KR20230105694A - Drug-coated balloon catheter and method for manufacturing the same, and drug composition for the same - Google Patents

Abstract

The present invention, herbs; a tube connected to the hub and configured to be inserted into a blood vessel; a balloon mounted to surround the tube and configured to be inflated by a fluid injected through the hub and the tube; and a drug-releasing coating layer coated on a surface of the balloon and configured to release a drug to a lesion site of the blood vessel when the balloon is inflated, wherein the drug-releasing coating layer comprises a drug and the drug to the balloon. A drug-coated balloon catheter formed by coating a drug composition containing mussel adhesive protein, which is a natural substance, as an adhesive fixative for adhesion and fixation, and a method for manufacturing the same, and a drug for drug-coated balloon catheter composition is provided.

Description

Drug-coated balloon catheter and manufacturing method thereof, and drug composition for drug-coated balloon catheter

The present invention relates to a balloon catheter inserted into a blood vessel and used in a procedure for vasodilation and drug application, a manufacturing method thereof, and a drug composition for coating.

In general, a catheter refers generically to a medical catheter inserted into the human body. In the medical field, catheters for various body insertions, such as catheters for blood vessel injection, coronary artery dilation, urethra insertion, airway insertion, and laparoscopic surgery catheters, are used.

Among them, a balloon catheter (PTCA) for coronary artery dilatation has, for example, a balloon for expansion formed near the tip of a guide tube inserted into a blood vessel. When fluid is introduced through the fluid injection tube communicating with the balloon, the balloon is inflated.

A drug may be applied to the surface of the balloon of the balloon catheter. Such a drug is configured so that when the balloon is inflated within the blood vessel and comes into contact with the inner wall of the blood vessel, it can directly act on the blood vessel and its adjacent tissue while penetrating the inner wall of the blood vessel.

However, while the balloon catheter enters the blood vessel and moves to the lesion site, the rate of loss of the drug coated on the balloon is high due to dissolution by blood flow and blood. In this case, there is a problem in that the drug is not absorbed in a sufficient amount into the inner wall of the blood vessel at the lesion site, and thus the treatment effect of the drug at the lesion site is lowered. In addition, even after balloon inflation, the drug cannot be continuously delivered to the lesion site, and thus the treatment effect is lowered.

One object of the present invention is a drug-coated balloon catheter and method for manufacturing the same, which stably adheres and fixes a drug that is affected by blood flow to a balloon so that the drug can be effectively delivered to a lesion site of a blood vessel, and a drug coating It is to provide a drug composition for a type balloon catheter.

Another object of the present invention is a drug-coated balloon catheter and method for manufacturing the same, and a drug-coated balloon catheter, which can minimize an immune inflammatory reaction by using a natural material with excellent biocompatibility for adhesive fixation of a drug, and a drug-coated balloon catheter To provide a drug composition.

A drug-coated balloon catheter according to an aspect of the present invention for realizing the above object is a hub; a tube connected to the hub and configured to be inserted into a blood vessel; a balloon mounted to surround the tube and configured to be inflated by a fluid injected through the hub and the tube; and a drug-releasing coating layer coated on a surface of the balloon and configured to release a drug to a lesion site of the blood vessel when the balloon is inflated, wherein the drug-releasing coating layer comprises a drug and the drug to the balloon. As an adhesive fixing agent for adhesion and fixation, it may be formed by coating a drug composition containing mussel adhesive protein, which is a natural substance.

Here, the drug may include at least one selected from the group consisting of cell growth inhibitors, restenosis inhibitors, re-epithelialization promoters, and anti-inflammatory agents.

Here, the cell proliferation inhibitor may include Everolimus.

Here, the drug composition further includes a dissolution inhibitor for preventing dissolution of the drug, and the dissolution inhibitor may include shellac, a natural substance.

Here, the drug composition may include 30 parts by weight to 70 parts by weight of the shellac based on 100 parts by weight of the drug.

Here, the drug composition may include 30 parts by weight to 70 parts by weight of the mussel adhesive protein based on 100 parts by weight of the drug.

Here, the drug composition includes 30 parts by weight to 70 parts by weight of each of the shellac and the mussel adhesive protein, based on 100 parts by weight of the drug, and the shellac and the mussel adhesive protein, based on 100 parts by weight of the drug. The mixture may contain 100 parts by weight.

