KR101182736B1 - Core-shell type nano fibrous Scaffolds and manufacturing method thereof - Google Patents

Abstract

The present invention relates to a core-shell-type nanofiber support and a method for manufacturing the same, and more particularly, to a core-shell-type nanofiber composed of a shell of a biocompatible hydrophobic synthetic polymer and a core mixed with a biocompatible natural polymer and a drug. It relates to a support and a method for producing the same. Therefore, the nanofiber support according to the present invention is supported by the drug in the core is directly attached to the wound or surgical site has the advantage that the drug is continuously released for a certain period of time do not need to administer the drug from time to time.

Description

Core-shell type nanofiber scaffolds and manufacturing method thereof {Core-shell type nano fibrous Scaffolds and manufacturing method}

The present invention relates to a nanofiber support in the form of a core-shell and a method for producing the same.

Nanofibers have a large surface area and high porosity [S. R. Bhattarai et al., Biomaterials 25 (2004) 2595-2602. The smaller the diameter of the nanofiber, the larger the ratio of area to volume. The large surface area not only creates a sufficient wet state but also has a three-dimensional structure similar to that of the extracellular matrix, which facilitates drug release and is effective for wound regeneration [W. J. Li et al., Biomaterials 26 (2005) 599-609].

The biocompatible and biodegradable polymer can be used both natural and synthetic polymers, for example, natural polymers such as collagen, gelatin, alginate, hyaluronic acid, or chitosan, polyethylene glycol, polylactic acid, polyglycolic acid, Synthetic polymers, such as polyester of poly (D, L-lactic-co-glycolic acid), poly (caprolactone), or poly (hydroxybutyrate), can be used, and can be used individually or in mixture of 2 or more types. Nanofibers can be prepared using the polymer. On the other hand, methods for producing nanofibers include self-assembly, phase separation, and electrospninning [L.A. Smith et al., Colloids and surfaces B: Biointerfaces 39 (2004) 125-131].

Nanofibers produced by electrospinning are formed from electrospinning by uniaxial extension of viscoelastic jets of polymer solutions or melts. The procedure uses an electric field to produce jets of one or more electrically charged polymer solutions from the surface of the solution to the surface of the collector. When a high voltage is applied to the polymer solution (or lysate), the filled injection of the solution is pulled toward the fixed collector. The injection stretches and flexes inwardly of the coil, which solidifies as the solvent evaporates to form a nanofiber whose precipitate on the grounded collector has a diameter within the nanometer range [J. Appl. Phys, 87, 4531, 2000, J. Appl. Phys, 89, 3018, 2001]. The nanofibers thus manufactured can be used in drug delivery systems or tissue engineering, and can be applied to various fields such as clothing, electrochemical, and environmental.

The use of the nanofibers can also be used in drug delivery systems. For example, US Pat. No. 5,648,506 proposes a form of soluble drug delivery in which the active agent is combined with a water soluble polymer, which raises the problem that the water soluble polymer may induce inflammatory complications in certain ophthalmic therapeutic applications.

In order to solve the above problems, the present inventors use a biocompatible hydrophobic synthetic polymer as a shell, a biocompatible natural polymer and a drug as a core, and fabricate a core-shell nanofiber support through a double nozzle electrospinning method. This fiber can be treated by continuous delivery of the drug using a core-shell-type nanofibrous support containing the drug in the core part without oral administration or additional administration of the drug, and treatment after the drug is released. There is an advantage.

Accordingly, an object of the present invention is to provide a core-shell nanofiber support in which a certain amount of drug is continuously released and delivered directly to a wound or surgical site without oral administration.

In order to achieve the above object, the present invention is a biocompatible natural polymer and a drug mixture core; And a core-shell nanofiber support composed of a shell of a biocompatible hydrophobic synthetic polymer.

