WO2024014624A1 - Photothermal microneedle patch containing gold nanoparticles - Google Patents

Abstract

The present invention relates to a photothermal microneedle patch containing gold nanoparticles. The patch of the present invention is a patch in which a skin-soluble microneedle containing a drug or a cosmetic composition is formed on a film containing gold nanoparticles, wherein, by adhering the photothermal microneedle patch to the skin with wrinkles, blemishes or the like around the eyes, and then inducing the photothermal effect of gold nanoparticles by using a near-infrared LED light source, dissolution of the microneedle in the skin is increased while raising the skin temperature up to about 40 °C, and the delivery efficiency of an oil-soluble substance into the skin is increased to the maximum level.

Description

Microneedle photothermal patch containing gold nanoparticles

The present invention is a microneedle photothermal patch containing gold nanoparticles that has the effect of increasing the efficiency of cosmetic/drug delivery into the skin by using the action of gold nanoparticles that cause an exothermic reaction in visible and near-infrared wavelengths of 400 to 1,400 nm. It's about.

Recently, mask products using LED light sources have been in the spotlight, and various LED masks have been developed based on the fact that skin treatment effects differ depending on the wavelength of the light source. However, because existing LED masks are expensive for the general public to purchase, the treatment is mainly performed at dermatology hospitals or skin care shops, and it is reported that the effect is insufficient compared to the cost and the healing speed is slow. Most of the representative LED masks sold at home and abroad use a mixture of UV and near-infrared wavelengths of light based on the skin improvement effect of each wavelength of light. Infrared rays have a wavelength of 700 nm ~ 1 mm, and depending on the wavelength, they are divided into IR-A (Near IR, λ = 750 ~ 1,400 nm), IR-B (Mid IR, λ = 1,400 ~ 3,000 nm), and IR-C (Far IR, λ = 3,000 nm ~ 1 mm). In the case of IR-B or IR-C, it penetrates to the epidermal layer, but about 65% of IR-A, which is near infrared ray, penetrates through the near infrared window of our body to the dermis layer and the subcutaneous fat layer below. It is known to happen. As there are few substances in our body that absorb light in the near infrared (NIR) region, it has the highest penetration power in the human body. Therefore, the near infrared wavelength region is called the near infrared window or optical window of our body and is widely used for medical treatment purposes. .

Metal nanoparticles such as gold have free electrons on the surface that vibrate through mutual interference with electromagnetic waves from external light, forming Surface Plasmon Resonance (SPR). For example, gold nanoparticles with a particle size of about 10 nm satisfy the SPR conditions at light with a wavelength of about 520 nm according to Mie theory and cause strong extinction (scattering + absorption) (Phys. Chem. Chem. Phys. , 2005, 7, 3258-3268; Solid State Physics, 1976, Brooks Cole). While spherical gold nanoparticles have the same SPR phenomenon in all directions, gold nanorods have different paths through which electron clouds vibrate in the longitudinal and transverse directions due to external electromagnetic waves, and the SPR conditions that occur in the longitudinal direction are different in the transverse direction. It is caused by light with a longer wavelength than the SPR conditions. In other words, as the aspect ratio increases, that is, as the length of the gold nanorod becomes longer, the absorption peak at long wavelengths red-shifts, generally at a wavelength in the near-infrared range of about 700 to 1,200 nm depending on the aspect ratio. Causes strong absorption. At this time, when light in the strong near-infrared range is irradiated to the gold nanorod, free electrons rapidly vibrate along the longitudinal axis of the gold nanorod and collide with the gold atom, converting into heat. This process of converting photon energy into heat energy is photoheat. It is called photothermal effect.

Meanwhile, the increase in transdermal drug absorption rate according to skin temperature has been proven through many academic studies, and an increase in blood flow in the dermal layer is observed without damage to skin tissue at a temperature of about 30 to 40 degrees Celsius. As an example of this, it was shown that the transdermal absorption rate of Lidocaine, a local anesthetic and anti-arrhythmic drug, is greatly improved by the thermophoresis effect when the skin temperature is above 32℃, which is due to the covalent lipid layer connecting the stratum corneum cells. This can be explained by increased liquidity.

Among the transdermal absorption routes of drugs, the direct passage through keratinocytes and the passage through the lipid layer between keratinocytes depend on the molecular weight of the drug, and polymers over 500 Dalton (1,000 g/mol) are difficult to penetrate. In addition, drug delivery through pores or sweat pores is relatively easy for polymers to pass through, but it is small at 0.1% of the total skin area and is filled with sebum, so the transdermal absorption rate is low.

For the above reasons, it is known that when drugs or beauty products are applied to the skin, the transdermal absorption rate is low at about 5% or less. Therefore, effectively delivering drugs through the skin barrier and transdermally is effective in the treatment of beauty, hair loss, various skin diseases, and arthritis. It is emerging as a key issue.

