KR20150061947A

KR20150061947A - Coating composition for porous drug releasing stent and drug releasing stent coated the thereof

Info

Publication number: KR20150061947A
Application number: KR1020130146353A
Authority: KR
Inventors: 나건; 정두용; 서은하
Original assignee: 가톨릭대학교 산학협력단
Priority date: 2013-11-28
Filing date: 2013-11-28
Publication date: 2015-06-05

Abstract

The present invention relates to a composition for stent coating for drug release for forming a polymer membrane having a porous structure containing a biocompatible hydrophilic polymer or a hydrophilic polysaccharide as an active ingredient, a stent coated with the composition, and a method for producing a stent coating film having a porous structure will be. The stent polymer coating having a porous structure coated with the composition according to the present invention can promote drug release when compared with conventional polymeric coatings and can increase the surface area of the coating depending on the pore size formed in the coating Therefore, it is possible to manufacture a medical stent capable of improving the therapeutic efficacy.

Description

TECHNICAL FIELD [0001] The present invention relates to a stent coating composition for forming a porous polymer membrane, and a coated drug delivery stent coated with the composition,

TECHNICAL FIELD The present invention relates to a composition for stent coating for forming a polymer film of porous structure and a drug-released stent coated with the composition.

The stent is a tube-shaped artificial prosthesis that is inserted into the human body to relieve the clogging of blood vessels and non-vascular tubular tissues. It is used for the purpose of enhancing the patient's convenience and treatment of focal disease, and its demand continuously increases worldwide There is a tendency.

Recently, drug-eluting stents (DES) coated with various drugs have been developed to improve the therapeutic efficacy of stents. Drug-eluting stents have been reported to effectively and consistently deliver topical medications and dramatically reduce stent restenosis.

The first developed drug - eluting stent was a drug - only coating system. The coating was so weak that it released a large amount of drug in the early stage and had a low restenosis and therapeutic effect. Therefore, in order to solve such a problem, a polymer drug-releasing coating agent has been developed and is attracting attention in the stent market.

In this concept, the drug-eluting stent, which is being developed using polymers, is produced in three representative forms: 1) a monolithic device type in which the drug is contained in the polymer matrix and whose drug release is controlled by the diffusion rate of the polymer matrix 2) the drug is contained in the central polymer matrix and is wrapped with a thin polymer film on the outer surface, and thus the drug (drug substance) There is a reservoir system in which the release is controlled (typically a cypher of Silicon Limousin encapsulated Johnson & Johnson), and 3) a drug eluting form surrounded by a drug-encapsulating polymeric coating throughout the surface of the stent There is a drug-eluting stent in film form.

The drug-eluting stent covered with a polymeric film has the advantage of being able to effectively prevent the in-stent restenosis (ISR) after stent insertion, but the polymer used (typically polyurethane or silicone) The diffusion of the drug from the stent coating film to the external environment is not effective depending on the characteristics, and thus it is difficult to control the drug release.

Theoretically, factors affecting drug diffusion from the stent coating to the surrounding environment include the drug's molecular weight, temperature, concentration difference, diffusion distance, surface area, and permeability, and thus the drug, ambient temperature, The control of the surface area is indispensable in order to control drug release.

On the other hand, the porous structure is one of the ways to increase the surface area, and can promote the release of the drug when the drug is enclosed therein. The porous structure is produced by using a blowing agent or by using a laser to produce a porous structure, but the effect is insufficient.

Therefore, a new development of an effective drug releasing stent having a porous structure is required.

Korea Patent Publication No. 2003-0004582

Accordingly, it is an object of the present invention to provide a method of manufacturing a stent having a porous structure capable of promoting drug release and having a wide surface area when compared with conventional general polymer coatings. Specifically, The present invention provides a composition for stent coating for drug release for forming a polymer film of a porous structure, which comprises a hydrophilic polymer or a hydrophilic polysaccharide as an active ingredient.

Another object of the present invention is to provide a drug releasing stent containing a polymeric coating of a porous structure coated with the composition of the present invention.

Yet another object of the present invention is to provide a method for preparing a drug, comprising dissolving a drug and polyurethane or silicone in tetrahydronofuran; Adding a biocompatible hydrophilic polymer or hydrophilic polysaccharide to the dissolved solution to prepare a coating composition; Coating a Teflon rod piled with a PTFE film with the coating composition; And drying the PTFE film coated with the composition for coating, and then eluting the biocompatible hydrophilic polymer or the hydrophilic polysaccharide in an aqueous solution. The present invention also provides a method for producing a stent coating film having a porous structure.

