CN111346073B - Transdermal drug delivery pharmaceutical composition and preparation method and application thereof - Google Patents

Abstract

The invention discloses a pharmaceutical composition for transdermal administration, comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a polymer dispersion carrier material, a hot melt protective agent and an optional melting agent, the The preparation method of the pharmaceutical composition for transdermal administration comprises: micronizing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a polymer dispersion carrier material and a hot-melt protective agent, optionally adding a melting agent, The mixture is uniformly mixed, then extruded through hot melt and micronized to obtain microparticles of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. In addition, the application of the above-mentioned pharmaceutical composition is also provided. The transdermal pharmaceutical composition can quickly absorb the compound represented by the formula (I), achieve the purpose of sedation before anesthesia without affecting breathing, and avoid the adverse psychological effects on children caused by intramuscular or intravenous acupuncture. Meanwhile, the pharmaceutical composition can also be used to prevent and/or treat ADHD in children.

Description

A kind of pharmaceutical composition for transdermal administration and its preparation method and application

technical field

The present invention relates to pharmaceutical preparation technology, and more particularly to a pharmaceutical composition for transdermal administration of a compound represented by formula (I) and a preparation method and application thereof.

Background technique

Ketamine (the corresponding racemic mixture of the dextro- and levo-enantiomers) is an N-methyl-D-aspartate (NMDA) receptor antagonist that produces a wide range of effects in humans, including sedation Pain, anesthesia, hallucinations, dissociative effects, elevated blood pressure and bronchiectasis. Ketamine is primarily used to induce and maintain general anesthesia. Other uses include sedation in intensive care, analgesia (particularly in emergency medicine), and treatment of bronchospasm. D-ketamine enantiomer (or S-(+) ketamine or esketamine) is a non-competitive and subtype non-selective activity-dependent NMDA receptor antagonist with a new and unique mechanism of action, It has higher potency or affinity for NMDA receptors, and therefore may allow lower effective doses and reduce side effects caused by dose escalation or continuous medication during the medication process.

The ketamine structure is shown below:

Chemical name: 2-(2-chlorophenyl)-2-(methylamino) cyclohexanone.

However, at present, ketamine or its isomer dexketamine is mainly used in the injection form, which needs to be used under the guidance of professional doctors in clinical practice, and the injection is often accompanied by injection pain, which makes it inconvenient for patients to take medication and has poor compliance. , often bring adverse psychological effects to patients, especially when used in young children, this situation is more likely to occur.

Therefore, it is necessary to develop a preparation, which can not only make the compound represented by formula (I) stably stored at room temperature, but also reduce the production cycle and production cost of the preparation, reduce side reactions and the number of times of administration, and make it convenient for patients to administer medicines , to facilitate patient self-management.

SUMMARY OF THE INVENTION

In order to overcome the deficiency of the pharmaceutical preparation of the compound shown in the formula (I) in the above-mentioned prior art in preparation and use, the present inventor has developed a pharmaceutical composition of the compound shown in the formula (I), especially a transdermal administration. pharmaceutical preparations.

The first object of the present invention is to provide a pharmaceutical composition for transdermal administration of the compound represented by formula (I).

The second object of the present invention is to provide a method for preparing the above-mentioned transdermal pharmaceutical composition.

The third object of the present invention is to provide the application of the above-mentioned transdermal pharmaceutical composition.

In an embodiment of the present invention, the present invention provides a pharmaceutical composition for transdermal administration of a compound represented by formula (I), the pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof , polymer dispersion carrier material, hot melt protective agent and optional melting agent,

Wherein, the preparation method of the pharmaceutical composition for transdermal administration comprises: micronizing the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, a polymer dispersion carrier material and a hot-melt protective agent, optionally The melting agent is added to the mixture, and the mixture is uniformly mixed to obtain a physical mixture, which is then hot-melt extruded and micronized to obtain the microparticles of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention, the present invention provides a pharmaceutical composition for transdermal administration of a compound represented by formula (I), wherein the compound represented by formula (I) is ketamine, lev-ketamine, dexamethasone Ketamine, or a non-equivalent (ie, non-1:1) mixture of lev-ketamine and dex-ketamine.

In one embodiment of the present invention, the present invention provides a pharmaceutical composition for transdermal administration of a compound represented by formula (I), wherein the pharmaceutically acceptable salt of the compound represented by formula (I) is hydrochloride, hydrobromide, besylate, tosylate, ethanesulfonate, tartrate, malate, or (S)-camphorsulfonate (e.g. dexketamine (S)-camphor one or more of sulfonates).

In one embodiment of the present invention, the present invention provides a pharmaceutical composition for transdermal administration of a compound represented by formula (I), wherein the polymer dispersion carrier material is selected from povidone (PVP-VA64 , povidone-S630, or K30) or Soluplus (polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer).

In one embodiment of the present invention, the present invention provides a pharmaceutical composition for transdermal administration of a compound represented by formula (I), wherein the melting agent is selected from polyethylene glycol, preferably polyethylene glycol The molecular weight is 2000-6000.

In one embodiment of the present invention, the present invention provides a pharmaceutical composition for transdermal administration of a compound represented by formula (I), wherein the hot-melt protective agent is magnesium stearate or talc.

In a preferred embodiment of the present invention, the present invention provides a pharmaceutical composition for transdermal administration of a compound represented by formula (I), wherein the compound represented by formula (I) or its pharmaceutically acceptable In the salt particles, the weight percentage of the compound represented by formula (I) or its pharmaceutically acceptable salt is 20-70%, the weight percentage of the polymer dispersion carrier material is 10-25%, and the weight percentage of the hot melt protective agent is 20-70%. It is 1-3%, and the weight percentage of polyethylene glycol is 10-65%.

In one embodiment of the present invention, the present invention provides a pharmaceutical composition for transdermal administration of a compound represented by formula (I), wherein the temperature of the hot melt extrusion is 100-180°C.

In one embodiment of the present invention, the present invention provides a pharmaceutical composition for transdermal administration of a compound represented by formula (I), wherein the compound represented by formula (I) or its pharmaceutically acceptable The diameter (particle diameter) of the fine particles of the salt is 100 to 300 nm, preferably 100 to 200 nm or 150 to 250 nm.

In one embodiment of the present invention, the present invention provides a pharmaceutical composition for transdermal administration of a compound represented by formula (I), wherein, in the transdermal administration of the compound represented by formula (I) In the composition, the content of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 1-300 mg/patch, preferably 5-120 mg/patch.

In an embodiment of the present invention, the present invention provides a pharmaceutical composition for transdermal administration of a compound represented by formula (I), wherein the pharmaceutical composition for transdermal administration comprises a compound represented by formula (I) or Its pharmaceutically acceptable salt, polymer dispersion carrier material, hot melt protective agent and optional melting agent, also include phospholipid, cholesterol, low molecular organic alcohol, water, transdermal absorption enhancer, antioxidant, pressure sensitive adhesive and polymer skeleton carrier materials.

In an embodiment of the present invention, the present invention provides a pharmaceutical composition for transdermal administration of a compound represented by formula (I), wherein the pharmaceutical composition for transdermal administration is a transdermal patch, the patch Also includes a release layer and a backing layer.

In an embodiment of the present invention, the present invention provides a pharmaceutical composition for transdermal administration of a compound represented by formula (I), wherein, the preparation method of a pharmaceutical composition for transdermal administration of a compound represented by formula (I) It also includes: preparing the microparticles of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof into an alcohol liposome, and stirring and dissolving the alcohol liposome with a transdermal absorption enhancer and an antioxidant; The pressure-sensitive adhesive is mixed evenly, and then mixed with the polymer skeleton carrier material; the organic solvent (ie, low molecular organic alcohol) in the alcohol liposome is removed by drying, and it is coated on the release layer, and then covered with a backing layer.

In an embodiment of the present invention, the present invention provides a pharmaceutical composition for transdermal administration of a compound represented by formula (I), wherein the alcohol liposome is composed of the compound represented by formula (I) or its The pharmaceutically acceptable salt is composed of microparticles, phospholipids, cholesterol, low-molecular-weight organic alcohol and water; preferably, the mass percentage composition of the alcohol liposome is: 5% to 80% of the compound represented by formula (I) or its pharmacy Microparticles of acceptable salts above, 1%-5% phospholipids, 0.1%-1% cholesterol, 20%-50% low-molecular-weight organic alcohols, and the balance is water; more preferably, 7-70% of formula (I) The microparticles of the indicated compound, 2.0-3.0% phospholipid, 0.2-0.5% cholesterol, 30-40% low molecular weight organic alcohol, and the balance are water.

