Intracranial drug balloon catheter and preparation method thereof

Abstract

The invention belongs to the technical field of medical instruments, and particularly relates to an intracranial drug balloon catheter and a preparation method thereof. A two-time spraying method is adopted, the humidity of carrier gas during two-time spraying is controlled, an amorphous-state drug coating and a crystalline-state combined drug coating are formed on the surface of the balloon catheter, and the drug can be released, permeated and stored within 90 s after the balloon catheter adheres to the wall; further, the technical effects of effectively and lastingly inhibiting the intimal hyperplasia and reducing the restenosis rate are achieved, and the method has excellent trafficability and traceability and can adapt to the complex environment condition of intracranial tortuous blood vessels; meanwhile, the drug coating firmness and release performance can be achieved at the same time, and neurotoxic complications caused by drug falling during in vitro, delivery and expansion are avoided.

Description

Technical Field

[0001] The present invention belongs to the technical field of medical devices, and particularly relates to an intracranial drug balloon catheter and a preparation method thereof. Background Art

[0002] Intracranial artery stenosis refers to the narrowing of the diameter of intracranial blood vessels caused by various reasons. The most common cause is intracranial atherosclerotic disease (ICAD), and intracranial atherosclerotic stenosis (ICAS) is one of the main causes of stroke globally. ICAD and ICAS are basically equivalent.

[0003] After the appearance of intracranial artery stenosis, the primary manifestation is the reduction of the arterial diameter, which affects hemodynamics and may lead to a decrease in cerebral blood supply. At the same time, the plaque causing the stenosis itself may be unstable and fall off, resulting in occlusion of distal intracranial blood vessels or thrombosis and occlusion of blood vessels, leading to stroke. The recurrence rate of cerebral ischemia and death in stroke patients with ICAS is higher than that of patients without ICAS.

[0004] Currently, the treatment methods for intracranial artery stenosis mainly include drug and surgical treatments. Among the surgical interventional interventions, there are mainly balloon angioplasty PTA (such as gateway balloon), balloon-expandable stent (such as Wingspan stent), self-expanding stent, catheter-released stent, and drug-eluting stent.

[0005] However, in the interventional treatment of intracranial artery stenosis, there are many limiting factors. For example, 2 minutes of intracranial balloon occlusion is the critical value; local dilation may cause apoptosis of surrounding nerves and distal detachment; the intracranial blood vessels are tortuous and complex, and there are many vascular positions with extremely demanding requirements for the passage and tracking of treatment devices.

[0006] Currently, among the treatment devices for intracranial artery stenosis, the existing bare balloons and stents have differences in compressive resistance, wall adhesion, and restenosis rate. Among them, the bare balloon is simple to operate, does not require stent implantation, and is safer. The disadvantage is that it cannot achieve rapid release, penetration, and storage of drugs simultaneously in a short time, resulting in a high restenosis rate after surgery. Summary of the Invention

[0007] The purpose of the present invention is to provide an intracranial drug balloon catheter and a preparation method thereof. The intracranial drug balloon catheter provided by the present invention can complete the operations of drug release, penetration, and storage within 90 seconds after the balloon catheter adheres to the wall, achieving the technical effects of effectively and persistently inhibiting intimal hyperplasia and reducing the restenosis rate.

[0008] To achieve the above purpose, the present invention provides the following technical solutions:

[0009] The present invention provides a preparation method of an intracranial drug balloon catheter, comprising the following steps:

[0010] The first carrier gas and the second carrier gas are respectively introduced into a saturated salt solution for treatment to obtain a first carrier gas with a first relative humidity and a second carrier gas with a second relative humidity;

[0011] The first carrier gas with the first relative humidity is used to spray a first drug solution on the surface of the balloon catheter for the first time and then dried to form a basal drug coating on the surface of the balloon catheter; the first drug solution includes an active drug, a drug carrier, and a polar solvent; the active drug in the basal drug coating is in an amorphous state, and the first relative humidity is the relative humidity capable of making the active drug form an amorphous state;

[0012] The second carrier gas with the second relative humidity is used to spray a second drug solution on the surface of the basal drug coating for the second time and then dried to form a surface drug coating on the surface of the basal drug coating, obtaining an intracranial drug balloon catheter; the second drug solution includes an active drug, a drug carrier, and a polar solvent; the active drug in the surface drug coating is in a crystalline state, and the second relative humidity is the relative humidity capable of making the active drug form a crystalline state.

[0013] Preferably, the saturated salt solution is in a supersaturated state, and the saturated salt solution is one or more of magnesium chloride salt solution, sodium bromide salt solution, potassium iodide salt solution, sodium chloride salt solution, potassium chloride salt solution, and potassium sulfate salt solution.

[0014] Preferably, the active drugs in the first drug solution and the second drug solution include any one or more of paclitaxel and its derivatives, sirolimus and its derivatives, and anticoagulant drugs.

[0015] Preferably, the first relative humidity is 25-28%, and the second relative humidity is 30-40%.

[0016] Preferably, the drug carriers in the first drug solution and the second drug solution include one or more of polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, nicotinamide, poloxamer, and fat-soluble compounds.

[0017] Preferably, the fat-soluble compound includes dibutylhydroxytoluene and / or butylhydroxyanisole.

[0018] Preferably, the mass ratio of the drug carrier to the active drug in the first drug solution and the second drug solution is independently (0.001-0.08):1.

