KR101224939B1 - Microneedle Having Improved Absorption Rate Of Active Agent - Google Patents

Abstract

The present invention relates to a microneedle with an improved rate of absorption of the active material. More specifically, the present invention relates to microneedles in which the active material can be rapidly administered by breaking down the microneedles upon attention, including hydrogel particles which swell rapidly upon contact with body fluids.

Description

Microneedle Having Improved Absorption Rate Of Active Agent

The present invention relates to a microneedle with an improved rate of absorption of the active substance, such as drugs, vaccines.

In general, the microneedle (microneedle) is used for the delivery of active substances such as drugs, vaccines, in vivo, detection of the analyte in the body and biopsy (biopsy). Drug delivery using microneedles is intended for the delivery of active substances through the skin rather than the biological circulation system such as blood vessels or lymphatic vessels. Therefore, the microneedle should have sufficient physical strength to allow skin penetration, and it is desirable that the pain is low. The shorter skin application time of the microneedle is advantageous in order to reduce pain as much as possible, in which case the active substance should be able to be delivered quickly.

Conventional microneedle is made of a material such as silicon, non-biodegradable polymer, metal, glass. These microneedles had long skin contact time in order for sufficient amounts of the active ingredient contained in the microneedles to spread into the body fluid. To overcome this problem, other means have been studied, such as, for example, electrical forces, which allow the active ingredient to escape from the microneedle into the body fluid for rapid and sufficient administration of the active ingredient.

In order to overcome this problem, microneedles using biodegradable polymers or water-soluble polymers have been developed, and in the case of microneedles using such polymers, in theory, they disintegrate or dissolve in the skin at the time of injection, thereby helping to spread the active substance contained in the microneedle. This can be However, microneedles made of biodegradable polymers have excellent biocompatibility but take at least several weeks to several months to decompose upon contact with water. Therefore, these microneedles are difficult to expect more than puncture the skin unless destroyed through other means. In addition, when it is made of water-soluble polymer, the time required for melting in contact with the tissue under the skin is in the range of several tens of minutes, which is an obstacle to commercialization of the microneedle.

Accordingly, there has been a constant need for microneedles that can deliver active substances faster when injected and have sufficient strength for skin penetration.

Therefore, the technical problem to be achieved by the present invention is to provide a microneedle that not only has sufficient strength for skin permeation, but also can rapidly release the active substance upon skin injection.

In order to achieve the above technical problem, the present invention provides a microneedle, characterized in that it comprises a hydrogel (hydrogel) particles that swell when contacted with water, preferably the present invention is the microneedle (in addition to the hydrogel particles) Provided is a microneedle, characterized in that the hydrogel particle forming material and the material is different from the swelling.

The present invention is based on the surprising finding that if microneedles made of biodegradable polymers, sugars and the like contain water swellable hydrogel particles, the microneedles can be very easily destroyed by swelling of the hydrogel particles by body fluid during skin injection. The basic concept of the invention is shown in FIG. In the case of microneedles made up of biodegradable polymers only, even though the entire microneedles are swollen, the surfaces are usually decomposed sequentially and the active substance is released, but in the case of the microneedles according to the present invention, the microneedles are not decomposed sequentially from the surface. The whole can be destroyed almost at once, so that the active material can be absorbed quickly.

Therefore, the microneedles of the present invention are more preferably made of a material having a lower swellability than the hydrogel particle forming material (in addition to the hydrogel particles).

When used in the present invention, 'hydrogel' refers to a three-dimensional hydrophilic polymer network structure that may contain a large amount of water when contacted with water, the degree of swelling of the hydrogel is hydrophilic, crosslinking degree of the polymer used And the porosity of the particles.

The material forming the hydrogel particles included in the microneedle of the present invention may be swollen at high speed when contacted with body fluid, and any material may be used as long as it is allowed to be used pharmaceutically or medically. Examples of natural polymers include hyaluronic acid, alginic acid, pectin, carrageenan, chondroitin (sulfate), dextran (sulfate), chitosan, polylysine, collagen, gelatin, Carboxymethyl chitin, fibrin, agarose, pullulan, cellulose and the like may be used. Among synthetic polymers, polyethylene oxide, poly (N-) isopropylacrylamide (PNIPAAm), polyacrylamide (PAAm), Polymers of hydrophilic monomers such as polymethacrylic acid, polymaleic acid, polyvinyl alcohol (PVA), polyethylene oxide (PEO), poly (N-) vinylpyrrolidone (PVP), poly (MMA-co-HEMA) (Poly copolymers such as (methyl methacrylate-co-hydroxylethyl methacrylate), poly (acrylonitrile (AN) -arylsulfonate), P (glucosyloxyethyl methacrylate) -sulphate (PEMA), or PEO-polyester (PLA, PCL, PLGA, etc.) derivatives, PEO-PPO-PEO terpolymer, N-carboxyhydride, etc. may be used alone or in combination, but is not limited thereto.