In order to accomplish the above object, the present invention provides a composition for stent coating for drug release for forming a polymer film of a porous structure, which comprises a biocompatible hydrophilic polymer or a hydrophilic polysaccharide as an active ingredient.

In one embodiment of the present invention, the biocompatible hydrophilic polymer may be selected from the group consisting of PEG (polyethylene glycol), glycerol, polyethyleneimine, polyacrylamide, and polyvinylpyrrolidone.

In one embodiment of the present invention, the hydrophilic polysaccharide may be selected from the group consisting of fluoran, hyaluronic acid, fucoidan and chitosan.

In one embodiment of the present invention, the drug may be selected from the group consisting of paclitaxel, gemcitabine, silolimus, mitomycin C and genes.

In one embodiment of the present invention, the biocompatible hydrophilic polymer or hydrophilic polysaccharide may be contained in an amount of 5 to 50% by weight based on the total weight% of the composition.

In one embodiment of the present invention, the polymer coating may be composed of polyurethane or silicone.

The present invention also provides a stent for drug release containing a polymeric coating of a porous structure coated with the composition of the present invention.

In one embodiment of the present invention, the drug may be located inside the capsule.

In one embodiment of the present invention, the coating may be composed of polyurethane or silicone.

In one embodiment of the present invention, the porous structure may have a pore size of 1 to 1000 μm.

Further, the present invention provides a method for preparing a drug, comprising dissolving a drug and polyurethane or silicone in tetrahydronofuran; Adding a biocompatible hydrophilic polymer or hydrophilic polysaccharide to the dissolved solution to prepare a coating composition; Coating a Teflon rod piled with a PTFE film with the coating composition; And drying the PTFE film coated with the composition for coating, followed by eluting the biocompatible hydrophilic polymer or the hydrophilic polysaccharide in an aqueous solution. The present invention also provides a method for producing a stent coating film having a porous structure.

In one embodiment of the present invention, the biocompatible hydrophilic polymer is selected from the group consisting of PEG (polyethylene glycol), glycerol, polyethyleneimine, polyacrylamide, and polyvinylpyrrolidone; The hydrophilic polysaccharide may be selected from the group consisting of fluoran, hyaluronic acid, fucoidan and chitosan.

In one embodiment of the present invention, the drying may be performed at a temperature above the Tg value of the biocompatible hydrophilic polymer or hydrophilic polysaccharide.

In one embodiment of the present invention, the porous structure may be a structure in which pores having a size of 1 to 1000 μm are formed on the stent coating film.

The present invention relates to a technique for providing a polymer coating for a stent coating having a porous structure capable of promoting drug release when compared with a conventional general polymer coating and having a wide surface area, The porous stent coating film and the medical tissue tent having the porous coating structure can broaden the surface area of the coating depending on the pore size formed in the coating and can promote drug release from the coating for stent coating, There is an effect that a medical stent can be manufactured.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a scanning electron microscope photograph of the surface of a non-porous structure of a stent coating film and the surface of a porous structure of a stent coating film.
2 is a scanning electron microscope (SEM) image of a section of a stent coating film having a porous structure.
FIG. 3 shows release curves of the drug in the stent coating film of the porous structure and the general stent coating film.

The inventors of the present invention are characterized in that they have developed a technique for widening the surface area of the coating film for stent coating for enhancing drug release in the coating for stent coating.

That is, the present invention can provide a stent coating composition for drug release for forming a polymeric membrane having a porous structure, which comprises a biocompatible hydrophilic polymer or a hydrophilic polysaccharide as an active ingredient. The polymeric coating having a porous structure coated with the composition A drug-releasing stent can be provided.

The present invention also provides a method for preparing a pharmaceutical composition comprising dissolving a drug and a polyurethane or silicone in tetrahydronofuran; Adding a biocompatible hydrophilic polymer or hydrophilic polysaccharide to the dissolved solution to prepare a coating composition; Coating a Teflon rod piled with a PTFE film with the coating composition; And drying the PTFE film coated with the composition for coating, and then eluting the biocompatible hydrophilic polymer or the hydrophilic polysaccharide in an aqueous solution. The present invention also provides a method for producing a stent coating film having a porous structure.