[0019] Preferably, the working parameters of the first spraying include: the temperature of the first carrier gas is 35 - 40°C, the flow rate of the first carrier gas is 1 - 1.25 L / min, the flow rate of the drug solution is 0.05 - 0.06 mL / min, the rotation speed of the balloon catheter is 1.5 - 2 r / s, and the moving speed of the nozzle is 5 - 7 mm / s;

[0020] The working parameters of the second spraying include: the temperature of the second carrier gas is 35 - 40°C, the flow rate of the second carrier gas is 1 - 1.25 L / min, the flow rate of the drug solution is 0.05 - 0.06 mL / min, the rotation speed of the balloon catheter is 1.5 - 2 r / s, and the moving speed of the nozzle is 5 - 7 mm / s.

[0021] The present invention provides an intracranial drug balloon catheter prepared by the preparation method according to the above technical solution, including a balloon catheter, a base drug coating covering the surface of the balloon catheter, and a surface drug coating covering the base drug coating; the active drug in the base drug coating is in an amorphous state, and the active drug in the surface drug coating is in a crystalline state.

[0022] Preferably, the mass ratio of the base drug coating to the surface drug coating is (0.01 - 2):1.

[0023] The invention provides a method for preparing an intracranial drug balloon catheter, comprising the following steps: respectively passing a first carrier gas and a second carrier gas into a saturated salt solution for treatment to obtain a first carrier gas with a first relative humidity and a second carrier gas with a second relative humidity; first spraying a first drug solution on the surface of a balloon catheter with the first carrier gas with the first relative humidity and then drying the first carrier gas, so as to form a base drug coating on the surface of the balloon catheter; the first drug solution comprises an active drug, a drug carrier and a polar solvent; the active drug in the base drug coating is in an amorphous state, and the first relative humidity is a relative humidity that can cause the active drug to form an amorphous state; second spraying a second drug solution on the surface of the base drug coating with a second carrier gas with a second relative humidity and then drying the second carrier gas, so as to form a surface drug coating on the surface of the base drug coating, so as to obtain an intracranial drug balloon catheter; the second drug solution comprises an active drug, a drug carrier and a polar solvent; the active drug in the surface drug coating is in a crystalline state, and the second relative humidity is a relative humidity that can cause the active drug to form a crystalline state. The preparation method provided by the present invention adopts a double spraying method, and by controlling the humidity of the carrier gas during the double spraying, a drug coating combining an amorphous drug coating and a crystalline drug coating is formed on the surface of the balloon catheter, wherein the amorphous drug coating is conducive to improving the ability of the drug coating to combine with the balloon catheter, thereby improving the firmness of the drug coating on the surface of the balloon catheter, and at the same time, the amorphous drug coating can be quickly released and penetrated after the balloon catheter adheres to the wall, thereby driving the surface crystalline drug to be released from the balloon catheter surface and penetrate into the blood vessel. At this time, the crystalline drug is more stable than the amorphous drug structure, because the crystalline drug can be realized in the blood vessel. The preparation method provided by the present invention realizes the coexistence of amorphous and crystalline drug coatings on the surface of the balloon catheter by regulating the spraying operation and the relative humidity of the carrier, and can complete the release, penetration and storage operations of the drug within 90 seconds after the balloon catheter is attached to the wall; thereby achieving the technical effects of effectively and lastingly inhibiting intimal hyperplasia and reducing the restenosis rate, and has excellent permeability and tracking properties, and can adapt to the complex environment of tortuous intracranial blood vessels; at the same time, the present invention can have both the firmness and release performance of the drug coating, avoiding the shedding of the drug in vitro, during transportation and during expansion, and causing neurotoxic complications.

[0024] Further, in the present invention, the drug carriers in the first drug solution and the second drug solution include one or more of polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, nicotinamide, poloxamer and fat-soluble compounds. The present invention preferably selects the above drug carriers to help form an amorphous drug coating and a crystalline drug coating when the relative humidity conditions of the carrier are suitable, thereby achieving rapid release, penetration and storage operation of the drug coating; thereby achieving effective and lasting technical effects of inhibiting intimal hyperplasia and reducing restenosis rate.

[0025] Further, in the present invention, the mass ratio of the drug carrier to the active drug in the first drug solution and the second drug solution is independently (0.001 - 0.08):1. The present invention preferably regulates the mass ratio relationship between the drug carrier and the active drug, which helps to form an amorphous drug coating and a crystalline drug coating when the relative humidity condition of the carrier is appropriate, so as to realize the rapid release, penetration and storage operation behaviors of the drug coating; and further achieve the technical effects of effectively and durably inhibiting intimal hyperplasia and reducing the restenosis rate.

[0026] Further, in the present invention, the working parameters of the first spraying include: the temperature of the first carrier gas is 35 - 40°C, the flow rate of the first carrier gas is 1 - 1.25 L / min, the flow rate of the drug solution is 0.05 - 0.06 mL / min, the rotation speed of the balloon catheter is 1.5 - 2 r / s, and the moving speed of the nozzle is 5 - 7 mm / s; the working parameters of the second spraying include: the temperature of the second carrier gas is 35 - 40°C, the flow rate of the second carrier gas is 1 - 1.25 L / min, the flow rate of the drug solution is 0.05 - 0.06 mL / min, the rotation speed of the balloon catheter is 1.5 - 2 r / s, and the moving speed of the nozzle is 5 - 7 mm / s. By regulating the working parameters of the two sprayings, the present invention can regulate the mass ratio relationship between the amorphous drug coating and the crystalline drug coating, and realize the coordination of the rapid release, penetration and storage of the drug coating; making the intracranial drug balloon catheter provided by the present invention have excellent passability and trackability, and can adapt to the complex environment of intracranial tortuous blood vessels. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 It is a schematic diagram of the device for the spraying operation in the embodiment of the present invention;

[0028] Figure 2 It is a schematic diagram of the spraying path in the embodiment of the present invention;

[0029] Figure 3 It is a scanning electron micrograph of the base drug coating in Example 1 of the present invention;

