CN111346073B

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

Info

Publication number: CN111346073B
Application number: CN201811570791.6A
Authority: CN
Inventors: 李莉娥; 曲龙妹; 田峦鸢; 吕金良; 吴有斌; 汪淼; 金芬; 陈雷; 郭建锋; 张丽娜; 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: 2022-06-10
Anticipated expiration: 2038-12-21
Also published as: CN111346073A

Abstract

The invention discloses a pharmaceutical composition for transdermal drug delivery, which comprises a compound shown as a formula (I) or pharmaceutically acceptable salt thereof, a macromolecular dispersion carrier material, a hot-melt protective agent and an optional fluxing agent, wherein the preparation method of the pharmaceutical composition for transdermal drug delivery comprises the following steps: micronizing the compound shown in the formula (I) or pharmaceutically acceptable salt thereof, a high molecular dispersion carrier material and a hot-melt protective agent, optionally adding a fluxing agent, uniformly mixing, and carrying out hot-melt extrusion and micronization to obtain the compound shown in the formula (I) or pharmaceutically acceptable salt thereof. In addition, the application of the pharmaceutical composition is also provided. The transdermal drug delivery pharmaceutical composition can enable the compound shown in the formula (I) to be rapidly absorbed, achieve the purpose of sedation before anesthesia without influencing respiration, and avoid the adverse psychological effect of intramuscular injection or intravenous injection acupuncture on children. Meanwhile, the pharmaceutical composition can also be used for preventing and/or treating the attention deficit hyperactivity disorder.

Description

Transdermal drug delivery pharmaceutical composition and preparation method and application thereof

Technical Field

The invention relates to a pharmaceutical preparation technology, in particular to a transdermal drug delivery pharmaceutical composition of a compound shown in a formula (I) and a preparation method and application thereof.

Background

Ketamine (a racemic mixture of the corresponding dextro-and levorotatory enantiomers) is an N-methyl-D-aspartate (NMDA) receptor antagonist that produces a wide range of effects in humans, including analgesia, anesthesia, hallucinations, dissociation, elevated blood pressure and bronchodilation. Ketamine is mainly used to induce and maintain general anesthesia. Other uses include sedation in intensive care, analgesia (particularly in emergency medicine) and the treatment of bronchospasm. The dextroketamine enantiomer (or S- (+) ketamine or esketamine) is an uncompetitive and subtype-independent activity-dependent NMDA receptor antagonist, and has a completely new and unique mechanism of action with higher potency or affinity for NMDA receptors, thus potentially allowing lower effective doses and reducing side effects due to increased doses or sustained dosing during administration.

Ketamine structure is shown below:

the chemical name is as follows: 2- (2-chlorophenyl) -2- (methylamino) cyclohexanone.

However, at present, the injection preparation mainly comprising ketamine or its isomer dexketamine is mainly used in the market, and needs to be used under the guidance of a professional doctor clinically, and injection pain is often accompanied during injection, so that patients are inconvenient to take medicine, compliance is poor, adverse psychological effects are often brought to the patients, and the situation is more likely to occur particularly when the injection preparation is used for young children.

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 prior art in preparation and use of the pharmaceutical preparation of the compound shown in the formula (I), the inventor develops a pharmaceutical composition of the compound shown in the formula (I), in particular a pharmaceutical preparation for transdermal administration.

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

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

The third object of the present invention is to provide the use of the above transdermal drug delivery composition.

In an embodiment of the present invention, the present invention provides a pharmaceutical composition for transdermal administration of a compound of formula (I), comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, a polymeric dispersion carrier material, a thermal melting protective agent, and optionally a flux enhancing agent,

wherein, the preparation method of the transdermal drug delivery composition comprises the following steps: micronizing the compound shown in the formula (I) or pharmaceutically acceptable salt thereof, a high molecular dispersion carrier material and a hot-melt protective agent, optionally adding a fluxing agent, uniformly mixing to obtain a physical mixture, and carrying out hot-melt extrusion and micronization to obtain the compound shown in the formula (I) or pharmaceutically acceptable salt thereof.

In one embodiment of the present invention, the present invention provides a pharmaceutical composition for transdermal administration of a compound of formula (I), wherein the compound of formula (I) is ketamine, levoketamine, dexketamine, or a mixture of a non-equal ratio (i.e. non-1: 1) of levoketamine to dexketamine.

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 one or more of hydrochloride, hydrobromide, benzenesulfonate, tosylate, ethanesulfonate, tartrate, malate, or (S) -camphorsulfonate (e.g., dexketamine (S) -camphorsulfonate).

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 polymeric dispersion carrier material is selected from povidone (PVP-VA64, povidone-S630, or K30) or Soluplus (polyvinyl 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 solubilizing agent is selected from polyethylene glycol, preferably polyethylene glycol with molecular weight of 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 in the fine particles of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the weight percentage of the compound represented by formula (I) or the pharmaceutically acceptable salt thereof is 20 to 70%, the weight percentage of the polymeric 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 the polyethylene glycol is 10 to 65%.

In one embodiment of the invention, the invention provides a transdermal drug delivery composition of a compound shown in formula (I), wherein the temperature of hot melt extrusion is 100-180 ℃.

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 diameter (particle size) of the fine particles of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 100 to 300nm, preferably 100 to 200nm or 150 to 250 nm.

In an embodiment of the invention, the invention provides a transdermal drug delivery composition of a compound shown in formula (I), wherein in the transdermal drug delivery composition of the compound shown in formula (I), the content of the compound shown in formula (I) or a pharmaceutically acceptable salt thereof is 1-300 mg/patch, preferably 5-120 mg/patch.

In an embodiment of the invention, the invention provides a transdermal drug delivery composition of a compound shown in formula (I), wherein the transdermal drug delivery composition comprises the compound shown in formula (I) or a pharmaceutically acceptable salt thereof, a polymeric dispersion carrier material, a hot-melt protective agent and optionally a flux enhancer, and further comprises phospholipid, cholesterol, low-molecular organic alcohol, water, a transdermal absorption enhancer, an antioxidant, pressure sensitive adhesive and a polymeric matrix carrier material.