Microneedles have been developed and commercialized to increase transdermal drug delivery efficiency. The global market share by microneedle type in 2020 is in the order of Solid, Hollow, and Dissolving. Solid and Hollow types made of metal or silicon have a needle length of 500μm or more and are mainly used for medical purposes, and the Dissolving type using biocompatible polymers has a needle length of 500μm or more. It is less than 500μm and is mainly used for beauty purposes. Dissolving type microneedles made of polymer materials have the advantage of being able to deliver macromolecular drugs directly intradermally without pain and without reducing the drug due to liver metabolism, and without the problems of bleeding/infection, which are problems with medical products. However, it has the disadvantage that it is difficult to insert into the dermal layer due to its low hardness, and the drug diffusion rate to the dermal layer is very slow due to the binding protein (Corneodesmosome) in the stratum corneum.

Accordingly, while researching various characteristics of the light-to-heat conversion effect of gold nanoparticles and gel patches using microneedles, the present inventors developed a microneedle photothermal patch containing gold nanoparticles with excellent cosmetic/drug delivery properties. The invention was completed.

[Prior art literature]

[Patent Document]

1. Republic of Korea Patent No. 10-1333962 (Title of Invention: Gold Nanoparticle Manufacturing Method, Applicant: Kumoh Institute of Technology Industry-Academic Cooperation Foundation, Registration Date: November 21, 2013)

2. Republic of Korea Patent No. 10-1819713 (Title of invention: Patch composition containing gold nanorods, Applicant: Kumoh Institute of Technology Industry-Academic Cooperation Foundation, Registration date: January 11, 2018)

3. Republic of Korea Patent No. 10-2367746 (Title of invention: Transdermal drug patch microneedle manufacturing method, Applicant: Dongwoo Global Co., Ltd., Registration date: February 22, 2022)

4. Republic of Korea Patent No. 10-2222704 (Title of invention: Microneedle adhesive patch based on hydrogel formulation, Applicant: Pohang University of Science and Technology Industry-Academic Cooperation Foundation, Registration date: February 25, 2021)

5. Republic of Korea Patent No. 10-1386442 (Title of the invention: Solid microstructure manufactured using the blowing method and its manufacturing method, Applicant: Raphas Co., Ltd., Registration date: April 11, 2014)

6. Republic of Korea Patent No. 10-1435888 (Title of Invention: Method for manufacturing biodegradable microneedles using hyaluronic acid, Applicant: Yonsei University Industry-Academic Cooperation Foundation, Registration date: August 25, 2014)

The purpose of the present invention is to provide a microneedle photothermal patch containing gold nanoparticles, which has the effect of increasing the efficiency of cosmetic/drug delivery into the skin by using the exothermic reaction of gold nanoparticles.

The present invention relates to a microneedle photothermal patch containing gold nanoparticles.

The patch may have a plurality of microneedles 100 formed on one side of a film 200 containing gold nanoparticles.

The film is preferably made of a biocompatible matrix material that is not toxic to the skin, and may preferably be made of a biodegradable resin. As an example, polyvinyl alcohol (PVA), polyhydroxybutyrate-valerate (PHBV), polyanhydrides, polyphosphazenes, polyorthoesters, polycaprolactone ( PCL), polylactic acid (PLA), polybutylene succinate (PBS), polybutylene adipate (PBA), polybutylene adipate-terephthalade (PBAT), polybutylene succinate-adipate (PBSA) and polybutylene succinate-terephthalate (PBST).

The film may contain more than 30 ppm of gold nanoparticles, preferably 30 to 1000 ppm. The thickness of the film may be about 20 to 100 μm, preferably 30 to 80 μm, and more preferably 40 to 60 μm.

The patch preferably has 120 to 150 microneedles formed on the skin-adhesive side of the film, based on a film area of '60 to 70' mm x '30 to 35' mm, and the average upper diameter of one microneedle is 30. It can be formed to be ~60㎛, with an average height of 200~600㎛, the strength of the microneedle is 0.05~0.2N, and the pH when formed as a needle is preferably 5.5~7.5.

The biocompatible matrix material can be used with a molecular weight of 10,000 to 30,000, preferably with a molecular weight of 15,000 to 25,000, and more preferably with a molecular weight of 18,000 to 20,000.

The gold nanoparticles are characterized by causing an exothermic reaction in visible and near-infrared wavelengths of 400 to 1,400 nm.

The gold nanoparticles of the present invention preferably have a rod shape, are characterized by an aspect ratio of 3 to 5, and are preferably 70 to 300 nm in length. In this case, the photothermal effect occurs at a wavelength in the near-infrared region of about 700 to 1,400 nm. (Photothermal effect) is excellent. The gold nanoparticle having the rod shape may have an axial surface plasmon resonance wavelength (λLSPR) of 800 ± 15 nm.

In addition, in the present invention, when manufacturing gold nanoparticles, all gold nanoparticles that cause an exothermic reaction in the visible and near-infrared wavelengths of 400 to 1,400 nm are manufactured through crystal growth control, such as plate-shaped prisms, star shapes, nanocages, etc. Gold nanoparticles can be used.

