CN1429547A - Coronary artery skeleton medicinal coating for preventing restenosis of blood vessel - Google Patents

Abstract

A coronary stent drug coating for preventing restenosis of blood vessels, which dissolves aliphatic polylactone and its copolymers in a solvent, dissolves evenly, adds paclitaxel to prevent restenosis of blood vessels, stirs, dissolves evenly and filters before using . The drug coating of the coronary stent can be coated on the surface of the coronary stent by a solution prepared by paclitaxel and a drug carrier by a solution spraying method or a solution dipping method. After coating evenly, evaporate the solvent in the air, then desolventize it at room temperature under vacuum for 48 hours, and sterilize it with ethylene oxide before use. The content of paclitaxel in the stent can be controlled by the concentration of paclitaxel, the concentration of the coating solution and the coating times of the coating.

Description

A coronary stent drug coating for preventing vascular restenosis

technical field

The invention relates to a coronary stent drug coating for preventing restenosis of blood vessels, which uses paclitaxel as anti-restenosis drug and biodegradable aliphatic polylactone as drug carrier.

Background technique

The popularization and application of coronary artery balloon angioplasty once brought good news to many patients with coronary heart disease, but the biggest defect of this treatment - restenosis of blood vessels has largely limited its curative effect. At present, the mechanism of vascular restenosis has been elucidated, indicating that the occurrence of vascular restenosis is related to multiple factors such as elastic recoil and thrombus formation in the early stage after surgery, smooth muscle migration and hyperplasia in the middle stage, and vascular remodeling in the late stage. In order to prevent the occurrence of restenosis, a lot of research has been carried out over the years, and treatment methods such as intravascular stents and rotary resection have appeared successively; at the same time, there have been many methods of prevention with drugs, such as the use of platelet GB IIb/IIIa recipients. body antagonists, etc., but so far there is no effective way to inhibit restenosis.

In recent years, clinicians have also tried a variety of methods to prevent vascular restenosis, but the restenosis rate after coronary balloon dilatation is still high, always maintained between 20-30%. In the case of 3mm, the incidence of restenosis is higher, and the incidence of restenosis in some subgroups of patients is as high as 50%, which has become a great limitation and obstacle for the treatment of coronary heart disease with interventional methods.

Intravascular radiotherapy with vascular stents containing radioactive substances has brought a glimmer of hope for the prevention of vascular restenosis, but due to the need to implement radiation protection for the preparation and use of vascular stents containing radioactive substances, the operating procedures are very complicated. There is a problem that the excrement containing radioactive substances must be prevented from polluting the environment, so its clinical use and promotion are also limited.

Coated stents are a new development of vascular stents. Stents coated with non-metallic elements such as carbon and silicon have appeared successively, and clinical trials have been carried out, but the most research shows that their effects are still not good. rate has hardly decreased. In addition, the newly developed phosphorylcholine-coated stent in recent years has a restenosis rate of about 18% in six months, and the curative effect is still unsatisfactory.

Cardiovascular pharmacology studies have found that a variety of drugs can produce significant inhibitory effects on vascular intima and smooth muscle cells in vitro, but the effect of systemic drugs is not good, and the reason may be related to the low blood drug concentration in systemic circulation. In addition, because the special part of the coronary artery is not suitable for placing drug sustained-release devices in the body, how to locally administer drugs and which drugs to use become the key to the study of drug sustained-release stents.