[0030] Figure 4 It is an electron micrograph of the two-layer drug coating prepared in Example 1 of the present invention;

[0031] In the figure, 1 is the nozzle bracket, 2 is the nozzle, 3 is the balloon catheter, and 4 is the balloon catheter rotation axis. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0032] The present invention provides a preparation method of an intracranial drug balloon catheter, comprising the following steps:

[0033] The first carrier gas and the second carrier gas are respectively introduced into a saturated salt solution for treatment to obtain a first carrier gas with a first relative humidity and a second carrier gas with a second relative humidity;

[0034] The first carrier gas with the first relative humidity is used to spray a first drug solution on the surface of the balloon catheter for the first time and then dried to form a base drug coating on the surface of the balloon catheter; the first drug solution includes an active drug, a drug carrier, and a polar solvent; the active drug in the base drug coating is in an amorphous state, and the first relative humidity is the relative humidity capable of making the active drug form an amorphous state;

[0035] The second carrier gas with the second relative humidity is used to spray a second drug solution on the surface of the base drug coating for the second time and then dried to form a surface drug coating on the surface of the base drug coating, obtaining an intracranial drug balloon catheter; the second drug solution includes an active drug, a drug carrier, and a polar solvent; the active drug in the surface drug coating is in a crystalline state, and the second relative humidity is the relative humidity capable of making the active drug form a crystalline state.

[0036] In the present invention, unless otherwise specified, all preparation raw materials / components are commercially available products well-known to those skilled in the art.

[0037] In the present invention, the first carrier gas and the second carrier gas are respectively introduced into a saturated salt solution for treatment to obtain a first carrier gas with a first relative humidity and a second carrier gas with a second relative humidity.

[0038] In the present invention, the first carrier is preferably nitrogen. In the present invention, the first relative humidity is the relative humidity capable of making the active drug form an amorphous state. In a specific embodiment of the present invention, the present invention preferably regulates the relative humidity of the first carrier gas through a saturated salt solution. The present invention preferably introduces the initial first carrier gas into the saturated salt solution and collects the first carrier gas overflowing from the saturated salt solution to obtain the first carrier gas with the first relative humidity. In the present invention, the saturated salt solution is preferably in a supersaturated state, and the supersaturated state means that there is salt precipitation at the bottom of the saturated salt solution. The saturated salt solution is preferably one or more of a saturated salt solution of magnesium chloride, a saturated salt solution of sodium bromide, a saturated salt solution of potassium iodide, a saturated salt solution of sodium chloride, a saturated salt solution of potassium chloride, and a saturated salt solution of potassium sulfate. The temperature of the saturated salt solution is preferably 25°C.

[0039] In a specific embodiment of the present invention, the first carrier gas with the first relative humidity is preferably obtained in a carrier gas humidity regulation system, and the carrier gas humidity regulation system preferably includes a saturated salt solution. In the present invention, the carrier gas humidity regulation system is preferably a closed-loop system, the carrier gas humidity regulation system preferably has a feedback loop, and the carrier gas humidity regulation system preferably selects different types of saturated salt solutions for regulating the first relative humidity state of the first carrier gas according to the first relative humidity value in the feedback.

[0040] In the present invention, when the active drug is sirolimus or paclitaxel, the first relative humidity is preferably 25-28%, and it can be 28% in the examples.

[0041] In a specific embodiment of the present invention, the second carrier is specifically preferably nitrogen. In the present invention, the second relative humidity is the relative humidity that can make the active drug form a crystalline state. In a specific embodiment of the present invention, the present invention preferably regulates the relative humidity of the second carrier gas through a saturated salt solution. The present invention preferably passes the initial second carrier gas into the saturated salt solution and collects the second carrier gas overflowing from the saturated salt solution to obtain the second carrier gas with the second relative humidity. In the present invention, the saturated salt solution is preferably in a supersaturated state, and the saturated salt solution is preferably one or more of a saturated salt solution of magnesium chloride, a saturated salt solution of sodium bromide, a saturated salt solution of potassium iodide, a saturated salt solution of sodium chloride, a saturated salt solution of potassium chloride, and a saturated salt solution of potassium sulfate. The temperature of the saturated salt solution is preferably 25°C.

[0042] In a specific embodiment of the present invention, the second carrier gas with the second relative humidity is preferably obtained in a carrier gas humidity regulation system, and the carrier gas humidity regulation system preferably includes a saturated salt solution. In the present invention, the carrier gas humidity regulation system is preferably a closed-loop system, the carrier gas humidity regulation system preferably has a feedback loop, and the carrier gas humidity regulation system preferably selects different types of saturated salt solutions for regulating the second relative humidity state of the second carrier gas according to the second relative humidity value in the feedback.

[0043] In the present invention, the crystal morphology in the drug coating has an important influence on the drug release effect. An ideal crystal morphology can help the drug release quickly and can also have a certain sustained-release effect after adsorbing to the blood vessel wall. However, during the production process, the crystal morphology is very difficult to control and is greatly affected by the environmental temperature and humidity. The main manifestations are whether the drug crystallizes, whether the crystal size is stable, whether the crystal sizes in all directions on the balloon surface are consistent, and whether large agglomerated particles are formed. Among them, temperature and humidity are the most difficult to control, and if the factory humidity is controlled and adjusted, the control cost will be greatly increased.

