examples 1 to 3, the blood drug concentration fluctuation coefficient is as low as 1.6, that is, the blood drug concentration fluctuation coefficient is reduced from 4.2 in Comparative Example 2 to 1.6, reducing the risk of peak-to-valley fluctuations.

[0040] 2. Glaucoma Risk Control Twenty healthy male rabbits weighing 2.5-3.0 kg were selected and randomly divided into five groups. The rabbits were allowed to adapt to the experimental environment for 3-5 days before the experiment, and were given normal diet and drinking water during the period. The trihexyphenidyl hydrochloride tablets obtained in each group of rabbits were orally administered with a single dose every day. After 28 days, the eye indexes of the rabbits were measured. The test results are shown in the following table: Table 2 Comparison of rabbit eye indicators Group Change in pupil diameter (mm) Change in aqueous humor outflow resistance (%) Peak intraocular pressure (mmHg) Example 1 +0.8±0.5 -7±6 17.4±0.6 Example 2 +0.5±0.2 -8±3 18.2±0.3 Example 3 +0.7±0.4 -10±5 16.5±0.6 Comparative Example 1 +2.6±0.2 +27±5 20.5±1.8 Comparative Example 2 +2.8±0.3 +35±5 28.7±1.2 It can be seen from Table 2 that the pupil dilation amplitude of rabbits in Examples 1 to 3 can be controlled within +0.8 mm, which is smaller than that in Comparative Examples 1 to 2. This is because the activation of peripheral cholinergic receptors by benzhexyphenidyl hydrochloride is reduced by phospholipid coating modification of benzhexyphenidyl hydrochloride and by controlling the nanoparticle size; while the comparative example does not use phospholipid coating modification and sustained-release technology, resulting in rapid release of benzhexyphenidyl hydrochloride and activation of the iris sphincter M3 receptor, causing pupil dilation and intraocular pressure of 28.7 mmHg, significantly increasing the risk of glaucoma.

[0041] 3. Improvement of mental symptoms Twelve beagle experimental dogs were randomly selected and randomly divided into three groups, four in each group, and placed in a 5m×5m soundproof observation room. The temperature of the test site was 24±1°C and the humidity was 50±5%. An infrared thermal imager and a three-dimensional motion tracking system were set up, and the experimental time was 9-11 am. Basic behavioral parameters, including food intake, sleep cycle and autonomous activity frequency, were recorded for three consecutive days, and then the benzhexol hydrochloride tablets of Example 2, Comparative Example 1 and Comparative Example 2 were orally administered to each group of beagle experimental dogs in a single dose every day. After 28 days, the mental symptoms of each group of beagle dogs were observed, and the results are shown in Table 3.

[0042] Table 3 Beagle dog psychiatric symptom score (APA standard scale) Group Anxiety Index Hallucination incidence / % Cognitive function score Pre-dose baseline 4.5±0.6 35 68±8 Example 228d 2.1±0.3 12 89±4 Comparative Example 128d 6.2±0.8 40 52±2 Comparative Example 228d 6.8±0.4 55 49±6 From Table 2 and Table 3, it can be seen that the present patent scheme adopts a drug release mechanism combining a quick-release layer with a sustained-release layer. On the one hand, by controlling the nanoparticle size of the quick-release layer, the passive retention probability of benzhexyphenidyl hydrochloride in the peripheral capillaries is reduced, the anticholinergic effect on the peripheral nerves is reduced, and the risk of glaucoma in patients is reduced; on the other hand, through the hydroxypropyl methylcellulose-chitosan gel skeleton in the sustained-release layer, the slow release of the remaining benzhexyphenidyl hydrochloride is controlled, the fluctuation of blood drug concentration is reduced, the activation of peripheral cholinergic receptors is continuously inhibited, and the risk of psychiatric symptoms is reduced.