In addition,

Preparing a shell polymer solution by mixing a biocompatible hydrophobic synthetic polymer and a volatile solvent;

Preparing a core polymer solution by mixing a drug, a biocompatible natural polymer, and a volatile solvent; And

Preparing a core-shell-type nanofiber support by injecting the shell polymer solution and the core polymer solution into a double nozzle electrospinning apparatus to perform electrospinning and removing residual solvent under vacuum;

It is another feature of the method for producing a core-shell-type nanofiber support comprising a.

Core-shell-type nanofiber support according to the present invention has the advantage that do not need to administer the drug from time to time by directly releasing a certain amount of drug by attaching directly to the wound or surgical site.

1 is a schematic diagram of a double nozzle electrospinning process.
2 is an example of application of a nanofiber support in the form of a core-shell.
FIG. 3 is a scanning electron micrograph of a core-shell type nanofiber support prepared in Example 1. FIG.
Figure 4 is a graph of drug release behavior of the nanofibers (a) of the PCL and the nanofiber support (b) of the core-shell form prepared in Example 1.

Hereinafter, the present invention will be described in detail.

The present invention relates to a core-shell-type nanofiber support composed of a shell of a biocompatible hydrophobic synthetic polymer and a core mixed with a biocompatible natural polymer and a drug, and a method of manufacturing the same.

The polymer in the shell of the present invention uses a hydrophobic polymer to prevent initial release when the drug in the core is released. Therefore, the biocompatible hydrophobic synthetic polymer is preferably at least one selected from the group consisting of polycaprolactone, polylactic acid, polyglycolic acid, and polylactic acid-glycolic acid copolymer gelatin. In addition, the biocompatible natural polymer is preferably at least one selected from the group consisting of alginate, chitosan, collagen and gelatin.

The nanofiber support according to the present invention preferably contains a drug such as an antibiotic so as not to cause inflammation in the wound or surgical site, and more preferably, a type of antibiotic in which the water-soluble antibiotic prevents the formation of inflammation of the nasal cavity. Do. Specific examples of the water-soluble antibiotics include cephatic antibiotics such as levofloxacin, cepradine cephradine, cefamandole, ceprozilil, ceforozil, cephatiam, and cephacller. Can be. The nanofiber support according to the present invention has a nanofiber diameter of 50 to 1000 nm, preferably 100 to 500 nm, and has a tensile strength of 0.1 to 15 MPa so that the nanofiber support is more easily folded or torn than conventional PCL to facilitate a support of a desired capacity. Can be attached directly to the wound or surgical site.

In addition, such a nanofiber support has the advantage that do not need to be administered from time to time because the drug contained in the nanofibers is continuously released in a certain amount 1 ~ 21 days.

Such a method of manufacturing the core-shell nanofiber support of the present invention is as follows.

First, a shell polymer solution is prepared by mixing a biocompatible hydrophobic synthetic polymer and a volatile solvent, and separately, a drug and a biocompatible natural polymer are mixed with a volatile solvent to prepare a core polymer solution.

The biocompatible polymer in the shell polymer solution is preferably used in an amount of 10 to 20 parts by weight based on 100 parts by weight of the total shell polymer solution, and if it is out of this range, it is difficult to maintain the shape of the fibers constituting the nanofiber support or electrospinning. There is a manufacturing problem such as not being.

The volatile solvent is tetrafluroethylene (TFE), acetone (acetone), trifluoroacetate (TFA), hexafluoroisopropanol (HFIP), methylene chloride (MC), chloroform (chloroform), dimethylsulfoxide (DMSO), dimethylformamide (DMF), tetrahydrofuran (THF), As one or more selected from the group consisting of acetic acid and formic acid, it is preferable that the biocompatible polymer can be dissolved.

The biocompatible polymer in the core polymer solution is preferably used in an amount of 0.5 to 5 parts by weight based on 100 parts by weight of the total core polymer solution. Outside the above range there is a problem that the continuous release of the drug is not. In addition, the drug in the core polymer solution is preferably used 1 to 30 parts by weight, and more preferably 5 to 20 parts by weight based on 100 parts by weight of the total core polymer solution. If too little drug is used, the drug is not exerted. If too much drug is used, there is a problem of initial burst upon drug release.