[0044] The applicant's previously published Chinese patents include: Patent Application No. CN201410673301.0, Publication No. CN104353132B, titled "Coating Process for Drug Coating on Implanted or Interventional Medical Devices"; Patent Application No. CN201410659293.4, Publication No. CN104324421B, titled "Preparation Method for Drug Coating of Therapeutic Balloon Dilatation Catheter". The content of the above two Chinese patents both involves introducing auxiliary solvent gas into the carrier gas, such as passing the carrier gas into water or a mixed solution of water and organic solvent, to help the drug precipitate in the form of fine particles. However, the humidity of saturated water vapor is relatively high, the crystals are small and dense, and it is difficult to achieve the ideal crystal size. At a certain temperature, different saturated salt solutions can provide a stable relative humidity (Table 1). In the present invention, the carrier gas (nitrogen) is passed through a specified saturated salt solution at a certain temperature (such as 25°C) to control the water content in the carrier gas, adjust the crystallization behavior of the crystals, and thus control the crystal size of the drug in the coating.

[0045] Table 1 Equilibrium relative humidity values of saturated salt water solutions at room temperature (25°C)

[0046] Component Relative humidity % Magnesium chloride 32.8±0.2 Sodium bromide 57.6±0.4 Potassium iodide 68.9±0.3 Sodium chloride 75.3±0.2 Potassium chloride 84.2±0.3 Potassium sulfate 97.3±0.5

[0047] In the present invention, the saturated salt solution used to treat the first carrier gas is the first saturated salt solution, and the saturated salt solution used to treat the second carrier gas is the second saturated salt solution; the first saturated salt solution and the second saturated salt solution are different; for example, the first saturated salt solution is a saturated magnesium chloride salt solution, and the second saturated salt solution is a saturated potassium chloride salt solution; for example, the first saturated salt solution is a saturated magnesium chloride salt solution, and the second saturated salt solution is a supersaturated sodium chloride salt solution. Using this combined saturated salt solution is beneficial to improving the interfacial transition between coatings and suppressing the influence of the surface drug coating on the substrate drug coating.

[0048] In the present invention, when the active drug is sirolimus or paclitaxel, the second relative humidity is preferably 30-40%, and in the examples, it can be 32% or 40%.

[0049] After obtaining the first carrier gas with the first relative humidity, the present invention uses the first carrier gas with the first relative humidity to spray a first drug solution on the surface of the balloon catheter for the first time and then dry it (hereinafter referred to as the first drying), to form a substrate drug coating on the surface of the balloon catheter; the first drug solution includes an active drug, a drug carrier, and a polar solvent; the active drug in the substrate drug coating is in an amorphous state, and the first relative humidity is the relative humidity that can make the active drug form an amorphous state.

[0050] In the present invention, the diameter of the balloon catheter is preferably 5 mm, and the length of the balloon catheter is preferably 30 mm.

[0051] In the present invention, the first drug solution comprises an active drug, a drug carrier and a polar solvent.

[0052] In the present invention, the active drug in the first drug solution preferably comprises a drug for treating vascular intimal hyperplasia, more preferably any one or more of paclitaxel and its derivatives, sirolimus and its derivatives, and anticoagulant drugs. In a specific embodiment of the present invention, the active drug in the first drug solution is sirolimus or paclitaxel.

[0053] In the present invention, the drug carrier in the first drug solution preferably comprises one or more of polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), nicotinamide, poloxamer and fat-soluble compounds, more preferably a fat-soluble compound. In the present invention, the fat-soluble compound is preferably a small molecule fat-soluble compound. The fat-soluble compound preferably comprises butylated hydroxytoluene (BHT) and / or butyl hydroxyanisole (BHA).

[0054] In the present invention, the polar solvent in the first drug solution preferably comprises water and a polar organic solvent, and the polar organic solvent comprises one or more of ethanol, methanol, n-hexane, isopropanol, acetone and acetonitrile.

[0055] In an embodiment of the present invention, the volume ratio of the water to the polar organic solvent is preferably (1 to 10):(1 to 10), and may be 1:1 in the embodiment.

[0056] In the present invention, the mass ratio of the drug carrier to the active drug in the first drug solution is preferably (0.001 to 0.08):1, more preferably (0.002 to 0.06):1, and further preferably (0.005 to 0.05):1.

[0057] In the present invention, the mass percentage content of the active drug in the first drug solution is preferably 25 to 40 mg / mL, and may be 25 mg / mL or 40 mg / mL in the embodiment.

[0058] In the present invention, the working parameters of the first spraying preferably include: the temperature of the first carrier gas is preferably 35 to 40 °C, the flow rate of the first carrier gas is preferably 1 to 1.25 L / min, the flow rate of the drug solution is preferably 0.05 to 0.06 mL / min, the rotational speed of the balloon catheter is preferably 1.5 to 2.0 r / s, and the moving speed of the nozzle is preferably 5 to 7 mm / s. In the present invention, the temperature of the first carrier gas is preferably the temperature before passing through the saturated salt solution.

[0059] In the present invention, the trajectory of the first spraying is preferably a spiral (i.e., the first spraying is preferably spiral spraying).

[0060] In the present invention, the first spraying is preferably carried out in an ultrasonic spraying device.

[0061] In the present invention, the temperature of the first drying is preferably room temperature, and the time of the first drying is preferably 5 - 30 min.

[0062] After obtaining the substrate drug coating, in the present invention, a second carrier gas with a second relative humidity is used to second-spray a second drug solution on the surface of the substrate drug coating and then dry it (hereinafter referred to as the second drying), so as to form a surface drug coating on the surface of the substrate drug coating, and an intracranial drug balloon catheter is obtained; the second drug solution includes an active drug, a drug carrier, and a polar solvent; the active drug in the surface drug coating is in a crystalline state, and the second relative humidity is a relative humidity capable of making the active drug form a crystalline state.

[0063] In the present invention, the second drug solution includes an active drug, a drug carrier, and a polar solvent.