According to the effect of paclitaxel on the microtubule system of cells, it can affect cell division, accelerate cell apoptosis, thereby inhibiting cell proliferation, migration and signal transduction performance. Lipid-soluble drugs can quickly penetrate the cell membrane and enter cells, which has the advantages of fast onset of action; and it can have a stabilizing effect on the cytoskeleton, thereby slowing down its metabolism in the cell to prolong the action time. There are many factors that affect the release behavior of paclitaxel in the drug coating of coronary stents. In addition to the geometry of the stent, the type of material that acts as a carrier of paclitaxel in the coating, the dissolution and diffusion speed of paclitaxel in the carrier material, and the density of the carrier material The degradation rate, as well as the concentration of paclitaxel in the coating and the distribution state in the carrier all have important influences. Among them, the nature of the carrier material has the greatest influence on the release behavior of paclitaxel. Because if a non-degradable material is used as the carrier of paclitaxel, there will be an initial burst of paclitaxel released in a large amount when the coronary stent is just implanted in the coronary artery, making the initial blood concentration of paclitaxel exceed the poisoning limit, and then followed by The reduction of paclitaxel content in the coating makes the release of paclitaxel less than the effective concentration to prevent restenosis; in addition, if the compatibility of the carrier material with paclitaxel is too poor, it will lead to slow diffusion speed of paclitaxel in the carrier, There is no release of paclitaxel in the initial stage of coronary stent implantation, so that the effective blood concentration of paclitaxel cannot be reached at the most prone stage of postoperative thrombosis, which is likely to cause coronary restenosis. Therefore, the two drug release behaviors formed due to the non-degradable drug carrier do not meet the clinical application requirements for preventing restenosis.

An ideal drug carrier should have "zero-order" (that is, "constant rate") release behavior, that is, the drug release rate does not change with time, so that the blood drug concentration can be continuously maintained at the level of the best therapeutic effect. When a biodegradable polymer material is used as a drug carrier, although the release rate of the drug from the carrier will also slow down with the decrease of the drug content, due to the gradual degradation of the drug carrier, the structure of the carrier becomes loose, making the The speed of dissolution and diffusion of drug molecules from the carrier to the body is accelerated, and the amount of drug release is increased. Therefore, when the biodegradation rate of the carrier is adjusted to be constant, the decrease of the drug release due to the decrease of the drug content can be offset by the increase of the drug release due to the acceleration of the dissolution and diffusion of the drug molecules. constant rate release. In addition, since the biodegradable polymer drug carrier can be degraded into small molecules or monomers due to the action of body fluids and enzymes in the physiological environment of the body, and finally absorbed or metabolized by the body, it also has the ability to be released after the drug is released. The advantage of not needing to take it out from the body is the most ideal drug carrier.

Contents of the invention

The object of the present invention is to provide a coronary stent drug coating for preventing vascular restenosis, which can realize constant release of the drug.

In order to achieve the above object, the present invention dissolves the aliphatic polylactone and its copolymer in a solvent, and after dissolving evenly, adds paclitaxel as a coronary stent drug for preventing restenosis of blood vessels, and uses it after stirring, dissolving evenly and filtering. The drug coating of the coronary stent can be coated on the surface of the coronary stent by a solution prepared by paclitaxel and a drug carrier by a solution spraying method or a solution dipping method. After coating evenly, volatilize the solvent in the air, then desolventize it at room temperature under vacuum for 48 hours, and sterilize it with ethylene oxide before use. The content of paclitaxel in the stent can be controlled by the concentration of paclitaxel, the concentration of the coating solution and the coating times of the coating.

Wherein, in parts by weight, including:

Paclitaxel 10 parts,

Drug carrier 100-10000 parts, preferably 200-8000 parts.

Described drug carrier is biodegradable aliphatic polylactone and copolymer thereof, and they can be: polylactide (PLA), polycaprolactone (PCL), poly (lactide-glycolide) (PLG ), poly(lactide-caprolactone) (PLC), poly(glycolide-caprolactone) (PGC) or poly(lactide-glycolide-caprolactone) (PGLC) random or Block copolymer; the molecular weight of aliphatic polylactone and its copolymer is 8,000-500,000.

In the poly(lactide-glycolide) (PLG), the content of polyglycolide can be from 1-60mol%, and the optimal ratio is 15-50mol%;

In the poly(lactide-caprolactone) (PLC), the content of polylactide can be from 1-99mol%, and the optimal ratio is 10 to 90mol%;

In the poly(glycolide-caprolactone) (PGC), the content of polyglycolide can be from 1 to 30mol%, and the optimal ratio is 3 to 20mol%;

In the poly(lactide-glycolide-caprolactone) (PGLC), the content of polyglycolide can be from 1 to 30mol%, and the optimum ratio is 3 to 20mol%; the content of polycaprolactone is the most A preferred ratio is 3 to 75 mol%.

