CN112023125B

CN112023125B - Crystalline coating and preparation method thereof, drug-loaded implant medical device and preparation method thereof

Info

Publication number: CN112023125B
Application number: CN202010397792.6A
Authority: CN
Inventors: 武金田; 李俊菲; 周奇; 章京; 汪晶
Original assignee: Shanghai Microport Medical Group Co Ltd
Current assignee: Shanghai Microport Medical Group Co Ltd
Priority date: 2019-06-03
Filing date: 2020-05-12
Publication date: 2023-03-21
Anticipated expiration: 2040-05-12
Also published as: CN112023125A

Abstract

The invention relates to a crystalline coating and a preparation method thereof, a medicine-carrying implantation medical apparatus and a preparation method thereof, wherein the preparation method of the medicine-carrying implantation medical apparatus comprises the following steps: providing a medical device body; depositing a drug on the medical device body to form a coating to be treated containing an amorphous drug; cracking turtles to form a cracking chemical layer on the coating to be treated; and (4) carrying out fumigation treatment to convert a preset amount of amorphous medicine in the cracked medicine layer into crystalline medicine. According to the preparation method of the drug-loaded implantable medical device, the control of physical forms such as crystallinity, particle size and crystal shape and uniformity of the drug on the medical device body can be realized only by controlling the technological conditions in the cracking treatment and fumigation steps of the tortoise, so that the control of the drug release rate is achieved, the safety is obviously improved, the usage amount of the drug is reduced, the shelf life is prolonged, and the same or better drug control release effect as that of a medical device containing a polymer coating is achieved.

Description

Crystalline coating and preparation method thereof, drug-loaded implant medical device and preparation method thereof

Technical Field

The invention relates to the technical field of medical instruments, in particular to a crystalline coating and a preparation method thereof, a drug-loaded implant medical instrument and a preparation method thereof.

Background

With the development of economy, medical devices are rapidly developed, and the demand and the requirement of the medical devices are higher and higher, especially the implanted medicated medical devices. When the body material of the device is definite, the coating mode of the medicine on the device influences the release behavior of the medicine, and further influences the curative effect of the device on a human body. For example, the commercially available drug-containing medical devices adopt a coating mode that a polymer contains a drug, and the polymer coating can realize the controlled release of the drug, but further research and study find that the polymer coating has the defects of cracking (cracking), peeling (flaking) and delaminating (delaminating), and the like, and also has the problems of allergy, inflammation, incomplete drug release and the like. The range of biological hazards is extensive and complex, and biological evaluation is required when a material needs to interact with tissue in order to perform its function. In the biological test, based on the simulation of in vitro test and animal test, the reaction possibly produced can only be warned in time, the same tissue reaction of human body can not be accurately and unmistakably reacted, and the reaction difference also exists between human bodies. Thus, the polymer is eliminated, as long as the device body and the drug can reduce the safety risk. For this reason, drug-containing medical devices without polymer coatings have been developed, but at present, the release is relatively fast, about 95% in 30 days, resulting in poor long-term therapeutic effect.

Different solid forms of the drug can show different physicochemical properties, and the difference in physicochemical properties affects the storage stability, solubility, dissolution rate and the like. The form of the medicine also has influence on the release and curative effect of the medicine, for example, the paclitaxel which is commonly used in the medicine balloon has a crystalline form and an amorphous form, the amorphous paclitaxel is most easily absorbed, but the retention time in the body is short; the crystallized paclitaxel has longer retention time in vivo, and can inhibit cell proliferation. The prior art US9056152 discloses a method for forming a drug coating on the surface of a medical device, in which the drug is applied to the surface of the medical device followed by grinding the drug to drug crystallites of 10 μm or less, and the drug crystallites are applied to the surface of the drug. If the step of applying the drug microcrystals is absent, the grown drug crystals migrate out of the main region and concentrate at a specific point, and the crystals concentrated at the specific point grow into very large needle-shaped crystals and the adhesion of the crystals to the surface of the medical device is poor. These studies indicate that the integrity of the drug coating on the device affects the in vivo release behavior of the drug and further affects the therapeutic efficacy. In addition, the uniformity of the drug coating can bring about controllable release behaviors, so that the drugs are uniformly distributed at the focus part, and the generation of toxic and side effects caused by overhigh local drug concentration and poor curative effect even drug resistance caused by overlow local drug concentration are avoided.

Disclosure of Invention

Based on the above, there is a need for a uniform crystalline coating which is safe and can effectively control the release of materials, a preparation method thereof, a drug-loaded implantable medical device and a preparation method thereof.

A method for preparing a crystalline coating, comprising the steps of:

providing a coating to be treated comprising an amorphous material;

cracking the turtles to form a cracked coating on the coating to be treated;

and (3) fumigating, and converting a preset amount of amorphous materials in the cracking coating into crystalline materials.

In one embodiment, the step of cracking the tortoise comprises:

placing the coating to be treated in any one of the following environments until the cracked coating is formed:

(1) the temperature is 5-40 ℃, and the wind speed is 0-1 m/s; wherein, the preferable temperature range is 15-40 ℃; the preferred wind speed range is 0.2 m/s-0.6 m/s;

(2) the temperature is 0-100 ℃, and the pressure is 1-95 kPa; wherein, the preferred temperature range is 10-60 ℃; the preferred pressure range is 50kPa to 80kPa;

(3) the temperature is minus 120 ℃ to minus 20 ℃, and the pressure is 5Pa to 1000Pa; wherein, the preferable temperature range is-80 ℃ to-30 ℃; the preferred pressure range is 50Pa to 500Pa.