In an embodiment of the present invention, the present invention provides a pharmaceutical composition for transdermal administration of a compound represented by formula (I), wherein the phospholipid is selected from soybean lecithin, phosphatidylcholine, phosphatidylethanolamine, One or more of dipalmitoyl phosphatidyl cholines.

In an embodiment of the present invention, the present invention provides a pharmaceutical composition for transdermal administration of a compound represented by formula (I), wherein the low-molecular-weight organic alcohol is selected from one of ethanol, propylene glycol, and isopropanol. species or several.

In an embodiment of the present invention, the present invention provides a pharmaceutical composition for transdermal administration of a compound represented by formula (I), wherein the pressure-sensitive adhesive is one or more of acrylic acid or acrylate.

酮、肉豆蔻酸异丙酯、薄荷油、松节油、薄荷醇、丁香挥发油、冰片、杜香萜烯、茉莉精油、玫瑰精油、辛夷精油、薰衣草精油中的一种或几种。In an embodiment of the present invention, the present invention provides a pharmaceutical composition for transdermal administration of a compound represented by formula (I), wherein the transdermal absorption enhancer is selected from lauryl nitrogen

One or more of ketone, isopropyl myristate, peppermint oil, turpentine oil, menthol, clove volatile oil, borneol, eucalyptene, jasmine essential oil, rose essential oil, capsicum essential oil, and lavender essential oil.

In an embodiment of the present invention, the present invention provides a pharmaceutical composition for transdermal administration of a compound represented by formula (I), wherein the antioxidant is selected from BHT, antioxidant 1010, bis(3) , 5-tert-butyl-4-hydroxyphenyl) sulfide, one of p-phenylenediamine and dihydroquinoline, two dodecyl alcohol ester, two tetradecyl alcohol ester and two octadecyl alcohol ester species or several. Here, BHT: also known as 2,6-di-tert-butyl-4-methylphenol, antioxidant 264, dibutylhydroxytoluene; antioxidant 1010 is tetra[beta-(3,5-di-tert-butyl] -4-Hydroxyphenyl)propionic acid]pentaerythritol ester.

In an embodiment of the present invention, the present invention provides a pharmaceutical composition for transdermal administration of a compound represented by formula (I), wherein the polymer skeleton carrier material is selected from polyvinylpyrrolidone, sodium polyacrylate, hydroxyl One or more of methyl cellulose, vinyl acetate-vinyl pyrrolidone copolymer, acrylic resin, and sodium carboxymethyl cellulose.

In an embodiment of the present invention, the present invention provides a pharmaceutical composition for transdermal administration of a compound represented by formula (I), wherein the release layer can be selected from 3M backing film Scotchpak.

In an embodiment of the present invention, the present invention provides a pharmaceutical composition for transdermal administration of a compound represented by formula (I), wherein the backing layer can be selected from CoTran or a non-woven fabric.

On the other hand, the present invention provides a method for preparing a pharmaceutical composition for transdermal administration of a compound represented by the above formula (I), comprising the following steps:

(1) micronizing the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, a polymer dispersion carrier material and a hot-melt protective agent, optionally adding a melting agent, mixing uniformly to obtain a physical mixture, and then Through hot melt extrusion and micronization, the microparticles of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof are obtained;

(2) The microparticles obtained in step (1) are prepared into alcohol liposomes.

In an embodiment of the present invention, the present invention provides a method for preparing a pharmaceutical composition for transdermal administration of a compound represented by formula (I), wherein the preparation process of the microparticles comprises:

(i) micronizing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a polymer dispersion carrier material and a hot-melt protective agent, optionally adding a solubilizer, and mixing uniformly to obtain a physical mixture;

(ii) setting the extrusion temperature of the twin-screw extruder to be 100 to 180°C, starting the screw after rising to the set temperature, adding the physical mixture obtained in step (i) into the extruder, and performing hot-melting, extrusion Pressing, extruding into spherical particles to obtain amorphous particles, and then micronizing them to obtain micronized amorphous particles.

In an embodiment of the present invention, the present invention provides a method for preparing a pharmaceutical composition for transdermal administration of a compound represented by formula (I), wherein the method for preparing the alcohol liposome comprises the following steps:

(i') weighing phospholipid, cholesterol, low molecular weight organic alcohol, microparticles of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and water;

(ii') dissolving phospholipid, cholesterol, and microparticles of the compound represented by formula (I) in low-molecular-weight organic alcohol, and heating to 30-45° C. to dissolve to obtain a mixed solution;

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

In a preferred embodiment of the present invention, the preparation method of the pharmaceutical composition for transdermal administration of the compound represented by the formula (I) provided by the present invention comprises the following steps:

(1) micronizing the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, a polymer dispersion carrier material and a hot-melt protective agent, optionally adding a melting agent, mixing uniformly to obtain a physical mixture, and then Through hot melt extrusion and micronization, the microparticles of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof are obtained;

(2) preparing the microparticles, low molecular organic alcohols, phospholipids, cholesterol and water obtained in step (1) into alcohol liposomes;

(3) stirring and dissolving the alcohol liposome prepared in step (2) with transdermal absorption enhancer and antioxidant;

(4) ultrasonically mixing the mixture obtained in step (3) with the pressure-sensitive adhesive uniformly, then mixing with the polymer skeleton carrier material, drying to remove the organic solvent (ie low molecular organic alcohol), coating on the release layer, and then covering Upper backing layer.

In a preferred embodiment of the present invention, the present invention provides a method for preparing a pharmaceutical composition for transdermal administration of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein step (1) comprises: formula ( 1) compound shown or its pharmaceutically acceptable salt is mixed with macromolecular carrier material, hot-melt protective agent and then micronized again, and then mixed with melting agent, in this step, add a small amount of hot-melt protective agent, micropowder The compound represented by the formula (I) or its pharmaceutically acceptable salt and the polymer carrier material can be fully mixed evenly during the chemical reaction, so as to improve its powder properties and fluidity, and at the same time, the compound represented by the formula (I) or its pharmaceutically acceptable salt can be protected. The stability of the pharmaceutically acceptable salt avoids the phenomenon that the compound is decomposed and generates impurities due to the high temperature of hot melt extrusion, so that the compound represented by the formula (I) or its pharmaceutically acceptable salt is prevented from forming an amorphous form. The phenomenon of the formation of mixed crystals, and then the phenomenon that the release of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof does not meet the purpose of the present invention (uniform, stable and sufficient release) occurs.

In a third aspect, the present invention provides the application of the transdermal pharmaceutical composition of the compound represented by the above formula (I) provided by the present invention for preventing and/or treating children with ADHD.

Compared with the prior art, the transdermal administration pharmaceutical composition of the compound shown in the formula (I) provided by the present invention can significantly improve the transdermal permeability of the drug, so that the drug can maintain a high blood drug concentration for a long time, ensuring that The continuous exertion of the drug effect can reduce the side effects of the drug, reduce the frequency of administration, and facilitate the self-management of the patient.

The pharmaceutical composition for transdermal administration of the compound represented by the formula (I) provided by the present invention, because of the stable system and high transdermal efficiency, is conducive to carrying the drug into the deep layer of the skin and promoting the transdermal absorption of the drug. has a wide range of applications.

The pharmaceutical composition for transdermal administration of the compound represented by the formula (I) provided by the present invention is based on the addition of a transdermal absorption enhancer on the basis of the alcohol liposome, and the compound represented by the formula (I) is prepared into amorphous particles, Prevent the active ingredient from precipitating in the form of crystals, and it is easy to make the drug enter the hair follicle through penetrating cells, through the intercellular space, and through the opening of the skin accessory pipeline to improve its targeting and promote skin transdermal absorption; alcohol liposome As a carrier for transdermal administration, the drug to be transdermal is encapsulated in alcohol liposomes, which improves the transdermal permeability of the drug, enhances the sustained and controlled release effect of the drug, and is conducive to the absorption of the drug into the systemic circulation, thereby exerting local Therapeutic or systemic action with the advantage of targeting the hair follicle. Compared with the prior art, the skin passage rate of the functional components is increased, and the dosage of the drug is greatly reduced, which fully exerts the efficacy of each component of the drug, facilitates the convenient treatment of patients by doctors, and has broad clinical applications. prospect.

The advantages of the present invention are that the pharmaceutical composition can control the plasma concentration of the compound represented by formula (I) and thereby obtain a therapeutic effect, reduce the systemic absorption of the drug, concentrate the drug on the lesion, and improve its local biological Utilization and targeting can reduce side effects; the hydrating phospholipids of the liposomes contained can promote the hydration of dry skin, make the skin delicate and smooth, and have a protective and cosmetic effect on the skin.