In an embodiment of the present invention, the present invention provides a transdermal drug delivery composition of the compound represented by formula (I), wherein the transdermal drug delivery composition is a transdermal patch, and the patch further comprises an anti-adhesion 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 the pharmaceutical composition for transdermal administration of a compound represented by formula (I) further comprises: preparing microparticles of the compound shown in the formula (I) or pharmaceutically acceptable salts thereof into alcohol liposome, and stirring and dissolving the alcohol liposome, a transdermal absorption enhancer and an antioxidant; then mixing with pressure sensitive adhesive, and then mixing with polymer skeleton carrier material; drying to remove organic solvent (i.e. low molecular organic alcohol) from the alcohol liposome, coating on the anti-sticking layer, and covering with 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 microparticles of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a phospholipid, cholesterol, a low molecular organic alcohol and water; preferably, the alcohol liposome comprises the following components in percentage by mass: 5 to 80 percent of compound shown in formula (I) or particles of 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, the composition comprises 7-70% of fine particles of the compound represented by the formula (I), 2.0-3.0% of phospholipid, 0.2-0.5% of cholesterol, 30-40% of low-molecular organic alcohol and the balance of water.

In an embodiment of the invention, the invention provides a pharmaceutical composition for transdermal administration of a compound shown as a formula (I), wherein the phospholipid is one or more selected from soybean lecithin, phosphatidylcholine, phosphatidylethanolamine and dipalmitoylphosphatidylcholine.

In the embodiment of the invention, the invention provides a transdermal administration pharmaceutical composition of the compound shown in the formula (I), wherein the low molecular organic alcohol is selected from one or more of ethanol, propylene glycol and isopropanol.

In the embodiment of the invention, the invention provides a transdermal drug delivery composition of a compound shown in a formula (I), wherein the pressure-sensitive adhesive is one or more of acrylic acid or acrylate.

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 transdermal absorption enhancer is selected from the group consisting of drugs for oral administration, and pharmaceutical preparations for oral administrationCinnamon bark nitrogen

One or more of ketone, isopropyl myristate, oleum Menthae Dementholatum, oleum Terebinthinae, menthol, flos Caryophylli volatile oil, Borneolum Syntheticum, juniper terpene, flos Jasmini sambac essential oil, oleum Rosae Rugosae, flos Magnoliae essential oil, and Lavender essential oil.

In an embodiment of the invention, the invention provides a pharmaceutical composition for transdermal administration of a compound shown as the formula (I), wherein the antioxidant is selected from one or more of BHT, antioxidant 1010, bis (3, 5-tertiary butyl-4-hydroxyphenyl) sulfide, p-phenylenediamine and dihydroquinoline, didodecanol ester, ditetradecanol ester and dioctadecanol ester. Here, BHT: also called 2, 6-di-tert-butyl-4-methylphenol, antioxidant 264 and dibutyl hydroxy toluene; the 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 polymeric matrix carrier material is selected from one or more of polyvinylpyrrolidone, sodium polyacrylate, hydroxymethyl 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 anti-adhesion layer can be selected from 3M Scotchpak backing film.

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 may be selected from one of CoTran and non-woven fabric.

In another aspect, the present invention provides a process for preparing a pharmaceutical composition for transdermal administration of a compound of formula (I) as described above, comprising the steps of:

(1) micronizing the compound shown in the formula (I) or pharmaceutically acceptable salt thereof, a high molecular dispersion carrier material and a hot-melt protective agent, optionally adding a fluxing agent, uniformly mixing to obtain a physical mixture, and carrying out hot-melt extrusion and micronization to obtain particles of the compound shown in the formula (I) or pharmaceutically acceptable salt thereof;

(2) Preparing the particles obtained in the step (1) into alcohol liposome.

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 process for preparing the microparticles comprises:

(i) micronizing a compound shown in formula (I) or pharmaceutically acceptable salt thereof, a high-molecular dispersion carrier material and a 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 in spherical particles to obtain amorphous particles, and micronizing the amorphous particles to obtain the 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 steps of:

(I') weighing phospholipid, cholesterol, low molecular organic alcohol, microparticles of the compound shown in the formula (I) or pharmaceutically acceptable salt thereof and water;

(ii') dissolving the phospholipid, cholesterol and the compound shown in the formula (I) in low-molecular organic alcohol, and heating to 30-45 ℃ to dissolve the mixture to obtain a mixed solution;

(iii ') adding water into the mixed solution obtained in the step (ii') under the stirring condition, continuously 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, the present invention provides a method for preparing a pharmaceutical composition for transdermal administration of a compound represented by formula (I), comprising the steps of:

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

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

(4) and (3) ultrasonically mixing the mixture obtained in the step (3) with a pressure-sensitive adhesive uniformly, then mixing with a high molecular skeleton carrier material, drying to remove an organic solvent (namely low molecular organic alcohol), coating on an anti-sticking layer, and then covering with a back lining layer.

In a preferred embodiment of the present invention, there is provided a method for preparing a pharmaceutical composition for transdermal administration of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein the 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 is mixed with a high molecular carrier material and a hot melt protective agent and then is micronized, and then the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof is mixed with the high molecular carrier material uniformly during micronization, so that the powder property and the fluidity of the compound are improved, the stability of the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof is protected, the phenomenon that the compound is decomposed and generates impurities due to the high temperature of hot melt extrusion is avoided, the phenomenon that mixed crystals are formed when the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof forms an amorphous form is avoided, and the release of the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof (uniform release, stable release, uniform release of the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof is not met, Sufficient).

In a third aspect, the invention provides the use of a pharmaceutical composition for transdermal administration of a compound of formula (I) as described above for the prevention and/or treatment of attention deficit hyperactivity disorder in children.

Compared with the prior art, the transdermal drug delivery pharmaceutical composition of the compound shown in the formula (I) provided by the invention can obviously improve the transdermal permeability of the drug, maintain high blood concentration of the drug for a long time, ensure the sustained exertion of the drug effect, reduce the side effect of the drug, reduce the drug delivery times and facilitate the self-management of patients.

The transdermal drug delivery pharmaceutical composition of the compound shown in the formula (I) provided by the invention is beneficial to carrying drugs into the deep layer of the skin and promoting the percutaneous absorption of the drugs due to stable system and high transdermal efficiency, and has wide application in the fields of external preparations, cosmetics and the like.