The material of the coronary stent can be stainless steel, nickel-titanium memory alloy, or biocompatible polymer plastic.

The solvent of the drug coating solution prepared from paclitaxel and drug carrier can be tetrahydrofuran, acetone, dichloromethane, or chloroform.

The concentration of the drug coating solution prepared by aliphatic polylactone and its copolymer solution and paclitaxel can be in the range of 0.5-5%.

The release cycle of paclitaxel in the anti-restenosis coronary stent drug coating of the present invention is one week to one month.

The feature of the present invention is that the key to preventing blood vessel restenosis is focused on inhibiting the smooth muscle cells in the media layer from migrating to the intima layer under the action of cytokines and cell growth factors to cause abnormal proliferation. Therefore, prevent the restenosis of blood vessels by inhibiting smooth muscle cells from the initial growth phase to the DNA synthesis phase.

Considering that intracoronary stents are one of the most commonly used methods in interventional treatment of coronary heart disease, about 40-70% of patients with coronary heart disease need surgical implantation of stents. Therefore, the stent is used as the medium for releasing the drug. After the coronary stent is implanted into the blood vessel, it is closely attached to the inner surface of the blood vessel, and the drug coated on the stent is released slowly, so that the drug can directly act on the local lesion. At the same time, since only a small amount of medicine enters the body, systemic adverse reactions caused by the medicine can also be avoided.

Aliphatic polylactones, such as polylactide (PLA), polyglycolide (PGA), and polycaprolactone (PCL), are biodegradable polymers that have been approved for use in vivo. They are non-toxic, have good biocompatibility and good physical and chemical properties. They can also be copolymerized, and the degradation rate, physical and chemical properties of the copolymer can be adjusted in a wide range by adjusting the components, composition, molecular weight and molecular weight distribution of the copolymer. performance, thereby adjusting their drug release rate, so that the drug release life can be adjusted from several days to several months, so it has been clinically applied and commercialized as a drug carrier for drugs such as cancer treatment, detoxification, infection and contraception (such as Decapeptyl®, Lupron Depot®, Zoladex®, Adriamycin® and Capronor®, etc.).

Detailed ways

Example 1: After 0.1 g of poly(lactide-glycolide) random copolymer (PLGA, lactide/glycolide=50/50 (mol/mol)) was dissolved in 5 ml of chloroform, 2 mg Paclitaxel, stirred, dissolved evenly and filtered, sprayed onto the surface of 316L stainless steel stent, volatilized the solvent in the air, then repeated spraying once, volatilized the solvent in the air and then desolvated at room temperature under vacuum for 48 hours, paclitaxel in the stent The content is 50μg. After being sterilized by ethylene oxide and implanted into the coronary artery of the dog, no thrombus was found two weeks later.

Example 2: 0.1 g poly(lactide-glycolide-caprolactone) random copolymer (PGLC, lactide/glycolide/caprolactone=45/45/10 (mol/mol)) After dissolving in 3ml of dichloromethane, add 2mg of paclitaxel, stir, dissolve evenly and filter, dip-coat on the surface of 316L stainless steel stent, volatilize the solvent in the air, and then desolventize at room temperature under vacuum for 48 hours, the The paclitaxel content was 85 μg. After sterilized by ethylene oxide, the canine coronary artery was implanted, and there was no thrombus formation after three weeks.

Example 3: 0.1 g poly(lactide-glycolide-caprolactone) random copolymer (PGLC, lactide/glycolide/caprolactone=45/45/10 (mol/mol)) After dissolving in 3ml of dichloromethane, add 2mg of paclitaxel, stir, dissolve evenly and filter, dip-coat on the surface of 316L stainless steel stent, volatilize the solvent in the air, then repeat the dip-coating again, volatilize the solvent in the air and then apply it in vacuum The solvent was desolvated at room temperature for 48 hours under conditions, and the content of paclitaxel in the scaffold was 250 μg. After being sterilized by ethylene oxide and implanted into the coronary artery of the dog, no thrombus was found after two months.

