CN111346098A - Topical pharmaceutical compositions of benzodiazepines, their preparation and use

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Abstract

Description

Claims

CN111346098A

Publication number: CN111346098A
Application number: CN201811577913.4A
Authority: CN
Inventors: 田峦鸢; 刘朋; 金芬; 曲龙妹; 郭建锋; 吴有斌; 汪淼; 吕金良; 李莉娥; 符义刚; 李仕群; 李�杰; 杜文涛
Original assignee: Yichang Humanwell Pharmaceutical Co Ltd
Current assignee: Yichang Humanwell Pharmaceutical Co Ltd
Priority date: 2018-12-21
Filing date: 2018-12-21
Publication date: 2020-06-30
Anticipated expiration: 2038-12-21
Also published as: CN111346098B

The invention discloses benzodiazepine

A topical pharmaceutical composition of a compound of the class comprising a benzodiazepine of formula (I)

A compound or its pharmaceutically acceptable salt, high-molecular dispersing carrier material, hot-melt protecting agent and optional flux, R in formula (I)₁And R₂The definition of (A) is detailed in the specification, the topical pharmaceutical composition is administered transdermally by external application to the skin; the method of preparing the topical composition comprises adding the benzodiazepine

Micronizing the compound, the high-molecular dispersion carrier material and the hot-melt protective agent, optionally adding a fluxing agent, uniformly mixing to obtain a physical mixture, hot-melt extruding and micronizing to obtain the benzodiazepine

The compound particles are prepared. Also provides the application of the pharmaceutical composition. The pharmaceutical composition can be used for calming heart, tranquilizing mind, inducing sleep, improving sleep quality, refreshing brain after use, and has no residue and accumulation in body, no influence on next day work, and full spirit.

Topical pharmaceutical compositions of benzodiazepines, their preparation and use

Technical Field

The invention relates to a pharmaceutical preparation technology, in particular to benzodiazepine

A topical pharmaceutical composition of compounds (i.e. compounds represented by formula (I)), and its preparation method and application are provided. The pharmaceutical composition can be used for calming heart, tranquilizing mind, improving sleep, and improving sleep quality.

Background

A compound of formula (I) (wherein, R₁Selected from hydrogen, methyl, ethyl, isopropyl; r₂Methyl, ethyl) is a novel benzodiazepine

The compound belongs to a short-acting sedative. The medicine can be clinically used for program sedation, general anesthesia induction and maintenance, ICU patient tranquilization and the like. Short-acting sedatives can rapidly restore consciousness and allow patients to be discharged as quickly as possible. The demand of the medicines is particularly urgent in the face of the current situation that the short-term hospitalization cases are gradually increased. Chinese patent CN103202815B reports a compound (R) shown as a formula (I)₁And R₂All methyl) salt, the freeze-drying process has long preparation period, about 5 days as one production period, large auxiliary material consumption and high industrial production cost, and the preparation is inconvenient to inject by professional medical personnel. Chinese patent CN101501019B reports that the compound (R) shown in formula (I)₁And R₂Both methyl) was stable upon storage at 5 ℃, but samples stored at 30 ℃/75% relative humidity (open) deliquesced, changed in color to yellow to orange, and showed a significant level reduction relative to the initial level. Therefore, the compound is extremely unstable at room temperature.

At present, most of the reports of documents are that the compound shown in the formula (I) is prepared into a freeze-dried powder injection preparation and then is used clinically, and the preparation process of the preparation has long production period and high production cost; the injection is prepared into solution temporarily to be used under the guidance of a professional doctor, and the injection is often accompanied with injection pain, so that the patient is inconvenient to take the injection and has poor compliance.

Therefore, there is a need to develop a formulation which can allow the compound represented by formula (I) to be stably stored at room temperature, and which can reduce the production cycle and production cost of the formulation, reduce side reactions and administration times, facilitate administration to patients, and facilitate self-management of patients.

Disclosure of Invention

In order to overcome the defects of the pharmaceutical preparation of the compound shown in the formula (I) in the prior art in preparation and use, the inventor develops the benzodiazepine shown in the formula (I)

A topical pharmaceutical composition of the compound.

The invention aims to provide the benzodiazepine shown in the formula (I)

A topical pharmaceutical composition of the compound.

It is a second object of the present invention to provide a process for the preparation of the above topical pharmaceutical composition.

A third object of the present invention is to provide the use of the above topical pharmaceutical composition.

In an embodiment of the present invention, there is provided a benzodiazepine of formula (I)

A topical pharmaceutical composition of the compound comprises a compound shown as a formula (I)Dinitrogen benzene

A compound or pharmaceutically acceptable salt thereof, a macromolecular dispersion carrier material, a hot-melt protective agent and an optional fluxing agent,

wherein R in the formula (I)₁Selected from hydrogen, methyl, ethyl, and isopropyl; r₂Is methyl, or ethyl;

the topical pharmaceutical composition is administered transdermally for external application to the skin;

the method of preparing the topical composition comprises adding the benzodiazepine

Micronizing the compound or pharmaceutically acceptable salt thereof, high molecular dispersion carrier material and hot-melt protective agent, optionally adding fluxing agent, mixing uniformly to obtain a physical mixture, hot-melt extruding and micronizing to obtain the benzodiazepine

Microparticles of the compound or a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention, there is provided a benzodiazepine of formula (I)

A topical pharmaceutical composition of compounds of the formula (I), wherein R₁Is methyl, R₂Is methyl; or, R₁Is methyl, R₂Is ethyl; or, R₁Is hydrogen, R₂Is methyl; or, R₁Is hydrogen, R₂Is ethyl; or, R₁Is ethyl, R₂Is methyl; or, R₁Is ethyl, R₂Is ethyl; or, R₁Is isopropyl, R₂Is methyl.

A topical pharmaceutical composition of a compound, wherein the benzodiazepine

The compounds include isomers, racemates, enantiomers, enantiomer mixtures, or isomer, racemate, enantiomer and enantiomer mixtures.

A topical pharmaceutical composition of a compound, wherein the benzodiazepine

The pharmaceutically acceptable salt of the compound is one or more of benzene sulfonate, toluene sulfonate, methane sulfonate, tartrate, malate, maleate, fumarate, hydrochloride, hydrobromide, sulfate or ethane sulfonate; preferably, it is one of benzene sulfonate, toluene sulfonate, or ethane sulfonate.

A topical pharmaceutical composition of class of compounds, wherein the polymeric dispersing carrier material is selected from povidone (PVP-VA64, povidone-S630 or K30) or Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer).

A topical pharmaceutical composition of class of compounds wherein said flux enhancer is selected from the group consisting of polyethylene glycol, preferably polyethylene glycol having a molecular weight of 2000-6000.

The pharmaceutical composition for the topical application of the compound, wherein the hot-melt protective agent is magnesium stearate or talcum powder.

In a preferred embodiment of the present invention, there is provided a benzodiazepine of formula (I)

A topical pharmaceutical composition of a compound in which the benzodiazepine is present

In the microparticles of the compound or the pharmaceutically acceptable salt thereof, the benzodiazepine shown in the formula (I)

The weight percentage of the compound or the pharmaceutically acceptable salt thereof is 6-40%, the weight percentage of the macromolecular dispersion carrier material is 20-50%, the weight percentage of the hot-melt protective agent is 1-3%, and the weight percentage of the fluxing agent is 35-70%.

The topical pharmaceutical composition of the compound is characterized in that the temperature of hot-melt extrusion is 100-180 ℃.

A topical pharmaceutical composition of a compound, wherein the benzodiazepine

The diameter (particle diameter) of the fine particles of the compound or the pharmaceutically acceptable salt thereof is 100nm to 300nm, preferably 100nm to 200nm or 150nm to 250 nm.

In a topical pharmaceutical composition of a compound of the class

The content of the compound or the pharmaceutically acceptable salt thereof is 0.1-50 mg per patch, preferably 0.5-30 mg per patch.

A topical pharmaceutical composition of a compound, wherein the benzodiazepine

The topical pharmaceutical composition of the compound also comprises phospholipid, cholesterol, low molecular organic alcohol, water, hot melt pressure sensitive adhesive and optional transdermal absorption enhancer.

In the embodiment of the invention, the invention provides a benzodiazepine shown in a formula (I)

A topical pharmaceutical composition of a compound, wherein the process for preparing the topical composition further comprises the step of adding the benzodiazepine

The particles of the compound or the pharmaceutically acceptable salt thereof are prepared into alcohol liposome, and then are mixed with the hot melt pressure sensitive adhesive and the optional transdermal absorption enhancer to prepare a matrix layer.

A topical pharmaceutical composition of a steroid, wherein said alcohol liposome is composed of said benzodiazepine

The compound or the pharmaceutically acceptable salt thereof, phospholipid, cholesterol, low molecular organic alcohol and water; preferably, the alcohol liposome comprises the following components in percentage by mass: 0.1 to 25 percent of benzodiazepine

The compound or the pharmaceutically acceptable salt thereof, 1 to 5 percent of phospholipid, 0.1 to 1 percent of cholesterol, 20 to 50 percent of low molecular organic alcohol and the balance of water; more preferably, 0.5 to 20% of dinitrogen benzene

Fine particles of a compound or a pharmaceutically acceptable salt thereof, 2.0 to 3.0% of phospholipid, 0.2 to 0.5% of cholesterol, 30 to 40% of low molecular weight organic alcohol, and the balance of water.

A topical pharmaceutical composition of a compound, wherein the phospholipid is selected from one or more of soy lecithin, phosphatidylcholine, phosphatidylethanolamine and dipalmitoylphosphatidylcholine.

