KR20150055325A - Microneedle system having improved absorbing rate of active ingredients - Google Patents

Abstract

The present invention relates to a micro-needle or micro-needle kit capable of warming up the skin to increase the skin absorption rate of the useful active ingredients. The micro-needle includes a substance activating a temperature receptor.

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 or microneedle kit in which the rate of skin absorption of a medical, pharmaceutical or cosmetically useful active ingredient 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 about 100 times faster than the conventional transdermal delivery system.

Micro needle-based delivery methods that are currently being used or under development include a solid form for applying a drug after forming a hole in the skin and a form for delivering the drug by needle administration itself, that is, a drug is contained in a needle- Coating type.

In general, microneedle is used for the delivery of active substances such as drugs, vaccines and the like in vivo, detection of biosolids, and biopsy. 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 electrical forces, for example, 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, Can be beneficial to 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. Therefore, these microneedles are hardly expected to play a role in puncturing the skin unless they are destroyed through other means.

SUMMARY OF THE INVENTION Accordingly, it is an object of the present invention to provide a micro needle or microneedle system which is excellent in consumer convenience and skin safety, is capable of effectively and rapidly releasing drugs and cosmetic efficacious ingredients that are difficult to penetrate and absorb skin, For example, a kit).

In order to solve the above problems, the present invention provides a microneedle which is dissolved or melted after perforating the skin, which comprises a substance activating a temperature receptor, a substance giving a thermal sensation, or a mixture thereof. The present invention also provides a microneedle kit, comprising: (1) a micro needle and (2) a composition or patch comprising a temperature receptor activating substance, a warming substance or a mixture thereof.

That is, the present invention can be applied to a composition or patch which is contained in a microneedle structure which is dissolvable, dissolved, melted or broken after piercing the skin, or applied to the pierced skin after perforation, A microneedle or microneedle kit in which a medical, pharmaceutical or cosmetic active ingredient can rapidly migrate into the skin.

The composition according to the present invention may be a general formulation of cosmetics such as skins, lotions, creams, essences, etc., and the composition and patch according to the present invention may be manufactured by a conventional method well known in the art.

The present invention is based on the fact that when the skin temperature is increased, the bilayer lipids of the stratum corneum are softened so that the pores are enlarged, facilitating the discharge of waste products and promoting skin absorption of the active ingredient , But the present invention is not limited to this theoretical assumption.

In the present invention, a substance involved in transient receptor potential vanilloid (TRPV) receptors may be used as the substance activating the temperature receptor. The TRP channel, a receptor that senses temperature, is a type of membrane protein, and various TRPV (transient receptor potential vanilloid) receptors are known depending on the temperature range. For example, ingredients that activate TRPV3 (32-39 ° C) include Camphor, Thymol, Carvacrol, Menthol, Eugenol, Vanillin, Cinnemaldehyde, incensole acetate or derivatives thereof, and another activator of TRPV4 (30-37 ° C), which is a warmth sensor, include barnauba extract, which is a health food, antipyretic, anti-inflammatory, digestive And vanillyl butyl ether, anandamide, and the like are present in addition to an extract of Kalmeg (Tshin) extract, which is an effective Ayurvedic medicine. On the other hand, the components that activate TRPV1 (above 42 ° C), which is a heat sensor, include capsaicin, camphor, resiniferatoxin, piperidine, polyamines, Olvanil and others. By administering these substances into the perforated skin to impart warmth or warmth, it was confirmed that the absorption amount of the active ingredient was increased without skin irritation.

Such temperature receptor activating substances may be used alone or in combination, and preferably 0.01 to 10% by weight based on the total weight of the micro needle, composition or patch.

In the present invention, examples of the substance giving a warmth or a heat sensation include polyols (glycerin, dipropylene glycol, propylene glycol, butylene glycol, sorbitol, polyethylene glycol, etc.) Synthetic zeolite, which is a kind of crystalline alluminosilicate mineral harmless to human body, can be used. For the purpose of the present invention, zeolite is preferable as the substance giving the thermal sensation.

The content of such a warming or hot feeling substance (particularly, zeolite) is preferably 1 to 20% by weight based on the total weight of the micro needle, composition or patch.

More preferably, the present invention is also based on the surprising discovery that the rate of skin absorption can be further increased when both the temperature activating substance and the warming substance (particularly preferably zeolite) are used together.

Accordingly, the micro needle according to the present invention includes both a material for activating the temperature receptor and a material (particularly preferably zeolite) which gives a thermal sensation, or a material for activating the temperature receptor and a material for imparting a thermal sensation to the composition and / (Particularly preferably zeolite), or the composition and / or the patch may include any one of a substance activating a temperature receptor and a substance giving a thermal sensation, and the other components not included in the composition or patch may include May be included in the micro needle.