A drug composition for a drug-coated balloon catheter according to another aspect of the present invention includes a drug for acting on a lesion site in a blood vessel; a dissolution inhibitor for preventing the drug from being dissolved by the bloodstream; and an adhesive fixing agent for attaching and fixing the drug to a balloon of a catheter to be inserted into the blood vessel, and the adhesive fixing agent may include mussel adhesive protein, which is a natural material.

Here, the drug may include everolimus, and the dissolution inhibitor may include shellac.

Here, with respect to 100 parts by weight of the drug, 30 parts by weight to 70 parts by weight of the shellac and 30 parts by weight to 70 parts by weight of the mussel adhesive protein are included, and with respect to 100 parts by weight of the drug, the shellac and the mussel The mixture of adhesive proteins may include 100 parts by weight.

A method for manufacturing a drug-coated balloon catheter according to another aspect of the present invention includes the steps of mixing a drug, shellac, and mussel adhesive protein in a solvent to produce a coating liquid; Applying the coating liquid to the surface of the balloon in a state where the balloon of the balloon catheter is inflated; and drying the coating liquid to form a drug-releasing coating layer on the surface of the balloon by curing the coating liquid.

Here, in the step of mixing the drug, shellac, and mussel adhesive protein in a solvent to create a coating liquid, the shellac is 30 to 70 parts by weight and the mussel adhesive protein is 30 parts by weight, based on 100 parts by weight of the drug. It may include mixing parts by weight to 70 parts by weight.

According to the drug-coated balloon catheter and method for manufacturing the same according to the present invention configured as described above, and the drug composition for the drug-coated balloon catheter, the balloon surface of the balloon catheter configured to be inserted into the lesion site in the human body is at the lesion site. A drug-releasing coating layer configured to release the drug is formed. The drug-releasing coating layer is coated with a drug composition containing a drug and mussel adhesive protein, which is a natural substance as an adhesive fixing agent for adhering and fixing the drug to a balloon, so that the drug It acts on the lesion site for a long time without leaving the balloon by blood flow, etc., so that the drug absorption rate at the lesion site can be improved.

In addition, since mussel adhesive protein used as an adhesive fixing agent and shellac used as a dissolution inhibitor are natural substances, the immune inflammatory response of the human body according to their use can be minimized.

1 is a perspective view showing a drug-coated balloon catheter 100 according to an embodiment of the present invention.
Figure 2 is a view for explaining the drug (D) for coating the balloon forming the drug release coating layer 150 of FIG.
Figure 3 is a graph showing the evaluation results for coating stability according to the composition ratio of the drug composition (D).
Figure 4 is a graph showing the evaluation results for the vascular absorption rate according to the composition ratio of the drug composition (D).
Figure 5 is a flow chart for explaining a method for manufacturing a drug-coated balloon catheter according to another embodiment of the present invention.

Hereinafter, a drug-coated balloon catheter according to a preferred embodiment of the present invention, a manufacturing method thereof, and a drug composition for a drug-coated balloon catheter will be described in detail with reference to the accompanying drawings. In this specification, the same or similar reference numerals are assigned to the same or similar components even in different embodiments, and the description is replaced with the first description.

1 is a perspective view showing a drug-coated balloon catheter 100 according to an embodiment of the present invention.

Referring to this figure, the drug-coated balloon catheter 100 may be composed of a hub 110, a tube 120, a soft tip 130, a balloon 140, and a drug release coating layer 150.

The hub 110 is a hollow cylindrical body. The hub 110 is formed of a shape and material that can be held by the operator. In terms of material, the hub 110 may be made of a plastic-based material.

The tube 120 is a hollow body extending to connect the hub 110 and the soft tip 130 . The tube 120 serves to transmit the force to the soft tip 130 when the operator holds the hub 110 and inserts the balloon 140 into the blood vessel. A portion of the tube 120 close to the soft tip 130 is inserted into a blood vessel with many curves, such as the heart, and may be made of a highly flexible material so as to be bent corresponding to the curve.

The soft tip 130 is a configuration that can be additionally attached to the tip of the tube 120. The soft tip 130 often collides with the inner wall of the blood vessel while entering the blood vessel from the tip of the catheter 100 . In order to prevent damage to blood vessels accordingly, the soft tip 130 may be formed of a material that is more ductile than the tube 120 .