The topical pharmaceutical composition of the compound is characterized in that the low molecular organic alcohol is selected from one or more of ethanol, propylene glycol and isopropanol.

The drug composition for the local application of the compound is characterized in that the hot-melt pressure-sensitive adhesive is prepared from a styrene-isoprene-styrene triblock copolymer (SIS), tackifying resin, an antioxidant and a plasticizer; preferably, the paint is prepared from the following components in percentage by mass: 30-40% of SIS, 10-20% of plasticizer, 40-50% of tackifying resin and 0.1-1% of antioxidant.

A topical pharmaceutical composition of class of compounds wherein said transdermal absorption enhancer is selected from the group consisting of lauryl nitrogen

One or more of ketone, oleum Menthae Dementholatum, oleum Terebinthinae, menthol, flos Caryophylli volatile oil, Borneolum Syntheticum, juniperberry terpene and isopropyl myristate.

The topical medicine composition of the compound is characterized in that the tackifying resin is selected from one or more of hydrogenated petroleum resin, terpene resin, C5 resin, acrylic resin and rosin resin.

The topical pharmaceutical composition of the compound is characterized in that the plasticizer is one or more selected from mineral oil, liquid paraffin, naphthenic oil and white mineral oil.

A topical pharmaceutical composition of compounds is provided, wherein the antioxidant is selected from one or more of BHT, antioxidant 1010, bis (3, 5-tertiary butyl-4-hydroxyphenyl) thioether, p-phenylenediamine, dihydroquinoline, bisdodecyl alcohol ester, bistetradecyl alcohol ester and bisoctadecyl alcohol ester, BHT is also called 2, 6-di-tert-butyl-4-methylphenol, antioxidant 264, dibutyl hydroxytoluene, and antioxidant 1010 is tetrakis [ β - (3, 5-di-tert-butyl-4-hydroxyphenyl) propionic acid]Pentaerythritol esters.

A topical pharmaceutical composition of a compound, wherein the benzodiazepine

The topical pharmaceutical composition of the compound is a transdermal patch, and comprises a matrix layer, an anti-sticking layer, and a back lining layer; said matrix layer is composed of said benzodiazepine

The alcohol liposome of the compound or the pharmaceutically acceptable salt thereof, the hot melt pressure sensitive adhesive and an optional transdermal absorption enhancer.

The topical pharmaceutical composition of the compound, wherein the anti-sticking layer can be high temperature resistant release paper.

A topical pharmaceutical composition of the class of compounds, wherein the backing layer may be a non-woven fabric.

In another aspect, the present invention provides a benzodiazepine of formula (I) above

A process for the preparation of a topical pharmaceutical composition of a compound of the class comprising the steps of:

(1) the dinitrogen benzene is added

Microparticles of a compound of class i or a pharmaceutically acceptable salt thereof;

(2) preparing the particles obtained in the step (1) into alcohol liposome;

(3) preparing hot-melt pressure-sensitive adhesive;

(4) and (3) uniformly stirring the hot-melt pressure-sensitive adhesive obtained in the step (3), the alcohol liposome obtained in the step (2) and an optional transdermal absorption enhancer.

In an embodiment of the present invention, there is provided benzodiazepines of the present invention

A process for the preparation of a topical pharmaceutical composition of a compound, wherein the process for the preparation of the microparticles comprises:

(i) diazoxide of formula (I)

Compounds of the classOr pharmaceutically acceptable salt thereof, a high molecular material and a hot melt protective agent are micronized, a plasticizer is optionally added, and the physical mixture is prepared after uniform mixing;

(ii) setting the extrusion temperature of a double-screw extruder to be 100-180 ℃, starting the screw after the temperature is raised to the set temperature, adding the physical mixture obtained in the step (i) into the extruder, performing hot melting and extrusion, extruding in spherical particles to obtain amorphous particles, and micronizing the amorphous particles to obtain the micronized amorphous particles.

The preparation method of the topical pharmaceutical composition of the compound, wherein the preparation process of the hot-melt pressure-sensitive adhesive comprises the following steps:

(a) preheating a reaction kettle to 150-180 ℃;

(b) adding SIS, and stirring at the rotating speed of 200-300 r/min for 10 min;

(c) and cooling to 120-180 ℃, then respectively adding a plasticizer, tackifying resin and an antioxidant, stirring at the rotating speed of 200-300 r/min for 60-90 min, and cooling to obtain the hot-melt pressure-sensitive adhesive.

The preparation method of the topical pharmaceutical composition of the compound comprises the following steps:

(I') weighing phospholipid, cholesterol, low molecular organic alcohol and benzodiazepine shown in formula (I)

Microparticles of a compound of class i or a pharmaceutically acceptable salt thereof, and water;

(ii') mixing phospholipid, cholesterol, and benzodiazepine represented by formula (I)

The compound or the pharmacy thereof canDissolving the received salt particles in low-molecular organic alcohol, and heating to 30-45 ℃ to dissolve the salt particles to obtain a mixed solution;

(iii ') adding water into the mixed solution obtained in the step (ii') under the stirring condition, continuing stirring for 1.2-3.0 h after the addition is finished, and then cooling to room temperature to obtain the alcohol liposome.

In a preferred embodiment of the present invention, there is provided benzodiazepines

(1) the dinitrogen benzene is added

(2) preparing the particles obtained in the step (1), low-molecular organic alcohol, phospholipid, cholesterol and water into alcohol liposome;

(3) preparing a styrene-isoprene-styrene triblock copolymer, tackifying resin, an antioxidant and a plasticizer into a hot-melt pressure-sensitive adhesive;

(4) heating the hot-melt pressure-sensitive adhesive obtained in the step (3) to 40-60 ℃ under the protection of nitrogen to melt, adding the alcohol liposome obtained in the step (2) and optional transdermal absorption enhancer, uniformly stirring, and cooling to obtain an ointment; alternatively, the patch can be coated on an anti-adhesion layer, cooled, and covered with a backing layer to obtain the patch.

In one embodiment of the present invention, there is provided benzodiazepines provided by the present invention

Topical application of a compoundA method for preparing a pharmaceutical composition, wherein step (1) comprises: in the step, a small amount of hot melt protective agent is added, the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof, the high molecular carrier material and the hot melt protective agent are mixed and then micronized, and then the mixture is uniformly mixed with the melting agent, so that the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof can be fully and uniformly mixed during micronization, the powder properties and the flowability of the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof can be improved, the stability of the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof can be protected, the compound is prevented from being decomposed and generating impurities due to high temperature of hot melt extrusion, the phenomenon of mixed crystals is avoided when the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof is formed into an amorphous form, and the release of the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof is not in accordance with the purposes, Sufficient).

In a third aspect, the present invention provides a benzodiazepine of the above formula (I)

Use of a topical pharmaceutical composition of a compound for calming the heart, tranquilizing the mind, hypnotizing, or improving sleep quality. The medicinal composition can be in the form of ointment, and can be directly applied to temple or cervical vertebra when in use, or can be compounded on release paper and applied to affected part when in use, so as to achieve the effects of calming heart, tranquilizing mind, hypnotizing, and improving sleep quality.

Compared with the prior art, the benzodiazepine shown in the formula (I) provided by the invention

The topical pharmaceutical composition of the compound can remarkably improve the transdermal permeability of the drug, ensure that the drug maintains high blood concentration for a long time, ensure the continuous exertion of the drug effect, reduce the side effect and the administration frequency and facilitate the self-management of patients. Moreover, the composition is more beneficial to the absorption of the body, and can effectively carry drug molecules to penetrate through the stratum corneum and even reach deeper layers of the skin.

The invention has the advantages that the pharmaceutical composition can control the plasma concentration of the compound shown in the formula (I) and obtain the treatment effect, is used for calming the heart, soothing the nerves, tranquilizing the mind, improving the sleep quality of a patient, is clear in mind after being used, has no residue and accumulation in the body, does not influence the work of the next day, and is full of spirit.

The transdermal drug delivery composition has good biocompatibility, can improve skin nutrition metabolism, promote proliferation of fiber cells, promote repair of skin wounds, reduce scars, enhance immunity and the like; the alcohol liposome is a transdermal drug delivery carrier, so that the defects of obvious liver first pass effect, low bioavailability and the like can be avoided, and gastrointestinal adverse reactions such as gastroenteritis, diarrhea, gastrointestinal bleeding and the like can be effectively avoided; the administration frequency is low, and the administration dosage can be self-managed; the transdermal drug delivery system can remarkably improve the transdermal permeation rate of the drug, and ensure that the drug concentration in blood reaches the treatment concentration, thereby quickly exerting the drug effect, and the bioavailability is equivalent to that of an injection; the transdermal drug delivery system has good physical and chemical stability, easy preparation condition meeting, convenient use, meeting the clinical drug requirement and good practical value.

Drawings

FIG. 1 shows a benzodiazepine of formula (I)

Compounds of the class (R)₁、R₂Is methyl) benzene sulfonate.

FIG. 2 shows a benzodiazepine of formula (I)

Compounds of the class (R)₁、R₂Methyl) benzenesulfonate forms a DSC pattern of microparticles with Soluplus.

FIG. 3 shows a benzodiazepine of formula (I)

Compounds of the class (R)₁、R₂Is methyl) benzene sulfonate.

FIG. 4 is a tableShown is a benzodiazepine of formula (I)

Compounds of the class (R)₁、R₂Is X-powder diffraction pattern of methyl) benzene sulfonate and Soluplus in physical mixing state.

