KR20110095590A - Effect of oxyfluorination on electrically controlled release of mwcnt/pva/paac composite microcapsules - Google Patents

Abstract

PURPOSE: A microcapsule for pH-sensitive drug delivery is provided to be applied in a pharmaeuctical, cosmetic, and fiber fields. CONSTITUTION: A method for preparing a microcapsule for pH-sensitive drug delivery comprises: a step of mixing multi-wall carbon nanotube, polyvinyl alcohol, pH-sensitive vinyl monomers, crosslinking agent, and soluble drug in a solvent to prepare a micro precursor solution; and a step of polymerizing and cross-linking the microcapsule precursor solution and drying. The multi-wall carbon nanotube is prepared by oxyfluorination using fluorine gas and oxygen gas at 0.1-5.0 bar for 1-30 minutes.

Description

Microcapsules for HT-sensitive drug delivery and preparation method thereof {Effect of oxyfluorination on electrically controlled release of MWCNT / PVA / PAAc composite microcapsules}

The present invention relates to a microcapsules for pH-sensitive drug delivery and a method for preparing the same.

A microcapsule is a carrier in which a special functional core material is surrounded by a fine polymer membrane having an average diameter of several microns. The microcapsules have the advantage of controlling the protection of volatile liquids or active substances, odors, tactile shielding, and the release timing and rate of encapsulated substances to the outside, and studies on microencapsulation of functional substances are used in medicine and pesticides. , Cosmetics as well as the textile industry is expanding widely.

This microencapsulation method is a system for encapsulating a functional core material into a specific encapsulant to control the sustained or accelerated release of the functional core material and its release rate in a desired environment. It is applied to insecticides, preparations, and fungicides in agriculture. In particular, the pharmaceutical field is attracting attention because it can be used as a target-oriented microcapsules that are selectively released at the desired site to increase the efficiency of the drug, and there is a demand for a technology that can effectively control the release rate of such microcapsules in the future. do.

Accordingly, the present inventors prepared a pH-sensitive drug delivery microcapsules encapsulating a functional core material having biocompatibility characteristics, and the pH-sensitive drug delivery microcapsules desired by using a difference in solubility according to pH change or voltage. By confirming that the release rate of the functional core material in the site can be controlled, the present invention has been completed.

It is an object of the present invention to provide a microcapsule for drug delivery, including pH-modified multi-walled carbon nanotubes modified by oxyfluorination treatment and a method for preparing the same.

More specifically, the drug delivery rate is controlled by improved dispersibility using a multi-walled carbon nanotube whose surface is modified with a hydrophilic group by an oxygen-containing fluorination method, and a pH-sensitive drug delivery microcapsule that responds to pH and a method of preparing the same To provide.

Hereinafter, a manufacturing method of the present invention will be described in detail with reference to the accompanying drawings. The drawings introduced below are provided as examples and may be exaggerated in order to sufficiently convey the spirit of the present invention to those skilled in the art.

Hereinafter, the technical and scientific terms used herein will be understood by those skilled in the art without departing from the scope of the present invention. Descriptions of known functions and configurations that may be unnecessarily blurred are omitted.

The present invention provides a pH-sensitive drug delivery microcapsules and a method for preparing the same.

The microcapsules for pH-sensitive drug delivery of the present invention are characterized by using multi-walled carbon nanotubes whose surface is hydrophilically modified by oxyfluorination treatment, and improving the dispersibility and drug according to the multi-walled carbon nanotubes. The rate of delivery is characterized.

In addition, the microcapsules for pH-sensitive drug delivery of the present invention is characterized in that the C-OOH functional group is present on the surface of the hydrophilic modified multi-walled carbon nanotubes, and also can control the drug release rate according to the introduction amount of the functional group. There is a characteristic.

Hereinafter, the present invention will be described in detail.

The present invention

a) preparing a microcapsule precursor solution by mixing a surface-modified multi-walled carbon nanotube and polyvinyl alcohol, a pH-sensitive vinyl monomer, a crosslinking agent, a water-soluble drug, and a solvent by an oxyfluorination treatment; And

b) preparing a pH-sensitive microcapsules by polymerizing, crosslinking and drying the microcapsule precursor solution;

It provides a method for producing a pH-sensitive drug delivery microcapsule comprising a.

