KR20160030793A - Microneedle system having improved absorbing rate of active ingredients - Google Patents

Abstract

The present invention relates to a microneedle system such as a kit including a composite which has a water-soluble microneedle and purified water, and a using method thereof. According to the microneedle system, active ingredients within a microneedle are quickly discharged to shorten the time for the active ingredients to be absorbed into a skin. Moreover, using convenience is improved, and skin stimulation can be reduced to improve stability.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention [0001] The present invention relates to a microneedle system,

The present invention relates to a microneedle kit in which the rate of skin absorption of active, pharmaceutical, or cosmetically useful active ingredients is improved.

The microneedle is a system that physically punctures the stratum corneum and delivers the drug through the channel. It can deliver the drug at a rate of about 100 times faster than the conventional transdermal delivery system.

The microneedle-based delivery method currently in use or under development is a solid type in which a drug is applied after forming perforations in the skin and a form in which the drug is delivered by the needle administration itself, that is, a drug is contained in the needle, Coating type.

Micro-needles are generally used for delivery of active substances such as drugs, vaccines and the like in vivo, for detection and biopsy of analytes in the body. The delivery of the pharmacologically or cosmetically active ingredient using micro needles is intended for the delivery of the active substance through the skin, not the vascular system such as blood vessels or lymphatic vessels. Therefore, the micro needle must have sufficient physical strength to the extent that penetration of the skin is possible, and it is also preferable that the pain is small. In order to reduce pain as much as possible, the shorter the application time of the microneedle is, the more advantageous it is, and in this case the active substance must be able to be delivered quickly.

Conventional microneedles are made of materials such as silicon, non-biodegradable polymers, metals, and glass. In the case of such a micro needle, a sufficient amount of the active ingredient contained in the micro needle has to be long in contact with the skin to spread into body fluids. To overcome this problem, other means have been explored, such as, for example, electrical forces, to cause the active ingredient to escape from the micro needle into the body fluid for rapid and sufficient administration of the active ingredient.

In order to overcome the above problems, a micro needle using a biodegradable polymer or a water-soluble polymer has been developed. In the case of a micro needle using such a polymer, the active agent contained in the micro needle is theoretically decomposed or dissolved in the skin during injection, It is expected to be helpful for the spread of However, the biodegradable polymer micro-needle has excellent biocompatibility, but it takes at least several weeks to several months to decompose on contact with water. Likewise, when the active ingredient is made of a water-soluble polymer, the micro needles must be dissolved in order to transfer the active ingredient to the skin. The time required for the active ingredient is about several minutes to several tens of minutes, and the stimulation of the adhesive used for attaching the micro- Side effects such as skin troubles that occur are problematic. In addition, since it has to be attached to the skin for a long period of time, it is a hindrance to the commercialization of the water-soluble micro needle because of the separation of the micro needle from the skin.

Accordingly, a problem to be solved by the present invention is to provide a micro needle system (for example, a kit) capable of rapidly releasing an active ingredient in a micro needle and shortening a time required for the active ingredient to be absorbed.

In order to solve the above problems, the present invention provides a water-soluble micro needle; And a composition comprising purified water. The microneedle kit may further include an instruction sheet including a usage instruction method.

Or (S1) attaching the water-soluble micro-needle to the skin to form a perforation; (S2) applying a composition comprising purified water to a water-soluble micro needle; And (S3) removing water-soluble micro-needles within a short time (preferably, 30 minutes) after adhering the skin, thereby improving the skin absorption rate of the active ingredient contained in the water-soluble micro-needle.

More specifically, the inclusion of purified water in a composition applied to water-soluble micro-needles after perforation of the skin permits the use of micro-needles capable of rapidly migrating into the skin for medical, pharmaceutical or cosmetic active ingredients and reducing skin irritation by the micro- Provide a kit.