FIG. 5 shows a benzodiazepine of formula (I)

Compounds of the class (R)₁、R₂Methyl) benzene sulfonate and Soluplus form an X-powder diffraction pattern of the particles.

FIG. 6 is a graph showing the cumulative amount of permeation through rat skin at various times for samples prepared in example 1 using a Franz transdermal diffusion apparatus; wherein a is alcohol liposome-Azone-compound shown in formula (I), b is alcohol liposome-compound shown in formula (I), and c is absolute ethyl alcohol-compound shown in formula (I).

FIG. 7 shows a benzodiazepine of formula (I)

Compounds of the class (R)₁、R₂Is the average concentration-time curve of the main drug in the animal blood plasma after the methyl) benzene sulfonate transdermal patch and the injection group are administrated.

FIG. 8 shows a benzodiazepine of formula (I)

Compounds of the class (R)₁、R₂Methyl) benzenesulfonate transdermal patch-mean concentration-time curve of the main drug in the animal plasma after administration of the sample of example 1 and the samples of comparative example 1 and comparative example 2.

Detailed Description

The present invention will be described in detail with reference to specific examples. The following examples will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that variations and modifications can be made by persons skilled in the art without departing from the spirit of the invention. All falling within the scope of the present invention. The invention is further described below with reference to examples:

the instrument comprises the following steps:

a drug hot melt extruder hartek HTGD-16, MS-ii mini blend extrusion tester, GSH-01 reaction vessel, TX 2003-1 hot melt coater, Franz transdermal diffusion apparatus, XTRA/3KW X-ray diffractometer (ARL, switzerland), Pyris1 thermal analyzer (PerkinElmer, usa).

Example 1 Compound (R) of formula (I)₁Is methyl, R₂Transdermal patch preparation for methyl) benzenesulfonate

(1) The compound (R) shown as the formula (I)₁Is methyl, R₂8g of methyl) benzene sulfonate, 7.4g of Solupluss and 0.5g of magnesium stearate are micronized, 14g of polyethylene glycol (molecular weight 2000) is added, and the mixture is uniformly mixed to prepare a physical mixture;

(2) setting the extrusion temperature of a double-screw extruder to be 120 ℃, starting the screw after the temperature is raised to the set temperature, adding the physical mixture obtained in the step (1) into the extruder, performing hot melting and extrusion, extruding the mixture in spherical particles to obtain amorphous particles, and micronizing the amorphous particles to obtain micronized amorphous particles, wherein the particle size is controlled to be about 100-150 nm.

(3) Weighing 3g of the micronized amorphous particles prepared in the step (2), 2g of soybean lecithin, 0.3g of cholesterol, 30g of absolute ethyl alcohol and 64.7g of water;

(4) mixing soybean lecithin, cholesterol, and compound (R) shown in formula (I)₁Is methyl, R₂Methyl) micronized amorphous particles are dissolved in absolute ethyl alcohol, and the mixture is heated to 30-45 ℃ to be dissolved to obtain a mixed solution;

(5) stirring the mixed solution obtained in the step (4) under the condition of 300R/min, adding distilled water, continuing stirring for 1.5h after the addition is finished, and then cooling to room temperature to obtain the compound (R) shown in the formula (I)₁Is methyl, R₂Methyl) alcohol liposomes.

(6) Preparing the hot-melt pressure-sensitive adhesive:

preheating a reaction kettle to 170 ℃, adding 108g of styrene-isoprene-styrene triblock copolymer (SIS) and stirring for 10min at the rotating speed of 200 r/min; cooling to 150 ℃, adding 140g of hydrogenated petroleum resin, 50g of liquid paraffin and 2g of BHT, stirring for 90min at the rotating speed of 200r/min, and cooling to obtain the product.

(7) Preparation of transdermal patch:

containing a compound (R) of formula (I)₁Is methyl, R₂Methyl) hot melt pressure sensitive adhesive transdermal patch formulation: a compound (R) of formula (I)₁Is methyl, R₂Methyl) alcohol liposome 5g, lauryl nitrogen

5g of ketone (Azone) and 90g of hot melt pressure sensitive adhesive.

The preparation method comprises the following steps: heating the hot-melt pressure-sensitive adhesive to be molten under the protection of nitrogen, and adding a compound (R) shown as a formula (I)₁Is methyl, R₂Is methyl) benzene sulfonate alcohol liposome, lauryl nitrogen

Uniformly mixing ketone (azo), coating on an anti-sticking layer (high temperature resistant release paper) with a coating thickness of 200 μm, cooling, covering with a backing layer (non-woven fabric), and punching into pieces with an area of 20-40 cm²Or a suitable size of a compound (R) containing the formula (I)₁Is methyl, R₂Is a hot melt pressure sensitive adhesive transdermal patch of methyl) benzene sulfonate.

Example 2 Compound (R) of formula (I)₁Is methyl, R₂Ethyl) transdermal patch preparation

(1) The compound (R) shown as the formula (I)₁Is methyl, R₂Ethyl) 0.9g, polyvidone (PVP-S630)3.1g and talcum powder 0.2g, micronizing, adding polyethylene glycol (molecular weight 4000)5.8g, and mixing to obtain physical mixture;

(2) setting the extrusion temperature of a double-screw extruder to be 120 ℃, starting the screw after the temperature is raised to the set temperature, adding the physical mixture obtained in the step (1) into the extruder, performing hot melting and extrusion, extruding the mixture in spherical particles to obtain amorphous particles, and micronizing the amorphous particles to obtain micronized amorphous particles, wherein the particle size is controlled to be about 150-175 nm.

(3) Weighing step (2)The prepared compound (R) shown as the formula (I)₁Is methyl, R₂Ethyl) micronized amorphous fine particles 0.3g, phosphatidylcholine 2g, cholesterol 0.3g, propylene glycol 30g, water 67.4 g;

(4) mixing phosphatidyl choline, cholesterol, and compound (R) of formula (I)₁Is methyl, R₂Ethyl) micronized amorphous particles are dissolved in propylene glycol, and the mixture is heated to 30-45 ℃ to be dissolved to obtain a mixed solution;

(5) stirring the mixed solution obtained in the step (4) under the condition of 300R/min, adding distilled water, continuing stirring for 1.5h after the addition is finished, and then cooling to room temperature to obtain the compound (R) shown in the formula (I)₁Is methyl, R₂Ethyl) alcohol liposomes.

(7) Preparing the hot-melt pressure-sensitive adhesive:

preheating a reaction kettle to 170 ℃, adding 108g of styrene-isoprene-styrene triblock copolymer (SIS) and stirring for 10min at the rotating speed of 200 r/min; cooling to 150 ℃, cooling to 140g of terpene resin, 50g of mineral oil and 10102 g of antioxidant, stirring for 90min at the rotating speed of 200r/min, and cooling to obtain the terpene resin oil.

(8) Preparation of transdermal patch:

containing a compound (R) of formula (I)₁Is methyl, R₂Ethyl) hot melt pressure sensitive adhesive transdermal patch formulation: a compound (R) of formula (I)₁Is methyl, R₂Ethyl) alcohol liposome 35g, isopropyl myristate 5g and hot-melt pressure-sensitive adhesive 60 g.

The preparation method comprises the following steps: heating the hot-melt pressure-sensitive adhesive to be molten under the protection of nitrogen, and adding a compound (R) shown as a formula (I)₁Is methyl, R₂Ethyl alcohol liposome and isopropyl myristate are uniformly mixed, coated on an anti-sticking layer (high temperature resistant release paper) with the coating thickness of 200 mu m, covered with a backing layer (non-woven fabric) after being cooled, and punched into a square meter with the area of 20-40 c or a proper size containing a compound (R) shown in the formula (I)₁Is methyl, R₂Ethyl) hot melt pressure sensitive adhesive transdermal patch.

Example 3 Compound (R) of formula (I)₁Is hydrogen, R₂Methyl) transdermal patch preparation

(1) Will be provided withA compound (R) of formula (I)₁Is hydrogen, R₂Methyl) 0.8g, polyvidone (PVP-K30)3g, magnesium stearate 0.2g, micronizing, adding polyethylene glycol (molecular weight 6000)6.0g, mixing well, and making into physical mixture;

(2) setting the extrusion temperature of a double-screw extruder to be 120 ℃, starting the screw after the temperature is raised to the set temperature, adding the physical mixture obtained in the step (1) into the extruder, performing hot melting and extrusion, extruding the mixture in spherical particles to obtain amorphous particles, and micronizing the amorphous particles to obtain micronized amorphous particles, wherein the particle size is controlled to be about 180-230 nm.

(3) Weighing the compound (R) shown in the formula (I) prepared in the step (2)₁Is hydrogen, R₂Methyl) micronized amorphous fine particles 7g, phosphatidylethanolamine 2g, cholesterol 0.3g, isopropanol 30g, water 60.7 g;

(4) phosphatidylethanolamine, cholesterol and a compound (R) shown as a formula (I)₁Is hydrogen, R₂Methyl) micronized amorphous particles are dissolved in isopropanol and heated to 30-45 ℃ to be dissolved to obtain a mixed solution;

(5) stirring the mixed solution obtained in the step (4) under the condition of 300R/min, adding distilled water, continuing stirring for 1.5h after the addition is finished, and then cooling to room temperature to obtain the compound (R) shown in the formula (I)₁Is hydrogen, R₂Methyl) alcohol liposomes.