The pharmaceutical composition for transdermal administration of the present invention has good biocompatibility, can improve skin nutrition metabolism, can promote the proliferation of fibroblasts, repair skin wounds, reduce scars, enhance immunity and the like; The carrier for skin administration can avoid the disadvantages of liver first-pass effect and low bioavailability, and can effectively avoid gastrointestinal adverse reactions such as gastroenteritis, diarrhea, and gastrointestinal bleeding; the number of administrations is small, and the dosage can be self-managed; the The transdermal drug delivery system can significantly improve the transdermal penetration rate of the drug, so that the drug concentration in the blood reaches the therapeutic concentration, so that the drug effect can be rapidly exerted, and the bioavailability is equivalent to the injection dosage form; the transdermal drug delivery system of the present invention is physically and chemically stable The property is good, the preparation conditions are easy to meet, the use is convenient, and the clinical medication requirements are met, and the method has good practical value.

Description of drawings

Fig. 1 represents the DSC chart of the compound hydrochloride represented by formula (I);

Figure 2 represents the DSC spectrum of the microparticles formed by the compound hydrochloride of formula (I) and povidone S630;

Fig. 3 represents the X-powder diffraction pattern of compound hydrochloride represented by formula (I);

Fig. 4 represents the X-powder diffraction pattern under the physical mixing state of compound hydrochloride shown in formula (I) and povidone S630;

Figure 5 represents the X-powder diffraction pattern of the compound hydrochloride represented by the formula (I) and povidone S630 to form microparticles;

Figure 6 shows the cumulative drug penetration through the mouse skin at different times measured by the sample prepared in Example 1 of the present application using a Franz transdermal diffusometer; wherein, a is alcohol liposome-Azone, and b is alcohol lipid plastid, c is absolute ethanol.

Figure 7 shows the average concentration-time curve of the main drug in the animal plasma of the sample prepared in Example 1 of the present application and the injection group after administration.

Figure 8 shows the mean concentration-time curve of the main drug in animal plasma after administration of different samples of the compound of formula (I) hydrochloride.

Detailed ways

The present invention will be described in detail with reference to specific embodiments. The following examples will help those skilled in the art to further understand the present invention, but do not limit the present invention in any form. It should be noted that, for those skilled in the art, several modifications and improvements can be made without departing from the concept of the present invention. These all belong to the protection scope of the present invention. Below in conjunction with example, the present invention is further described:

instrument:

Drug hot melt extruder hartek HTGD-16, MS-Ⅱ small blending extrusion test machine, GSH-01 reactor, TX2003-1 hot melt coating machine, Franz transdermal diffusometer, XTRA/3KW X-ray diffraction (Switzerland ARL company), XTRA/3KW X-ray diffractometer (Switzerland ARL company), Pyris 1 thermal analyzer (American PerkinElmer company).

Example 1 Preparation of transdermal patch of compound represented by formula (I) (dexketamine) hydrochloride

(1) Micronize 5 g of compound (dexketamine) hydrochloride represented by formula (I), 2 g of povidone (PVP-S630), 0.12 g of magnesium stearate, and add 2.88 g of polyethylene glycol (molecular weight 2000) , mixed uniformly to obtain a physical mixture;

(2) Set the extrusion temperature of the twin-screw extruder to be 120°C, start the screw after rising to the set temperature, add the physical mixture in the step (1) to the extruder, and then heat-melt and extrude, It is extruded into spherical particles to obtain amorphous particles, which are then micronized to obtain micronized amorphous particles, and the particle size is controlled at about 100-150 nm.

(3) Weigh 5 g of micronized amorphous particles prepared in step (2), 0.2 g of soybean lecithin, 0.03 g of cholesterol, 3 g of dehydrated alcohol, and 1.77 g of water;

(4) dissolving soybean lecithin, cholesterol, and the compound hydrochloride represented by formula (I) in micronized amorphous particles in absolute ethanol, and heating to 30-45° C. to dissolve them to obtain a mixed solution;

(5) the mixed solution obtained in the step (4) is stirred under the condition of 300r/min and added with distilled water, after the addition, the stirring is continued for 1.5h, and then cooled to room temperature to obtain the alcohol liposome of the compound represented by the formula (I) .

(6) Preparation of transdermal patch:

酮(Azone)0.7g，抗氧剂1010 0.2g搅拌溶解，与丙烯酸3g超声混合均匀，然后与聚乙烯吡咯烷酮4g、羟丙甲纤维素2g加热至60℃混合均匀，干燥除去有机溶剂即乙醇，冷却后涂布于防粘层(Scotchpak)上，涂布厚度为100μm，冷却后覆盖上背衬层(无纺布)，冲切成面积为2～4cm²或合适大小的含有该化合物的透皮贴剂。Add alcohol liposome 1g, lauryl nitrogen prepared by above-mentioned steps (5)

0.7g of ketone (Azone), 0.2g of antioxidant 1010, stirred and dissolved, mixed with 3g of acrylic acid by ultrasonic, then heated to 60°C with 4g of polyvinylpyrrolidone and 2g of hypromellose and mixed well, dried to remove the organic solvent, namely ethanol, After cooling, coat on the anti-sticking layer (Scotchpak) with a coating thickness of 100 μm, cover with a backing layer (non-woven fabric) after cooling, and punch out a transparent layer containing the compound with an area of 2-4 cm ² or a suitable size. skin patch.

Example 2 Preparation of transdermal patch of compound (ketamine) represented by formula (I)

(1) Micronize compound (ketamine) 6g and povidone (PVP-S630) 1g, magnesium stearate 0.18g shown in formula (I), add polyethylene glycol (molecular weight 3000) 2.82g, mix well, produce a physical mixture;

(2) Set the extrusion temperature of the twin-screw extruder to be 100°C, start the screw after rising to the set temperature, add the physical mixture in the step (1) into the extruder, and then heat-melt and extrude, It is extruded into spherical particles to obtain amorphous particles, which are then micronized to obtain micronized amorphous particles, and the particle size is controlled at about 150-200 nm.

(3) Weigh 5 g of micronized amorphous particles prepared in step (2), 0.2 g of phosphatidylcholine, 0.08 g of cholesterol, 3 g of propylene glycol, and 1.72 g of water;

(4) dissolving phosphatidylcholine, cholesterol, and the compound represented by formula (I) into micronized amorphous particles in propylene glycol, and heating to 30-45° C. to dissolve them to obtain a mixed solution;

(5) the mixed solution obtained in the step (4) is stirred under the condition of 200r/min and added with distilled water, after the addition, the stirring is continued for 1.5h, and then cooled to room temperature to obtain the alcohol liposome of the compound represented by the formula (I) .

(6) Preparation of transdermal patch:

Add 1 g of alcohol liposomes prepared in the above step (5), 0.4 g of jasmine essential oil, 0.4 g of rose essential oil, and 0.2 g of BHT, stir and dissolve, mix with 2 g of acrylic acid ultrasonically, and then heat with 6 g of acrylic resin to 50 ° C to mix evenly, dry Remove the organic solvent ie propylene glycol, coat on the anti-stick layer (Scotchpak) after cooling, the coating thickness is 100μm, cover with the backing layer (CoTran) after cooling, punch out the area of ² ～4cm2 or suitable size containing Transdermal patches of the compound.

Example 3 Preparation of the transdermal patch of the compound represented by formula (I) (levoketamine)

(1) Micronize 7 g of the compound represented by formula (I) (levoketamine), 1.5 g of povidone (PVP-VA64) and 0.2 of talc, add 1.3 g of polyethylene glycol (molecular weight 4000), mix well, and prepare a physical mixture;

(2) Set the extrusion temperature of the twin-screw extruder to be 140°C, start the screw after rising to the set temperature, add the physical mixture in the step (1) to the extruder, and then heat-melt and extrude, It is extruded into spherical particles to obtain amorphous particles, which are then micronized to obtain micronized amorphous particles, and the particle size is controlled at about 250-300 nm.

(3) Weigh 7g of micronized amorphous particles prepared in step (2), 2g of dipalmitoyl phosphatidylcholine, 0.3g of cholesterol, 30g of dehydrated alcohol, and 60.7g of water;

(4) dissolving dipalmitoyl phosphatidylcholine, cholesterol, and the compound represented by formula (I) into micronized amorphous particles in absolute ethanol, and heating to 30-45° C. to dissolve to obtain a mixed solution;

(5) the mixed solution obtained in the step (4) is stirred under the condition of 300r/min and added with distilled water, after the addition, the stirring is continued for 1.5h, and then cooled to room temperature to obtain the alcohol liposome of the compound represented by the formula (I) .