The transdermal drug delivery composition of the compound shown in the formula (I) provided by the invention is characterized in that a transdermal absorption enhancer is added on the basis of an alcohol liposome, and the compound shown in the formula (I) is prepared into amorphous particles, so that active ingredients are prevented from being separated out in a crystal form, the drug is easy to enter through penetrating cells, penetrate through cell gaps and enter hair follicles through openings of skin accessory pipelines, the targeting property of the drug is improved, and the transdermal absorption of skin is promoted; the alcohol liposome is used as a transdermal administration carrier, and the drug to be transdermal is encapsulated in the alcohol liposome, so that the transdermal permeability of the drug is improved, the sustained and controlled release effect of the drug is enhanced, the drug is favorably absorbed and enters the systemic circulation, the local treatment or the systemic treatment effect is exerted, and the advantage of targeting hair follicles is achieved. Compared with the prior art, the skin passing rate of the active ingredients is increased by times, the dosage of the medicine is greatly reduced, the pharmacodynamic action of each component of the medicine is fully exerted, the medicine is convenient for doctors to conveniently treat patients, and the medicine has wide clinical application prospect.

The invention has the advantages that the medicine composition can provide the plasma concentration of the compound shown in the formula (I) and obtain the treatment effect, reduce the systemic absorption of the medicine, concentrate the medicine on the focus part, improve the local bioavailability and the targeting property of the medicine and reduce the side effect; the hydrated phospholipid of the liposome can promote the hydration of dry skin, so that the skin is fine and smooth, and has the effects of protecting and beautifying the skin.

The transdermal drug delivery composition has good biocompatibility, can improve skin nutrition metabolism, can promote proliferation of fiber cells, repair skin wounds, reduce scars, enhance immunity and the like; the alcohol liposome is a transdermal drug delivery carrier, so that the defects of 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 DSC of the hydrochloride salt of a compound of formula (I);

FIG. 2 shows a DSC of the hydrochloride salt of the compound of formula (I) in the form of microparticles with Povidone S630;

FIG. 3 shows an X-ray powder diffraction pattern of the hydrochloride salt of the compound of formula (I);

FIG. 4 shows the X-powder diffraction pattern of the hydrochloride salt of the compound of formula (I) physically mixed with povidone S630;

FIG. 5 shows an X-powder diffraction pattern of the hydrochloride salt of the compound of formula (I) in combination with povidone S630 as formed into microparticles;

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

FIG. 7 is a graph showing the mean concentration of the principal drug in the plasma of animals after administration of the sample and injection solution groups prepared in example 1 of the present application versus time.

FIG. 8 is a graph showing the mean concentration of the principal agent in the plasma of animals following administration of different samples of the hydrochloride salt of the compound of formula (I) versus time.

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 (swiss ARL), Pyris 1 thermal analyzer (PerkinElmer, usa).

EXAMPLE 1 transdermal patch preparation of Compound (Deketamine) hydrochloride of formula (I)

(1) Micronizing 5g of compound (dexketamine) hydrochloride shown in formula (I), 2g of povidone (PVP-S630) and 0.12g of magnesium stearate, adding 2.88g of polyethylene glycol (molecular weight 2000), and mixing to obtain 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 5g of the micronized amorphous particles prepared in the step (2), 0.2g of soybean lecithin, 0.03g of cholesterol, 3g of absolute ethyl alcohol and 1.77g of water;

(4) dissolving soybean lecithin, cholesterol and micronized amorphous particles of a compound hydrochloride shown in a formula (I) in absolute ethyl alcohol, and heating to 30-45 ℃ to dissolve the materials to obtain a mixed solution;

(5) And (4) stirring the mixed solution obtained in the step (4) at the speed 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 alcohol liposome of the compound shown in the formula (I).

(6) Preparation of transdermal patch:

adding 1g of the alcohol liposome prepared in the step (5) and lauryl nitrogen

0.7g of ketone (Azone) and 10100.2 g of antioxidant are stirred and dissolved, the mixture is uniformly mixed with 3g of acrylic acid by ultrasonic, then the mixture is uniformly mixed with 4g of polyvinylpyrrolidone and 2g of hydroxypropyl methylcellulose by heating to 60 ℃, the organic solvent, namely ethanol, is removed by drying, the mixture is coated on an anti-sticking layer (Scotchpak) after being cooled, the coating thickness is 100 mu m, the backing layer (non-woven fabric) is covered after being cooled, and the non-woven fabric is punched into a piece with the area of 2-4 cm²Or a suitable size transdermal patch containing the compound.

Example 2 transdermal patch preparation of Compound (ketamine) of formula (I)

(1) Micronizing 6g of compound (ketamine) shown in formula (I), 1g of povidone (PVP-S630) and 0.18g of magnesium stearate, adding 2.82g of polyethylene glycol (molecular weight 3000), and mixing to obtain a physical mixture;

(2) setting the extrusion temperature of a double-screw extruder to be 100 ℃, 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 5g of micronized amorphous particles prepared in the step (2), 0.2g of phosphatidylcholine, 0.08g of cholesterol, 3g of propylene glycol and 1.72g of water;

(4) dissolving phosphatidylcholine, cholesterol and micronized amorphous particles of a compound shown in a formula (I) in propylene glycol, and heating to 30-45 ℃ to dissolve the micronized amorphous particles to obtain a mixed solution;

(5) stirring the mixed solution obtained in the step (4) under the condition of 200r/min, adding distilled water, continuing stirring for 1.5h after the addition is finished, and then cooling to room temperature to obtain the alcohol liposome of the compound shown in the formula (I).

(6) Preparation of transdermal patch:

adding 1g of the alcohol liposome prepared in the step (5), 0.4g of jasmine essential oil, 0.4g of rose essential oil and 0.2g of BHT, stirring for dissolving, mixing with 2g of acrylic acid by ultrasonic wave, mixing with 6g of acrylic resin by heating to 50 deg.C, drying to remove organic solvent (propylene glycol), cooling, and coating on the surface of the substrateCoating 100 μm thick on the anti-sticking layer (Scotchpak), cooling, covering with a back lining layer (CoTran), and punching to 2-4 cm area²Or a suitable size transdermal patch containing the compound.