[0064] In the present invention, the active drug in the second drug solution preferably includes a drug for treating vascular intimal hyperplasia, more preferably includes any one or more of paclitaxel and its derivatives, sirolimus and its derivatives, and anticoagulant drugs. In a specific embodiment of the present invention, the active drug in the second drug solution is sirolimus or paclitaxel.

[0065] In the present invention, the drug carrier in the second drug solution preferably includes one or more of polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), nicotinamide, poloxamer, and fat-soluble compounds, more preferably includes fat-soluble compounds. In the present invention, the fat-soluble compound is preferably a small molecule fat-soluble compound. The fat-soluble compound preferably includes butylated hydroxytoluene (BHT) and / or butylhydroxyanisole (BHA).

[0066] In the present invention, the polar solvent in the second drug solution preferably includes water and polar organic solvents, and the polar organic solvents include one or more of ethanol, methanol, n-hexane, isopropanol, acetone, and acetonitrile.

[0067] In an embodiment of the present invention, the volume ratio of the water to the polar organic solvent is preferably (1 - 10):(1 - 10), and it can be 1:1 in the embodiment.

[0068] In the present invention, the mass ratio of the drug carrier to the active drug in the second drug solution is preferably (0.001 - 0.08):1, more preferably (0.002 - 0.06):1, and further preferably (0.005 - 0.05):1.

[0069] In the present invention, the mass percentage content of the active drug in the second drug solution is preferably 25 to 40 mg / mL.

[0070] In the present invention, the working parameters of the second spraying preferably include: the temperature of the second carrier gas is preferably 40°C, the flow rate of the second carrier gas is preferably 1 to 1.25 L / min, the flow rate of the drug solution is preferably 0.05 to 0.06 mL / min, the rotation speed of the balloon catheter is preferably 1.5 to 2.0 r / s, and the moving speed of the nozzle is preferably 5 to 7 mm / s. In the present invention, the temperature of the second carrier gas is preferably the temperature before passing through the saturated salt solution.

[0071] In the present invention, the trajectory of the second spraying is preferably a helix (i.e., the second spraying is preferably spiral spraying).

[0072] In the present invention, the second spraying is preferably carried out in an ultrasonic spraying device.

[0073] In the present invention, the temperature of the second drying is preferably room temperature, and the time of the second drying is preferably 5 to 30 min.

[0074] The present invention provides an intracranial drug balloon catheter prepared by the preparation method described in the above technical solution, including a balloon catheter, a base drug coating covering the surface of the balloon catheter, and a surface drug coating covering the base drug coating; the active drug in the base drug coating is in an amorphous state, and the active drug in the surface drug coating is in a crystalline state.

[0075] In the present invention, the mass ratio of the base drug coating to the surface drug coating is (0.01 to 2):1.

[0076] In the present invention, in the surface drug coating, the crystal particle size of the active drug is preferably 100 nm to 5 μm.

[0077] The intracranial drug balloon catheter provided by the present invention is preferably applied to the treatment of intracranial artery stenosis.

[0078] Under the conditions of having both the firmness and release performance of the drug coating, the present invention realizes the release, penetration, and storage operation behaviors of the drug within 90 s after the balloon adheres to the wall by adding a drug carrier (liposoluble compound) to the drug solution and controlling the mass ratio and two-layer distribution mode of the amorphous state and the crystalline state in the drug coating; thereby achieving the expected effect of effectively and durably inhibiting intimal hyperplasia and reducing the restenosis rate.

[0079] The present invention further controls the ratio, distribution pattern, and crystal size of the amorphous state and crystalline state in the drug coating by adjusting the temperature and relative humidity of the carrier gas in the ultrasonic spraying process, enabling the intracranial drug - loaded balloon catheter of the present invention to have excellent passability and trackability and adapt to the complex environment of tortuous intracranial blood vessels.

[0080] To further illustrate the present invention, the technical solutions provided by the present invention will be described in detail below in conjunction with the accompanying drawings and embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0081] Example 1

[0082] Prepare the drug solution for spraying: Mix butylated hydroxytoluene (BHT), sirolimus, water, and ethanol (the volume ratio of water to ethanol is 1:1) to prepare a liquid medicine; the mass ratio of BHT to sirolimus is 0.05:1; the mass percentage content of sirolimus in the drug solution is 40 mg / mL. Place the above - mentioned solution in an oven and heat it at 50°C until the drug is completely dissolved (shake it an appropriate number of times during the dissolution process to accelerate dissolution) until the liquid medicine is clear and transparent;

[0083] Set the temperature of the carrier gas (nitrogen) to 40°C, pass the carrier gas (nitrogen) into a saturated salt solution of magnesium chloride, and collect the nitrogen overflowing from the saturated salt solution of magnesium chloride to obtain nitrogen with a relative humidity of 28%;

[0084] Take 10 intracranial balloon catheters with a balloon diameter of 5 mm and a balloon length of 30 mm; install the balloon catheter to be sprayed on the spraying machine, close the protective cover of the spraying machine, start the ultrasonic spraying program, control the flow rate of the carrier gas with a relative humidity of 28% to be 1.4 L / min, and then connect it to the carrier gas channel of the ultrasonic nozzle; load the prepared clear drug solution into the ultrasonic spraying device, and set the spraying parameters: the spraying trajectory is spiral spraying, the moving speed of the nozzle is 7 mm / s, the flow rate of the drug solution injected by the injection pump is 0.06 mL / min, the balloon rotation speed is 2.0 r / s, and spray from the proximal end to the distal end of the balloon; dry at room temperature for 10 min to form a base drug coating on the surface of the balloon catheter (as Figure 3 shown), and the sirolimus in the base drug coating is in an amorphous state;

