KR101302703B1 - Drug eluting stent of graft copolymers composed of poly(3-hydroxyoctanoate) and biodegradable polymer - Google Patents

Abstract

The present invention is formed by graft co-polymerization of poly (3-hydroxyoctanoate, (PHO))) to a biodegradable polyester or polyether-based polymer when absorbed into the human body It is a drug carrier by synthesis of graft copolymer of polyhydroxyoctanoate and biodegradable polymer formed by supporting a hydrophobic drug on a graft copolymer polymer, and a non-vascular drug release therapeutic stent using the same. The polyester or polyether polymer is polylactide glycolide (poly (DL-lactide-co-glyucolide), PLGA) and the graft copolymer polymer is PLGA in the hydroxyl group of PHO. The graft copolymer is formed by covalently bonding the carboxyl group of and the hydrophobic drug is paclitaxel. In the present invention, the drug-release therapeutic stent may be provided to have a local drug release control function, and thus may have an effect of providing a stent capable of preventing restenosis and treating a local site after surgery.

Description

Drug carriers by synthesis of graft copolymers of polyhydroxyoctanoate and biodegradable polymers and non-blood drug-releasing therapeutic stents (Drug eluting stent of graft copolymers composed of poly (3-hydroxyoctanoate) and biodegradable polymer }

The present invention relates to a therapeutic stent, and more particularly, by adding polyhydroxyoctanoate to a polymer having biodegradability in the human body, developing a drug carrier having improved drug release control ability and introducing the same into a non-vascular stent. The present invention relates to a drug carrier by synthesizing graft copolymers of polyhydroxyoctanoate and biodegradable polymers, which improve local treatment and prevent proliferation resistance, and a non-blood drug-releasing therapeutic stent using the same.

Cholangiocarcinoma is a disease with a small tumor size, and in most cases, local metastasis rather than systemic metastasis is a high possibility of local treatment. Malignant tumors of the extrahepatic bile ducts can be surgically resected at the time of diagnosis, with only 5 to 30% of cases. Local recurrence after surgery has a 5 year survival rate of around 10% and an average survival time of 7 months. Tumors do not respond well to chemotherapy or radiation therapy. Therefore, in most cases, the treatment of bile duct cancer is a conventional method, and the purpose of the treatment is to reduce obstructive jaundice, and bile drainage or metal drainage tube (stent) insertion is performed by surgical method, interventional radiography, or endoscopy.

Non-vascular stents, which are commonly used in the trachea, bronchus, esophagus and bile ducts, have similarities to prevent two problems. The first is internal growth due to a positive tissue response. This is a foreign body reaction to the stent, benign hyperplasia of the tissue occurs to narrow the lumen and is similar to the restenosis chain reaction of blood vessels. Secondly, malignant hyperproliferation occurs in the inserted stent to treat the obstruction of the internal pathway of the cancer. Therefore, the main goal of the development of the gastrointestinal tract is to prevent the overgrowth of these tumors.

Stents used to mitigate stenosis are usually made of metals such as stainless steel, nickel titanium (nitinol) and cobalt chromium. Increasing the diameter in a placed position after entering the body through a thin diameter ejection tool is called an expandable stent. It is most often used for vascular structures, and it is also used for non-vascular structures such as bile ducts, airways, and gastrointestinal tract.

Currently used stents mechanically widen the gut and bile ducts blocked by cancer to relieve symptoms but have no effect on the cancer itself. As a result, cancer progresses and becomes blocked again, which shortens the life of the patient and reduces the quality of life. Therefore, drug-eluting stents (DES), which impose anti-cancer effects on the function of the existing stents, can inhibit the proliferation of cancer and prolong the period of the stent clogging again. DES, which is a concept of local drug delivery where the drug is slowly released by coating the drug on the existing stent and shows its local effect, is mainly used in vascular stents, and various coating technologies are developed to maximize the local drug effect. have. However, research and development on DES is still insignificant in non-vascular stents including the digestive tract.

DES is usually composed of a polymer that adheres to a polymer that controls drug release by coating a drug on an existing bare or encapsulated metal stent. The technology of supporting the drug on the stent can be divided into three categories. There are a method of directly attaching a drug to a metal stent, a method of loading a drug into a porous metal stent, and a method of supporting a drug in a polymer coated on the stent.