(6) Preparation of transdermal patch:

Add 1 g of alcohol liposomes prepared in the above step (5), 0.4 g of clove volatile oil, 0.4 g of borneol, and 0.2 g of p-phenylenediamine for stirring and dissolving, ultrasonically mix with 3 g of acrylate, and then copolymerize with vinyl acetate-vinyl pyrrolidone 5 g of the material was heated to 45°C and mixed evenly, dried to remove the organic solvent (ie ethanol), coated on the anti-stick layer (Scotchpak) after cooling, with a coating thickness of 100 μm, covered with a backing layer (non-woven fabric) after cooling, and punched. A transdermal patch containing the compound with an area of 4 cm ² was formed.

Example 4 Preparation of the transdermal patch of the compound represented by formula (I) (ketamine hydrochloride)

(1) compound (ketamine hydrochloride) 5g and Soluplus 2g, talcum powder 0.1g shown in formula (I) are micronized, add polyethylene glycol (molecular weight 5000) 2.9g, mix homogeneously, make physical mixture;

(2) The extrusion temperature of the twin-screw extruder is set to 150°C, the screw is started after rising to the set temperature, the physical mixture in step (1) is added to the extruder, and after hot melting and extrusion, It is extruded into spherical particles to obtain amorphous particles, which are then micronized to obtain micronized amorphous particles, and the particle size is controlled at about 120-180 nm.

(3) Weigh 2 g of micronized amorphous particles prepared in step (2), 0.2 g of phosphatidylethanolamine, 0.03 g of cholesterol, 3.1 g of isopropanol, and 4.67 g of water;

(4) dissolving phosphatidylethanolamine, cholesterol, and the compound represented by formula (I) into micronized amorphous particles in isopropanol, and heating to 30-45° C. to dissolve them to obtain a mixed solution;

(5) the mixed solution obtained in the step (4) is stirred under the condition of 500r/min and added with distilled water, after the addition, the stirring is continued for 1.5h, and then cooled to room temperature to obtain the alcohol liposome of the compound represented by the formula (I) .

(6) Preparation of transdermal patch:

Add 0.1 g of alcohol liposome prepared in the above step (5), 0.5 g of menthol, 0.4 g of turpentine, 1 g of bis(3,5-tertiary butyl-4-hydroxyphenyl) sulfide, stir and dissolve, and mix with acrylate. 2g ultrasonically mixed uniformly, then heated to 70°C with 3g of sodium polyacrylate and 3g of sodium carboxymethyl cellulose, mixed uniformly, dried to remove the organic solvent, namely ethanol, and coated on the anti-stick layer (Scotchpak) after cooling to a thickness of 150 μm, covered with a backing layer (non-woven fabric) after cooling, and punched into a transdermal patch containing the compound with an area of 2-4 cm ² or an appropriate size.

Example 5 Preparation of transdermal patch of compound represented by formula (I) ((S)-camphorsulfonate of dexketamine)

(1) The compound represented by formula (I) ((S)-camphorsulfonate of dexketamine) 6 g, povidone (K30) 1.5 g, and magnesium stearate 0.1 g were micronized, and polyethylene glycol ( Molecular weight 5000) 2.4g, mixed evenly to obtain a physical mixture;

(2) The extrusion temperature of the twin-screw extruder is set to 160°C, the screw is started after rising to the set temperature, the physical mixture in step (1) is added to the extruder, and after hot-melting and extrusion, It is extruded into spherical particles to obtain amorphous particles, which are then micronized to obtain micronized amorphous particles, and the particle size is controlled at about 120-180 nm.

(3) Weigh 3 g of micronized amorphous particles prepared in step (2), 0.2 g of soybean lecithin, 0.05 g of cholesterol, 3.1 g of dehydrated alcohol, and 3.65 g of water;

(4) dissolving soybean lecithin, cholesterol, and the compound represented by formula (I) into micronized amorphous particles in absolute ethanol, and heating to 30-45° C. to dissolve them to obtain a mixed solution;

(5) the mixed solution obtained in the step (4) is stirred under the condition of 350r/min and added with distilled water, after the addition, the stirring is continued for 2.5h, and then cooled to room temperature to obtain the alcohol liposome of the compound represented by the formula (I) .

(6) Preparation of transdermal patch:

Add 1 g of alcohol liposomes prepared in the above step (5), 0.7 g of terpene, 0.5 g of dihydroquinoline, and stir to dissolve, and 2 g of acrylic acid is ultrasonically mixed, and then mixed with 2.8 g of polyvinylpyrrolidone, carboxymethyl cellulose 3 g of sodium was heated to 70°C, mixed evenly, dried to remove the organic solvent (ie ethanol), coated on the anti-sticking layer (Scotchpak) after cooling, with a coating thickness of 150 μm, covered with a backing layer (CoTran) after cooling, and cut into areas A transdermal patch containing the compound of 2-4 cm ² or suitable size.

Example 6 Preparation of transdermal patch of compound represented by formula (I) (benzenesulfonate of dexketamine)

(1) Micronize 5 g of compound represented by formula (I) (benzenesulfonate of dexketamine), 2 g of povidone (PVP-VA64) and 0.3 g of talc, and add 2.7 g of polyethylene glycol (molecular weight 2000) , mixed uniformly to obtain a physical mixture;

(2) Set the extrusion temperature of the twin-screw extruder to be 170°C, start the screw after rising to the set temperature, add the physical mixture in the step (1) to the extruder, and heat-melt and extrude, It is extruded into spherical particles to obtain amorphous particles, which are then micronized to obtain micronized amorphous particles, and the particle size is controlled at about 100-150 nm.

(3) Weigh 2 g of micronized amorphous particles prepared in step (2), 0.2 g of soybean lecithin, 0.07 g of cholesterol, 3 g of absolute ethanol, and 4.73 g of water.

(4) dissolving soybean lecithin, cholesterol, and the compound represented by formula (I) into micronized amorphous particles in absolute ethanol, and heating to 30-45° C. to dissolve them to obtain a mixed solution;

(5) the mixed solution obtained in the step (4) is stirred under the condition of 300r/min and added with distilled water, after the addition, the stirring is continued for 1.5h, and then cooled to room temperature to obtain the alcohol liposome of the compound represented by the formula (I) .

(6) Preparation of transdermal patch:

酮(Azone)0.8g，双十八碳醇酯0.2g搅拌溶解，与丙烯酸5g超声混合均匀，然后与辛夷精油2g、薰衣草精油1g加热至60℃混合均匀，干燥除去有机溶剂即乙醇，冷却后涂布于防粘层(Scotchpak)上，涂布厚度为120μm，冷却后覆盖上背衬层(CoTran)，冲切成面积为2～4cm²或合适大小的含有该化合物的透皮贴剂。Add alcohol liposome 1g, lauryl nitrogen prepared by above-mentioned steps (5)

0.8g of ketone (Azone), 0.2g of dioctadecyl alcohol ester, stirred and dissolved, mixed with 5g of acrylic acid by ultrasonic, and then mixed with 2g of Xinyi essential oil and 1g of lavender essential oil by heating to 60℃, and dried to remove the organic solvent, namely ethanol, after cooling Coat on the release layer (Scotchpak) with a coating thickness of 120 μm, cover with a backing layer (CoTran) after cooling, and punch out a transdermal patch containing the compound with an area of 2-4 cm ² or an appropriate size.

Example 7 Preparation of the transdermal patch of the compound represented by formula (I) (the ethyl sulfonate of levoketamine)

(1) Micronize 5 g of compound represented by formula (I) (the ethanesulfonate of levoketamine), 2 g of povidone (PVP-VA64), and 0.1 g of magnesium stearate, and add polyethylene glycol (molecular weight 5000) 2.9g, mixed evenly to obtain a physical mixture;

(2) The extrusion temperature of the twin-screw extruder is set to 180°C, the screw is started after rising to the set temperature, the physical mixture in step (1) is added to the extruder, and after hot melting and extrusion, It is extruded into spherical particles to obtain amorphous particles, which are then micronized to obtain micronized amorphous particles, and the particle size is controlled at about 120-180 nm.

(3) Weigh 2g of micronized amorphous particles prepared in step (2), 0.2g of phosphatidylethanolamine, 0.03g of cholesterol, 3g of isopropanol, and 4.77g of water;

(4) dissolving phosphatidylethanolamine, cholesterol, and the compound represented by formula (I) into micronized amorphous particles in isopropanol, and heating to 30-45° C. to dissolve them to obtain a mixed solution;

(5) the mixed solution obtained in the step (4) is stirred under the condition of 500r/min and added with distilled water, after the addition, the stirring is continued for 1.5h, and then cooled to room temperature to obtain the alcohol liposome of the compound represented by the formula (I) .

