KR101008001B1 - Controlled Drug Release System by fluorination based on biodegradable Nano-Fibers and Manufacturing Method Thereof - Google Patents

Abstract

The present invention relates to a biodegradable nanofiber with improved drug delivery sustained release and a method for producing the same, the method for producing a biodegradable nanofiber with enhanced drug delivery sustained release according to the present invention, (1) a polymer precursor, a water-soluble drug And mixing the solvent; (2) electrospinning the mixture obtained in step (1) to obtain nanofibers; (3) crosslinking the nanofibers by radiation treatment to the nanofibers obtained through the process of 'step (2)'; And (4) modifying the surface of the crosslinked nanofibers by fluorination of the crosslinked nanofibers obtained through the process of 'step (3)'.

According to the present invention, the hydrophobic functional group is introduced to the surface of the nanofiber formed by electrospinning and radiation treatment by fluorine treatment, thereby suppressing the decomposition rate of the biodegradable polymer. Therefore, the release rate of the drug contained in the nanofibers is suppressed, thereby controlling the release rate of the drug.

Drug delivery, sustained release, fluorine, fluorine treatment, nanofiber, electrospinning

Description

 Controlled Drug Release System by fluorination based on biodegradable Nano-Fibers and Manufacturing Method Thereof}

The present invention relates to electrospun nanofibers and a method for preparing the same, which are locally implantable drug delivery sustained release by fluorine treatment, and more particularly, to form crosslinked nanofibers through electrospinning and radiation treatment, The present invention relates to an electrospun nanofiber for a drug delivery device and a method of manufacturing the same by introducing a hydrophobic functional group on the surface by direct fluorination.

Generally, a specific medicine is used to treat a disease or damaged part of a human body. A drug delivery system (DDS) is used for the purpose of maximizing a therapeutic effect and minimizing side effects of the human body. ought. Drug delivery systems are commonly referred to as simple combinations of drugs to highly functional formulations, including transdermal delivery, oral delivery, mucosal delivery, implant delivery and injection ( It has been developed in various ways such as parenteral delivery and applied to patients through various paths of the human body. Among these methods, the transplant delivery method has been widely used as an effective method of directly delivering a drug delivery system containing a drug to a patient's body and delivering the drug directly to a required site. Recently, as a research on this, the drug delivery system is biodegraded in the body, and there is no need to remove the system after drug delivery, and research on materials that do not require secondary surgery is in progress. These studies are mainly based on biodegradable materials, but the problem of adjusting the drug delivery rate remains a problem to be solved prior to practical use because biodegradable materials have a high decomposition rate in a hydrophilic solution.

The present invention has been made to solve the above problems, to form a cross-linked drug delivery nanofibers through the electrospinning method and radiation treatment, fluorine treatment to introduce a hydrophobic functional group on the surface, finally to sustained release It is an object of the present invention to provide an improved drug delivery device and a method of manufacturing the same.

The present invention provides a method for producing biodegradable nanofibers with improved drug delivery sustained release, the method for producing biodegradable nanofibers with enhanced drug delivery sustained release,

(1) mixing a polymer precursor, a water soluble drug, and a solvent;

(2) electrospinning the mixture obtained in step (1) to obtain nanofibers;

(3) crosslinking the nanofibers by radiation treatment to the nanofibers obtained through the process of 'step (2)'; And

(4) fluorinating the crosslinked nanofibers obtained through the process of 'step (3)' to modify the surface of the crosslinked nanofibers.

The polymer precursor is a biodegradable polymer, preferably selected from the group consisting of Poly caprolactone (PCL), Poly Lactic acid (PLA), Polyester, Poly Glycolic acid (PGA), Poly vinylalcohol (PVA), and mixtures thereof.

The mixing ratio of the polymer precursor and the drug is preferably 99 to 20: 1 to 80 wt%, more preferably 90 to 70:10 to 30 wt%.