(6) Preparing the hot-melt pressure-sensitive adhesive:

preheating a reaction kettle to 170 ℃, adding 108g of styrene-isoprene-styrene triblock copolymer (SIS) and stirring for 10min at the rotating speed of 200 r/min; cooling to 150 ℃, cooling to 140g of C5 resin, 50g of naphthenic oil and 2g of didodecanol ester, stirring for 90min at the rotating speed of 200r/min, and cooling to obtain the product.

(7) Preparation of transdermal patch:

containing a compound (R) of formula (I)₁Is hydrogen, R₂Methyl) hot melt pressure sensitive adhesive transdermal patch formulation: a compound (R) of formula (I)₁Is hydrogen, R₂Methyl) alcohol liposome 4g, clove volatile oil 5g and hot melt pressure sensitive adhesive 91 g.

The preparation method comprises the following steps: under the protection of nitrogen, the hot-melt pressure-sensitive adhesive is put intoHeating to melt, adding a compound (R) of formula (I)₁Is hydrogen, R₂Methyl alcohol liposome and clove volatile oil are uniformly mixed, coated on an anti-sticking layer (high temperature resistant release paper) with the coating thickness of 200 mu m, covered with a backing layer (non-woven fabric) after being cooled, punched into square meters with the area of 20-40 c or proper size and containing the compound (R) shown in the formula (I)₁Is hydrogen, R₂Methyl) hot melt pressure sensitive adhesive transdermal patch.

Example 4 Compound (R) of formula (I)₁Is hydrogen, R₂Ethyl) transdermal patch preparation

(1) The compound (R) shown as the formula (I)₁Is hydrogen, R₂Ethyl) 0.6g, polyvidone (PVP-VA64)3.5g, pulvis Talci 0.3g, micronizing, adding polyethylene glycol (molecular weight 4000)5.6g, mixing well, and making into physical mixture;

(2) setting the extrusion temperature of a double-screw extruder to be 150 ℃, starting the screw after the temperature is raised to the set temperature, adding the physical mixture obtained in the step (1) into the extruder, performing hot melting and extrusion, extruding the mixture in spherical particles to obtain amorphous particles, and micronizing the amorphous particles to obtain micronized amorphous particles, wherein the particle size is controlled to be about 210-250 nm.

(3) Weighing the compound (R) shown in the formula (I) prepared in the step (2)₁Is hydrogen, R₂Ethyl) micronized amorphous fine particles 16.5g, dipalmitoyl phosphatidylcholine 3g, cholesterol 0.5g, absolute ethyl alcohol 30g, water 50 g;

(4) dipalmitoylphosphatidylcholine, cholesterol, and a compound (R) of formula (I)₁Is hydrogen, R₂Ethyl) micronized amorphous particles are dissolved in absolute ethyl alcohol, and the mixture is heated to 30-45 ℃ to be dissolved to obtain a mixed solution;

(5) stirring the mixed solution obtained in the step (4) under the condition of 300R/min, adding distilled water, continuing stirring for 1.5h after the addition is finished, and then cooling to room temperature to obtain the compound (R) shown in the formula (I)₁Is hydrogen, R₂Ethyl) alcohol liposomes.

(6) Preparing the hot-melt pressure-sensitive adhesive:

preheating a reaction kettle to 170 ℃, adding 108g of styrene-isoprene-styrene triblock copolymer (SIS) and stirring for 10min at the rotating speed of 200 r/min; cooling to 150 ℃, cooling to 140g of acrylic resin, 50g of white mineral oil and 2g of p-phenylenediamine, stirring for 90min at the rotating speed of 200r/min, and cooling to obtain the acrylic resin.

(7) Preparation of transdermal patch:

containing a compound (R) of formula (I)₁Is hydrogen, R₂Ethyl) hot melt pressure sensitive adhesive transdermal patch formulation: 5g of alcohol liposome, 5g of dolichone terpene and 90g of hot-melt pressure-sensitive adhesive.

The preparation method comprises the following steps: heating hot-melt pressure-sensitive adhesive to melt under the protection of nitrogen, adding alcohol liposome and daphne odora terpene, mixing uniformly, coating on an anti-sticking layer (high-temperature resistant release paper) with a coating thickness of 200 μm, cooling, covering with a backing layer (non-woven fabric), and punching into square meters with an area of 20-40 c or a proper size containing a compound (R) shown in formula (I)₁Is hydrogen, R₂Ethyl) hot melt pressure sensitive adhesive transdermal patch.

Example 5 Compound (R) of formula (I)₁Is ethyl, R₂Methyl) transdermal patch preparation

(1) The compound (R) shown as the formula (I)₁Is ethyl, R₂Methyl) 0.8g, polyvidone (PVP-S630)3.5g, magnesium stearate 0.2g, micronizing, adding polyethylene glycol (molecular weight 4000)5.5g, mixing to obtain physical mixture;

(2) setting the extrusion temperature of a double-screw extruder to be 120 ℃, starting the screw after the temperature is raised to the set temperature, adding the physical mixture obtained in the step (1) into the extruder, performing hot melting and extrusion, extruding the mixture in spherical particles to obtain amorphous particles, and micronizing the amorphous particles to obtain micronized amorphous particles, wherein the particle size is controlled to be about 250-300 nm.

(3) Weighing the compound (R) shown in the formula (I) prepared in the step (2)₁Is ethyl, R₂Methyl) micronized amorphous fine particles 20g, soya bean lecithin 2g, cholesterol 0.3g, absolute ethyl alcohol 30g, water 47.7 g;

(4) mixing soybean lecithin, cholesterol, and compound (R) shown in formula (I)₁Is ethyl, R₂Methyl) micronized amorphous fine particles are dissolved in absolute ethyl alcohol and heated to 30-45 ℃ to be dissolvedObtaining a mixed solution;

(5) stirring the mixed solution obtained in the step (4) under the condition of 300R/min, adding distilled water, continuing stirring for 1.5h after the addition is finished, and then cooling to room temperature to obtain the compound (R) shown in the formula (I)₁Is ethyl, R₂Methyl) alcohol liposomes.

(6) Preparing the hot-melt pressure-sensitive adhesive:

(7) Preparation of transdermal patch:

containing a compound (R) of formula (I)₁Is ethyl, R₂Methyl) hot melt pressure sensitive adhesive transdermal patch formulation: a compound (R) of formula (I)₁Is ethyl, R₂Methyl) alcohol liposome 2g, peppermint oil 2.9g, borneol 2.1g and hot melt pressure sensitive adhesive 93 g.

The preparation method comprises the following steps: heating hot melt pressure sensitive adhesive under nitrogen protection to melt, adding alcohol liposome, oleum Menthae Dementholatum and Borneolum Syntheticum, mixing, coating on anti-sticking layer (high temperature resistant release paper) with thickness of 200 μm, cooling, covering with backing layer (non-woven fabric), and punching into square meter (40 c) containing compound (R) shown in formula (I)₁Is ethyl, R₂Methyl) hot melt pressure sensitive adhesive transdermal patch.

Example 6 Compound (R) of formula (I)₁Is ethyl, R₂Ethyl) transdermal patch preparation

(1) The compound (R) shown as the formula (I)₁Is ethyl, R₂Ethyl) 0.9g, povidone (PVP-S630)3.0g and magnesium stearate 0.1g for micronization, adding polyethylene glycol (molecular weight 4000)6.0g, mixing well to obtain physical mixture;

(3) Weighing the compound (R) shown in the formula (I) prepared in the step (2)₁Is ethyl, R₂Ethyl group) micronized amorphous fine particles 7g, soybean lecithin 2g, cholesterol 0.3g, absolute ethyl alcohol 30g, and water 60.7 g;

(4) mixing soybean lecithin, cholesterol, and compound (R) shown in formula (I)₁Is ethyl, R₂Ethyl) micronized amorphous particles are dissolved in absolute ethyl alcohol, and the mixture is heated to 30-45 ℃ to be dissolved to obtain a mixed solution;

(5) stirring the mixed solution obtained in the step (4) under the condition of 300R/min, adding distilled water, continuing stirring for 1.5h after the addition is finished, and then cooling to room temperature to obtain the compound (R) shown in the formula (I)₁Is ethyl, R₂Ethyl) alcohol liposomes.

(6) Preparing the hot-melt pressure-sensitive adhesive:

preheating a reaction kettle to 170 ℃, adding 108g of styrene-isoprene-styrene triblock copolymer (SIS) and stirring for 10min at the rotating speed of 200 r/min; cooling to 150 ℃, cooling to 140g of rosin resin, 50g of liquid paraffin and 2g of dihydroquinoline, stirring for 90min at the rotating speed of 200r/min, and cooling to obtain the rosin oil.

(7) Preparation of transdermal patch:

containing a compound (R) of formula (I)₁Is ethyl, R₂Ethyl) hot melt pressure sensitive adhesive transdermal patch formulation: (I) the compound (R)₁Is ethyl, R₂Ethyl) liposome 0.2g, menthol 5g, turpentine 10g and hot-melt pressure-sensitive adhesive 84.8 g.

The preparation method comprises the following steps: heating the hot-melt pressure-sensitive adhesive to be molten under the protection of nitrogen, and adding the compound (R) shown in the formula (I)₁Is ethyl, R₂Ethyl alcohol liposome, menthol and turpentine oil, uniformly mixing, coating on an anti-sticking layer (high-temperature resistant release paper) with a coating thickness of 200 μm, cooling, covering with a backing layer (non-woven fabric), and punching into square meters with an area of 20-40 c or a proper size containing the compound (R) shown in (I)₁Is ethyl, R₂Ethyl) hot melt pressure sensitive adhesive transdermal patch.

