KR101686628B1

KR101686628B1 - Drug and photothermal therapy capable hybrid stent and a method of manufacturing the same

Info

Publication number: KR101686628B1
Application number: KR1020150070831A
Authority: KR
Inventors: 강대환; 김도형; 이혜림; 곽태원; 정영일; 김수진
Original assignee: 부산대학교 산학협력단; 부산대학교병원
Priority date: 2015-05-21
Filing date: 2015-05-21
Publication date: 2016-12-14
Also published as: KR20160136802A

Abstract

The present invention relates to a hybrid stent capable of drug and photothermal therapy and a method of manufacturing the same, comprising the steps of: forming a photothermal film that generates heat through light irradiation on a surface of a stent; And a step of laminating a drug-carrying film containing a drug on the surface of the photothermographic film. Thus, the photothermographic film and the drug-carrying film are laminated on the stent, thereby releasing the drug primarily, and the secondary heat is generated through the irradiation of light to obtain the effect of continuous photothermal treatment.

Description

TECHNICAL FIELD [0001] The present invention relates to a hybrid stent capable of performing drug and phototherapy, and a method for manufacturing the hybrid stent.

The present invention relates to a hybrid stent capable of treatment with drugs and photothermal therapies, and a method of manufacturing the same. More particularly, the present invention relates to a stent for stably implanting a photothermal film and a drug- The present invention relates to a hybrid stent capable of continuous photothermal therapy, and a method of manufacturing the hybrid stent.

A stent is a technique that can be used to prevent flow when blood or body fluids such as blood vessels, stomachs, and bile ducts are not flowing smoothly due to malignant or benign disease. It is a cylindrical medical material used for normalization.

The stent is divided into a blood vessel stent and a non-blood vessel stent. Vascular stents are stents used for vascular disease. They are installed when the arterial diameter narrows due to the arterial sclerosis and deposition of arterial thrombosis or lipid, and the flow of blood flow is not smooth. It is mainly used in the iliac arteries of the pelvis supplying the blood flow to the legs, the carotid arteries supplying blood to the brain, and the renal arteries supplying blood to the kidneys.

Non-vascular stents are used to solve the problems of ingestion of food and defecation due to tumor or stenosis after surgery in the esophagus, duodenum, large intestine, rectum and the like. In addition, gastrointestinal cancer such as gastric cancer, esophageal cancer, colon cancer, biliary tract cancer, pancreatic cancer, liver cancer, etc. can be found in such a state that operation can not be performed. The advanced gastrointestinal cancer prevents digestive organs and causes symptoms such as dysphagia, vomiting, Cause. Therefore, a non-vascular stent may be used to open the digestive tract.

The medical stent is made of a shape memory alloy such as stainless steel, nickel titanium, and cobalt chromium, and is inserted into the body through a thin diameter treatment device. Among them, non-vessel stents are commonly used in the organs, bronchi, esophagus, and femoral joints. These non-vessel stents commonly need to solve two problems. The first is internal proliferation that narrows the lumen by generating a positive hyperplasia of the tissue due to foreign body reaction to the inserted stent. The second is malignant hyperstimulation in the stent inserted to treat the obstruction of the body passageway by cancer. Thus, the primary goal of functional stents used in the digestive tract is to prevent the overexpression of these tumors.

Drug-releasing stents in functional stents have limitations in cancer treatment. Drug-releasing stents are limited in the amount of drug that can be carried on the stent, and it is difficult to control the rate of drug release. In addition, the cancer treatment is not likely to be cured because the cancer cells grow again when the drug is released through the stent. This is also a limitation of the drug-eluting stent. In addition, since the activity of anticancer drugs is different for each specific cancer cell, for example, when the drug used for inhibiting the proliferation of blood vessels is applied to a stenosed gastric canal stented by cancer, the therapeutic effect is not high. In order to overcome the limitations of these drug-eluting stents, various functional stents are required to be developed. Recently, the development of stents capable of treating lesions through fever has attracted attention.