Additionally, the film can cause an exothermic reaction at 40 to 45°C at a light output of 20 to 51 mW/cm ² .

The film may be formed by forming a biocompatible matrix material into a film form through a blowing method. Preferably, the biocompatible matrix material may be dissolved in a solvent at 80-90°C, gold nanoparticles added, mixed, blown, and dried at 140-160°C. The solvent is water, and the biocompatible matrix material can be mixed with water at a weight ratio of 1:0.1 to 1:5. Alternatively, it may be manufactured by melting and blowing the biocompatible matrix material at a temperature of 200°C or higher, preferably 200 to 250°C.

The microneedles may be formed by dropping a plurality of needle compositions on one side of the film and then using a blowing-prepared solid microstructures (BSM, or Droplet extension; DEN) method. (In this case, instillation has the same meaning as spotting). The composition for needles may have a viscosity of 10,000 to 200,000 cSt.

The microneedles preferably include (step a) dropping a plurality of needle compositions on one side of a film containing gold nanoparticles; (Step b) bringing the protrusions of the support for needle production into contact with the needle composition; (step c) lifting the support; (Step d) blowing the lifted needle composition to solidify the needle composition; And (step e) cutting the solidified needle composition to form microneedles in a solid state.

The support for manufacturing needles is formed on one side of a plate with protrusions corresponding to the number of needles to be manufactured, and when the protrusions come into contact with a plurality of needle compositions dropped on a film, the needle composition lifts due to the viscosity of the needle composition. It has the role of being able to dry in a dry state. The support for manufacturing the needle is formed with one or more air vents, so that air for drying the composition for needles can be blown through the air vents.

The needle composition (or microneedle) may include a thickener. The thickening agent includes hyaluronic acid and its salts, polyvinylpyrrolidone, cellulose polymer, dextran, gelatin, glycerin, polyethylene glycol, polysorbate, propylene glycol, povidone, carbomer, and gum gum. (gum ghatti), guar gum, glucomannan, glucosamine, dammer resin, rennet casein, locust bean gum, microfibrillated cellulose, psyllium seed gum. ), xanthan gum, arabino galactan, gum arabic, alginic acid, gelatin, gellan gum, carrageenan, karaya gum, curdlan, chitosan, chitin, tara gum ( It may include one selected from the group consisting of tara gum, tamarind gum, tragacanth gum, furcelleran, pectin, and pullulan.

The needle composition (or microneedle) of the patch of the present invention may contain (enclose) a drug. The above drugs include skin cancer treatments, allergy suppressants, atopy suppressants, anti-inflammatory drugs, painkillers, anti-arthritis drugs, antispasmodics, antidepressants, antipsychotics, tranquilizers, anti-anxiety drugs, narcotic antagonists, anti-Parkinson's disease drugs, cholinergic agonists, anticancer drugs, and anti-inflammatory drugs. Angiogenesis inhibitors, immunosuppressants, antivirals, antibiotics, appetite suppressants, analgesics, anticholinergics, antihistamines, antimigraine drugs, hormones, coronary, cerebrovascular or peripheral vasodilators, contraceptives, antithrombotic agents, diuretics, antihypertensive agents. Alternatively, it may include, but is not limited to, a treatment for cardiovascular disease. can be selected Additionally, the drug may be selected in the form of chemical drugs, protein drugs, peptide drugs, nucleic acid molecules for gene therapy, nanoparticles, etc.

In the present invention, the form of the drug that can be contained in the needle composition (or microneedle) is not particularly limited. For example, the drug may include chemical drugs, protein drugs, peptide drugs, nucleic acid molecules for gene therapy, nanoparticles, etc.

Protein drugs or peptide drugs that can be contained in the needle composition (or microneedle) are not particularly limited, and include hormones, hormone analogs, enzymes, enzyme inhibitors, signal transduction proteins or parts thereof, antibodies or parts thereof, and single chain antibodies. , binding proteins or their binding domains, antigens, attachment proteins, structural proteins, regulatory proteins, toxin proteins, cytokines, transcriptional regulatory factors, blood coagulation factors, vaccines, etc., but are not limited thereto. More specifically, the protein medicine or peptide medicine contains insulin, IGF-1 (insulin-like growth factor 1), growth hormone, erythropoietin, G-CSFs (granulocyte-colony stimulating factors), and GM-CSFs ( granulocyte/macrophage-colony stimulating factors), interferon alpha, interferon beta, interferon gamma, interleukin-1 alpha and beta, interleukin-3, interleukin-4, interleukin-6, interleukin-2, EGFs (epidermal growth factors), calcitonin ( calcitonin), ACTH (adrenocorticotropic hormone), TNF (tumor necrosis factor), atobisban, buserelin, cetrorelix, deslorelin, desmopressin ( desmopressin, dynorphin A (1-13), elcatonin, eleidosin, eptifibatide, growth hormone releasing hormone-II (GHRH-II), gona Gonadorelin, goserelin, histrelin, leuprorelin, lypressin, octreotide, oxytocin, pitressin , secretin, sincalide, terlipressin, thymopentin, thymosine α1, triptorelin, bivalirudin, carbeto Carbetocin, cyclosporine, exedine, lanreotide, LHRH (luteinizing hormone-releasing hormone), nafarelin, parathyroid hormone, pramlintide, T-20 ( It may include one selected from enfuvirtide, thymalfasin, and ziconotide.