Non-degradable polymers such as polyurethane (PU), polyethylene, Teflon, polytetrafluoroethylene (PTFE) and poly (lactide) (PLA), poly (glycolide) (PGA) and copolymers thereof Biodegradable polymers such as co-glycolide (PLGA), poly (ε-carolactone) (PCL), and poly (lactide-co-carolactone) can be used.

Biodegradable polymers have the advantage that the drug is released properly by diffusion as the polymer inserted into the body is decomposed, but synthetic polymers such as PLA and PLGA lower the surrounding pH by producing excess lactic acid during biodegradation. Due to the disadvantage that tissue necrosis may occur, it is urgent to develop new biodegradable polymers having various physical properties.

Therefore, the present inventors intend to develop a polymer carrier having improved drug support and drug release control function by changing the physical properties of such known biodegradable polymer materials, and to provide a non-vascular drug release therapeutic stent using the same.

The present invention is designed to meet the above demands, and an object of the present invention is to develop a polymer carrier having improved drug support and drug release control function by changing the physical properties of known biodegradable polymer materials and releasing a non-vascular drug using the same. To provide a type therapeutic stent. The anti-cancer effect is given to the existing gastroenterological stent, and a biodegradable polymer and a PHO copolymer are formed so that the anticancer drug is loaded there. The biodegradable polymer coated on is first decomposed, and then the hydrolysis of PHO is accelerated through the generated pore, thereby providing a non-vascular drug release polymer carrier with improved drug release control.

It is another object of the present invention to provide a non-vascular drug-release therapeutic stent, wherein the drug-release polymer carrier is coated on a stent.

According to an aspect of the present invention for achieving the above object, polyhydroxyoctanoate (poly (3-hydroxyoctanoate)) in a polyester (polyester) or polyether-based polymer having a biodegradable upon absorption in the human body , (PHO))), a graft copolymer polymer formed by graft copolymerization, and a hydrophobic drug supported on a drug carrier by synthesis of graft copolymer of polyhydroxyoctanoate and biodegradable polymer. There is this.

Preferably, the polyester (polyester) or polyether (polyether) polymer, the polylactide glycol (poly (L-lactide-co-glyucolide), PLGA), polylactide (poly (L-lactide) (PLA)), polyglycolide (PGA), poly (ε-carolactone (PCL)), polylactidecaprolactone (poly (L-lactide-co-carolactone)), and poly It is one of the lactide caprolactone (poly (DL-lactide-co-carolactone) polydioxanone), and more preferably polylactic acid (poly (L-lactide-co-glyucolide), PLGA).

In addition, the graft copolymer polymer is a graft copolymer formed by covalently bonding a carboxyl group of PLGA to a hydroxyl group of PHO, and the hydrophobic drug is paclitaxel.

On the other hand, another feature of the present invention is a non-blood drug-releasing therapeutic stent, polyhydroxyoctanoate (poly ( Graft copolymer formed by graft co-polymerization of 3-hydroxyoctanoate), (PHO))) A non-blood drug-releasing therapeutic stent coated with a drug carrier by synthesizing a copolymer. Wherein the polyester (polyester) or polyether (polyether) polymer is polylactide glycol (poly (L-lactide-co-glyucolide), PLGA), the graft copolymer polymer is a hydroxyl (hydroxyl) of PHO ) Is a graft copolymer formed by covalently bonding a carboxyl group of PLGA to a group, and the hydrophobic drug is paclitaxel.

In the present invention, the drug-release therapeutic stent may be provided to have a local drug release control function, and thus may have an effect of providing a stent capable of preventing restenosis and treating a local site after surgery.

1 is a diagram showing a method for synthesizing a PHO / PLGA graft copolymer according to one embodiment of the present invention.
2 is a diagram illustrating the chemical structure of the PHO / PLGA graft copolymer according to an embodiment of the present invention by NMR.
3 is a scanning electron microscope photograph of a PHO / PLGA graft copolymer polymer in accordance with an embodiment of the present invention coated with bare metal stent carrying paclitaxel as an anticancer agent.
Figure 4 is a view showing the drug release trend of paclitaxel using the paclitaxel release stent according to the present invention.