A balloon 140 is installed on the side of the free end of the tube 120 to enclose it. The balloon 140 is a fluid supplied through the hub 110 and the tube 120 and is configured to be inflated by, for example, the pressure of a contrast agent. Thereby, the balloon 140 expands blood vessels in a location desired by the operator to improve blood vessel blockage. The operator can also determine his position through the contrast agent injected into the balloon 140.

The drug release coating layer 150 is formed by coating the surface of the balloon 140 with the drug composition (D). The drug composition (D) includes a drug to be absorbed into the lesion site of blood vessels, and the drug is released from the drug release coating layer 150 toward the lesion site.

The drug composition (D) forming the drug release coating layer 150 will be described with reference to FIG. 2 . Figure 2 is a view for explaining the drug (D) for coating the balloon forming the drug release coating layer 150 of FIG.

Referring to this figure, the drug composition (D) may include a drug, an adhesive fixing agent, and a dissolution inhibitor.

The drug may include at least one selected from the group consisting of cell growth inhibitors, restenosis inhibitors, re-epithelialization promoters, and anti-inflammatory agents. Accordingly, the drugs are everolimus, sirolimus, paclitaxel, heparin, amoxicillin, spaclitaxel, doxorubicin, ganciclovir, verapramil It may be selected from the group consisting of (verapramil), clonidine, simvastatin, and combinations thereof.

Among them, everolimus is a cell proliferation inhibitor that inhibits cell division and angiogenesis, and is a type of mTOR inhibitor. Together with Exmesstan (trade name: Aromasin), it is used for the treatment of postmenopausal advanced breast cancer patients who are hormone receptor positive, human epidermal growth factor receptor 2 (HER2) negative, and surgically removed It is also used in the treatment of difficult pancreatic, lung, and gastrointestinal neuroendocrine tumors. In addition, it is used for the treatment of advanced renal cancer and subependymal giant cell astrocytoma.

A dissolution inhibitor is an element for preventing dissolution of a drug, eg everolimus, in the blood. Specifically, the dissolution inhibitor prevents everolimus from being dissolved by blood in the blood vessel V while the balloon 140 moves along the blood vessel V in a state where the balloon 140 is contracted to the tube 120 (see FIG. 1). It can be prevented. To this end, the dissolution inhibitor may include a natural resin such as shellac. Shellac is a kind of natural resin extracted from bodily fluids or secretions of rock scale insects, and has excellent oil resistance and moisture resistance. Due to these characteristics, shellac is widely used in daily life, such as being used in the pharmaceutical field to perform a function to deliver pills to the intestine without being absorbed, or used in chocolate to prevent moisture penetration and perform a glossy function.

The adhesive fixing agent is a component that adheres and fixes the drug to the balloon 140. As the adhesive fixing agent, mussel adhesive protein (MAP), a natural material, may be used. Mussel adhesive protein is an adhesive made of protein that mussels make to live by adhering to surfaces such as rocks in water. As a result, the mussel adhesive protein has a property of expressing adhesive ability even in the blood, and serves to improve drug delivery performance to blood vessels and prevent drug loss in blood flow. Mussel adhesive protein is harmless to the human body and biodegradable, so it can be said to be an innovative bioadhesive that can be used in our body. Mussel adhesive protein can be directly extracted from mussels, but technology for obtaining large quantities through microbial culture is being developed to increase economic feasibility.

In the above drug composition (D), the composition ratio between the drug and other components will be described with reference to FIGS. 3 and 4 .

First, Figure 3 is a graph showing the evaluation results for coating stability according to the composition ratio of the drug composition (D).

