KR102123508B1 - The method for manufacturing of electroconductive micro-needle patch and electroconductive micro-needle patch manufactured thereby - Google Patents

Abstract

The present invention relates to a method for manufacturing an electroconductive micro needle patch and an electroconductive micro needle patch prepared thereby, and more specifically, to prepare an aqueous solution of a mixture comprising an acrylic acid polymer, alginate, an electroconductive monomer and water. To do; Putting the aqueous solution of the mixture into a mold for molding a microneedle and irradiating it to prepare a primary crosslinked hydrogel; And preparing a secondary crosslinked hydrogel by immersing the primary crosslinked hydrogel in a solution containing calcium ions; Micro needle patches produced by this method; And an electrically conductive polymer in which an acrylic acid polymer, calcium alginate, and an electrically conductive monomer are polymerized and primaryly crosslinked by irradiation, and secondaryly crosslinked by calcium ions. The ionized nutritional substance or drug can be effectively delivered to the inside of the skin by electrical repulsion using the electroconductive microneedle patch.

Description

The method for manufacturing of electroconductive micro-needle patch and electroconductive micro-needle patch manufactured thereby}

The present invention relates to a method for manufacturing an electroconductive microneedle patch and an electroconductive microneedle patch manufactured thereby, more specifically, to effectively deliver an ionized nutritional substance or drug into the skin by electrical repulsion by an electric potential difference of microcurrent. It relates to a method for manufacturing an electrically conductive micro needle patch and an electrically conductive micro needle patch manufactured thereby.

Because transdermal absorbents are applied to the skin to administer the drug, the patient's compliance and preference are high, and the drug is continuously administered at a constant blood level, and recently, the drug is directly absorbed into the skin without undergoing liver metabolism. The global formulation market continues to grow. Despite the many advantages of these transdermal drug delivery patches, there are still many disadvantages due to the limitations of the patch design that can deliver drugs into the skin and the complicated manufacturing process, and the absence of relatively expensive drug carriers and highly elastic body-friendly polymer materials. have. In particular, it is required to develop and manufacture a micro needle patch capable of direct drug delivery into the skin for rapid drug absorption and continuous drug delivery.

On the other hand, as disclosed in Korean Patent Registration No. 10-1873337 B1, the micro-needle-type patch can solve the problems of the conventional oral drug administration and the injection drug delivery system of metal needles, which allows patients to administer injections themselves. In addition, it has the advantage of being safe as a patch material applied to existing skin and delivering drugs to the body quickly and with high efficiency, like a regular hypodermic syringe without pain.

However, the existing microneedle patch has a major problem that the penetration rate or delivery power of the drug is low only by drug delivery by physical skin penetration, and thus, as disclosed in Japanese Patent Application Publication No. 2011-236311, a conductive hydrogel is applied and However, as the use of continuous harmful chemicals due to crosslinking using a chemical crosslinking agent, the use of harmful solvents, etc. is required for physical and functional processing of the material, degradation of human toxicity and biocompatibility due to these harmful ingredients is a problem.

Accordingly, it is expected that it can be widely applied in related fields when an electroconductive hydrogel micro needle patch capable of expressing excellent electroconductivity without including a chemical cross-linking agent causing skin irritation is provided.

One aspect of the present invention is to provide a method for manufacturing a microneedle patch having excellent electrical conductivity using radiation.

Another aspect of the present invention is to provide a microneedle patch manufactured by the method for manufacturing an electrically conductive microneedle patch of the present invention.

Another aspect of the invention is to provide an electrically conductive micro needle patch.

One aspect of the present invention is an acrylic acid polymer, Preparing an aqueous mixture solution comprising alginate, an electrically conductive monomer, and water; Putting the aqueous solution of the mixture into a microneedle molding frame and irradiating it to prepare a primary crosslinked hydrogel; And immersing the primary crosslinked hydrogel in a solution containing calcium ions to prepare a secondary crosslinked hydrogel.

Another aspect of the present invention provides an electrically conductive micro needle patch manufactured by the method of manufacturing the electrically conductive micro needle patch.

Another aspect of the present invention provides an electroconductive microneedle patch comprising an electroconductive polymer in which an acrylic acid polymer, calcium alginate and an electroconductive monomer are polymerized and primary crosslinked by irradiation, and secondary crosslinked by calcium ions. do.

According to the manufacturing method of the electroconductive microneedle patch of the present invention, it is possible to simultaneously perform crosslinking and sterilization of biocompatible polymer materials without the use of harmful chemical crosslinking agents, and there is no need for extraction and washing processes, thus simplifying the process to make the technology practical. You can contribute to On the other hand, the electroconductive microneedle patch obtained by the present invention exhibits excellent electrical conductivity, and it is possible to easily adjust conductivity.