The needle composition (or microneedle) may include (enclose) a cosmetic composition. The cosmetic composition may include a wrinkle improving agent, a skin aging inhibitor, a skin whitening agent, an antioxidant, a skin anti-inflammatory agent, a moisturizer, or a hair growth agent.

The wrinkle improvement agent is a substance that inhibits MMP-1, an extracellular matrix (ECM) proteolytic enzyme, and includes silicic acid, N-Methyl-Lserine, and isoflavonoids ( Isoflavonoids, Dehydroepiendrosterone, Paoniflorin, etc. can be selected, and Benzastatins, a substance that prevents skin aging by removing free radicals that promote the breakdown of ECM, Coenzyme Q10, etc. can be used, and in addition, adenosine, ascorbyl glucoside, kinetin, auxin, peptide, etc., which are known to have various anti-wrinkle effects. Retinol, retinyl palmitate, polyethoxylated retinamide, alpha hydroxyl acid, etc. are available.

The whitening agent is arbutin, niacinamide, ascorbic acid, magnesium ascorbyl phosphate, ascorbyl acid-2-glucoside, and mulberry extract. , Ethyl ascorbyl ether, oil-soluble licorice extract, etc. can be used.

The moisturizing agent may be one or more selected from the group consisting of hydroxyproline, glycerin, glycerol, urea, amino acids, lactate, and pyroglutamic acid.

The needle composition for the manufacture of microneedles may, if necessary, be thinly applied to the entire film and dried for ease of attachment to the film before instillation. The thickness after drying is preferably thinner than the biocompatible matrix material film.

In another aspect, if necessary, an adhesive sheet with a larger area than the film may be attached to the film on one side opposite to where the microneedles are formed, in order to facilitate adhesion of the film to the skin. Adhesive sheets can be made of any adhesive material that does not cause friction or damage to the skin, and can also be manufactured in a form that adheres closely to the skin, such as hydrogel.

In the composition for needles, each raw material included may be dissolved in a solvent. The solvent used at this time is not particularly limited, and solvents include water, anhydrous or hydrous lower alcohols having 1-4 carbon atoms, acetone, ethyl acetate, chloroform, 1,3-butylene glycol, hexane, diethyl ether, or butyl acetate. It can be used, preferably water or lower alcohol, and most preferably water.

In the present invention, gold nanoparticles can be produced through the following method.

(Step 1) Add sodium borohydride aqueous solution to a mixed solution of hexadecylcetyltrimethylammonium bromide aqueous solution and hydrogen tetrachloroaurate(III) tetrahydrate aqueous solution to create a solution containing gold seeds. manufacture,

After mixing the aqueous solution of chloroauric acid, hexadecylcetyltrimethylammonium bromide, and benzyldimethylhexadecylammonium chloride, the aqueous solution of silver nitrate, which is a catalyst for the synthesis of gold nanoparticles, and the aqueous solution of ascorbic acid, which is a reducing agent, are added under stirring to form a growth solution. manufacturing step; and,

(Step 2) Mixing and stirring the solution containing the gold seeds and the growth solution, centrifuging to remove the upper layer solution, and dispersing the remaining solution in distilled water to obtain a solution containing gold nanoparticles; can be manufactured.

At this time, in the first step, the volume and concentration of each solution are not greatly limited, but preferably the aqueous solution of hexadecylcetyltrimethylammonium bromide is 0.05-5mM, hydrogen tetrachloroaurate (III) tetrahydrate It is preferable to use an aqueous solution with a concentration of 0.05 to 5mM and an aqueous sodium borohydride solution with a concentration of 1 to 50mM, and the mixing ratio of each solution is preferably 1:0.1 to 5:0.05 to 0.5 by volume.

In addition, in the first step, the solution containing gold seeds is preferably aged for at least 90 minutes after preparation. The longer time is not greatly limited, but it is preferably used after aging for 90 minutes to 6 hours.

In the second step, the solution containing gold seeds and the growth solution of gold nanoparticles may be mixed at a volume ratio of 1:500 to 2000.