In consideration of the degree and speed of swelling when injected into the body, the physical strength of the microneedle, and the like, the hydrogel particles of the present invention are more preferably made of poly (N-) isopropylacrylamide (PNIPAAm).

These hydrogel particles may have hundreds of nanometers in diameter (eg, 100 nm, 200) after drying, entanglement or curing of the polymer, in order to be uniformly included in the microneedle and to have a desirable effect on the mechanical strength of the microneedle. nm, 300 nm, 400 nm, 500 nm, 600 nm, 700 nm, 800 nm, etc.) for several tens of micrometers (eg, 10, 20, 30, 40, 50, 60, 70, 80, 90 micrometers) Is preferably. In addition to the above advantages it is easy to adjust its position within the microneedle matrix when this size is achieved. In addition, such hydrogel particles are preferably swollen rapidly upon contact with body fluids in order to achieve the object of the present invention, such volume changes may be reversible or irreversible.

In addition to the hydrogel particles, the microneedle of the present invention may be formed of a matrix of a material well known to those skilled in the art, but in order to achieve the object of the present invention, the matrix forming material may be a hydrogel particle. It must be a material different from the material forming it. Such microneedle matrix forming materials include poly (lactide), poly (glycolide), poly (lactide-co-glycolide), polyanhydride, polyorthoester and polyetherester. biodegradable polymers such as polyetherester, polycaprolactone, polyesteramide, poly (butyric acid), poly (valeric acid), polyurethane, or copolymers thereof; Polyacrylates, ethylene-vinylacetate polymers, acrylic substituted cellulose acetates, non-degradable polyurethanes, polystyrenes, polyvinyl chlorides, polyvinyl fluorides, poly (vinyl imidazoles), chlorosulphonate polyolefins, polyethylene Non-biodegradable polymers such as oxides or copolymers thereof; Cellulose series such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polymethacrylate, hydroxypropylmethyl cellulose (HPMC), ethyl cellulose (EC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose Or water-soluble polymers including starch series such as cyclodextrin may be used alone or in combination, but is not limited thereto. However, biodegradable polymers are preferred in view of ease of breakage of the microneedle.

The active substance which may be included in the microneedle of the present invention may be any substance which is allowed to be used pharmaceutically, medically or cosmetically, such as a small molecular weight compound (chemical compound), an active substance such as a protein or an antibody, a vaccine or a cosmetic ingredient. Can be.

For example, interferon, erythropoietin (EPO), follicle stimulating hormone (FSH), parathyroid hormone (PTH), granulocyte macrophage colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-) CSF), human chorionic gonadotropin, progesterone, calcitonin, glucagon, GNRH antagonist, insulin, human growth hormone (GHD), testosterone, lidocaine, diclofenac, oxybutynin, ketoprofen, alendronate, enna Prill maleate, phenylpropanolamine, chromoline, isotretinoin, oxytocin, paroxetine, flurbiprofen, certalin, venlafaxine, leuprolide, risperidone, galantamine, ethanoxaprine, an anticoagulant, etanercept, pain Drugs such as fentanyl, filgrastin, anticoagulant heparin, parathyroid hormone (PTH), somatropin, growth hormone sumatriptan, etc. The other may be administered by using the micro needles, and type A, type B and hepatitis C; HIV vaccine; influenza; diphtheria; tetanus; whooping cough; Lyme disease; hydrophobia; Pneumococcal; yellow fever; cholera; Vaccinia; Tuberculosis; German measles; Measles; things to see; Rotavirus; Botulism; Vaccines such as herpes virus can be inoculated using the microneedle according to the invention. In addition, cosmetic ingredients such as botox toxin can be administered using the microneedle of the present invention.