Examples7 Compound (R) of formula (I)₁Is isopropyl, R₂Methyl) transdermal patch preparation

(1) The compound (R) shown as the formula (I)₁Is isopropyl, R₂Methyl) 0.9g, polyvidone (PVP-S630)4.4g, magnesium stearate 0.2g, micronizing, adding polyethylene glycol (molecular weight 4000)4.5g, mixing to obtain physical mixture;

(2) setting the extrusion temperature of a double-screw extruder to be 120 ℃, starting the screw after the temperature is raised to the set temperature, adding the physical mixture obtained in the step (1) into the extruder, performing hot melting and extrusion, extruding the mixture in spherical particles to obtain amorphous particles, and micronizing the amorphous particles to obtain micronized amorphous particles, wherein the particle size is controlled to be about 100-130 nm.

(3) Weighing the compound (R) shown in the formula (I) prepared in the step (2)₁Is isopropyl, R₂Methyl) micronized amorphous fine particles 1g, soya lecithin 2g, cholesterol 0.3g, absolute ethyl alcohol 39g, water 57.7 g;

(4) mixing soybean lecithin, cholesterol, and compound (R) shown in formula (I)₁Is isopropyl, R₂Methyl) micronized amorphous particles are dissolved in absolute ethyl alcohol, and the mixture is heated to 30-45 ℃ to be dissolved to obtain a mixed solution;

(5) stirring the mixed solution obtained in the step (4) under the condition of 300R/min, adding distilled water, continuing stirring for 1.5h after the addition is finished, and then cooling to room temperature to obtain the compound (R) shown in the formula (I)₁Is isopropyl, R₂Methyl) alcohol liposomes.

(6) Preparing the hot-melt pressure-sensitive adhesive:

preheating a reaction kettle to 170 ℃, adding 108g of styrene-isoprene-styrene triblock copolymer (SIS) and stirring for 10min at the rotating speed of 200 r/min; cooling to 150 ℃, adding 140g of hydrogenated petroleum resin, 50g of liquid paraffin and 2g of bis (3, 5-tertiary butyl-4-hydroxyphenyl) thioether, stirring for 90min at the rotating speed of 200r/min, and cooling to obtain the catalyst.

(7) Preparation of transdermal patch:

containing a compound (R) of formula (I)₁Is isopropyl, R₂Methyl) hot melt pressure sensitive adhesive transdermal patch formulation: formula (I)The compound (R)₁Is isopropyl, R₂Methyl) alcohol liposome 0.5g, hot melt pressure sensitive adhesive 99.5 g.

The preparation method comprises the following steps: heating the hot-melt pressure-sensitive adhesive to be molten under the protection of nitrogen, adding alcohol liposome, uniformly mixing, coating on an anti-sticking layer (high-temperature resistant release paper) with a coating thickness of 200 mu m, cooling, covering a back lining layer (non-woven fabric), and punching into a square meter with an area of 20-40 c or a proper size containing a compound (R) shown in formula (I)₁Is isopropyl, R₂Methyl) hot melt pressure sensitive adhesive transdermal patch.

Example 8 Compound (R) of formula (I)₁Is isopropyl, R₂Ethyl) transdermal patch preparation

(1) The compound (R) shown as the formula (I)₁Is isopropyl, R₂Ethyl) 0.8g, Soluplus 2.5g and magnesium stearate 0.2g, adding polyethylene glycol (molecular weight 4000)6.5g, mixing well, and making into physical mixture;

(2) setting the extrusion temperature of a double-screw extruder to be 120 ℃, starting the screw after the temperature is raised to the set temperature, adding the physical mixture obtained in the step (1) into the extruder, performing hot melting and extrusion, extruding the mixture in spherical particles to obtain amorphous particles, and micronizing the amorphous particles to obtain micronized amorphous particles, wherein the particle size is controlled to be about 120-175 nm.

(3) Weighing the compound (R) shown in the formula (I) prepared in the step (2)₁Is isopropyl, R₂Ethyl group) micronized amorphous fine particles 0.7g, soybean lecithin 2g, cholesterol 0.4g, absolute ethyl alcohol 36.6g, and water 60.3 g;

(4) mixing soybean lecithin, cholesterol, and compound (R) shown in formula (I)₁Is isopropyl, R₂Ethyl) micronized amorphous particles are dissolved in absolute ethyl alcohol, and the mixture is heated to 30-45 ℃ to be dissolved to obtain a mixed solution;

(5) stirring the mixed solution obtained in the step (2) under the condition of 300R/min, adding distilled water, continuing stirring for 1.5h after the addition is finished, and then cooling to room temperature to obtain the compound (R) shown in the formula (I)₁Is isopropyl, R₂Ethyl) alcohol liposomes.

(6) Preparing the hot-melt pressure-sensitive adhesive:

(7) Preparation of transdermal patch:

containing a compound (R) of formula (I)₁Is isopropyl, R₂Ethyl) hot melt pressure sensitive adhesive transdermal patch formulation: a compound (R) of formula (I)₁Is isopropyl, R₂Ethyl group) alcohol liposome 0.2g, menthol 3g, borneol 2g and hot-melt pressure-sensitive adhesive 94.8 g.

The preparation method comprises the following steps: heating the hot-melt pressure-sensitive adhesive to be molten under the protection of nitrogen, and adding a compound (R) shown as a formula (I)₁Is isopropyl, R₂Ethyl alcohol liposome, menthol and borneol are uniformly mixed, coated on an anti-sticking layer (high-temperature resistant release paper) with the coating thickness of 200 mu m, covered with a backing layer (non-woven fabric) after being cooled, and punched into a square meter with the area of 20-40 c or a proper size containing a compound (R) shown in the formula (I)₁Is isopropyl, R₂Ethyl) hot melt pressure sensitive adhesive transdermal patch.

Example 9 Compound (R) of formula (I)₁Is methyl, R₂Preparation of methyl) benzene sulfonate transdermal patch

(1) The compound (R) shown as the formula (I)₁Is methyl, R₂0.9g of methyl) benzene sulfonate, 3.6g of povidone (PVP-S630) and 0.3g of talcum powder are micronized, 5.2g of polyethylene glycol (molecular weight 4000) is added, and the mixture is uniformly mixed to prepare a physical mixture;

(2) setting the extrusion temperature of a double-screw extruder to be 120 ℃, starting the screw after the temperature is raised to the set temperature, adding the physical mixture obtained in the step (1) into the extruder, performing hot melting and extrusion, extruding the mixture in spherical particles to obtain amorphous particles, and micronizing the amorphous particles to obtain micronized amorphous particles, wherein the particle size is controlled to be about 150-190 nm.

(3) Weighing the compound (R) shown in the formula (I) prepared in the step (2)₁Is methyl, R₂Is methyl) benzenesulfonate7g of micronized amorphous particles, 2g of soybean lecithin, 0.3g of cholesterol, 30g of absolute ethyl alcohol and 60.7g of water;

(4) mixing soybean lecithin, cholesterol, and compound (R) shown in formula (I)₁Is methyl, R₂Methyl) benzene sulfonate micronized amorphous particles are dissolved in absolute ethyl alcohol, and the mixture is heated to 30-45 ℃ to be dissolved to obtain a mixed solution;

(5) stirring the mixed solution obtained in the step (2) under the condition of 300R/min, adding distilled water, continuing stirring for 1.5h after the addition is finished, and then cooling to room temperature to obtain the compound (R) shown in the formula (I)₁Is methyl, R₂Methyl) benzenesulfonate.

(6) Preparing the hot-melt pressure-sensitive adhesive:

(7) Preparation of transdermal patch:

containing a compound (R) of formula (I)₁Is methyl, R₂Hot melt pressure sensitive adhesive transdermal patch formulation for methyl) benzene sulfonate: a compound (R) of formula (I)₁Is methyl, R₂Methyl) benzene sulfonate alcohol liposome 2g, menthol 3g, borneol 2g and hot melt pressure sensitive adhesive 93 g.

The preparation method comprises the following steps: heating the hot-melt pressure-sensitive adhesive to be molten under the protection of nitrogen, and adding a compound (R) shown as a formula (I)₁Is methyl, R₂Methyl) benzene sulfonate alcohol liposome, menthol and borneol are uniformly mixed, coated on an anti-sticking layer (high-temperature resistant release paper) with the coating thickness of 200 mu m, covered with a back lining layer (non-woven fabric) after being cooled, and punched into a square meter with the area of 20-40 c or a proper size containing a compound (R) shown in the formula (I)₁Is methyl, R₂Is a hot melt pressure sensitive adhesive transdermal patch of methyl) benzene sulfonate.

Example 10 Compound (R) of formula (I)₁Is methyl, R₂Is ethyl) tosylate transdermal patch preparation

(1) The compound (R) shown as the formula (I)₁Is methyl, R₂Ethyl) tosylate 0.9g, polyvidone (PVP-S630)2.5g and magnesium stearate 0.3g are micronized, polyethylene glycol (molecular weight 4000)6.3g is added, and the mixture is mixed uniformly to prepare a physical mixture;

(2) setting the extrusion temperature of a double-screw extruder to be 120 ℃, starting the screw after the temperature is raised to the set temperature, adding the physical mixture obtained in the step (1) into the extruder, performing hot melting and extrusion, extruding the mixture in spherical particles to obtain amorphous particles, and micronizing the amorphous particles to obtain micronized amorphous particles, wherein the particle size is controlled to be about 150-200 nm.