Referring to this figure, the experimental contents and results of the ratio of the weight of shellac as a dissolution inhibitor and the weight of mussel adhesive protein as an adhesion fixative to the weight of everolimus as a drug are shown in Table 1 and FIG. 3 below.

type 1 type 2 type 3 type 4 type 5 Everolimus 100 100 100 100 100 shellac 20 30 50 70 80 mussel adhesive protein 80 70 50 30 20

Referring to the above experimental results, 100 parts by weight of a mixture of shellac and mussel adhesive protein was also mixed with respect to 100 parts by weight of everolimus. If the composition ratio of shellac and mussel adhesive protein to everolimus is less than the set composition ratio, the coating shape becomes non-uniform. In the opposite case, the coating thickness becomes excessive and the amount of drug becomes insufficient. Therefore, with respect to 100 parts by weight of everolimus, types 1 to 5 were tested while maintaining the mixture of shellac and mussel adhesive protein at 100 parts by weight, while changing the amount of shellac and mussel adhesive protein. For example, in Type 1 the shellac is 20 parts by weight while the mussel adhesive protein is 80 parts by weight. In the case of type 5, shellac is 80 parts by weight, and mussel adhesive protein is mixed with 20 parts by weight.

The test subject is a PBS 1X solution. The test method is to measure the amount of everolimus, a drug remaining in the balloon, after immersing the balloon 140 on which the drug-releasing coating layer 150 is formed in the above solution for 60 seconds. The result value uses the average value after repeating the experiment three times.

As a result, the everolimus survival rate is highest in type 3 at 95%, and type 2 is very close at 94%. Others Type 4 is 90%, Type 5 is 85%, still showing a high retention rate. However, type 1 is 72%, which is significantly lower than other types by at least 15% and up to 20%.

From these results, type 1 is excluded because it has a low survival rate and lacks stability. Accordingly, the pharmaceutical composition (D) preferably contains 30 to 80 parts by weight of shellac and 20 to 70 parts by weight of mussel adhesive protein, based on 100 parts by weight of everolimus.

Next, Figure 4 is a graph showing the evaluation results for the vascular absorption rate according to the composition ratio of the drug composition (D).

Referring to this figure, the contents and results of experiments on the weight ratio of shellac as a dissolution inhibitor and mussel adhesive protein as an adhesion fixative to the weight of everolimus as a drug are shown in Table 2 and FIG. 4 below.

type 1 type 2 type 3 type 4 type 5 Everolimus 100 100 100 100 100 shellac 20 30 50 70 80 mussel adhesive protein 80 70 50 30 20

Referring to the above experimental results, as in the previous experiment, 100 parts by weight of a mixture of shellac and mussel adhesive protein was also mixed with 100 parts by weight of everolimus. Types 1 to 5 were tested with varying amounts of shellac and mussel adhesive proteins. For example, in Type 1 the shellac is 20 parts by weight while the mussel adhesive protein is 80 parts by weight. In the case of type 5, shellac is 80 parts by weight, and mussel adhesive protein is mixed with 20 parts by weight.

The test subject is the inner wall of the blood vessels of the femoral arteries of minipigs. The experimental method is to measure the amount of everolimus delivered to the blood vessel after inflating the balloon (140, see FIG. 1 above) on which the drug-releasing coating layer 150 is formed against the inner wall of the blood vessel for 30 seconds. To this end, blood vessels immersed in distilled water are pulverized in the aqueous phase (suspension of several μm or less) through a grinder, and then centrifuged after adding a drug solvent to obtain a supernatant, which is then subjected to qualitative and quantitative analysis by HPLC drug test method. The result value uses the average value after repeating the experiment three times.

As a result, the absorption rate of everolimus is the highest at 84% for type 3, and very close to it at 80% for type 2. The other type 4 still shows a high absorption rate at 77%. However, Type 1 is 43% and Type 5 is 49%, which is a minimum of 35% and a maximum of 50% less than other types.

From these results, types 1 and 5 are excluded because their vascular absorption rates are remarkably low. Accordingly, the pharmaceutical composition (D) preferably contains 30 to 70 parts by weight of shellac and 30 to 70 parts by weight of mussel adhesive protein, based on 100 parts by weight of everolimus.

Based on the results of the above two experiments, considering both coating stability and drug absorption rate, the drug composition (D) was composed of 30 to 70 parts by weight of shellac and 30 parts by weight of mussel adhesive protein, relative to 100 parts by weight of everolimus. It can be seen that it is preferable to include 70 parts by weight to 70 parts by weight. In addition, with respect to 100 parts by weight of everolimus, it is preferable that the weight of the mixture of shellac and mussel adhesive protein is also mixed at 100 parts by weight.

A method for manufacturing a drug-coated balloon catheter using the above liquid composition will be described with reference to FIG. 5 .