Basically, the present invention intends to give an anticancer effect to an existing gastroenterological stent, and forms a copolymer of PHO with a biodegradable polymer such as PLA / PLGA so that the anticancer drug is loaded therein so that PLA / PLGA is biodegradable in the human body. Complementing the disadvantage of the slow PHO, the PLA / PLGA coated on the stent is first decomposed and then the hydrolysis of the PHO is accelerated through the generated pore to provide a drug-free therapeutic stent with improved drug release control. do. The details will be described below.

1. Selection of Biodegradable Polymers

In order to manufacture a non-vascular drug-releasing therapeutic stent, biodegradability must be provided to perform the role of the polymer carrier coated on the stent. For this purpose, it should be those that can be used clinically as a polyester-based or polyether-based polymer. These types include polylactide glycol (poly (L-lactide-co-glycolide), PLGA), polylactide glycolide (poly (DL-lactide-co-glycolide), PLGA), polylactide (poly L-lactide, (PLA)), poly (DL-lactide, (PLA)), polyglycolide (PGA), polycaprolactone (poly (ε-carolactone) (PCL)), poly Polymers such as lactide caprolactone (poly (L-lactide-co-carolactone)), polylactide caprolactone (poly (DL-lactide-co-carolactone)), and polydioxanone can be used. .

2. Copolymers Bonded with Biodegradable Polymers

When coating the stent with the above polyester or polyether-based polymer alone, cracks may occur and cause the stent to malfunction and malfunction. In addition, the biodegradable polymer is biodegradable in the human body to produce lactic acid (lactic acid) to cause tissue necrosis should be able to suppress such side effects as much as possible. Therefore, in the present invention, a material having less elasticity than the biodegradable polymer to prevent cracking during stent coating, and to make biodegradability more slowly in the human body to produce less lactic acid. It should be selected and formed a copolymer with the biodegradable polymer carrier described above to form a polymer drug carrier.

As such a material, polyhydroxyoctanoate (PHO) is a suitable material.

In the following description, polyhydroxyalkanoates (PHA) is a secondary product in an environment in which some bacteria lack an dissolved oxygen content or a nutrient such as nitrogen, phosphorus, and sulfur in the presence of an excessive carbon source. It is a storage material stored in the body. The unit of PHA is 3-hydroxyalkanoate (3HA) consisting of three carbon atoms, and R groups of various lengths can be connected to the third carbon. The PHA can be classified into two types according to the R group attached to the unit 3HA. The unit 3HA produced according to the synthesis route for synthesizing PHA is composed of PHA having 4 to 5 carbon atoms in short chain length PHA (scl-PHA), 6 PHAs consisting of more than one carbon are called medium chain length PHAs (mcl-PHAs). Depending on the bacteria that biosynthesize PHA, it is possible to produce PHAs with a wide variety of properties.

Pseudomonas oleovorans is a bacterium that biosynthesizes mcl-PHA. P. oleovorans uses octanoate as a single carbon source, hydroxyoctanoate (3HO) with 8 carbon atoms as the unit, accounting for about 90% of the polymer, and hydroxy with 6 carbon atoms. 3-hydroxyhexanoate (3HHx) biosynthesizes the polyhydroxyoctanoate (PHO) which takes up the remainder. PHO has a molecular weight of about 50,000 and has a glass transition temperature ( Tg ) of -45 ° C and a melting point ( Tm ) of 53 ° C. Due to the low glass transition temperature, PHO is an elastomer and is elastic when made into a film. In nature, PHO can be biodegraded by hydrolysis or PHA degrading enzymes produced by bacteria. However, since PHO degrading enzymes do not exist in the human body, they are dependent on hydrolysis. In addition, PHO may be used as a carrier for supporting drugs in the form of nanoparticles and films, and is more suitable for supporting hydrophobic drugs than hydrophilic drugs because of its hydrophobic nature.

Hereinafter, a specific embodiment of the drug-release therapeutic stand coated with a drug and coated on the stent to form a polymer carrier by copolymerizing the above-described biodegradable polymer and polyhydroxyalkanoate (PHO) Shall be.