Korea Patent Office Registration No. 10-1187842 Korea Patent Office Registration No. 10-1328660 Korea Patent Office Registration No. 10-1477517

SUMMARY OF THE INVENTION Accordingly, it is an object of the present invention to provide a hybrid stent in which a photothermographic film and a drug-carrying membrane are laminated on a stent to emit drugs firstly, and secondarily irradiated with light to generate continuous heat treatment.

The above-described object is achieved by a method of manufacturing a stent, comprising: forming a photothermal film on a surface of a stent, And a step of laminating a drug supporting membrane including a drug on the surface of the photothermographic film. The method for manufacturing a hybrid stent according to claim 1,

The step of forming the photothermographic film may include the steps of: dissolving the carbonaceous material and the non-degradable polymer, which generate heat through light irradiation, in a solvent to form a polymer-carbonaceous material mixture; And forming a photothermal film on the surface of the stent using the polymer-carbonaceous material mixture.

The carbon material may include at least one selected from the group consisting of activated carbon, graphite, graphene, soft carbon, hard carbon, carbon black, carbon nano tube, The non-decomposable polymer is preferably selected from the group consisting of silicon (CNT), carbon nano fiber (CNF), modified carbon, carbon composite and mixtures thereof And 0.1 to 1 part by weight of the carbon material is mixed with 100 parts by weight of the non-degradable polymer.

In addition, the step of forming the drug-transporting layer by laminating the drug-supporting membrane comprises: dissolving the drug and the biodegradable polymer in a solvent to form a polymer-drug mixture; And forming the drug supporting membrane on the surface of the photothermographic film using the polymer-drug mixture, wherein the drug supporting membrane is electrospinning or ultrasonic spraying to form a lamination interface with the photothermal film. Or may be formed on the surface of the photothermographic film through a phase transition method so as not to form a lamination interface with the photothermographic film.

The biodegradable polymer may be selected from the group consisting of poly (ε-caprolactone), PCL, polyurethane, polylactic acid, PLA, poly (glycolic acid) , PGA), poly (lactic-co-glycolic acid) (PLGA), and mixtures thereof, and the light is preferably near-infrared light having a wavelength of 600 to 1200 nm.

The above object is also achieved by a stent comprising: a stent; A photothermal film formed on the surface of the stent and generating heat through light irradiation; And a drug supporting membrane laminated on the surface of the photothermographic film, and a hybrid stent capable of photo-thermal therapy.

Preferably, the photothermographic film comprises a carbonaceous material and a non-degradable polymer that generate heat through light irradiation, and the drug-carrying membrane includes the drug and a biodegradable polymer. The light is preferably near-infrared light having a wavelength of 600 to 1200 nm.

According to the above-described structure of the present invention, the photothermographic film and the drug-carrying membrane are laminated on the stent, releasing the drug first, and secondarily irradiated with light to obtain the effect of continuous photothermal treatment.

1 is a flowchart of a hybrid stent manufacturing method according to an embodiment of the present invention,
2 is a stent photograph of Comparative Examples and Examples,
3 is a cross-sectional view of an embodiment stent,
FIG. 4 is a graph showing the amount of drug released from the drug-supporting membrane with time,
FIG. 5 is a photograph comparing tumor sizes induced in nude mice,
FIG. 6 is a graph showing the temperature of the stent of the comparative example and the example according to the intensity of light,
7 is a photograph showing the anticancer effect of the culture plate according to the comparative example and the example,
8 is a photograph showing body temperature of a nude mouse in which a photothermographic film of the embodiment is inserted.

Hereinafter, a drug and photothermal healing hybrid stent according to an embodiment of the present invention and a method of manufacturing the hybrid stent will be described with reference to the drawings.

First, as shown in FIG. 1, a polymer and a carbon material are mixed (S1).