1 shows an exemplary process of the method for manufacturing the electroconductive microneedle patch of the present invention.
2A shows the morphological changes upon wetting of Comparative Examples 1 and 2. 2B shows the morphological changes upon wetting of Examples 1 and 2. Figure 2c shows a graph comparing the size of the hydrogels of Examples 1 and 2 and Comparative Examples 1 and 2. Figure 2d shows a graph comparing the rate of change in size when wetting the hydrogels of Examples 1 and 2 and Comparative Examples 1 and 2.
Figure 3 shows a graph comparing the swelling degree of the hydrogels of Examples 1 and 2 and Comparative Examples 1 and 2.
Figure 4 shows a graph comparing the conductivity of the hydrogels of Examples 1 and 2 and Comparative Examples 1 and 2.
FIG. 5A is an image obtained by scanning electron microscopy (SEM) of the structure of the primary cross-linked microneedle patch in Example 1. 5B is an image obtained by scanning electron microscope (SEM) of the structure of the secondary crosslinked microneedle patch obtained in Example 1. FIG.
Figure 6 shows a graph comparing the gelation rate of the primary cross-linked hydrogel according to the content of polyacrylic acid when preparing an exemplary electroconductive micro-needle patch of the present invention.
Figure 7 shows a graph comparing the gelation rate of the primary cross-linked hydrogel according to the content of alginate in the manufacture of an exemplary electroconductive micro needle patch of the present invention.
Figure 8 shows a graph comparing the gelation rate of the primary cross-linked hydrogel according to the content of the aniline monomer when preparing an exemplary electroconductive micro-needle patch of the present invention.
Figure 9 shows a graph comparing the gelation rate of the secondary cross-linked hydrogel according to the concentration of CaCl ₂ when manufacturing an exemplary electroconductive micro-needle patch of the present invention.
10 is an image obtained by scanning electron microscopy (SEM) of the structures of the hydrogels of Examples 3 and 4 and Comparative Examples 3 and 4. Comparative Example 3 is shown in (a), Comparative Example 4 in (b), Example 3 in (c), and Example 4 in (d).

Hereinafter, preferred embodiments of the present invention will be described with reference to the accompanying drawings. However, embodiments of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below.

The present invention provides a method of manufacturing an electroconductive micro needle patch capable of delivering iontophoresis (iontophoresis) drugs prepared using radiation crosslinking technology.

According to the manufacturing method of the electroconductive microneedle patch according to the present invention, the content of moisture is controlled according to the degree of crosslinking, and the conductivity can be controlled according to the radiation dose, so that the movement of ions of the ionic drug can be more actively induced Even if it does not contain a cross-linking agent and a preservative that causes skin irritation, cross-linking and sterilization of the polymer can be simultaneously performed through radiation.

The'electroconductive micro needle patch' referred to in the present invention is made of a'secondary crosslinked hydrogel' obtained in the present invention, which means that it is manufactured in the form of a microneedle patch, and within this specification, the'electroconductive micro needle patch'. Patch' and'secondary crosslinked hydrogel' can be used interchangeably.

The'acrylic acid-based polymer' referred to in the present invention may be expressed as'polyacrylic acid', and may be used interchangeably.

More specifically, the method of manufacturing the electroconductive microneedle patch of the present invention comprises the steps of preparing an aqueous solution of a mixture comprising an acrylic acid polymer, an alginate, an electroconductive monomer and water; Putting the aqueous solution of the mixture into a mold for molding a microneedle and irradiating it to prepare a primary crosslinked hydrogel; And immersing the primary crosslinked hydrogel in a solution containing calcium ions to prepare a secondary crosslinked hydrogel.

According to the present invention, the acrylic acid-based polymer may be at least one polymer selected from the group consisting of polyacrylic acid, polymethacrylic acid, at least one monovalent metal salt, divalent metal salt, ammonium salt and organic amine salt of these acids.

Meanwhile, the electroconductive monomer may be at least one monomer selected from the group consisting of aniline, acetylene, phenylene, pyrrole, thiophene, phenylene sulfide, furan, thienylene vinylene, diethylene and derivatives thereof, For example, the derivative of aniline may be at least one selected from the group consisting of alkylaniline having 1 to 5 carbon atoms, alkoxy aniline having 1 to 5 carbon atoms, dialkoxy aniline having 1 to 5 carbon atoms, sulfonyl aniline, and nitro aniline. .

It is more preferable that the acrylic acid-based polymer is polyacrylic acid and the electrically conductive monomer is aniline.

Further, the mixture aqueous solution is 5 to 30% by weight of polyvinylpyrrolidone, polylactic acid, polylactyl glycolic acid, polylactide, polyglycolic acid, polyethylene glycol based on the total weight of the mixture aqueous solution , Polycaprolactone, polyamino acid, polypropylene fumarate, polygamma glutamic acid, at least one polymer selected from the group consisting of polyvinyl alcohol and polyethyleneimine or collagen, albumin, dextran, fibrin, elastin, gelatin, hyaluronic acid It may further include at least one biocompatible polymer selected from the group consisting of.