Example 4: 0.2 g poly(lactide-glycolide-caprolactone) block copolymer (PGLC, lactide/glycolide/caprolactone=27/63/10 (mol/mol)) After dissolving in 6ml of dichloromethane, add 2mg of paclitaxel, stir, dissolve evenly and filter, then dip-coat on the surface of 316L stainless steel stent, evaporate the solvent in the air and then repeat the dip-coating again, and then desolventize at room temperature under vacuum After 48 hours, use after sterilizing with ethylene oxide. The paclitaxel content in the stent was 200 μg.

Example 5: After 0.1 g of poly(glycolide-caprolactone) random copolymer (PGC, glycolide/caprolactone=30/70 (mol/mol)) was dissolved in 10 ml of dichloromethane, 2 mg Paclitaxel, stirred, dissolved evenly and filtered, sprayed onto the surface of 316L stainless steel stent, volatilized the solvent in the air, then repeated the spraying twice, volatilized the solvent in the air, desolvated at room temperature for 48 hours under vacuum conditions, and passed the epoxy Use after ethane sterilization. The paclitaxel content in the stent was 100 μg.

Embodiment 6: The operation is the same as that of Embodiment 4, using a nickel-titanium memory alloy stent, and the content of paclitaxel in the stent is 200 μg.

Embodiment 7: The operation is the same as that of Embodiment 5, using a polycaprolactone stent, and the content of paclitaxel in the stent is 100 μg.

Comparative Example 1: Same as Example 1, but without paclitaxel. Dissolve 0.1 g of poly(lactide-glycolide) random copolymer (PLGA, lactide/glycolide = 50/50 (mol/mol)) in 5 ml of chloroform and filter, then spray to 316 L On the surface of the stainless steel stent, the solvent was evaporated in the air, and then sprayed again, and the solvent was evaporated in the air, and then desolvated at room temperature under vacuum for 48 hours, sterilized by ethylene oxide, and then implanted into the canine coronary artery. Angiographic examination after one month revealed vascular stenotic changes.

Control Example 2: A 316L stainless steel stent sterilized by ethylene oxide was directly implanted into the canine coronary artery, and imaging changes of vascular stenosis were seen after two months.

Animal Experiment Example 1: The experimental animal is a mongrel dog, male, weighing 25kg. Femoral artery incision was performed after general anesthesia. A 7F catheter sheath was inserted into the femoral artery, and the catheter was sent along the femoral artery to the opening of the left circumflex branch. A guide wire was inserted into the left circumflex branch, and a stainless steel stent (3.0 × 16 mm) containing 50 μg of paclitaxel was loaded onto the balloon catheter and sent into the middle segment of the left circumflex branch along the guide wire. The operation method is completely consistent with the human body operation process. After 3 hours of observation, no thrombus was found. Angiographic examinations were repeated at the second and fourth weeks, and no abnormal imaging changes of blood vessels were found.

Animal Experiment Example 2: The experimental animal was a mongrel dog, male, weighing 27kg. Femoral artery incision was performed after general anesthesia. A 7F catheter sheath was inserted into the femoral artery, and the catheter was sent along the femoral artery to the opening of the left circumflex branch. A guide wire was inserted into the left circumflex branch, and a balloon catheter was sent to the middle section of the left circumflex branch for pre-injury. Then, a stainless steel stent (3.0×16mm) containing 85 μg of paclitaxel was loaded on the balloon catheter and sent into the left circumflex branch along the guide wire. The middle segment of the circumflex branch. The operation method is completely consistent with the human body operation process. After 4 hours of observation, no thrombus was found. Angiographic examination was repeated in the third week, and no abnormal changes were found.

Animal Experiment Example 3: The experimental animal was a mongrel dog, male, weighing 29kg. Femoral artery incision was performed after general anesthesia. A 7F catheter sheath was inserted into the femoral artery, and the catheter was sent along the femoral artery to the opening of the left circumflex branch. A guide wire was inserted into the left circumflex branch, and a balloon catheter was sent to the middle section of the left circumflex branch for pre-injury. Then, a stainless steel stent (3.0×16mm) containing 250 μg of paclitaxel was loaded on the balloon catheter and sent into the left circumflex branch along the guide wire. The middle segment of the circumflex branch. Angiographic examination was repeated at the first and second month after operation, and no abnormal changes were found.