(6) Preparation of transdermal patch:

Add 2 g of alcohol liposomes, 0.5 g of menthol, 0.2 g of turpentine, and 0.3 g of didodecyl ester prepared in the above step (5) by stirring and dissolving, and ultrasonically mixed with 2 g of acrylate, and then mixed with 3 g of sodium polyacrylate, carboxylate 2 g of sodium methyl cellulose was heated to 70°C and mixed evenly, dried to remove the organic solvent i.e. isopropanol, cooled and coated on the release layer (Scotchpak) with a coating thickness of 200 μm, and then covered with a backing layer (without spun cloth), punched into a transdermal patch containing the compound with an area of 2-4 cm ² or an appropriate size.

Example 8 Preparation of transdermal patch of compound represented by formula (I) (hydrobromide of ketamine)

(1) Micronize 2 g of compound represented by formula (I) (hydrobromide of ketamine), 1.5 g of povidone (PVP-VA64), and 0.3 g of magnesium stearate, and add polyethylene glycol (molecular weight 5000) 6.2g, mixed evenly to obtain a physical mixture;

(2) Set the extrusion temperature of the twin-screw extruder to be 100°C, start the screw after rising to the set temperature, add the physical mixture in the step (1) into the extruder, and then heat-melt and extrude, It is extruded into spherical particles to obtain amorphous particles, which are then micronized to obtain micronized amorphous particles, and the particle size is controlled at about 120-180 nm.

(3) Weigh 5g of micronized amorphous particles prepared in step (2), 0.2g of phosphatidylethanolamine, 0.05g of cholesterol, 3g of dehydrated alcohol, and 1.75g of water;

(4) dissolving phosphatidylethanolamine, cholesterol, and the compound represented by formula (I) into micronized amorphous particles in absolute ethanol, and heating to 30-45° C. to dissolve them to obtain a mixed solution;

(5) the mixed solution obtained in the step (4) is stirred under the condition of 500r/min and added with distilled water, after the addition, the stirring is continued for 1.5h, and then cooled to room temperature to obtain the alcohol liposome of the compound represented by the formula (I) .

(6) Preparation of transdermal patch:

Add 0.1 g of alcohol liposomes, 0.5 g of menthol, 0.2 g of turpentine, and 0.3 g of ditetradecyl ester prepared in the above step (5), stirring and dissolving, and ultrasonically mixing with 2.99 g of acrylate, then with 3 g of sodium polyacrylate , 3 g of sodium carboxymethyl cellulose was heated to 70 ° C and mixed evenly, dried to remove the organic solvent, i.e. ethanol, and then coated on the anti-sticking layer (Scotchpak) after cooling, with a coating thickness of 150 μm, and then covered with a backing layer (without spun cloth), punched into a transdermal patch containing the compound with an area of 2-4 cm ² or an appropriate size.

Example 9 Preparation of transdermal patch of compound represented by formula (I) (tartrate of dexketamine)

(1) Micronize the compound represented by formula (I) (tartrate of dexketamine) 7g, povidone (PVP-VA64) 1.5g, talc 0.1g, add polyethylene glycol (molecular weight 5000) 1.4g, Mix evenly to obtain a physical mixture;

(2) Set the extrusion temperature of the twin-screw extruder to be 120°C, start the screw after rising to the set temperature, add the physical mixture in the step (1) to the extruder, and then heat-melt and extrude, It is extruded into spherical particles to obtain amorphous particles, which are then micronized to obtain micronized amorphous particles, and the particle size is controlled at about 120-180 nm.

(3) Weigh 3 g of micronized amorphous particles prepared in step (2), 0.2 g of phosphatidylethanolamine, 0.05 g of cholesterol, 3 g of isopropanol, and 3.75 g of water;

(4) dissolving phosphatidylethanolamine, cholesterol, and the compound represented by formula (I) into micronized amorphous particles in isopropanol, and heating to 30-45° C. to dissolve them to obtain a mixed solution;

(5) the mixed solution obtained in the step (4) is stirred under the condition of 500r/min and added with distilled water, after the addition, the stirring is continued for 1.5h, and then cooled to room temperature to obtain the alcohol liposome of the compound represented by the formula (I) .

(6) Preparation of transdermal patch:

Add 0.1 g of alcohol liposomes, 0.5 g of menthol, 0.2 g of turpentine, and 0.3 g of ditetradecyl ester prepared in the above step (5), stir and dissolve, and ultrasonically mix with 2.9 g of acrylate, and then mix with 3 g of sodium polyacrylate. , 3 g of sodium carboxymethyl cellulose was heated to 70 ° C and mixed evenly, dried to remove the organic solvent, i.e. ethanol, and then coated on the anti-sticking layer (Scotchpak) after cooling, with a coating thickness of 150 μm, and then covered with a backing layer (without spun cloth), punched into a transdermal patch containing the compound with an area of 2-4 cm ² or an appropriate size.

Example 10 Preparation of transdermal patch of compound represented by formula (I) (malate of ketamine)

(1) Micronize 5 g of the compound represented by formula (I) (malate of ketamine), 1.5 g of povidone (PVP-VA64), 0.2 g of talc, and add 3.3 g of polyethylene glycol (molecular weight 5000), Mix evenly to obtain a physical mixture;

(2) The extrusion temperature of the twin-screw extruder is set to 150°C, the screw is started after rising to the set temperature, the physical mixture in step (1) is added to the extruder, and after hot melting and extrusion, It is extruded into spherical particles to obtain amorphous particles, which are then micronized to obtain micronized amorphous particles, and the particle size is controlled at about 120-180 nm.

(3) Weigh 1 g of micronized amorphous particles prepared in step (2), 0.2 g of phosphatidylethanolamine, 0.05 g of cholesterol, 3 g of isopropanol, and 5.75 g of water;

(4) dissolving phosphatidylethanolamine, cholesterol, and the compound represented by formula (I) into micronized amorphous particles in isopropanol, and heating to 30-45° C. to dissolve them to obtain a mixed solution;

(5) the mixed solution obtained in the step (4) is stirred under the condition of 500r/min and added with distilled water, after the addition, the stirring is continued for 1.5h, and then cooled to room temperature to obtain the alcohol liposome of the compound represented by the formula (I) .

(6) Preparation of transdermal patch:

Add 0.1 g of alcohol liposomes, 0.5 g of menthol, 0.2 g of turpentine, and 0.3 g of ditetradecyl ester prepared in the above step (5), stir and dissolve, and ultrasonically mix with 2.9 g of acrylate, and then mix with 3 g of sodium polyacrylate. , 3 g of sodium carboxymethyl cellulose was heated to 70 ° C and mixed evenly, dried to remove the organic solvent, i.e. ethanol, and then coated on the anti-sticking layer (Scotchpak) after cooling, with a coating thickness of 150 μm, and then covered with a backing layer (without spun cloth), punched into a transdermal patch containing the compound with an area of 2-4 cm ² or an appropriate size.

Example 11 Stability test of the transdermal drug delivery system of the compound hydrochloride represented by formula (I) of the present invention

The compound shown in formula (I) includes the following 4 impurities in EP8.0:

The inventors conducted long-term stability experiments on the samples prepared in Example 1 in an environment of 20-30° C. and 60%±5% humidity.

HPLC detection conditions are the methods included in EP8.0.

It can be seen that the pharmaceutical preparation (Example 1) obtained by the present invention is kept at room temperature for up to three years, and its quality still meets the quality standard and is very stable.

Example 12 In vitro skin permeability test of the transdermal drug delivery system of the compound hydrochloride represented by formula (I) of the present invention

The samples prepared in Example 1 of the present invention were subjected to an in vitro skin permeability test by using a Franz transdermal diffuser. The results are shown in Figure 6. The specific operations are as follows: one mouse was injected intraperitoneally with sodium pentobarbital (40 mg/kg). After anesthesia, the mice were sacrificed, and the abdominal rat hair was removed with an electric razor, and the dehaired rat skin was removed. Remove the subcutaneous fat with absorbent cotton soaked with normal saline and set aside. Take the prepared mouse skin and fix it in the Franz diffusion cell, the effective area of transdermal diffusion is about 2.92cm ² , and the volume of the receiving cell is about 12 mL, so that the liquid surface is in close contact with the inner layer of the skin, and the receiving liquid is PBS (pH7. 4), volume 12mL. The whole experimental process was kept at a constant temperature of (37±0.2) °C and stirred at 300 r/min.

