KR20040080112A - Manufacture Method for Durg release controlled /Eluting using biocompatibility polymer Coated stents - Google Patents

Abstract

PURPOSE: A method for manufacturing a drug release controlling type stent using a biocompatible polymer for coronary stenting is provided to control a drug release period and to lower a restenosis rate after performing a coronary stenting operation. CONSTITUTION: The manufacture method comprises: washing stent to remove foreign matter attached on the surface of the stent; immobilizing biomolecules through a covalent bond of stent polysulfone; synthesizing polysulfone having isocyanate attached thereto and attaching a carboxyl group to the synthesized polysulfone; producing morpholinoethanesufone; and mixing the stent with adipic acid in a PH 3-6 MES buffer solution.

Description

Manufacturing Method for Durg release controlled / Eluting using biocompatibility polymer Coated stents

Since percutaneous transluminal coronary angioplasty (PTPA) was first performed in humans, many significant achievements and advances have been made in the field of coronary intervention. In the field of the treatment of ischemic heart disease, interventional procedure is currently considered the most common and general treatment. A major contribution to this development is the development of coronary stent implantation. The development of stenting has contributed to making the intervention safe and generalized by quickly and safely overcoming the various complications and acute closures due to dissection. In general, within one year after the procedure, a new problem called restenosis is encountered, and the incidence rate is about 20% according to various stents, and the lesion is a long lesion and a small vessel lesion. Small vessel lesions showed higher restenosis rates.

The pathophysiological process involved in restenosis was thought to be caused by a variety of substances through cell surface receptors, and research has been conducted that treatment can prevent restenosis, but has shown little effect. Ultimately, this is accomplished through a step known as a cell cycle at the cellular DNA level.

Since activation of the cell cycle has important implications for pathophysiological processes such as normal physiological growth and cell differentiation and restenosis, appropriate regulation thereof provides the basis for the treatment of restenosis, and in particular in the present invention, drug release regulation. Drugs included in drug release controlled coated stents are using drugs having an effect on the cell cycle of the stomach.

When foreign surfaces are exposed to blood, proteins, other blood components, and coagulation reactions become active, resulting in clots on the stent surface. Therefore, stent thrombosis remains an existing problem during the interventional procedure, especially when there are diseases such as small blood vessels, acute myocardial infarction, and complete vessel occlusion.

Therefore, an object of the present invention is to control the drug release period, thereby significantly reducing the restenosis rate after the procedure by applying the drug release controlled biocompatible polymer to the cardiovascular stent.

In the case of cardiovascular stent intervention, the development of long-term topical drug administration system for the prevention of restenosis after surgery is performed. The process of preparing coated stents includes mixing of biocompatible polymers and stent supports. The present invention relates to a method for preparing a controlled release coating stent in which a coating composition is continuously applied to a stent support using a stirring chamber, and the drug is uniformly distributed in the coating layer.

The controlled release coated drug of the present invention prevents premature release of drug components into blood by using an amorphous biocompatible polymer as a binder of the drug substance. The release of biomolecules through covalent bonding of stent-modified polysulfones for the stent immobilization of biomolecules, which is very important in coating stent manufacturing process same.

In order to synthesize a polysulfone polymer having an amine group, 3-aminopropyltriethoxysilane is dissolved and dried in a mixed solvent of ethanol and distilled water. Polysulfone with isocyanate is synthesized in polysulfone with polyamine and attached with amine group in the final step. To determine the solution to activate the carboxylated stent for immobilization of biomolecules, the stent is mixed with adipic acid in MES buffer and injected into it to remove cardiovascular thrombus ( Taxol) and then stent is added to the MES buffer solution to be immobilized in the biomaterial erythrocyte-heparan sulfate (EHS) and stirred.

The key parameters of the coating process optimization should be controlling key variables such as viscosity and surface tension determination, coating layer thicknesses determination, and curing temperature determination. Particularly necessary solvent selection needs to have the property that the drug can be dispersed throughout the solvent.

It is composed of the drug component and biocompatible polymer to be included in the stent coating solution, the thinner the coating layer is applied to the drug support, the faster the components of therapeutic agent is released, the thicker one is released slowly, the risk of drug residue Because of this, it is necessary to maintain a constant film thickness.

1 is a perspective view showing a cardiovascular stent of the present invention, Figure 2 is a simplified view showing the coating process of the present invention.

Referring to Figure 2, the coating method of the present invention will be described in detail.

Biocompatible metals preferred as the stent material include stainless steel, tantalum, nitimol, gold, and the like, and the polymer materials for coating may use the materials listed below.

Polylactide poly (L-lactide) (PLLA), polyglycolide (PGA), polylactide copolymer poly (L-lactide-co-D, L-lactide) (PLLA / PLA), polyethylene oxide polyethylene oxide (PEO), polydioxanone (PDS), polycaprolactone (PCL), polyphosphazene, polyanhydrides (PAN), polyamino acid, poly (hydroxy butyrate ), Polyacrylates, polyacrylamids, polyurethanes, polysiloxanes and copolymers thereof.

In order to remove the substance on the surface of the entire stent for surface treatment of the support, the stent is washed with a mixed solvent of ethanol and distilled water and dried at 50-70 degrees for 12-24 hours using a vacuum oven under 0.01 mtorr.