In the present invention, the oxygen fluorination (oxyfluorination) treatment of step a) is a multi-walled carbon nanotube using a mixed gas of fluorine gas and oxygen gas in the reactor for a total pressure of 0.1 to 5.0 bar for 1 to 30 minutes It is characterized by being manufactured by treatment.

The fluorine gas is selected from nitrogen trifluoride (NF ₃ ), carbon tetrafluoride (CF ₄ ), carbon trifluoride (CHF ₃ ), trichloro octafluoride (C ₃ F ₈ ) and carbon tetrafluorocarbon (C ₄ F ₈ ). At least one, and the mixed gas of the fluorine gas and oxygen gas is used by mixing the mixing ratio of fluorine and oxygen gas in a volume ratio of 5 to 15: 85 to 95.

The fluorine gas used in the oxygen fluorination treatment of the present invention forms a radical capable of bonding with oxygen by breaking a portion of a strongly bonded carbon bond due to its high reactivity, and the oxygen gas is bonded to the surface of a multi-walled carbon nanotube. It binds to a functional group containing oxygen to impart hydrophilicity.

Introduction of the hydrophilic functional group on the surface of the multi-walled carbon nanotubes has the advantage of improving the dispersibility which is a disadvantage of the existing multi-walled carbon nanotubes. This oxygen-oxyfluoride treatment is a surface treatment by diffusion of fluorine gas, which can be treated in any form such as gels, films, and fibers, and the surface treatment is performed by operating the device under low vacuum (10 ^-1 torr) below room temperature. The apparatus is also relatively simple and has the advantage that the fluorine gas and the hydrocarbon group on the surface of the polymer spontaneously react to eliminate the need for an initiator and a catalyst for initiating the surface treatment reaction.

According to the present invention, in the oxygen fluorination treatment, the total pressure in the reactor has a significant meaning that the pressure ratio of fluorine gas and oxygen gas is important, and the release rate of the functional core material can be controlled by the pressure ratio of fluorine gas and oxygen gas. It has an effect.

More specifically, in the oxygen fluorination treatment, the pressure ratio of oxygen gas and fluorine gas is treated at a ratio of 7: 3, 5: 5, and 3: 7, respectively, using a multi-walled carbon nanotube having a modified surface. As a result of evaluating the dispersibility of the multi-walled carbon nanotubes, it was confirmed that the permeability was lowered as the ratio of oxygen gas to fluorine gas increased, and the dispersibility was improved and the dispersibility was improved. See FIGS. 4 and 5.

This improves the electrical conductivity of the pH-sensitive drug delivery microcapsules of the present invention by improving the dispersibility of the present invention, and more specifically, the drug release according to the change in the voltage of the pH-sensitive drug delivery microcapsules, the supply voltage The cumulative drug release concentration increased as the intensity increased. See FIG. 9.

In the present invention, the oxyfluorination is to modify the surface of the multi-walled carbon nanotubes to hydrophilic without damaging the multi-walled carbon nanotubes, three-dimensional according to the aggregation phenomenon of the existing multi-walled carbon nanotubes It is a fundamental solution to the problem of inhibiting dispersibility caused by disruption of network structure, which is important in the present invention.

In the present invention, the microcapsule precursor solution of step a) is 0.01 to 1.0 parts by weight of the surface-modified multi-walled carbon nanotubes by oxyfluorination treatment, based on 100 parts by weight of the solvent, polyvinyl alcohol 0.5 to It is prepared by mixing 5.0 parts by weight, 0.5 to 5.0 parts by weight of a pH-sensitive vinyl monomer, 1 to 5 parts by weight of a crosslinking agent, and 0.05 to 1.0 parts by weight of a water-soluble drug.