Take the sample prepared in Example 1 of the present invention and add it to the upper supply chamber, seal it with plastic wrap, and cover it with a layer of tin foil to protect it from light. At the specified time (1, 2, 4, 6, 8), 2.0 mL of the receiving solution was extracted, and 2.0 mL of the same-temperature receiving solution was immediately supplemented to obtain the receiving solution containing the drug, which was stored in a refrigerator at 4°C. After the receiving liquid of the sample is filtered by filter paper and diluted with PBS, the absorption value of the dye is measured with a UV-2550 ultraviolet spectrophotometer, and the cumulative amount of the sample passing through the skin is obtained by calculating (calculation method is well known in the art) over time, and Maximum penetration through the skin. The results are shown in Figure 6, the alcohol liposome containing the compound represented by the formula (I) of Azone can penetrate the skin, and the compound represented by the alcohol liposome carrier (I) and the anhydrous ethanol carrier represented by the formula (I) can penetrate the skin. Compared with the shown compounds, the transdermal efficiency is high and the drug accumulation through the skin is the largest. It is shown that the compound represented by the alcohol liposome carrier (I) containing Azone can penetrate the skin, and compared with other groups, the test group has higher skin penetration efficiency and the largest accumulation of drugs through the skin.

Example 13 Comparison of pharmacokinetics of the compound of formula (I) hydrochloride transdermal preparation and injection in SD rats of the present invention

The test selected 24 SD rats, half male and half male, and randomly divided into the transdermal preparation group (group A) of the embodiment of the present invention 1 and the compound (dexketamine) hydrochloride injection group of formula (I) (group B, DE4312016A1) Preparation method of Example 2) two groups, 12 animals in each group were tested. The transdermal preparation of the compound of formula (I) (dexketamine) (sample prepared in Example 1 of the present invention) was affixed to the upper back of the animals in group A at 0.2 g/kg to ensure that the transdermal patch was in complete contact with the skin; B Group animals were injected intraperitoneally with 0.2 g/kg injection. After the administration, the blood collection points of group A were: 2, 5, 10, 20, 30, 45, 60, 120, 180, 240, 360, 480, 600min; the blood collection points of group B were: 2, 5, 10, 20, 30, 45, 60, 120, 180, 240, 360, 480, 600, 720, 840min. About 0.4 ml of whole blood was collected from the rat tail vein at these time points. After the blood samples were collected, they were placed in an anticoagulant tube (1000IU/ml, about 10μl) with heparin sodium, centrifuged at 4°C and 4000rpm for 5min, and the plasma was separated and the concentration of the main drug in the plasma was detected by LC-MS/MS. The main metabolic kinetic parameters t _1/2 , T _max , C _max , AUC were calculated using WinNonlin (V6.2).

The experimental results (see Figure 7) are as follows:

Table 1. Metabolic kinetic parameters required in animals after administration of compound of formula (I) (dexketamine hydrochloride) transdermal patch and injection group

After comparing the pharmacokinetic parameters t _1/2 , T _max , C _max , and AUC of the transdermal preparation of Example 1 of the present invention and the injection group in SD rats, it was found that compared with the injection, the bioavailability was basically the same , but the transdermal preparation group has a certain slow and controlled release function, which can prolong the action time of the drug to a certain extent and reduce the number of medication.

The preparation method of dexketamine hydrochloride is prepared with reference to the preparation method of Example 8 of Patent CN107750245A.

The preparation method of dexketamine hydrochloride injection was prepared with reference to the preparation method of Example 2 of DE4312016A1.

Example 14 Test of skin reaction of the transdermal drug delivery system of the present invention

skin reaction grade

Grade 4: Erythema, blistering and bullae formation

Grade 3: Erythema, blistering; no bullae

Grade 2: Erythema covers the entire patch area; no blistering

Grade 1: Slight erythema covering less than the entire patch area

Grade 0: Minimal or no response at patch site

Two samples of Examples 1-10 were taken and affixed to 20 depilated rats respectively. After 24 hours, it was found that the products of Examples 1-10 had no skin irritation, and the grade was 0.

Example 15 DSC and X-powder diffraction detection of the compound represented by formula (I)

Take the compound hydrochloride shown in formula (I), compound hydrochloride shown in formula (I) and povidone S630 to form microparticles and the physical mixture of compound hydrochloride shown in formula (I) and S630 to carry out DSC, X - Powder diffraction was detected, and the results are shown in Figures 1 to 5. It can be seen from the figure that after hot-melt extrusion, the compound represented by formula (I) changes from a polymorphic state to an amorphous state, which is more conducive to the absorption of the drug, and the amorphous state is also proved in the preparation research. of stability.

Detection conditions:

Powder X-ray Diffraction (PXRD)

Instrument: XTRA/3KW X-ray diffractometer (Switzerland ARL Company)

Target: Cu-Kα radiation

Wavelength: 1.5406A

Pipe pressure: 40KV

Pipe flow: 40mA

Step size: 0.02°

Scanning speed: 10°/min

Differential Scanning Calorimetry (DSC)

Instrument: Pyris 1 thermal analyzer (PerkinElmer, USA)

Example 16 Pharmacodynamic test of compound represented by formula (I)

In order to further clarify the effect of the pharmaceutical composition of the present invention, a pharmacodynamic test was carried out using mice.

1 Test material

1.1 Experimental animals

SPF grade KM juvenile male mice, 8 weeks old, body weight (20±2) grams, Shanghai Slack Laboratory Animal Co., Ltd.

1.2 Test Drugs

Test drug: the pharmaceutical composition prepared in Example 1 of the present invention.

Positive control drug: methylphenidate hydrochloride for injection, 20 mg, Suzhou First Pharmaceutical Co., Ltd.

2 Test content

2.1 The effect of traditional Chinese medicine composition for the treatment of children with ADHD on the behavior of mice

2.1.1 Animal grouping and administration

Thirty male KM mice were randomly divided into a treatment group, a positive control group and a blank control group, 10 in each group. The mice in the treatment group were given the pharmaceutical composition prepared in Example 1, the mice in the positive control group were injected with methylphenidate hydrochloride for injection, and the mice in the blank group were given the same volume of 0.9% saline as the positive control group. The doses of the treatment group and the positive control group were equivalent to 10 times the clinical dose of children. The drug was administered in the morning, once a day, for 28 consecutive days.

2.1.2 Determination of indicators

The activities of the mice were recorded before and after the administration, and each mouse was observed for 30 minutes, once a day.

(1) Spontaneous activity time of mice before and after treatment;

(2) The number of erection movements of mice before and after treatment;

(3) Times of rod climbing time of mice before and after treatment.

2.1.3 Data processing

表示。SPSS11.5 software package was used for statistical analysis, and paired t test was used for comparison before and after treatment.

express.

2.1.4 Test results

The results are shown in Tables 2, 3, and 4.

Table 2 Activity time of mice before and after administration

Note: Compared with blank group, positive control group p<0.05; treatment group p<0.01.

The results showed that compared with the blank group, the activity time of the mice in the positive control group was significantly different (p<0.05); compared with the other two mice, there was a significant difference in the activity time of the mice in the treatment group (p<0.05). 0.01).

The results showed that the activity time of the mice in the treatment group was significantly reduced.

Table 3 The number of erecting movements of mice before and after treatment

group Day 7 Day 14 Day 21 Day 28 blank group 18.32±4.13 14.16±3.18 15.26±4.06 14.05±3.08 positive control group 32.15±16.03 22.53±15.05 20.18±16.13 19.05±15.08 therapy group 25.12±11.23 17.16±9.15 16.43±10.18 15.08±11.18

Note: Compared with the blank group, the positive control group p<0.05; the treatment group p<0.05.

The results showed that compared with the blank group, the number of erecting movements of the mice in the positive control group was significantly different (p<0.05); compared with the mice in the treatment group, the number of erecting movements was significantly different (p<0.05). p<0.05).

The results showed that the number of times the mice in the treatment group stood up significantly decreased.

Table 4 The rod climbing time of mice before and after treatment

group Day 7 Day 14 Day 21 Day 28 blank group 10.46±2.10 10.06±2.18 9.89±2.19 9.15±2.01 positive control group 12.56±7.92 11.86±8.19 11.35±7.53 12.16±7.54 therapy group 12.12±3.53 10.56±3.09 9.16±3.01 8.15±2.57

Note: Compared with the blank group, the positive control group p<0.05; the treatment group p<0.05.