In one embodiment, the step of fumigating comprises the steps of:

placing the cracked coating in a vapor atmosphere containing a material that converts the amorphous material to the crystalline material;

taking out and drying to obtain the crystalline coating.

A preparation method of a drug-loaded implantable medical device comprises the following steps:

providing a medical device body;

depositing a drug on the medical device body to form a coating to be treated comprising an amorphous drug;

cracking turtles to form a cracking chemical layer on the coating to be treated;

and (3) performing fumigation treatment to convert a preset amount of amorphous medicine in the cracked medicine layer into crystalline medicine.

In one embodiment, the step of cracking the tortoise comprises:

placing the medical device body containing the amorphous drug in any one of the following environments until a cracking drug layer is generated:

(1) the temperature is 5-40 ℃, and the wind speed is 0-1 m/s; wherein, the preferred temperature range is 15-40 ℃; the preferred wind speed range is 0.2 m/s-0.6 m/s;

In one embodiment, the cracking time of the tortoise is 1-48 h; preferably, the time for the cracking treatment is 4 to 48h,8 to 48h,12 to 48h and 20 to 48h. More preferably, the time for the cracking treatment is 12 to 24 hours.

In one embodiment, the step of fumigating comprises the steps of:

placing the medical device body with the crazing drug layer in a vapor atmosphere containing the amorphous drug converted into the crystalline drug;

taking out and drying to obtain the medical device for carrying medicine implantation.

In one embodiment, the temperature of the fumigation treatment is 0-60 ℃.

In one embodiment, the solvent forming the vapor atmosphere is a single solvent or a mixed solvent; wherein the solubility of the single solvent is less than or equal to 10mg/mL;

the mixed solvent comprises a good solvent and a poor solvent, the solubility of the good solvent is greater than 10mg/mL, and the solubility of the poor solvent is less than or equal to 10mg/mL.

In one embodiment, the good solvent accounts for 5 to 25 volume percent of the mixed solvent.

In one embodiment, the single solvent is selected from: petroleum ether, n-hexane, n-heptane or diethyl ether;

the good solvent in the mixed solvent is selected from one or more of alkyl acetate, C1-C6 alkyl alcohol, acetonitrile, tetrahydrofuran, acetone, nitromethane, dichloromethane and trichloromethane; the poor solvent in the mixed solvent is selected from: one or more of water, petroleum ether, n-hexane, n-heptane and diethyl ether.

In one embodiment, the mixed solvent is selected from: a combination of methanol and water, a combination of tetrahydrofuran and water, a combination of acetone and water, a combination of ethanol and water, a combination of acetonitrile and water, a combination of ethyl acetate and diethyl ether, a combination of ethyl acetate and n-hexane, a combination of ethyl acetate and heptane, a combination of n-propyl acetate and water, a combination of n-propyl acetate and diethyl ether, a combination of n-propyl acetate and n-hexane, a combination of n-propyl acetate and n-heptane, a combination of n-butyl acetate and n-hexane, a combination of n-butyl acetate and n-heptane, a combination of n-pentyl acetate and n-hexane, a combination of n-pentyl acetate and n-heptane, a combination of ethyl acetate and petroleum ether, a combination of n-propyl acetate and petroleum ether, a combination of dichloromethane and n-hexane, a combination of diethyl ether and n-heptane, a combination of n-hexane and n-heptane, tetrahydrofuran, a combination of ethanol and water, a combination of ethanol, diethyl ether and water, or a combination of n-propyl acetate, ethanol and water.

In one embodiment, the grain size of the crystalline drug formed in the fumigating step is 2 μm to 25 μm; and/or

The crystal grain shape of the crystalline drug formed in the fumigation treatment step is needle-shaped, oval, rhombic, spherical or dendritic.

In one embodiment, before the step of fumigating, after the step of cracking the tortoise, the method further comprises the following steps:

and depositing a solvent on the cracking chemical layer to form crystal grains.

In one embodiment, the step of fumigating further comprises the following steps:

and depositing a medically acceptable antioxidant on the medical appliance body formed with the crystalline drug to form a protective layer.

In one embodiment, the antioxidant is selected from: one or more of dibutyl hydroxy toluene, butyl hydroxy anisol, tert-butyl hydroquinone, gallic acid and derivatives, vitamin E, vitamin C, tea polyphenols and phytic acid.

The medicine-carrying implantation medical apparatus prepared by the preparation method of the medicine-carrying implantation medical apparatus.

The preparation method of the crystalline coating comprises the steps of firstly forming a coating to be treated containing amorphous materials, then carrying out turtle cracking treatment on the coating, and then carrying out fumigation to convert amorphous medicines in a cracking medicine layer into crystalline medicines. Thus, the control of physical forms such as the crystallinity, the particle size, the crystal shape and the like of the coating material can be realized by controlling the process conditions in the cracking treatment and fumigation steps of the tortoise, thereby achieving the control of the release rate of the material. The preparation method is simple and convenient to operate, low in cost and suitable for industrial production and application.