The polyvinyl alcohol has a molecular weight of 5000 to 200000, more preferably 31000 to 50000 is suitable for the living body, good reactivity and good mechanical strength. In addition, the vinyl monomer is an acrylic monomer (acrylic acid), methacrylic acid (methacrylic acid), methacrylamide (methacryl amide), hydroxyethyl methacrylate (hydroxyethyl methacrylate), glycidyl One or more selected from acrylate (glycidyl acrylate), cinnamic acid (cinnamic acid), vinylpyrrolidone (vinylpyrrolidone) and methyl methacrylate (methyl meta acrylate) is used, preferably pKa is 3 to 6 In this preferred and more specific example, acrylic acid having a pKa of 4.7 is used.

The acrylic acid has an effect of helping to release the drug continuously for a long time as the pH is increased by the ion repulsion of the carboxyl group, which is a functional group of acrylic acid, to increase the interval between polymer chains. See FIG. 10.

In the present invention, the crosslinking agent is a mixture of glutaraldehyde (GA) and ethylene glycol dimethacrylate (EGDMA) to form an interpenetrating polymer network (IPN) form of polyvinyl alcohol and acrylic acid. use.

The permeable polymer network refers to a polymer having at least two network structures that are at least partially cross-linked on a molecular scale but are not covalent and not separated until the chemical bond is broken.

In the present invention, the pH-sensitive drug delivery microcapsules including the multi-walled carbon nanotubes whose surface is modified by the oxygen-containing fluorination treatment is a polymer precursor corresponding to polyvinyl alcohol and a vinyl monomer corresponding to acrylic acid is a permeable polymer network (interpenetrating polymer network, IPN) is characterized in that it is manufactured in the form.

In the present invention, the water-soluble drug is characterized in that coomasiebrilliant blue. Distilled water is mentioned as a specific example of the solvent used for aqueous solution in this invention.

In the present invention, the polymerization and crosslinking reaction conditions of step b) are stirred at room temperature for 10 minutes to 1 hour, and then remove oxygen to react at room temperature to 50 to 100 ° C for 1 hour to 3 hours to deliver pH-sensitive drugs. Prepare microcapsules.

The polymerization uses a free radical polymerization method, and reacting at 50 to 100 ° C. for 1 hour to 3 hours may effectively exhibit the physical properties of the present invention.

The present invention provides a pH-sensitive drug delivery microcapsules prepared according to the above production method.

The present invention provides a drug delivery device using the pH-sensitive drug delivery microcapsules prepared according to the preparation method as a drug carrier.

The pH-sensitive drug delivery microcapsules are characterized in that it comprises a multi-walled carbon nanotube surface modified with a C-OOH functional group contained in the microcapsules, the drug release rate can be adjusted according to the introduction amount of the functional There is a characteristic.

Microcapsules for pH-sensitive drug delivery according to the present invention are three-dimensional according to the aggregation phenomenon of existing multi-walled carbon nanotubes using multi-walled carbon nanotubes whose surface is modified by oxyfluorination treatment. There is an advantage that can fundamentally solve the problem of the inhibition of dispersion caused by the disruption of the network structure.

In addition, the pH-sensitive drug delivery microcapsules according to the present invention can be widely used in the pharmaceutical, cosmetics, pesticides and textile fields that require the release rate and target orientation of the functional core material by using it as a carrier.