The results showed that, compared with the blank group, the mice in the positive control group had significant differences in the climbing time (p<0.05); compared with the other groups, the mice in the treatment group had significant differences in the climbing time (p<0.05). <0.05).

The results showed that the rod climbing time of the mice in the treatment group was significantly reduced.

2.2 The effect of the drug composition for the treatment of children with ADHD on the body weight of mice

2.2.1 Animal grouping and administration

Thirty male KM mice were randomly divided into groups, 10 in each group, which were blank group, positive control group and treatment group. The mice in the treatment group were given the pharmaceutical composition prepared in Example 1, the mice in the positive control group were injected with methylphenidate hydrochloride for injection, and the mice in the blank group were given the same volume of 0.9% saline as the positive control group. The doses of the treatment group and the positive control group were equivalent to 10 times the clinical dose of children. The drug was administered in the morning, once a day, for 28 consecutive days.

2.2.2 Determination of indicators

The body weight of mice was measured every 7 days during the experiment.

2.2.3 Data processing

表示。SPSS11.5 software package was used for statistical analysis, and paired t test was used for comparison before and after treatment.

express.

2.2.4 Test results

The results are shown in Table 5.

Table 5 Mice activity time before and after administration

group Day 8 Day 22 Day 29 blank group 27.13±1.06 34.15±0.79 45.98±0.86 positive control group 23.00±0.95 33.18±1.04 42.15±0.98 therapy group 23.08±1.08 22.71±1.01 43.18±0.89

Note: Compared with the blank group, the positive control group p<0.05; the treatment group p<0.05.

The results showed that compared with the blank group, the weight change of the mice in the positive control group was significant (p<0.05); the weight change of the mice in the treatment group was significant (p<0.05).

The results showed that the weight of the mice in the treatment group increased significantly.

2.3 The effect of the drug composition for treating children with ADHD on the content of DA in mice

2.3.1 Animal grouping and administration

36 male KM mice with ADHD were randomly divided into 12 mice in each group. They were blank group, positive control group and treatment group, respectively. The mice in the treatment group were given the pharmaceutical composition prepared in Example 1, the mice in the positive control group were injected with methylphenidate hydrochloride for injection, and the mice in the blank group were given the same volume of 0.9% saline as the positive control group. The doses of the treatment group and the positive control group were equivalent to 10 times the clinical dose of children. The drug was administered in the morning, once a day, for 28 consecutive days. Mice were sacrificed after administration to collect blood samples: two weeks after administration, 6 mice were randomly selected for 1 day of fasting and blood samples were collected; 4 weeks after administration, the remaining mice were sacrificed to collect blood samples . The specific steps are as follows: anesthetize the mice with chloral hydrate, and collect blood from the orbit after anesthesia. Laboratory regulations place mouse cadavers. Immediately put the blood sample into a centrifuge, set the temperature to 4°C, and set the rotation speed to 3000 r·min ^-1 , centrifuge for 20 min, extract 100 μl of plasma, add 100 μl of pre-cooled 0.6% perchloric acid, and mix in a vortex mixer. After mixing, put it in the refrigerator for 10 minutes. Take out the test sample from the refrigerator, set the temperature of the centrifuge to 4°C, the rotation speed is 12000 r·min ^-1 , centrifuge for 15 min, take 100 μl of the supernatant and put it in an EP tube and store it at a constant temperature for testing.

2.3.2 Determination of indicators

The changes of DA content in mice were measured 2 weeks and 4 weeks after drug administration.

2.3.3 Data processing

表示。SPSS11.5 software package was used for statistical analysis, and paired t test was used for comparison before and after treatment.

express.

2.3.4 Test results

The results are shown in Table 6.

Table 6 DA content in mice

group Day 15 Day 29 blank group 20.445±0.2735 20.430±0.331 positive control group 18.509±1.508 10.965±0.621 therapy group 18.183±2.215 11.701±1.816

Note: Compared with the blank group, the positive control group p<0.05; the treatment group p<0.05.

The results showed that compared with the blank group, the changes of DA content in the mice in the positive control group were significant (p<0.05); the changes in the DA content in the mice in the treatment group were significant (p<0.05).

The results showed that the treatment group had a significant effect on the changes of DA content in the mice, and could significantly reduce the DA content in the mice's plasma.

2.4 The effect of the drug composition for treating children with ADHD on the serum S100β protein of mice

2.4.1 Animal grouping and administration

30 male KM mice were randomly divided into groups, 10 in each group. They were blank group, positive control group and treatment group, respectively. The mice in the treatment group were given the pharmaceutical composition prepared in Example 1, the mice in the positive control group were injected with methylphenidate hydrochloride for injection, and the mice in the blank group were given the same volume of 0.9% normal saline as the positive control group. The doses of the treatment group and the positive control group were equivalent to 10 times the clinical dose of children. The drug was administered in the morning, once a day, for 28 consecutive days. . Blood samples were collected from mice after administration: 4 weeks after administration, mouse plasma was collected and refrigerated at 4°C. The serum S100β protein content of mice was detected by BCA method.

2.4.2 Determination of indicators

The serum S100β protein content of the mice was measured 4 weeks after administration.

2.4.3 Data processing

表示。SPSS11.5 software package was used for statistical analysis, and paired t test was used for comparison before and after treatment.

express.

2.4.4 Test results

The results are shown in Table 7.

Table 7 Serum S100β protein content of mice

group Number of samples S100β protein content (mg/ml) blank group 10 0.4523±0.0156 positive control group 10 0.6105±0.0103 therapy group 10 0.5056±0.0309

Note: Compared with the blank group, the positive control group p<0.05; the treatment group p<0.05.

The results showed that compared with the blank group, the serum S100β protein content of the mice in the positive control group was significantly changed (p<0.05); the serum S100β protein content of the mice in the treatment group was significantly changed (p<0.05).

The results showed that the treatment group had significant changes in serum S100β protein content, which could significantly increase the serum S100β protein content of mice.

Comparative Example 1 Preparation of compound compound represented by formula (I) (dexketamine hydrochloride) (polymorph X-powder diffraction pattern shown in Figure 3) transdermal patch

(1) 0.25 g of the compound represented by formula (I) (dexketamine hydrochloride), 0.2 g of soybean lecithin, 0.03 g of cholesterol, 3 g of absolute ethanol, and 6.52 g of water;

(2) dissolving soybean lecithin, cholesterol, and compound particles represented by formula (I) in absolute ethanol, and heating to 30-45° C. to dissolve them to obtain a mixed solution;

(3) the mixed solution obtained in the step (2) is stirred under the condition of 300r/min and added with distilled water, after the addition, the stirring is continued for 1.5h, and then cooled to room temperature to obtain the alcohol liposome of the compound represented by the formula (I) .

(4) Preparation of transdermal patch:

酮(Azone)0.7g，抗氧剂1010 0.2g搅拌溶解，与丙烯酸3g超声混合均匀，然后与聚乙烯吡咯烷酮4g、羟丙甲纤维素2g加热至60℃混合均匀，干燥除去有机溶剂即乙醇，冷却后涂布于防粘层(Scotchpak)上，涂布厚度为100μm，冷却后覆盖上背衬层(无纺布)，冲切成面积为2～4cm²或合适大小的含有该化合物的透皮贴剂。Add alcohol liposome 1g, lauryl nitrogen prepared by above-mentioned steps (3)

0.7g of ketone (Azone), 0.2g of antioxidant 1010, stirred and dissolved, mixed with 3g of acrylic acid by ultrasonic, then heated to 60°C with 4g of polyvinylpyrrolidone and 2g of hypromellose and mixed well, dried to remove the organic solvent, namely ethanol, After cooling, coat on the anti-sticking layer (Scotchpak) with a coating thickness of 100 μm, cover with a backing layer (non-woven fabric) after cooling, and punch out a transparent layer containing the compound with an area of 2-4 cm ² or a suitable size. skin patch.

Figure 3 Preparation method of crystal form:

13.5g of the compound represented by formula (I) (dexketamine hydrochloride) was heated and dissolved in 12ml of acetone, cooled and crystallized (0-5°C), filtered, and washed with a small amount of ethyl acetate; dried under reduced pressure at 45-60°C to obtain 10.1 g, X-powder diffraction detection was carried out, and the crystal form shown in Figure 3 was obtained. In the present application, the above-mentioned crystalline form of the compound represented by formula (I) (dexketamine hydrochloride) is used as API (active ingredient, or bulk drug).