The solution containing the polymer is mixed with a curing agent and stirred, and a solution in which carbon material is uniformly dispersed is added to form a polymer-carbonaceous mixed solution. The amount of the carbon material is preferably 0.1 to 1 part by weight based on 100 parts by weight of the polymer. When the carbon material is less than 0.1 part by weight, the degree of heat generation is low even when irradiated with light. When the carbon material is more than 1 part by weight, it is difficult to control the temperature rise, and normal cells may be killed. Therefore, the carbon material is suitably added in an amount of 0.1 to 1 part by weight based on 100 parts by weight of the polymer, most preferably 0.2 part by weight.

Here, the polymer is most preferably a silicone which is harmless when inserted into the human body and does not undergo biodegradation. When the biodegradation of the polymer occurs, the carbonaceous material mixed with the polymer is discharged from the polymer and travels into the body. When the carbonaceous material is discharged, it is not disposed at a desired site. Therefore, even if light is irradiated, the treatment is not performed properly. Instead, carbonaceous material adheres to normal cells, and normal cells can be killed. In order to prevent such problems, it is preferable to use a material that does not undergo biodegradation.

Carbon materials include activated carbon, graphite, graphene, soft carbon, hard carbon, carbon black, carbon nano tube (CNT) , Carbon nanofibers (CNF), modified carbon, carbon composites, and mixtures thereof. Among them, graphene is most preferred because it has a high thermal conductivity of 13 times as much as copper, twice that of carbon nanotubes, and has the highest conductivity among existing materials.

A photothermographic film is formed using a polymer-carbon material mixture (S2).

A photo-thermal film is formed so as to surround the outer surface of the prepared stent using the polymer-carbonaceous material mixture prepared in the step S1. A photothermal film is a film that generates heat when irradiating light. The stent is inserted into the metal rod so that the photothermal film is formed only on the outer surface of the stent, and the metal rod is supported on the polymer-carbon material mixture. The metal rod supported on the polymer-carbonaceous material mixture is rotated to uniformly apply the silicone-carbonaceous material mixture to the outer surface of the stent. Subsequently, the metal rod is taken out to evaporate the solvent contained in the polymer-carbonaceous mixed solution, and only the photothermal film made of the polymer-carbon material is dried so as to remain in the stent.

When a metal rod is supported on a polymer-carbon material mixture, a polymer-carbon material, which was present as a liquid, undergoes a phase transition to a solid around the metal rod, and when it is taken out and dried, a photothermal film is formed. The step of drying the photothermographic film is preferably performed at 20 to 100 ° C. The solvent may remain on the photothermographic film when it is dried at below 20 ° C, and the state of the polymer may change if it exceeds 100 ° C.

The biodegradable polymer and the drug are mixed (S1 ')

To form a polymer-drug mixture in which a solution in which the biodegradable polymer is dissolved and a solution in which the drug is dissolved is mixed. Like the photothermographic film, the drug-supporting membrane disposed on the surface of the stent is harmless to the human body since it is implanted in the human body and biodegradable so that the drug carried in the polymer can be released. Therefore biodegradable polymers are used. Biodegradable polymers include poly (ε-caprolactone), PCL, urethane, PU, poly (lactic acid), PLA, But are not limited to, those selected from the group consisting of poly (glycolic acid), PGA (poly (lactic-co-glycolic acid)) and mixtures thereof.

Examples of the solvent for dissolving the biodegradable polymer include chloroform, dichloromethane, tetrahydrofuran, tetrahydropyran, ethanol, isopropanol, acetone, And mixtures thereof.

The drug may be an anticancer agent, an immunosuppressive agent, an antithrombotic agent, an inflammation inhibitor, an antibiotic, a natural substance-derived proliferation inhibitor, and more specifically, sorafenib, paclitaxel, curcumin, heparin, &Lt; / RTI > albumin, and mixtures thereof. In addition to this, various drugs can be mixed. In the case of a drug, it is preferable that the drug is firstly dissolved in dimethyl sulfoxide (DMSO), which is capable of dissolving the drug, and then mixed with the biodegradable polymer since it is not easily dissolved when the drug is directly added to a solvent for dissolving the biodegradable polymer .

A drug-carrying film is laminated on the outer surface of the photothermographic film (S3).