1 is a schematic view showing a fluorine treatment apparatus for producing a multi-walled carbon nanotubes used in the manufacture of microcapsules according to the present invention,
2 is a result of analyzing the surface of the multi-walled carbon nanotubes according to the oxygen-containing fluorination treatment through XPS,
FIG. 3 shows the results of analysis of functional groups of multi-walled carbon nanotubes whose surface is modified by oxygen fluorination using FT-IR (Fourier transform spectroscopy).
4 is a result of measuring the dispersibility of the multi-walled carbon nanotubes surface modified by oxygen-containing fluorination with a spectrophotometer,
5 is a result of dispersing the surface of the multi-walled carbon nanotubes modified by the oxygen-containing fluorination of the present invention in an aqueous polyvinyl alcohol solution and the dispersibility thereof by an optical microscope,
(a: manufacture example 1, b: manufacture example 2, c: manufacture example 3, d: no treatment)
Figure 6 is a photograph showing the observation of the surface of the pH-sensitive drug delivery microcapsules according to the invention by FE-SEM,
(a: Example 1, b: Example 2, c: Example 3, d: Comparative Example 1)
7 is a result of confirming the electrical conductivity of the pH-sensitive drug delivery microcapsules according to the present invention by the four probe method,
8 is a view showing the principle of drug release used for the drug accumulation release evaluation of the pH-sensitive drug delivery microcapsules according to the present invention,
(a: schematic diagram of the device, b: principle of use)
9 is a result of measuring the drug release cumulative concentration according to the voltage of the pH-sensitive drug delivery microcapsules of the present invention prepared by the preparation method of Example 1 at a constant pH,
10 is a result of measuring the drug release cumulative concentration according to the pH change of the pH-sensitive drug delivery microcapsules of the present invention prepared by the manufacturing method of Example 1 at a constant voltage,
11 is a result of measuring the release accumulation concentration of the released drug of the pH-sensitive drug delivery microcapsules according to the present invention at a constant voltage (10 V) and pH (pH 10),
12 is a result confirming the cytotoxicity of the pH-sensitive drug delivery microcapsules according to the present invention.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

[ Manufacturing example  1] Oxygen-containing fluorine (oxygen gas: fluorine gas = 7: 3) Modified Multiwall  Manufacture of Carbon Nanotubes

In order to manufacture multi-walled carbon nanotubes having a hydrophilic functional group introduced to the surface by using oxyfluorination, the multi-walled carbon nanotubes were surface treated using the fluorination apparatus of FIG. 1. As a pretreatment step for removing impurities in the oxygen fluorination reaction, the multi-walled carbon nanotubes were treated at room temperature at 10 ⁻⁶ torr for 30 minutes.

Oxygen-containing fluorination treatment is a mixed gas of fluorine gas and oxygen gas in a 10: 90 volume ratio, the total pressure of the mixed gas is 1.0 bar, the ratio of oxygen gas pressure and fluorine gas pressure is 7: 3 5 minutes at.

Through the above process, a multi-walled carbon nanotube having a surface modified by a hydrophilic functional group of C-OOH was obtained by an oxygen fluorination method.

[ Manufacturing example  2] Oxygen-containing fluorine (oxygen gas: fluorine gas = 5: 5) surface Modified Multiwall  Manufacture of Carbon Nanotubes

The preparation process of Preparation Example 1 was the same, and the ratio of oxygen gas pressure and fluorine gas pressure was 5: 5 at the ratio of oxygen fluorination treatment, and the surface was modified by C-OOH hydrophilic functional group by oxygen fluorination method. Wall carbon nanotubes were obtained.

[ Manufacturing example  3] Oxygen-containing fluorine (oxygen gas: fluorine gas = 3: 7) Modified Multiwall  Manufacture of Carbon Nanotubes

The manufacturing process of Preparation Example 1 is the same, and the ratio of oxygen gas pressure and fluorine gas pressure is a oxyfluorinated fluorination process at a ratio of 3: 7 and the surface is modified by a hydrophilic functional group of C-OOH by oxyfluorine fluorination method. Wall carbon nanotubes were obtained.

The naming of the oxygen-containing fluorinated multi-walled carbon nanotubes prepared in Preparation Examples 1 to 3 is shown in Table 1 below.

Example 1 Preparation of microcapsules for pH sensitive drug delivery

In order to prepare a microcapsule precursor solution, a polyvinyl alcohol aqueous solution was prepared by mixing a weight average molecular weight of 42,000 polyvinyl alcohol (PVA, aldrich chemical co.) And distilled water to be 1: 9.

In addition, acrylic acid (acrylic acid) and distilled water by mixing the weight ratio of 1: 4 to prepare an acrylic acid aqueous solution. 20 ml of the polyvinyl alcohol aqueous solution prepared above and 10 ml of an acrylic acid solution were mixed, and 100 ml of n-hexane as a solvent and 6 ml of span 80 as an emulsifier were added to the mixture, followed by the model drug Kumashibrillant Blue R-250 ( 0.2 g of coomassie brilliant blue R-250) and 0.1 g of the multi-walled carbon nanotubes of Preparation Example 1 were added and mixed.