The preparation method of the medicine-carrying implantation medical appliance comprises the steps of firstly depositing amorphous-state medicine on an appliance body, then carrying out turtle cracking treatment on the appliance body, and then carrying out fumigation to convert the amorphous-state medicine in a cracking medicine layer into crystalline-state medicine so as to form a uniform crystalline-state medicine coating. Therefore, the control of physical forms such as crystallinity, particle size, crystal shape and the like of the medicine on the medical appliance body can be realized by controlling the technological conditions in the cracking treatment and fumigation steps of the tortoise, so that the control of the medicine release rate is realized, the safety is obviously improved, the use amount of the medicine is reduced, the shelf life is prolonged, and the controlled release effect of the medicine which is the same as or better than that of the medicine appliance containing the polymer coating is realized. The preparation method is simple and convenient to operate, low in cost and suitable for industrial production and application.

Drawings

FIG. 1 is a scanning electron microscope image of the surface of a medical device after a crazing treatment;

wherein 1a is a scanning electron microscope image of the drug-loaded implantable medical device of example 1; 1b is a scanning electron micrograph of the drug-loaded implantable medical device of example 2; 1c is a scanning electron micrograph of the drug-loaded implantable medical device of example 3;

FIG. 2 is a scanning electron microscope image of a drug-loaded implanted medical instrument turtle after cracking treatment and fumigation treatment;

wherein 2a is a scanning electron microscope image of the drug-loaded implantable medical device turtle of example 4 after cracking treatment; and 2b is a scanning electron microscope image of the drug-loaded implanted medical device of example 4 after fumigation.

Detailed Description

In order that the invention may be more fully understood, a more particular description of the invention will now be rendered by reference to specific embodiments thereof that are illustrated in the appended drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

The preparation method of the crystalline coating layer according to an embodiment of the present invention includes the steps of:

s101: providing a coating to be treated comprising an amorphous material;

the percentage of the amorphous material in the coating to be treated in step S101 is not particularly limited, and it may be a coating to be treated formed by all amorphous materials, or a coating to be treated formed by combining amorphous materials and crystalline materials in a certain ratio, and preferably mainly amorphous materials.

Step S101 may form a to-be-treated coating layer containing an amorphous material on the surface of the to-be-treated device by a method such as dipping, spraying, or the like.

S102: cracking the tortoise to form a cracked coating on the coating to be treated;

it is understood that the cracking treatment means cracking the coating turtle to be treated to form cracks, micropores, and the like having regular or irregular shapes. In one embodiment, the step of crazing comprises: placing the coating to be treated in any one of the following environments until a cracked coating is formed:

(2) the temperature is 0-100 ℃, and the pressure is 1-95 kPa; wherein, the preferable temperature range is 10-60 ℃; the preferred pressure range is 50kPa to 80kPa;

S103: and (4) fumigating, and converting a preset amount of amorphous materials in the cracking coating into crystalline materials.

It is understood that the fumigation treatment refers to the treatment of the cracked coating with solvent vapor. The release speed of the coating can be adjusted by adjusting the proportion of the crystalline drug and the crystalline form.

In one embodiment, the step of fumigating comprises the steps of: placing the cracked coating in a vapor atmosphere containing a material that converts the amorphous material to a crystalline state;

taking out and drying to obtain the uniform crystal coating.

The invention also provides the crystalline coating prepared by the preparation method of the crystalline coating.

The invention also provides application of the preparation method of the crystalline coating in preparation of medical devices.

The preparation method of the medicine-carrying implantation medical instrument provided by the embodiment of the invention comprises the following steps:

s201: a medical device body is provided.

The drug-loaded implantable medical device can be used in vivo or in vitro, and can be used for a short time or permanently implanted for a long time. In addition, the medical devices described above may provide medical and/or diagnostic devices for heart rhythm disorders, heart failure, valvular diseases, vascular diseases, diabetes, neurological diseases and disorders, orthopedic surgery, neurosurgery, oncology, ophthalmology and ENT procedures. Medical devices to which the present invention relates include, but are not limited to, the following: stents, stent grafts, anastomotic connectors, synthetic patches, leads, electrodes, needles, guidewires, catheters, sensors, surgical instruments, angioplasty balloons, wound drains, shunt tubes (shunts), tubes, infusion sleeves (infusion sleeves), urethral cannulas, pellets, implants, blood oxygenators, pumps, vascular grafts, embedded intervention cartridges (vascucessors), heart valves, annuloplasty rings, sutures, surgical clips, surgical staples, pacemakers, implantable defibrillators, neurostimulators, orthopedic instruments, cerebrospinal fluid shunts, implantable drug pumps, vertebral cages, artificial intervertebral discs, nucleus pulposus replacement instruments, ear tubes, intraocular lenses, and any tube used in interventional procedures. Wherein, the stent includes, but is not limited to, coronary artery stent, peripheral blood vessel stent, intracranial blood vessel stent, urethra stent, esophagus stent.

The material of the medical device body is not particularly limited, and may be one or more selected from the group consisting of metal, ceramic, carbon, and polymer. In one embodiment, the material of the medical device body is selected from one or more of cobalt-based alloy, platinum alloy, stainless steel, titanium alloy, active ceramic, carbon, polylactic acid and the like.