Immobilization of biomolecules through covalent bonding of stent modified polysulfone was developed as follows for stent immobilization of biomolecules, which is the most important step of the coating stent manufacturing process.

As shown in (Scheme 1), polysulfone synthesizes a polymer having an amine group attached thereto. For the amination of the stent, aminopropyltriethoxysilane (3-aminopropyl-triethoxysilane) was maintained at 10-50 degrees for 12-24 hours as 2 wt% (wt%) in a mixed solvent of ethanol and distilled water (weight ratio 1: 1). After washing five times with distilled water and dried at 30-70 degrees.

As shown in (Scheme 2), polysulfone having an isocyanate is synthesized with polysulfone having a amine group attached thereto, and a carboxyl group is attached in the final step. The suitable activation and immobilization temperature of the polymer during the carboxylation process should be maintained at -10-10 degrees and 0.1M concentration in polysulfone-buffer (MES, morpholinoethanesufone).

To determine the solution to activate the carboxylated stent for immobilization of biomolecules as shown in Scheme 3, the stent was added 0.1% of adipic acid in MES buffer of PH 3-6. Mix at M concentration. Herein, 0.01 to 0.001 mg of the drug (including taxol) injected to remove the blood clot in the cardiovascular vessel is maintained at 0.1-0.05M in a CME-CDI solvent, and then stirred for 5-15 hours at -5-5 ° C. After stirring, the reactor was washed with distilled water and dried.

The carboxyl group of the stent is activated with CME-CDI to coat the drug-containing carboxylated stent. Buffer for stent impregnation (MES) The concentration of 4M in 4M CME-CDI at 0.1M concentration for 10-5 hours. In order to immobilize the biomaterial erythrocyte-heparan sulphate (EHS), the stent should be added to another reactor, and the reaction solution is slowly stirred after adding 0.1-10 mg of EHS to 100 ml of 01 N MES buffer.

Stirring conditions are maintained for 10 minutes to 20 hours at -4-4 degrees, then the stent is taken out and kept refrigerated at -5--20 degrees. 5 successive washes in distilled water for 5 minutes-5 hours to wash the coated stent. After washing, dry at 50 ° C. for 1 hour to 24 hours. The key parameters of the coating process optimization should be controlling key variables such as determining viscosity and surface tension, determining coating layer thicknesses, and curing temperature. Particularly necessary solvent selection needs to have the property that the drug can be dispersed throughout the solvent.

Stir with a Teflon-coated stirrer at 300-700 rpm in a closed reaction chamber containing the coating solution, circulate the solution at a pressure of 1-3 torr at room temperature, and allow the stent surface to be applied to the solution at the proper position during the circulation process. Place the stent. The circulation time of the solution is suitable for 3-5 hours.

It is composed of the drug component and biocompatible polymer to be included in the stent coating solution, the thinner the coating layer is applied to the drug support, the faster the components of therapeutic agent is released, the thicker one is released slowly, the risk of drug residue For this reason, it is necessary to maintain a constant film thickness (preferably 0.1 to 0.2 mm).

One of ordinary skill in the art may readily select and prepare the components according to the use of the drug and the solubility in water. Drug components mainly include taxol, etc., which have anticancer function, but can be used without limitation in its kind.

In general, anti-thrombogenic agents, anti-proliferative agents, growth factors, and radiochemicals as drug substance can be easily eluted from the coating polymer matrix. have. Particularly preferred drugs include Taxol and its derivatives, colchicine, lovastatin, trapidil, hirudin, ticlopidine and growth factors VEGF, TGF-beta , IGF, PDGF, FGF and the like.

(Scheme 1)

(Scheme 2)

(Scheme 3)

The controlled release coated drug of the present invention prevents premature release of drug components into blood by using an amorphous biocompatible polymer as a binder of the drug substance. Excellent release control at

Claims (3)

Stent cleaning process to remove material on the surface of the stent. Immobilization of biomolecules via covalent bonding of stent modified polysulfones for stent immobilization of biomolecules, the most important step in the post-wash coating stent manufacturing process: Synthesis of polysulfone (Polysulfone) isocyanate attached to the polysulfone (Polysulfone) to which the amine group is attached as shown in (Scheme 2) and the carboxyl group attachment step in the final step: Polysulfone-buffer (MES, morpholinoethanesufone) manufacturing process: To determine the solution to activate the carboxylated stent for immobilization of biomolecules as shown in Scheme 3, the stent was added 0.1% of adipic acid in MES buffer of PH 3-6. Mixing with M concentration: In the immobilization of biomolecules through covalent bonding of stent-modified polysulfones, 0.011-0.001 mg of drug (including taxol) to remove cardiovascular thrombi was maintained at 0.1-0.05M in CME-CDI solvent. Stirring 5-15 hours under 5-5 degrees: After stirring and washing with distilled water in the reactor and drying step: Activating the carboxyl group of the stent with CME-CDI: A teflon-coated stirrer is stirred at 300-700 rpm in a closed reaction chamber containing a coating solution and circulated at a pressure of 1-3 torr at room temperature.