The aqueous mixture solution may include 0.08% to 4.0% by weight of an acrylic acid-based polymer, 0.01 to 0.5% by weight of an alginate, and 0.1 to 5.0% by weight of an electrically conductive monomer, and more preferably acrylic, based on the total weight of the aqueous mixture. It contains 0.08 to 1.6% by weight of an acid-based polymer, 0.01 to 0.2% by weight of an alginate, and 0.1 to 2.0% by weight of an electrically conductive monomer. More preferably, it contains 0.4 to 0.8% by weight of acrylic acid-based polymer, 0.01 to 0.1% by weight of alginate and 0.1 to 1.0% by weight of electrically conductive monomer.

The acrylic acid-based polymer is a component that induces gelation of the hydrogel. When the acrylic acid-based polymer content is less than 0.08% by weight, physical properties due to low gelation rate upon irradiation are low. There is a problem of wrinkles, and when it exceeds 4.0% by weight, there is no shrinkage phenomenon, but there is a problem that the hydrogel is easily broken due to the high crosslinking structure according to a high gelation rate.

Meanwhile, the acrylic acid-based polymer of the present invention preferably has a weight average molecular weight of 450,000 to 1,250,000. When the weight-average molecular weight of the acrylic acid-based polymer is less than 450,000, there is a problem that the hydrogel is not sufficiently crosslinked, and when it exceeds 1,250,000, there is a problem that the viscosity is high and economically inefficient.

The alginate is a component that performs secondary crosslinking with calcium ions in the secondary crosslinking step, and when the content of alginate is less than 0.01% by weight, secondary crosslinking is insufficient, and if it exceeds 0.5% by weight, a low gel The physical properties according to the conversion rate are low, and when drying, the hydrogel has a problem of wrinkles due to shrinkage.

On the other hand, the electroconductive monomer is a component for imparting electroconductivity to the hydrogel, and when the content of the electroconductive monomer is less than 0.1% by weight, there is a problem that the electrical conductivity is insufficient, and when it exceeds 5.0% by weight, depending on the low gelation rate Due to the low physical properties, there is a problem in that the hydrogel wrinkles due to shrinkage during drying.

The microneedle molding mold of the present invention may be formed of at least one material selected from the group consisting of silicone and polydimethylsiloxane, but is not limited thereto, and is not deformed by irradiation, and is used in hydrogels. It can be formed of any other suitable material that does not affect.

According to the present invention, the radiation is selected from the group consisting of gamma rays, x-rays, electron beams, and ultraviolet rays, and it is preferable to use gamma rays.

According to the present invention, the primary crosslinking by irradiation causes polymerization of the electrically conductive monomer, and when the radiation dose is increased, it is possible to obtain improved electrical conductivity while increasing the polymerization of the electrically conductive monomer.

The crosslinking reaction by radiation is generally a crosslinking reaction of an acrylic acid polymer hydrogel when irradiated with radiation. H or OH radicals, which are secondary free radicals generated by radiolysis of water molecules, are molecular chains of acrylic acid polymers. A radical is formed on the cross-linked hydrogel of a three-dimensional network structure containing water. However, at a radiation dose with low ionization energy, it is difficult to form radicals in the molecular chain of the acrylic acid polymer, resulting in a low crosslinking reaction of the acrylic acid polymer, and at a high radiation dose, the gelation rate of the acrylic acid polymer is high, resulting in increased mechanical properties. There is a problem in molding processing because it has a property to break even at low external pressure.

Therefore, the radiation dose is preferably 10 to 100 kGy, and more preferably 30 to 50 kGy. When the dose of radiation is less than 10kGy, there is a problem that the conductivity is not improved as desired because the electrically conductive monomer does not sufficiently form a polymer. When the radiation dose exceeds 100 kGy, there is a problem that the alginate decomposes.

In addition, the irradiation may be performed at a dose per hour of 5 kGy/h to 15 kGy/h. If the radiation dose per hour is less than 5 kGy/h, a problem may occur in which the process execution time is prolonged, and when it exceeds 15 kGy/h, alginate may decompose.

According to the present invention, the solution containing calcium ions is a solution containing at least one calcium precursor selected from the group consisting of calcium chloride, calcium carbonate, calcium sulfate, and calcium hydroxide, but is not limited to those that can release calcium ions. . More preferably, the calcium solution is a calcium chloride solution.

The solvent of the solution containing the calcium ion may be water, for example, distilled water.

At this time, the concentration of calcium ions in the solution containing the calcium ions is preferably 0.1 to 10% by weight. If the concentration of calcium ions is less than 0.1% by weight, there is a problem that secondary crosslinking does not occur sufficiently, and if the concentration of calcium ions exceeds 10% by weight, the amount of calcium participating in the secondary crosslinking is limited, so the process efficiency is poor. there is a problem.

According to the present invention, in order to provide a second cross-linked hydrogel, the step of preparing a second cross-linked hydrogel is performed by immersing the first cross-linked hydrogel in a solution containing calcium ions for 30 minutes to 90 minutes. . When immersed for less than 30 minutes, calcium ions and alginate do not sufficiently bond, so that secondary crosslinking is not sufficiently achieved. When immersed for more than 90 minutes, calcium ions and alginate do not bond anymore, which is undesirable in the process economy.

