KR20090111565A - Polymeric coating technique of curved-surface containing medical material or device - Google Patents

Abstract

PURPOSE: A high molecular coating technology of the medical material or the apparatus is provided, which maximizes local effect of delivery of drug. CONSTITUTION: A high molecular coating technology is constituted as follows. PLGA is used as a polymer. Polyethylene glycol, triethylcitrate, and the mixture thereof are used as a softening agent. When the dexamethasone sodium is used as drug, dexamethasone is discharged by spraying solution including poly 0.5-2 weight%, polyethylene glycol, triethylcitrate or mixture thereof 0.5-10 weight%, and dexamethasone sodium 0.1-5 weight% using an air brush.

Description

Polymer coating technique of curved-surface containing medical material or device

The present invention relates to a method for thinly and uniformly coating a medical material or device with a specific polymer. The present invention also relates to a method of coating a medical material or device such that a specific drug is released at a constant rate through a uniform polymer coating on the medical material or device.

A biomedical material (biomaterial) is a material used for diagnosing or treating a disease, or for replacing a part of a body damaged by a disease or an accident, and may be made of various materials such as metal, ceramic, and polymer.

Recently, research has been conducted to reduce the side effects of implantation of a medical material or device by coating a specific polymer on a medical material or device, or to locally deliver a drug by coating a polymer and a drug together. Localized delivery of these drugs has been reported to maximize the therapeutic effect and reduce side effects that may occur during systemic delivery.

Currently, the coating of such medical materials, especially implantable preparations, has been studied in the field of drug delivery or anti-cancer drug delivery in the transmucosal and mucosal areas. For example, studies have been conducted to immobilize heparin to the polymer surface or to simply release it as a coating or drug delivery system, and in fact, heparin sustained-release catheter (Anthron from Toray) and heparin-fixed catheter (Duraflow) , Cardiopulmonary (Terumo) has been commercialized. It has also been reported that drug-coated stents (drug-coated stents, drug-eluting stents) can dramatically lower the rate of restenosis within the stents by effectively and continuously delivering drugs locally.

In film coating of such medical materials / devices, the uniform film coating is very important in terms of achieving the purpose of the polymer coating, and in the case of drug-containing coatings, the release of the drug and the therapeutic effect thereof are It is very important in terms of securing. Especially for medical devices / materials that are thin and curved, such as lenses and ocular tension rings, the uniform formation of the film is a very important factor.

Accordingly, the present invention provides a method for thinly and uniformly coating a medical material or device, particularly a material or device having a curved surface, with a specific polymer.

The present invention also provides a method of coating a medical material or device such that a specific drug is released at a constant rate through a uniform polymer coating on the medical material or device.

In order to achieve the above technical problem, the present invention provides a method for coating a medical device or material, in particular a medical device or material having a curved surface by spraying a polymer solution with an airbrush (airbrush). Through the method according to the invention it was possible to produce a uniform polymer film having a thin thickness of less than 0.01 mm.

Polymers used in the polymer solution of the present invention include polyurethane, polyethylene, terephthalate, PLLA-poly-glycolic acid copolymer, polycaprolactone, poly (hydroxybutyrate / hydroxyvalerate) copolymer, poly ( Vinylpyrrolidone), polytetrafluoroethylene, poly (2-hydroxyethylmethacrylate), poly (etheruretan urea), silicone, acrylic, epoxide, polyester. Urethanes, phaline, polyphosphazine polymers, fluorine polymers, polyamides, polyolefins and the like can be used alone or in combination.

Of these polymers, poly (lactic-co-glycolic acid) (PLGA) is more preferred because PLGA is stable to mechanical stress, ie mechanical consumption, stress during surgical procedures, exposure to organic solvents, and temperature changes. It is biodegradable and does not need to be removed again when administered into the body, and in particular, when used in combination with a drug, PLGA is biodegradable and easy to control to release the drug at a desired rate.