In addition, the outer surface of the apparatus may be provided with grooves for holding drugs, the shape and number of the grooves are not particularly limited, the grooves may be in the shape of a long strip, a square, an ellipse, a circle, a diamond or other regular or irregular patterns, the distribution of the grooves on each basic unit is not particularly limited, the grooves may be arranged in a specific regular manner or randomly, the grooves may be continuous or discontinuous, the grooves may be distributed over the surface of the body or only exist in certain regions, the grooves may be distributed with uniform density, or distributed in different ways with different density in different regions, and the width and depth of the grooves may be adjusted as required.

S202: depositing a drug on the medical device body to form a coating to be treated comprising an amorphous drug.

The percentage of the amorphous drug contained in the coating to be processed in the drug deposited in step S102 is not particularly limited, and may contain only the amorphous drug, or may be a combination of the amorphous and crystalline drugs in a certain ratio, and preferably exists mainly in the form of the amorphous drug. The amorphous drug is in a thermodynamically unstable high free energy state, and the solubility and dissolution rate of the amorphous drug are high, so that the release rate is high, the release period is unstable, and the curative effect of the device is influenced after the amorphous drug is implanted.

Wherein the deposited drug may be a drug for treating cardiovascular diseases, an anti-tumor active drug or an anti-inflammatory active drug, etc., including but not limited to one or more of Paclitaxel (Paclitaxel), docetaxel (Docetaxel), copper aspirin (Copper aspirin), tacrolimus (Tacrolimus), hydroxycamptothecin (Hydroxy camptothecin), vinblastine (Vinblastine), lenvatinib, trovatinib, simvastatin, lovastatin, telmisartan, alprostadil, genistein, estradiol, levofloxacin, rapamycin (Rapamycin), and Rapamycin derivatives, without being particularly limited thereto. Among them, the rapamycin derivatives may be Zotarolimus (Zotarolimus), everolimus (Everolimus), bimesomus (Biolimus A9), 7-O-desmethylrapamycin (Novolimus), temsirolimus (Temsirolimus), ridaforolimus (Ridaforolimus), and the like.

The proper solvent can be selected according to the type of the medicine to be dissolved to prepare a medicine solution, and then the medicine solution is deposited on the medical appliance body. The solvent in which the drug solution is formulated is preferably a good solvent for the drug, including, but not limited to, one or more of alkyl acetate, C1-C6 alkyl alcohol, acetonitrile, tetrahydrofuran, acetone, nitromethane, methylene chloride, and chloroform. Wherein the alkyl acetate can be methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, n-pentyl acetate, or isoamyl acetate; the C1-C6 alkyl alcohol can be methanol, ethanol, propanol, isopropanol, butanol, isobutanol, or the like.

In step S202, the deposition may be performed by spraying, dipping, coating, or the like, and preferably by spraying. The amount of the single spraying and the number of spraying can be adjusted according to the thickness of the medicine to be deposited, and is not particularly limited. Preferably, the volume of the medicine sprayed in one time is 300 pL-600 pL, and the spraying is completed by 1-25 times to form a medicine layer with a uniform surface, so that the subsequent steps can be favorably carried out. The temperature of spraying is not particularly limited, and the spraying temperature is preferably 20 to 40 ℃.

It is understood that, in step S202, the location on the medical device body where the drug is deposited is not particularly limited, and the drug may be deposited on the entire medical device body or only a partial region of the medical device body. In addition, when a plurality of medicaments are required to be deposited, one medicament can be deposited in one partial area of the device, the other partial area of the device can be deposited with the other medicament, or the medicaments can be mixed and deposited in the whole or partial area of the medical device body. In one embodiment, the medical device body is formed with a plurality of grooves in which the drug is deposited.

In addition, the concentration of the drug deposited at different positions on the medical device body may be the same or different, and is not particularly limited herein.

S203: cracking the tortoise to form a cracking chemical layer on the coating to be treated.

It is understood that the cracking treatment refers to treating the drug deposited on the medical device body to form a drug layer with regular or irregular cracks or micropores. The shape of the micro pores is not particularly limited, and may be a circular pore, or a regular or irregular pore, and some micro pores may be interconnected to form a crack in the entire drug layer. The formation of the cracking drug layer is beneficial to the conversion of amorphous drugs to crystalline drugs in the subsequent fumigation step, and the shape and the quantity of micropores in the drug layer can be controlled by controlling the cracking treatment conditions of the tortoise, so that the grain size, the proportion of the crystalline drugs and the like in the subsequent step can be controlled in an auxiliary way, and the medical device implanted with the drug can have longer release time or higher blood concentration.

The cracking treatment method of turtles is not particularly limited, and a conventional cracking treatment method of turtles can be employed.

Wherein the step of the crazing treatment comprises: placing the coating to be treated in any one of the following environments until the cracked coating is formed:

(1) the temperature is 5-40 ℃, and the wind speed is 0-1 m/s; in one embodiment, the temperature is 20-30 ℃, the wind speed is 0.2-0.6 m/s, and the treatment time is 1-48 h.

(2) The temperature is 0-100 ℃, and the pressure is 1-95 kPa; in one embodiment, the temperature is 20-40 ℃, the pressure is 50-80 kPa, and the time is 20-36 h.

(3) The temperature is minus 120 ℃ to minus 20 ℃, and the pressure is 5Pa to 1000Pa; in one embodiment, the cracking treatment of the tortoise is carried out by a freeze dryer for 4-36 h.