In the step of crosslinking the nanofibers of the 'step (3)', it is preferable to set the irradiation amount to 100 to 200 kGy and the irradiation time to 0.5 to 2 hours.

In the step of modifying the surface by the fluorination treatment of step (4), the surface of the cross-linked nanofibers is brought into direct contact with the cross-linked nanofibers by fluorine gas or a mixed gas of fluorine gas and inert gas. The fluorine gas is fluorine (F ₂ ), nitrogen trifluoride (NF ₃ ), CF ₄ (carbon tetrafluoride), CHF ₃ (carbon trifluoride), C ₃ F ₈ ( Preference is given to a group selected from the group consisting of tritiated tricarbon), C ₄ F ₈ (tetrafluorocarbon) and mixtures thereof.

In the case of modifying the surface of the crosslinked nanofiber by directly contacting the crosslinked nanofiber with fluorine gas, the pressure of the fluorine gas is preferably 0.01 to 0.2 bar, and the crosslinked nanofiber with fluorine gas. In the case of modifying the surface of the crosslinked nanofibers by bringing the mixed gas of inert gas into direct contact, the partial pressure of the fluorine gas is preferably 0.01 to 0.2 bar.

Preferably, the cross-linked nanofibers and the fluorine gas or the mixed gas of the fluorine gas and the inert gas are 1 to 60 minutes.

In another aspect, the present invention provides a biodegradable nanofibers with improved hydrophobic drug delivery by introducing a hydrophobic functional group to the surface of the nanofibers formed by electrospinning and radiation treatment by fluorine treatment.

According to the present invention, the hydrophobic functional group is introduced to the surface of the nanofiber formed by electrospinning and radiation treatment by fluorine treatment, thereby suppressing the decomposition rate of the biodegradable polymer. Therefore, the release rate of the drug contained in the nanofibers is suppressed, thereby controlling the release rate of the drug.

Hereinafter, the present invention will be described in detail.

The present invention provides a method for producing biodegradable nanofibers having enhanced drug delivery sustained release, and the method for preparing biodegradable nanofibers having enhanced drug delivery sustained release comprises the following process. In other words,

(1) mixing a polymer precursor, a water soluble drug, and a solvent;

(2) electrospinning the mixture obtained in step (1) to obtain nanofibers;

(3) crosslinking the nanofibers by radiation treatment to the nanofibers obtained through the process of 'step (2)'; And

(4) fluorinating the crosslinked nanofibers obtained through the process of 'step (3)' to modify the surface of the crosslinked nanofibers.

The polymer precursor used in the 'step (1)' uses a biodegradable polymer that has been proven to be harmless to the human body. That is, the polymer precursor may be used as long as it is a biodegradable polymer that has been proved to be harmless to the human body, and in detail, poly caprolactone (PCL), Poly Lactic acid (PLA), polyester, and poly glycic acid (PGA) , Poly vinylalcohol (PVA) and mixtures thereof.

The drug to be mixed in the 'step (1)' is a water-soluble drug. Since the present invention relates to biodegradable nanofibers with enhanced drug delivery sustained release, the drug used must be water soluble. The drug may be used as long as it is a water-soluble drug, for example, Ambisome, Doxil, Atenolol, Gleevec, Paclitaxel, Macugen, Lupron Depot, Nutropin, Depot, Declage, OctoDex, Metformine, Fluticasone, Cyclosporline, Venalfaxin, Sumatriptan, Nifedipine, Leuprolide, Salmeterol, Divalproex, Diclofenac, Gosereline, Dudesonide, Bupropion, Fentanyl, Ipratropium, Metoprolol, Albuterol, Calcitonin, Ipratropium, Nifedipine, Glipizide, Progesterone, Diltiazem, Nimphoterecine, Can be used have.

The solvent used in the 'step (1)' may dissolve biodegradable polymers and water-soluble drugs, and any solvent may be used as long as the solvent is harmless to the human body. For example, dimethylformaldehyde and N-methylpyrrolidone tetra Organic solvents such as hydrofuran, chloroform or water may be used.