Example 3 transdermal patch preparation of Compound (Leketamine) of formula (I)

(1) Micronizing 7g of a compound (levoketamine) shown in a formula (I), 1.5g of povidone (PVP-VA64) and 0.2g of talcum powder, adding 1.3g of polyethylene glycol (molecular weight 4000), and uniformly mixing to obtain a physical mixture;

(2) Setting the extrusion temperature of a double-screw extruder to be 140 ℃, 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 7g of micronized amorphous particles prepared in the step (2), 2g of dipalmitoyl phosphatidylcholine, 0.3g of cholesterol, 30g of absolute ethyl alcohol and 60.7g of water;

(4) dissolving dipalmitoyl phosphatidylcholine, cholesterol and micronized amorphous particles of a compound shown in a formula (I) in absolute ethyl alcohol, and heating to 30-45 ℃ to dissolve the micronized amorphous particles to obtain a mixed solution;

(6) Preparation of transdermal patch:

adding 1g of the alcohol liposome prepared in the step (5), 0.4g of clove volatile oil, 0.4g of borneol and 0.2g of p-phenylenediamine, stirring and dissolving, uniformly mixing with 3g of acrylate by ultrasonic, then uniformly mixing with 5g of vinyl acetate-vinyl pyrrolidone copolymer by heating to 45 ℃, drying to remove an organic solvent, namely ethanol, cooling, coating on an anti-sticking layer (Scotchpak), coating the anti-sticking layer with the thickness of 100 mu m, cooling, covering a back lining layer (non-woven fabric), and punching into pieces with the area of 4cm ²The transdermal patch containing the compound.

EXAMPLE 4 transdermal patch preparation of Compound (ketamine hydrochloride) represented by formula (I)

(1) Micronizing 5g of compound (ketamine hydrochloride) shown in formula (I), 2g of Soluplus and 0.1g of talcum powder, adding 2.9g of polyethylene glycol (with molecular weight of 5000), and mixing uniformly to obtain a 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 120-180 nm.

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

(4) dissolving phosphatidyl ethanolamine, cholesterol and compound micronized amorphous particles shown in a formula (I) in isopropanol, and heating to 30-45 ℃ to dissolve the micronized amorphous particles to obtain a mixed solution;

(5) and (4) stirring the mixed solution obtained in the step (4) under the condition of 500r/min, adding distilled water, continuing stirring for 1.5h after the addition is finished, and then cooling to room temperature to obtain the alcohol liposome of the compound shown in the formula (I).

(6) Preparation of transdermal patch:

adding 0.1g of alcohol liposome prepared in the step (5), 0.5g of menthol, 0.4g of turpentine and 1g of bis (3, 5-tertiary butyl-4-hydroxyphenyl) thioether prepared in the step (5), stirring and dissolving, mixing with 2g of acrylate by ultrasonic waves, heating 3g of sodium polyacrylate and 3g of sodium carboxymethylcellulose to 70 ℃, mixing uniformly, drying to remove an organic solvent, namely ethanol, coating on an anti-sticking layer (Scotchpak) after cooling, covering a back lining layer (non-woven fabric) after cooling, and punching into pieces with the area of 2-4 cm²Or a suitable size transdermal patch containing the compound.

EXAMPLE 5 transdermal patch preparation of Compound of formula (I) (S-Camphor sulfonate of Dexamine)

(1) Micronizing 6g of compound (S-camphorsulfonate of dexketamine) shown in formula (I), 1.5g of povidone (K30) and 0.1g of magnesium stearate, adding 2.4g of polyethylene glycol (molecular weight 5000), and mixing to obtain physical mixture;

(2) setting the extrusion temperature of a double-screw extruder to be 160 ℃, 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 120-180 nm.

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

(4) dissolving soybean lecithin, cholesterol and micronized amorphous particles of a compound shown in a formula (I) in absolute ethyl alcohol, and heating to 30-45 ℃ to dissolve the materials to obtain a mixed solution;

(5) and (4) stirring the mixed solution obtained in the step (4) under the condition of 350r/min, adding distilled water, continuing stirring for 2.5h after the addition is finished, and then cooling to room temperature to obtain the alcohol liposome of the compound shown in the formula (I).

(6) Preparation of transdermal patch:

adding 1g of the alcohol liposome prepared in the step (5), 0.7g of dolichone and 0.5g of dihydroquinoline, stirring and dissolving, uniformly mixing with 2g of acrylic acid by ultrasonic waves, then uniformly mixing with 2.8g of polyvinylpyrrolidone and 3g of sodium carboxymethylcellulose by heating to 70 ℃, drying to remove an organic solvent, namely ethanol, coating the mixture on an anti-sticking layer (Scotchpak) after cooling, wherein the coating thickness is 150 mu m, coating a back lining layer (CoTran) after cooling, and punching the mixture into pieces with the area of 2-4 cm²Or a suitable size transdermal patch containing the compound.

EXAMPLE 6 transdermal patch preparation of Compound (Benzenesulfonate salt of dexketamine) of formula (I)

(1) Micronizing 5g of a compound (benzene sulfonate of dexketamine) shown in formula (I), 2g of povidone (PVP-VA64) and 0.3g of talcum powder, adding 2.7g of polyethylene glycol (molecular weight 2000), and uniformly mixing to obtain a physical mixture;

(2) setting the extrusion temperature of a double-screw extruder to 170 ℃, 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 with the particle size controlled to be about 100-150 nm.

(3) Weighing 2g of the micronized amorphous particles prepared in the step (2), 0.2g of soybean lecithin, 0.07 g of cholesterol, 3g of absolute ethyl alcohol and 4.73g of water.

(6) Preparation of transdermal patch:

adding 1g of the alcohol liposome prepared in the step (5) and lauryl nitrogen

0.8g of ketone (Azone) and 0.2g of dioctadecyl alcohol ester are stirred and dissolved, the mixture is uniformly mixed with 5g of acrylic acid by ultrasound, then the mixture is uniformly mixed with 2g of magnolia flower essential oil and 1g of lavender essential oil by heating to 60 ℃, the organic solvent, namely ethanol, is removed by drying, the mixture is coated on an anti-sticking layer (Scotchpak) after cooling, the coating thickness is 120 mu m, a back lining layer (Cotran) is covered after cooling, and the mixture is punched into a piece with the area of 2-4 cm²Or a suitable size transdermal patch containing the compound.