A drug-carrying membrane which is in direct contact with the lesion portion is formed on the outer surface of the photothermographic film in order to chemically treat the lesion. The polymer-drug mixture prepared in step S1 may be used to laminate the drug-carrying membrane on the outer surface of the photothermographic film by using electrospinning, phase transition, ultrasonic spray, or the like, Obtain an included stent.

At this time, as a method of laminating the photothermographic film and the drug-carrying membrane so as to be separated from each other, electrospinning or ultrasonic spraying can be used. The present invention relates to a method of injecting a polymer-drug mixture into a photothermographic film in the state that a photothermographic film is formed on a stent, and the drug-carrying membrane is directly laminated with the lamination interface formed on the outer surface without any change in the photothermographic film. Therefore, the photothermographic film and the drug supporting membrane are in contact with each other so as not to be separated from each other, but they are not mixed with each other and a layer is formed.

A method of forming a drug-carrying membrane using a phase transition other than electrospinning or ultrasonic spraying includes a method in which a stent having a photothermographic film is supported on a polymer-drug mixture and taken out and dried to form a polymer-drug mixture on the outer surface of the photothermographic film, Method. This is because the outer surface of the photothermographic film is semi-solidified by the mixed polymer-drug solution when the stent is supported by the polymer-drug mixture. When the drug-transporting film is formed on the photothermal film, the region where the photothermal film and the drug- A separate lamination interface is not formed. That is, although the photothermographic film and the drug-carrying membrane have different functions in different configurations, the boundary lines are not distinguished from each other, so that there is no problem of being separated from each other by external force.

After the stent with the photothermographic film and the drug-carrying membrane is first dried at room temperature, the surface of the drug-supporting membrane is washed with distilled water, and then dried at about 30 ° C. Finally, the hybrid stent including the photothermographic film and the drug- .

In the hybrid stent formed from steps S1 to S3, the photo-thermal membrane and the drug-supporting membrane each have a thickness of 40 to 100 mu m. When the photothermographic film and the drug-carrying membrane are less than 40 탆, the carbon material or the drug can not be sufficiently supported, and the membrane is thin and easily damaged by external force. When the thickness is more than 100 탆, the thickness of the entire film is increased, which is not easy to insert into human body and use.

When the hybrid stent manufactured by the above method is inserted into the human body, the drug-carrying membrane formed on the outermost layer of the stent is biodegraded and the loaded drug is released. After a long period of time, the drug is released from the drug-bearing membrane and the polymer is biodegraded. If the light is irradiated from outside to the stent, the cells present in the lesion can be necrotized.

Here, near-infrared light is used as the light, and it is preferable that the wavelength is 600 to 1200 nm which corresponds to the near-infrared ray. In case of visible light, penetration is low and light energy is weak. Therefore, when the stent is inserted close to the skin, it is difficult to reach the stent. In addition, ultraviolet radiation of short wavelength causes necrosis of normal cells outside the lesion, which is also undesirable.

The near-infrared rays are preferably irradiated so that the surface temperature of the stent becomes 40 to 50 DEG C by irradiation with a short-term in-vivo light through an endoscope or a catheter. The exothermic temperature range of 40 to 50 占 폚 is a temperature range that can induce the death of cancer cells and can cause necrosis of normal cells at a temperature exceeding 50 占 폚. When the temperature is less than 40 占 폚, It can not induce death.

First, 10 g of the silicon solution was mixed with the curing agent, and then mixed homogeneously by stirring for 1 hour. Thereafter, a solution in which graphene was uniformly dispersed was added and mixed so that the graphene concentration was 0.2 part by weight relative to 100 parts by weight of silicon. A mixed solution of silicon and graphene was uniformly mixed through agitation and then defoamed by vacuum pump for 1 hour to remove gas. After removing the gas, a stent with a diameter of 1 cm and a length of 5 cm was inserted into a metal rod, and the metal rod was rotated at 100 rpm to uniformly apply a silicon-graphene mixed solution to the surface, thereby producing a photothermal film having a uniform thickness. After drying for 3 days at room temperature, the metal rod was heat-treated in an oven at 60 ° C for 24 hours to remove all of the solvent.