In the second step, the volume and concentration of each solution or sample for preparing the growth solution are also not greatly limited, but preferably 300 to 3000 ml of 0.5 to 5mM chloroauric acid (HAuCl ₄ ·4H ₂ O) is used. , aqueous solution of a mixture of hexadecylcetyltrimethylammonium bromide (CTAB) and sodium oleate (NaOL) (40-300 mM hexadecylcetyltrimethylammonium bromide (CTAB) and 30-70 mM sodium oleate (NaOL)) 300~ After mixing with 3000 ml, it can be prepared by adding 20-70 ml of 1-10mM silver nitrate aqueous solution, which is a catalyst for the synthesis of gold nanoparticles, and adding 10-20 ml of 50-100mM ascorbic acid aqueous solution, which is a reducing agent, under stirring.

In the second step, the solution containing the gold nanoparticles is centrifuged again, the upper solution is removed, and the remaining solution is dispersed in distilled water. A washing step may be added 1 to 3 times, through which hexadecylcetyltrimethylammonium bromide is produced. is removed, allowing a solution containing more purified gold nanoparticles to be obtained.

Through this step, gold nanoparticles with a 9000-1500 ppm Au concentration (μg Au/ml) can be obtained, preferably with a yield of 70-80%.

The present invention relates to a microneedle photothermal patch containing gold nanoparticles. The patch of the present invention is made by forming skin-soluble microneedles containing a drug or cosmetic composition on a film containing gold nanoparticles. After attaching the microneedle photothermal patch to the skin where skin wrinkles or blemishes, such as around the eyes, are formed, near-infrared rays are applied. By inducing the photothermal effect of gold nanoparticles using an LED light source, the skin temperature is increased to about 40℃, increasing the dissolution of microneedles in the skin and increasing the delivery efficiency of useful substances to the skin to the maximum.

Figure 1 is a transmission electron microscope photograph of gold nanoparticles prepared in Example 1 of the present invention.

Figure 2 is a graph showing the UV-Vis absorption spectrum of gold nanoparticles prepared in Example 1 of the present invention.

Figure 3 is a graph showing the cytotoxicity of gold nanoparticles prepared in Example 1 of the present invention.

Figure 4 is a photograph of a film containing gold nanoparticles and a graph showing the results of confirming the photothermal effect of the film containing gold nanoparticles.

Figure 5 is a perspective view of the microneedle photothermal patch manufactured in Example 4 of the present invention (100: microneedle 200: film containing gold nanoparticles).

Figure 6 is a photograph of the microneedle photothermal patch manufactured in Example 4 of the present invention.

Figure 7 is a graph showing the process of adjusting the optical power to raise the microneedle photothermal patch manufactured in Example 4 of the present invention to around 40°C, the target temperature.

Figure 8 is a photograph confirming that the microneedles created in the patch were dissolved into the skin due to the photothermal effect through laser irradiation.

Figure 9 is a photograph showing the standards for skin patch reaction.

Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, it is provided to ensure that the content introduced here is thorough and complete, and to sufficiently convey the spirit of the present invention to those skilled in the art.

<Example 1. Preparation of gold nanoparticles>

Previously, when manufacturing gold nanoparticles, a mixed solution of hexadecylcetyltrimethylammonium bromide (CTAB) and Benzylhexadecylammonium chloride (BDAC) was used in the gold growth solution, but in this case, the surface plasmon resonance (LSPR) of the gold nanoparticles was used. It was not easy to manufacture gold nanorods with an absorption wavelength (λLSPR) of about 716 nm and a peak of about 785 to 815 nm that responds to a near-infrared LED of about 790 nm. Accordingly, in the present invention, NaOL (Sodium Oleate) was used instead of Benzylhexadecylammonium chloride (BDAC) to synthesize gold nanoparticles using a more improved method.

Example 1-1. Gold seed synthesis

To synthesize gold nanoparticles having a rod shape, gold seeds were first synthesized. Gold seed is prepared by mixing 5 ml of 0.5 mM hexadecylcetyltrimethylammonium bromide (CTAB) aqueous solution and 5 ml of 0.5mM hydrogen tetrachloroaurate(III) tetrahydrate (HAuCl ₄ ·4H ₂ O) aqueous solution with 0.01 M NaBH ₄ aqueous solution cooled to about 4°C. After adding 0.6 ml, vortexing was performed for 3 minutes to prepare a solution containing gold seeds with a size of 2 to 3 nm. The synthesized seed solution was aged at room temperature for more than 2 hours and 30 minutes before use and used to grow gold nanoparticles.

Example 1-2. Growth solution preparation

A gold nanoparticle growth solution was prepared to convert gold seeds into gold nanoparticles. First, 1mM HAuCl ₄ 4H ₂ O After mixing 1,000 ㎖ of the aqueous solution with 1,000 ㎖ of a mixed aqueous solution of hexadecylcetyltrimethylammonium bromide (CTAB) and NaOL (Sodium Oleate) (CTAB 150mM, NaOL 50mM, NaOL/CTAB is about 1/3), the gold nanoparticle synthesis catalyst A 4 mM (50 mL) aqueous solution of AgNO ₃ was added, and 79 mM (14 mL) of an aqueous solution of Ascorbic acid, a reducing agent, was added under stirring. At this time, the color of the solution changes from dark yellow to colorless as Au(III) is reduced to Au(I).

