KR20150061949A - Coating composition for drug releasing stent comprising penetration enhancer and drug releasing stent coated the thereof - Google Patents

Abstract

The present invention relates to a composition for coating a drug-releasing stent including a penetration enhancer, a drug-releasing stent coated with the composition, and a method for manufacturing the stent. The stent coated with a composition for coating a drug-releasing stent including a penetration enhancer, in accordance with the present invention, has an effect of releasing a drug and a penetration enhancer at the same time from a coated film, and increasing drug permeability to tissues, thereby enhancing a therapeutic effect compared to a conventional medical stent.

Description

[0001] The present invention relates to a composition for drug-eluting stent coating containing an absorption promoting agent and a drug-releasing stent coated with the composition,

The present invention relates to a composition for drug release stent coating containing an absorption enhancer 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 developed using polymers, is produced in three representative forms: 1. The drug is contained in the polymer matrix, and the monolithic device type in which drug release is controlled by the diffusion rate of the polymer matrix (For example, "Taxus" from Boston Scientific, which is typically packed with paclitaxel). 2. The drug is contained in the central polymer matrix and is wrapped with a thin polymer film on the surface, There is a reservoir system in which drug release is controlled (typically, Cypher is a Johnson & Johnson company with a sealant). 3. Drug eluting, which is wrapped in a drug-encapsulated polymeric coating throughout the surface of the stent There is a drug-eluting stent in film form.

However, there are several reports of poor clinical efficacy when drug-eluting stents are compared to stents that do not release the drug. The main reasons for this are: 1. Low penetration rate of the drug and 2. Non-fixed displacement of the stent. The low tissue penetration rate of the drug is caused by the fact that the released drug does not penetrate deeply from the surface of the stent coating.

Methods for increasing the tissue penetration rate of drugs include iontophoresis, use of cancer target peptides, and increase of tissue penetration rate using a laser, but it is difficult to apply the technology to the body. As another method, there is a method using an absorption promoting agent, which is mainly used in researches on skin, digestive machines and the like, and absorption promoting agent can help absorption of a drug into tissues. (1) chemical enhancement, (2) physical enhancement, (3) biochemical enhancement, (4) supersaturation enhancement, and (5) bioconvertable prodrug, etc. However, there is also a problem that the effect is insufficient, and there is no example in which such an absorption promoting agent is used for manufacturing a stent.

Therefore, it is necessary to develop a new stent manufacturing method that can improve drug permeability in human tissue.

Korea Patent Publication No. 2003-0004582

Accordingly, an object of the present invention is to provide a composition for stent coating for drug release containing an absorption promoting agent.

Another object of the present invention is to provide a drug releasing stent containing a polymer coating coated with a composition for stent coating for drug release containing an absorption promoting agent.

It is still another object of the present invention to provide a method for manufacturing a drug-releasing stent containing an absorption promoting agent, characterized by coating the medical stent with the composition of the present invention.

In order to achieve the above object, the present invention provides a composition for stent coating for drug release containing an absorption promoting agent.

In one embodiment of the present invention, the absorption promoter is selected from the group consisting of erpene, terpenoid, essential oil, pyrrolidone, fatty acid, ester, sulfoxide, alcohol, glycol, glyceride, azone, phospholipid, cyclodextrin inclusion, sodium caprate, , Dodecyl-N, N-Dimethylamino Acetate, pluronic, sodium lauryl sulfate, phenyl piperazine, and oleic acid.

In one embodiment of the present invention, the absorption promoting agent is a low molecular weight substance having a weight of 1000 g / mol or less and may be contained in an amount of 0.5 to 30% by weight based on the total weight of the composition.

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

The present invention also provides a stent for drug release containing a polymer coating coated with a composition for stent coating for drug release containing an absorption promoting agent.

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 drug may be located inside the capsule.

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

Further, the present invention provides a method for preparing a drug-releasing stent containing an absorption promoting agent, characterized by coating the composition of the present invention on a medical stent.

In one embodiment of the present invention, the coating may dip the stent into the composition of the present invention or spray or apply the composition of the present invention to the surface of the stent.

The present invention relates to a composition for stent coating for drug release containing an absorption enhancer, a drug-releasing stent coated with the composition, and a method for producing the stent. The stent coated with the composition for stent coating for drug release containing the absorption promoting agent according to the present invention has an effect that the drug and the absorption promoting agent can be simultaneously released from the coated film and the effect of enhancing the penetration rate of the drug into the tissue And thus the therapeutic effect can be improved as compared with the conventional medical stent.