Such active material may be present around the hydrogel particles in the matrix of the microneedle and may also be present within the hydrogel particles. If the active substance is present in the hydrogel particles, the sustained or controlled delivery effect of the active substance may be achieved by controlling the release of the active substance of the hydrogel particles.

Hydrogel particles and microneedles according to the present invention may be prepared according to methods commonly known in the art. For example, the hydrogel particles may be prepared by preparing a solution of the hydrogel forming material and spray-drying it, or by preparing an emulsion with a solution of the hydrogel particle forming material and then cooling or drying the hydrogel. The particles may be prepared by a method of preparing the particles or pulverizing the particles having a desired size, but are not limited thereto.

In the case of microneedles containing hydrogel particles, hydrogel particles are prepared by adding a pre-prepared hydrogel particle to a microneedle manufacturing mold and then adding a molten microneedle matrix forming polymer, or the hydrogel particles and the microneedle matrix material are added to the mold. It can be prepared by centrifugation at high speed to put, or by inserting a large particle containing particles into a mold using a molding process, but is not limited thereto.

Preferably, the microneedle of the present invention may also comprise a phase change material, the phase of which is transferred from solid phase to liquid phase by body temperature or by external thermal stimulation upon skin injection. Including such phase change material, the microneedles can be destroyed more rapidly by changing the phase of the phase change material in the microneedle to liquid phase after the skin injection. The phase change material is particularly preferably a material having a melting point between 20 and 50 ° C. The phase change material may be melted using body temperature or may be melted by external thermal stimulation.

Phase change materials can be largely divided into organic and inorganic. As organic materials, waxes and non-waxing fatty acids, and water-soluble polymers can be used. As the wax, paraffin wax, beeswax, carnauba wax, candelila wax, bayberry wax, Japan wax and the like can be used. The wax is generally 10 to 50 carbon atoms, in particular, a wax having 16 to 22 carbon atoms is preferable. The fatty acid may be butyl stearate, capric-lauric acid, dimethyl sabacate, capric acid, or the like, but is not limited thereto. As the water-soluble polymer, polyethylene oxide or a copolymer thereof may be used, but is not limited thereto. Minerals are hydrated salts or mixtures thereof. Hydrated salts include Mn (NO ₃ ) ₂ · 6H ₂ O, CaCl ₂ · 6H ₂ O, LiNO ₃ · 3H ₂ O, Na ₂ SO ₄ · 10H ₂ O, Na ₂ HPO ₄ · 10H ₂ O, MgCl ₂ 6H ₂ O, sodium acetate pentahydrate, and the like may be used, but is not limited thereto. These phase change materials can be used in combination to ensure the desired melting temperature.

The present invention provides microneedles that can be destroyed quickly during skin injection to deliver the active material quickly and sufficiently.

1 is a view showing the basic concept of an embodiment of the present invention.
Figure 2 is a microscope enlarged picture of PNIPAAm particles prepared according to an embodiment of the present invention.
Figure 3 is the result of measuring the swelling property when water is added to the hydrogel particles according to the present invention.
4 is an enlarged photograph of a hydrogel particle-containing microneedle prepared according to an embodiment of the present invention.
5 to 7 are the results showing the degree of destruction of the hydrogel particle-containing microneedle prepared in accordance with an embodiment of the present invention in the body fluid.
8 is a result of evaluating the mechanical strength of the microneedle including the hydrogel particles prepared according to an embodiment of the present invention.
9 is a pig skin injection result of a microneedle containing calcein as a drug model material, prepared according to one embodiment of the present invention. The left picture is the fluorescence image just before administration, and the right picture is the fluorescence image 15 minutes after administration.

Hereinafter, embodiments of the present invention will be described in detail to facilitate understanding of the present invention. However, the embodiments according to the present invention can be modified into various other forms, and the scope of the present invention should not be construed as being limited to the following embodiments. Embodiments of the invention are provided to more fully describe the present invention to those skilled in the art.

Example 1 Confirmation of Swellability of Hydrogel Particles

PNIPAAm (Poly (N-isopropylacrylamide)) hydrogel particles were prepared by the following method, and the swelling properties of the prepared particles were confirmed.