Example 1-3. Gold nanoparticle growth and washing

When 2.4 mL of the aged gold seed solution prepared in Example 1-1 is added to the gold nanoparticle growth solution (2064 mL) under stirring, the color of the solution changes from colorless to wine color within about 1 hour, and the color of the solution changes for another 24 hours. By reacting, a solution containing gold nanoparticles (aspect ratio approximately 4, length: approximately 88 nm, width: approximately 22 nm) was obtained. Next, to remove excess CTAB in the solution, the solution was centrifuged at 15,000 rpm for 20 minutes, the upper layer solution was removed, and the remaining solution was dispersed in 200 ml of distilled water. This washing process was repeated twice to prepare the final gold nanoparticle solution. The concentration of the final gold nanoparticle solution was measured using AAS (Atomic absorption spectroscopy) analysis to prepare a gold nanoparticle solution with a concentration of about 1,096 ppm.

Meanwhile, gold nanoparticles were additionally manufactured by applying BDAC as in the existing method, and gold nanoparticles with an aspect ratio of about 4, a length of about 60 nm, and a width of about 15 nm were obtained.

<Example 2. Transmission electron micrograph of gold nanoparticles>

The state of the gold nanoparticles prepared in Example 1 was photographed using a transmission electron microscope (TEM) and shown in Figure 1. At this time, the size of the synthesized gold nanoparticles was uniform on the TEM of about 88 nm in length and about 22 nm in diameter, and the same pattern was shown through repeated experiments, and the longitudinal surface plasmon resonance wavelength (λLSPR) was about It was confirmed to be a gold nanoparticle of 800 ± 15 nm.

In this case, it can be seen that gold nanoparticles were manufactured under the most effective conditions for causing a photothermal reaction at 790 nm, which is the wavelength of most LED masks used on the market.

However, the λLSPR of the gold nanoparticles manufactured using the existing method using BDAC instead of NaOL was found to be about 710 nm, as expected, making it unsuitable for use at 790 nm, the wavelength of the LED mask.

Therefore, from now on, only gold nanoparticles to which NaOL was applied were used in the experiment.

<Example 3. Cytotoxicity test according to gold nanoparticles and light source wavelength>

The tetrazolium assay using the MTT ([3-(4,5)-dimethylthiahiazo-2-yl]-2,5-diphenyltetrazolium bromide) reagent is performed by treating cells with a yellow water-soluble MTT reagent, causing the formation of tetrazolium by dehydrogenase in the mitochondria. Because the ring structure is reduced to formazan crystals, living cells can be quantitatively evaluated by dissolving these crystals in DMSO and measuring the amount of formazan crystals produced by spectroscopic methods.

To confirm the cytotoxicity of synthesized gold nanoparticles, MTT assay was performed on BLO-11 (mouse muscle fibroblast cell) cells. As a result, even if the concentration of gold nanoparticles was increased to 200 μg Au/mL (ppm), As shown in Figure 3, the cell survival rate was over 80%, confirming that there was almost no cytotoxicity. Therefore, it can be seen that the photothermal patch to be manufactured in the present invention will be safe even if gold nanoparticles are included at a concentration of 200 μg Au/mL (ppm) or less.

<Example 4. Preparation of microneedle patch>

Example 4-1. Preparation of films containing gold nanoparticles

A film containing gold nanoparticles having a rod shape to be used as a skin adhesive patch is prepared by mixing the gold nanoparticles prepared in Example 1 with polyvinyl alcohol (PVA) with a molecular weight of 18,000 to 20,000 mw at different concentrations (60 to 120 ppm). It was manufactured by molding into a film using a blowing method. At this time, when producing a film using PVA containing gold nanoparticles using a conventional spreading method, bubbles are formed when the solvent is removed, which is not desirable.

For this purpose, PVA was mixed with water at a weight ratio of 1:2, dissolved at a temperature of 80~90℃, blown, and dried at about 150℃. The thickness of the final film containing gold nanoparticles was about 50㎛.

A photograph of this film is shown on the left side of Figure 4. As a result of the experiment, it was confirmed that the gold nanoparticle content in the film exhibited a photothermal effect of 40 to 45 ℃ at a content of 100ppm or more. Among the experimental results, representatively, the content of gold nanoparticles (GNR) having a rod shape in the film was 60ppm. The results of 120ppm and 120ppm are graphed on the right side of Figure 4.

Example 4-2. Preparation of composition for needles

Next, a needle composition was prepared by mixing the following raw materials. The needle composition included 1g sodium hyaluronate, 1g sucrose, 0.1g niacinamide, 10g cyclodextrin, 0.1g soybean oil, and 0.01g sodium hydroxide. , 1g of allantoin, 1g of panthenol, 0.1g of adenosine, 0.1g of acetyloctapeptide-3, 0.1g of BHT, and the remainder of purified water were mixed to make a total of 100g. This composition for needles is only an example and is not limited thereto.