The shell polymer solution and the core polymer solution are respectively injected into a double nozzle electrospinning apparatus to perform electrospinning, and residual solvent is removed under vacuum to prepare a core-shell nanofiber support.

At this time, the electrospinning voltage of 5 to 25 kV, spinning rate of 0.01 to 0.5 ml / h (preferably shell polymer solution spinning rate of 0.1 to 0.5 ml / h and core polymer solution spinning rate of 0.001 to 0.001 ml / m ), 0.05 to 0.5 ml of spinning amount (preferably 0.1 to 0.5 ml of shell polymer solution spinning and 0.05 to 0.1 ml of core polymer spinning), and 1 to 20 cm spinning distance. In addition, the needle size of the double nozzle electrospinning device nozzle for polymer solution injection is preferably 15 to 32 gauge, the shell polymer solution injection needle size is 15 to 22 gauge, the core polymer solution injection needle size is 23 to 32 gauge More preferred.

The spin-finished core-shell nanofiber support is removed from the residual polymer solvent for 30 to 60 hours after being put in a vacuum.

The prepared core-shell nanofiber support is used to attach to the wound or surgical site.

Accordingly, the present invention can be used as a transdermal administration of the nano-fiber support in the form of a core-shell, and in particular, it is used continuously in a nasal cavity for a certain period of time without the hassle of oral administration from time to time by attaching to a wound site or an otolaryngology surgical site. Can be maintained.

Hereinafter, the present invention will be described in more detail by way of examples. It should be noted, however, that the following examples are illustrative of the invention and are not intended to limit the scope of the invention.

Example  1: Preparation of core-shell type nanofiber support

Shell Polymer Solution Preparation

As a shell solution, TFE and formic acid were mixed at a weight ratio of 4: 1, and 1.6 g of PCL and 8.4 g of TFE and formic acid were mixed at room temperature (25 ° C.) to prepare a shell polymer solution.

Core Polymer Solution Manufacturing

A core polymer solution was prepared by adding 0.0125 g of chitosan, 4.4875 g of 0.2 M acetic acid, and 0.054 g of levopoloxaine into a vial and stirring at room temperature (25 ° C.).

Nanofiber Support

8 ml of the prepared shell polymer solution and 4.5 ml of the core polymer solution were respectively injected into a double nozzle electrospinning apparatus (see FIG. 1).

At this time, the electrospinning voltage is 16 kV and the shell polymer solution spinning rate of 0.4 ml / h, the core polymer solution spinning rate of 0.12 ml / h, the shell polymer solution spinning amount of 0.3 ml, the core polymer solution spinning amount of 0.09 ml, 10 cm Was carried out for 1 hour and 40 minutes under the conditions of the spinning distance of 18 gauge shell polymer solution injection needle size and 27 gauge core polymer solution injection needle size.

Then, the remaining solvent was removed by standing in a vacuum for 48 hours to prepare a nano-fiber support in the form of a shell-core.

Experimental Example  1: check the nanofiber structure

The diameter of the nanofibers and the core-shell structure of the nanofiber support prepared in Example 1 were confirmed by scanning electron microscope (SEM, TEM).

As shown in FIG. 3, the core-shell structure was confirmed, and the diameter of the nanofibers was found to be about 200 nm.

Experimental Example  2

Tensile strength and elasticity of the nanofiber support prepared in Example 1 were measured using a universal testing machine (UTM), and the results are shown in Table 1.

[Table 1]

As shown in Table 1, the nanofiber support of Example 1 is significantly lower than the conventional PCL tensile strength and modulus of elasticity can be attached to the wound or surgical site by folding or tearing a certain area arbitrarily according to the desired capacity [Fig. Reference].

Experimental Example  3

The drug release behavior was confirmed using the nanofibers containing the antibiotic prepared in Example 1.

The nanofibers containing the antibiotics were placed in a phosphate buffer solution (pH 7.4 PBS) in a 37 ℃ water bath and drug behavior was measured.