In the present invention, the micro-molding mold used in the method for manufacturing an electrically conductive micro-needle patch may include a deeper intaglio polygonal cone, a cone, or a combination thereof in addition to the patch-shaped intaglio so that the shape of the microneedle can be obtained. In this case, the height (depth) of the polygonal cone or cone may be 10 to 10,000 μm, preferably 50 to 8,000 μm, more preferably 100 to 5,000 μm, 400 to 2,000 μm, and most preferably 400 to 1,000 μm. have.

The microneedle type is not limited to the maximum height of the structure, but the skin is from the epidermis, the stratum corneum (e.g., less than 20 μm from the epidermis), the epidermis (e.g., the distance from the epidermis 100 Since it is composed of less than µm), and dermis (eg, 300 to 2,500 µm from the epidermis), the length of the needle is 10 to 1,000 µm, preferably 100 to 800 µm, for efficient drug delivery. More preferably, it may be 200 to 500 μm.

In addition, the inner angle of the corner of the vertex or the vertex of the cone may be 30 to 80 degrees, the underside of the polygonal pyramid may be a closed hexagonal shape, n-shaped, circular or elliptical, etc., where n may be a natural number of 3 or more. The area of the bottom of the polygonal cone or cone may be 200 μm ² to 450 μm ² .

The shape of the needle may be appropriately changed as necessary, but when the height of the polygonal cone or cone is less than 10 μm, it is difficult to form micropores on the skin, so a microneedle patch is not sufficiently inserted into the percutaneous layer, so that the desired component is not absorbed into the body There is a problem that can not be, and if the height exceeds 1000㎛, the microneedle patch may damage the skin, or it may be difficult to maintain the needle shape, which may cause problems such as an increase in the defect rate of the microneedle patch product.

When the minimum inner angle of the vertex of the polygonal cone or the cone is less than 30 degrees, the microneedle end is excessively thin and the strength is lowered, and when inserted into the skin, there is a problem that the microneedle does not maintain its shape and is broken or deformed, and exceeds 80 degrees. The microneedles are not sharp enough, which can cause unnecessary cuts on the skin when inserted.

In the method of manufacturing the electroconductive microneedle patch of the present invention, when a mixture aqueous solution containing an acrylic acid polymer, alginate, electroconductive monomer and water is first immersed in a calcium solution, the microneedle is subsequently formed by calcium alginate formation. Since it is difficult to prepare a hydrogel having a specific form, secondary crosslinking by calcium ions must be performed subsequently to irradiation.

According to the method of manufacturing the electroconductive microneedle patch of the present invention, it is possible to simultaneously perform crosslinking and sterilization of biocompatible polymer materials without the use of harmful chemical crosslinking agents, and simplification of the process is not necessary since no extraction and washing process is required.

According to another aspect of the present invention, there is provided an electroconductive microneedle patch obtained according to the method of manufacturing the electroconductive microneedle patch of the present invention. The electroconductive micro needle patch may be coated with a nutritional substance, a drug, or a combination thereof at the distal end of the needle.

The nutritional substance or drug is not limited in its kind, but may include, for example, anti-cancer agents, anti-allergic agents, hormones, proliferative factors, vaccines, analgesics, biological agents, gene therapy drugs, and allergen test substances.

In addition, the microneedle of the present invention may have a tip portion at the upper end of the needle, and may have a tapered structure. Accordingly, the maximum diameter of the structure may appear at the bottom of the structure.

On the other hand, according to the present invention, there is provided an electrically conductive microneedle patch comprising an electrically conductive polymer in which an acrylic acid polymer, calcium alginate, and an electrically conductive monomer are polymerized by irradiation.

The electroconductive microneedle patch obtained by the present invention exhibits excellent electroconductivity, and the conductivity can be easily adjusted.

Hereinafter, the present invention will be described in more detail through specific examples. The following examples are only examples for helping the understanding of the present invention, and the scope of the present invention is not limited thereto.

Example

1. Preparation of microneedle patch

Example 1

The water-soluble polymer was dissolved in 1000 mL of tertiary distilled water for 1 to 3 days so that the concentration of polyacrylic acid (weight average molecular weight 1,250,000) was 1% by weight. Further, the concentration of alginate was dissolved in 1000 mL of tertiary distilled water for 1 to 3 days at room temperature so that the concentration was 1% by weight. In addition, aniline, an electroconductive monomer, was dissolved in 1000 mL of 0.1M HCl at room temperature for 1 day so that the concentration of the aniline solution was 10% by weight.

Then, the three aqueous solutions were mixed to a total volume of 1000 mL in a constant volume ratio (polyacrylic acid aqueous solution: alginate aqueous solution: aniline solution = 80:10:10), and based on the total weight of the aqueous mixture solution, 0.8 weight of acrylic acid polymer %, alginate 0.1% by weight and aniline monomer 1% by weight. Then, the mixed solution was stirred until bubbles disappeared with a homogenizer (Primix coporation, coporation, T. K. Homomixer MarkII). As a result, an aqueous mixture solution containing polyacrylic acid, alginate, aniline and water was prepared.