In another container, 100 ml of solvent n-hexane was added, and 1 ml of an aqueous solution of glutaraldehyde (25 wt% solution in water, aldrich chemical co.) Was used as a crosslinking agent of polyvinyl alcohol and ethylene glycol dimethacrylate, a crosslinking agent of acrylic acid. 1 mL of acrylate (ethyleneglycoldimethacrylate, 98%) was mixed and 6 mL of Span 80, an emulsifier, was added and stirred.

The mixture of the two vessels prepared above was put into a reactor, 20 ml of a 1% potassium persulfate aqueous solution, which was a thermal initiator, was mixed, followed by stirring at room temperature for 30 minutes. Nitrogen gas was flowed into the stirred solution for 20 minutes to remove oxygen, and stirred at 1500 rpm for 2 hours at 65 ° C. to prepare a microcapsule for pH-sensitive drug delivery by a free radical polymerization method.

In order to purify the prepared microcapsules for pH-sensitive drug delivery, and then washed several times using petroleum ether and distilled water, the n-hexane solvent was evaporated under vacuum at 50 ℃.

Through the above process to obtain a microcapsules to improve the dispersibility of the multi-walled carbon nanotubes in the pH-sensitive drug delivery microcapsules.

[Example 2]

The preparation process of Example 1 was the same, and the pH-sensitive drug delivery microcapsules were prepared using the multi-walled carbon nanotubes of Preparation Example 2.

Example 3

The preparation process of Example 1 was the same, and the pH-sensitive drug delivery microcapsules were prepared using the multi-walled carbon nanotubes of Preparation Example 3.

Comparative Example 1

The preparation process of Example 1 was the same, and the pH-sensitive drug delivery microcapsules were prepared using multi-walled carbon nanotubes without the oxygen fluorination treatment.

The pH-sensitive drug delivery microcapsules using the multi-walled carbon nanotubes omitting the oxygen-oxygenated fluorination treatment used in Comparative Example 1, Examples 1 to 3 and the multi-walled carbon nanotubes treated with the oxygen-oxyfluorinated treatment Naming is shown in Table 2 below.

[ Test Example  One] Oxygen Oxide Fluoride  According to treatment Multiwall  Investigation of chemical composition on the surface of carbon nanotubes

X-ray photoelectron spectroscopy (XPS) (Thermo Electron Co., MultiLab) changes in chemical composition of the surface of the multi-walled carbon nanotubes used in Examples 1 to 3 and Comparative Example 1 by introduction of hydrophilic functional groups using oxygen-containing fluorination. 2000).

The chemical composition change was investigated through the amount of carbon, oxygen and fluorine to the degree of change in the hydrophilicity in the chemical bond of each of the multi-walled carbon nanotubes used in Examples 1 to 3 and Comparative Example 1, the results It is shown in Figure 2, the chemical bond energy value of each element is shown in Table 3 below.

As a result, as can be seen in FIG. 2 and Table 3, the peak of F1s is lowered as the ratio of oxygen gas pressure in oxygen fluorination is increased from 30% (preparation example 3) to 70% (preparation example 1) of the total gas pressure. On the contrary, it was seen that the O1s peak was increased.

In addition, it was confirmed that the higher the ratio of oxygen gas in oxygen fluorination, the higher the 285.9 eV binding energy value indicating CO bond and the 286.7 eV binding energy value indicating C = O bond at the C1s peak. It was confirmed that the surface functional groups of the multi-walled carbon nanotubes used in Example 1 were most modified to be hydrophilic.

[ Test Example  2] Oxygen Oxide Fluoride  Investigation of functional group introduction by treatment

In order to investigate the functional group introduction according to the oxygen fluorination treatment, the multi-walled carbon nanotubes used in Examples 3 to 3 and Comparative Example 1 were observed by an infrared spectroscopy [FT-IR (Fourier transform spectroscopy)].