In the cracking step, the turtle may be processed under a constant temperature and/or a constant pressure, or may be processed in a gradient temperature raising mode, a gradient temperature lowering mode, a gradient temperature raising mode and then a gradient temperature lowering mode, a gradient pressure lowering mode, a gradual temperature raising mode, a gradual temperature lowering mode, a gradual temperature raising mode and then a gradual temperature lowering mode, a gradual pressure lowering mode and the like.

S204: and applying a solvent on the cracking chemical layer to form partial crystal grains.

It should be noted that step S204 may be omitted. By forming the grains first, the subsequent fumigation step can be facilitated. It is understood that the grain size in this step is not particularly limited, and preferably small grains are formed, and the grains are grown to form a crystalline drug of a desired size by fumigation. In this step, the solvent may be deposited by spraying, dipping, or the like.

The solvent in step S204 may be the same as or different from the solvent used for fumigation in step S205, specifically, the solvent in step S204 may be a single solvent or a mixed solvent; wherein the single solvent is selected from: petroleum ether, n-hexane, n-heptane, diethyl ether, etc.; the mixed solvent comprises: a good solvent and a poor solvent, wherein the good solvent is selected from one or more of alkyl acetate, C1-C6 alkyl alcohol, acetonitrile, tetrahydrofuran, acetone, nitromethane, dichloromethane, trichloromethane and the like; the poor solvent is selected from: one or more of water, petroleum ether, n-hexane, n-heptane, diethyl ether, etc. Preferably, the mixed solvent is ethyl acetate/n-hexane, ethyl acetate/n-heptane.

S205: and (4) carrying out fumigation treatment to convert a preset amount of amorphous medicine in the cracked medicine layer into crystalline medicine.

In step S205, all amorphous drugs or part of amorphous drugs may be converted into crystalline drugs, and the fumigation parameters are adjusted as needed. Adjust through proportion and the crystallization form of crystalline state medicine on the medical instrument body, realize the medicine release rate's that the medicine carrying was implanted medical instrument regulation, reduce the use amount of medicine, improve shelf life, reach the same or better medicine control release effect with the medical instrument that contains polymer coating. In one embodiment, the crystallinity of the drug on the medical device body is 1% to 100%,15% to 100%,25% to 100%,40% to 100%,50% to 100%, preferably 50% to 100%.

It is understood that in the present invention, fumigation refers to the mechanical treatment of the preconditioner with solvent vapors. In the invention, the amorphous medicine in the cracked medicine layer is converted into the crystalline medicine in a fumigating mode. The cracking drug layer contains a certain micropore structure, so that conversion of amorphous drugs in fumigation is facilitated, conversion of the amorphous drugs on the medical appliance body can be effectively controlled through control of micropore conditions in the step S203 and control of fumigation process conditions in the step S204, crystalline drugs with proper sizes and excellent physical properties are formed, and control of drug release rate is achieved.

Specifically, the fumigating step comprises the following steps: and (3) placing the medical appliance body with the cracked drug layer in a steam atmosphere containing amorphous drugs converted into crystalline drugs, taking out and drying after a drug layer with preset crystallinity is formed, and thus obtaining the drug-loaded implantable medical appliance. The vapor atmosphere refers to an atmosphere formed by evaporation of a solvent used for crystallization. The medical device body on which the cracked drug layer is formed can be hung on a solvent bottle containing a solvent (the medical device body does not contact the liquid surface of the solvent), and in the process, the solvent can be oscillated to promote the volatilization of the solvent. In addition, the medical device body of the cracked drug layer may be suspended in a sealed space, and a vapor atmosphere for drug crystallization may be introduced into the sealed solvent, which is not particularly limited herein.

The fumigation condition is closely related to the proportion of the crystalline drug. In one embodiment, the conditions of fumigation are: the temperature is 0-60 ℃. In addition, the temperature of fumigation can be kept constant, the crystallinity of the medicine on the medical appliance for medicine loading implantation can be adjusted by adjusting the fumigation time, and then the release speed of the medicine can be controlled, so that the medicine is convenient and fast. Specifically, the fumigating time can be 0.25h to 120h, and preferably the fumigating time is 4h to 24h.

In the fumigating step, the solvent forming the steam atmosphere can be a single solvent or a mixed solvent; wherein, the mixed solvent includes: a good solvent and a poor solvent, wherein the solubility of the good solvent is more than 10mg/mL; the solubility of the poor solvent is less than or equal to 10mg/mL, and the proportion of the good solvent is preferably 1-99%, 2-75%, 3-60%, 4-35%, 5-25%, preferably 5-25%.

In one embodiment, the single solvent is selected from: petroleum ether, n-hexane, n-heptane, diethyl ether, etc. The good solvent in the mixed solvent is selected from one or more of alkyl acetate, C1-C6 alkyl alcohol, acetonitrile, tetrahydrofuran, acetone, nitromethane, dichloromethane, trichloromethane and the like; the poor solvent is selected from: one or more of water, petroleum ether, n-hexane, n-heptane, diethyl ether, etc.