The mixing ratio of the polymer precursor and the drug is preferably 99 to 20: 1 to 80 wt%, more preferably 90 to 70:10 to 30 wt%. If the mixing ratio of the drug is less than 1 wt%, the amount of the drug may be too small to achieve the therapeutic effect to be achieved. If the mixing ratio of the drug is greater than 80 wt%, nanofibers may not be formed properly. There is a problem. In addition, in consideration of the therapeutic effect and smooth fiber formation by the drug, the mixing ratio of the polymer precursor and the drug is more preferably in the range of 90 to 70:10 to 30 wt%.

In the step of obtaining the nanofibers of the 'step (2)', since the nanofibers are manufactured using a conventional electrospinning method, detailed description thereof will be omitted. In describing the conditions for producing nanofibers by electrospinning during the completion of the present invention, the application voltage is fixed at 10,000 to 20,000 V, and the distance between the syringe tip and the collector [TCD (tip to collector distance)] 10-15 cm and the rotation speed of the collector were 100-200 rpm, and it manufactured. The above conditions will vary depending on the size and conditions of the electrospinning apparatus, but one thing is clear is that the fiber obtained from the high voltage, the fast rotational speed of the collector, and the short TCD has a thinner diameter.

In the step of crosslinking the nanofibers of the 'step (3)', it is preferable to set the irradiation amount to 100 to 200 kGy and the irradiation time to 0.5 to 2 hours. If the radiation dose is less than 100 kGy and the irradiation time is less than 0.5 hours, sufficient crosslinking of the polymer is not achieved. If the radiation dose is greater than 200 kGy and the irradiation time is more than 2 hours, the desired degree of crosslinking has already been achieved. This is because unnecessary energy is wasted.

In the step of modifying the surface by the fluorination treatment of step (4), the surface of the cross-linked nanofibers is brought into direct contact with the cross-linked nanofibers by fluorine gas or a mixed gas of fluorine gas and inert gas. Modified. That is, the surface of the crosslinked nanofibers is modified by directly contacting the crosslinked nanofibers in the reactor with fluorine gas alone or a mixed gas of fluorine gas and inert gas.

The fluorine gas may be used as long as it is a fluorine gas that causes a fluorination reaction on the surface of the nanofibers. For example, fluorine (F ₂ ), nitrogen trifluoride (NF ₃ ), CF ₄ (carbon tetrafluoride), CHF ₃ (carbon trifluorofluorocarbons), C ₃ F ₈ (trifluorocarbons), C ₄ F ₈ (carbon tetrafluorocarbons), and mixtures thereof.

In the case of modifying the surface of the crosslinked nanofiber by directly contacting the crosslinked nanofiber with fluorine gas, the pressure of the fluorine gas is preferably 0.01 to 0.2 bar. If the pressure of the fluorine gas is lower than 0.01 bar there is a problem that the desired fluorine treatment, that is, the hydrophobic functional group is not sufficiently introduced into the surface of the cross-linked nanofibers. In addition, when the pressure of the fluorine gas is higher than 0.2 bar there is a fear that the hydrophobic functional group is excessively introduced to the surface of the cross-linked nanofibers to lose the decomposition of the biodegradable polymer.

In addition, even in the case of modifying the surface of the crosslinked nanofibers by allowing a mixed gas of fluorine gas and an inert gas to directly contact the crosslinked nanofibers, the partial pressure of the fluorine gas is preferably 0.01 to 0.2 bar, and specific examples thereof. The reason is the same as when fluorine gas is used alone.

In addition, the time that the cross-linked nanofibers and fluorine gas or a mixed gas of fluorine gas and inert gas is in direct contact is 1 to 60 minutes. If the contact time is less than 1 minute, there is a problem that the desired fluorine treatment, that is, the hydrophobic functional groups are not sufficiently introduced into the surface of the crosslinked nanofibers. In addition, when the contact time is greater than 60 minutes, the hydrophobic functional group is excessively introduced on the surface of the crosslinked nanofiber, which may cause the degradation of the biodegradable polymer.