Thereafter, the aqueous solution of the mixture was poured into a Petri dish (9.5 mm 9.5 9.5 mm), and then a microneedle-type silicone mold having a needle height of 700 μm (Polydimehtylsiloxane) was immersed in a Petri dish containing a mixed solution. At this time, the shape of the needle is more specifically, the area of the bottom surface is 150㎛ ² , the inner shape of the vertex is the shape of a square pyramid with a 65 degree (°), such intaglio 9 microneedle formed per 1 cm ² area A mold silicone mold was used.

Then, gamma rays (Cobalt 60, MDS Nordion, Ottawa, Canada) were irradiated at a dose of 10 kGy/h per hour at a total dose of 50 kGy to the microneedle molding frame into which the mixture aqueous solution was injected, and the primary crosslinked hydrogel Was prepared. The image of the primary cross-linked hydrogel thus formed is shown in FIG. 5A. The primary cross-linked hydrogel has a semi-interpeneterating network.

The primary crosslinked hydrogel obtained above was immersed in 100 mL of a calcium chloride aqueous solution containing 1% by weight of calcium chloride (CaCl ₂ ) for 60 minutes to prepare a second crosslinked hydrogel to obtain an electroconductive microneedle patch. .

Thereafter, after washing three times with tertiary distilled water to remove unreacted polyacrylic acid, alginate, aniline and calcium ions, and then drying at room temperature for 2 days, the mold is separated to prepare a second crosslinked hydrogel. Did.

The image obtained by scanning the secondary cross-linked hydrogel with a scanning electron microscope (SEM) is shown in FIG. 5B. As can be seen in Figure 5b, a microneedle patch made of a hydrogel secondary cross-linked using a calcium solution has a more clearly formed needle shape.

The method for manufacturing the electrically conductive microneedle patch as described above is schematically illustrated in FIG. 1.

Example 2

In Example 1, a microneedle patch was manufactured by the same process as in Example 1, except that radiation was irradiated with a total dose of 10 kGy during irradiation.

Example 3

A microneedle patch was prepared in the same manner as in Example 1, except that the concentration of the aqueous solution of polyacrylic acid in Example 1 was 0.1% by weight, the concentration of the alginate solution was 1.0% by weight, and the concentration of the aniline solution was 5.0% by weight. Did.

Example 4

A microneedle patch was prepared in the same manner as in Example 1, except that the concentration of the aqueous solution of polyacrylic acid in Example 1 was 1.0% by weight, the concentration of 0.5% by weight of the alginate aqueous solution, and the concentration of 5.0% by weight of the aniline solution. Did.

Comparative Example 1

In Example 1, a primary cross-linked hydrogel was prepared by irradiating radiation with a radiation dose of 50 kGy, and a microneedle patch was prepared by the same process as in Example 1, except that it was not immersed in a calcium solution.

Comparative Example 2

In Example 1, a primary cross-linked hydrogel was prepared by irradiating radiation with a radiation dose of 10 kGy, and a microneedle patch was prepared by the same process as in Example 1, except that it was not immersed in a calcium solution.

Comparative Example 3

After preparing the primary cross-linked hydrogel in Example 3, and washing the primary cross-linked hydrogel three times with distilled water without immersing the hydrogel in calcium solution, and then drying at room temperature for 2 days, A microneedle patch was prepared by the same process as in Example 3, except that the mold was separated.

Comparative Example 4

After preparing the first cross-linked hydrogel in Example 4, and washing the first cross-linked hydrogel three times with distilled water without immersing the hydrogel in calcium solution, and then dried at room temperature for 2 days, A microneedle patch was prepared by the same process as in Example 4, except that the mold was separated.

2. Measurement of the gelation rate of the hydrogel

The method for measuring the gelation rate of a hydrogel in the present invention is as follows. First, to remove the remaining acrylic acid polymer, alginate, and electroconductive monomer that does not participate in the crosslinking reaction by irradiation, it is washed with tertiary distilled water at 30° C. for 72 hours. The hydrogel that has undergone the washing process is placed in an oven at 70° C. and dried for 48 hours. After that, the weight of the dried gel after washing with water (W _d ) and the weight of the dried hydrogel used initially before washing with water (W _i ) were measured and substituted into Equation (1) to express the gelation rate as a percentage.

Gelation rate (%) = W _d /W _i X 100 .....Equation (1)

Using this, the gelation rate of the primary crosslinked hydrogel according to the content of polyacrylic acid, alginate and electroconductive monomer and the gelling rate of the secondary crosslinked hydrogel according to the concentration of the calcium solution were measured.