In one embodiment, the mixed solvent is selected from: a combination of methanol and water, a combination of tetrahydrofuran and water, a combination of acetone and water, a combination of ethanol and water, a combination of acetonitrile and water, a combination of ethyl acetate and diethyl ether, a combination of ethyl acetate and n-hexane, a combination of ethyl acetate and heptane, a combination of n-propyl acetate and water, a combination of n-propyl acetate and diethyl ether, a combination of n-propyl acetate and n-hexane, a combination of n-propyl acetate and n-heptane, a combination of n-butyl acetate and n-hexane, a combination of n-butyl acetate and n-heptane, a combination of n-pentyl acetate and n-hexane, a combination of n-pentyl acetate and n-heptane, a combination of ethyl acetate and petroleum ether, a combination of n-propyl acetate and petroleum ether, a combination of dichloromethane and n-hexane, a combination of diethyl ether and n-heptane, a combination of n-hexane and n-heptane, tetrahydrofuran, a combination of ethanol and water, a combination of ethanol, diethyl ether and water, or a combination of n-propyl acetate, ethanol and water, and the like.

In one embodiment, the mixed solvent is a combination of alkyl acetate and n-hexane, preferably a combination of ethyl acetate and n-hexane.

The size and shape of crystal particles can be controlled by adjusting the solvent for fumigation, the fumigation time, the temperature and other parameters. In one embodiment, the grain size of the crystalline drug formed in the fumigating step is 0.01 μm to 2000 μm, preferably 2 μm to 25 μm. The crystal grain shape of the crystalline drug formed in the fumigating step is regular or irregular, such as: needle, oval, diamond, rhombus, sphere, or tree, etc.

S206: and depositing a medically acceptable antioxidant on the medical appliance body formed with the crystalline drug to form a protective layer.

It should be noted that step S206 may be omitted. The protective layer formed in step S206 can make the surface of the drug coating more smooth and flat, further improving the shelf life.

Wherein the antioxidant can be a synthetic antioxidant or a natural antioxidant. In one embodiment, the antioxidant is selected from: one or more of dibutyl hydroxy toluene, butyl hydroxy anisol, tert-butyl hydroquinone, gallic acid and its derivatives, vitamin E, vitamin C, tea polyphenols and phytic acid.

The preparation method of the medicine-carrying implantation medical appliance comprises the steps of firstly depositing the medicine containing the amorphous medicine on the medical appliance body, then carrying out turtle cracking treatment on the medicine, and then carrying out fumigation to convert the amorphous medicine in the cracking medicine layer into the crystalline medicine. Therefore, the control of physical forms such as the proportion of crystalline drugs, the particle size, the crystal shape and the like on the medical appliance body can be realized by controlling the technological conditions in the cracking treatment and fumigation steps of the tortoise, so that the control of the drug release rate is realized, the safety is obviously improved, the usage amount of the drugs is reduced, the shelf life is prolonged, and the controlled drug release effect which is the same as or better than that of a drug appliance containing a polymer coating is achieved. The preparation method is simple and convenient to operate, low in cost and suitable for industrial production and application.

The invention also provides a medicine-carrying implantation medical appliance prepared by the method. The drug-loaded implantable medical device can well control the drug release effect, and further can realize longer release time or higher drug concentration according to requirements.

The present invention will be described below with reference to specific embodiments.

1. Turtle cracking processing parameter investigation

Example 1

(1) Dissolving a certain amount of estradiol with ethanol/acetone, and placing estradiol on the surface of an apparatus by adopting a spraying method.

(2) The sprayed instrument is placed in a glass surface dish and treated for 45 hours under the conditions that the temperature is 22 ℃ and the wind speed is 0.3 m/s.

(3) And (3) observing the condition of micropores or cracks on the surface of the medicine on the surface of the device by a scanning electron microscope, specifically referring to 1a in figure 1.

Example 2

(1) A certain amount of estradiol is dissolved by ethanol/acetone, and the estradiol is placed on the surface of the instrument by a spraying method.

(2) The sprayed device was placed in a vacuum oven at 25 ℃ and 80kPa for 2h, and the temperature was raised to 30 ℃ and the pressure was reduced to 55kPa for a further 12h.

(3) And (3) observing the condition of micropores or cracks on the surface of the medicine on the surface of the device by a scanning electron microscope, specifically referring to 1b in figure 1.

Example 3

(2) Freezing the sprayed device with liquid nitrogen, placing in a freeze dryer, setting to-40 deg.C, treating at 200Pa for 4 hr, changing to-50 deg.C, treating at 50Pa, and continuing for 20 hr.

(3) And (5) observing the surface crack condition of the medicine on the surface of the instrument by a scanning electron microscope, and particularly referring to c in fig. 1.

As can be seen from fig. 1, the treatment method of example 1 has a smaller number of cracks (see 1a in fig. 1), the treatment method of example 2 has a larger number of cracks than example 1 (see 1b in fig. 1), and the treatment method of example 3 has the largest number of cracks (see 1c in fig. 1).

2. Fumigation treatment parameter investigation

Example 4

(1) Spraying: dissolving a certain amount of Docetaxel (Docetaxel) in ethyl acetate, and placing Docetaxel (Docetaxel) on the surface of an instrument by a spraying method.

(2) Cracking turtle: the sprayed device was placed in a vacuum oven at 22 ℃ and 60kPa for 24h. At this time, the drug on the device is mainly amorphous, and the scanning electron micrograph is shown as 2a in fig. 2.