That is, at low fluorine pressure and short reaction time, hydrophobic functional groups may not be sufficiently introduced into the surface of the cross-linked nanofibers, and at high fluorine pressure and long reaction time, perfluorination may be caused to lose the degradation of the biodegradable polymer. There is a concern. Therefore, it is important to introduce a sufficient CF functional group, not CF ₂ , to the cross-linked nanofiber surface by performing a fluorination reaction at an appropriate fluorine pressure and reaction time. The introduction of overlying CF ₂ functional groups causes the degradation of biodegradable polymers to be lost.

In another aspect, the present invention provides a biodegradable nanofibers with improved hydrophobic drug delivery by introducing a hydrophobic functional group to the surface of the nanofibers formed by electrospinning and radiation treatment by fluorine treatment.

Hereinafter, the present invention will be described in more detail based on Examples and Test Examples.

Example

Nanofibers were prepared under various conditions.

Example  One

First, in order to know the change in the chemical composition of the nanofibers before and after the fluorine treatment, nanofibers were prepared in a state in which no drug was mixed. Looking at the specific process to prepare a mixture by dissolving polyvinyl alcohol in distilled water, it was electrospun (Elctro spining) to prepare a nanofiber. The conditions of electrospinning were a voltage of 20 kV, a distance between the collector and the spinneret spinneret tip (TCD) of 10 cm, a syringe pump flow rate of 1.0 ml / h, and a collector speed of 110 rpm. The diameter of the obtained nanofibers was measured at 200 to 250 nm. In order to crosslink the electrospun nanofibers, irradiation was performed at 150 kGy for 1 hour. Next, a fluorine treatment was performed using the fluorine treatment equipment shown in FIG. 1 and using a mixed gas of fluorine (F ₂ ) gas and an inert gas. The pressure (partial pressure) of the fluorine gas was 0 bar (unfluorine treated), 0.01 bar, 0.1 bar, 0.25 bar, and the fluorine treatment time was 10 minutes. Specific manufacturing conditions are shown in Table 1.

Example  2

Nanofibers were prepared under the same conditions as in Example 1. However, in the step of forming the first mixture, a water-soluble drug Ambisome was mixed in a weight ratio of 1: 1 in polyvinyl alcohol and dissolved in distilled water to prepare a mixture. Except for this, nanofibers were manufactured through the same process as in Example 1, and the specific conditions are shown in Table 1.

Example  3

Nanofibers were prepared to determine whether the drug was modified and the rate of drug release. In order to clearly understand this, plution blue was mixed with polyvinyl alcohol in a weight ratio of 1: 1, and this was dissolved in distilled water to prepare a mixture. Except for this, nanofibers were manufactured through the same process as in Example 1, and specific conditions are shown in Table 1 below.

Example  4

Nanofibers were prepared to investigate the effects of nanofiber diameter and drug release rate. Nanofibers were prepared by the same process as in Example 3. However, the conditions of electrospinning were set to a voltage of 15 kV, a distance (TCD) between the collector and the radiator spinneret tip 15 cm, a syringe pump flow rate of 1.5 ml / h, and a collector speed of 90 rpm. The diameter of the obtained nanofibers was measured at 400 to 500 nm.

   [Table 1] Manufacturing conditions according to the embodiment

exam  Yes

In Example 1, X-ray Photoelectron Spectroscopy (XPS) peaks were separated and analyzed in order to determine the change in the chemical composition of the nanofiber surface before and after the fluorination treatment. It was. As shown, CF 1 was not formed in Example 1-1, which was not treated with fluorine, and Example 1-2, which was treated with fluorine at 0.01 bar, and Example 1-3, which was treated with fluorine at 0.1 bar, in CF. A bond was formed, and in Example 1-4 where the fluorination was performed at 0.25 bar, it was confirmed that CF and CF ₂ bonds were formed due to perfluorination.