A drug supporting membrane is laminated on the outer surface of the photothermographic film manufactured by this method. First, 1 g of biodegradable polymer, poly (ε-caprolactone) (PCL), was added to 10 ml of dichloromethane, and the solution was stirred at room temperature for 6 hours to prepare a polymer solution.

Separately from the polymer solution, 1 g of Sorafenib, an anticancer agent, was completely dissolved in 5 ml of dimethyl sulfoxide (DMSO), and 1.65 ml of the solution was injected into the polymer solution using a micropipette. The polymer solution mixed with the anticancer agent was coated on the metal rod formed with the photothermographic film by electrospinning to form the drug - carrying membrane. The metal rod on which the drug-carrying membrane was formed was dried at room temperature for about 2 hours, and then washed with distilled water for 2 hours to wash the remaining solvent. Then, the metal rod and the stent were separated from each other and dried at 30 ° C for 6 hours to finally prepare a hybrid stent in which a photothermographic film and a drug-supporting membrane were laminated.

10 g of the silicone solution was mixed with the curing agent and then mixed homogeneously by stirring for 1 hour. Then, distilled water was added instead of graphene, and the mixture was mixed so that the concentration of distilled water was 0.2 parts by weight relative to 100 parts by weight of silicone. The mixed solution of silicon and distilled water was uniformly mixed through agitation and degassed by vacuum pump for 1 hour to remove gas. After removing the gas, a stent with a diameter of 1 cm and a length of 5 cm was inserted into a metal rod, and the metal rod was rotated at 100 rpm so as to uniformly apply a silicon-distilled water mixture to the surface. After drying for 3 days at room temperature, the metal rod was heat-treated in an oven at 60 ° C for 24 hours to remove all of the solvent.

FIG. 2 is a photograph of a stent manufactured through Comparative Examples and Examples. FIG. 2 is a photograph of a hybrid stent of a non-filmed stent, a comparative stent made only through silicon, a photothermographic film, and a drug-carrying membrane.

FIG. 3 is a cross-sectional view of a stent manufactured through an embodiment, wherein a Graphene-Silicon covered membrane is formed of a metal stent made of graphene-silicon. Because the stent is typically in the form of a grid, some are placed inside the stent, even though the photothermal film is formed with the stent embedded in the metal rod. On the outer surface of the photothermographic film, a drug-loaded membrane containing a drug is laminated.

FIG. 4 is a graph showing the amount of the drug released from the drug-supporting membrane for treating the lesion in the first pass, and a drug-bearing membrane containing sorafenip at 2, 5, 7, and 10 parts by weight based on 100 parts by weight of the polymer. Regardless of the loading concentration of sorapenib in the drug - loaded membrane, it was released constantly and about 17% of its total weight was released within one month. From this point onwards, it was confirmed that a certain amount was released steadily.

FIG. 5 shows that the tumor size is significantly reduced compared to the control (control), which induces the back cancer of nude mice and inserting the drug-bearing membrane bearing sorapenib into the tumor tissue to confirm that the tumor size is reduced. Thus, it was confirmed that when a drug-supporting membrane comprising a biodegradable polymer and a drug is used, the drug can be released and the lesion can be treated.

FIG. 6 is a graph showing changes in temperature with time in the stent of the comparative example and the example according to intensity of light. In the box blocking heat transfer from the outside, the stents of the comparative example and the example were placed on the mercury thermometer, and the amount of irradiated light was varied, and the temperature change with time was measured. In the case of the comparative example, it was confirmed that even if the intensity of light is increased, it is difficult to increase the temperature to 40 ° C or more. On the contrary, the photothermographic film including the graphene-silicon layer according to the embodiment of the present invention has an increased temperature as the intensity of light is controlled.

FIG. 7 is a photograph showing the distribution of cancer cells after attaching a photothermographic film bearing graphene to the bottom of a culture plate where the cancer cells are cultured, irradiating 808 nm laser at 2 W / cm 2 for 5 minutes or 10 minutes. As a result, it was confirmed that about 90% of the cancer cells were killed even in the 5-minute irradiation.