EXAMPLE 7 transdermal Patch preparation of Compound (Ethanesulfonate salt of Leketamine) of formula (I)

(1) Micronizing 5g of compound (ethanesulfonate of levoketamine) shown in formula (I), 2g of povidone (PVP-VA64) and 0.1g of magnesium stearate, adding 2.9g of polyethylene glycol (molecular weight 5000), and mixing to obtain a physical mixture;

(2) setting the extrusion temperature of a double-screw extruder to be 180 ℃, 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 120-180 nm.

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

(6) Preparation of transdermal patch:

adding 2g of alcohol liposome prepared in the step (5), 0.5g of menthol, 0.2g of turpentine and 0.3g of docosanol ester, stirring and dissolving, ultrasonically mixing with 2g of acrylate uniformly, then heating with 3g of sodium polyacrylate and 2g of sodium carboxymethylcellulose to 70 ℃, uniformly mixing, drying to remove an organic solvent, namely isopropanol, cooling, coating on an anti-sticking layer (Scotchpak), wherein the coating thickness is 200 mu m, cooling, covering a back lining layer (non-woven fabric), and punching into an area of 2-4 cm²Or a suitable size transdermal patch containing the compound.

EXAMPLE 8 transdermal patch preparation of Compound (hydrobromide salt of ketamine) of formula (I)

(1) Micronizing 2g of a compound (hydrobromate of ketamine) shown in formula (I), 1.5g of povidone (PVP-VA64) and 0.3g of magnesium stearate, adding 6.2g of polyethylene glycol (with a molecular weight of 5000), and mixing uniformly to obtain a physical mixture;

(2) Setting the extrusion temperature of a double-screw extruder to be 100 ℃, 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 120-180 nm.

(3) Weighing 5g of micronized amorphous particles prepared in the step (2), 0.2g of phosphatidylethanolamine, 0.05g of cholesterol, 3g of absolute ethyl alcohol and 1.75g of water;

(4) dissolving phosphatidyl ethanolamine, cholesterol and compound micronized amorphous particles shown in formula (I) in absolute ethyl alcohol, and heating to 30-45 ℃ to dissolve the micronized amorphous particles to obtain a mixed solution;

(6) Preparation of transdermal patch:

adding 0.1g of alcohol liposome prepared in the step (5), 0.5g of menthol, 0.2g of turpentine and 0.3g of ditetradecanol ester, stirring and dissolving, uniformly mixing with 2.99g of acrylate by ultrasonic, then heating 3g of sodium polyacrylate and 3g of sodium carboxymethylcellulose to 70 ℃, uniformly mixing, drying to remove an organic solvent, namely ethanol, coating on an anti-sticking layer (Scotchpak) after cooling, coating the anti-sticking layer with the thickness of 150 mu m, covering a back lining layer (non-woven fabric) after cooling, and punching into pieces with the area of 2-4 cm ²Or a suitable size transdermal patch containing the compound.

EXAMPLE 9 transdermal Patch preparation of Compound (tartrate salt of dexketamine) of formula (I)

(1) Micronizing 7g of a compound (tartrate of dexketamine) shown in formula (I), 1.5g of povidone (PVP-VA64) and 0.1g of talcum powder, adding 1.4g of polyethylene glycol (with molecular weight of 5000), and mixing uniformly to obtain 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 120-180 nm.

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

(6) Preparation of transdermal patch:

adding 0.1g of alcohol liposome prepared in the step (5), 0.5g of menthol, 0.2g of turpentine and 0.3g of ditetradecanol ester, stirring and dissolving, uniformly mixing with 2.9g of acrylate by ultrasonic, then heating 3g of sodium polyacrylate and 3g of sodium carboxymethylcellulose to 70 ℃, uniformly mixing, drying to remove an organic solvent, namely ethanol, coating on an anti-sticking layer (Scotchpak) after cooling, coating the anti-sticking layer with the thickness of 150 mu m, covering a back lining layer (non-woven fabric) after cooling, and punching into pieces with the area of 2-4 cm²Or a suitable size transdermal patch containing the compound.

EXAMPLE 10 transdermal Patch preparation of Compound of formula (I) (Malate salt of ketamine)

(1) Micronizing 5g of compound (ketamine malate) shown in formula (I), 1.5g of povidone (PVP-VA64) and 0.2g of talcum powder, adding 3.3g of polyethylene glycol (with molecular weight of 5000), and mixing to obtain a physical mixture;

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

(6) Preparation of transdermal patch:

EXAMPLE 11 stability testing of a transdermal delivery System for the hydrochloride salt of the Compound of formula (I) according to the invention

The compound of formula (I) contains the following 4 impurities in EP 8.0:

the inventor conducts a long-term stability experiment on the sample prepared in example 1 in an environment with the temperature of 20-30 ℃ and the humidity of 60% +/-5%.

The HPLC detection conditions were as described in EP 8.0.

It can be seen that the quality of the pharmaceutical formulation (example 1) obtained by the present invention is still very stable, meeting the quality standards, when left at room temperature for up to three years.

EXAMPLE 12 in vitro skin penetration test of transdermal delivery System of hydrochloride salt of Compound of formula (I) according to the invention

Franz transdermal application was carried out on the samples prepared in example 1 of the present inventionThe results of the in vitro skin permeability test performed by the diffusion apparatus are shown in FIG. 6, and the specific operation is as follows: one mouse was anesthetized by intraperitoneal injection of pentobarbital sodium (40mg/kg), the mouse was sacrificed, 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 (37 +/-0.2) DEG C and stirred at the speed of 300 r/min.

The sample prepared in the invention example 1 is added into an upper supply chamber, sealed by a preservative film and covered with a layer of tinfoil paper to avoid light. 2.0mL of the receiving solution was withdrawn at a predetermined time (1, 2, 4, 6, 8) 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 alcohol liposomes containing the compound represented by formula (I) of Azone were able to permeate the skin, and the transdermal efficiency was high and the amount of accumulated drug permeating the skin was the greatest as compared with the case where the compound represented by formula (I) was loaded on the alcohol liposomes and the case where the compound represented by formula (I) was loaded on anhydrous 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.