As a result, as with the third also the oxygen gas used for the fluorination of oxygen: appears in the higher pressure of the oxygen gas of the pressure ratio of the fluorine gas peak ratio of the hydroxyl group and the carbonyl group of 3600cm ^-1 and 1632cm ^-1 are larger The peaks of the CF bonds and the CF ₂ bonds of 1030cm ^-1 and 1160cm ^-1 appear to be small. From the above results, it was observed that the functional groups introduced depend on the ratio of the pressure of oxygen gas: fluorine gas used for oxygen fluorination.

Test Example 3 Evaluation of Dispersibility of Multi-Walled Carbon Nanotubes Treated with Oxygen-Fluorofluorination

(1) UV-Vis spectrophotometer measurement

In order to investigate the dispersibility of the multi-walled carbon nanotubes according to the oxygen-containing fluorination treatment, the multi-walled carbon nanotubes used in Examples 1 to 3 and Comparative Example 1 were mixed with an aqueous polyvinyl alcohol solution and sonicated for 1 hour. Was measured with a spectrophotometer (UV-Vis spectrophotometer) at 635 nm for 4 days.

As a result, it was observed that the permeability of the multi-walled carbon nanotubes treated with oxyfluorine was lower than the multi-walled carbon nanotubes without any treatment as shown in FIG. Among them, the higher the oxygen gas ratio in the oxygen gas: fluorine gas ratio, the lower the permeability. As a result, it was observed that the higher the ratio of the oxygen gas used for oxygen fluorination, the greater the dispersibility.

(2) Optical microscope observation

In order to evaluate the dispersibility of the multi-walled carbon nanotubes according to the oxygen-containing fluorination treatment, the multi-walled carbon nanotubes used in Examples 1 to 3 and Comparative Example 1 were mixed with an aqueous polyvinyl alcohol solution and observed with an optical microscope.

As a result, as can be seen in FIG. 5, as the pressure ratio of oxygen gas to oxygen gas used for oxygen fluorination is reduced, the aggregation of multi-walled carbon nanotubes decreases as well as the polyvinyl alcohol aqueous solution increases. Dispersion could be observed.

[ Test Example  4] pH  Surface Observation of Sensitive Drug Delivery Microcapsules

As a result of observing the pH-sensitive drug delivery microcapsules prepared in Examples 1 to 3 and Comparative Example 1 using a scanning electron microscope, as shown in FIG. 6, the oxygen gas used for oxygen fluorination: pressure of fluorine gas As the pressure ratio of the oxygen gas in the ratio increases, it was confirmed that the surface of the microcapsules was well prepared.

[ Test Example  5] pH  Electroconductivity Investigation of Sensitive Drug Delivery Microcapsules

After dipping the pH sensitive drug delivery microcapsules powder prepared in Examples 1 to 3 and Comparative Example 1 in a pH 7 buffer solution for 24 hours, the buffer solution is filtered. The microcapsules filtered from the filter paper were prepared into pellets having a diameter of 10 mm and a thickness of 2 mm, and the resistance of the pellets was measured by four probe points (DASOL ENG, Korea).

The electrical conductivity (four point probe) of the measured resistance is represented by the following Equation 1.

As a result, as can be seen in Figure 7, it can be seen that the electrical conductivity increased as the pressure ratio of oxygen gas in the pressure ratio of oxygen gas: fluorine gas used for oxygen fluorination. This means that the electrical conductivity is improved due to the increase in dispersibility of the multi-walled carbon nanotubes of Preparation Examples 1 to 3 used in the microcapsules for pH sensitive drug delivery.

[Test Example 6] Drug release investigation of pH-sensitive drug delivery microcapsules

Drug release evaluation of the pH-sensitive drug delivery microcapsules prepared in Examples 1 to 3 and Comparative Example 1 was measured by a spectrophotometer by extracting the release solution every hour using the drug diffusion evaluation (franz diffusion cell) of FIG. .