(1) Measurement of gelation rate of primary crosslinked hydrogel

i) Gelation rate of the primary crosslinked hydrogel according to the content of acrylic acid polymer

In Example 1 of the present invention, the alginate content is 0.05 wt% and the aniline monomer content is 0.5 wt% based on the total mixture aqueous solution, and the polyacrylic acid content is 0.08 wt%, 0.4 wt%, 0.8 wt% and 1.6 The first cross-linked hydrogel was prepared through the same process as in Example 1, except that it was weight %, and was not immersed in a calcium solution, and there was no washing and drying process. The gelation rate according to formula (1) of the prepared primary crosslinked hydrogel is shown in FIG. 6, and the gelation rate according to the radiation dose (10, 25, 50, 75 kGy) in each polyacrylic acid content is also shown.

As a result, it was confirmed that as the content of polyacrylic acid increased to 0.08% by weight, 0.4% by weight, 0.8% by weight, and 1.6% by weight, the gelation rate increased from about 40% to about 95% or more. In addition, it was confirmed that the gelation rate slightly increased even when the radiation dose increased from 10 kGy to 75 kGy.

However, it was found that the degree of gel formation due to crosslinking was different because chains were bonded at 10 kGy or more, and when the content of polyacrylic acid was less than 0.08 wt%, the gelation rate tended to be significantly lowered.

Ii) Gelation rate of the primary crosslinked hydrogel according to the content of alginate

In Example 1 of the present invention, the content of the polyacrylic acid is 0.8% by weight, and the content of the aniline monomer is 0.5% by weight based on the total aqueous solution of the mixture, and the content of the alginate is 0.01% by weight, 0.05% by weight, 0.1% by weight, and It was assumed to be 0.2% by weight, and was not immersed in a calcium solution, and a primary crosslinked hydrogel was prepared through the same process as in Example 1, except that there was no washing and drying process. The gelation rate according to formula (1) of the prepared primary crosslinked hydrogel was shown in FIG. 7, and the gelation rate according to the radiation dose (10, 25, 50, 75 kGy) in the content of each alginate was also shown.

As a result, it was confirmed that as the content of alginate increased to 0.01% by weight, 0.05% by weight, 0.1% by weight, and 0.2% by weight, the gelation rate decreased from about 95% to about 40%.

However, when the content of the alginate is 0.01% to 0.05% by weight, having a high gelation rate even when the radiation dose is increased from 10kGy to 75kGy, a high gelation rate of at least 95% can be achieved even with a polyacrylic acid content of 0.8% by weight. It may be because the low concentration of alginate does not participate in crosslinking even when the irradiation dose increases, so it is believed that the crosslinking reaction is not affected.

On the other hand, when the content of the alginate is 0.05% by weight to 0.2% by weight, when the irradiation amount increases from 10kGy to 75kGy, it was confirmed that although the overall gelation rate is low, the gelation rate itself increases by 5% or more. It is judged that the total content of the primary crosslinked hydrogel is higher than the content of polyacrylic acid per unit volume, so that the physical bonding strength of the primary crosslinked hydrogel is increased according to the increase in ionization energy of radiation, thereby increasing the gelation rate. do.

Iv) Gelation rate of the primary crosslinked hydrogel according to the content of the electrically conductive monomer

In Example 1 of the present invention, the content of the polyacrylic acid is 0.8 wt%, the content of alginate is 0.05 wt% based on the total aqueous solution of the mixture, and the aniline monomer content is 0.1 wt%, 0.5 wt%, 1.0 wt%, and It was assumed to be 2.0% by weight, and was not immersed in a calcium solution, and a primary crosslinked hydrogel was prepared through the same process as in Example 1, except that there was no washing and drying process. The gelation rate according to formula (1) of the prepared primary crosslinked hydrogel is shown in FIG. 8, and the gelation rate according to the radiation dose (10, 25, 50, 75 kGy) in the content of each aniline monomer is also shown.

As a result, when the content of the aniline monomer was 0.1% by weight, 0.5% by weight, 1.0% by weight, and 2.0% by weight, it was confirmed that the gelation rate of the primary crosslinked hydrogel was about 90% or more.

However, when the aniline content is 0.1% by weight and 0.5% by weight, having a high gelation rate even when the radiation dose is increased from 10kGy to 75kGy, a high gelation rate of more than 95% can be achieved even with a polyacrylic acid content of 0.8% by weight. It is possible that the low concentration of alginate does not participate in crosslinking even when the irradiation dose increases, so it is believed that the crosslinking reaction is not affected.

On the other hand, the reason that the gelation rate was lowered when the aniline content was 1.0% by weight or more was increased in the total content of the primary cross-linked hydrogel than the content of polyacrylic acid per unit volume, and the viscosity of the solution was diluted to reduce the viscosity of the polyacrylic acid. This is because the cross-linked chains are obstructed.

(2) Measurement of the gelation rate of the second cross-linked hydrogel

When preparing the second cross-linked hydrogel in Example 1, the content of the polyacrylic acid is 0.8% by weight, the content of alginate is 0.05% by weight, and the content of aniline monomer is 0.5% by weight, based on the entire mixture aqueous solution, CaCl _{A second} cross-linked hydrogel was prepared through the same process as in Example 1, except that the content of CaCl _{2 in} the aqueous solution was 0.1 wt%, 1.0 wt%, 5.0 wt%, and 10 wt%. The gelation rate of the prepared secondary crosslinked hydrogel is shown in FIG. 9, and the gelation rate according to irradiation at the concentration of each calcium solution is also shown.