EXAMPLE 13 comparison of pharmacokinetics in SD rats of a transdermal formulation and injection of the compound of formula (I) of the present invention

24 SD rats, male and female halves, were selected for testing, and randomly divided into two groups, a transdermal formulation group (group A) according to example 1 of the present invention and a compound of formula (I) (dexketamine) hydrochloride injection group (group B, preparation method of DE4312016A1 example 2), and 12 rats were tested per group. A transdermal preparation of the compound of formula (I) (dexketamine) (sample prepared according to the invention from example 1), was applied at 0.2g/kg to the group A animalsThe upper part of the back of the object ensures that the transdermal patch is completely contacted with the skin; group B animals were injected with 0.2g/kg of injection via the abdominal cavity. The blood draw points for group a after the end of dosing were: 2. 5, 10, 20, 30, 45, 60, 120, 180, 240, 360, 480, 600 min; the blood draw points for group B were: 2. 5, 10, 20, 30, 45, 60, 120, 180, 240, 360, 480, 600, 720, 840 min. Approximately 0.4ml of whole blood was collected from the tail vein of rats at these time points. After blood collection, the blood sample was placed in an anticoagulation tube (1000IU/ml, about 10. mu.l) containing heparin sodium, centrifuged at 4000rpm for 5min at 4 ℃, and plasma was separated and the concentration of the principal drug in the plasma was measured by LC-MS/MS. 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 transdermal patch and injection administration of the Compound of formula (I) (dexketamine hydrochloride)

Comparative pharmacokinetic parameters t of transdermal preparations and injection groups of example 1 of the present invention in SD rats_1/2、T_max、C_maxAnd the bioavailability is basically consistent after AUC, but the transdermal preparation group has a certain sustained and controlled release function, so that the action time of the medicament can be prolonged to a certain extent, and the administration frequency is reduced.

The preparation method of dexketamine hydrochloride is carried out according to the preparation method of example 8 in patent CN 107750245A.

The preparation method of the dexketamine hydrochloride injection is prepared by referring to the preparation method of DE4312016A1 in example 2.

Example 14 transdermal drug delivery system of the present invention was 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 1-10 were each applied to 20 rats with depilated backs and 24 hours later, the products of examples 1-10 were found to have no skin irritation and a rating of 0.

EXAMPLE 15 DSC and X-ray powder diffraction detection of Compound represented by formula (I)

The results of DSC and X-powder diffraction analysis of the hydrochloride salt of the compound represented by formula (I), the fine particles of the hydrochloride salt of the compound represented by formula (I) and povidone S630, and the physical mixture of the hydrochloride salt of the compound represented by formula (I) and povidone S630 are shown in fig. 1 to 5. As can be seen from the figure, after hot-melt extrusion, the compound shown in formula (I) is converted from a polycrystalline state to an amorphous state, which is more beneficial to the absorption of the drug and is proved to be stable in preparation research.

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-Kalpha 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: pyris 1 thermal analyzer (PerkinElmer, USA)

EXAMPLE 16 pharmacodynamic test of Compound represented by formula (I)

In order to further clarify the effects of the pharmaceutical composition of the present invention, pharmacodynamic tests were performed using mice.

1 test Material

1.1 test animals

SPF grade KM young male mice, 8 weeks old, body mass (20. + -.2) grams, Shanghai Slek laboratory animals GmbH.

1.2 test drugs

The test drugs are: the pharmaceutical composition prepared in example 1 of the present invention.

Positive control drug: methylphenidate hydrochloride for injection, 20mg, suzhou first pharmaceutical co.

2 test content

2.1 Effect of the Chinese medicinal composition for treating hyperactivity in infants on mouse behavior

2.1.1 animals were divided and administered

30 male KM mice were randomly divided into treatment, positive control, blank control groups, 10 per group. The treatment group mice were administered with the pharmaceutical composition prepared in example 1, the positive control group mice were injected with methylphenidate hydrochloride for injection, and the blank group mice were administered with 0.9% physiological saline of the same volume as the positive control group. The dose of the treatment group and the positive control group is 10 times of the clinical dose of children. The medicine is administered 1 time/day in the morning for 28 days.

2.1.2 index determination

The activity of the mice was recorded by videography before and after administration, and each mouse was observed for 30 minutes once a day

(1) Time of spontaneous activity of mice before and after treatment;

(2) the number of times the mice stood up before and after treatment;

(3) the number of times of climbing the rod by the mouse before and after treatment.

2.1.3 data processing

Statistical analysis using the SPSS11.5 software package, comparison before and after treatment with paired t-tests, data results and

and (4) showing.

2.1.4 test results

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

TABLE 2 mouse Activity time before and after dosing

Note: positive control p <0.05 compared to blank; treatment group p < 0.01.

The result shows that compared with the blank group, the positive control group mice have significant significance on the activity time difference (p < 0.05); the mice in the treatment group had significant differences in the activity time (p <0.01) compared to the remaining two mice.

The results show that the mice in the treatment group had significantly reduced activity time.

TABLE 3 number of mouse erection events before and after treatment

Group of	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
					Treatment group	25.12±11.23	17.16±9.15	16.43±10.18	15.08±11.18

Note: p <0.05 in the positive control group compared to the blank group; treatment group p < 0.05.

The result shows that compared with the blank group, the difference of the times of the vertical movement of the mice in the positive control group has significant significance (p is less than 0.05); the difference in the number of vertical movements between the treated mice and the other mice was significant (p < 0.05).

The results show that the number of erections of mice in the treatment group is significantly reduced.

TABLE 4 Pole-climbing time before and after treatment

Group of	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
					Treatment group	12.12±3.53	10.56±3.09	9.16±3.01	8.15±2.57

The result shows that compared with the blank group, the rod climbing time difference of the mice in the positive control group has significant significance (p is less than 0.05); the difference of rod climbing time of the mice in the treatment group is significant compared with the mice in the rest groups (p < 0.05).

The results show that the rod climbing time of the mice in the treatment group is obviously reduced.

2.2 Effect of the pharmaceutical composition for treating attention deficit hyperactivity disorder on the body weight of mice

2.2.1 animals were divided and administered

30 male KM mice were randomly grouped into 10 groups, blank, positive control and treatment groups, respectively. The treatment group mice were administered with the pharmaceutical composition prepared in example 1, the positive control group mice were injected with methylphenidate hydrochloride for injection, and the blank group mice were administered with 0.9% physiological saline of the same volume as the positive control group. The dose of the treatment group and the positive control group is 10 times of the clinical dose of children. The medicine is administered 1 time/day in the morning for 28 days.