(1) Investigation of drug release by change of voltage

In order to measure the release accumulation of the released drug of the pH-sensitive drug delivery microcapsules, 0.5 g of the pH-sensitive drug delivery microcapsules prepared in Example 1 was placed on a nylon net and the drug was released. In contact with each pH 2, 7, 10 buffer solution in the evaluation cell (1 ml) was taken every hour. The test solution was maintained at 37 ± 3 ℃ and the stirring speed in the cell was fixed for 48 hours. Nylon nets were supplied from a DC power supply (ITECH, IT6721) via copper wire and the voltages supplied were increased to 0, 3, 5 and 10.

The emission cumulative concentration of the released drug was measured at 541 nm using a spectrophotometer (Optizen 2120 UV, Mecasys, Korea), and the cumulative amount released of the released drug was used in the following Equation 2.

Mt represents the amount of drug released in Example 1 over time, and M represents the total amount of coumasibrillant blue.

The drug release cumulative concentration measured at pH 10 for evaluating the released drug (coumashibrillant blue) of the microcapsules according to the voltage of the pH-sensitive drug delivery microcapsules prepared in Example 1 is shown in FIG.

As a result, as can be seen in Figure 9, it was observed that the drug release cumulative concentration increases as the intensity of the voltage supplied to the nylon net (nylon net) increases. This is because the multi-walled carbon nanotubes are modified by the oxygen-containing fluorination treatment so that they are well dispersed in the microcapsule and thus the electrical conductivity between the multi-walled carbon nanotubes in the microcapsule is improved. .

(2) pH Investigation into drug release

In order to evaluate the released drug (Coomasibrillant Blue) of the microcapsules according to the pH change of the pH-sensitive drug delivery microcapsules prepared in Example 1, the voltage was kept constant at 10V, and the measured drug release accumulation concentration was 10 is shown.

As a result, as can be seen in Figure 10, the pH-sensitive drug delivery microcapsules of Example 1 was confirmed that the drug is continuously released for 24 hours or more according to the pH change, and also pH 7 and pH than from pH 2 It was found that more drug was released at pH 10 longer than at 7.

From the above results, it can be seen that the spacing between the polymer chains is increased as the pH is increased by the ion repulsive force of the carboxyl group, which is a functional group of acrylic acid used in the microcapsules for pH sensitive drug delivery.

(2) constant pH  And investigation of drug release according to constant voltage

The pH-sensitive drug delivery microcapsules of Examples 1 to 3 and Comparative Example 1 was constantly maintained at a voltage of 10V under the condition of pH 10, the pH-sensitive drug delivery of Examples 1 to 3 and Comparative Example 1 of the present invention The drug release cumulative concentration of the released drug (coumashibrillant blue) of the microcapsules was investigated.

As a result, as can be seen from FIG. 11, the drug release of the microcapsules containing the multi-walled carbon nanotubes of Preparation Example 1 having a high pressure ratio of oxygen gas at the pressure of oxygen gas: fluorine gas used for oxygen fluorination. The cumulative concentration was found to be the highest.

The above results also confirm that the surface of the multi-walled carbon nanotubes are modified by a hydrophilic group by oxygen fluorination to improve the dispersibility of the multi-walled carbon nanotubes with a hydrophilic solvent, and thus release the drug well.

[ Test Example  7] pH  Cytotoxicity Assessment of Sensitive Drug Delivery Microcapsules

Cells for performing cytotoxicity experiments were mouse fibroblasts (L929). Cytotoxicity of mouse fibroblasts (L929) was measured for cell viability using the CCK-8 (Cell counting kit-8, Dojindo Lab., Japan) analysis. The fibroblasts of the mouse (L929) at 37 ° C. were fed 5% CO ₂ in DMEM medium containing 10% FBS (Fetal Bovine Serum), penicillin (5000 units / ml) and streptomycin (50 μg / ml). Incubated.

0.1-g of each of the pH-sensitive drug delivery microcapsules of Examples 1 to 3 and Comparative Example 1 was collected, and 96-well of fibroblasts of the mouse cultured at a cell concentration of 5 × 10 ³ cells / well for 24 hours. After addition to the culture plate the solvent was extracted and diluted. Next, after adding CCK-8 (Cell counting Kit-8) to this solvent and incubating for 2 hours, the OD value was measured at 450 nm using an ELISA microplate reader (Bio-Tak instruments.Winooski. VT.USA). The survival rate was confirmed.