The PLGA polymer is preferably 0.5-2% by weight relative to the total weight of the solution in terms of uniformity, flexibility, and ease of manufacture of the formed polymer film.

The present invention also provides a method for coating a medical device or material comprising the softening agent in the polymer solution by spraying with an airbrush (polyethylene glycol, triethyl citrate or a mixture thereof). This is preferred.

In view of the uniformity and flexibility of the formed polymer film and the release pattern of the contained drug, the content of such softener is preferably 0.5-10% by weight.

The polymeric coating formed according to the present invention may contain a drug, which drug may be released at a constant rate in the body. As such, when the drug is contained, it is desirable to allow a therapeutically effective amount of the drug to be released continuously for as long as possible for the drug to be released from the surface. Early burst release is a high release rate that occurs immediately after transplantation and causes many side effects in actual treatment. This problem is an important matter that must be urgently improved in the use of a drug-release medical device, and for this purpose, it is essential to form a uniform film on the curved portion.

In this respect, the content ratio of the polymer, the softening agent and the drug is very important, and the composition is used when using PLGA as a polymer, polyethylene glycol, triethyl citrate or a mixture thereof as a softening agent, and dexamethasone sodium as a drug. 0.5-2% by weight of poly (lactic-co-glycolic acid) relative to total weight; 0.5-10% by weight of polyethylene glycol, triethyl citrate or mixtures thereof; And, preferably, a medical device or material having a polymeric coating that releases dexamethasone by spraying a solution comprising 0.1-5% by weight of dexamethasone sodium with an airbrush.

Other drugs to which the technique of the present invention can be applied include anticancer drugs abyssin, aclarubicin, acodazole, acronycin, adojeresin, araosine, aldeskryne, alloputinol sodium, altretamine, Amioglutetidemide, Amonafide, Amprigen, Amsacrine, Androgen, Anguadin, Apidicholine Glycinate, Asari, Asparaginase, 5-Azacytidine, Azatypine, Bacillus Calmet- Guerin, Soluble Confectionery Antipol, Beta-2'-Deoxythioguanosine, Bizenzene Hydrochloride, Bleomycin Sulfate, Busulsulfan, Beautyionine Sulfoxyma Inn, BWA 773U82, BW 502U83-HCL, BW 7U85 mesylate, ceracemide, calbetatimer, carboplatin, carmustine, chloroambucil, chloroquinoxaline-sulfonamide, chlorozotocin, chromomycin A3, cisplatin, cladribine, corticosteroid, corynebac Therium Faro , CPT-11, crisnatol, cyclocytidine, cyclophosphamide, citrabine, cytembena, dabis mariate, dacarbazine, dactinomycin, dinorubicin hydrochloride, deazuridine, dexarazin Phosphorus, dianhydrogalactitol, diazquine, dibro-modulitol, daidenim B, diethyldithiocarbamet, diglycoaldehyde, dihydro-5-azidatidine, doxorubicin, ekainomycin, eda Trexate, edelfosine, epronitine, solution of elliot, elsamutrucin, epirubicin, estrammustine phosphate, estrogen, etanidazole, ethiophos, eposide, padrazole, pazarabine, Fenretinide, Filgratim, Finasteride, Flavone Acetic Acid, Proxuridine, Frudarabine Phosphate, 5-Fluorouracil, Fluorsol, Plutamide, Gallium Nitrate, Gemcitabine, Goserelin Cetate, Hepsulpam, Hexamethylene Bisacetamine, Homoheringtonine, Hydrazine Sulfate, 4-Hydroxyandrostenedione, Hydroxyurea, Idarubicin Hydrochloride, Iphosphamide, Interferon Alpha, Interferon Beta, Interferon Gamma, Interleukin-1 Alpha, Interleukin-1 Beta, Interleukin-3, Interleukin-4, Interleukin-6, 4-Ipomiaol, Ipoplatin, Asotretinoin, Leucovorin Calcium, Leuprolide Acetate, Levamisol, Lipo Somal daurubicin, doxorubicin encapsulated in liposomes, lomusstein, ronidamine, maytansine, mechlorethamine hydrochloride, melfaran, menogaryl, mulbaron, 6-mercaptopruin, mesna, bacillus calmet Methanol extract of guerin, methotrexate, N-methylformamide, mifepristone, mitoguazone, mitomycin-C, mitolane, mitozantron hydrochloride Ride, mononuclear / macrophage stimulator, nabilone, napoxidine, neocardinostatin, octriotide acetate, ormaplatin, oxalineplatin, paclitaxel, pala, pentostatin, peperazinion, fibrobromone , Pyrarubicin, pyretrexim, pyroxectron hydrochloride, pixy-321, plycamycin, porphamer sodium, prednimestein, procarbazine, progestin, pyrazopurin, lazozein, salgramostim , Semersteine, spirogermanium, spyrromersteine, straptonigreen, straptozosin, sulfofener, suramin sodium, tamoxifen, tazotere, tegaper, teponiside, trephthalamidine, theroxylone, Thioguanine, Thiotepa, Samydine Injection, Tiazopurin, Topotecan, Torremifen, Trethioine, Trifluoroperazine Hydrochloride, Trifluridine, Trimmetrexate, Tumor necrosis Now, uracil mustard, vinblastine sulphate, vincristine sulphate, vindesine, vinorelbine, vinjoridin, yoshi 864, zorubicin and the like can be used.