(3) Weighing the compound (R) shown in the formula (I) prepared in the step (2)₁Is methyl, R₂Ethyl) tosylate micronized amorphous fine particles 7g, soybean lecithin 2g, cholesterol 0.3g, absolute ethyl alcohol 30g, water 60.7 g;

(4) mixing soybean lecithin, cholesterol, and compound (R) shown in formula (I)₁Is methyl, R₂Ethyl) tosylate micronized amorphous particles are dissolved in absolute ethyl alcohol, and the mixture is heated to 30 to 45 ℃ to be dissolved to obtain a mixed solution;

(5) stirring the mixed solution obtained in the step (4) under the condition of 300R/min, adding distilled water, continuing stirring for 1.5h after the addition is finished, and then cooling to room temperature to obtain the compound (R) shown in the formula (I)₁Is methyl, R₂Ethyl) tosylate salt.

(6) Preparing the hot-melt pressure-sensitive adhesive:

(7) Preparation of transdermal patch:

containing a compound (R) of formula (I)₁Is methyl, R₂Ethyl) tosylate in a hot melt pressure sensitive adhesive transdermal patch formulation: a compound (R) of formula (I)₁Is methyl, R₂Ethyl) tosylate alcohol liposome 1.5g,5g of menthol, 10g of turpentine and 83.5g of hot melt pressure sensitive adhesive.

The preparation method comprises the following steps: heating the hot-melt pressure-sensitive adhesive to be molten under the protection of nitrogen, and adding a compound (R) shown as a formula (I)₁Is methyl, R₂Ethyl) tosylate alcohol liposome, menthol and turpentine are evenly mixed, coated on an anti-sticking layer (high temperature resistant release paper) with the coating thickness of 200 mu m, covered with a back lining layer (non-woven fabric) after being cooled, and punched into square meters with the area of 20-40 c or proper size containing the compound (R) shown in the formula (I)₁Is methyl, R₂Ethyl) tosylate hot melt pressure sensitive adhesive transdermal patch.

Example 11 Compound (R) of formula (I)₁Is hydrogen, R₂Is ethyl) ethanesulfonate transdermal patch preparation

(1) The compound (R) shown as the formula (I)₁Is hydrogen, R₂2g of ethyl) ethanesulfonate, 3g of povidone (PVP-VA64) and 0.1g of magnesium stearate are micronized, 4.9g of polyethylene glycol (molecular weight 4000) is added, and the mixture is uniformly mixed to prepare a physical mixture;

(2) setting the extrusion temperature of a double-screw extruder to be 120 ℃, starting the screw after the temperature is raised to the set temperature, adding the physical mixture obtained in the step (1) into the extruder, performing hot melting and extrusion, extruding the mixture in spherical particles to obtain amorphous particles, and micronizing the amorphous particles to obtain micronized amorphous particles, wherein the particle size is controlled to be about 175-220 nm.

(3) Weighing the compound (R) shown in the formula (I) prepared in the step (2)₁Is hydrogen, R₂Ethyl) ethanesulfonate micronized amorphous fine particles 3g, soybean lecithin 2g, cholesterol 0.3g, absolute ethyl alcohol 30g, and water 64.7 g;

(4) mixing soybean lecithin, cholesterol, and compound (R) shown in formula (I)₁Is hydrogen, R₂Dissolving micronized ethyl) ethanesulfonate amorphous particles in absolute ethyl alcohol, and heating to 30-45 ℃ to dissolve the micronized ethyl) ethanesulfonate amorphous particles to obtain a mixed solution;

(5) stirring the mixed solution obtained in the step (4) under the condition of 300R/min, adding distilled water, continuing stirring for 1.5h after the addition is finished, and then cooling to room temperature to obtain the compound (R) shown in the formula (I)₁Is hydrogen, R₂Ethyl) ethanesulfonate.

(6) Preparing the hot-melt pressure-sensitive adhesive:

(7) Preparation of transdermal patch:

containing a compound (R) of formula (I)₁Is hydrogen, R₂Ethyl) ethanesulfonate for hot melt pressure sensitive adhesive transdermal patch formulation: a compound (R) of formula (I)₁Is hydrogen, R₂Ethyl) ethanesulfonate alcohol liposome 5g, peppermint oil 2.9g, borneol 2.1g and hot-melt pressure-sensitive adhesive 90 g.

The preparation method comprises the following steps: heating the hot-melt pressure-sensitive adhesive to be molten under the protection of nitrogen, adding alcohol liposome, peppermint oil and borneol, uniformly mixing, coating on an anti-sticking layer (high-temperature resistant release paper), wherein the coating thickness is 200 mu m, covering a back lining layer (non-woven fabric) after cooling, and punching into a square meter with the area of 20-40 c or a square meter with the proper size containing a compound (R) shown in formula (I)₁Is hydrogen, R₂Is ethyl) ethanesulfonate.

Example 12 Compound (R) of formula (I)₁Is isopropyl, R₂Methyl) hydrobromide transdermal patch preparation

(1) The compound (R) shown as the formula (I)₁Is isopropyl, R₂4g of methyl) hydrobromide, 2g of povidone (PVP-K30) and 0.2g of talcum powder are micronized, 3.8g of polyethylene glycol (with the molecular weight of 6000) is added, and the mixture is uniformly mixed to prepare a physical mixture;

(2) setting the extrusion temperature of a double-screw extruder to be 120 ℃, starting the screw after the temperature is raised to the set temperature, adding the physical mixture obtained in the step (1) into the extruder, performing hot melting and extrusion, extruding the mixture in spherical particles to obtain amorphous particles, and micronizing the amorphous particles to obtain micronized amorphous particles, wherein the particle size is controlled to be about 180-250 nm.

(3) Weighing the compound of formula (I) prepared in the step (2)Compound (R)₁Is isopropyl, R₂Methyl) micronized amorphous fine particles of hydrobromide, 7g of phosphatidylethanolamine, 2g of cholesterol, 0.3g of isopropanol, 30g of water and 60.7g of water;

(4) phosphatidylethanolamine, cholesterol and a compound (R) shown as a formula (I)₁Is isopropyl, R₂Methyl) hydrobromate micronized amorphous particles are dissolved in isopropanol and heated to 30-45 ℃ to be dissolved to obtain a mixed solution;

(5) stirring the mixed solution obtained in the step (4) under the condition of 300R/min, adding distilled water, continuing stirring for 1.5h after the addition is finished, and then cooling to room temperature to obtain the compound (R) shown in the formula (I)₁Is isopropyl, R₂Methyl) hydrobromide.

(6) Preparing the hot-melt pressure-sensitive adhesive:

(7) Preparation of transdermal patch:

containing a compound (R) of formula (I)₁Is isopropyl, R₂Methyl) hydrobromide, hot melt pressure sensitive adhesive transdermal patch formulation: a compound (R) of formula (I)₁Is isopropyl, R₂Methyl) hydrobromate alcohol liposome 1.5g, clove volatile oil 5g and hot melt pressure sensitive adhesive 93.5 g.

The preparation method comprises the following steps: heating the hot-melt pressure-sensitive adhesive to be molten under the protection of nitrogen, and adding a compound (R) shown as a formula (I)₁Is isopropyl, R₂Methyl) hydrobromate alcohol liposome and clove volatile oil are uniformly mixed, coated on an anti-sticking layer (high-temperature resistant release paper) with the coating thickness of 200 mu m, covered with a backing layer (non-woven fabric) after being cooled, and punched into square meters with the area of 20-40 c or proper size containing the compound (R) shown in the formula (I)₁Is isopropyl, R₂Methyl) hydrobromide in the form of a hot-melt pressure-sensitive adhesive transdermal patch.

Comparative example 1 Compound (R) of formula (I)₁Is methyl, R₂Is methyl, benzene sulfonate polymorphic type) transdermal patch preparation

(1) The compound (R) shown as the formula (I)₁Is methyl, R₂The X-powder diffraction pattern of the benzene sulfonate crystal form is shown in figure 3) 0.8g of the benzene sulfonate crystal form is micronized, and the particle size is controlled to be about 100-150 nm.

(2) Weighing 3g of the amorphous particles prepared in the step (2), 2g of soybean lecithin, 0.3g of cholesterol, 30g of absolute ethyl alcohol and 64.7g of water;

(3) mixing soybean lecithin, cholesterol, and compound (R) shown in formula (I)₁Is methyl, R₂Methyl, benzene sulfonate) particles are dissolved in absolute ethyl alcohol, and the mixture is heated to 30-45 ℃ to be dissolved to obtain a mixed solution;

(4) stirring the mixed solution obtained in the step (4) under the condition of 300R/min, adding distilled water, continuing stirring for 1.5h after the addition is finished, and then cooling to room temperature to obtain the compound (R) shown in the formula (I)₁Is methyl, R₂Methyl,).

(5) Preparing the hot-melt pressure-sensitive adhesive:

(6) Preparation of transdermal patch:

containing a compound (R) of formula (I)₁Is methyl, R₂Methyl, benzene sulfonate) hot melt pressure sensitive adhesive transdermal patch formulation: a compound (R) of formula (I)₁Is methyl, R₂Methyl, benzenesulfonate) alcohol liposome 5g, lauryl nitrogen

5g of ketone and 90g of hot melt pressure sensitive adhesive.