As a result of confirming the cell viability of the extraction solvent concentration of the pH-sensitive drug delivery microcapsules of Examples 1 to 3 and Comparative Example 1, it was confirmed that the cell viability is 80% or more as shown in FIG.

From the above results, it was confirmed that the microcapsules for pH-sensitive drug delivery of Examples 1 to 3 of the present invention are non-toxic harmless to the human body, which is also a result confirming that the human body can be used for therapeutic purposes.

1. Fluorine gas container 2. Nitrogen gas container
3. Oxygen gas container 4. Temporary storage container
5. Sodium fluoride pellets 6. Reactor
7. Pressure Gauge 8. Aluminum Dioxide
9. Glass valve 10. Liquefied Nitrogen
11. Vacuum pump

Claims (11)

a) preparing a microcapsule precursor solution by mixing a surface-modified multi-walled carbon nanotube and polyvinyl alcohol, a pH-sensitive vinyl monomer, a crosslinking agent, a water-soluble drug, and a solvent by an oxyfluorination treatment; And
b) preparing a pH-sensitive microcapsules by polymerizing, crosslinking and drying the microcapsule precursor solution;
Method of producing a microcapsule for pH sensitive drug delivery comprising a. The method of claim 1,
Oxygen fluorination (oxyfluorination) treatment of step a) is prepared by treating the multi-walled carbon nanotubes with a mixed gas of fluorine gas and oxygen gas in the reactor for a total pressure of 0.1 to 5.0 bar for 1 to 30 minutes Method of producing a microcapsule for sensitive drug delivery. The method of claim 2,
The oxygen fluorination (oxyfluorination) is a method of producing a pH-sensitive drug delivery microcapsules for modifying the surface of the multi-walled carbon nanotubes hydrophilic. The method of claim 2,
The mixed gas of the fluorine gas and oxygen gas is a mixture ratio of fluorine and oxygen gas is 5 to 15: 85 to 95 volume ratio of the method for producing a microcapsule for pH sensitive drug delivery. The method of claim 1,
The microcapsule precursor solution of step a) is 0.01 to 1.0 parts by weight of the multi-walled carbon nanotubes modified by oxyfluorination treatment, 0.5 to 5.0 parts by weight of polyvinyl alcohol, based on 100 parts by weight of the solvent. A method for producing a pH-sensitive drug delivery microcapsules prepared by mixing 0.5 to 5.0 parts by weight of sensitive vinyl monomer, 1 to 5 parts by weight of crosslinking agent, and 0.05 to 1.0 parts by weight of water-soluble drug. 6. The method of claim 5,
The polyvinyl alcohol has a molecular weight of 5000 to 200000 pH-sensitive drug delivery method for producing microcapsules. 6. The method of claim 5,
The vinyl monomers are acrylic acid, methacrylic acid, methacrylamide, hydroxyethyl methacrylate, glycidyl acrylate, cinnamic acid. (cinnamic acid), vinylpyrrolidone (vinylpyrrolidone) and methyl methacrylate (methyl meta acrylate) is a method of producing a microcapsule for pH-sensitive drug delivery is at least one selected from. 6. The method of claim 5,
The crosslinking agent is a method for preparing a microcapsule for pH-sensitive drug delivery is a mixture of glutaraldehyde (GA) and ethylene glycol dimethacrylate (EGDMA). 6. The method of claim 5,
The water-soluble drug is a coomassie brilliant blue (coomassie brilliant blue) method of producing a microcapsule for pH-sensitive drug delivery. The method of claim 1,
The polymerization and crosslinking reaction conditions of step b) are the pH-sensitive drug delivery microcapsules prepared by reacting for 1 hour to 3 hours at room temperature to 50 to 100 ℃ by removing oxygen after stirring for 10 minutes to 1 hour at room temperature Manufacturing method. A microcapsule for pH sensitive drug delivery prepared by the method according to claim 1.

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