Animal experiment example 1 in the control group: the experimental animal was a mongrel dog, male, weighing 24 kg, and underwent femoral arteriotomy after general anesthesia. A 7F catheter sheath was inserted into the femoral artery, and the catheter was sent along the femoral artery to the opening of the left circumflex branch. , send a guide wire into the left circumflex branch, send a balloon catheter to the middle of the left circumflex branch for pre-injury, and then load a stainless steel stent (3.0×16mm) that does not contain paclitaxel but is only coated with polylactone into the balloon On the catheter, it is sent into the middle section of the left circumflex branch along the guide wire. The operation method is completely consistent with the human body operation process. After 4 hours of observation, no thrombus was found. Angiographic examination was repeated in the fourth week, and no abnormal changes were found.

Animal experiment example 2 of the control group: experimental animals 8 mongrel dogs, male, with an average weight of 26kg, underwent femoral artery incision after general anesthesia, inserted a 7F catheter sheath into the femoral artery, and sent the catheter along the femoral artery to the left circumflex branch At the opening, a guide wire was sent into the left circumflex branch, and a balloon catheter was sent to the middle section of the left circumflex branch for pre-injury. Then, a 316L stainless steel stent (3.0×15--16mm) was loaded on the balloon catheter, along the guide wire. into the middle of the left circumflex branch. The operation method is completely consistent with the human body operation process. Angiographic examination was repeated at the first, second, and sixth months, and 7 animals showed imaging changes of vascular stenosis successively.

Claims (5)

1. A coronary stent drug coating for preventing vascular restenosis, the preparation method of which is: Dissolve the drug carrier in the solvent and add the drug evenly, stir to dissolve and filter, then evenly coat the drug solution on the surface of the coronary stent, evaporate the solvent in the air, and then desolventize at room temperature under vacuum for 48 hours, and then pass through ethylene oxide Alkane sterilization is characterized in that: The drug carrier is aliphatic polylactone and its copolymer; The drug is paclitaxel; Wherein, in parts by weight, including: Paclitaxel 10 parts, Drug carrier 100-10000 parts, The concentration of the drug solution is in the range of 0.5-5%. 2. The drug coating for coronary stents according to claim 1, wherein said biodegradable aliphatic polylactone and its copolymers are polylactide, polycaprolactone, poly(lactide) -glycolide), poly(lactide-caprolactone), poly(lactide-caprolactone) or poly(lactide-glycolide-caprolactone) random or block copolymers; The molecular weight of the aliphatic polylactone and its copolymer is 8000-500000; In the poly(lactide-glycolide), the content of polyglycolide is 1-60mol%; In the poly(lactide-caprolactone), the content of polylactide is 1-99mol%; In the poly(glycolide-caprolactone), the content of polyglycolide is 1-30mol%; In the poly(lactide-glycolide-caprolactone), the content of polyglycolide is 1 to 30 mol%, and the content of polycaprolactone is 3 to 75 mol%; The coronary stent is made of stainless steel, nickel-titanium memory alloy or biocompatible polymer plastic; The solvent is tetrahydrofuran, acetone, dichloromethane or trichloromethane. 3. The drug coating for a coronary stent according to claim 1, wherein the drug carrier is 200-8000 parts by weight. 4. The coronary stent drug coating according to claim 1 or 2, characterized in that: In the poly(lactide-caprolactone), the content of polylactide is 10-90mol%; In the poly(lactide-glycolide), the content of polyglycolide is 15-50mol%; In the poly(glycolide-caprolactone), the content of polyglycolide is 3-20mol%; In the poly(lactide-glycolide-caprolactone), the content of polyglycolide is 3-20mol%. 5. The drug coating for coronary stent according to claim 1, characterized in that the release period of the paclitaxel is one week to one month.