The preparation method comprises the following steps: heating the hot-melt pressure-sensitive adhesive to melt under the protection of nitrogen, adding alcohol liposome and lauryl nitrogen

Mixing ketone (Azone), coating on release layer (high temperature resistant release paper) to a thickness of 200 μm, cooling, covering with backing layer (non-woven fabric), and punching to obtain sheet with area of 40cm²Containing a compound (R) of formula (I)₁Is methyl, R₂Methyl, benzene sulfonate) through a hot melt pressure sensitive adhesive.

The preparation method of the crystal form in figure 3 comprises the following steps:

13.6g of Compound (R) of formula (I)₁Is methyl, R₂Methyl, benzene sulfonate) is heated and dissolved in 10ml of methanol and 10ml of ethanol, cooled and crystallized (0-5 ℃), filtered, decompressed and dried at 40-50 ℃ to obtain 10.2g, and X-powder diffraction detection is carried out to obtain the crystal form shown in figure 3. The compounds of formula (I) (R) are used in the present application₁Is methyl, R₂Methyl, besylate) the above crystal forms as API (active ingredient, or drug substance).

Comparative example 2 Compound (R) of formula (I)₁Is methyl, R₂For methyl, besylate polymorph) transdermal patch preparation (prior art-CN 107929268A)

The present inventors refer to the preparation method of example 1 of Chinese patent CN107929268A, and the compound (R) shown in formula (I) is prepared₁Is methyl, R₂Methyl, benzenesulfonate) was prepared as a transdermal patch, and the preparation method thereof was as follows:

1) the active ingredient of the compound (R) shown as the formula (I)₁Is methyl, R₂Methyl, benzene sulfonate) in ethanol to obtain a drug-containing solution;

2) adding sodium hydroxide as a stabilizer and polyethylene glycol 400 as a transdermal absorption enhancer into the acrylate pressure-sensitive adhesive 87-2287 serving as a medicine base matrix, then adding propylene glycol as a dispersant, adjusting the viscosity of the adhesive solution to 1500cp at 25 ℃, and stirring at 6000rpm for 2 hours;

3) adding the product obtained in the step 2) into the product obtained in the step 1), and stirring at the speed of 1000rpm for 20 min;

4) coating the product obtained in the step 3) on a back lining layer, wherein the coating thickness is 0.25mm, drying at 90 ℃ for 0.5 hour to volatilize the solvent ethanol, and covering with an anti-adhesion layer to obtain the transdermal patch product.

EXAMPLE 13 stability testing of transdermal drug delivery systems

A compound (R) of formula (I)₁、R₂All methyl) are prone to the following 4 impurities during preparation and storage:

a compound R represented by the formula (I)₁、R₂Taking the methyl as an example, the sample prepared in the example 1 is subjected to a long-term stability experiment in an environment with the temperature of 20-30 ℃ and the humidity of 60% +/-5%.

The HPLC detection conditions were as follows:

column: YMC ODS-AQ,250X 4.6mm,3 μm particle size

Mobile phase: a: 0.01% trifluoroacetic acid in water

B: 0.01% trifluoroacetic acid in acetonitrile

Gradient:

Flow rate: 1.0ml/min

Column temperature: 40 deg.C

And (3) detection: UV of 230nm

Injection volume: 10 μ l

The placing conditions are as follows: 25 +/-5 ℃; RH 60% +/-5%

Therefore, the quality of the medicinal preparation obtained by the invention still meets the quality standard and is very stable when the medicinal preparation is placed at room temperature for three years, and R₁Is hydrogen, ethyl, isopropyl, R₂Similar results were obtained with hydrogen and ethyl.

Example 14 in vitro skin Permeability test

The results of in vitro skin permeability tests performed on the samples prepared in example 1 of the present invention using a Franz transdermal diffusion apparatus are shown in fig. 6, and the specific operations are as follows: one mouse was anesthetized by intraperitoneal injection of pentobarbital sodium (40mg/kg), then the mouse was sacrificed by exsanguination, abdominal mouse hairs were removed by an electric razor, and the skin of the unhaired mouse was removed. Removing subcutaneous fat with absorbent cotton soaked with normal saline solution for use. Fixing prepared mouse skin in Franz diffusion cell, and transdermal diffusion effective area is about 2.92cm²The receiving tank had a volume of about 12mL, and the liquid surface was brought into close contact with the inner layer of the skin, and the receiving liquid was PBS (pH7.4) and had a volume of 12 mL. The whole experimental process is kept at the constant temperature of 37 plus 0.2 ℃ and stirred at the speed of 300 r/min.

The sample prepared in example 1 was placed in the upper supply chamber and sealed with a wrap film while being covered with a layer of tinfoil paper to protect it from light. 2.0mL of the receiving solution was withdrawn at a predetermined time (1, 2, 4, 6, 8, 10 hours), and 2.0mL of the homothermal receiving solution was immediately supplemented to obtain a receiving solution containing the drug, which was stored in a refrigerator at 4 ℃. After the receiving solution of the sample is filtered by filter paper and diluted by PBS solution, the absorption value of the dye is measured by a UV-2550 ultraviolet spectrophotometer, and the cumulative amount of the sample penetrating through the skin along with the change of the time and the maximum value of the sample penetrating through the skin are obtained through calculation (the calculation method is well known in the art). As a result, as shown in fig. 6, the transdermal patch containing the compound represented by formula (I) of Azone was permeable to the skin, and the transdermal patch had high transdermal efficiency and the maximum drug accumulation amount through the skin, as compared with the transdermal patch in which the compound represented by formula (I) was loaded into alcohol liposomes or the transdermal patch in which the compound represented by formula (I) was loaded into absolute ethanol. It is demonstrated that the compound of formula (I) carried by the alcohol liposome containing the Azone can permeate through the skin, and compared with other groups, the experimental group has high transdermal efficiency and the largest drug accumulation amount penetrating through the skin.

Similar results were obtained when testing samples prepared in other examples.

Example 15 Compound (R) of formula (I) of the present invention₁、R₂All methyl) benzenesulfonate transdermal patch and injection for comparison of pharmacokinetics in cynomolgus monkey

The test was carried out on 6 monkeys, each half of the monkeys, randomly divided into two groups of transdermal group (group a) and injection solution group (group B, lyophilized powder for injection, prepared in CN105726495A example 1, diluted with 0.9% sodium chloride solution at the time of use) of example 1 of the present invention. A transdermal patch containing 10mg of the compound of formula (I) (sample prepared in example 1 of the present invention) was applied to the upper back of group a animals to ensure complete contact of the patch with the skin; group B animals were given an equal amount of injection by intravenous infusion at a rate of 30mg/kg/h for 5 min. The blood draw points for group a after the end of dosing were: 5min, 10min, 20min, 30min, 1h, 1.5h, 2h, 3h, 4h, 6h, 6.5h, 7h, 8h, 10h and 12 h; the blood draw points for group B were: 5min, 10min, 20min, 30min, 1h, 1.5h, 2h, 3h, 4h and 6 h. Approximately 0.4ml of whole blood was collected intravenously from the anterior/posterior limb (non-drug-administered limb) at these time points. After blood sample collection, the device is placedCentrifuging at 4000rpm for 5min at 4 deg.C in an anticoagulation tube (1000IU/ml, about 10 μ l) containing heparin sodium, separating plasma, and detecting the concentration of principal drug in the plasma by LC-MS/MS method. Calculation of the Primary Metabolic kinetic parameter t Using WinNonlin (V6.2)_1/2，T_max，C_max，AUC。

The experimental results (see fig. 7) are as follows:

TABLE 1 Metabolic kinetic parameters required in animals following administration of Compound of formula (I) (R1, R2 are both methyl) benzenesulfonate transdermal patches and injectable solutions

Comparing the pharmacokinetic parameters t of the transdermal patch and the injection of the Compound of formula (I) in cynomolgus monkeys_1/2、T_max、C_maxAnd the bioavailability is basically consistent after AUC, but the transdermal patch group has a certain sustained and controlled release function, so that the action time of the medicine can be prolonged to a certain extent, and the medicine taking frequency is reduced.

EXAMPLE 16 Observation of the Strength of the hypnotic Effect of the transdermal formulations of the Compound of formula (I) (samples prepared in example 1) and diazepam in mice

20 mice were randomly divided into two groups, namely the transdermal formulation group of the compound of formula (I) (group a, inventive example 1) and the diazepam group (group B, diazepam tablets, available from heilongjianfu and pharmaceutical groups ltd). The transdermal preparation is pasted on the back of the mice in the group A according to 4mg/kg, and the same amount of diazepam is orally administrated to the mice in the group B. After the administration, the influence of A, B groups of drugs on the sleep time of mice was observed by the positive reflex process. After the mouse positive turning reflex is finished, collecting an end-point blood sample, centrifuging at 4000rpm for 5min, separating plasma, and detecting whether the plasma contains the main drug by using an LC-MS/MS method. After the righting reflex was over, no compound of formula (I) was detected in the mice of group a, and diazepam was still detectable in the blood of the mice of group B. The results of the mouse orthotropic reflex were as follows:

TABLE 2 comparison of the transdermal preparation of the Compound of formula (I) and diazepam groups for the sleep Effect in mice

Compared with the diazepam group, the mice in the transdermal preparation group of the compound shown in the formula (I) have shorter sleep time and longer sleep maintenance time, and the compound shown in the formula (I) has no residue in vivo after the righting reflex of the mice disappears. The results show that the transdermal preparation of the compound shown in the formula (I) has better sleep induction effect on mice than diazepam.