3 g of NIPAAm, 0.12 g of BIS, and 0.3 g of APS were added to 30 ml of distilled water and mixed for 30 minutes with a stirrer. 3.75 g of SPAN80 (surfactant) and 150 ml of hexane were placed in a flask, and the aqueous solution was sealed while stirring at a speed of 600-700 RPM. 3 ml of TEMED was added while adding nitrogen gas, and then stirred at 400 RPM at room temperature for 4 hours. Thereafter, 400 ml of acetone and 400 ml of distilled water were added to form a precipitate while stirring for 2 hours. This process was repeated three times, and the desired hydrogel particles were obtained by repeating distilled water 600 ml, stirring for 2 hours, and precipitation for 1 hour 5 times. The particles obtained were analyzed in size and distribution using an electron microscope, and the results are shown in FIG. 2. As shown in FIG. 2, the average particle size was 20 micrometers in diameter, with a diameter of at least 10 micrometers and a maximum of 50 micrometers, and the shape was spherical.

The hydrogel particles thus prepared were observed for volume change when they were contacted with water using a microscope equipped with a video recorder. The particles were placed on a glass slide and the slide was placed again on a thermostat set at 32 ° C. The magnification of the microscope was set to x200, and water was dropped on the particles to observe changes in the particles. The change in size of the resulting particles is shown in FIG. As shown in FIG. 3, the hydrogel particles having an average diameter of 20 microns upon drying swelled to about 60 micrometers in diameter after 10 minutes of contact with water in an aqueous solution.

Example 2 Preparation of Microneedle Containing Hydrogel Particles

Example 2-1 Preparation of PLGA Microneedle Containing PNIPAAm Microparticles

First, PNIPAAm (Poly (N-isopropylacrylamide)) hydrogel particles were prepared as in Example 1. Thereafter, 50 mg of the prepared hydrogel particles were sprayed onto the tip of the microneedle mold, and 0.5 mg of the particles were put into the microneedle mold using a plastic spatula. At this time, the particle size is 10 to 50 micrometers in diameter. PLGA (poly (lactic-co-glycplic acid)) was pelletized into a microneedle mold, melted at about 140 ° C, vacuumed at about 100 Pa to fill the rest of the particles with a polymer melt, and the sample was kept at room temperature. The microneedles were prepared by leaving the sample to stand at room temperature to remove the sample from the mold.

An enlarged photograph of the manufactured microneedle is shown in FIG. 4. As shown in Figure 4, it can be seen that the PNIPAAm hydrogel particles are contained between the PLGA forming the microneedle.

<Example 2-2> Preparation of CMC microneedle containing PNIPAAm (Poly (N-isopropylacrylamide)) hydrogel particles

10 mg of hydrogel particles were evenly spread over the mold surface and the particles were placed into the needle holes of the mold using a centrifuge. At this time, the rotation speed was 4000 rpm and the rotation time was about 15 minutes. Particles remaining on the surface were removed using a tape. Thereafter, 0.1 g of 30% (w / w) CMC was placed in a mold and first centrifuged at 4000 rpm, 4 ° C., and 10 minutes to allow the CMC to evenly enter the microneedle mold. Thereafter, the CMC was dried by centrifugation again at 4000 rpm, 25 ° C. for 3 hours. The dried sample was separated from the mold to obtain a microneedle sample.

Example 3 Evaluation of Ease of Fracture of Microneedle Containing PNIPAAm Hydrogel Particles

Ease of destruction of the microneedle including the hydrogel particles prepared in Example 2-1 was evaluated by the following method.

PLGA (poly-lactic-co-glycolic acid) microneedle containing hydrogel particles was prepared and then the degree of destruction after contact with water and PLGA microneedle without hydrogel was compared. First, the change after the water contact of the hydrogel-containing PLGA microneedle was observed over time. Each sample was placed in a thermostat at 32 ° C and the water was dropped. After 3 seconds, 5 minutes, 10 minutes, and 150 minutes of contact time, the residue of the sample was quickly dried after absorbing with a cotton swab. Was observed. The results are shown in FIGS. 5 to 7. As shown in FIGS. 5 and 6, over time, the destruction of the microneedle proceeded rapidly and the mechanical strength of the microneedle dropped sharply by swelling of the hydrogel within a few seconds after contact with water. The effect of hydrogels was significantly different when compared to microneedles made only of biodegradable polymers, which were not affected by moisture within a few hours. As shown in FIG. 7, the microneedle containing the hydrogel particles caused a rapid volume change as soon as it was in contact with water, but the PLGA needle did not change mechanically and apparently. As shown in Figures 5 and 6, the microneedle comprising the hydrogel particles according to the present invention will rapidly break the microneedle upon administration in the body, so that the active substance contained in the microneedle will spread quickly and in sufficient amount into the body fluid.