Referring to FIG. 5, first, a coating liquid must be generated (S1). To this end, as described above, everolimus, shellac, and mussel adhesive protein must be mixed in a solvent.

Their mixing ratio is as described above. For uniform mixing and dissolution stability of the mixed components, the coating liquid may be sonicated for about 10 minutes.

As a next step, the coating liquid may be applied to the surface of the balloon while the balloon is inflated (S3).

Finally, by drying the coating liquid, the drug-releasing coating layer according to the curing of the coating liquid on the surface of the balloon is completed (S5). Drying of the coating liquid may be achieved by placing it at room temperature for 2 hours.

The drug-coated balloon catheter and its manufacturing method, and the drug composition for the drug-coated balloon catheter as described above are not limited to the configuration and operation of the above-described embodiments. The above embodiments may be configured so that various modifications can be made by selectively combining all or part of each embodiment.

100: drug-coated balloon catheter 110: hub
120: tube 130: soft tip
140: balloon 150: drug release coating layer

Claims (12)

Herb;
a tube connected to the hub and configured to be inserted into a blood vessel;
a balloon mounted to surround the tube and configured to be inflated by a fluid injected through the hub and the tube; and
A drug-releasing coating layer coated on the surface of the balloon and configured to release the drug to the lesion site of the blood vessel when the balloon is inflated;
The drug-releasing coating layer,
A drug-coated balloon catheter formed by coating a drug composition containing a drug and a natural material, mussel adhesive protein, as an adhesive fixative for fixing the drug to the balloon by adhesion.
According to claim 1,
The drug is
A drug-coated balloon catheter comprising at least one selected from the group consisting of cell growth inhibitors, restenosis inhibitors, re-epithelialization promoters, and anti-inflammatory agents.
According to claim 2,
The cell proliferation inhibitor,
A drug-coated balloon catheter containing Everolimus.
According to claim 1,
The drug composition,
Further comprising a dissolution inhibitor for preventing dissolution of the drug,
The dissolution inhibitor,
A drug-coated balloon catheter containing shellac, a natural material.
According to claim 4,
The drug composition,
The drug-coated balloon catheter comprising 30 parts by weight to 70 parts by weight of the shellac based on 100 parts by weight of the drug.
According to claim 1,
The drug composition,
Based on 100 parts by weight of the drug, the mussel adhesive protein comprises 30 parts by weight to 70 parts by weight, the drug-coated balloon catheter.
According to claim 4,
The drug composition,
Based on 100 parts by weight of the drug, each of the shellac and the mussel adhesive protein comprises 30 parts by weight to 70 parts by weight,
The drug-coated balloon catheter, wherein the mixture of the shellac and the mussel adhesive protein comprises 100 parts by weight based on 100 parts by weight of the drug.
drugs for acting on lesion sites within blood vessels;
a dissolution inhibitor for preventing the drug from being dissolved by the bloodstream; and
An adhesive fixing agent for attaching and fixing the drug to the balloon of the catheter to be inserted into the blood vessel,
The adhesive fixing agent,
A drug composition for a drug-coated balloon catheter comprising mussel adhesive protein, which is a natural substance.
According to claim 8,
The drug includes everolimus,
The dissolution inhibitor comprises shellac, a drug composition for a drug-coated balloon catheter.
According to claim 9,
30 parts by weight to 70 parts by weight of the shellac and 30 parts by weight to 70 parts by weight of the mussel adhesive protein, based on 100 parts by weight of the drug;
A drug composition for a drug-coated balloon catheter comprising 100 parts by weight of a mixture of the shellac and the mussel adhesive protein, based on 100 parts by weight of the drug.
mixing the drug, shellac, and mussel adhesive protein in a solvent to create a coating liquid;
Applying the coating liquid to the surface of the balloon in a state where the balloon of the balloon catheter is inflated; and
A method for manufacturing a drug-coated balloon catheter comprising the step of drying the coating liquid and forming a drug-releasing coating layer on the surface of the balloon according to the curing of the coating liquid.
According to claim 11,
The step of mixing the drug, shellac, and mussel adhesive protein in a solvent to create a coating solution,
A method for manufacturing a drug-coated balloon catheter comprising mixing 30 parts by weight to 70 parts by weight of the shellac and 30 parts by weight to 70 parts by weight of the mussel adhesive protein with respect to 100 parts by weight of the drug.

Images