Fig. 8 is a photograph showing that a silicone film of a comparative example and a graphene-carrying photothermographic film of Example were inserted under a cancer tissue by causing a back arm of a nude mouse, and irradiated with a laser of 808 nm at 2 W / cm 2 for 10 minutes. The temperature was increased to 39.7 ℃ only in the region where the photothermographic film was irradiated by laser irradiation, and it was confirmed that the cancer tissue was completely destroyed after 3 days.

As described above, in the hybrid stent of the present invention, the drug is firstly released from the drug-bearing membrane to primarily treat the lesion, and after the drug is completely released, the lesion is treated secondarily by heating the photothermographic film by irradiating light The stent can be used continuously for long periods of time without the need to replace the stent.

Claims

A method of manufacturing a hybrid stent capable of drug and phototherapy,
Forming a photothermal film on the surface of the stent, the photothermal film generating heat through light irradiation;
Depositing a drug-carrying film containing a drug on the surface of the photothermographic film,
The forming of the photothermographic film may include:
Dissolving a carbonaceous material and a non-degradable polymer that generate heat through light irradiation in a solvent to form a polymer-carbonaceous material mixture;
And forming a photothermographic film on the surface of the stent using the polymer-carbonaceous material mixture. The method for manufacturing a hybrid stent according to claim 1,

delete

The method according to claim 1,
The carbon material,
Carbon black, carbon nanotubes (CNTs), carbon nanotubes, carbon nanotubes, carbon nanotubes, carbon nanotubes, carbon nanotubes, carbon nanotubes, A method for preparing a hybrid stent according to any one of claims 1 to 3, wherein the polymer is selected from the group consisting of carbon nanofibers (CNF), modified carbon, carbon composite, and mixtures thereof.

The method according to claim 1,
Wherein the non-degradable polymer is silicone. &Lt; RTI ID = 0.0 > 8. < / RTI >

The method according to claim 1,
Wherein the carbon material is mixed in an amount of 0.1 to 1 part by weight with respect to 100 parts by weight of the non-degradable polymer.

The method according to claim 1,
The step of stacking the drug-
Dissolving the drug and the biodegradable polymer in a solvent to form a polymer-drug mixture;
And forming the drug-supporting membrane on the surface of the photothermographic film by using the polymer-drug mixture solution. &Lt; RTI ID = 0.0 > 8. < / RTI >

The method according to claim 6,
Wherein the drug supporting membrane is formed on the surface of the photothermographic film through electrospinning or ultrasonic spray to form a lamination interface with the photothermographic film.

The method according to claim 6,
Wherein the drug-supporting membrane is formed on the surface of the photothermographic film through a phase transition method so as not to form a lamination interface with the photothermographic film.

The method according to claim 6,
The biodegradable polymer may contain,
Poly (ε-caprolactone), PCL, Polyurethane, PU, PLA, Poly (glycolic acid), PGA, PLGA poly (lactic-co-glycollic acid) and mixtures thereof. < / RTI >

The method according to claim 1,
Wherein the light is near-infrared light having a wavelength of 600 to 1,200 nm. &Lt; RTI ID = 0.0 > 8. < / RTI >

In drug and phototherapy-compatible hybrid stents,
A stent;
A photothermal film formed on the surface of the stent and generating heat through light irradiation;
And a drug carrying membrane laminated on the surface of the photothermographic film,
Wherein the photothermographic film comprises a carbonaceous material and a non-degradable polymer that generate heat through irradiation of light, and a hybrid stent capable of photo-thermal therapy.

delete

12. The method of claim 11,
Wherein the drug-supporting membrane comprises the drug and a biodegradable polymer. 2. The hybrid stent according to claim 1, wherein the drug-supporting membrane comprises the drug and the biodegradable polymer.

12. The method of claim 11,
Wherein the light is a near-infrared ray having a wavelength of 600 to 1200 nm.