Example 4-3. Formation of microneedles

The composition for needles prepared in this way was dropped on the PVA film containing gold nanoparticles. At this time, when the composition was dropped on the film, it was set so that 133 ± 15 microneedles were formed based on the film area of '60 ~ 70' mm x '30 ~ 35' mm.

For the production of needle shapes, each composition dropped on the film was brought into contact with the protrusions of the support for needle production. Due to the viscosity of the composition itself, the needle composition was blown into the film-composition-protrusion connected state and solidified. Afterwards, the solidified needle composition was cut to form microneedles on the PVA film.

These microneedles are characterized by penetrating into the skin and dissolving into the skin, thereby increasing the absorption rate of the drug or cosmetic composition contained within the needle into the skin.

Example 4-4. Manufacturing of microneedle photothermal patch for eye area

Each film on which microneedles were formed was divided into 66 mm x 31 mm to provide a patch for alleviating wrinkles around the eyes. Approximately 148 microneedles were formed per divided film area, and the total weight of each individual film was 631.5 mg. Based on one microneedle, the upper diameter was 39.13㎛, the average height was 354.87㎛, the strength was about 0.157N, and the pH was about 6.0.

<Example 5. Photothermal test to confirm temperature rise>

Perspective views and photographs of the microneedle photothermal patch are shown in Figures 5 and 6, and a photothermal test was performed using the microneedle photothermal patch manufactured in this way.

The results are shown in Figure 7. Based on the near-infrared LED output of 83 mW/cm ² (74 J/cm ² ), the temperature of the patch between 40 and 70% of its optical power is found to be appropriate for controlling the target temperature. When using it as a skin patch, the optical power of the LED lamp is set to 70% and then maintained at 40%, and the temperature of the microneedle photothermal patch is maintained at 40°C by turning the LED on and off using the temperature sensor built into the LED device. It was confirmed that this would be appropriate for delivering a drug or cosmetic composition to the skin. Therefore, the final adjusted near-infrared LED output was 20 to 51 mW/cm ² (18 to 46 J/cm ² ).

<Example 6. Photothermal test for dissolution of microneedles in the skin>

In addition, even if microneedles are formed on the PVA film, if the photothermal effect is not supported when it is attached to the skin and laser irradiated using an LED, it may affect the solubility in the skin.

Accordingly, the microneedle photothermal patch of Example 4 was adhered to the skin around the eyes, an LED device was installed, and a laser was irradiated. At this time, a PVA film that did not contain gold nanoparticles was used as a control.

As a result, as shown in Figure 8, it can be confirmed that the degree to which microneedles are dissolved in the skin varies depending on the presence or absence of gold nanoparticles in the PVA film, and that the microneedles are dissolved in the skin only when gold nanoparticles are contained and a photothermal effect occurs. It can be seen that appears completely.

Due to this, it is confirmed that when a cosmetic composition or drug is included in the needle, the degree of absorption into the skin will be significantly different.

<Example 7. Skin irritation test>

For 32 women aged 20 to 59 years (average 47.4 ± 7.0 years), 1 cm2 of the microneedle photothermal patch of Example 4 was applied to the back and removed 24 hours later. International contact was made 30 minutes and 48 hours after the patch was removed. According to the International Contact Dermatitis Research Group (ICDRG) criteria (see Table 1 and Figure 9), the researcher read the skin reactivity through visual evaluation and confirmed the skin irritation index range. As a result, the average skin reactivity of the microneedle photothermal patch was It was 0.24, and according to the judgment criteria, it was judged to be almost non-irritating.

Mark	Score	Evaluation standard
-	0	0
±	0.5	0.5
+	One	One
++	2	2
Average skin reactivity (Mean Score) = (Σ(Score × No.of Responders))/(3(Maximum Score)×No.of Total Subjects))×100×(1/2)

<Example 8. Confirmation of whitening and wrinkle improvement effects>

Example 8-1. Evaluation using devices

Twenty women aged 30 to 59 years (average 50.1 ± 6.3 years) were tested for improvement in wrinkles under the eyes and skin brightness after using the near-infrared LED device and the microneedle photothermal patch of Example 4 for 15 minutes a day for 4 weeks. The evaluation was performed and is shown in Tables 2 and 3 below.