After the perforation is formed in the skin, the present inventors have found that the rate of dissolution (melting, decomposition or destruction) of the micro needle is the most important factor for the skin delivery rate of the active substance contained in the micro needle, (Such as melting, dissolution or destruction) of a water-soluble micro-needle using a composition containing purified water has been studied in view of the excellent effect of promoting the skin absorption rate of the active ingredient in the water-soluble micro-needle. However, the present invention is not limited to these theoretical assumptions.

The composition containing purified water according to the present invention is for dissolving (melting, decomposing or breaking) the micro needle, and is preferably contained in an amount of 80% by weight or more based on the total weight of the micro needle kit, more preferably 80-90 % ≪ / RTI > by weight. If it is contained in an amount of less than 80% by weight, the micro needle can not be sufficiently dissolved.

The composition containing the purified water according to the present invention is not particularly limited in its formulation and may be any known external skin preparation of the present invention. For example, it may be a general ointment, a softening agent, a convergent lotion, a nutritional lotion, A body lotion, a body cream, a body oil, a body essence, a foundation, a lotion, a gel, a patch and a spray, and the like, and can be manufactured by a conventional method known in the field of the present invention .

The purified water may be contained in an amount of 50 wt% or more, more preferably 80 wt% or more, and most preferably 100 wt%, based on the total weight of the composition. In addition to purified water, the composition may further contain substances that can be added conventionally in the art.

The microneedles according to the present invention are water-soluble micro-needles that are dissolved (melted, decomposed or destroyed) in water (purified water), and any material that is soluble in water may be used to form the water- Soluble polymers, saccharides or mixtures thereof may be used. Examples of the water-soluble polymer include polyvinyl alcohol, carboxyvinyl polymer, acrylic vinyl polymer, carboxymethylcellulose, hyaluronic acid, hydroxyethylcellulose, xanthan gum, locust bean gum, ethylene-vinyl acetate polymer, acrylic substituted cellulose acetate, Polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG), polyethyleneglycol (PEG), polyvinylpyrrolidone, polyvinylpyrrolidone, poly (vinylimidazole), chlorosulphonate polyolefins, Hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), hydroxypropylcellulose (HPC), carboxymethylcellulose, cyclodextrin, sodium-carboxymethylcellulose (Na-CMC), vinylpyrrolidone Don-vinyl acetate copolymer, and monomers forming such a polymer The selected one or more water-soluble polymers in the group consisting of copolymers may be used alone or in combination, but is not limited thereto. Examples of the saccharides include, but are not limited to, Xylose, Sucrose, Maltose, Lactose, Trehalose, and mixtures thereof. Preferably, a mixture of carboxymethyl cellulose, hyaluronic acid, and saccharides (more preferably, trehalose) is used in consideration of the skin permeation intensity of the micro needle, the dissolution rate in application of water (purified water), and the ease of absorption of the active ingredient (Most preferably, glycerin) and a surfactant (most preferably, PEG-40 hydrogenated castor oil) can be mixed and used.

The water-soluble macromolecules and saccharides forming the water-soluble micro-needle according to the present invention may contain 20 to 100% by weight, more preferably 30 to 40% by weight, of the water-soluble polymer, based on the total weight of the material and the active ingredient, And the saccharide may be contained in an amount of 20 to 50% by weight, more preferably 30 to 40% by weight .

Preferably, the microneedle according to the present invention may further include a plasticizer, a surfactant, a preservative, an anti-inflammatory agent, and the like in addition to the above-mentioned components. More preferably 25 to 35% by weight, based on the total weight of the active ingredient and the material forming the water-soluble micro needle. More specifically, the plasticizer may contain 5 to 30% by weight, more preferably 25 to 30% by weight %, And the surfactant may be contained in an amount of 5 to 20% by weight, more preferably 5 to 15% by weight.

Examples of the plasticizer include polyols such as ethylene glycol, propylene glycol, dipropylene glycole, butylene glycol, glycerine, etc., And glycerin can be preferably used.