Example 4 Mechanical Strength Evaluation of Microneedle Including PNIPAAm Hydrogel Particles

To see the change in the mechanical strength of the microneedle according to the addition of the hydrogel, the PLGA microneedle and the CMC microneedles containing 50% hydrogel were stabbed in pig skin and stained with trypan blue to form a hole in the skin successfully. Observed. The results are shown in Fig. As shown in Figure 8, the microneedle successfully formed a hole in the pig skin. Therefore, it can be seen that the addition of the hydrogel particles minimizes the loss of mechanical strength of the microneedle, and rapidly delivers the active ingredient by breaking the microneedle in the skin.

Example 5 Preparation and Evaluation of a Microneedle Containing a Drug

Calcein (Calcein, Sigma) was used as the water soluble drug model. Hydrogel particles were dispersed for 30 minutes in a 1 mM solution of calcein to equilibrate. The particles were then filtered through a 200 nm pore size filter, the calcein solution remaining on the surface with an ethanol solution, and dried.

The microneedle was prepared by PLGA melting after the dry particles were filled in the mold by the method described in Example 2-1. Microneedles containing hydrogel particles containing calcein were inserted into pig skin (full thickness) and after 15 minutes the microneedles were recovered to observe the change in the needles. The results are shown in FIG.

As shown in Fig. 9, hydrogel particles containing the drug model calcein are dispersed evenly in the microneedle (left photo), and after 15 minutes, the hydrogel particles are swollen in the pig skin, and a part of the microneedle Only a portion of the microneedles left on the skin and destroyed was recovered (pictured right).

Claims (6)

Microneedle, characterized in that it comprises hydrogel particles that swell upon contact with water. The microneedle of claim 1, wherein the microneedle is made of a material different from the hydrogel particle-forming material in addition to the hydrogel particle. The microneedle of claim 1, wherein the microneedle is made of a material having a swelling property smaller than that of the hydrogel particle forming material in addition to the hydrogel particle. The method of claim 2 or 3, wherein the microneedle, in addition to the hydrogel particles, poly (lactide), poly (glycolide), poly (lactide-co-glycolide), polyanhydride, poly Orthoesters, polyetheresters, polycaprolactones, polyesteramides, poly (butyric acids), poly (valeric acids), polyurethanes, polyacrylates, ethylene Vinyl acetate polymer, acrylic substituted cellulose acetate, non-degradable polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly (vinyl imidazole), chlorosulphonate polyolefins, polyethylene oxide, polyvinyl film Lollidon (PVP), Polyethyleneglycol (PEG), Polymethacrylate, Hydroxypropylmethylcellulose (HPMC), Ethyl cellulose Agarose (EC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose, cyclo dextrin, and microneedle, characterized in that consisting of one or more materials selected from the group consisting of a copolymer of monomers forming these polymers. The method of claim 1, wherein the hydrogel particles are hyaluronic acid (hyaluronic acid), alginic acid (alginic acid), pectin, carrageenan, chondroitin (sulfate), dextran (sulfate), chitosan, polylysine (polylysine) , Collagen, gelatin, carboxymethyl chitin, fibrin, agarose, pullulan, cellulose, polyethylene oxide, poly (N-) isopropylacrylamide (PNIPAAm), polyacrylamide (PAAm), polymethacrylic acid, Polymaleic acid, polyvinyl alcohol (PVA), polyethylene oxide (PEO), poly (N-) vinylpyrrolidone (PVP), poly (methyl methacrylate-co-hydroxyethyl methacrylate) (poly (MMA- co-HEMA) (Poly (methyl methacrylate-co-hydroxylethyl methacrylate)), poly (acrylonitrile-arylsulfonate), poly (glucosyloxyethyl methacrylate-sulfate) (P (GEMA ( glucosyloxyethyl methacrylate) -sulfate)), poly Group consisting of ethylene oxide (PEO) -polyester derivatives, polyethylene oxide-polypropylene oxide-polyethylene oxide (PEO-PPO-PEO) terpolymers, N-carboxyhydrides and copolymers of monomers forming these polymers Microneedle, characterized in that made of at least one material selected from. The microneedle of claim 5, wherein the hydrogel particles are made of poly (N-) isopropylacrylamide (PNIPAAm).

Images