The SEM photograph of the sample prepared according to Example 2 is shown in FIG. 3. As shown in the figure, in Example 2-4, in which fluorine treatment was performed under high fluorine gas pressure (0.25 bar), it was confirmed that the fiber phase was lost due to perfluorination and the shape was changed.

Next, in order to investigate the change in the amount of fluorine introduced on the surface of the nanofiber according to the fluorine treatment pressure, an elemental analysis using XPS was performed on the sample prepared according to Example 2, which is shown in FIG. 4. As can be seen from the figure, the fluorine content was increased as the fluorine treatment was performed under high fluorine gas pressure.

Figure 5 shows the experimental results for checking whether the drug is modified during the fluorine treatment. That is, the emission test was performed on the sample prepared according to Example 3, and the sample was analyzed using IR spectrometer data of the solution released 5 days after the start of the experiment. It was confirmed that the released solution was Pluorblue solution, and thus the drug was not modified in the fluorination process. It was also found that more drug was present inside the fibers.

6 shows experimental results for confirming the effect of the fluorine treatment pressure on the release rate. That is, Figure 6 is a test performed on the sample prepared according to Example 3, and shows this. As can be seen from the figure, in the case of Example 3-3 having a fluorine gas pressure of 0.1 bar compared to Example 3-2 having a fluorine gas pressure of 0.01 bar, the sustained release effect was increased due to the introduction of more hydrophobic functional groups. Able to know. On the other hand, in the case of Example 4-4 treated with fluorine at a high fluorine gas pressure (0.25 bar), it was confirmed that the drug is hardly released due to perfluorination. Therefore, it was confirmed that it is important to maintain a proper fluorine gas pressure in the fluorine treatment.

7 and 8 illustrate the effect of the diameter of the nanofibers on the release of the drug and shows it. FIG. 7 shows the results of drug release when the diameters of the nanofibers are different for Examples 3-1 and 4-1, that is, without the fluorine treatment. As can be seen from the figure, in the case where the fluorine treatment was not performed, it can be seen that Example 3-1, in which the diameter of the fiber is thin, releases the drug faster. This is because, when the diameter of the fiber is thin, the specific surface area that can be released is large and the release rate is relatively fast.

FIG. 8 shows the drug release results when the diameters of the nanofibers are different when the fluorine treatment is performed at the same pressure of 0.1 bar of fluorine gas. As can be seen from the figure, it can be seen that in the case of fluorine treatment, the release of the drug is relatively slow in Example 3-3, in which the diameter of the fiber is thinner, compared to Example 4-3, in which the diameter of the fiber is thick. This is because the case in which the diameter of the fiber is thin provides more effectively the surface area in which hydrophobic functional groups can be introduced during fluorination.

Although the present invention has been described with reference to the above-described embodiments and the accompanying drawings, other embodiments may be configured within the spirit and scope of the present invention. Therefore, the scope of the present invention is defined by the appended claims and equivalents thereof, and is not limited by the specific embodiments described herein.

1 is a schematic view showing a fluorine treatment device for producing nanofibers for fluorine-treated drug delivery device according to the present invention.

<Description of the code>

One. . . Fluorine gas container 2.. . Nitrogen gas container

3. . Oxygen gas container 4.. . Temporary storage containers

5. . Sodium fluoride pellets 6.. . Reactor

7. . Pressure gauge 8.. . Dialunium trioxide

9. . 10. Glass Valves. . Liquefied nitrogen

11. . Vacuum pump

FIG. 2 shows the X-ray Photoelectron Spectroscopy (XPS) peaks deconvolutionally to determine the change in chemical composition of the surface of the nanofibers before and after fluorination.

Figure 3 shows a SEM picture of the samples prepared by the embodiment of the present invention.

4 is an elemental analysis graph using XPS to investigate the change in the amount of fluorine on the fiber surface according to the fluorine treatment pressure.