(3) Fumigating treatment: suspending the device, placing in the center of a bottle (without immersion solution) filled with dichloromethane/methanol and n-hexane, sealing, placing in a 25 deg.C constant temperature oscillator at 30rpm for 169h, taking out the device, drying in a fume hood for 24h, and observing the change of the drug coating morphology under a scanning electron microscope, as shown in 2b of FIG. 2. And (3) amplifying the scanning electron microscope picture in the figure 2 to 2000 times, and measuring the maximum sizes of the crystal grains at different angles, wherein the measurement result is between 2 and 25 mu m.

As can be seen by comparing 2a and 2b in fig. 2, the amorphous drug converts to a crystalline drug after fumigation.

(4) Uniformity characterization: and scanning different positions of the crystalline coating by using micro-Raman, wherein the peak shape of the crystalline coating is consistent with the intensity of the corresponding characteristic peak. Scanning different depths at the same position by using micro Raman, scanning the surface, scanning different depths downwards, 5 microns, 10 microns, 15 microns, 20 microns, 25 microns, 30 microns and the like, wherein the peak shapes are consistent with the intensities of the corresponding characteristic peaks. The crystalline coating is characterized by multiple scans and microscopic Raman at different depths, which shows that the crystalline coating has uniformity.

Example 5

(1) Spraying: the umirolimus is dissolved with n-propyl acetate and is deposited within the instrument surface using a spray process.

(2) Cracking turtle: the sprayed instrument is placed in a glass surface dish and treated for 24 hours under the conditions that the temperature is 25 ℃ and the wind speed is 0.4 m/s.

(3) Fumigating, suspending the apparatus, placing in the center of a bottle (without immersion solution) containing ethyl acetate and n-hexane, sealing, placing in a 25 deg.C constant temperature oscillator at 30rpm for 20h, taking out the apparatus, drying in a fume hood for 24h, and observing the change of drug coating morphology under scanning electron microscope.

Example 6

(1) And (3) spraying, namely dissolving a certain amount of levofloxacin by using ethyl acetate, and placing the levofloxacin on the surface of an apparatus by adopting a spraying method.

(2) And (3) cracking turtles, namely placing the sprayed instrument in a glass surface dish, and treating for 12 hours at the temperature of 30 ℃ and the wind speed of 0.4 m/s.

(3) Fumigating, hanging the apparatus, placing in the center of a bottle (without immersion solution) filled with ethyl acetate and n-hexane, sealing, placing in a 30 deg.C constant temperature oscillator at 30rpm for 18h, taking out the apparatus, drying in a fume hood for 24h, and observing the change of the drug coating form under a scanning electron microscope.

Example 7

(1) And (3) spraying, namely dissolving a certain amount of alprostadil in tetrahydrofuran solution, and placing the rapamycin on the surface of the instrument by adopting a spraying method.

(2) Cracking tortoise, freezing the sprayed apparatus in a refrigerator at-30 deg.C for 24 hr, and treating in a freeze drier at-30 deg.C under 150Pa for 36 hr.

(3) Fumigating, hanging the apparatus, placing in the center of bottle (without immersion solution) containing ethanol, diethyl ether and water, sealing, placing in refrigerator at 4 deg.C, standing for 3 days, standing at room temperature for 8 hr, taking out, drying in fume hood for 24 hr, and observing the change of drug coating form under scanning electron microscope.

3. In vitro simulated release assay

(1) Preparation of drug-loaded implantation instrument to be tested

Experimental groups: dissolving a certain amount of simvastatin by using ethyl acetate, and placing the simvastatin in the groove of the instrument by adopting a spraying method. The sprayed device was placed in a vacuum oven at 25 ℃ and 100Pa for 24h. The apparatus was suspended, placed in the centre of a bottle containing methanol and water (without immersion solution), sealed, placed in a 30 ℃ thermostatted shaker at 30rpm, 1697 h after which the apparatus was removed and dried in a fume hood for 24h.

Control group: basically the same as the experimental group, except that the step of drug spraying treatment is performed only on the surface of the medical device, specifically: dissolving a certain amount of simvastatin by using ethyl acetate, and placing the simvastatin on the surface of an apparatus by adopting a spraying method. The sprayed device was placed in a vacuum oven at 25 ℃ and 100Pa for 24h.

(2) In vitro simulated release medium: medium a was phosphate buffered saline (PBS, pH =7.4, gibco sterile grade) and medium B was phosphate buffered saline plus 5% isopropanol (AR, national drug) (PBS +5% isopropanol, pH = 7.4).

(3) The experimental conditions are as follows: carefully placing a medicine carrying instrument into a 15mL sterile centrifuge tube, slowly and gently adding 10mL of medium A or medium B along the wall, covering a cover, sealing by using a sealing film, and placing into a shaking table at 37 ℃ at 60rpm; each set of 6 replicates. The device was removed at preset time points 1h, 8h, 1d, 3d, 7d, 14d, 2d1 and 28d and the remaining liquid on the device was carefully aspirated off with the nonwoven. Wherein, the residual medicine on the elution apparatus is soaked in 10mL of methanol for 3 parallel samples; the amount of drug remaining on the device was measured by High Performance Liquid Chromatography (HPLC). And shooting a scanning electron microscope by the other 3 parallel samples to observe the coating condition. The test results are shown in table 1:

TABLE 1

As can be seen from the results in table 1, the simvastatin-containing drug device obtained by the method of the embodiment has a sustained-release effect, which indicates that the drug-loaded coating technology provided by the invention has potential to replace the original sustained-release technical effect realized by carriers such as polymers, and is expected to completely solve the clinical adverse reactions brought by the drug carriers such as polymers. Scanning electron microscopy shows that the coating does not obviously fall off in the early release stage, which shows that the coating has good adhesion and good firmness; the early release coating was relatively intact, indicating uniform release. As the release proceeds, the coating thins until the release is completely invisible. Its homogeneous crystalline coating is expected to achieve relatively uniform drug tissue concentrations at the site of the lesion.