- Conducted by device evaluation: PRIMOS-CR (Canfield Scientific, Inc., USA, wrinkles under the eyes), VISIA-CR (Canfield Scientific, Inc., USA, skin brightness)

user	Wrinkle value under the eyes (%)
	Before use	1 week	2 weeks	4 weeks
User average values for products containing gold nanoparticles	28.2	22.0	19.7	15.1
User average values for products without gold nanoparticles	28.2	25.6	24.1	23.4
※: Friedman Test, Wilcoxon Signed Rank Test with Bonferroni correction

user	Skin brightness under eyes (%)
	Before use	1 week	2 weeks	4 weeks
User average values for products containing gold nanoparticles	72.4	73.3	73.8	75.4
User average values for products without gold nanoparticles	72.4	72.9	73.1	73.2
※: Repeated Measures ANOVA, Bonferroni correction

As a result, for the microneedle photothermal patch manufactured in the present invention, the overall wrinkle value under the eyes was confirmed to be reduced and skin brightness increased, as shown in Tables 2 and 3, confirming that there is a significant skin improvement effect compared to before use. . In particular, the wrinkle improvement effect was found to be reduced by more than half after 4 weeks of using the microneedle photothermal patch containing gold nanoparticles.

Example 8-2. User Rating

Next, when the four-week experiment with the same people was completed, skin moisture, adhesion, hygiene, and overall feeling of use were confirmed through a survey.

- Validity evaluation: Survey self-evaluation of test subjects (5-point scoring method - 4 points: very good, 0 points: very bad)

	skin moisturized	Adhesion	hygiene	feeling of use
User average values for products containing gold nanoparticles	3.5	3.4	3.5	3.05
User average values for products without gold nanoparticles	2.1	2.6	2.9	2.34

As a result, for the microneedle photothermal patch manufactured in the present invention, the overall satisfaction with use was 3.0 or more with a maximum of 4.0, as shown in Table 4, showing very high satisfaction. In terms of adhesion and feeling of use, it was confirmed that patches that did not contain gold nanoparticles were evaluated as low in satisfaction because the photothermal effect was not sufficiently observed and skin adhesion was not increased. Hygiene was also found to be more affected by the thermal effect. there is.

<Example 9. Adverse reaction evaluation>

Meanwhile, as a result of adverse reaction evaluation by the researcher and self-assessment of adverse reactions by the test subjects, abnormalities such as erythema (reddening), edema (swelling), and scaling (scaling) due to use of the test product were observed in all test subjects during the 4-week test period. No reaction was observed. Additionally, no adverse reactions such as itching, stinging pain, burning, stiffness, or tingling were observed in all test subjects.

[Explanation of symbols]

100: Microneedle 200: Film containing gold nanoparticles

Claims (11)

1. A microneedle photothermal patch, characterized in that a plurality of microneedles (100) are formed on one side of a film (200) containing gold nanoparticles.
2. According to paragraph 1,

   The film is made of polyvinyl alcohol (PVA), polyhydroxybutyrate-valerate (PHBV), polyanhydrides, polyphosphazenes, polyorthoesters, and polycaprolactone (PCL). ), polylactic acid (PLA), polybutylene succinate (PBS), polybutylene adipate (PBA), polybutylene adipate-terephthalade (PBAT), polybutylene succinate-adipate (PBSA), and Microneedle photothermal patch, characterized in that it is a film made of a material selected from polybutylene succinate-terephthalate (PBST).
3. According to paragraph 1,

   The film is a microneedle photothermal patch, characterized in that formed through a blowing method.
4. According to paragraph 1,

   A microneedle photothermal patch, characterized in that the film contains more than 30ppm of gold nanoparticles.
5. According to paragraph 1,

   The gold nanoparticles are a microneedle photothermal patch, characterized in that they cause an exothermic reaction in visible and near-infrared wavelengths of 400 to 1,400 nm.
6. According to paragraph 1,

   The microneedle is a microneedle photothermal patch, characterized in that the needle composition is dropped in plural numbers on one side of the film and then formed through blowing-prepared solid microstructures (BSM).
7. According to clause 6,

   The composition for the needle is a microneedle photothermal patch, characterized in that it contains a thickener.
8. According to clause 6,

   A microneedle photothermal patch, characterized in that the needle composition contains a drug.
9. According to clause 8,

   The above drugs include skin cancer treatments, allergy suppressants, atopy suppressants, anti-inflammatory drugs, painkillers, anti-arthritis drugs, antispasmodics, antidepressants, antipsychotics, tranquilizers, anti-anxiety drugs, narcotic antagonists, anti-Parkinson's disease drugs, cholinergic agonists, anticancer drugs, and anti-inflammatory drugs. Angiogenesis inhibitors, immunosuppressants, antivirals, antibiotics, appetite suppressants, analgesics, anticholinergics, antihistamines, antimigraine drugs, hormones, coronary, cerebrovascular or peripheral vasodilators, contraceptives, antithrombotic agents, diuretics, antihypertensive agents. Or a microneedle photothermal patch selected from cardiovascular disease treatments.
10. According to clause 8,

    A microneedle photothermal patch, characterized in that the composition for the needle includes a cosmetic composition.
11. According to clause 10,

    The cosmetic composition is a microneedle photothermal patch comprising a wrinkle improving agent, a skin aging inhibitor, a skin whitening agent, an antioxidant, a skin anti-inflammatory agent, a moisturizer, or a hair growth agent.

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