FIG. 1 is a photograph of a surface of a polyurethane-based stent coating film containing 10% of sodium caprate as an absorption promoter.
Figure 2 is a photograph of the surface of a polyurethane-based coating for stent coating containing 10% pluronic as an absorption promoter.
FIG. 3 is a photograph of the surface of a coating of a stent coating containing a polyurethane-based cyclodextran-paclitaxel inclusion material as an absorption promoter.
FIG. 4 is a photograph of the surface of a polyurethane-based stent coating film containing 2% of phenyl piperazine and sodium lauryl sulfate as an absorption promoter.
5 is a photograph of a surface of a polyurethane-based coating for coating a stent without absorption promoter.
FIG. 6 is a drug release curve of a polyurethane-based stent coating film containing phenyl piperazine and sodium lauryl sulfate as an absorption enhancer.
FIG. 7 is a drug release curve of a polyurethane-based stent coating film containing sodium caprate as an absorption enhancer.

The present invention relates to a stent coating composition containing an absorption promoting agent and a drug-releasing stent including a coating coated with the composition.

The present inventors newly devised a drug releasing stent coating film containing an absorption promoter based on the existing fact that the absorption enhancer improves drug permeability in human tissues such as skin and digestive system.

Further, the present inventors have found that the drug and the absorption enhancer can be simultaneously released from the coating for stent coating of the present invention.

Accordingly, the present inventors prepared a stent coating solution containing an absorption promoting agent, prepared a coating film using the same, and provided a drug releasing stent having the coating film thus prepared.

The absorption promoting agent used in the present invention is a low molecular weight substance having a molecular weight of 1000 g / mol or less, and has a form of promoting tissue permeation of cells and tissues, or enhancing drug absorption into the cell gap.

Examples of the absorption promoting agent include, but are not limited to, terpenes, terpenoids, essential oils, pyrrolidones, fatty acid and esters, sulfoxides and derivatives thereof, chemical absorption promoters such as alcohols, glycols, glycerides, , Phospholipids, cyclodextrin inclusion compounds, sodium caprate, Clofibric Acid, Dodecyl-N, N-Dimethylamino Acetate, pluronic, sodium lauryl sulfate, phenyl piperazine and oleic acid.

Drug release from the stent coating film containing the absorption enhancer may be promoted depending on the type of absorption promoter, which differs depending on the hydrophilic-hydrophobic coefficient of the absorption promoter. According to one embodiment of the present invention, phenyl piperazine has the effect of accelerating the initial release of the drug, but the sodium caprate has no effect on drug release.

The absorption promoting agent may be used in an amount of 0.5 to 30% by weight with respect to the coating for stent coating, and one or more absorption accelerators may be used in one stent coating film. The surface properties may vary depending on the physical properties of the absorption promoting agent.

According to one embodiment of the present invention, when pluronic is used, it can be confirmed by using a scanning electron microscope that the surface becomes gradually smooth in the case of a polyurethane-based stent coating film containing 5-15% pluonic. In addition, when cyclodextrin inclusion product is used, it can be confirmed that the drug is enclosed in a spherical particle form, and when sodium caprate is used, the sodium caprate is located on the surface.

The present invention also provides a composition for stent coating for drug release containing an absorption promoting agent and can provide a drug releasing stent containing a polymer coating coated with a composition for stent coating for drug release containing an absorption promoting agent .

Further, the present invention can provide a method for manufacturing a drug-releasing stent containing an absorption promoting agent, characterized by coating the composition of the present invention on a medical stent.

Here, in the stent manufacturing method, the coating may be performed by immersing the stent into the composition of the present invention or spraying or applying the composition of the present invention to the surface of the stent.

Hereinafter, the present invention will be described in more detail with reference to 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.

< Example  1>

As an absorption promoter Sodium caprate 10% by weight of drug release Stent  Coating film manufacturing

85 mg of paclitaxel and 500 mg of polyurethane are uniformly dissolved in 10 ml of tetrahydrofuran, and then 65 mg of sodium caprate is added and mixed evenly. Then, a Teflon rod wrapped with PTFE film was coated by dip coating method. The polyurethane coated PTFE film containing paclitaxel was then dried at room temperature.