Compared with the prior art, the technical scheme provided by the invention overcomes the technical problems of migration, slipping and the like caused by insufficient adhesion of a medicament deposited on the surface of an apparatus in the prior art, simultaneously overcomes the technical problems of complicated working procedures and low efficiency of medicament microcrystal preparation, and can obtain a medicament coating with high adhesion and uniform crystal size through cracking treatment and fumigation of turtles.

The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims

1. A preparation method of a medicine-carrying implantation medical apparatus is characterized by comprising the following steps:

providing a medical device body;

depositing a drug on the medical device body to form a coating to be treated comprising an amorphous drug; the medicines in the coating to be treated are in an amorphous state;

a fumigation treatment, which converts a predetermined amount of amorphous drug in the cracked drug layer into crystalline drug;

the turtle cracking treatment comprises the following steps:

placing the medical device body containing the amorphous drug in any one of the following environments until a cracked drug layer is generated:

(1) the temperature is 5-40 ℃, and the wind speed is 0-1 m/s;

(2) the temperature is 0-100 ℃, and the pressure is 1-95 kPa;

(3) the temperature is minus 120 ℃ to minus 20 ℃, and the pressure is 5Pa to 1000Pa;

the cracking treatment time of the turtles is 1-48 h;

the step of fumigation treatment comprises the following steps: placing the medical device body with the crazing drug layer in a vapor atmosphere containing the amorphous drug converted into the crystalline drug;

the temperature of the fumigation treatment is 0-60 ℃, and the time of the fumigation treatment is 4-24 h;

the solvent forming the vapor atmosphere is a single solvent or a mixed solvent; wherein the solubility of the single solvent is less than or equal to 10mg/mL; the mixed solvent comprises a good solvent and a poor solvent, the solubility of the good solvent is more than 10mg/mL, and the solubility of the poor solvent is less than or equal to 10mg/mL;

the good solvent accounts for 5 to 25 percent of the volume percentage of the mixed solvent;

after the fumigation treatment, the crystallinity of the medicine on the medical appliance body is 50-100%.

2. The method of making a drug-loaded implantable medical device of claim 1, wherein the step of fumigating further comprises the steps of:

3. The method of making a drug-loaded implantable medical device of claim 1, wherein the single solvent is selected from the group consisting of: petroleum ether, n-hexane, n-heptane or diethyl ether;

4. The method of preparing a drug-loaded implantable medical device according to claim 3, wherein the mixed solvent is selected from the group consisting of: a combination of methanol and water, a combination of tetrahydrofuran and water, a combination of acetone and water, a combination of ethanol and water, a combination of acetonitrile and water, a combination of ethyl acetate and diethyl ether, a combination of ethyl acetate and n-hexane, a combination of ethyl acetate and heptane, a combination of n-propyl acetate and water, a combination of n-propyl acetate and diethyl ether, a combination of n-propyl acetate and n-hexane, a combination of n-propyl acetate and n-heptane, a combination of n-butyl acetate and n-hexane, a combination of n-butyl acetate and n-heptane, a combination of n-pentyl acetate and n-hexane, a combination of n-pentyl acetate and n-heptane, a combination of ethyl acetate and petroleum ether, a combination of n-propyl acetate and petroleum ether, a combination of dichloromethane and n-hexane, a combination of diethyl ether and n-heptane, a combination of n-hexane and n-heptane, tetrahydrofuran, a combination of ethanol and water, a combination of ethanol, diethyl ether and water, or a combination of n-propyl acetate, ethanol and water.

5. The method of claim 1, wherein the grain size of the crystalline drug formed in the fumigating step is 2 μm to 25 μm.

6. The method of claim 1, wherein the crystalline drug particles formed in the fumigating step are needle-like, oval, diamond-like, rhombic, spherical, or dendritic in shape.

7. The method of preparing a drug-loaded implantable medical device according to claim 1, wherein the step of cracking the turtle before the step of fumigating further comprises the steps of:

and applying a solvent on the cracking chemical layer to form crystal grains.

8. The method of preparing a medicated implantable medical device according to claim 1, further comprising the following steps after the step of fumigating:

depositing a medically acceptable antioxidant on the body of the medical device containing the crystalline drug to form a protective layer.

9. The method of making a drug-loaded implantable medical device of claim 8, wherein the antioxidant is selected from the group consisting of: one or more of dibutyl hydroxy toluene, butyl hydroxy anisole, tert-butyl hydroquinone, gallic acid and its derivatives, vitamin E, vitamin C, tea polyphenols and phytic acid.

10. A drug-loaded implantable medical device prepared by the method of any one of claims 1 to 9.