Example

Synthesis of Graft Copolmyer of Poly (3-hydroxyoctanoate, PHO) and Poly (DL-lactide-co-glycolide, PLGA)

1 illustrates a method for synthesizing a PHO / PLGA graft copolymer. The graft copolymer was synthesized by covalently binding the carboxyl group of PLGA to the hydroxyl group of PHO. In this case, poly (L-lactide-co-glycolide), poly (L-lactide) (PLA), poly (DL-lactide), polyglycolide (PGA), and poly (ε-carolactone) which are graft copolymerized into PLGA-like terms. (PCL), poly (L-lactide-co-carolactone), poly (DL-lactide-co-carolactone) polydioxanone polyester, polyether-based polymers can be used. Specifically, 500 mg of poly (3-hydroxyoctanoate) (PHO) and an appropriate amount of poly (DL-lactide-co-glycolide) (PLGA) were added to tetrahydroxyfuran (THF, tetrahydroxyfuran) or methylene chloride (MC, Dissolve in methylene chloride,), dimethyl sulfoxide (DMSO, dimethylsulfoxide), add about 1.5 times N-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) of PLGA, and stir for about 2 days. After stirring for 2 days, precipitated and purified by diethyl ether. Repeat this process three more times. As described above, instead of PLGA, PLA, PGA, PCL, poly (L-lactide-co-carolactone), poly (DL-lactide-co-carolactone) polydioxanone polyester, polyether-based polymers may be used.

2. Characterization of polymer

The chemical structure of the polymer synthesized in ¹ was analyzed using ¹ H nuclear magnetic resonance (NMR) spectra. 2 is a result of analyzing the chemical structure of the synthesized PHO / PLGA graft copolymer by NMR, it is shown that both the characteristic peak of PHO and the characteristic peak of PLGA as shown, PLGA is a graft copolymer in PHO It was found that well synthesized.

 The molecular weight was analyzed by gel-permeation chromatography (GPC). Table 1 shows the characteristics of the molecular weight of the PHO / PLGA graft copolymers. As shown in the table, PHO / PLGA graft copolymers have almost increased molecular weight by the molecular weight of PLGA as shown in the table. It was found that the copolymer was synthesized by PLGA graft.

PLGA molecular weight (GPC): Mw, 15,800 g / mol; Mn, 11,900 g / mol; PDI, 1.33.

+ Degree of substitution of PLGA. [(Mw of PHO / PLGA-Mw of PHO) / Mw of PLGA] * 100

3. Stent coating of drug-supported PHO / PLGA graft copolymer polymer

Paclitaxel was used as a drug, and PHO / PLGA graft copolymer polymer containing 10% of paclitaxel was dissolved in chloroform. Stent coating was performed using a bio spray coating system (model: EBS 100 es-biocoater, NanoNC, Korea). Coating equipment is used for electrospray / electrospinning experiments. The organic solvent or aqueous solution is used to form nanostructures such as nanoparticles or nanofibers at very high voltages. The electrospray consists of a high voltage to electrolyze the solvent, a pump to push the solvent out, an X-Y robotic system, and a drum roll collector. The dissolution rate of the electrospray device was fixed at 100 ul per minute and a voltage of 10 kv was used. The electrospray was 10 kv and the rolling collector was rotated at 800 rpm. After electrospraying, the film formed on the rolling collector was dried for 3 hours, and the tube-shaped film was carefully separated from the rolling collector and weighed. The coating rate was calculated by measuring the weight of the film produced by the electrospray method. [Coating rate = (weight of final film / amount of initial polymer + amount of drug) x100]

4. Surface analysis of coated stents

The surface of the stent coated with the drug-supported PHO / PLGA graft copolymer polymer was identified by scanning electron microscopy (SEM). 3 is a scanning electron micrograph coated on bare metal stent using PHO / PLGA graft copolymer polymer carrying paclitaxel. Even when magnified by 1200 times, as shown in FIG. 3, the surface of the polymer coated on the surface of the stent has a smooth surface without agglomeration of drugs and no crack is found, indicating that the drug release can be controlled.