[0085] Set the temperature of the carrier gas (nitrogen) to 40°C, pass the carrier gas (nitrogen) into a saturated salt solution of potassium chloride, collect the nitrogen gas overflowing from the saturated salt solution of potassium chloride, and obtain nitrogen gas with a relative humidity of 40%; close the protective cover of the spraying machine, start the ultrasonic spraying program, control the flow rate of the carrier gas with a relative humidity of 40% to be 1.25 L / min, and then connect it to the carrier gas channel of the ultrasonic nozzle; load the prepared clear drug solution into the ultrasonic spraying equipment, and set the spraying parameters: the spraying trajectory is spiral spraying, the moving speed of the nozzle is 7 mm / s, the flow rate of the drug solution delivered by the injection pump is 0.06 mL / min, the rotation speed of the balloon is 2.0 r / s, spray from the proximal end to the distal end of the balloon, and dry at room temperature for 10 min to form a surface drug coating on the surface of the base drug coating (as Figure 4 shown); the sirolimus in the surface drug coating is in a crystalline state;

[0086] After folding and winding all the drug balloons, put on the protective sleeve.

[0087] Comparative Example 1

[0088] Prepare the drug solution for spraying: Mix butylated hydroxytoluene (BHT), sirolimus drug, water, and ethanol (the volume ratio of water to ethanol is 1:1) to prepare a drug solution; the mass ratio of BHT to sirolimus is 0.05:1; the mass percentage content of sirolimus in the drug solution is 40 mg / mL. Place the above solution in an oven and heat it at 50°C until the drug is completely dissolved (shake it appropriately during the dissolution process to accelerate dissolution) until the drug solution is clear and transparent;

[0089] Set the temperature of the carrier gas (nitrogen) to 40°C, pass the carrier gas (nitrogen) into a saturated magnesium chloride salt solution (temperature 25°C), collect the nitrogen gas overflowing from the saturated salt solution, and obtain nitrogen gas with a relative humidity of 28%;

[0090] Take 10 intracranial balloon catheters with a balloon diameter of 5 mm and a balloon length of 30 mm; install the balloon catheter to be sprayed on the spraying machine, close the protective cover of the spraying machine, start the ultrasonic spraying program, control the flow rate of the carrier gas with a relative humidity of 28% to be 1.4 L / min, and then connect it to the carrier gas channel of the ultrasonic nozzle; load the prepared clear drug solution into the ultrasonic spraying equipment, and set the spraying parameters: the moving speed of the nozzle is 9 mm / s, the flow rate of the drug solution injected by the injection pump is 0.06 mL / min, the rotation speed of the balloon is 2.0 r / s, repeat from the proximal end to the distal end of the balloon; dry at room temperature for 10 min to form a base drug coating on the surface of the balloon catheter. After folding and winding all the drug balloons, put on the protective sleeve.

[0091] Comparative Example 2

[0092] Prepare the drug solution for spraying: Mix dibutylhydroxytoluene (BHT), sirolimus drug, water, and ethanol to prepare the liquid medicine; the mass ratio of BHT to sirolimus is 0.05:1; the mass percentage content of sirolimus in the drug solution is 40 mg / mL. Place the above solution in an oven and heat it at 50 °C until the drug is completely dissolved (shake it an appropriate number of times during the dissolution process to accelerate dissolution) until the liquid medicine is clear and transparent;

[0093] Set the temperature of the carrier gas (nitrogen) to 40 °C, pass the carrier gas (nitrogen) into a saturated potassium chloride salt solution (temperature 25 °C), and collect the nitrogen gas overflowing from the saturated salt solution to obtain nitrogen gas with a relative humidity of 40%;

[0094] Take 10 intracranial balloon catheters with a balloon diameter of 5 mm and a balloon length of 30 mm; install the balloon catheter to be sprayed on the spraying machine, close the protective cover of the spraying machine, start the ultrasonic spraying program, control the flow rate of the carrier gas with a relative humidity of 40% to be 1.4 L / min, and then connect it to the carrier gas channel of the ultrasonic nozzle; load the prepared clear drug solution into the ultrasonic spraying equipment, and set the spraying parameters: the moving speed of the nozzle is 7 mm / s, the flow rate of the drug solution delivered by the injection pump is 6 mL / min, the rotation speed of the balloon is 2.0 r / s, and dry it at room temperature for 10 min to form a surface drug coating on the surface of the balloon catheter;

[0095] After folding and winding all the drug balloons, put on the protective sleeve.

[0096] Test Example 1

[0097] Test the firmness of the drug coatings prepared in Test Example 1 and Comparative Examples 1 and 2

[0098] The test method is as follows: Place the test model in a constant temperature water bath at 37 ± 2 °C, push the guiding catheter to the designated part of the catheter of the test model. Then push the guide wire until it passes through the test model. Push the drug-loaded balloon in the negative pressure state along the guide wire out of the test model for an in vitro simulation delivery experiment, put the balloon protruding from the test model into a test tube for elution, collect the residual drug on the balloon surface, and use HPLC to test the concentration of the collected liquid, and calculate the coating firmness according to Equation 1.

[0099] Coating firmness (%) = 1 - (residual drug content on the balloon surface / original drug content on the balloon surface) Equation 1.

[0100] Test Example 2

[0101] Test the in vitro release rate of the drug coatings prepared in Test Example 1 and Comparative Examples 1 and 2

[0102] An in vitro simulation experiment was carried out using the drug-loaded balloons prepared in Example 1 and Comparative Examples 1 and 2. After the balloon was expanded to the nominal diameter and depressurized in vitro, the drug content in the vascular model system was measured and calculated according to Equation 2.

[0103] In vitro drug release rate (%) = drug content in the vascular model system / original drug content on the balloon surface Equation 2.