In the present invention, when a hydrophilic material (biocompatible hydrophilic polymer or hydrophilic polysaccharide) is used to form the porous structure of the stent coating, the surface area of the coating is varied depending on the concentration of the hydrophilic material contained in the stent coating solution .

Therefore, in one embodiment, the present inventors prepared a stent coating solution containing PEG, which is a hydrophilic material, coated with a film-forming polymer using a dip coating method, and then removed the paper to form a porous structure.

PEG, which is a hydrophilic material used in an embodiment of the present invention, is a biocompatible polymer having high water solubility and can be easily removed by hydration from an insoluble support such as a stent coating or applying heat of Tg or more, A structure can be formed.

Drug release from the coating for porous stent coating is promoted as the concentration of PEG increases, which is due to the increase in surface area by PEG. Promotion of drug release can reduce the amount of drug remaining in the polymer coating for stent coating such as polyurethane and silicone, and can reduce the diffusion distance of the polymer layer of the drug according to the characteristic of the porous structure.

The hydrophilic materials usable in the present invention include, but are not limited to, synthetic polymers such as PEG (polyethylene glycol), glycerol, polyethyleneimine, polyacrylamide, and polyvinylpyrrolidone; As the hydrophilic polysaccharide, pluran, hyaluronic acid, fucoidan, chitosan and the like can be used. In addition, salt components such as polyamino acid and peptide, NaCl or KCl can be used. When the hydrophilic material is immersed in a polymer-based coating insoluble in water, it is removed from the coating by a diffusion phenomenon due to a concentration difference, and the surface area can be widened.

Such a hydrophilic substance can be used at a concentration of 5 to 50% by weight based on the total weight of the polymer when preparing the coating film for porous stent coating, and the porous structure can be formed due to the use of such a substance.

The porous structure is uniformly formed not only on the surface of the film but also inside the film. This is possible when the hydrophilic material is evenly distributed on the film-forming solution. For example, when the film and the film-forming polymer (polyurethane or silicone) (E. G., Tetrahydrofuran). &Lt; / RTI >

The drugs that can be used in the present invention include, but are not limited to, paclitaxel, gemcitabine, sirolimus, and mitomycin C, and these drugs may be located inside the capsule.

Further, the polymer film is composed mainly of polyurethane or silicon, and the porous structure formed in the polymer film has a diameter The size can be between 1 and 1000 um.

A detailed description of a method for manufacturing a stent coating film having a porous structure according to the present invention will be described in more detail with reference to the following examples.

It will be apparent to those skilled in the art that these preparations and examples are merely intended to illustrate the present invention only and that the scope of the present invention is not limited to these examples.

&Lt; Example 1 >

PEG Of porous polyurethane-based drug release Stent Coating film manufacturing

&Lt; 1-1 > Preparation of coating film for drug releasing stent coating using 10% PEG-containing coating solution

85 mg of paclitaxel and 500 mg of polyurethane were evenly dissolved in 10 ml of tetrahydrofuran and 58.5 mg of PEG was added. Then, a Teflon rod wrapped with PTFE film is coated by dip coating method. The polyurethane coated PTFE film containing prakl texel was dried at room temperature. PEG was eluted on distilled water for 3 days to form porosity and the formed coating was dried in a dryer at 60 ° C.

&Lt; 1-2 > Preparation of coating film for drug release stent coating using 20% PEG-containing coating solution

85 mg of paclitaxel and 500 mg of polyurethane were uniformly dissolved in 10 ml of tetrahydrofuran and then 117 mg of PEG was added. Then, a Teflon rod wrapped with a PTFE film was coated by a dip coating method, and a polyurethane coated PTFE film containing prakltexel was dried at room temperature. After the PEG was eluted on the distilled water for 3 days to form the porosity, the formed film was dried in a dryer at 60 ° C.

&Lt; 1-3 > Coating film for drug releasing stent coating using 30% PEG-containing coating solution

85 mg of paclitaxel and 500 mg of polyurethane were uniformly dissolved in 10 ml of tetrahydrofuran and 175.5 mg of PEG was added. Then, a Teflon rod wrapped with a PTFE film was coated by a dip coating method, and a polyurethane coated PTFE film containing prakltexel was dried at room temperature. After the PEG was eluted on the distilled water for 3 days to form the porosity, the formed film was dried in a dryer at 60 ° C.