Preferably, one or more of the micro-needles, compositions and patches according to the present invention may comprise an active substance (e.g., a drug). 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, interferons, erythropoietin (EPO), follicle stimulating hormone (FSH), parathyroid hormone (PTH), granulocyte macrophage colony stimulating factor (G-CSF), granulocyte- macrophage colony stimulating factor (GM- (GHD), testosterone, lidocaine, diclofenac, oxybutynin, ketoprofen, alendronate, enanthorrhoids, and the like), human chorionic gonadotropin, human chorionic gonadotropin, progesterone, calcitonin, glucagon, GNRH antagonist, insulin, human growth hormone Etanercept, etanercept, which is a therapeutic agent for rheumatoid arthritis, pain, and the like, which is a therapeutic agent for rheumatoid arthritis, which is an anticoagulant, rheumatol, Drugs such as fentanyl, peplastatin, heparin as an anticoagulant, parathyroid hormone (PTH), somatropin, and growth hormone sumatriptan, which are therapeutic agents, It can be administered using a different 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.

Examples of the material constituting the micro needle according to the present invention include poly (lactide), poly (glycolide), poly (lactide-co-glycolide), polyanhydride, polyorthoester, , Biodegradable polymers such as polyetherester, polycaprolactone, polyesteramide, poly (butyric acid), poly (valeric acid), polyurethane or copolymers thereof, and poly But are not limited to, acrylate, ethylene-vinyl acetate polymer, acrylic substituted cellulose acetate, non-degradable polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly (vinylimidazole), chlorosulphonate polyolefins, Or non-biodegradable polymers such as copolymers thereof may be used singly or in combination , And the like.

However, poly (lactide), poly (glycolide), poly (lactide-co-glycolide), and poly (lactide-co-glycolide) are examples of substances that form the structure of the micro needle in view of biocompatibility of the micro needle, ease of absorption of the active ingredient, Biodegradable polymers such as polyanhydrides, polyorthoesters, polyether esters, polycaprolactones, polyester amides, poly (butyric acid), poly (valeric acid), polyurethanes or copolymers thereof (Lactides), poly (glycolides) and poly (lactide-co-glycolides) are even more preferred.

In addition, as the micro needle according to the present invention, a micro needle made of glass, metal or the like may be used.

The present invention can provide a microneedle or mite needle system (kit) in which a medical, pharmaceutical or cosmetic active ingredient can quickly migrate into the skin by containing ingredients that impart warmth or a sense of warmth or by activating temperature receptors have.

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.
Figure 1 is a schematic illustration of one embodiment of the present invention. (1) and (2) show a kit consisting of a patch containing a micronee needle and a hot material, or a kit consisting of a common formulation of cosmetics such as skins, lotions, creams, essences, etc., Show. (3) schematically shows a microneedle containing a heating material at the tip of a water-soluble needle, and (4) schematically shows a soluble micro needle patch impregnated with a heating material. (5) shows that the present invention can be applied to a method in which a hollow microneedle is used and a hot component and a drug are injected through a hollow tip after needle punching.
FIG. 2 is a photograph showing that the drug (calcine) penetration effect (skin permeability) is increased in the examples according to the present invention.

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.

<Experiment group>

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

Comparative Example 1 Solid Micro Needle After punching Calcein solution (including Calcein solution)
Drug or cream, 25mmol 1%) Application Example 1 After punching solid micro needle, apply Calcein solution (1% of vanilyl butyl ether) (1% of 25 mmol) Example 2 After the solid micro needle punching, Calcein-containing non-water cream formulations (Calcein) containing vanilyl butyl ether (1%) and zeolite (5%),
Containing drug or cream, 25mmol 1%) Application Comparative Example 2 After the solid micro needle punching, a hydrocolloid patch was applied after application of a Calcein solution (drug or cream containing 25% of calcein, 1% of 25 mmol) Example 3 After the solid micro needle punching, apply Calcein solution (Calcein-containing drug or cream, 25mmol 1%) and apply hydrocolloid patch containing vanilyl butyl ether (1%) as thermal material Example 4 After punching solid micro needles, apply Calcein solution (containing 25% of calcein or 1% of cream) and apply hydrocolloid patch containing thermal material vanilyl butyl ether (1%) and zeolite 5%

All percentages used in the comparative examples and examples of the present invention refer to weight%.

In Table 1, vanillyl butyl ether (manufactured by CORUM INC.) Is a synthetic component that imparts an effect such as promoting blood circulation through heat sensation.