Example 17 transdermal drug delivery systems of the present invention were tested for skin response

Grade of skin reaction

Grade 4: erythema, blistering and bullous formation

Grade 3: erythema, blistering; without bulla

Grade 2: erythema covers the entire patch area; has no foaming

Grade 1: slight erythema covers less than the entire patch area

Grade 0: minimal or no reaction at the patch site

2 samples of examples 1 to 12 according to the invention were each applied to 24 rats depilated on the back, and after 24 hours, the products of examples 1 to 12 were found to be free of skin irritation.

Example 18 Compound (R) of formula (I)₁Is methyl, R₂DSC, X-powder diffraction detection of methyl) benzenesulfonate

Respectively taking a compound (R) shown as a formula (I)₁、R₂Is methyl benzene sulfonate, a compound (R) shown as a formula (I)₁、R₂Is methyl benzene sulfonate and Soluplus to form particles and a compound (R) shown as a formula (I)₁、R₂The results of DSC and X-powder diffraction of the physical mixture of methyl) benzene sulfonate and Soluplus are shown in figures 1-5, and the results show that the compound (R) shown in the formula (I) is obtained after hot melt extrusion₁、R₂All are methyl) from a polycrystalline state toThe amorphous state is more beneficial to the absorption of the drug, and the stability of the amorphous state is proved in the preparation research and is more stable than the conventional amorphous state.

Detection conditions are as follows:

powder X-ray diffraction (PXRD)

The instrument comprises the following steps: XTRA/3KW X-ray diffractometer (Swiss ARL company)

Target Cu-K α radiation

Wavelength: 1.5406A

Pipe pressure: 40KV

Pipe flow: 40mA

Step length: 0.02 degree

Scanning speed: 10 °/min

Differential Scanning Calorimetry (DSC)

The instrument comprises the following steps: pyris1 thermal analyzer (PerkinElmer, USA)

Example 19 Compound (R) of formula (I)₁Is methyl, R₂Pharmacokinetic comparison of the sample of inventive example 1, which is a methyl) benzenesulfonate, with comparative examples 1, 2

The test uses 18 monkeys, each half male and female, randomly divided into three groups, i.e., the compound of formula (I) the sample of example 1 (group A) of the present invention, and the compound of formula (I) (R)₁Is methyl, R₂Being methyl) benzenesulfonate comparative example 1 (group B) and a compound of formula (I) (R)₁Is methyl, R₂Methyl) benzenesulfonate comparative example 2 (group C), 6 of each group were tested. Transdermal patches containing different samples of the compound of formula (I) were applied to the upper back of A, B, C three groups of animals, respectively, to ensure complete contact of the transdermal patch with the skin. At the end of dosing, A, B, C three groups of blood draw points were: 5min, 10min, 20min, 35min, 65min, 95min, 125min, 185min, 245min, 365min, 390min, 420min, 480min, 600min, 720 min. Approximately 0.4ml of whole blood was collected intravenously from the anterior/posterior limb (non-drug-administered limb) at these time points. After blood collection, the sample was placed in an anticoagulation tube (1000IU/ml, about 10. mu.l) containing heparin sodium,

centrifuging at 4000rpm for 5min, separating plasma and using LC-MS/MSThe method of (1) detects the concentration of the principal agent in the blood plasma. The main metabolic kinetic parameters t1/2, Tmax, Cmax, AUC were calculated using WinNonlin (V6.2).

The experimental results (see fig. 8) are as follows:

TABLE 3 Compound of formula (I) (R) for different samples₁、R₂All methyl) benzenesulfonate transdermal patch administered with pharmacokinetic parameters in animals

Comparing pharmacokinetic parameters t1/2, Tmax, Cmax and AUC of different samples of the compound transdermal patch A, B, C group of the formula (I) in the cynomolgus monkey, the absorption speed of the compound transdermal patch of the formula (I) in the group A by the cynomolgus monkey is higher than that of the compound transdermal patch of the group B, C in two groups, the drug effect duration of the transdermal patch of the group A in the cynomolgus monkey is higher than that of the compound transdermal patch of the group B, C in two groups, and the bioavailability is also higher than that of the compound transdermal patch of the group B, C in two groups.

The foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the present invention is not limited to the specific embodiments described above, and that various changes and modifications may be made by one skilled in the art within the scope of the appended claims without departing from the spirit of the invention.

time (min)

1. Benzodiazepine shown in formula (I)

the process for preparing the topical pharmaceutical composition comprises the step of adding the benzodiazepine

Microparticles of the compound or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition of claim 1, wherein R in formula (I)₁Is methyl, R₂Is methyl; or, R₁Is methyl, R₂Is ethyl; or, R₁Is hydrogen, R₂Is methyl; or, R₁Is hydrogen, R₂Is ethyl; or, R₁Is ethyl, R₂Is methyl; or, R₁Is ethyl, R₂Is ethyl; or, R₁Is isopropyl, R₂Is methyl.

3. The pharmaceutical composition of claim 1, wherein the benzodiazepine

The pharmaceutically acceptable salt of the compound is benzene sulfonate, toluene sulfonate, methane sulfonate, tartrate, malate, maleate, fumarate, hydrochloride, hydrobromide,One or more of sulfate and ethanesulfonate; preferably, it is a benzenesulfonate, tosylate, or ethanesulfonate.

4. The pharmaceutical composition according to claim 1, wherein the polymeric dispersing carrier material is selected from povidone or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer;

or, the fluxing agent is selected from polyethylene glycol, preferably the molecular weight of the polyethylene glycol is 2000-6000; or

The hot-melt protective agent is magnesium stearate or talcum powder.

5. The pharmaceutical composition of claim 4, wherein the process for preparing the topical pharmaceutical composition further comprises adding the benzodiazepine

Preparing alcohol liposome from the particles of the compound or the pharmaceutically acceptable salt thereof, and mixing the alcohol liposome with the hot-melt pressure-sensitive adhesive and an optional transdermal absorption enhancer to prepare a matrix layer; the alcohol liposome is composed of the benzodiazepine

The compound or the pharmaceutically acceptable salt thereof, phospholipid, cholesterol, low molecular organic alcohol and water.

6. The pharmaceutical composition according to claim 1, wherein the temperature of the hot-melt extrusion is 100 to 180 ℃.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein in the benzodiazepine

8. The pharmaceutical composition according to claim 5, wherein the low molecular organic alcohol is selected from one or more of ethanol, propylene glycol and isopropanol;

the phospholipid is selected from one or more of soybean lecithin, phosphatidylcholine, phosphatidylethanolamine and dipalmitoylphosphatidylcholine;

the hot-melt pressure-sensitive adhesive consists of a styrene-isoprene-styrene triblock copolymer, tackifying resin, an antioxidant and a plasticizer;

the skin penetration enhancer is selected from one or more of laurocapram, oleum Menthae Dementholatum, oleum Terebinthinae, menthol, flos Caryophylli volatile oil, Borneolum Syntheticum, cadinane, and isopropyl myristate.

9. The pharmaceutical composition of claim 8, wherein the tackifying resin is selected from one or more of hydrogenated petroleum resin, terpene resin, C5 resin, acrylic resin and rosin resin;

the plasticizer is selected from one or more of mineral oil, liquid paraffin, naphthenic oil and white mineral oil;

the antioxidant is selected from one or more of 2, 6-di-tert-butyl-4-methylphenol, antioxidant 1010, bis (3, 5-tert-butyl-4-hydroxyphenyl) sulfide, p-phenylenediamine, dihydroquinoline, didodecanol ester, ditetradecanol ester and dioctadecyl alcohol ester.

10. The pharmaceutical composition of claim 1, wherein the benzodiazepine

Compounds of the class or their pharmaceuticalsThe diameter of the fine particles of the above acceptable salt is 100 to 300nm, preferably 100 to 200nm or 150 to 250 nm.

11. The pharmaceutical composition of claim 1, wherein the benzodiazepine is present

In a topical pharmaceutical composition of a compound of the class

12. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 11, comprising the steps of:

(1) the dinitrogen benzene is added

(2) preparing the particles obtained in the step (1) into alcohol liposome;

(3) preparing hot-melt pressure-sensitive adhesive;

13. The production method according to claim 12, wherein the microparticle production process includes:

(i) diazoxide of formula (I)

Micronizing the compound or pharmaceutically acceptable salt thereof, the high molecular material and the hot-melt protective agent, optionally adding a fluxing agent, and uniformly mixing to obtain a physical mixture;

(ii) setting the extrusion temperature of a double-screw extruder to be 100-180 ℃, starting the screw after the temperature is raised to the set temperature, adding the physical mixture obtained in the step (i) into the extruder, performing hot melting and extrusion, extruding the mixture in spherical particles to obtain amorphous particles, and micronizing the amorphous particles to obtain micronized amorphous particles;

the preparation process of the hot-melt pressure-sensitive adhesive comprises the following steps:

(a) preheating a reaction kettle to 150-180 ℃;

(b) adding a styrene-isoprene-styrene triblock copolymer, and stirring at a rotation speed of 200-300 r/min for 10 min;

(c) cooling to 120-180 ℃, then respectively adding a plasticizer, tackifying resin and an antioxidant, stirring at the rotating speed of 200-300 r/min for 60-90 min, and cooling to obtain the hot-melt pressure-sensitive adhesive;

the preparation method of the alcohol liposome comprises the following steps:

Dissolving the particles of the compound or the pharmaceutically acceptable salt thereof in low-molecular organic alcohol, and heating to 30-45 ℃ to dissolve the particles to obtain a mixed solution;

14. Use of a pharmaceutical composition according to any one of claims 1 to 11 in the manufacture of a medicament for soothing the nerves, tranquilizing the mind, or improving sleep.