At this time, when the content of CaCl ₂ is 0.1% by weight or more, all gelation rates were found to be 99% or more. Through this, it was found that the alginate was almost participating in the crosslinking reaction at all concentrations.

3. Measurement of hydrogel size change according to water content

In each microneedle patch prepared according to Examples 1 and 2 and Comparative Examples 1 and 2, the size change of the hydrogel according to the moisture content was measured.

In this experiment, the hydrogel (diameter 8 mm) dried in a glass dish was immersed in distilled water at 37° C. for 48 hours, then taken out and wiped off the surface of the hydrogel to measure the length. The strain was measured by measuring the swelled length (L _s ) and the length of the dried gel (L _d ) and substituting it into equation (2) to express the strain as a percentage. The observation results are shown in FIGS. 2A and 2B.

Strain (%) = (L _s -L _d )/L _d X 100 ........(2)

In addition, the results of comparing the size of each hydrogel shown in FIGS. 2A and 2B are illustrated graphically in FIG. 2C, and the results of comparing the size change during wetting of each hydrogel are graphically illustrated in FIG. 2D.

As a result, the hydrogel (primary crosslinked hydrogel) of Comparative Example 2, which was not immersed in the calcium solution, had a diameter of the hydrogel when wet increased by about 3.3 times (about 27 mm) than when dried (about 8 mm), and Comparative Example 1 The hydrogel was found to be about 2.8 times larger (about 22 mm) in diameter than when wet (about 8 mm) when wet. On the other hand, the hydrogels prepared according to Examples 1 and 2 immersed in a calcium solution after irradiation were found to have no difference in shape of the hydrogel when wet.

Also, referring to FIG. 2D, it was confirmed that the strain of the hydrogel of Comparative Example 2 was about 330%, and the strain of the hydrogel of Comparative Example 1 was about 280%. On the other hand, the hydrogels prepared according to Examples 1 and 2 immersed in calcium solution after irradiation had a hydrogel strain of 0% when wet, and it was confirmed that there was no change in the size of the hydrogel according to the moisture content.

4. Measurement of hydrogel swelling

The swelling degree of the hydrogel was measured in each hydrogel prepared according to Examples 1 and 2 and Comparative Examples 1 and 2. To measure the degree of swelling, the dried hydrogel (diameter 8 mm) was immersed in distilled water at 37° C. for 48 hours, then taken out and wiped off the surface of the hydrogel to measure the length. A graph comparing the results according to this is shown in FIG. 3. At this time, the degree of swelling was measured by measuring the swollen gel weight (W _s ) and the dried gel weight (W _d ), and then substituting it in Eq. (3) to express the degree of swelling as a percentage.

Swelling degree (%) = (W _S -W _d )/W _d X 100 ........(3)

As a result, as shown in FIG. 3, the hydrogel of Comparative Example 2 had a swelling degree of about 8000%, and the hydrogel of Comparative Example 1 had a swelling degree of about 7000%. On the other hand, the hydrogels of Examples 1 and 2 had a swelling degree close to 0%. As in the above 2. It can be confirmed that the hydrogel of the present invention finally obtained after being immersed in a calcium solution has no change in the shape of the hydrogel when wet and can maintain its shape.

The size, strain, and swelling degree of the hydrogel increased significantly in the primary crosslinked hydrogel than in the secondary crosslinked hydrogel because the moisture content increased in the three-dimensional network structure of the molecular chain of the alginate physically crosslinked by radiation. Furthermore, in the second cross-linked hydrogel, the molecular chains of polyaniline and alginate form a network structure of the interpenetrating structure so that moisture cannot penetrate into the hydrogel due to the alginate chemically cross-linked by the added calcium. Water is not absorbed.

5. Measurement of conductivity of hydrogel

The conductivity in each hydrogel prepared according to Examples 1 and 2 and Comparative Examples 1 and 2 was measured. The four-point probe method (Modysystems, Korea) was used to measure the conductivity, and was measured using a linear scan voltammetry ranging from -1V to 1V. The size of the sample used for the analysis was 1 x 1 cm, and the thickness was measured using a soner calipers (Vernier calipers, Mitutoyo, Japan). In addition, the resistance was analyzed using an I-V (Current-Voltage) curve, and a graph comparing the results is shown in FIG. 4. At this time, the electrical conductivity was analyzed by substituting in equation (4) using the thickness and resistance of the sample.

Electrical conductivity (S/cm) = 1/(Sample thickness X resistance) .....(4)

As a result, the conductivity of the hydrogels of Comparative Examples 1 and 2 was 0 s/cm, but the conductivity of the hydrogel of Example 1 was about 0.017 s/cm, and the conductivity of the hydrogel of Example 2 was about 0.007 s. /cm. This shows that the conductivity of the final product, hydrogel, can be significantly improved according to the irradiation amount of radiation during the manufacturing process of the electroconductive microneedle patch of the present invention.