Figure 5 shows the IR data of the solution released 5 days after the start of the release experiment.

6 shows experimental results for confirming the effect of the fluorine treatment pressure on the release rate.

7 and 8 illustrate the effect of the diameter of the nanofibers on the release of the drug and shows it. FIG. 7 shows Example 3-1 and Example 4-1, and FIG. 8 shows Example 3-3 and Example 4-3.

Claims (12)

(1) mixing a polymer precursor, a water soluble drug, and a solvent; (2) electrospinning the mixture obtained in step (1) to obtain nanofibers; (3) crosslinking the nanofibers by radiation treatment to the nanofibers obtained through the process of 'step (2)'; And (4) fluorination of the crosslinked nanofibers obtained through the process of 'step (3)' to modify the surface of the crosslinked nanofibers; Method for producing biodegradable nanofibers. The method of claim 1, The polymer precursor is a biodegradable polymer, characterized in that the drug delivery sustained release is enhanced biodegradable nanofibers by the fluorine treatment characterized in that. The method of claim 2, The biodegradable polymer is Drug delivery sustained release by fluorine treatment characterized in that it is selected from the group consisting of Poly caprolactone (PCL), Poly Lactic acid (PLA), Polyester, Poly Glycolic acid (PGA), Poly vinylalcohol (PVA) and mixtures thereof. Method for Producing Enhanced Biodegradable Nanofibers. The method of claim 1, The mixing ratio of the polymer precursor and the drug is 99 to 20: 1 to 80 wt%, the method of producing biodegradable nanofibers with improved drug delivery sustained release by fluorine treatment. The method of claim 4, wherein The mixing ratio of the polymer precursor and the drug is 90 to 70: 10 to 30 wt%, the method of producing biodegradable nanofibers with improved drug delivery sustained release by fluorine treatment. The method of claim 1, In the step of crosslinking the nanofibers of the 'step (3)', the drug delivery sustained release is enhanced by fluorine treatment, characterized in that the irradiation dose is 100 to 200 kGy, and the irradiation time is 0.5 to 2 hours. Method for producing biodegradable nanofibers. The method of claim 1, In the step of modifying the surface by the fluorination treatment of step (4), the surface of the cross-linked nanofibers is brought into direct contact with the cross-linked nanofibers by fluorine gas or a mixed gas of fluorine gas and inert gas. A method for producing biodegradable nanofibers having improved drug delivery sustained release by fluorine treatment, characterized in that for modifying. The method of claim 7, wherein The fluorine gas is fluorine (F ₂ ), nitrogen trifluoride (NF ₃ ), CF ₄ (carbon tetrafluoride), CHF ₃ (carbon trifluoride), C ₃ F ₈ (octa-differentiated tricarbon) that causes a fluorination reaction on the surface of the nanofibers , C ₄ F ₈ (carbon tetrafluorocarbon) and a mixture thereof, a method for producing biodegradable nanofibers having enhanced drug delivery sustained release by fluorine treatment. The method of claim 7, wherein In the case of modifying the surface of the crosslinked nanofiber by directly contacting the crosslinked nanofiber with fluorine gas, the pressure of the fluorine gas is 0.01 to 0.2 bar. Method for Producing Enhanced Biodegradable Nanofibers. The method of claim 7, wherein In the case of modifying the surface of the crosslinked nanofiber by allowing the crosslinked nanofiber to directly contact a mixed gas of fluorine gas and an inert gas, the partial pressure of the fluorine gas is 0.01 to 0.2 bar by fluorine treatment. Method for producing biodegradable nanofibers with enhanced drug delivery sustained release. The method of claim 7, wherein The time for direct contact between the cross-linked nanofibers and fluorine gas or a mixed gas of fluorine gas and inert gas is 1 to 60 minutes. Biodegradable nanofibers with improved drug delivery sustained release prepared by the method of any one of claims 1 to 11.

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