As the surfactant, a nonionic surfactant may be preferably used. Examples of the surfactant include hydrogenated vegetable oils, octyldodeceth, ceteareth, ceteth, etc., alone or in combination. PEG-10 glyceryl isostearate, PEG-15 glyceryl isostearate, PEG-20 glyceryl isostearate, PEG-10 glyceryl isostearate, Hydrogenated castor oil, PEG-30 hydrogenated castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-80 hydrogenated castor oil, PEG-60 hydrogenated castor oil triisostearate, 12, Ceteth-10, Ceteth-12, Ceteth-15 and Ceteth-17 may be used alone or in combination, and preferably PEG-40 hydrogenated castor oil may be used. Preferably, the microneedles according to the present invention may comprise one or more active substances (e. G., Drugs), and additionally one or more active substances in the composition. The active substance that can be delivered to the micro needle or the micro needle kit according to the present invention may be a pharmaceutical compound such as a chemical compound, a protein, an antibody, etc., a vaccine, a cosmetic ingredient, etc. May be any permissible material.

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- , Human growth hormone (GHD), testosterone, lidocaine, diclofenac, oxybutynin, ketoprofen, alendronate, enanthryl, Etanercept, which is a therapeutic agent for rheumatoid arthritis, and a therapeutic agent for pain, which is a therapeutic agent for rheumatoid arthritis, which is a therapeutic agent for rheumatoid arthritis, which is a therapeutic agent for rheumatoid arthritis, Drugs such as fentanyl, peplgastine, heparin as an anticoagulant, parathyroid hormone (PTH), somatropin, and growth hormone sumatriptan are preferred according to the present invention It is administered by the system, and also A-type, B-type and C-type hepatitis; HIV vaccine; influenza; diphtheria; tetanus; whooping cough; Lyme disease; hydrophobia; Pneumococcus; yellow fever; cholera; Vaccinia; Tuberculosis; German measles; Measles; things to see; Rotavirus; Botulism; A vaccine such as a herpes virus can be inoculated using the system according to the present invention. In addition, it is also possible to use other drugs such as botox toxin, diosmetin, magnesium ascorbyl phosphate, mace lignan, alfalfa, acetyl phytosphingosine, ascorbyl glucoside, asialicoside, arbutin, Cosmetic ingredients such as ethoxylated retinamide, flangenidine, hydroxyproline, human oligopeptide-1, retinol and the like can be administered using the system of the present invention.

Methods for improving the rate of skin absorption of active ingredients in aqueous micro-needles using a micro needle kit according to the present invention are as follows:

(S1) attaching a water-soluble micro-needle to the skin to form a perforation; (S2) applying a composition comprising purified water to a water-soluble micro needle; And (S3) removing the water-soluble micro-needles within 30 minutes after adhering the skin. The skin refers to the skin of mammals, poultry, etc., and preferably refers to human skin.

The micro needle kit according to the present invention may further include an instruction sheet including a usage instruction method. In the instructions for use described above, a method of applying a composition containing purified water to micro needles can be described.

The method of applying the composition including the purified water to the water-soluble micro needle is not limited as long as the method capable of dissolving the micro needle with the purified water is possible, for example, a method of applying the composition around the aqueous micro needle, a method of spraying, , And the like, but the present invention is not limited thereto.

When a composition containing purified water is applied to a water-soluble micro-needle, dissolution of the water-soluble micro-needle is started, and the active ingredient contained in the micro needle can be sufficiently transferred to the skin by the fusion of the micro needle within a short time. However, the time for removing the water-soluble micro-needles after adhering the skin may vary depending on the type of the substance forming the water-soluble micro-needle, the kind of the active substance, the skin region, etc., preferably within 30 minutes.

According to the present invention, it is possible to rapidly release the active ingredient in the microneedles, shorten the time required for these active ingredients to be absorbed into the skin, improve convenience of use, And the stability can be improved.

BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings, which are incorporated in and constitute a part of the specification, illustrate exemplary embodiments of the invention and, together with the description of the invention, It should not be construed as limited.
FIG. 1 is a photograph showing that the embodiment according to the present invention shows an improvement in percutaneous permeation effect of a drug (polyhedrin) compared to a comparative example. Comparative Example 1, Comparative Example 1, Comparative Example 2, FIG. 1e: Comparative Example 3, FIG. 1f: Comparative Example 4, FIG. 1g: Comparative Example 5
FIG. 2 is a photograph showing that the embodiment according to the present invention shows reduced skin irritation compared to the comparative example. FIGS. 2A to 2C show Example 2, Comparative Example 1, Comparative Example 2, and Comparative Example 3 from the left side to the right side of the red square. Figure 2a: Immediately after removal, Figure 2b: After 1 hour of removal, Figure 2c: After 2 hours of removal,
FIG. 3 is a photograph showing that the embodiment according to the present invention shows faster recording of the tips of the microneedles compared to the comparative example. Figure 3a: Example 1, Figure 3b: Comparative Example 1, Figure 3b: Comparative Example 2, Figure 3c: Comparative Example 3

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.

≪ Preparation of micro needle >

The microneedles according to the present invention were prepared by dissolving CARBOXYLMETHYL CELLULOSE, HYALURONIC ACID, TREHALOSE in purified water, GLYCERIN heated to 50 DEG C and POLYDATIN in a solution of PEG-40 HYDROGENATED CASTOR OIL was added. The solution was cast into a silicon microneedle mold and then centrifuged at 3000 rpm for 10 minutes to fill the fine mold with the solution. The filled mold was dried in a drying oven at 70 ° C for 3 hours, and the micro needles were separated from the silicone mold using an adhesive film.

Ingredients Weight ratio (%) CARBOXYLMETHYL CELLULOSE 15.0 HYALURONIC ACID 18.0 TREHALOSE 33.0 PEG-40 HYDROGENATED CASTOR OIL 9.0 GLYCERIN 20.0 POLYDATIN 5.0 Total 100.0

<Experiment group>

The experimental group as shown in Table 1 below was set and evaluated.

Example 1 After punching with a micro needle for 10 seconds, 300 μl of purified water was poured for 10 seconds and immediately removed Example 2 After punching with a micro needle for 10 seconds, 300 μl of purified water was poured for 10 seconds, Comparative Example 1 After punching for 10 seconds with a micro needle, attach for 30 minutes and remove Comparative Example 2 After punching for 10 seconds with a micro needle, attach for 1 hour and remove Comparative Example 3 After punching for 10 seconds with a micro needle, after attaching for 2 hours, remove Comparative Example 4 After punching for 10 seconds with a micro needle, attach for 4 hours and remove Comparative Example 5 After punching for 10 seconds with a micro needle, after attaching for 8 hours, remove

EXPERIMENTAL EXAMPLE 1 Percutaneous Transmission Experiment of Polydatin Impregnated Water-Soluble Microneedles

After performing Example 1-2 and Comparative Example 1-5, the degree of increase of the transmittance of the active material (Table 3) and the degree of increase of the skin transmissibility of the micro needle (Table 4) according to purified water treatment were confirmed. The concrete experimental method was as follows.

1) A water-soluble micro needle was placed on a pig skin of 2 cm X 2 cm X 0.7 mm (width X length X thickness), and then pressed for 10 seconds to form a puncture on the pig skin, and then stored in a 37 ° C chamber.

2) The water-soluble micro needle was removed after a certain time elapsed.

3) After removing the residues from the skin, the skin was immersed in a water bath at 65 ° C for 10 seconds, removed, and the epidermis was removed with a cotton swab.

4) After removing the epidermis, the skin tissue was disrupted with a homogenizer and then polyadatine was extracted with methanol and analyzed by high performance liquid chromatography (HPLC).

5-1) The amount of polyadin contained in the sample before the experiment and the amount of polyadin extracted from the skin after the experiment were analyzed to calculate the skin permeability of the polyadin.

5-2) The amount of microneedles prior to the experiment and the amount of microneedles after the experiment were measured to calculate the skin transmission rate of the mite needle.

The experimental results are shown in Table 3 (skin permeability of polyadin) and Table 4 (skin transmissibility of micro needle).