< Example  2>

As an absorption promoter pluronic This 10% by weight drug release Stent  Coating film manufacturing

85 mg of paclitaxel and 500 mg of polyurethane are uniformly dissolved in 10 ml of tetrahydrofuran and mixed with 65 mg of pluronic F127. Coat the Teflon rod wrapped with PTFE film by dip coating method. The polyurethane coated PTFE film containing prakl texel was dried at room temperature.

< Example  3>

As an absorption promoter Cyclodextrin The inclusion cargo  Drug release included Stent  Coating film manufacturing

85 mg of paclitaxel and 85 mg of cyclodextrin were placed in a solution of acetone: water (1: 1 v / v), mixed evenly, and acetone was volatilized to prepare the inclusion product. The above inclusion product is lyophilized and again dispersed in 10 ml of tetrahydrofuran. 500 mg of polyurethane is added and dissolved evenly. 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.

< Example  4>

As an absorption promoter phenyl piperazine and Sodium lauryl sulfate Drug release with Stent  Coating film manufacturing

85 mg of paclitaxel and 500 mg of polyurethane are uniformly dissolved in 10 ml of tetrahydrofuran. Add phenyl piperazine and sodium lauryl sulfate and mix evenly. Coat the Teflon rod wrapped with PTFE film by dip coating method. The polyurethane coated PTFE film containing prakl texel was dried at room temperature.

< Comparative Example  1]>

Drug release without absorption enhancer Stent  Coating film manufacturing

85 mg of paclitaxel and 500 mg of polyurethane are evenly dissolved in 10 ml of tetrahydrofuran and mixed evenly. Coat the Teflon rod wrapped with PTFE film by dip coating method. The polyurethane coated PTFE film containing prakl texel was dried at room temperature.

< Experimental Example  1>

Surface observation by scanning electron microscope

To confirm the surface of the stent coating containing the absorption promoter, the dried coating was plated for 45 seconds and then observed with a scanning electron microscope. In this experiment, stent coatings prepared by the methods of Examples 1 to 4 were used.

As shown in FIG. 1, it can be seen that the sodium caprate is located on the surface of the stent coating film containing the sodium caprate. In the case of the coating film for the stent coating containing the pluronic, as shown in FIG. 2, As shown in FIG. 3, it was confirmed that the coating film for stent coating containing the cyclodextrin inclusion product is located in the coating film in the form of particles. In the case of the coating film using phenyl piperazine and sodium lauryl sulfate as shown in FIG. 4, And it was confirmed that it became smooth.

< Experimental Example  2>

Comparison of drug release with addition of absorption enhancer

The drug release rate was analyzed from the stent coating film containing the absorption enhancer according to the present invention. In this experiment, a stent coating film prepared in the same manner as in Examples 1 to 4 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. 6 to FIG. 7, drug release was promoted in Example 4 compared to Example 5 in the control group, and in Example 1, there was no effect on drug release.

< Experimental Example  3>

Comparison of tissue penetration efficiency of released drug with absorption enhancer addition

In order to confirm the penetration efficiency of the polymeric coating for stent coating comprising the absorption promoter according to the present invention, a film containing a fluorescent material having a physical property similar to that of the drug was inserted into the animal, and after a certain period of time, The penetration efficiency of the fluorescent material was compared by a microscope.

As a result, the drug of the polymer coating for stent coating containing the absorption enhancer of the present invention showed superior tissue penetration efficiency as compared with 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 (10)

A composition for stent coating for drug release containing an absorption promoting agent. The method according to claim 1,
The absorption promoter may be selected from the group consisting of erpene, terpenoid, essential oil, pyrrolidone, fatty acid, ester, sulfoxide, alcohol, glycol, glyceride, Azone, phospholipid, cyclodextrin inclusion, sodium caprate, Clofibric Acid, Dodecyl-N, , pluronic, sodium lauryl sulfate, phenyl piperazine, and oleic acid. The method according to claim 1,
Wherein the absorption promoting agent is a low molecular weight substance having a weight of 1000 g / mol or less and is contained in an amount of 0.5 to 30% by weight based on the total weight of the composition. The method according to claim 1,
Wherein said medicament is selected from the group consisting of paclitaxel, gemcitabine, silolimus, mitomycin C and genes. A drug releasing stent containing a polymeric coating coated with a composition for stent coating for drug release containing an absorption promoting agent. 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. A method for preparing a drug-releasing stent containing an absorption promoting agent, which comprises coating the composition of claim 1 on a medical stent. 10. The method of claim 9,
Wherein the coating comprises immersing the stent in the composition of claim 1 or spraying or applying the composition of claim 1 to the surface of the stent.

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