[0043] The specific implementation of the present invention described above does not constitute a limitation on the protection scope of the present invention. Any other corresponding changes and modifications made based on the technical concept of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. A method for preparing benzhexol hydrochloride tablets, characterized in that: The following steps are involved: S1. Evenly mix acetophenone, paraformaldehyde and piperidine hydrochloride, add 5wt% 1-butyl-3-methylimidazolium chloride solution as a catalyst, react in a water bath at 40°C for 4-6h, and perform vacuum distillation after the reaction. Wash the obtained solid precipitate with anhydrous ethanol and vacuum dry to obtain acetophenone piperidine hydrochloride; S2, using cyclopentyl methyl ether and n-hexane as solvent, magnesium powder and phenylpropiophenone piperidine hydrochloride were mixed and dissolved, and stirred in a water bath at 25-30°C and 300W ultrasonic power for 3h, and chlorocyclohexane was added thereto in a gradient dropwise manner, and after stirring, the mixture was acidified with hydrochloric acid, introduced into a supercritical CO2 reactor, and acetone was injected at a pressure of 8MPa and a temperature of 35°C, and needle-shaped crystals of benzhexol hydrochloride were obtained after crystallization; S3, dissolving benzhexol hydrochloride needle-shaped crystals, soybean lecithin and cholesterol in 70wt% ethanol solution, stirring and mixing in a 45°C water bath for 40min, and performing high-pressure homogenization after the stirring is completed to control the powder outlet particle size to be 160-200nm, and freeze-drying the obtained powder to obtain modified benzhexol hydrochloride; S4. The modified benzhexol hydrochloride, mannitol and tartaric acid are mixed evenly and then filled into the mold hole for compaction to serve as a quick-release layer. Under a nitrogen atmosphere, hydroxypropyl methylcellulose, chitosan and grape seed ceramide are compounded to serve as a sustained-release layer. Finally, double-layer simultaneous compression is performed, and after compression, the tablets are coated to obtain benzhexol hydrochloride tablets.

2. The method for preparing the benzhexol hydrochloride tablets according to claim 1, characterized in that: In step S1, the mass ratio of the acetophenone, paraformaldehyde and piperidine hydrochloride is 1:1.1:1.05, and the added amount of the 1-butyl-3-methylimidazole chloride solution is 2wt% of the acetophenone.

3. The method for preparing the benzhexol hydrochloride tablets according to claim 1, characterized in that: In step S2, the mass ratio of cyclopentyl methyl ether to n-hexane is 1:1; the mass ratio of the magnesium powder, chlorocyclohexane and phenylacetone piperidine is 1.5:1:1.3; the concentration of hydrochloric acid used in the hydrochloric acid acidification is 10wt%~12wt%, and the pH of the solution after acidification is 1.5~2.0; the mass ratio of CO2 to acetone is 9:

1.

4. The method for preparing the benzhexol hydrochloride tablets according to claim 1, characterized in that: In step S3, the mass ratio of the benzhexol hydrochloride needle-shaped crystals, soybean lecithin and cholesterol is 1:0.8:0.2; the parameters of the high-pressure homogenization are: homogenization pressure is 800 bar, cycle homogenization is performed 3 times, and outlet temperature is ≦50°C.

5. The method for preparing a benzhexol hydrochloride tablet according to claim 1, characterized in that: In step S3, the specific steps of freeze drying are: drying at -40°C for 4 hours under normal pressure, then drying at -20~10°C for 18 hours under a vacuum degree of 0.1 mbar, and finally drying at 25°C for 6 hours under a vacuum degree of 0.05 mbar.

6. The method for preparing the benzhexol hydrochloride tablets according to claim 1, characterized in that: In step S4, by mass, the modified benzhexol hydrochloride is 40-60 parts, mannitol is 35-55 parts, and tartaric acid is 5-8 parts; the hydroxypropyl methylcellulose is 60-70 parts, chitosan is 25-35 parts, and grape seed ceramide is 5 parts; the filling amount of the immediate release layer is 150 mg / hole, and the pre-compression pressure is 2 kN; the filling amount of the sustained release layer is 100 mg / hole; the parameters of the double-layer synchronous compression are set as: initial pressure 5 kN for 0.5 s, main pressure 7 kN for 2.0 s, and holding pressure 5 kN for 1.5 s.

7. The method for preparing the benzhexol hydrochloride tablets according to claim 1, characterized in that: In step S4, the coating method of the benzhexol hydrochloride tablets is as follows: polyvinyl alcohol is dissolved in deionized water at a mass ratio of 6:100, stirred in a water bath at 80°C for 15 minutes, cooled to 40°C, filtered with a 0.22 μm filter membrane, and the inlet air temperature is set to 38-42°C, the outlet air temperature is 31-33°C, the atomization pressure is 1.0 bar, the pot speed is 12 rpm, and the spray rate is 20 mL / min for coating. After the tablet weight gain reaches 1.7-2.3%, the coating is stopped.

8. The method for preparing the benzhexol hydrochloride tablets according to claim 1, characterized in that: In step S2, the gradient addition process of chlorocyclohexane is specifically as follows: adding at a speed of 1.5 mL / min, with each gradient interval of 10 min, and the addition gradient is 20%, 30%, 30%, and 20%.

9. The benzhexyphenidyl hydrochloride tablets prepared according to the preparation method of the benzhexyphenidyl hydrochloride tablets according to claim 1.