Example 1 Example 2 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Transmittance (%) 4.21 16.41 0.08 1.02 1.78 1.85 1.94

Example 1 Example 2 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Delivery rate (%) 98 98 5 7 15 42 62

As can be seen from Table 3, it was found that the skin permeability of polyadin, the active ingredient, was much better than that of Comparative Examples 1 to 5 in Examples 1 to 2.

The skin transmissibility of the water-soluble micro needles can be confirmed from FIG. 1 together with Table 4. As can be seen from Table 4 and FIG. 1, when the water-soluble micro needle was placed on the skin of the pig and panned for 10 seconds and stored at 37 ° C, the shape of the micro needle tip was almost maintained until 2 hours after the start of the experiment. After 4 hours, all of the tip of the micro needle had melted. After 8 hours, it was observed that the micro needle base was partially melted and transferred to the skin. As a result of measuring the weight of the micro needle before and after the experiment, it was confirmed that more than 40% of the micro needle was delivered to the skin after 4 hours or more after the experiment. On the other hand, it was observed that more than 90% of the micro needle component was transferred to the skin when the water-soluble micro needle was placed on the skin of the pig, poured for 10 seconds, and then 300 μl of purified water was dropped.

Experimental Example 2 Skin irritation experiment of water-soluble micro needle

The water-soluble micro needle was attached to the inside of a human arm according to Example 2 and Comparative Examples 1 to 3. After a certain period of time had elapsed, the skin irritation index was measured according to the elapsed time after the removal, The results are shown in Table 5, and the resulting photographs are shown in Fig.

After 30 minutes of removal After 1 hour of removal After 2 hours of removal Example 2 0.00 0.00 0.00 Comparative Example 1 4.25 2.87 0.12 Comparative Example 2 4.11 3.78 2.21 Comparative Example 3 4.15 3.42 2.34

As can be seen from Table 5 and FIG. 2, when the water-soluble micro-needle was attached to the skin for a long period of time, skin irritation was induced, but no skin irritation was observed according to the present invention.

Experimental Example 3: Solubility test of water-soluble micro needle tip

According to Example 2 and Comparative Examples 1 to 3, the water-soluble micro needle was attached to the inside of the human arm. After a certain time had elapsed, the solubility of the water-soluble micro needle tip was confirmed.

Fig. 3 shows the result of microscopic observation, and Table 6 shows the water-soluble micro needle transmission rate.

Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 Delivery rate (%) 98 8 21 51

The shape of the tip portion of the micro needle was maintained until 1 hour after the start of the experiment, but it was confirmed that the tip portion of the needle melted after 2 hours (FIG. 3). In addition, 50% or more of the microneedle component was transferred to the skin after 2 hours had elapsed from adhering to the human skin, and when the experiment was conducted against the pig skin, it showed a similar type of fusibility after 4 hours 1). On the other hand, when 300 μl was dropped after attaching the water-soluble micro needle to the skin, 98% or more of the micro needle component was delivered to the skin. In the case of the example, the water micro needle was completely dissolved and the remaining micro needle was not found.

Claims (6)

Water-soluble micro needles; And
Lt; RTI ID = 0.0 &gt; 1, &lt; / RTI &gt; purified water. The microneedle kit according to claim 1, wherein purified water is at least 50% by weight based on the total weight of the composition. The microneedle kit according to claim 1, wherein the water-soluble micro-needle is formed from carboxymethyl cellulose, hyaluronic acid, a saccharide or a mixture thereof. The microneedle kit according to claim 3, wherein the water-soluble micro-needle is formed by further comprising a plasticizer, a surfactant, or a mixture thereof. The microneedle kit according to claim 1, wherein at least one selected from the group consisting of the water-soluble micro-needles and the composition comprises an active material. Attaching the water-soluble micro-needles to the skin to form perforations;
Applying a composition comprising purified water to a water soluble micro needle; And
A method of improving the rate of skin absorption of an active ingredient contained in a water-soluble micro-needle comprising removing water-soluble micro-needles within 30 minutes after skin attachment.

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