&Lt; Preparation of micro needle >

Micro-needles according to the present invention may be prepared according to methods commonly known in the art. For the evaluation of Examples and Comparative Examples of the present invention, Beauty Lab (trade name) of Mighty System was purchased and tested.

<Evaluation 1> Experimental design of percutaneous permeation for confirmation of effectiveness of thermal material

Confocal image microscope was used to observe whether the transmittance (skin penetration depth) was increased by the thermal material after 4 hours from the application of Examples 1 to 4 and Comparative Examples 1 and 2. Specific experimental methods were as follows.

1. Place a 250 μm tall solid solid micro needle on a porcine skin (2 cm × 2 cm × 0.7 mm) and press it with a force of 5 kg for 10 seconds to create a hole in the porcine skin.

2. Apply a sample containing 1% 25 mM calcein solution and leave at room temperature (Comparative Example 1).

2. Apply a drug containing 1% 25 mM calcein solution and vanillyl butyl ether (1%) as a thermal material and leave at room temperature (Example 1).

2. Apply non-aqueous formulation cream containing 1% of 25 mM calcein solution and vanillyl butyl ether (1%) and zeolite (5%) as thermal material and leave at room temperature (Example 2).

2. Apply a drug containing 1% of 25 mM calcein solution and place it with a hydrocolloid patch at room temperature (Comparative Example 2).

2. Apply a drug containing 1% of 25 mM calcein solution and place a hydrocolloid patch containing vanillyl butyl ether (1%) as a thermal material and leave it at room temperature (Example 3).

2. After applying a drug containing 1% of 25 mM calcein solution, place a hydrocolloid patch containing vanillylbutylether (1%) and zeolite (5%) as a thermal material and leave it at room temperature (Example 4) .

3. Measure skin penetration depth with confocal image after a certain time. For qualitative observation, we observed with fluorescence microscope and observed with a confocal microscope to observe the distribution of calcein, a fluorescent substance in the skin. The results are shown in Fig.

As shown in FIG. 2, in Comparative Example 1, a relatively low skin permeation rate could be confirmed, and it was confirmed that the Examples in which a heat material was contained, particularly Examples 3 and 4, transmitted a relatively large amount of calcein there was.

Claims (13)

A microneedle which is dissolved or melted after perforation of the skin, characterized in that it comprises a substance which activates a temperature receptor, a substance giving a thermal sensation, or a mixture thereof. 2. The microneedle of claim 1, wherein the microneedles further comprise an active material. 2. The microneedle of claim 1, wherein the microneedles comprise both a material that activates a temperature receptor and a material that provides a thermal sensation. 4. The method of claim 1 or 3, wherein the temperature activating material is selected from the group consisting of Camphor, Thymol, Carvacrol, Menthol, Eugenol, Vanillin, Cinnemaldehyde, Incensole acetate, Barnabas Extract, Calmeg Extract, Vanillyl Butyl Ether, Anandamide, Capsaicin, Camphor, Reginiferatoxin Wherein the micro needle is at least one selected from the group consisting of Resiniferatoxin, Piperidine, Polyamines and Olvanil. The microneedle according to any one of claims 1 to 3, wherein the material providing the thermal sensation is at least one selected from the group consisting of polyol and zeolite. The microneedle according to claim 5, wherein the material giving the thermal sensation is zeolite. Micro needle and
A composition or patch comprising a substance that activates a temperature receptor, a substance that promotes thermal sensation, or a mixture thereof
Wherein the micro needle kit comprises: 8. The microneedle kit of claim 7, wherein at least one of the microneedles, the composition, and the patches further comprises an active material. 8. The microneedle kit of claim 7, wherein the composition or patch comprises both a temperature activating substance and a warming substance. 8. The micro-needle according to claim 7, wherein the composition or patch comprises any one of a material that activates a temperature receptor and a material that promotes thermal sensation, and the other component not included in the composition or patch is included in the micro- Needle kit. 11. A method according to any one of claims 7, 9 and 10, wherein the substance activating the temperature receptor is selected from the group consisting of Camphor, Thymol, Carvacrol, Menthol, Eugenol, Vanillin, Cinnemaldehyde, Incensole acetate, Barnabas Extract, Calmeg Extract, Vanilyl Butyl Ether, Anandamide, Capsaicin, Camphor Wherein the microcapsule is at least one selected from the group consisting of Camphor, Resiniferatoxin, Piperidine, Polyamines and Olvanil. The microneedle kit according to any one of claims 7, 9 and 10, wherein the material providing the thermal sensation is at least one selected from the group consisting of polyol and zeolite. 13. The microneedle kit according to claim 12, wherein the material providing the thermal sensation is a zeolite.

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