In the second cross-linked hydrogel, polyaniline polymer chains become three-dimensional network structures of interpenetrating structures by polymerization of aniline, and have electrical conductivity, and as the amount of radiation increases, the density per unit area of the molecular chain increases in the network structure, increasing the electrical conductivity. Increases.

6. Hydrogel Morphological Analysis

Each hydrogel was photographed using a scanning electron microscope (FE-SEM, Hitachi S-4800, Japan) to observe the morphological characteristics of each hydrogel prepared according to Examples 3, 4 and Comparative Examples 3 and 4. . At this time, in order to remove the polymer remaining without participating in the crosslinking reaction, the hydrogel immersed at 30°C for 72 hours was washed with distilled water three or more times, placed in an oven at 70°C and dried for 48 hours. The dried sample was subjected to platinum coating for 60 seconds using a sputter coater to obtain a high-resolution image, and confirmed under an electron beam of 15 kV and a distance of 8.3 mm. Each hydrogel photographed at this time is shown in FIG. 10, Comparative Example 3 is shown in (a), Comparative Example 4 is shown in (b), Example 3 is shown in (c), and Example 4 is shown in (d). Did.

As a result, the hydrogel of Example 3 and Comparative Example 3 was dried, the polymer concentration of the hydrogel was low, and as the water evaporated, the volume of the microneedle was reduced, confirming that a needle shape different from the microneedle molding mold was manufactured. Could.

In addition, when Example 4 and Comparative Example 4 and Example 3 and Comparative Example 3 were compared, it was confirmed that when the content of polyacrylic acid increased and the content of alginate decreased, a microneedle of about 650 μm was prepared. In addition, a more sophisticated microneedle was prepared in Example 4 than Comparative Example 4, and it was confirmed that the physical properties were improved, so that the tip of the needle was sharp and would not bend when penetrating into the skin.

Although the embodiments of the present invention have been described in detail above, the scope of rights of the present invention is not limited thereto, and it is possible that various modifications and variations are possible without departing from the technical spirit of the present invention described in the claims. It will be apparent to those of ordinary skill in the field.

Claims (15)

Preparing an aqueous mixture solution containing an acrylic acid polymer, alginate, an electrically conductive monomer, and water;
Putting the aqueous solution of the mixture into a microneedle molding frame and irradiating it to prepare a primary crosslinked hydrogel; And
Preparing a second crosslinked hydrogel by immersing the first crosslinked hydrogel in a solution containing calcium ions
Including, electroconductive micro needle patch manufacturing method.
The method of claim 1, wherein the acrylic acid-based polymer is at least one polymer selected from the group consisting of polyacrylic acid, polymethacrylic acid, at least one monovalent metal salt, divalent metal salt, ammonium salt and organic amine salt of these acids, Method for manufacturing an electrically conductive micro needle patch.
The method of claim 1, wherein the electrically conductive monomer is at least one monomer selected from the group consisting of aniline, acetylene, phenylene, pyrrole, thiophene, phenylene sulfide, furan, thienylene vinylene, diethylene and derivatives thereof. Phosphorus, electroconductive micro needle patch manufacturing method.
According to claim 1, wherein the aqueous solution of the mixture, based on the total weight of the aqueous solution of the mixture, comprises 0.08% to 4.0% by weight of acrylic acid polymer, 0.01 to 0.2% by weight of alginate, and 0.1 to 2.0% by weight of electrically conductive monomer, Method for manufacturing an electrically conductive micro needle patch.
The method of claim 1, wherein the microneedle mold is formed of at least one material selected from the group consisting of silicone and polydimethylsiloxane.
The method of claim 1, wherein the radiation is selected from the group consisting of gamma rays, x-rays, electron beams, and ultraviolet rays.
The method of claim 1, wherein the irradiation is performed at a dose of 10 kGy to 100 kGy.
The method of claim 1, wherein the irradiation is performed at a dose per hour of 5 kGy/h to 15 kGy/h.
The method of claim 1, wherein the solution containing the calcium ion is calcium chloride, calcium carbonate, calcium sulfate and calcium hydroxide A method of manufacturing an electroconductive micro needle patch, which is a solution containing at least one calcium precursor selected from the group consisting of.
The method of claim 1, wherein the solvent of the solution containing the calcium ion is water.
The method of claim 1, wherein the concentration of calcium ions in the solution containing the calcium ions is 0.1 to 10% by weight, a method for manufacturing an electrically conductive microneedle patch.
The method according to claim 1, wherein the immersion is performed for 30 minutes to 90 minutes.
The method of claim 1, wherein the microneedle forming mold comprises an intaglio polygonal cone, a cone, or a combination thereof.
An electroconductive microneedle patch obtained by the method according to any one of claims 1 to 13.
An electroconductive microneedle patch comprising an acrylic polymer, calcium alginate and an electroconductive polymer polymerized and primary crosslinked by irradiation and secondary crosslinked by calcium ions.

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