2.2.2 index determination

The body weight of the mice was measured 1 time every 7 days during the experiment.

2.2.3 data processing

Statistical analysis was performed using the SPSS11.5 software package, comparison before and after treatment using paired t-tests, data results in

And (4) showing.

2.2.4 test results

The results are shown in Table 5.

TABLE 5 mouse Activity time before and after dosing

Group of	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
				Treatment group	23.08±1.08	22.71±1.01	43.18±0.89

The results show that the weight change of the mice in the positive control group has significant significance compared with the blank group (p < 0.05); the change of the body weight of the mice in the treatment group has significant significance (p < 0.05).

The results show that the body weight of the mice in the treatment group is obviously increased.

2.3 Effect of the pharmaceutical composition for treating attention deficit hyperactivity disorder on the content of DA in mice

2.3.1 animals were divided and administered

36 male hyperkinetic KM mice were randomly grouped into 12 mice per group. Blank group, positive control group and treatment group. The treatment group mice were administered with the pharmaceutical composition prepared in example 1, the positive control group mice were injected with methylphenidate hydrochloride for injection, and the blank group mice were administered with 0.9% physiological saline of the same volume as the positive control group. The dose of the treatment group and the positive control group is 10 times of the clinical dose of children. The medicine is administered 1 time/day in the morning for 28 days. Mice were sacrificed after dosing to collect blood samples: after two weeks of administration, fasting was performed for 1 day, and 6 mice were randomly selected from 3 groups of mice, sacrificed, and blood samples were collected; after 4 weeks of dosing, the remaining mice were sacrificed and blood samples were collected. The method comprises the following specific steps: using chloral hydrate Anaesthetizing the mouse, carrying out the orbit after the anesthesia and getting blood, the volume of getting blood is 0.5 ~ 0.8ml, and the blood sample holds with the EDTA coagulation tube that is equipped with the precooling, later kills the mouse, places the mouse corpse according to the regulation in laboratory. Immediately placing the blood sample into a centrifuge, setting the temperature at 4 deg.C and the rotation speed at 3000 r.min^-1Centrifuging for 20min, collecting 100 μ l of plasma, adding 100 μ l of precooled 0.6% perchloric acid, mixing in a vortex shaking mixer, and standing in a refrigerator for 10 min. Taking out the detection sample from the refrigerator, setting the temperature of the centrifuge at 4 deg.C, and rotating at 12000 r.min^-1Centrifuging for 15min, and placing 100 μ l of supernatant in an EP tube for constant temperature storage.

2.3.2 index determination

Changes in DA content in mice were measured 2 weeks and 4 weeks after drug administration, respectively.

2.3.3 data processing

and (4) showing.

2.3.4 test results

The results are shown in Table 6.

TABLE 6 DA content in mice

Group of	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
			Treatment group	18.183±2.215	11.701±1.816

The result shows that compared with a blank group, the change of the content of DA in the mice of the positive control group has significant significance (p is less than 0.05); the change of DA content in the mice of the treatment group has significant significance (p is less than 0.05).

The result shows that the treatment group has significant significance on the change of the DA content in the body of the mouse, and can obviously reduce the DA content in the plasma of the mouse.

2.4 Effect of the pharmaceutical composition for treating hyperactivity in infants on mouse serum S100 beta protein

2.4.1 animals were divided and administered

30 male KM mice were randomly grouped into groups of 10 mice each. Blank group, positive control group and treatment group. The treatment group mice were administered with the pharmaceutical composition prepared in example 1, the positive control group mice were injected with methylphenidate hydrochloride for injection, and the blank group mice were administered with 0.9% physiological saline of the same volume as the positive control group. The dose of the treatment group and the positive control group is 10 times of the clinical dose of children. The medicine is administered 1 time/day in the morning for 28 days. . Blood samples were collected from mice after dosing: mouse plasma was collected 4 weeks after dosing and refrigerated at 4 ℃. The serum S100 beta protein content of the mice was measured by the BCA method.

2.4.2 index determination

Serum S100 β protein content of the mice was measured 4 weeks after the administration.

2.4.3 data processing

and (4) showing.

2.4.4 test results

The results are shown in Table 7.

TABLE 7 serum S100. beta. protein content in mice

Group of	Number of samples	S100 beta protein content (mg/ml)
			Blank group	10	0.4523±0.0156
Positive control group	10	0.6105±0.0103
			Treatment group	10	0.5056±0.0309

The result shows that compared with a blank group, the content change of the S100 beta protein in the serum of the mice of the positive control group has significant significance (p is less than 0.05); the S100 beta protein content in the serum of the treated mice has significance (p is less than 0.05).

The result shows that the treatment group has significant meaning on the change of the serum S100 beta protein content, and can obviously increase the mouse serum S100 beta protein content.

Comparative example 1 preparation of transdermal patch of Compound (dexketamine hydrochloride) of formula (I) (polymorphic form X-powder diffraction pattern is shown in FIG. 3)

(1) 0.25g of a compound (dexketamine hydrochloride) shown in formula (I), 0.2g of soybean lecithin, 0.03g of cholesterol, 3g of absolute ethyl alcohol and 6.52g of water;

(2) dissolving soybean lecithin, cholesterol and compound particles shown in a formula (I) in absolute ethyl alcohol, and heating to 30-45 ℃ to dissolve the mixture to obtain a mixed solution;

(3) 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 alcohol liposome of the compound shown in the formula (I).

(4) Preparation of transdermal patch:

adding 1g of the alcohol liposome prepared in the step (3) and lauryl nitrogen

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

13.5g of the compound (dexketamine hydrochloride) shown in the formula (I) is heated and dissolved in 12ml of acetone, cooled and crystallized (0-5 ℃), filtered, and washed by a small amount of ethyl glacial acetate; drying at 45-60 ℃ under reduced pressure to obtain 10.1g, and carrying out X-powder diffraction detection to obtain the crystal form shown in figure 3. The compound (dexketamine hydrochloride) shown in formula (I) in the crystal form is used as an API (active ingredient or bulk drug).