5. Evaluation of Drug Release Trend in PHO / PLGA Graft Polymer-coated Paclitaxel Release Stents

The prepared drug-release stent was placed in 10 ml of RPMI medium containing 10% FBS and gently stirred in a 37 ^° C. incubator to induce drug release. Every 10 ml of medium was obtained and replaced with fresh 10 ml of medium. The obtained medium immediately measured the concentration of paclitaxel using HPLC. The Flexar HPLC system (PerkinElmer) consists of a Solvent Manager 5-CH Degasser, an autosampler, a quaternary LC pump, a column oven and an UV / VIS detector. Chromatography was performed on a guard column (SecurityGuard Guard Catridge Kit, Phenomenex) and C18 column (Brownlee C18, 5um, 150 x 4.6, PerkinElmer) at 37 ° C. Paclitaxel was flowed into the fluidized bed solution (Acetonitrile / DW: 60/40) at a rate of 1ml / min and measured at 227nm. The chromatogram obtained was analyzed by software system (Chromera 2.1, PerkinElmer). The amount of released drug obtained at each time of harvest was cumulatively expressed as a percentage of the amount of drug initially added. Figure 4 is an illustration of the drug release trend of paclitaxel using the paclitaxel release stent. As shown, it can be seen that 20% of the drug coated on the stent is released slowly over about two weeks.

As described above, in the present embodiment, paclitaxel, a hydrophobic drug, was dissolved in PHO / PLGA graft copolymer polymer and successfully coated on a metal stent using an electric spraying device. In addition, the prepared drug-release stent was found to be a sustained-release drug-release stent capable of successfully releasing paclitaxel for a long time.

And, "This research was made with the support of the Ministry of Health and Welfare's medical research and development project. (Task ID: A091047)"

Claims (7)

Graft formed by graft co-polymerization of poly (3-hydroxyoctanoate, (PHO))) on a biodegradable polyester or polyether-based polymer having absorption in the human body A drug carrier by synthesizing graft copolymer of polyhydroxyoctanoate and a biodegradable polymer, characterized in that it is formed by supporting a hydrophobic drug in a copolymer polymer. The method of claim 1, wherein the polyester (polyester) or polyether (polyether) polymer,
Poly (L-lactide-co-glyucolide, PLGA), polylactide glycol (poly (DL-lactide-co-glyucolide, PLGA), poly (L-lactide) (PLA )), Polylactide (poly (DL-lactide, (PLA)), polyglycolide (PGA), polycaprolactone (poly (ε-carolactone) (PCL)), polylactidecaprolactone (poly (L-lactide-co-carolactone), and polyhydroxyoctanoate, characterized in that one of poly (DL-lactide-co-carolactone), polydioxanone (polydioxanone) and Drug carrier by synthesis of graft copolymer of biodegradable polymer. The method of claim 2, wherein the polyester (polyester) or polyether (polyether) polymer,
A drug carrier by the synthesis of graft copolymers of polyhydroxyoctanoate and biodegradable polymers, characterized in that the polylactide glycol (poly (DL-lactide-co-glyucolide), PLGA). The method of claim 3, wherein the graft copolymer polymer,
Drug fence by synthesis of graft copolymer of polyhydroxyoctanoate and biodegradable polymer which covalently bonds the carboxyl group of PLGA to the hydroxyl group of PHO to form graft copolymer retard. The method according to any one of claims 1 to 4, wherein the hydrophobic drug,
A drug carrier by synthesizing graft copolymer of polyhydroxyoctanoate and biodegradable polymer, characterized in that it is paclitaxel. In the non-vascular drug release stent,
Graft formed by graft co-polymerization of poly (3-hydroxyoctanoate, (PHO))) on a biodegradable polyester or polyether-based polymer having absorption in the human body Non-vascular drug release coated with drug carriers by graft copolymer synthesis of polyhydroxyoctanoate and biodegradable polymers, characterized in that a polymer drug carrier having a hydrophobic drug loaded on the copolymer polymer is coated on the surface of the stent. Mold treatment stents. The method according to claim 6,
The polyester (polyester) or polyether (polyether) polymer is polylactide glycol (poly (DL-lactide-co-glyucolide), PLGA),
The graft copolymer polymer is a graft copolymer formed by covalently bonding a carboxyl group of PLGA to a hydroxyl group of PHO,
The hydrophobic drug is a non-blood drug-releasing therapeutic stent coated with a drug carrier by the synthesis of graft copolymers of polyhydroxyoctanoate and biodegradable polymer, characterized in that paclitaxel.

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