The drug release time is 1 hour, 3 hours, 6 hours, 12 hours, 24 hours, 48 hours, 96 hours, 168 hours, 240 hours and 336 hours, and the concentration and absorbance of the drug released from the nanofibers with a UV-spectrophotometer. Was measured at a wavelength of 331.20 nm.

Figure 4 (a) shows a PCL nanofiber prepared by a single nozzle electrospinning method, (b) shows a nanofiber of Example 1, the initial drug release behavior is controlled in the nanofiber of Example 1 drug It was confirmed that the release behavior continued to appear.

Claims (18)

A core mixed with at least one biocompatible natural polymer and a drug selected from the group consisting of alginate, chitosan, collagen and gelatin; And
Shell of polycaprolactone, a biocompatible hydrophobic synthetic polymer
Nanofibrous support in the form of core-shell for intranasal wound or surgical site attachment.
delete delete The nanofibrous support according to claim 1, wherein the drug is an antibiotic for intranasal wound or surgical site attachment.
The nanofiber support according to claim 1, wherein the drug is a water-soluble antibiotic in the form of a core-shell for intranasal wound or surgical site attachment.
The method of claim 5, wherein the water-soluble antibiotics in the group consisting of levofloxacin, cepradine (cephradine), cefamandole (cefamandole), cefprozil, Cefotiam (Cefotiam) and Cefaclor (Cefaclor) At least one selected nanofibrous support in the form of a core-shell for intranasal wound or surgical site attachment.
The nanofibrous support of claim 1, wherein the nanofibers have a diameter of 50 to 1000 nm.
The nanofiber support according to claim 1, wherein the tensile strength of the nanofibers is 0.1 to 15 MPa.
The nanofiber support according to claim 1, wherein the nanofibers are in the form of a core-shell for attachment to an intranasal wound or surgical site where the drug is released for 1 to 21 days.
Preparing a shell polymer solution by mixing polycaprolactone, which is a biocompatible hydrophobic synthetic polymer, and a volatile solvent;
Preparing a core polymer solution by mixing one or more biocompatible natural polymers and volatile solvents selected from the group consisting of drugs, alginates, chitosan, collagen and gelatin; And
Preparing a core-shell-type nanofiber support by injecting the shell polymer solution and the core polymer solution into a double nozzle electrospinning apparatus to perform electrospinning and removing residual solvent under vacuum;
Method for producing a nano-fiber support in the form of a core-shell for nasal wound or surgical site attachment comprising a.
The method of claim 10, wherein the biocompatible hydrophobic synthetic polymer in the shell polymer solution is 10 to 20 parts by weight based on 100 parts by weight of the total shell polymer solution. .
The method of claim 10, wherein the volatile solvent is tetrafluroethylene (TFE), acetone (acetone), trifluoroacetate (TFA), hexafluoroisopropanol (HFIP), methylene chloride (MC), chloroform (dimethylform), dimethylsulfoxide (DMSO), dimethylformamide (DMF) , THF (tetrahydrofuran), acetic acid (acetic acid) and formic acid (formic acid), at least one selected from the group, the method for producing a core-shell type nanofiber support for intranasal wound site or surgical site dissolving the polymer.
The method of claim 10, wherein the biocompatible natural polymer in the core polymer solution is 0.5 to 5 parts by weight based on 100 parts by weight of the total core polymer solution.
The method of claim 10, wherein the drug in the core polymer solution is 1 to 30 parts by weight based on 100 parts by weight of the total core polymer solution.
The method of claim 10, wherein the electrospinning is performed at a voltage of 5 to 25 kV.
The method of claim 10, wherein the electrospinning is performed in the form of a core-shell type nanofiber support for attachment to an intranasal wound or a surgical site, which is performed at a spinning rate of 0.01 to 0.5 ml / h.
The method of claim 10, wherein the electrospinning is performed in the nasal wound or surgical site attachment core-shell-type nanofiber support for a spin distance of 1 to 20 cm.
A transdermal agent for attachment to an intranasal wound or surgical site using the core-shell nanofiber support of claim 1.

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