Comparative example 2 preparation of transdermal patch (prior art) of Compound (Dechloramine Ketone hydrochloride) of formula (I) (polymorphic form X-powder diffraction Pattern is shown in FIG. 3)

The present inventors refer to the preparation method of example 1 of patent CN107929268A, and prepared the compound represented by formula (I) (prepared as a transdermal patch, which is prepared as follows:

1) Dissolving an active component compound (hydrochloric acid dexketamine) shown in formula (I) in ethanol to obtain a medicine-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 dispersing agent, 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 mi;

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 then covering an anti-sticking layer to obtain the transdermal patch product.

Example 17 pharmacokinetics of transdermal patch of compound of formula (I) (dexketamine) in SD rats by comparing different crystal forms and different techniques

The test was conducted by selecting 36 SD rats, each half male and female, and randomly dividing into three groups, i.e., 12 rats per group, which are samples of example 1 (group A), comparative example 1 (group B) and comparative example 2 (group C). Transdermal preparations containing 0.2g/kg of compounds of formula (I) with different crystal forms and different technologies are respectively stuck to the upper parts of the backs of A, B, C three groups of animals to ensure that the transdermal patches are completely contacted with the skin. A, B, C three groups of blood sampling points after the end of administration were: 2. 5, 10, 20, 30, 45, 60, 120, 180, 240, 360, 480, 600, 720, 840, 960 min. At these time points approximately 0.4ml of whole blood was collected from the tail vein of SD rats. Blood circulation After sample collection, the sample is placed in an anticoagulation tube (1000IU/ml, about 10 mu l) containing heparin sodium, centrifuged at 4000rpm for 5min at 4 ℃, and plasma is separated and the concentration of the main drug in the plasma is detected by an 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. 8) are as follows:

TABLE 8 pharmacokinetic parameters in animals following transdermal patch administration of different crystalline forms of the compound of formula (I)

Comparison of the pharmacokinetic parameters t of different samples of transdermal formulations of Compound of formula (I) (Dexoketamine) in SD rats_1/2、T_max、C_maxAfter AUC, the SD rat finds that the transdermal absorption speed of the compound of formula (I) in the group A is higher than that of the compound of the formula (I) in the group B, C, and the AUC area of the group A transdermal patch in the SD rat is higher than that of the group B, C.

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.

Claims

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

Wherein the macromolecular dispersion carrier material is polyvidone or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer;

optionally, the fluxing agent is selected from polyethylene glycol;

the preparation method of the pharmaceutical composition for transdermal administration comprises the following steps: micronizing the compound shown in the formula (I) or pharmaceutically acceptable salt thereof, a high molecular dispersion carrier material and a hot-melt protective agent, optionally adding a fluxing agent, uniformly mixing to obtain a physical mixture, and carrying out hot-melt extrusion and micronization to obtain particles of the compound shown in the formula (I) or pharmaceutically acceptable salt thereof; the hot-melt protective agent is magnesium stearate or talcum powder; the temperature of the hot-melting extrusion is 100-180 ℃; and is

The preparation method of the pharmaceutical composition for transdermal administration of the compound shown in the formula (I) further comprises the following steps: preparing microparticles of the compound shown in the formula (I) or pharmaceutically acceptable salts thereof into alcohol liposome, and stirring and dissolving the alcohol liposome, a transdermal absorption enhancer and an antioxidant; then mixing with pressure sensitive adhesive, and then mixing with polymer skeleton carrier material; drying to remove low molecular organic alcohol in the alcohol liposome, coating on the anti-sticking layer, and covering with a back lining layer; here, the alcohol liposome is composed of microparticles of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, a phospholipid, cholesterol, a low-molecular organic alcohol and water; and is

The transdermal drug delivery composition is a transdermal patch, and the transdermal patch further comprises an anti-sticking layer and a back lining layer.

2. The pharmaceutical composition of claim 1, wherein the compound of formula (I) is ketamine, levoketamine, dexketamine, or a mixture of an unequal ratio of levoketamine to dexketamine;

optionally, the pharmaceutically acceptable salt is a hydrochloride, hydrobromide, besylate, tosylate, esylate, tartrate, malate, or (S) -camphorsulfonate.

3. The pharmaceutical composition of claim 1, wherein the molecular weight of the polyethylene glycol is 2000-6000.

4. The pharmaceutical composition according to claim 1, wherein the fine particles of the compound of formula (I) or the pharmaceutically acceptable salt thereof comprise 20-70 wt%, 10-25 wt% of the polymeric dispersion carrier material, 1-3 wt% of the thermal melting protective agent, and 10-65 wt% of the polyethylene glycol.

5. The pharmaceutical composition according to claim 1, wherein the diameter of the fine particles of the compound represented by the formula (I) or the pharmaceutically acceptable salt thereof is 100 to 300 nm.

6. The pharmaceutical composition according to claim 5, wherein the diameter of the fine particles of the compound represented by the formula (I) or the pharmaceutically acceptable salt thereof is 100 to 200 nm.

7. The pharmaceutical composition according to claim 5, wherein the diameter of the fine particles of the compound represented by the formula (I) or the pharmaceutically acceptable salt thereof is 150 to 250 nm.

8. The pharmaceutical composition according to claim 1, wherein the low molecular organic alcohol is selected from one or more of ethanol, propylene glycol and isopropanol;

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

optionally, the macromolecular skeleton carrier is one or more of polyvinylpyrrolidone, sodium polyacrylate, hydroxymethyl cellulose, vinyl acetate-vinyl pyrrolidone copolymer, acrylic resin and sodium carboxymethyl cellulose;

optionally, 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.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the pharmaceutical composition is a transdermal patch in which the content of the compound represented by formula (I) is 1 to 300mg per patch.

10. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition is a transdermal patch, and the content of the compound represented by the formula (I) in the transdermal patch is 5-120 mg/patch.

11. A process for the preparation of a pharmaceutical composition according to any one of claims 1-10, comprising the steps of:

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

12. The production method according to claim 11, wherein the process for producing the fine particles comprises:

13. The method for producing according to claim 11, wherein the method for producing alcohol liposomes comprises the steps of:

(ii') dissolving fine particles of phospholipid, cholesterol, the compound shown in the formula (I) or pharmaceutically acceptable salts thereof in low-molecular organic alcohol, and heating to 30-45 ℃ to dissolve the fine 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 water is added, and then cooling to room temperature to obtain the alcohol liposome.

14. Use of a pharmaceutical composition according to any one of claims 1-10 for the preparation of a medicament for the prevention and/or treatment of attention deficit hyperactivity disorder.