[0104] Test Example 3

[0105] Test on the release microparticles of the drug coatings prepared in Test Example 1 and Comparative Examples 1 and 2

[0106] An in vitro simulation experiment was carried out using the prepared drug-loaded balloon, and the number of microparticles in the vascular model after the product was inserted, delivered, expanded, depressurized, and withdrawn through the vascular model was collected. The particle size ranges collected were 2 - 5 μm, 5 - 10 μm, and ≥ 10 μm, respectively.

[0107] The test results of Test Examples 1 - 3 are shown in Table 2, and the proportion of released microparticles in Table 2 is the proportion of the number.

[0108] Table 2 Test results of the performance of the drug coatings prepared in Example 1 and Comparative Examples 1 and 2

[0109]

[0110]

[0111] Example 2

[0112] Prepare the drug solution for spraying: Mix butylated hydroxytoluene (BHT), paclitaxel, and ethanol to prepare the drug solution; the mass ratio of BHT to paclitaxel is 0.05:1; the mass content of paclitaxel in the drug solution is 40 mg / mL. Place the above solution in an oven and heat it at 50 °C until the drug is completely dissolved (shake it an appropriate number of times during the dissolution process to accelerate dissolution) until the drug solution is clear and transparent;

[0113] Set the temperature of the carrier gas (nitrogen) to 40 °C, pass the carrier gas (nitrogen) into the saturated salt solution of magnesium chloride (temperature 25 °C), and collect the nitrogen overflowing from the saturated salt solution of magnesium chloride to obtain nitrogen with a relative humidity of 28%;

[0114] Take 10 intracranial balloon catheters with a balloon diameter of 5 mm and a balloon length of 30 mm; install the balloon catheter to be sprayed on the spraying machine, close the protective cover of the spraying machine, start the ultrasonic spraying program, control the carrier gas flow rate with a relative humidity of 28% to be 1.4 L / min, and then connect it to the carrier gas channel of the ultrasonic nozzle; load the prepared clear drug solution into the ultrasonic spraying equipment, and set the spraying parameters: the spraying trajectory is spiral spraying, the moving speed of the nozzle is 9 mm / s, the flow rate of the drug solution injected by the injection pump is 0.06 mL / min, the balloon rotation speed is 2.0 r / s, and spray repeatedly from the proximal end to the distal end of the balloon; dry at room temperature for 20 min to form a basal drug coating on the surface of the balloon catheter, and the paclitaxel in the basal drug coating is in an amorphous state;

[0115] Set the temperature of the carrier gas (nitrogen) to 40 °C, pass the carrier gas (nitrogen) into the saturated salt solution of sodium chloride (temperature 25 °C), collect the nitrogen overflowing from the saturated salt solution of sodium chloride to obtain nitrogen with a relative humidity of 32%; close the protective cover of the spraying machine, start the ultrasonic spraying program, control the carrier gas flow rate with a relative humidity of 32% to be 1.4 L / min, and then connect it to the carrier gas channel of the ultrasonic nozzle; the spraying trajectory is spiral spraying, load the prepared clear drug solution into the ultrasonic spraying equipment, and set the spraying parameters: the moving speed of the nozzle is 7 mm / s, the flow rate of the drug solution transported by the injection pump is 6 mL / min, the balloon rotation speed is 2.0 r / s, spray from the proximal end to the distal end of the balloon, and dry at room temperature for 20 min to form a surface drug coating on the surface of the basal drug coating; the paclitaxel in the surface drug coating is in a crystalline state;

[0116] After folding and winding all the drug balloons, put on the protective sleeve.

[0117] Observe the crystal morphology

[0118] Observe the crystal morphology on the surface of the balloon under an optical microscope and an electron scanning microscope. In the SEM photo at 5K magnification, use Image J software to assist in measuring the crystal length, which is 5 ± 3 μm (n = 30).

[0119] In vitro release rate test

[0120] Conduct an in vitro simulation experiment with the drug-loaded balloon prepared in Example 2, perform transportation, dilation, and retraction in the simulation pipeline, and then collect the drug in the pipeline and the drug remaining on the surface of the balloon with a certain volume of methanol respectively, test the concentration of the collected solution by HPLC, and calculate the in vitro drug release rate to be 71% ± 7% (n = 3).

[0121] Example 3

[0122] Prepare the drug solution for spraying: Mix dibutylhydroxytoluene (BHT), paclitaxel, and ethanol to prepare the liquid medicine; the mass ratio of BHT to paclitaxel is 0.05:1; the mass content of paclitaxel in the drug solution is 25 mg / mL. Place the above solution in an oven and heat it at 50 °C until the drug is completely dissolved (shake it an appropriate number of times during the dissolution process to accelerate dissolution) until the liquid medicine is clear and transparent;

[0123] Set the temperature of the carrier gas (nitrogen) to 40 °C, pass the carrier gas (nitrogen) into the saturated salt solution of magnesium chloride (temperature 25 °C), collect the nitrogen overflowing from the saturated salt solution of magnesium chloride, and obtain nitrogen with a relative humidity of 28%;

[0124] Take 10 intracranial balloon catheters with a balloon diameter of 5 mm and a balloon length of 30 mm; install the balloon catheter to be sprayed on the spraying machine, close the protective cover of the spraying machine, start the ultrasonic spraying program, control the flow rate of the carrier gas with a relative humidity of 28% to be 1.4 L / min, and then connect it to the carrier gas channel of the ultrasonic nozzle; load the prepared clear drug solution into the ultrasonic spraying equipment, and set the spraying parameters: the spraying trajectory is spiral spraying, the moving speed of the nozzle is 9 mm / s, the flow rate of the drug solution injected by the injection pump is 0.06 mL / min, the balloon rotation speed is 2.0 r / s, and spray repeatedly 2 times from the proximal end to the distal end of the balloon; dry at room temperature for 20 min to form a basal drug coating on the surface of the balloon catheter, and the paclitaxel in the basal drug coating is in an amorphous state;