Other drugs to which the technique of the present invention may be applied may be anti-inflammatory non-steroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitors, glucocorticoids, and the like, and the non-steroidal anti-inflammatory drugs may include aspirin, diclofenac, Indomethacin, Sulindac, Ketoprofen, Fluroprofen, Ibropropene, Naprobene, Pyro Seacam, Tenoshchem, Tolmethine, Ketorolac, Oxaproscene, Mephenamic Acid, Pen Propene, Nambutmethone, Acetaminophen, etc. may be used, and the glucocorticoid may be hydrocortisone, coltizone, prednisone, prednisolone, methylprednisolone, meprednison, triamcinolone, paramethasone, frprednisolone, dexamethasone , Fludrocortisone, desoxycholicosterone and the like can be used.

In the present invention, the solvent of the polymer, the drug, and the softening agent when forming the film through the airbrush is acetic acid, acetonitrile, benzene, butanol, carbon tetrachloride, chlorobenzene, chlorohexane. Chloroform, 1,2 dichloroethane, diethyl ether, diethylene glycol, 1,2-dimethoxyethane, dimethylethane, dimethylformamide, dimethylsulfoxide, ethanol, ethyl acetate, ethyleneglycol, heptane, hexane, Methanol, methyl t-butyl ether, methylene chloride, pentane, petroleum ether, propanol, pyridine, tetrahydrofuran, toluene, distilled water, triethyl amine, xylene and mixtures thereof can be used.

The technique according to the invention can be used for stents, ocular lenses, ocular tension rings, catheters and the like.

The present invention provides a manufacturing method capable of forming a uniform polymer film, this production method can maximize the local delivery effect of the drug.

The present invention also provides a manufacturing method capable of forming a polymer film which releases dexamethasone at an appropriate release rate.

Hereinafter, examples and the like will be described in detail to help understand the present invention. However, embodiments according to the present invention can be modified in many different forms, the scope of the invention should not be construed as limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

EXAMPLES Coating of Polymers and Drugs

After dissolving poly (lactic-co-glycolic acid) (PLGA), a hydrophobic polymer, in ethyl acetate, airbrush (Model Spray-Work HG Super Fine Double Action Airbrush, Tamiya, Sprayed onto a medical device by spraying the coating onto a medical device using an airbrush, and the organic solvent in which the drug and the polymer were dissolved was sprayed at a distance of 5 cm from the coating object by using an airbrush, and the drug and the plasticizer were added to the film. When sprayed, the mixture was dissolved or dissolved in an organic solvent, and then left at room temperature for 2 days to evaporate the solvent, and the drug and PLGA remained on the surface to form a thin film.