&Lt; Comparative Example 1 &

Non-porous polyurethane based drug release stent coating coatings

85 mg of praklitaxel and 500 mg of polyurethane were uniformly dissolved in 10 ml of tetrahydrofuran and coated with a PTFE film coated with a dip coating method. The polyurethane coated PTFE film containing paclitaxel was then dried at room temperature.

< Experimental Example 1>

Surface observation by scanning electron microscope

In order to confirm the porosity of the coatings prepared in Example 1 and Comparative Example 1, the dried coatings were coated with platinum for 45 seconds and then observed with a scanning electron microscope. In order to confirm the internal structure of the coating, when observing with a scanning electron microscope, the sample was observed by scanning electron microscope at an angle of 70 °.

As a result, as shown in FIG. 1, in the case of the non-porous stent coating layer group as the control group, no pores were formed on the surface, while in the case of the porous stent, pores were formed on the surface there was. Also, as shown in FIG. 2, it was confirmed that pores formed were also present in the coating film.

< Experimental Example 2>

Comparison of drug release according to porosity

The drug release rate was analyzed from the porous stent coatings of the present invention containing the drug. In this experiment, a stent coating film prepared by the method of Example 1 and Comparative Example 1 was used.

Specifically, 3.2 cm ² of the dried film was added to a pH 7.4 PBS buffer containing 0.1% of tween 20, and then the supernatant was extracted at a predetermined time interval at 37 ° C and 50 rpm. Using HPLC-UV, And quantified at 214 nm.

As a result, as shown in FIG. 3, the release of the internal drug (paclitaxel) increased with time in the case of the porous stent, compared with the non-porous stent coating layer in the control group.

The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

Claims

A composition for stent coating for drug release for forming a polymeric coating of porous structure, comprising a biocompatible hydrophilic polymer or a hydrophilic polysaccharide as an active ingredient.

The method according to claim 1,
Wherein the biocompatible hydrophilic polymer is selected from the group consisting of PEG (polyethylene glycol), glycerol, polyethyleneimine, polyacrylamide, and polyvinylpyrrolidone.

The method according to claim 1,
Wherein the hydrophilic polysaccharide is selected from the group consisting of fluoran, hyaluronic acid, fucoidan and chitosan.

The method according to claim 1,
Wherein said medicament is selected from the group consisting of paclitaxel, gemcitabine, silolimus, mitomycin C and genes.

The method according to claim 1,
Wherein the biocompatible hydrophilic polymer or hydrophilic polysaccharide comprises from 5 to 50% by weight based on the total weight% of the composition.

The method according to claim 1,
Wherein the polymer coating is comprised of polyurethane or silicone.

A drug release stent containing a polymeric coating of a porous structure coated with the composition of claim 1.

6. The method of claim 5,
Wherein said medicament is selected from the group consisting of paclitaxel, gemcitabine, silolimus, mitomycin C and genes.

6. The method of claim 5,
Wherein the drug is located inside the capsule.

6. The method of claim 5,
Wherein the coating is composed of polyurethane or silicone.

6. The method of claim 5,
Wherein the porous structure has a pore size between 1 and 1000 um.

Dissolving the drug and polyurethane or silicone in tetrahydronofuran;
Adding a biocompatible hydrophilic polymer or hydrophilic polysaccharide to the dissolved solution to prepare a coating composition;
Coating a Teflon rod piled with a PTFE film with the coating composition; And
Drying a PTFE film coated with a coating composition, and then eluting the biocompatible hydrophilic polymer or hydrophilic polysaccharide in an aqueous solution.

13. The method of claim 12,
Wherein the drug is selected from the group consisting of paclitaxel, gemcitabine, silolimus, mitomycin C and genes.

13. The method of claim 12,
Wherein the biocompatible hydrophilic polymer is selected from the group consisting of PEG (polyethylene glycol), glycerol, polyethyleneimine, polyacrylamide, and polyvinylpyrrolidone; Wherein the hydrophilic polysaccharide is selected from the group consisting of fluoran, hyaluronic acid, fucoidan and chitosan.

13. The method of claim 12,
Wherein the drying process is performed at a temperature above the Tg value of the biocompatible hydrophilic polymer or the hydrophilic polysaccharide.

13. The method of claim 12,
Wherein the porous structure is a structure in which pores having a size of 1 to 1000 mu m are formed on the stent coating film.