Comparative Example 2 Compound (dexketamine hydrochloride) represented by formula (I) (polymorph X-powder diffraction pattern shown in Figure 3) Preparation of transdermal patch (prior art) Preparation of transdermal patch (now technology)

With reference to the preparation method of the embodiment 1 of patent CN107929268A, the present inventor prepared the compound represented by formula (I) as a transdermal patch, and its preparation method was as follows:

1) dissolving the compound shown in the active ingredient formula (I) (dexketamine hydrochloride) in ethanol to obtain a drug-containing solution;

2) Add stabilizer sodium hydroxide and transdermal absorption enhancer polyethylene glycol 400 to the base acrylate pressure-sensitive adhesive 87-2287 in the drugstore, and then add dispersant propylene glycol to adjust the viscosity of the glue solution to 1500cp at 25°C , stir for 2 hours at a speed of 6000rpm;

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

4) Coating the product obtained in step 3) on the backing layer with a coating thickness of 0.25 mm, drying at 90° C. for 0.5 hours to evaporate the solvent ethanol, and then covering with an anti-adhesive layer to obtain a transdermal patch product.

Example 17 Comparison of the pharmacokinetics of compound of formula (I) (dexketamine) transdermal patch with different crystal forms and different technologies in SD rats

36 SD rats, half male and half male, were randomly divided into three groups for use in the test, which were respectively the sample of Example 1 of the application (Group A), the sample of Comparative Example 1 (Group B) and the sample of Comparative Example 2 (Group C), respectively. 12 animals in each group were tested. The transdermal preparations containing 0.2 g/kg of the compound of formula (I) with different crystal forms and different technologies were respectively attached to the upper back of the animals in groups A, B and C to ensure that the transdermal patch was in complete contact with the skin. After the administration, the blood collection points of groups A, B and C were: 2, 5, 10, 20, 30, 45, 60, 120, 180, 240, 360, 480, 600, 720, 840, 960 min. About 0.4 ml of whole blood was collected from the tail vein of SD rats at these time points. After the blood samples were collected, they were placed in an anticoagulant tube (1000IU/ml, about 10μl) with heparin sodium, centrifuged at 4°C and 4000rpm for 5min, and the plasma was separated and the concentration of the main drug in the plasma was detected by LC-MS/MS. The main metabolic kinetic parameters t _1/2 , T _max , C _max , AUC were calculated using WinNonlin (V6.2).

The experimental results (see Figure 8) are as follows:

Table 8. Pharmacokinetic parameters in animals after transdermal administration of compounds of formula (I) with different crystal forms and different technologies

After comparing the pharmacokinetic parameters t _1/2 , T _max , C _max , and AUC of different sample formula (I) compound (dexketamine) transdermal preparations in SD rats, it was found that SD rats were more sensitive to group A formula (I). ) The absorption rate of compound transdermal patch was faster than that of group B and C, and the AUC area of transdermal patch in group A was higher than that in group B and C in SD rats.

Specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the above-mentioned specific embodiments, and those skilled in the art can make various variations or modifications within the scope of the claims, which do not affect the essential content of the present invention.

Claims (14)

1. a pharmaceutical composition for transdermal administration, the pharmaceutical composition comprises a compound shown in formula (I) or a pharmaceutically acceptable salt thereof, a macromolecular dispersion carrier material, a hot-melt protective agent and an optional additive. flux,

Wherein, the polymer dispersion carrier material is povidone or polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; Optionally, the solubilizer is selected from polyethylene glycols; The preparation method of the pharmaceutical composition for transdermal administration comprises: micronizing the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, a polymer dispersion carrier material and a hot-melt protective agent, optionally Adding a melting agent, mixing uniformly to obtain a physical mixture, and then extruding and micronizing through hot melt to obtain particles of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof; the hot melt protective agent is Magnesium stearate or talc; the temperature of the hot melt extrusion is 100-180°C; and The preparation method of the pharmaceutical composition for transdermal administration of the compound represented by the formula (I) further comprises: preparing the microparticles of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof into an alcohol liposome , the alcohol liposome is stirred and dissolved with transdermal absorption enhancer and antioxidant; then mixed with pressure-sensitive adhesive evenly, and then mixed with the polymer skeleton carrier material; dried to remove low-molecular-weight organic alcohol in the alcohol liposome, coated It is clothed on the release layer, and then covered with the backing layer; here, the alcohol liposome is composed of the microparticles of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, phospholipids, cholesterol, low-molecular-weight organic consisting of alcohol and water; and The pharmaceutical composition for transdermal administration is a transdermal patch, and the transdermal patch further includes a release layer and a backing layer. 2. pharmaceutical composition according to claim 1, wherein, the compound shown in formula (I) is ketamine, levoketamine, dexketamine or the non-equivalent mixture of levoketamine and dexketamine; Optionally, the pharmaceutically acceptable salt is hydrochloride, hydrobromide, besylate, tosylate, ethanesulfonate, tartrate, malate, or (S)-camphor Sulfonate. 3. The pharmaceutical composition according to claim 1, wherein the molecular weight of the polyethylene glycol is 2000-6000. 4. The pharmaceutical composition according to claim 1, wherein, in the microparticles of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof The weight percentage of the salt is 20 to 70%, the weight percentage of the polymer dispersion carrier material is 10 to 25%, the weight percentage of the hot melt protective agent is 1 to 3%, and the weight percentage of polyethylene glycol is 10 to 65%. . 5 . The pharmaceutical composition according to claim 1 , wherein the microparticles of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof have a diameter of 100-300 nm. 6 . 6 . The pharmaceutical composition according to claim 5 , wherein the microparticles of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof have a diameter of 100-200 nm. 7 . 7 . The pharmaceutical composition according to claim 5 , wherein the microparticles of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof have a diameter of 150-250 nm. 8 . 8. pharmaceutical composition according to claim 1, wherein, described low molecular organic alcohol is selected from one or more in ethanol, propylene glycol, isopropanol; Optionally, the phospholipid is selected from one or more of soybean lecithin, phosphatidylcholine, phosphatidylethanolamine, dipalmitoyl phosphatidylcholine; Optionally, the polymer skeleton carrier is one of polyvinylpyrrolidone, sodium polyacrylate, hydroxymethylcellulose, vinyl acetate-vinylpyrrolidone copolymer, acrylic resin, and sodium carboxymethylcellulose or several; Optionally, the antioxidant is selected from 2,6-di-tert-butyl-4-methylphenol, Antioxidant 1010, bis(3,5-tert-butyl-4-hydroxyphenyl)sulfide, One or more of p-phenylenediamine, dihydroquinoline, didodecyl alcohol ester, ditetradecyl alcohol ester and dioctadecyl alcohol ester. 9. The pharmaceutical composition according to any one of claims 1-8, wherein the pharmaceutical composition is a transdermal patch, and in the transdermal patch, the content of the compound represented by formula (I) For 1 ~ 300mg / patch. 10. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition is a transdermal patch, and in the transdermal patch, the content of the compound represented by formula (I) is 5-120 mg/patch piece. 11. The preparation method of the pharmaceutical composition according to any one of claims 1-10, comprising the steps: (1) micronizing the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, a polymer dispersion carrier material and a hot-melt protective agent, optionally adding a melting agent, mixing uniformly to obtain a physical mixture, and then Through hot melt extrusion and micronization, the microparticles of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof are obtained; (2) The microparticles obtained in step (1) are prepared into alcohol liposomes. 12. The preparation method according to claim 11, wherein the preparation process of the microparticles comprises: (i) micronizing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a polymer dispersion carrier material and a hot-melt protective agent, optionally adding a solubilizer, and mixing uniformly to obtain a physical mixture; (ii) setting the extrusion temperature of the twin-screw extruder to be 100 to 180°C, starting the screw after rising to the set temperature, adding the physical mixture obtained in step (i) into the extruder, and performing hot-melting, extrusion Pressing, extruding into spherical particles to obtain amorphous particles, and then micronizing them to obtain micronized amorphous particles. 13. preparation method according to claim 11, wherein, the preparation method of described alcohol liposome comprises the following steps: (i') weighing microparticles and water of phospholipid, cholesterol, low-molecular-weight organic alcohol, compound represented by formula (I) or a pharmaceutically acceptable salt thereof; (ii') dissolving the microparticles of phospholipid, cholesterol, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof in a low-molecular-weight organic alcohol, and heating to 30-45° C. to dissolve to obtain a mixed solution; (iii') adding water to the mixed solution obtained in step (ii') under stirring conditions, and continuing to stir for 1.2-3.0 h after the addition, and then cooling to room temperature to obtain alcohol liposomes. 14. Use of the pharmaceutical composition according to any one of claims 1-10 in the preparation of a medicament for preventing and/or treating ADHD in children.

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