Experimental Example 1 Evaluation of Uniformity of Prepared Polymer Coatings

After preparing the polymer film, its uniformity was observed through a microscope. It was confirmed that film formation of the curved surface and the thin material of 0.01 mm or less through the airbrush is made uniform. Softeners and drug-containing polymers were also found to form uniform coatings. An enlarged photograph of the prepared polymer coating is shown in FIG. 1.

Experimental Example 2 Evaluation of Effect According to Contents of Polymer, Softener and Drug

The uniformity of the formed film thickness, the flexibility of the film, the release rate of the drug, and the like were evaluated to evaluate the influence of the content of the PLGA, the softener and the drug content.

As a result, the concentration of the polymer was most suitable 0.5-2% by weight, the concentration of the drug is preferably 0.1-5% by weight, the amount of the softener is preferably 0.5-10% by weight, more preferably 0.5-5% by weight. Dexamethasone sodium (dexamethasone sodium) was used as a drug, and poly (ethylene glycol) and triethyl citrate were used as a softening agent.

Experimental Example 3 Flexibility Evaluation

The flexibility of the polymer coating was evaluated through the film elongation method. To evaluate the flexibility, a 0.01 mm thick rectangular film (1.0 cm × 1.0 cm, 0.6 mg) was fixed between the mounting plates and pulled at a rate of 10 mm / min using a puncture probe. Thereafter, the point at which the film was broken and the change in film thickness were measured.

Softener  Evaluation of the impact on the flexibility of the polymer coating

Polyethylene glycol and triethyl citrate were added to the polymer solution at concentrations of 0.5, 1, 2 and 5% (w / w), respectively, to determine the effect of the softening agent, and a coating was formed through an airbrush. Flexibility was evaluated. The PLGA film was found to be more easily broken without increasing the amount of softener. When 5% of the softening agent was added, the film was broken when the film was stretched by about 6 times. The result is shown in FIG. 2. As shown in FIG. 2, polyethylene glycol showed better flexibility than triethyl citrate.

In addition, as the concentration of the drug (dexamethasone sodium) increases, the flexibility of the film is confirmed to be weak. When the concentration of the drug was added to 5%, the flexibility of the coating was found to decrease by about 20%.

Evaluate the effect of film length, width and thickness on cladding flexibility

The length was adjusted to 1-3cm, the width was 0.5-2cm, the thickness was adjusted to 10-30um to evaluate the flexibility. As a result of evaluation, the length did not significantly affect the flexibility of the film, and the flexibility increased as the width and thickness increased.

1 is an enlarged photograph of a polymer coating prepared according to an embodiment of the present invention.

Figure 2 is a result of the evaluation of the flexibility of the polymer coating prepared according to an embodiment of the present invention. 2 is the result of using polyethylene glycol as a softener, and the result of using triethyl citrate as a softener. PLGA was used at 1% by weight.

Claims (6)

A method of coating a medical device or material by spraying a polymer solution with an airbrush. The method of claim 1 wherein the polymer is poly (lactic-co-glycolic acid). The method of claim 2 wherein the content of the polymer in the solution is characterized in that 0.5-2% by weight. The method of claim 1 wherein the solution comprises a softening agent which is polyethylene glycol, triethyl citrate or mixtures thereof. The method of claim 4, wherein the content of the softening agent is 0.5-10% by weight. 0.5-2% by weight of poly (lactic-co-glycolic acid) relative to the total weight of the composition; 0.5-10% by weight of polyethylene glycol, triethyl citrate or mixtures thereof; And a polymer coating which releases dexamethasone by spraying a solution comprising 0.1-5% by weight of dexamethasone sodium with an airbrush.

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