[0125] Set the temperature of the carrier gas (nitrogen) to 40 °C, pass the carrier gas (nitrogen) into the saturated salt solution of sodium chloride (temperature 25 °C), collect the nitrogen overflowing from the saturated salt solution of sodium chloride, and obtain nitrogen with a relative humidity of 32%; close the protective cover of the spraying machine, start the ultrasonic spraying program, control the flow rate of the carrier gas with a relative humidity of 32% to be 1.4 L / min, and then connect it to the carrier gas channel of the ultrasonic nozzle; the spraying trajectory is spiral spraying, load the prepared clear drug solution into the ultrasonic spraying equipment, and set the spraying parameters: the moving speed of the nozzle is 7 mm / s, the flow rate of the drug solution transported by the injection pump is 6 mL / min, the balloon rotation speed is 2.0 r / s, spray from the proximal end to the distal end of the balloon, and dry at room temperature for 20 min to form a surface drug coating on the surface of the basal drug coating; the paclitaxel in the surface drug coating is in a crystalline state;

[0126] After folding and winding all the drug balloons, put on the protective sleeve.

[0127] Observe the crystal morphology

[0128] Observe the crystal morphology on the surface of the balloon under an optical microscope and an electron scanning microscope. In the 5K-fold SEM photo, use Image J software to assist in measuring the crystal length, which is 15 ± 6 μm (n = 30).

[0129] In vitro release rate test

[0130] An in vitro simulation experiment was carried out using the drug-loaded balloon prepared in Example 3. It was transported, expanded, and withdrawn in a simulated pipeline. After that, drugs in the pipeline and drugs remaining on the surface of the balloon were collected with a certain volume of methanol, the concentration of the collected solution was tested by HPLC, and the in vitro drug release rate was calculated to be 89% ± 5% (n = 3).

[0131] Although the above embodiments have described the present invention in detail, they are only a part of the embodiments of the present invention, not all of them. Other embodiments can be obtained according to these embodiments without creative efforts, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A preparation method of an intracranial drug balloon catheter, characterized in that, It includes the following steps: Respectively introduce the first carrier gas and the second carrier gas into a saturated salt solution for treatment to obtain a first carrier gas with a first relative humidity and a second carrier gas with a second relative humidity; Use the first carrier gas with the first relative humidity to first spray a first drug solution on the surface of the balloon catheter and then dry it to form a base drug coating on the surface of the balloon catheter; The first drug solution includes an active drug, a drug carrier, and a polar solvent; the active drug in the base drug coating is in an amorphous form, and the first relative humidity is the relative humidity capable of making the active drug form an amorphous form; Use the second carrier gas with the second relative humidity to second spray a second drug solution on the surface of the base drug coating and then dry it to form a surface drug coating on the surface of the base drug coating, obtaining an intracranial drug balloon catheter; the second drug solution includes an active drug, a drug carrier, and a polar solvent; the active drug in the surface drug coating is in a crystalline form, and the second relative humidity is the relative humidity capable of making the active drug form a crystalline form.

2. The preparation method according to claim 1, characterized in that The saturated salt solution is in a supersaturated state, and the saturated salt solution is one or more of magnesium chloride salt solution, sodium bromide salt solution, potassium iodide salt solution, sodium chloride salt solution, potassium chloride salt solution, and potassium sulfate salt solution.

3. The preparation method according to claim 1, wherein The active drug in the first drug solution and the second drug solution includes any one or more of paclitaxel and its derivatives, sirolimus and its derivatives, and anticoagulant drugs.

4. The preparation method according to claim 1 or 3, characterized in that, The first relative humidity is 25 - 28%, and the second relative humidity is 30 - 40%.

5. The preparation method according to claim 1, wherein The drug carrier in the first drug solution and the second drug solution includes one or more of polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, nicotinamide, poloxamer, and fat-soluble compounds.

6. The preparation method according to claim 5, characterized in that, The fat-soluble compound includes dibutylhydroxytoluene and / or butylhydroxyanisole.

7. The preparation method according to claim 1 or 5, characterized in that, The mass ratio of the drug carrier to the active drug in the first drug solution and the second drug solution is independently (0.001 - 0.08):

1.

8. The preparation method according to claim 1, wherein, The working parameters of the first spraying include: the temperature of the first carrier gas is 35 - 40°C, the flow rate of the first carrier gas is 1 - 1.25 L / min, the flow rate of the drug solution is 0.05 - 0.06 mL / min, the rotation speed of the balloon catheter is 1.5 - 2 r / s, and the moving speed of the nozzle is 5 - 7 mm / s; The working parameters of the second spraying include: the temperature of the second carrier gas is 35 - 40°C, the flow rate of the second carrier gas is 1 - 1.25 L / min, the flow rate of the drug solution is 0.05 - 0.06 mL / min, the rotation speed of the balloon catheter is 1.5 - 2 r / s, and the moving speed of the nozzle is 5 - 7 mm / s.

9. An intracranial drug balloon catheter prepared by the preparation method according to any one of claims 1 to 8, characterized in that, It includes a balloon catheter, a base drug coating covering the surface of the balloon catheter, and a surface drug coating covering the base drug coating; The active drug in the base drug coating is in an amorphous form, and the active drug in the surface drug coating is in a crystalline form.

10. The drug-loaded balloon catheter according to claim 9, characterized in that, The mass ratio of the base drug coating to the surface drug coating is (0.01 - 2):1.

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